How aortic valve disease is managed continues to evolve, with novel approaches for both aortic valve stenosis and regurgitation.^1–8 Indeed, because of the spectrum of procedures, a multispecialty committee was formed to provide a detailed guideline to help physicians work through the various options.⁴

See related article

The paper by Aksoy and colleagues in this issue of the Journal gives further insight into the complexities of decision-making.

As a rule, the indications for a procedure to treat aortic valvular disease continue to be based on whether the patient develops certain symptoms (fatigue, exertional dyspnea, shortness of breath, syncope, chest pain), myocardial deterioration, reduced ejection fraction, or ventricular dilatation.⁴ Furthermore, the options depend on whether the patient has comorbid disease and is a candidate for surgical aortic valve replacement.

OPEN SURGERY: THE MAINSTAY OF TREATMENT

Open surgery—including in recent years minimally invasive J-incision “keyhole” repair or replacement—has been the mainstay of treatment. The results of surgical aortic valve repair have been excellent, so that 10 years after surgery 95% of patients who have undergone a modified David reimplantation operation have not needed a repeat operation.³ The results are comparable for repair of bicuspid aortic valves.^2,3

Furthermore, surgical aortic valve replacement has become very safe. At Cleveland Clinic in 2011, only 3 (0.6%) of 479 patients died during isolated aortic valve replacement, and in 2012 the mortality rate was even better, with only 1 death (0.2%) among 495 patients as of November 2012.

GOOD RESULTS WITH TRANSCATHETER AORTIC VALVE REPLACEMENT

For a new valve procedure to be accepted into practice, it must be easy to do, safe, and consistently good in performance measures such as producing low gradients, eliminating aortic regurgitation, and leading to high rates of long-term freedom from reoperation and of survival. To see if percutaneous aortic valve replacement meets these criteria, it was evaluated by both us at Cleveland Clinic and our colleagues at other institutions in the laboratory and also in feasibility trials in the United States.

The subsequent Placement of Transcatheter Aortic Valves (PARTNER) trial established the benefit of this procedure in terms of superior survival for patients who could not undergo surgery.⁸ Hence, the transcatheter device was approved for patients who cannot undergo surgery who meet certain criteria (valve area < 0.8 cm²; mean gradient > 40 mm Hg or peak gradient > 64 mm Hg). Of note, the cost per procedure was $78,000, or approximately $50,000 per year of life saved.

The PARTNER A trial showed that the risk of death after transcatheter aortic valve replacement was as low as after open surgery, although the risk of stroke or transient ischemic attack risk was higher—indeed, with the transfemoral approach it was 3 times higher (4.6% vs 1.4%, P < .05).^9,10 Furthermore, half the patients had perivalvular leakage after the new procedure, and even mild leakage reduced the survival rate at 2 years.¹¹

Nevertheless, we have now done nearly 400 transcatheter aortic valve replacement procedures in patients who could not undergo open surgery or who would have been at extreme risk during surgery. With the transfemoral approach, in 267 patients, 1 patient died (0.4%), and 2 had strokes (0.7%). (In the rest of the patients, we used alternatives to the transfemoral approach, such as the transaortic, transapical, and transaxillary approaches, also with good results.)

Thus, transcatheter aortic valve replacement in properly selected patients can meet the above criteria.

COSTS AND THE FUTURE

Based on the PARTNER trial results, the Centers for Medicare and Medicaid Services (CMS) agreed to pay for this procedure at the same rate as for surgical aortic valve replacement for patients who cannot or should not undergo surgery, with the approval of two surgeons and within the context of a national registry.¹⁰

The reimbursement is adjusted for geographic area. In the United States, for example, hospitals on the East Coast or West Coast receive $88,000 to $94,000 per case, while most other areas receive $32,000 to $62,000.

The surgeon and cardiologist share the professional fee of approximately $2,500, although typically we have a team of eight to 10 physicians (representing the fields of anesthesia, echocardiography, surgery, and cardiology) in the operating room for every procedure, in addition to nursing and technical staff. The challenge for institutions and providers, however, is that the device costs $32,500, and CMS reimbursement does not cover the cost of both the valve and the procedure in many localities. This may affect how widely the valve is eventually used.

While many more options are available now for management of aortic valve disease (minimally invasive repair or replacement, and newer devices), the future usage of transcatheter aortic valve replacement may become dependent on costs, newer devices, cheaper iterations, competition, and CMS reimbursement.

There are now two additional trials, SURTAVI and PARTNER A2, evaluating transcatheter vs open aortic valve replacement in lower-risk patients. The issues that will have to be addressed with new iterations are the risk of stroke and transient ischemic attack, perivalvular leakage, and the costs of the devices.

Newer reports would suggest that the results with transcatheter aortic valve replacement in inoperable and high-risk patients continue to improve as experience evolves.

How aortic valve disease is managed continues to evolve, with novel approaches for both aortic valve stenosis and regurgitation.^1–8 Indeed, because of the spectrum of procedures, a multispecialty committee was formed to provide a detailed guideline to help physicians work through the various options.⁴

See related article

The paper by Aksoy and colleagues in this issue of the Journal gives further insight into the complexities of decision-making.

As a rule, the indications for a procedure to treat aortic valvular disease continue to be based on whether the patient develops certain symptoms (fatigue, exertional dyspnea, shortness of breath, syncope, chest pain), myocardial deterioration, reduced ejection fraction, or ventricular dilatation.⁴ Furthermore, the options depend on whether the patient has comorbid disease and is a candidate for surgical aortic valve replacement.

OPEN SURGERY: THE MAINSTAY OF TREATMENT

Open surgery—including in recent years minimally invasive J-incision “keyhole” repair or replacement—has been the mainstay of treatment. The results of surgical aortic valve repair have been excellent, so that 10 years after surgery 95% of patients who have undergone a modified David reimplantation operation have not needed a repeat operation.³ The results are comparable for repair of bicuspid aortic valves.^2,3

Furthermore, surgical aortic valve replacement has become very safe. At Cleveland Clinic in 2011, only 3 (0.6%) of 479 patients died during isolated aortic valve replacement, and in 2012 the mortality rate was even better, with only 1 death (0.2%) among 495 patients as of November 2012.

GOOD RESULTS WITH TRANSCATHETER AORTIC VALVE REPLACEMENT

For a new valve procedure to be accepted into practice, it must be easy to do, safe, and consistently good in performance measures such as producing low gradients, eliminating aortic regurgitation, and leading to high rates of long-term freedom from reoperation and of survival. To see if percutaneous aortic valve replacement meets these criteria, it was evaluated by both us at Cleveland Clinic and our colleagues at other institutions in the laboratory and also in feasibility trials in the United States.

The subsequent Placement of Transcatheter Aortic Valves (PARTNER) trial established the benefit of this procedure in terms of superior survival for patients who could not undergo surgery.⁸ Hence, the transcatheter device was approved for patients who cannot undergo surgery who meet certain criteria (valve area < 0.8 cm²; mean gradient > 40 mm Hg or peak gradient > 64 mm Hg). Of note, the cost per procedure was $78,000, or approximately $50,000 per year of life saved.

The PARTNER A trial showed that the risk of death after transcatheter aortic valve replacement was as low as after open surgery, although the risk of stroke or transient ischemic attack risk was higher—indeed, with the transfemoral approach it was 3 times higher (4.6% vs 1.4%, P < .05).^9,10 Furthermore, half the patients had perivalvular leakage after the new procedure, and even mild leakage reduced the survival rate at 2 years.¹¹

Nevertheless, we have now done nearly 400 transcatheter aortic valve replacement procedures in patients who could not undergo open surgery or who would have been at extreme risk during surgery. With the transfemoral approach, in 267 patients, 1 patient died (0.4%), and 2 had strokes (0.7%). (In the rest of the patients, we used alternatives to the transfemoral approach, such as the transaortic, transapical, and transaxillary approaches, also with good results.)

Thus, transcatheter aortic valve replacement in properly selected patients can meet the above criteria.

COSTS AND THE FUTURE

Based on the PARTNER trial results, the Centers for Medicare and Medicaid Services (CMS) agreed to pay for this procedure at the same rate as for surgical aortic valve replacement for patients who cannot or should not undergo surgery, with the approval of two surgeons and within the context of a national registry.¹⁰

The reimbursement is adjusted for geographic area. In the United States, for example, hospitals on the East Coast or West Coast receive $88,000 to $94,000 per case, while most other areas receive $32,000 to $62,000.

The surgeon and cardiologist share the professional fee of approximately $2,500, although typically we have a team of eight to 10 physicians (representing the fields of anesthesia, echocardiography, surgery, and cardiology) in the operating room for every procedure, in addition to nursing and technical staff. The challenge for institutions and providers, however, is that the device costs $32,500, and CMS reimbursement does not cover the cost of both the valve and the procedure in many localities. This may affect how widely the valve is eventually used.

While many more options are available now for management of aortic valve disease (minimally invasive repair or replacement, and newer devices), the future usage of transcatheter aortic valve replacement may become dependent on costs, newer devices, cheaper iterations, competition, and CMS reimbursement.

There are now two additional trials, SURTAVI and PARTNER A2, evaluating transcatheter vs open aortic valve replacement in lower-risk patients. The issues that will have to be addressed with new iterations are the risk of stroke and transient ischemic attack, perivalvular leakage, and the costs of the devices.

Newer reports would suggest that the results with transcatheter aortic valve replacement in inoperable and high-risk patients continue to improve as experience evolves.

How aortic valve disease is managed continues to evolve, with novel approaches for both aortic valve stenosis and regurgitation.^1–8 Indeed, because of the spectrum of procedures, a multispecialty committee was formed to provide a detailed guideline to help physicians work through the various options.⁴

See related article

The paper by Aksoy and colleagues in this issue of the Journal gives further insight into the complexities of decision-making.

As a rule, the indications for a procedure to treat aortic valvular disease continue to be based on whether the patient develops certain symptoms (fatigue, exertional dyspnea, shortness of breath, syncope, chest pain), myocardial deterioration, reduced ejection fraction, or ventricular dilatation.⁴ Furthermore, the options depend on whether the patient has comorbid disease and is a candidate for surgical aortic valve replacement.

OPEN SURGERY: THE MAINSTAY OF TREATMENT

Open surgery—including in recent years minimally invasive J-incision “keyhole” repair or replacement—has been the mainstay of treatment. The results of surgical aortic valve repair have been excellent, so that 10 years after surgery 95% of patients who have undergone a modified David reimplantation operation have not needed a repeat operation.³ The results are comparable for repair of bicuspid aortic valves.^2,3

Furthermore, surgical aortic valve replacement has become very safe. At Cleveland Clinic in 2011, only 3 (0.6%) of 479 patients died during isolated aortic valve replacement, and in 2012 the mortality rate was even better, with only 1 death (0.2%) among 495 patients as of November 2012.

GOOD RESULTS WITH TRANSCATHETER AORTIC VALVE REPLACEMENT

For a new valve procedure to be accepted into practice, it must be easy to do, safe, and consistently good in performance measures such as producing low gradients, eliminating aortic regurgitation, and leading to high rates of long-term freedom from reoperation and of survival. To see if percutaneous aortic valve replacement meets these criteria, it was evaluated by both us at Cleveland Clinic and our colleagues at other institutions in the laboratory and also in feasibility trials in the United States.

The subsequent Placement of Transcatheter Aortic Valves (PARTNER) trial established the benefit of this procedure in terms of superior survival for patients who could not undergo surgery.⁸ Hence, the transcatheter device was approved for patients who cannot undergo surgery who meet certain criteria (valve area < 0.8 cm²; mean gradient > 40 mm Hg or peak gradient > 64 mm Hg). Of note, the cost per procedure was $78,000, or approximately $50,000 per year of life saved.

The PARTNER A trial showed that the risk of death after transcatheter aortic valve replacement was as low as after open surgery, although the risk of stroke or transient ischemic attack risk was higher—indeed, with the transfemoral approach it was 3 times higher (4.6% vs 1.4%, P < .05).^9,10 Furthermore, half the patients had perivalvular leakage after the new procedure, and even mild leakage reduced the survival rate at 2 years.¹¹

Nevertheless, we have now done nearly 400 transcatheter aortic valve replacement procedures in patients who could not undergo open surgery or who would have been at extreme risk during surgery. With the transfemoral approach, in 267 patients, 1 patient died (0.4%), and 2 had strokes (0.7%). (In the rest of the patients, we used alternatives to the transfemoral approach, such as the transaortic, transapical, and transaxillary approaches, also with good results.)

Thus, transcatheter aortic valve replacement in properly selected patients can meet the above criteria.

COSTS AND THE FUTURE

Based on the PARTNER trial results, the Centers for Medicare and Medicaid Services (CMS) agreed to pay for this procedure at the same rate as for surgical aortic valve replacement for patients who cannot or should not undergo surgery, with the approval of two surgeons and within the context of a national registry.¹⁰

The reimbursement is adjusted for geographic area. In the United States, for example, hospitals on the East Coast or West Coast receive $88,000 to $94,000 per case, while most other areas receive $32,000 to $62,000.

The surgeon and cardiologist share the professional fee of approximately $2,500, although typically we have a team of eight to 10 physicians (representing the fields of anesthesia, echocardiography, surgery, and cardiology) in the operating room for every procedure, in addition to nursing and technical staff. The challenge for institutions and providers, however, is that the device costs $32,500, and CMS reimbursement does not cover the cost of both the valve and the procedure in many localities. This may affect how widely the valve is eventually used.

While many more options are available now for management of aortic valve disease (minimally invasive repair or replacement, and newer devices), the future usage of transcatheter aortic valve replacement may become dependent on costs, newer devices, cheaper iterations, competition, and CMS reimbursement.

There are now two additional trials, SURTAVI and PARTNER A2, evaluating transcatheter vs open aortic valve replacement in lower-risk patients. The issues that will have to be addressed with new iterations are the risk of stroke and transient ischemic attack, perivalvular leakage, and the costs of the devices.

Newer reports would suggest that the results with transcatheter aortic valve replacement in inoperable and high-risk patients continue to improve as experience evolves.

Some members of the public may have noticed the conclusions of a recent study¹ that said that if an older postmenopausal woman has her bone mineral density measured to screen for osteoporosis and has a normal or only mildly low result, she does not need to come back for another measurement for approximately 15 years.

See related editorial

We believe this interpretation of the study’s findings is overly simplistic and may have the unfortunate result of causing some people to neglect their bone health. Moreover, the study looked mainly at baseline T scores as the determinant of the subsequent screening interval. However, clinicians must carefully consider a variety of clinical risk factors when deciding how often to obtain bone mineral density measurements. The ultimate goal is to not miss the window of opportunity for early detection and treatment when it would matter the most (ie, before fractures develop).

Here, we will review this recent study, its findings, and its implications.

OSTEOPOROSIS POSES AN ENORMOUS PUBLIC HEALTH PROBLEM

If we consider only the hip, an estimated 10 million people in the United States have osteoporosis (T score ≤ −2.5 or a preexisting fragility fracture), and 33.6 million have osteopenia (T score −1.01 to −2.49).² The number of people with osteopenia can be assumed to be much higher if other skeletal sites are considered.

By increasing the risk of fragility fractures, osteoporosis poses an enormous public health problem. The surgeon general’s report points out that one of every two white women over age 50 will experience an osteoporosis-related fracture in her lifetime.³ Of all osteoporosis-related fractures, those of the hip carry the worse clinical outcome. Approximately one in five elderly people who experience an osteoporosis-related hip fracture need long-term nursing home care, and as many as 20% die within 1 year.³

In recognition of the burden of osteoporosis, the US Preventive Services Task Force (USPSTF)⁴ and other scientific bodies^2,3 recommend an initial bone mineral density test for all women age 65 and older. Dual-energy x-ray absorptiometry (DXA) is considered the gold standard for bone mineral density testing. Although the patient population that should receive an initial bone mineral density test has been clearly identified (see below), guidelines on the optimal frequency of testing do not exist, as data have been lacking. Recognizing this knowledge gap, Gourlay et al¹ attempted to answer the question of how often elderly postmenopausal women should be retested.

WHEN DO 10% OF ELDERLY POSTMENOPAUSAL WOMEN REACH A T SCORE OF −2.5?

Gourlay et al¹ analyzed data from 4,957 women in the Study of Osteoporotic Fractures. These women were predominantly white, were at least 67 years old and ambulatory, and had normal bone mineral density or osteopenia and no history of hip or clinical vertebral fracture at baseline. They had been recruited between 1986 and 1988 at sites in Baltimore, MD, Minneapolis, MN, the Monongahela Valley near Pittsburgh, PA, and Portland, OR.

DXA of the hip had been performed at baseline and at multiple times thereafter. The average follow-up time was 8 years.

The primary outcome measured was how long it took for 10% of the patients to reach a T score of −2.5 or less at the femoral neck or total hip as they progressed from having normal bone mineral density to osteoporosis or from osteopenia to osteoporosis and before they developed a fracture or needed treatment for osteoporosis.

Clinical risk factors such as age, body mass index, estrogen use at baseline, fracture after age 50, current smoking, current or past use of glucocorticoids, and self-reported rheumatoid arthritis were included as covariates in time-to-event analyses.

ANSWER: 16.8 YEARS (IF NORMAL AT BASELINE)

The authors estimated that 10% of women would make the transition to osteoporosis before having a hip or clinical vertebral fracture in the following intervals:

• 16.8 years in women whose bone mineral density was normal at baseline (T score at femoral neck and total hip of −1.00 or higher)
• 17.3 years in women who had mild osteopenia at baseline (T score −1.01 to −1.49)
• 4.7 years in women with moderate osteopenia at baseline (T score −1.5 to −1.99)
• 1.1 years in women with advanced osteopenia at baseline (T score −2.00 to −2.49).

The authors also found that body mass index and current estrogen use were the only clinical risk factors that influenced these intervals; other clinical factors such as a fracture after age 50, current smoking, previous or current use of oral glucocorticoids, and self-reported rheumatoid arthritis did not.

They concluded that osteoporosis would develop in fewer than 10% of women if the rescreening interval was lengthened to 15 years for women with normal density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.

WHAT DOES THIS MEAN FOR THE PRACTICING CLINICIAN?

Who needs an initial DXA test according to current guidelines?

The USPSTF,⁴ the National Osteoporosis Foundation (NOF),⁵ the International Society for Clinical Densitometry (ISCD),⁶ and the American Association of Clinical Endocrinologists (AACE)⁷ propose that the following groups should undergo DXA:

• All women age 65 and older
• All postmenopausal women who have had a fragility fracture or who have one or more risk factors for osteoporosis (height loss, body mass index < 20 kg/m², family history of osteoporosis, active smoking, excessive alcohol consumption)
• Adults who have a condition (eg, rheumatoid arthritis) or are taking a medication (eg, glucocorticoids in a daily dose ≥ 5 mg of prednisone or its equivalent for ≥ 3 months) associated with low bone mass or bone loss
• Anyone being considered for drug therapy for osteoporosis, discontinuing therapy for osteoporosis (including estrogen), or being treated for osteoporosis, to monitor the effect of treatment.

Assessing fracture risk. Although clinicians have traditionally relied on bone mineral density obtained by DXA to estimate fracture risk, the World Health Organization has developed a computer-based algorithm that calculates an individual’s 10-year fracture probability from easily obtained clinical risk factors with or without adding femoral-neck bone mineral density. The Fracture Risk Assessment tool, or FRAX, has attracted intense interest since its introduction in 2007 and has been endorsed by the USPSTF⁴ and by other scientific societies, including the NOF⁵ and the ISCD.⁸ In fact, the most recent USPSTF guidelines,⁴ which recommend screening all women age 65 and older, call for using FRAX to identify younger women at higher risk of fracture.

According to FRAX, a 65-year-old white woman who has no risk factors has a 9.3% chance of developing a major osteoporotic fracture in the next 10 years. And if a younger woman (between the ages of 50 and 64) has a fracture risk as high or higher than a 65-year-old white woman who has no risk factors, then she too should be screened by DXA.

The FRAX calculator is available online at www.shef.ac.uk/FRAX.

What are the current recommendations about follow-up DXA testing?

In eligible patients, the Centers for Medicare and Medicaid Services will pay for a DXA scan every 2 years. This interval is based on the concept that in an otherwise healthy person, it takes a minimum of 2 years to see a significant change in bone mineral density that can be attributed to a biological change in the bone and not just chance. The USPSTF⁴ and scientific societies such as the NOF⁵ generally agree with the Medicare guidelines of retesting every 2 years but recognize certain clinical situations that may warrant more frequent retesting (see below).

But the real question is how long the DXA screening interval can be extended so that meaningful information can still be obtained to help make management decisions and before a complication such as a fracture occurs. While there is convincing evidence to support the recommendations for an initial DXA test, data to answer the question of how long the resting interval should be are lacking.

Before the study by Gourlay et al,¹ the only data on repeat DXA came from work by Hillier et al.⁹ But those investigators asked a different question. They were interested in how well repeated measurements predicted fractures. They used the same population that Gourlay et al did but evaluated fractures, not T scores. They concluded that in healthy, adult postmenopausal women, repeating the bone mineral density measurement up to 8 years later adds little value to initial measurement for predicting incident fractures.

Clinical factors also count

The T score should not be the only major factor determining the interval for bone mineral density testing in elderly women; clinical risk factors also should be kept in mind.

Gourlay et al concluded that age and T scores are the key predictive factors in determining the bone mineral density testing interval in elderly, postmenopausal women for screening purposes.¹ In their statistical model, clinical risk factors such as fracture after age 50, current smoking, previous or current use of glucocorticoids, and self-reported rheumatoid arthritis did not influence the testing interval. They say that clinicians should not feel compelled to shorten the testing interval when these risk factors are present.

Readers may take this to mean that if these results were strictly applied to a 70-year-old white woman receiving oral glucocorticoids for rheumatoid arthritis and who has a baseline T score of −1.45, then her next test may be postponed by 15 years (given that both these factors did not influence the testing interval). Readers may also conclude that if this patient’s T score were −1.51, then her screening interval would be 5 years and not 15 years.

However, Gourlay et al say¹ that clinicians can choose to shorten the testing interval if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in their analysis.

Soon after this study1 was published, Lewiecki et al¹⁰ and others^11–13 published critical commentaries addressing controversial issues surrounding the study. They highlighted the importance of considering clinical risk factors for fracture in addition to the femoral neck and total hip T scores. In response to these comments, Gourlay et al clarified that their results were not generalizable to patients with secondary osteoporosis, such as those taking glucocorticoids or those who have rheumatic diseases.¹⁴

Readers should keep in mind that clinical risk factors make independent contributions to fracture risk (Figure 1).¹⁵

Readers should also recognize the following groups in whom the results of the study by Gourlay et al are not applicable since they were not included in their study:

• Men
• Women other than white women
• Women already diagnosed with osteoporosis and on bisphosphonates or any other osteoporosis treatment (except for estrogen). The findings also do not apply to:
• Patients who experience a significant decline in health status or who develop new clinical conditions (such as hyperparathyroidism, paraproteinemias, or type 2 diabetes) or who use medications such as glucocorticoids that cause rapid bone loss. Changes in clinical situations such as these may necessitate more frequent bone mineral density testing in spite of a “good” baseline T score.
• Perimenopausal women or women who received their first bone mineral density test before age 65. Perimenopause and menopause may trigger rapid bone loss, which may be as much as one T-score point (ie, 1 standard deviation) at the spine and femoral neck.¹⁶ Therefore, testing done during this time cannot be used as the basis of future monitoring.

Gourlay et al¹ did not take into account asymptomatic spinal fractures; they used only clinical vertebral fractures in their risk estimates of spinal fractures. Ascertainment of morphometric spinal fractures may be methodologically challenging, but if the study had included these fractures, the outcomes and conclusions could have been very different.

Vertebral fractures are present in as many as 14% to 33% of postmenopausal women¹⁷ and indicate osteoporosis (regardless of the bone mineral density). Moreover, most vertebral fractures are clinically silent and escape detection, and approximately only one in three radiographically defined vertebral fractures is reported clinically.^18,19 Given the prevalence of these fractures, we and others¹⁰ have noted that the results of the Gourlay study may be biased toward longer screening intervals because they did not account for morphometric vertebral fractures.

Gourlay et al used T scores only of the femoral neck and total hip and not those of the lumbar spine. Some studies have found that hip measurements may be superior to spine measurements for overall osteoporotic fracture prediction.^20,21 However, lumbar spine bone mineral density is predictive of fracture at other skeletal sites,^22,23 is a widely accepted skeletal site measurement, and is used to diagnose osteoporosis. Moreover, the lumbar spine T score can be −2.5 or higher even if the total hip or femoral neck T score is lower than −2.5.

More fractures occur in people with osteopenia than with osteoporosis

Osteoporosis imparts a much higher risk of fracture than does osteopenia. However, if one recognizes the much greater prevalence of osteopenia (33.6 million people) compared with osteoporosis (10 million),² it is not hard to appreciate that the number of fractures is higher in the osteopenic group than in those with osteoporosis based on T scores. Siris et al²⁴ point out that at least half of osteoporotic fractures are in patients with osteopenia, who comprise a larger segment of the population than those with osteoporosis.

Some clinical trials have shown that bisphosphonates are not effective in preventing clinical fractures in women who do not have osteoporosis.^25,26 However, clinicians must recognize that while bisphosphonates may not be as effective in preventing fractures in the osteopenic group with no other clinical risk factors, the presence of multiple clinical risk factors incrementally increases the fracture risk (which can be assessed via FRAX) and may require starting drug therapy earlier.

Women with vertebral fractures are considered to have clinical osteoporosis even if they have T scores in the osteopenic range, and must be considered for drug therapy.

The public health burden of fractures will not decrease unless individuals with low bone mineral density who are at an increased risk of fracture are identified and treated.²⁴

Is DXA testing overused or underused? does it decrease the rate of fractures?

The study of Gourlay et al¹ captured a lot of media attention, with many newspapers and blogs claiming that women may be getting tested too often.^27,28 However, in reality, this test is highly underutilized. The 2011 Healthcare Effectiveness Data and Information Set report noted that 71.0% of women in Medicare health maintenance organizations and 75.0% of women in Medicare preferred provider organizations ever had a bone mineral density test for osteoporosis.²⁹ While these numbers may not appear to be too far from the target, they are a poor gauge of DXA use as they include all types of bone mineral density tests in a woman’s lifetime, including even heel tests at health fairs.

Central DXA is used far less than one might expect. King and Fiorentino, in a recent analysis, showed that only about 14% of fee-for-service Medicare beneficiaries 65 years and older had one or more DXA tests in 2010.³⁰ DXA retesting also does not seem to be an issue, with only 1 in 10 elderly women reporting having had a repeat test at 2-year intervals, and fewer than 1 in 100 tested reported testing more frequently.³⁰

Some members of the public may have noticed the conclusions of a recent study¹ that said that if an older postmenopausal woman has her bone mineral density measured to screen for osteoporosis and has a normal or only mildly low result, she does not need to come back for another measurement for approximately 15 years.

See related editorial

We believe this interpretation of the study’s findings is overly simplistic and may have the unfortunate result of causing some people to neglect their bone health. Moreover, the study looked mainly at baseline T scores as the determinant of the subsequent screening interval. However, clinicians must carefully consider a variety of clinical risk factors when deciding how often to obtain bone mineral density measurements. The ultimate goal is to not miss the window of opportunity for early detection and treatment when it would matter the most (ie, before fractures develop).

Here, we will review this recent study, its findings, and its implications.

OSTEOPOROSIS POSES AN ENORMOUS PUBLIC HEALTH PROBLEM

If we consider only the hip, an estimated 10 million people in the United States have osteoporosis (T score ≤ −2.5 or a preexisting fragility fracture), and 33.6 million have osteopenia (T score −1.01 to −2.49).² The number of people with osteopenia can be assumed to be much higher if other skeletal sites are considered.

By increasing the risk of fragility fractures, osteoporosis poses an enormous public health problem. The surgeon general’s report points out that one of every two white women over age 50 will experience an osteoporosis-related fracture in her lifetime.³ Of all osteoporosis-related fractures, those of the hip carry the worse clinical outcome. Approximately one in five elderly people who experience an osteoporosis-related hip fracture need long-term nursing home care, and as many as 20% die within 1 year.³

In recognition of the burden of osteoporosis, the US Preventive Services Task Force (USPSTF)⁴ and other scientific bodies^2,3 recommend an initial bone mineral density test for all women age 65 and older. Dual-energy x-ray absorptiometry (DXA) is considered the gold standard for bone mineral density testing. Although the patient population that should receive an initial bone mineral density test has been clearly identified (see below), guidelines on the optimal frequency of testing do not exist, as data have been lacking. Recognizing this knowledge gap, Gourlay et al¹ attempted to answer the question of how often elderly postmenopausal women should be retested.

WHEN DO 10% OF ELDERLY POSTMENOPAUSAL WOMEN REACH A T SCORE OF −2.5?

Gourlay et al¹ analyzed data from 4,957 women in the Study of Osteoporotic Fractures. These women were predominantly white, were at least 67 years old and ambulatory, and had normal bone mineral density or osteopenia and no history of hip or clinical vertebral fracture at baseline. They had been recruited between 1986 and 1988 at sites in Baltimore, MD, Minneapolis, MN, the Monongahela Valley near Pittsburgh, PA, and Portland, OR.

DXA of the hip had been performed at baseline and at multiple times thereafter. The average follow-up time was 8 years.

The primary outcome measured was how long it took for 10% of the patients to reach a T score of −2.5 or less at the femoral neck or total hip as they progressed from having normal bone mineral density to osteoporosis or from osteopenia to osteoporosis and before they developed a fracture or needed treatment for osteoporosis.

Clinical risk factors such as age, body mass index, estrogen use at baseline, fracture after age 50, current smoking, current or past use of glucocorticoids, and self-reported rheumatoid arthritis were included as covariates in time-to-event analyses.

ANSWER: 16.8 YEARS (IF NORMAL AT BASELINE)

The authors estimated that 10% of women would make the transition to osteoporosis before having a hip or clinical vertebral fracture in the following intervals:

• 16.8 years in women whose bone mineral density was normal at baseline (T score at femoral neck and total hip of −1.00 or higher)
• 17.3 years in women who had mild osteopenia at baseline (T score −1.01 to −1.49)
• 4.7 years in women with moderate osteopenia at baseline (T score −1.5 to −1.99)
• 1.1 years in women with advanced osteopenia at baseline (T score −2.00 to −2.49).

The authors also found that body mass index and current estrogen use were the only clinical risk factors that influenced these intervals; other clinical factors such as a fracture after age 50, current smoking, previous or current use of oral glucocorticoids, and self-reported rheumatoid arthritis did not.

They concluded that osteoporosis would develop in fewer than 10% of women if the rescreening interval was lengthened to 15 years for women with normal density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.

WHAT DOES THIS MEAN FOR THE PRACTICING CLINICIAN?

Who needs an initial DXA test according to current guidelines?

The USPSTF,⁴ the National Osteoporosis Foundation (NOF),⁵ the International Society for Clinical Densitometry (ISCD),⁶ and the American Association of Clinical Endocrinologists (AACE)⁷ propose that the following groups should undergo DXA:

• All women age 65 and older
• All postmenopausal women who have had a fragility fracture or who have one or more risk factors for osteoporosis (height loss, body mass index < 20 kg/m², family history of osteoporosis, active smoking, excessive alcohol consumption)
• Adults who have a condition (eg, rheumatoid arthritis) or are taking a medication (eg, glucocorticoids in a daily dose ≥ 5 mg of prednisone or its equivalent for ≥ 3 months) associated with low bone mass or bone loss
• Anyone being considered for drug therapy for osteoporosis, discontinuing therapy for osteoporosis (including estrogen), or being treated for osteoporosis, to monitor the effect of treatment.

Assessing fracture risk. Although clinicians have traditionally relied on bone mineral density obtained by DXA to estimate fracture risk, the World Health Organization has developed a computer-based algorithm that calculates an individual’s 10-year fracture probability from easily obtained clinical risk factors with or without adding femoral-neck bone mineral density. The Fracture Risk Assessment tool, or FRAX, has attracted intense interest since its introduction in 2007 and has been endorsed by the USPSTF⁴ and by other scientific societies, including the NOF⁵ and the ISCD.⁸ In fact, the most recent USPSTF guidelines,⁴ which recommend screening all women age 65 and older, call for using FRAX to identify younger women at higher risk of fracture.

According to FRAX, a 65-year-old white woman who has no risk factors has a 9.3% chance of developing a major osteoporotic fracture in the next 10 years. And if a younger woman (between the ages of 50 and 64) has a fracture risk as high or higher than a 65-year-old white woman who has no risk factors, then she too should be screened by DXA.

The FRAX calculator is available online at www.shef.ac.uk/FRAX.

What are the current recommendations about follow-up DXA testing?

In eligible patients, the Centers for Medicare and Medicaid Services will pay for a DXA scan every 2 years. This interval is based on the concept that in an otherwise healthy person, it takes a minimum of 2 years to see a significant change in bone mineral density that can be attributed to a biological change in the bone and not just chance. The USPSTF⁴ and scientific societies such as the NOF⁵ generally agree with the Medicare guidelines of retesting every 2 years but recognize certain clinical situations that may warrant more frequent retesting (see below).

But the real question is how long the DXA screening interval can be extended so that meaningful information can still be obtained to help make management decisions and before a complication such as a fracture occurs. While there is convincing evidence to support the recommendations for an initial DXA test, data to answer the question of how long the resting interval should be are lacking.

Before the study by Gourlay et al,¹ the only data on repeat DXA came from work by Hillier et al.⁹ But those investigators asked a different question. They were interested in how well repeated measurements predicted fractures. They used the same population that Gourlay et al did but evaluated fractures, not T scores. They concluded that in healthy, adult postmenopausal women, repeating the bone mineral density measurement up to 8 years later adds little value to initial measurement for predicting incident fractures.

Clinical factors also count

The T score should not be the only major factor determining the interval for bone mineral density testing in elderly women; clinical risk factors also should be kept in mind.

Gourlay et al concluded that age and T scores are the key predictive factors in determining the bone mineral density testing interval in elderly, postmenopausal women for screening purposes.¹ In their statistical model, clinical risk factors such as fracture after age 50, current smoking, previous or current use of glucocorticoids, and self-reported rheumatoid arthritis did not influence the testing interval. They say that clinicians should not feel compelled to shorten the testing interval when these risk factors are present.

Readers may take this to mean that if these results were strictly applied to a 70-year-old white woman receiving oral glucocorticoids for rheumatoid arthritis and who has a baseline T score of −1.45, then her next test may be postponed by 15 years (given that both these factors did not influence the testing interval). Readers may also conclude that if this patient’s T score were −1.51, then her screening interval would be 5 years and not 15 years.

However, Gourlay et al say¹ that clinicians can choose to shorten the testing interval if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in their analysis.

Soon after this study1 was published, Lewiecki et al¹⁰ and others^11–13 published critical commentaries addressing controversial issues surrounding the study. They highlighted the importance of considering clinical risk factors for fracture in addition to the femoral neck and total hip T scores. In response to these comments, Gourlay et al clarified that their results were not generalizable to patients with secondary osteoporosis, such as those taking glucocorticoids or those who have rheumatic diseases.¹⁴

Readers should keep in mind that clinical risk factors make independent contributions to fracture risk (Figure 1).¹⁵

Readers should also recognize the following groups in whom the results of the study by Gourlay et al are not applicable since they were not included in their study:

• Men
• Women other than white women
• Women already diagnosed with osteoporosis and on bisphosphonates or any other osteoporosis treatment (except for estrogen). The findings also do not apply to:
• Patients who experience a significant decline in health status or who develop new clinical conditions (such as hyperparathyroidism, paraproteinemias, or type 2 diabetes) or who use medications such as glucocorticoids that cause rapid bone loss. Changes in clinical situations such as these may necessitate more frequent bone mineral density testing in spite of a “good” baseline T score.
• Perimenopausal women or women who received their first bone mineral density test before age 65. Perimenopause and menopause may trigger rapid bone loss, which may be as much as one T-score point (ie, 1 standard deviation) at the spine and femoral neck.¹⁶ Therefore, testing done during this time cannot be used as the basis of future monitoring.

Gourlay et al¹ did not take into account asymptomatic spinal fractures; they used only clinical vertebral fractures in their risk estimates of spinal fractures. Ascertainment of morphometric spinal fractures may be methodologically challenging, but if the study had included these fractures, the outcomes and conclusions could have been very different.

Vertebral fractures are present in as many as 14% to 33% of postmenopausal women¹⁷ and indicate osteoporosis (regardless of the bone mineral density). Moreover, most vertebral fractures are clinically silent and escape detection, and approximately only one in three radiographically defined vertebral fractures is reported clinically.^18,19 Given the prevalence of these fractures, we and others¹⁰ have noted that the results of the Gourlay study may be biased toward longer screening intervals because they did not account for morphometric vertebral fractures.

Gourlay et al used T scores only of the femoral neck and total hip and not those of the lumbar spine. Some studies have found that hip measurements may be superior to spine measurements for overall osteoporotic fracture prediction.^20,21 However, lumbar spine bone mineral density is predictive of fracture at other skeletal sites,^22,23 is a widely accepted skeletal site measurement, and is used to diagnose osteoporosis. Moreover, the lumbar spine T score can be −2.5 or higher even if the total hip or femoral neck T score is lower than −2.5.

More fractures occur in people with osteopenia than with osteoporosis

Osteoporosis imparts a much higher risk of fracture than does osteopenia. However, if one recognizes the much greater prevalence of osteopenia (33.6 million people) compared with osteoporosis (10 million),² it is not hard to appreciate that the number of fractures is higher in the osteopenic group than in those with osteoporosis based on T scores. Siris et al²⁴ point out that at least half of osteoporotic fractures are in patients with osteopenia, who comprise a larger segment of the population than those with osteoporosis.

Some clinical trials have shown that bisphosphonates are not effective in preventing clinical fractures in women who do not have osteoporosis.^25,26 However, clinicians must recognize that while bisphosphonates may not be as effective in preventing fractures in the osteopenic group with no other clinical risk factors, the presence of multiple clinical risk factors incrementally increases the fracture risk (which can be assessed via FRAX) and may require starting drug therapy earlier.

Women with vertebral fractures are considered to have clinical osteoporosis even if they have T scores in the osteopenic range, and must be considered for drug therapy.

The public health burden of fractures will not decrease unless individuals with low bone mineral density who are at an increased risk of fracture are identified and treated.²⁴

Is DXA testing overused or underused? does it decrease the rate of fractures?

The study of Gourlay et al¹ captured a lot of media attention, with many newspapers and blogs claiming that women may be getting tested too often.^27,28 However, in reality, this test is highly underutilized. The 2011 Healthcare Effectiveness Data and Information Set report noted that 71.0% of women in Medicare health maintenance organizations and 75.0% of women in Medicare preferred provider organizations ever had a bone mineral density test for osteoporosis.²⁹ While these numbers may not appear to be too far from the target, they are a poor gauge of DXA use as they include all types of bone mineral density tests in a woman’s lifetime, including even heel tests at health fairs.

Central DXA is used far less than one might expect. King and Fiorentino, in a recent analysis, showed that only about 14% of fee-for-service Medicare beneficiaries 65 years and older had one or more DXA tests in 2010.³⁰ DXA retesting also does not seem to be an issue, with only 1 in 10 elderly women reporting having had a repeat test at 2-year intervals, and fewer than 1 in 100 tested reported testing more frequently.³⁰

Some members of the public may have noticed the conclusions of a recent study¹ that said that if an older postmenopausal woman has her bone mineral density measured to screen for osteoporosis and has a normal or only mildly low result, she does not need to come back for another measurement for approximately 15 years.

See related editorial

We believe this interpretation of the study’s findings is overly simplistic and may have the unfortunate result of causing some people to neglect their bone health. Moreover, the study looked mainly at baseline T scores as the determinant of the subsequent screening interval. However, clinicians must carefully consider a variety of clinical risk factors when deciding how often to obtain bone mineral density measurements. The ultimate goal is to not miss the window of opportunity for early detection and treatment when it would matter the most (ie, before fractures develop).

Here, we will review this recent study, its findings, and its implications.

OSTEOPOROSIS POSES AN ENORMOUS PUBLIC HEALTH PROBLEM

If we consider only the hip, an estimated 10 million people in the United States have osteoporosis (T score ≤ −2.5 or a preexisting fragility fracture), and 33.6 million have osteopenia (T score −1.01 to −2.49).² The number of people with osteopenia can be assumed to be much higher if other skeletal sites are considered.

By increasing the risk of fragility fractures, osteoporosis poses an enormous public health problem. The surgeon general’s report points out that one of every two white women over age 50 will experience an osteoporosis-related fracture in her lifetime.³ Of all osteoporosis-related fractures, those of the hip carry the worse clinical outcome. Approximately one in five elderly people who experience an osteoporosis-related hip fracture need long-term nursing home care, and as many as 20% die within 1 year.³

In recognition of the burden of osteoporosis, the US Preventive Services Task Force (USPSTF)⁴ and other scientific bodies^2,3 recommend an initial bone mineral density test for all women age 65 and older. Dual-energy x-ray absorptiometry (DXA) is considered the gold standard for bone mineral density testing. Although the patient population that should receive an initial bone mineral density test has been clearly identified (see below), guidelines on the optimal frequency of testing do not exist, as data have been lacking. Recognizing this knowledge gap, Gourlay et al¹ attempted to answer the question of how often elderly postmenopausal women should be retested.

WHEN DO 10% OF ELDERLY POSTMENOPAUSAL WOMEN REACH A T SCORE OF −2.5?

Gourlay et al¹ analyzed data from 4,957 women in the Study of Osteoporotic Fractures. These women were predominantly white, were at least 67 years old and ambulatory, and had normal bone mineral density or osteopenia and no history of hip or clinical vertebral fracture at baseline. They had been recruited between 1986 and 1988 at sites in Baltimore, MD, Minneapolis, MN, the Monongahela Valley near Pittsburgh, PA, and Portland, OR.

DXA of the hip had been performed at baseline and at multiple times thereafter. The average follow-up time was 8 years.

The primary outcome measured was how long it took for 10% of the patients to reach a T score of −2.5 or less at the femoral neck or total hip as they progressed from having normal bone mineral density to osteoporosis or from osteopenia to osteoporosis and before they developed a fracture or needed treatment for osteoporosis.

Clinical risk factors such as age, body mass index, estrogen use at baseline, fracture after age 50, current smoking, current or past use of glucocorticoids, and self-reported rheumatoid arthritis were included as covariates in time-to-event analyses.

ANSWER: 16.8 YEARS (IF NORMAL AT BASELINE)

The authors estimated that 10% of women would make the transition to osteoporosis before having a hip or clinical vertebral fracture in the following intervals:

• 16.8 years in women whose bone mineral density was normal at baseline (T score at femoral neck and total hip of −1.00 or higher)
• 17.3 years in women who had mild osteopenia at baseline (T score −1.01 to −1.49)
• 4.7 years in women with moderate osteopenia at baseline (T score −1.5 to −1.99)
• 1.1 years in women with advanced osteopenia at baseline (T score −2.00 to −2.49).

The authors also found that body mass index and current estrogen use were the only clinical risk factors that influenced these intervals; other clinical factors such as a fracture after age 50, current smoking, previous or current use of oral glucocorticoids, and self-reported rheumatoid arthritis did not.

They concluded that osteoporosis would develop in fewer than 10% of women if the rescreening interval was lengthened to 15 years for women with normal density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.

WHAT DOES THIS MEAN FOR THE PRACTICING CLINICIAN?

Who needs an initial DXA test according to current guidelines?

The USPSTF,⁴ the National Osteoporosis Foundation (NOF),⁵ the International Society for Clinical Densitometry (ISCD),⁶ and the American Association of Clinical Endocrinologists (AACE)⁷ propose that the following groups should undergo DXA:

• All women age 65 and older
• All postmenopausal women who have had a fragility fracture or who have one or more risk factors for osteoporosis (height loss, body mass index < 20 kg/m², family history of osteoporosis, active smoking, excessive alcohol consumption)
• Adults who have a condition (eg, rheumatoid arthritis) or are taking a medication (eg, glucocorticoids in a daily dose ≥ 5 mg of prednisone or its equivalent for ≥ 3 months) associated with low bone mass or bone loss
• Anyone being considered for drug therapy for osteoporosis, discontinuing therapy for osteoporosis (including estrogen), or being treated for osteoporosis, to monitor the effect of treatment.

Assessing fracture risk. Although clinicians have traditionally relied on bone mineral density obtained by DXA to estimate fracture risk, the World Health Organization has developed a computer-based algorithm that calculates an individual’s 10-year fracture probability from easily obtained clinical risk factors with or without adding femoral-neck bone mineral density. The Fracture Risk Assessment tool, or FRAX, has attracted intense interest since its introduction in 2007 and has been endorsed by the USPSTF⁴ and by other scientific societies, including the NOF⁵ and the ISCD.⁸ In fact, the most recent USPSTF guidelines,⁴ which recommend screening all women age 65 and older, call for using FRAX to identify younger women at higher risk of fracture.

According to FRAX, a 65-year-old white woman who has no risk factors has a 9.3% chance of developing a major osteoporotic fracture in the next 10 years. And if a younger woman (between the ages of 50 and 64) has a fracture risk as high or higher than a 65-year-old white woman who has no risk factors, then she too should be screened by DXA.

The FRAX calculator is available online at www.shef.ac.uk/FRAX.

What are the current recommendations about follow-up DXA testing?

In eligible patients, the Centers for Medicare and Medicaid Services will pay for a DXA scan every 2 years. This interval is based on the concept that in an otherwise healthy person, it takes a minimum of 2 years to see a significant change in bone mineral density that can be attributed to a biological change in the bone and not just chance. The USPSTF⁴ and scientific societies such as the NOF⁵ generally agree with the Medicare guidelines of retesting every 2 years but recognize certain clinical situations that may warrant more frequent retesting (see below).

But the real question is how long the DXA screening interval can be extended so that meaningful information can still be obtained to help make management decisions and before a complication such as a fracture occurs. While there is convincing evidence to support the recommendations for an initial DXA test, data to answer the question of how long the resting interval should be are lacking.

Before the study by Gourlay et al,¹ the only data on repeat DXA came from work by Hillier et al.⁹ But those investigators asked a different question. They were interested in how well repeated measurements predicted fractures. They used the same population that Gourlay et al did but evaluated fractures, not T scores. They concluded that in healthy, adult postmenopausal women, repeating the bone mineral density measurement up to 8 years later adds little value to initial measurement for predicting incident fractures.

Clinical factors also count

The T score should not be the only major factor determining the interval for bone mineral density testing in elderly women; clinical risk factors also should be kept in mind.

Gourlay et al concluded that age and T scores are the key predictive factors in determining the bone mineral density testing interval in elderly, postmenopausal women for screening purposes.¹ In their statistical model, clinical risk factors such as fracture after age 50, current smoking, previous or current use of glucocorticoids, and self-reported rheumatoid arthritis did not influence the testing interval. They say that clinicians should not feel compelled to shorten the testing interval when these risk factors are present.

Readers may take this to mean that if these results were strictly applied to a 70-year-old white woman receiving oral glucocorticoids for rheumatoid arthritis and who has a baseline T score of −1.45, then her next test may be postponed by 15 years (given that both these factors did not influence the testing interval). Readers may also conclude that if this patient’s T score were −1.51, then her screening interval would be 5 years and not 15 years.

However, Gourlay et al say¹ that clinicians can choose to shorten the testing interval if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in their analysis.

Soon after this study1 was published, Lewiecki et al¹⁰ and others^11–13 published critical commentaries addressing controversial issues surrounding the study. They highlighted the importance of considering clinical risk factors for fracture in addition to the femoral neck and total hip T scores. In response to these comments, Gourlay et al clarified that their results were not generalizable to patients with secondary osteoporosis, such as those taking glucocorticoids or those who have rheumatic diseases.¹⁴

Readers should keep in mind that clinical risk factors make independent contributions to fracture risk (Figure 1).¹⁵

Readers should also recognize the following groups in whom the results of the study by Gourlay et al are not applicable since they were not included in their study:

• Men
• Women other than white women
• Women already diagnosed with osteoporosis and on bisphosphonates or any other osteoporosis treatment (except for estrogen). The findings also do not apply to:
• Patients who experience a significant decline in health status or who develop new clinical conditions (such as hyperparathyroidism, paraproteinemias, or type 2 diabetes) or who use medications such as glucocorticoids that cause rapid bone loss. Changes in clinical situations such as these may necessitate more frequent bone mineral density testing in spite of a “good” baseline T score.
• Perimenopausal women or women who received their first bone mineral density test before age 65. Perimenopause and menopause may trigger rapid bone loss, which may be as much as one T-score point (ie, 1 standard deviation) at the spine and femoral neck.¹⁶ Therefore, testing done during this time cannot be used as the basis of future monitoring.

Gourlay et al¹ did not take into account asymptomatic spinal fractures; they used only clinical vertebral fractures in their risk estimates of spinal fractures. Ascertainment of morphometric spinal fractures may be methodologically challenging, but if the study had included these fractures, the outcomes and conclusions could have been very different.

Vertebral fractures are present in as many as 14% to 33% of postmenopausal women¹⁷ and indicate osteoporosis (regardless of the bone mineral density). Moreover, most vertebral fractures are clinically silent and escape detection, and approximately only one in three radiographically defined vertebral fractures is reported clinically.^18,19 Given the prevalence of these fractures, we and others¹⁰ have noted that the results of the Gourlay study may be biased toward longer screening intervals because they did not account for morphometric vertebral fractures.

Gourlay et al used T scores only of the femoral neck and total hip and not those of the lumbar spine. Some studies have found that hip measurements may be superior to spine measurements for overall osteoporotic fracture prediction.^20,21 However, lumbar spine bone mineral density is predictive of fracture at other skeletal sites,^22,23 is a widely accepted skeletal site measurement, and is used to diagnose osteoporosis. Moreover, the lumbar spine T score can be −2.5 or higher even if the total hip or femoral neck T score is lower than −2.5.

More fractures occur in people with osteopenia than with osteoporosis

Osteoporosis imparts a much higher risk of fracture than does osteopenia. However, if one recognizes the much greater prevalence of osteopenia (33.6 million people) compared with osteoporosis (10 million),² it is not hard to appreciate that the number of fractures is higher in the osteopenic group than in those with osteoporosis based on T scores. Siris et al²⁴ point out that at least half of osteoporotic fractures are in patients with osteopenia, who comprise a larger segment of the population than those with osteoporosis.

Some clinical trials have shown that bisphosphonates are not effective in preventing clinical fractures in women who do not have osteoporosis.^25,26 However, clinicians must recognize that while bisphosphonates may not be as effective in preventing fractures in the osteopenic group with no other clinical risk factors, the presence of multiple clinical risk factors incrementally increases the fracture risk (which can be assessed via FRAX) and may require starting drug therapy earlier.

Women with vertebral fractures are considered to have clinical osteoporosis even if they have T scores in the osteopenic range, and must be considered for drug therapy.

The public health burden of fractures will not decrease unless individuals with low bone mineral density who are at an increased risk of fracture are identified and treated.²⁴

Is DXA testing overused or underused? does it decrease the rate of fractures?

The study of Gourlay et al¹ captured a lot of media attention, with many newspapers and blogs claiming that women may be getting tested too often.^27,28 However, in reality, this test is highly underutilized. The 2011 Healthcare Effectiveness Data and Information Set report noted that 71.0% of women in Medicare health maintenance organizations and 75.0% of women in Medicare preferred provider organizations ever had a bone mineral density test for osteoporosis.²⁹ While these numbers may not appear to be too far from the target, they are a poor gauge of DXA use as they include all types of bone mineral density tests in a woman’s lifetime, including even heel tests at health fairs.

Central DXA is used far less than one might expect. King and Fiorentino, in a recent analysis, showed that only about 14% of fee-for-service Medicare beneficiaries 65 years and older had one or more DXA tests in 2010.³⁰ DXA retesting also does not seem to be an issue, with only 1 in 10 elderly women reporting having had a repeat test at 2-year intervals, and fewer than 1 in 100 tested reported testing more frequently.³⁰

In 2010, the United States Preventive Services Task Force recommended screening for osteoporosis by measuring bone mineral density in women age 65 and older and also in younger women if their fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors.

See related article

But what should be the interval between screenings? The Task Force stated that evidence on the optimum screening interval is lacking, that 2 years may be the minimum interval due to precision error, but that longer intervals may be necessary to improve fracture risk prediction.¹ They also cited a study showing that repeating the test up to 8 years after an initial test did not improve the ability of screening to predict fractures.² This was recently confirmed in a study from Canada.³

GOURLAY ET AL: TEST AGAIN IN 1 TO 15 YEARS

In response to this information void, Gourlay and colleagues⁴ analyzed data from the Study of Osteoporotic Fractures. Because these investigators were interested in the interval between screening measurements of bone mineral density, they included only women who did not already have osteoporosis or take medication for osteoporosis. They wanted to know how long it took for 10% of women to develop osteoporosis, and found that this interval varied from 1 to 15 years depending on the initial bone density.

I did not think these results were surprising. The durations in which osteoporosis developed were similar to what one would predict from cross-sectional reference ranges. The average woman loses a little less than 1% of bone density per year after age 65. A T score of −1.0 is 22% higher than a T score of −2.5, so on average it would take more than 20 years to go from early osteopenia to osteoporosis.

AN ONGOING DEBATE ON SCREENING

The report generated a debate about the value and timing of repeated screening.^5,6

In their article “More bone density testing is needed, not less,”⁵ Lewiecki et al criticized the Gourlay analysis because it did not include spine measurements or screen for asymptomatic vertebral fractures, and because it did not include enough clinical risk factors.^5,6 They claimed that media attention suggested that dual-energy absorptiometry (DXA) was overused and expensive, citing three news reports. One of the news reports did misinterpret the Gourlay study and suggested that fewer women should be screened.⁷ The others, however, accurately described the findings that many women did not need to undergo DXA every 2 years.^8,9

In this issue of the Cleveland Clinic Journal of Medicine, Doshi and colleagues express their opinion that the interval between bone mineral density testings should be guided by an assessment of clinical risk factors and not just T scores.¹⁰

Doshi et al are also concerned about erroneous conclusions drawn by the media. However, when I reviewed the news reports that they cited, I thought the reports were well written and conveyed the results appropriately. One report, by Alice Park,¹¹ cautioned: “doctors need to remain flexible in advising women about when to get tested. A patient who has a normal T score but then develops cancer and loses a lot of weight, for example, may be more vulnerable to developing osteoporosis and therefore may need to get screened before the 15-year interval.”¹¹ The other, by Gina Kolata, also explained that those taking high doses of corticosteroids for another medical condition would lose bone rapidly, but the findings “cover most normal women.”⁹ Neither report discouraged patients from getting screening in the first place.

Both Lewiecki et al and Doshi et al say that clinical factors should be considered, but do not specify which factors should be included in addition to the ones already evaluated by Gourlay et al (age, body mass index, estrogen use at baseline, any fracture after 50 years of age, current smoking, current or past use of oral glucocorticoids, and self-reported rheumatoid arthritis). These did not change the estimated time to develop osteoporosis for 90% of the study participants.

Furthermore, Gourlay et al had already noted that “clinicians may choose to reevaluate patients before our estimated screening intervals if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in our analyses.”⁴ Thus, patients with serious diseases should undergo DXA not for screening but for monitoring disease progression, and the Gourlay study results do not apply to them.

PATIENTS ON GLUCOCORTICOIDS: A SPECIAL SUBSET

Patients who are treated with glucocorticoids deserve further discussion. Consider the example described by Doshi et al of a woman with rheumatoid arthritis, taking prednisone, with a T score of −1.4. She would have to lose about 17% of her bone density to reach a T score at the osteoporosis level. One clinical trial in patients taking glucocorticoids, most of whom had rheumatoid arthritis, reported a loss of 2% after 2 years in the placebo group,¹² so it is unlikely that this patient would have bone density in the osteoporosis range for at least several years.

However, clinicians know that these patients get fractures, especially in the spine, even with a normal bone density. Therefore, vertebral fracture assessment would be more important than bone density screening in this patient. Currently, there is uncertainty about the best time to initiate treatment in patients taking these glucocortical steroids, as well as the choice of initial medication. More research about long-term benefits of treatment are especially needed in this population.

VERTEBRAL FRACTURES: NO FIRM RECOMMENDATIONS

Doshi et al state that the Gourlay study was biased towards longer screening intervals because it included women with asymptomatic vertebral fractures. This does not make sense, because women who have untreated asymptomatic fractures would not be expected to lose bone at a slower rate. This does not mean that the asymptomatic fractures are trivial.

Instead of getting more frequent bone density measurements, I think it would be more logical to evaluate vertebral fractures using radiographs or vertebral fracture assessment, but we can’t make a firm recommendation without studies of the effectiveness of screening for vertebral fractures.

WHAT ABOUT OSTEOPENIA?

Critics of the Gourlay study point out that most fractures occur in the osteopenic population. This is true, but it does not mean that bone density should be measured more frequently. The bisphosphonates are not effective at preventing a first fracture unless the T score is lower than −2.5.¹³ Patients who have risk factors in addition to osteopenia may have a higher risk of fracture, but it is not clear if this can be treated with medication. For example, rodeo riders have a high fracture risk, but they would not benefit from taking alendronate. In some cases, such as people who smoke or drink alcohol to excess, treating the risk factor would be more appropriate.

As Doshi et al and others have noted, the study by Gourlay et al has limitations, and of course clinical judgment must be used in implementing the findings of any study. But doctors should not order unnecessary and expensive tests, and physicians who perform bone densitometry should not recommend frequent repeat testing that does not benefit the patient.

In 2010, the United States Preventive Services Task Force recommended screening for osteoporosis by measuring bone mineral density in women age 65 and older and also in younger women if their fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors.

See related article

But what should be the interval between screenings? The Task Force stated that evidence on the optimum screening interval is lacking, that 2 years may be the minimum interval due to precision error, but that longer intervals may be necessary to improve fracture risk prediction.¹ They also cited a study showing that repeating the test up to 8 years after an initial test did not improve the ability of screening to predict fractures.² This was recently confirmed in a study from Canada.³

GOURLAY ET AL: TEST AGAIN IN 1 TO 15 YEARS

In response to this information void, Gourlay and colleagues⁴ analyzed data from the Study of Osteoporotic Fractures. Because these investigators were interested in the interval between screening measurements of bone mineral density, they included only women who did not already have osteoporosis or take medication for osteoporosis. They wanted to know how long it took for 10% of women to develop osteoporosis, and found that this interval varied from 1 to 15 years depending on the initial bone density.

I did not think these results were surprising. The durations in which osteoporosis developed were similar to what one would predict from cross-sectional reference ranges. The average woman loses a little less than 1% of bone density per year after age 65. A T score of −1.0 is 22% higher than a T score of −2.5, so on average it would take more than 20 years to go from early osteopenia to osteoporosis.

AN ONGOING DEBATE ON SCREENING

The report generated a debate about the value and timing of repeated screening.^5,6

In their article “More bone density testing is needed, not less,”⁵ Lewiecki et al criticized the Gourlay analysis because it did not include spine measurements or screen for asymptomatic vertebral fractures, and because it did not include enough clinical risk factors.^5,6 They claimed that media attention suggested that dual-energy absorptiometry (DXA) was overused and expensive, citing three news reports. One of the news reports did misinterpret the Gourlay study and suggested that fewer women should be screened.⁷ The others, however, accurately described the findings that many women did not need to undergo DXA every 2 years.^8,9

In this issue of the Cleveland Clinic Journal of Medicine, Doshi and colleagues express their opinion that the interval between bone mineral density testings should be guided by an assessment of clinical risk factors and not just T scores.¹⁰

Doshi et al are also concerned about erroneous conclusions drawn by the media. However, when I reviewed the news reports that they cited, I thought the reports were well written and conveyed the results appropriately. One report, by Alice Park,¹¹ cautioned: “doctors need to remain flexible in advising women about when to get tested. A patient who has a normal T score but then develops cancer and loses a lot of weight, for example, may be more vulnerable to developing osteoporosis and therefore may need to get screened before the 15-year interval.”¹¹ The other, by Gina Kolata, also explained that those taking high doses of corticosteroids for another medical condition would lose bone rapidly, but the findings “cover most normal women.”⁹ Neither report discouraged patients from getting screening in the first place.

Both Lewiecki et al and Doshi et al say that clinical factors should be considered, but do not specify which factors should be included in addition to the ones already evaluated by Gourlay et al (age, body mass index, estrogen use at baseline, any fracture after 50 years of age, current smoking, current or past use of oral glucocorticoids, and self-reported rheumatoid arthritis). These did not change the estimated time to develop osteoporosis for 90% of the study participants.

Furthermore, Gourlay et al had already noted that “clinicians may choose to reevaluate patients before our estimated screening intervals if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in our analyses.”⁴ Thus, patients with serious diseases should undergo DXA not for screening but for monitoring disease progression, and the Gourlay study results do not apply to them.

PATIENTS ON GLUCOCORTICOIDS: A SPECIAL SUBSET

Patients who are treated with glucocorticoids deserve further discussion. Consider the example described by Doshi et al of a woman with rheumatoid arthritis, taking prednisone, with a T score of −1.4. She would have to lose about 17% of her bone density to reach a T score at the osteoporosis level. One clinical trial in patients taking glucocorticoids, most of whom had rheumatoid arthritis, reported a loss of 2% after 2 years in the placebo group,¹² so it is unlikely that this patient would have bone density in the osteoporosis range for at least several years.

However, clinicians know that these patients get fractures, especially in the spine, even with a normal bone density. Therefore, vertebral fracture assessment would be more important than bone density screening in this patient. Currently, there is uncertainty about the best time to initiate treatment in patients taking these glucocortical steroids, as well as the choice of initial medication. More research about long-term benefits of treatment are especially needed in this population.

VERTEBRAL FRACTURES: NO FIRM RECOMMENDATIONS

Doshi et al state that the Gourlay study was biased towards longer screening intervals because it included women with asymptomatic vertebral fractures. This does not make sense, because women who have untreated asymptomatic fractures would not be expected to lose bone at a slower rate. This does not mean that the asymptomatic fractures are trivial.

Instead of getting more frequent bone density measurements, I think it would be more logical to evaluate vertebral fractures using radiographs or vertebral fracture assessment, but we can’t make a firm recommendation without studies of the effectiveness of screening for vertebral fractures.

WHAT ABOUT OSTEOPENIA?

Critics of the Gourlay study point out that most fractures occur in the osteopenic population. This is true, but it does not mean that bone density should be measured more frequently. The bisphosphonates are not effective at preventing a first fracture unless the T score is lower than −2.5.¹³ Patients who have risk factors in addition to osteopenia may have a higher risk of fracture, but it is not clear if this can be treated with medication. For example, rodeo riders have a high fracture risk, but they would not benefit from taking alendronate. In some cases, such as people who smoke or drink alcohol to excess, treating the risk factor would be more appropriate.

As Doshi et al and others have noted, the study by Gourlay et al has limitations, and of course clinical judgment must be used in implementing the findings of any study. But doctors should not order unnecessary and expensive tests, and physicians who perform bone densitometry should not recommend frequent repeat testing that does not benefit the patient.

In 2010, the United States Preventive Services Task Force recommended screening for osteoporosis by measuring bone mineral density in women age 65 and older and also in younger women if their fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors.

See related article

But what should be the interval between screenings? The Task Force stated that evidence on the optimum screening interval is lacking, that 2 years may be the minimum interval due to precision error, but that longer intervals may be necessary to improve fracture risk prediction.¹ They also cited a study showing that repeating the test up to 8 years after an initial test did not improve the ability of screening to predict fractures.² This was recently confirmed in a study from Canada.³

GOURLAY ET AL: TEST AGAIN IN 1 TO 15 YEARS

In response to this information void, Gourlay and colleagues⁴ analyzed data from the Study of Osteoporotic Fractures. Because these investigators were interested in the interval between screening measurements of bone mineral density, they included only women who did not already have osteoporosis or take medication for osteoporosis. They wanted to know how long it took for 10% of women to develop osteoporosis, and found that this interval varied from 1 to 15 years depending on the initial bone density.

I did not think these results were surprising. The durations in which osteoporosis developed were similar to what one would predict from cross-sectional reference ranges. The average woman loses a little less than 1% of bone density per year after age 65. A T score of −1.0 is 22% higher than a T score of −2.5, so on average it would take more than 20 years to go from early osteopenia to osteoporosis.

AN ONGOING DEBATE ON SCREENING

The report generated a debate about the value and timing of repeated screening.^5,6

In their article “More bone density testing is needed, not less,”⁵ Lewiecki et al criticized the Gourlay analysis because it did not include spine measurements or screen for asymptomatic vertebral fractures, and because it did not include enough clinical risk factors.^5,6 They claimed that media attention suggested that dual-energy absorptiometry (DXA) was overused and expensive, citing three news reports. One of the news reports did misinterpret the Gourlay study and suggested that fewer women should be screened.⁷ The others, however, accurately described the findings that many women did not need to undergo DXA every 2 years.^8,9

In this issue of the Cleveland Clinic Journal of Medicine, Doshi and colleagues express their opinion that the interval between bone mineral density testings should be guided by an assessment of clinical risk factors and not just T scores.¹⁰

Doshi et al are also concerned about erroneous conclusions drawn by the media. However, when I reviewed the news reports that they cited, I thought the reports were well written and conveyed the results appropriately. One report, by Alice Park,¹¹ cautioned: “doctors need to remain flexible in advising women about when to get tested. A patient who has a normal T score but then develops cancer and loses a lot of weight, for example, may be more vulnerable to developing osteoporosis and therefore may need to get screened before the 15-year interval.”¹¹ The other, by Gina Kolata, also explained that those taking high doses of corticosteroids for another medical condition would lose bone rapidly, but the findings “cover most normal women.”⁹ Neither report discouraged patients from getting screening in the first place.

Both Lewiecki et al and Doshi et al say that clinical factors should be considered, but do not specify which factors should be included in addition to the ones already evaluated by Gourlay et al (age, body mass index, estrogen use at baseline, any fracture after 50 years of age, current smoking, current or past use of oral glucocorticoids, and self-reported rheumatoid arthritis). These did not change the estimated time to develop osteoporosis for 90% of the study participants.

Furthermore, Gourlay et al had already noted that “clinicians may choose to reevaluate patients before our estimated screening intervals if there is evidence of decreased activity or mobility, weight loss, or other risk factors not considered in our analyses.”⁴ Thus, patients with serious diseases should undergo DXA not for screening but for monitoring disease progression, and the Gourlay study results do not apply to them.

PATIENTS ON GLUCOCORTICOIDS: A SPECIAL SUBSET

Patients who are treated with glucocorticoids deserve further discussion. Consider the example described by Doshi et al of a woman with rheumatoid arthritis, taking prednisone, with a T score of −1.4. She would have to lose about 17% of her bone density to reach a T score at the osteoporosis level. One clinical trial in patients taking glucocorticoids, most of whom had rheumatoid arthritis, reported a loss of 2% after 2 years in the placebo group,¹² so it is unlikely that this patient would have bone density in the osteoporosis range for at least several years.

However, clinicians know that these patients get fractures, especially in the spine, even with a normal bone density. Therefore, vertebral fracture assessment would be more important than bone density screening in this patient. Currently, there is uncertainty about the best time to initiate treatment in patients taking these glucocortical steroids, as well as the choice of initial medication. More research about long-term benefits of treatment are especially needed in this population.

VERTEBRAL FRACTURES: NO FIRM RECOMMENDATIONS

Doshi et al state that the Gourlay study was biased towards longer screening intervals because it included women with asymptomatic vertebral fractures. This does not make sense, because women who have untreated asymptomatic fractures would not be expected to lose bone at a slower rate. This does not mean that the asymptomatic fractures are trivial.

Instead of getting more frequent bone density measurements, I think it would be more logical to evaluate vertebral fractures using radiographs or vertebral fracture assessment, but we can’t make a firm recommendation without studies of the effectiveness of screening for vertebral fractures.

WHAT ABOUT OSTEOPENIA?

Critics of the Gourlay study point out that most fractures occur in the osteopenic population. This is true, but it does not mean that bone density should be measured more frequently. The bisphosphonates are not effective at preventing a first fracture unless the T score is lower than −2.5.¹³ Patients who have risk factors in addition to osteopenia may have a higher risk of fracture, but it is not clear if this can be treated with medication. For example, rodeo riders have a high fracture risk, but they would not benefit from taking alendronate. In some cases, such as people who smoke or drink alcohol to excess, treating the risk factor would be more appropriate.

As Doshi et al and others have noted, the study by Gourlay et al has limitations, and of course clinical judgment must be used in implementing the findings of any study. But doctors should not order unnecessary and expensive tests, and physicians who perform bone densitometry should not recommend frequent repeat testing that does not benefit the patient.

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.

A 19-year-old woman with no significant cardiac or pulmonary history presented with exertional dyspnea, which had begun a few months earlier. Auscultation revealed a loud pulmonary component of the second heart sound and a diastolic murmur heard along the upper left sternal border. Her 12-lead electrocardiogram is shown in Figure 1.

Q: Which of the following can cause prominent R waves in lead V₁?

• Normal variant in young adults
• Wolff-Parkinson-White syndrome
• Posterior wall myocardial infarction
• Right ventricular hypertrophy
• All of the above

A: The correct answer is all of the above.

The patient’s electrocardiogram shows a right atrial abnormality and right ventricular hypertrophy. Right atrial enlargement is evidenced by a prominent initial P wave in V₁ with an amplitude of at least 1.5 mm (0.15 mV). A P wave taller than 2.5 mm (0.25 mV) in lead II may also suggest a right atrial abnormality.¹

Multiple criteria exist for the diagnosis of right ventricular hypertrophy. Tall R waves in V₁ with an R/S ratio greater than 1 (ie, the R wave amplitude is more than the S wave depth) is commonly used.² Deep S waves with an R/S ratio less than 1 in V₆ is another criterion. Tall R waves of amplitude greater than 7 mm in V₁ by themselves may represent right ventricular hypertrophy. Most of the electrocardiographic criteria are specific but not sensitive for this diagnosis.³

Other causes of tall R waves in V₁ are given in Table 1.

Q: Which of the following diseases can present with an electrocardiographic pattern of right ventricular hypertrophy in young patients?

• Pulmonary hypertension
• Atrial septal defect
• Tetralogy of Fallot
• Pulmonary stenosis
• All of the above

A: The correct answer is all of the above.⁴

Our patient underwent multiple investigations. On echocardiography, her estimated right ventricular pressure was 80 mm Hg, and on cardiac catheterization her mean pulmonary arterial pressure was 55 mm Hg and her pulmonary capillary wedge pressure was 6 mm Hg. She was diagnosed with pulmonary arterial hypertension, which was the cause of her right ventricular hypertrophy. She eventually underwent bilateral lung transplantation.

A 19-year-old woman with no significant cardiac or pulmonary history presented with exertional dyspnea, which had begun a few months earlier. Auscultation revealed a loud pulmonary component of the second heart sound and a diastolic murmur heard along the upper left sternal border. Her 12-lead electrocardiogram is shown in Figure 1.

Q: Which of the following can cause prominent R waves in lead V₁?

• Normal variant in young adults
• Wolff-Parkinson-White syndrome
• Posterior wall myocardial infarction
• Right ventricular hypertrophy
• All of the above

A: The correct answer is all of the above.

The patient’s electrocardiogram shows a right atrial abnormality and right ventricular hypertrophy. Right atrial enlargement is evidenced by a prominent initial P wave in V₁ with an amplitude of at least 1.5 mm (0.15 mV). A P wave taller than 2.5 mm (0.25 mV) in lead II may also suggest a right atrial abnormality.¹

Multiple criteria exist for the diagnosis of right ventricular hypertrophy. Tall R waves in V₁ with an R/S ratio greater than 1 (ie, the R wave amplitude is more than the S wave depth) is commonly used.² Deep S waves with an R/S ratio less than 1 in V₆ is another criterion. Tall R waves of amplitude greater than 7 mm in V₁ by themselves may represent right ventricular hypertrophy. Most of the electrocardiographic criteria are specific but not sensitive for this diagnosis.³

Other causes of tall R waves in V₁ are given in Table 1.

Q: Which of the following diseases can present with an electrocardiographic pattern of right ventricular hypertrophy in young patients?

• Pulmonary hypertension
• Atrial septal defect
• Tetralogy of Fallot
• Pulmonary stenosis
• All of the above

A: The correct answer is all of the above.⁴

Our patient underwent multiple investigations. On echocardiography, her estimated right ventricular pressure was 80 mm Hg, and on cardiac catheterization her mean pulmonary arterial pressure was 55 mm Hg and her pulmonary capillary wedge pressure was 6 mm Hg. She was diagnosed with pulmonary arterial hypertension, which was the cause of her right ventricular hypertrophy. She eventually underwent bilateral lung transplantation.

A 19-year-old woman with no significant cardiac or pulmonary history presented with exertional dyspnea, which had begun a few months earlier. Auscultation revealed a loud pulmonary component of the second heart sound and a diastolic murmur heard along the upper left sternal border. Her 12-lead electrocardiogram is shown in Figure 1.

Q: Which of the following can cause prominent R waves in lead V₁?

• Normal variant in young adults
• Wolff-Parkinson-White syndrome
• Posterior wall myocardial infarction
• Right ventricular hypertrophy
• All of the above

A: The correct answer is all of the above.

The patient’s electrocardiogram shows a right atrial abnormality and right ventricular hypertrophy. Right atrial enlargement is evidenced by a prominent initial P wave in V₁ with an amplitude of at least 1.5 mm (0.15 mV). A P wave taller than 2.5 mm (0.25 mV) in lead II may also suggest a right atrial abnormality.¹

Multiple criteria exist for the diagnosis of right ventricular hypertrophy. Tall R waves in V₁ with an R/S ratio greater than 1 (ie, the R wave amplitude is more than the S wave depth) is commonly used.² Deep S waves with an R/S ratio less than 1 in V₆ is another criterion. Tall R waves of amplitude greater than 7 mm in V₁ by themselves may represent right ventricular hypertrophy. Most of the electrocardiographic criteria are specific but not sensitive for this diagnosis.³

Other causes of tall R waves in V₁ are given in Table 1.

Q: Which of the following diseases can present with an electrocardiographic pattern of right ventricular hypertrophy in young patients?

• Pulmonary hypertension
• Atrial septal defect
• Tetralogy of Fallot
• Pulmonary stenosis
• All of the above

A: The correct answer is all of the above.⁴

Our patient underwent multiple investigations. On echocardiography, her estimated right ventricular pressure was 80 mm Hg, and on cardiac catheterization her mean pulmonary arterial pressure was 55 mm Hg and her pulmonary capillary wedge pressure was 6 mm Hg. She was diagnosed with pulmonary arterial hypertension, which was the cause of her right ventricular hypertrophy. She eventually underwent bilateral lung transplantation.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Why individual clinicians make specific decisions usually can be sorted out. But our behavior as a group is more difficult to understand and, even when there are pressing and convincing reasons to change, behavior is difficult to alter.

In this issue, Drs. Federico Perez and David Van Duin discuss the emergence of carbapenem-resistant bacteria, dubbed “superbugs” by the media. Antibiotic resistance is not new; it was reported in Staphylococcus species within several years of the introduction of penicillin.¹ However, it has been increasing in prevalence and molecular complexity after years of relatively promiscuous antibiotic use. As the percentage of inpatients with immunosuppression and frailty increases in this environment of known antibiotic resistance, initial empiric antibiotic choices will by necessity include drugs likely to further promote development of resistant strains. But why do physicians still prescribe antibiotics for uncomplicated upper respiratory tract infections and asymptomatic bacteriuria, despite numerous studies and guidelines suggesting this practice has little benefit? Is it because patients expect a prescription in return for their copayment? Is it the path of least resistance? Or do physicians not accept the data showing that it is unnecessary?

Dr. Gerald Appel discusses diabetic nephropathy, an area that involves resistance of another kind, ie, the apparent resistance of physicians and patients to achieving evidence-based treatment targets. We hold controlled trials as the Holy Grail of evidence-based medicine, yet we seem to have an aversion to following guidelines based on trial-derived evidence. (I do not refer here to blind guideline adherence, ignoring individual patient characteristics.)

So how can physicians’ behavior be altered and our resistance to change be reduced? Experiments are under way, such as paying physicians based on their performance, linking patients’ insurance rates to achieving selected outcomes, and linking physician practice self-review to certification. Perhaps naively, I continue to believe that the most effective impetus to changing personal practice is the dissemination of data from high-quality trials (tempered by our accumulated experience and keeping our eyes wide open), coupled with our desire to do the best for our patients.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

Diabetes is on the rise, and so is diabetic nephropathy. In view of this epidemic, physicians should consider strategies to detect and control kidney disease in their diabetic patients.

This article will focus on kidney disease in adult-onset type 2 diabetes. Although it has different pathogenetic mechanisms than type 1 diabetes, the clinical course of the two conditions is very similar in terms of the prevalence of proteinuria after diagnosis, the progression to renal failure after the onset of proteinuria, and treatment options.¹

DIABETES AND DIABETIC KIDNEY DISEASE ARE ON THE RISE

The incidence of diabetes increases with age, and with the aging of the baby boomers, its prevalence is growing dramatically. The 2005– 2008 National Health and Nutrition Examination Survey estimated the prevalence as 3.7% in adults age 20 to 44, 13.7% at age 45 to 64, and 26.9% in people age 65 and older. The obesity epidemic is also contributing to the increase in diabetes in all age groups.

Diabetic kidney disease has increased in the United States from about 4 million cases 20 years ago to about 7 million in 2005–2008.² Diabetes is the major cause of end-stage renal disease in the developed world, accounting for 40% to 50% of cases. Other major causes are hypertension (27%) and glomerulonephritis (13%).³

Physicians in nearly every field of medicine now care for patients with diabetic nephropathy. The classic presentation—a patient who has impaired vision, fluid retention with edema, and hypertension—is commonly seen in dialysis units and ophthalmology and cardiovascular clinics.

CLINICAL PROGRESSION

Early in the course of diabetic nephropathy, blood pressure is normal and microalbuminuria is not evident, but many patients have a high glomerular filtration rate (GFR), indicating temporarily “enhanced” renal function or hyperfiltration. The next stage is characterized by microalbuminuria, correlating with glomerular mesangial expansion: the GFR falls back into the normal range and blood pressure starts to increase. Finally, macroalbuminuria occurs, accompanied by rising blood pressure and a declining GFR, correlating with the histologic appearance of glomerulosclerosis and Kimmelstiel-Wilson nodules.⁴

Hypertension develops in 5% of patients by 10 years after type 1 diabetes is diagnosed, 33% by 20 years, and 70% by 40 years. In contrast, 40% of patients with type 2 diabetes have high blood pressure at diagnosis.

Unfortunately, in most cases, this progression is a one-way street, so it is critical to intervene to try to slow the progression early in the course of the disease process.

SCREENING FOR DIABETIC NEPHROPATHY

Nephropathy screening guidelines for patients with diabetes are provided in Table 1.⁵

Blood pressure should be monitored at each office visit (Table 1). The goal for adults with diabetes should be to reduce blood pressure to 130/80 mm Hg. Reduction beyond this level may be associated with an increased mortality rate.⁶ Very high blood pressure (> 180 mm Hg systolic) should be lowered slowly. Lowering blood pressure delays the progression from microalbuminuria (30–299 mg/day or 20–199 μg/min) to macroalbuminuria (> 300 mg/day or > 200 μg/min) and slows the progression to renal failure.

Urinary albumin. Proteinuria takes 5 to 10 years to develop after the onset of diabetes. Because it is possible for patients with type 2 diabetes to have had the disease for some time before being diagnosed, urinary albumin screening should be performed at diagnosis and annually thereafter. Patients with type 1 are usually diagnosed with diabetes at or near onset of disease; therefore, annual screening for urinary albumin can begin 5 years after diagnosis.⁵

Proteinuria can be measured in different ways (Table 2). The basic screening test for clinical proteinuria is the urine dipstick, which is very sensitive to albumin and relatively insensitive to other proteins. “Trace-positive” results are common in healthy people, so proteinuria is not confirmed unless a patient has repeatedly positive results.

Microalbuminuria is important to measure, especially if it helps determine therapy. It is not detectable by the urinary dipstick, but can be measured in the following ways:

• Measurement of the albumin-creatinine ratio in a random spot collection
• 24-hour collection (creatinine should simultaneously be measured and creatinine clearance calculated)
• Timed collection (4 hours or overnight).

The first method is preferred, and any positive test result must be confirmed by repeat analyses of urinary albumin before a patient is diagnosed with microalbuminuria.

Occasionally a patient presenting with proteinuria but normal blood sugar and hemoglobin A_1c will have a biopsy that reveals morphologic changes of classic diabetic nephropathy. Most such patients have a history of hyperglycemia, indicating that they actually have been diabetic.

Proteinuria is the strongest predictor of renal outcomes. The Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL) study was a randomized, placebo-controlled trial in more than 1,500 patients with type 2 diabetes to test the effects of losartan on renal outcome. Those with high albuminuria (> 3.0 g albumin/g creatinine) at baseline were five times more likely to reach a renal end point and were eight times more likely to have progression to end-stage renal disease than patients with low albuminuria (< 1.5 g/g).⁷ The degree of albuminuria after 6 months of treatment showed similar predictive trends, indicating that monitoring and treating proteinuria are extremely important goals.

STRATEGY 1 TO LIMIT RENAL INJURY: REDUCE BLOOD PRESSURE

Blood pressure control improves renal and cardiovascular function.

As early as 1983, Parving et al,⁸ in a study of only 10 insulin-dependent diabetic patients, showed strong evidence that early aggressive antihypertensive treatment improved the course of diabetic nephropathy. During the mean pretreatment period of 29 months, the GFR decreased significantly and the urinary albumin excretion rate and arterial blood pressure rose significantly. During the mean 39-month period of antihypertensive treatment with metoprolol, hydralazine, and furosemide or a thiazide, mean arterial blood pressure fell from 144/97 to 128/84 mm Hg and urinary albumin excretion from 977 to 433 μg/ min. The rate of decline in GFR slowed from 0.91 mL/min/month before treatment to 0.39 mL/min/month during treatment.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial⁹ enrolled more than 11,000 patients internationally with type 2 diabetes at high risk for cardiovascular events. In addition to standard therapy, blood pressure was intensively controlled in one group with a combination of the angiotensin-converting enzyme (ACE) inhibitor perindopril and the diuretic indapamide. The intensive-therapy group achieved blood pressures less than 140/80 mm Hg and had a mean reduction of systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg vs controls. Despite these apparently modest reductions, the intensively controlled group had a significant 9% reduction of the primary outcome of combined macrovascular events (cardiovascular death, myocardial infarction, and stroke) and microvascular events (new or worsening nephropathy, or retinopathy).¹⁰

A meta-analysis of studies of patients with type 2 diabetes found reduced nephropathy with systolic blood pressure control to less than 130 mm Hg.¹¹

The United Kingdom Prospective Diabetes Study (UKPDS) is a series of studies of diabetes. The original study in 1998 enrolled 5,102 patients with newly diagnosed type 2 diabetes.¹² The more than 1,000 patients with hypertension were randomized to either tight blood pressure control or regular care. The intensive treatment group had a mean blood pressure reduction of 9 mm Hg systolic and 3 mm Hg diastolic, along with major reductions in all diabetes end points, diabetes deaths, microvascular disease, and stroke over a median follow-up of 8.4 years.

Continuous blood pressure control is critical

Tight blood pressure control must be maintained to have continued benefit. During the 10 years following the UKPDS, no attempts were made to maintain the previously assigned therapies. A follow-up study¹³ of 884 UKPDS patients found that blood pressures were the same again between the two groups 2 years after the trial was stopped, and no beneficial legacy effect from previous blood pressure control was evident on end points.

Control below 120 mm Hg systolic not needed

Blood pressure control slows kidney disease and prevents major macrovascular disease, but there is no evidence that lowering systolic blood pressure below 120 mm Hg provides additional benefit. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹⁴ more than 10,000 patients with type 2 diabetes and existing cardiovascular disease or additional cardiovascular risk factors were randomized to a goal of systolic blood pressure less than 120 mm Hg or less than 140 mm Hg (actual mean systolic pressures were 119 vs 134 mm Hg, respectively). Over nearly 5 years, there was no difference in cardiovascular events or deaths between the two groups.¹⁵

Since 1997, six international organizations have revised their recommended blood pressure goals in diabetes mellitus and renal diseases. Randomized clinical trials and observational studies have demonstrated the importance of blood pressure control to the level of 125/75 to 140/80 mm Hg. The National Kidney Foundation, the American Diabetes Association, and the Canadian Hypertension Society have developed consensus guidelines for blood pressure control to less than 130/80 mm Hg.^16–21 Table 3 summarizes blood pressure goals for patients with diabetes.

STRATEGY 2: CONTROL BLOOD SUGAR

Recommendations for blood sugar goals are more controversial.

The Diabetes Control and Complications Trial²² provided early evidence that tight blood sugar control slows the development of microalbuminuria and macroalbuminuria. The study randomized more than 1,400 patients with type 1 diabetes to either standard therapy (1 or 2 daily insulin injections) or intensive therapy (an external insulin pump or 3 or more insulin injections guided by frequent blood glucose monitoring) to keep blood glucose levels close to normal. About half the patients had mild retinopathy at baseline and the others had no retinopathy. After 6.5 years, intensive therapy was found to significantly delay the onset and slow the progression of diabetic retinopathy and nephropathy.

The Kumamoto Study²³ randomized 110 patients with type 2 diabetes and either no retinopathy (primary prevention cohort) or simple retinopathy (secondary prevention cohort) to receive either multiple insulin injections or conventional insulin therapy over 8 years. Intensive therapy led to lower rates of retinopathy (7.7% vs 32% in primary prevention and 19% vs 44% in secondary prevention) and progressive nephropathy (7% vs 28% in primary prevention at 6 years and 11% vs 32% in secondary prevention).

In addition to studying the effects of blood pressure control, the UKPDS also studied the effects of intensive blood glucose control.^24,25 Nearly 4,000 patients with newly diagnosed type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin, or to conventional treatment with diet. Over 10 years, the mean hemoglobin A_1c was reduced to 7.0% in the intensive group and 7.9% in the conventional group. The risk of any diabetes-related end point was 12% lower in the intensive group, 10% lower for diabetes-related death, and 6% lower for all-cause mortality. There was also a 25% reduction in microvascular disease (retinopathy and nephropathy). However, the intensive group had more hypoglycemic episodes than the conventional group and a tendency to some increase in macrovascular events. A legacy effect was evident: patients who had intensive treatment had less microvascular disease progression years after stopping therapy.

Earlier trials provided strong evidence that blood glucose control prevents or slows retinopathy and nephropathy. The critical question is, “At what expense?” Although diabetes is the most common cause of kidney failure in the United States, most people with diabetes do not die of kidney failure, but of cardiovascular disease. Two recent large trials had different results regarding glycemic control below hemoglobin A_1c of 7.0% and macrovascular risk, creating a controversy about what recommendations are best.

The ADVANCE trial, enrolling 11,140 patients with type 2 diabetes, was largely conducted in Australia and used the sulfonylurea glipizide for glycemic control. Compared with the group that received standard therapy (n=5,569), the intensive-treatment group (n=5,571) achieved mean hemoglobin A_1c levels of 6.5% compared with 7.3% in the standard group, and had less nephropathy, less microalbuminuria, less doubling of creatinine, and a lower rate of end-stage renal disease (4% vs 5% in the standard therapy group). No difference between the two groups was found in retinopathy. Rates of all-cause mortality did not differ between the groups.⁹

The ACCORD trial had more than 10,000 subjects with type 2 diabetes and took place mostly in the United States. Using mainly rosiglitazone for intensive therapy, the intensive group achieved hemoglobin A_1c levels of 6.4% vs 7.5% in the standard-therapy group. The trial was stopped early, at 3.7 years, because of a higher risk of death and cardiovascular events in the group with intensive glycemic control. However, the intensive-therapy group did have a significant decrease in microvascular renal outcomes and a reduction in the progression of retinopathy.^14,26

In summary, tighter glycemic control improves microvascular complications—both retinopathy and nephropathy—in patients with type 2 diabetes. The benefit of intensive therapy on macrovascular complications (stroke, myocardial infarction) in long-standing diabetes has not been convincingly demonstrated in randomized trials. The UKPDS suggested that maintaining a hemoglobin A_1c of 7% in patients newly diagnosed with type 2 diabetes confers long-term cardiovascular benefits. The target hemoglobin A_1c for type 2 diabetes should be tailored to the patient: 7% is a reasonable goal for most patients, but the goal should be higher for the elderly and frail. Reducing the risk of cardiovascular death is still best done by controlling blood pressure, reducing lipids, quitting smoking, and losing weight.

STRATEGY 3: INHIBIT THE RENIN-ANGIOTENSIN-ALDOSTERONE AXIS

Components of the renin-angiotensin-aldo-sterone system are present not only in the circulation but also in many tissues, including the heart, brain, kidney, blood vessels, and adrenal glands. The role of renin-angiotensin-aldosterone system blockers in treating and preventing diabetic nephropathy has become controversial in recent years with findings from new studies.

The renin-angiotensin-aldosterone system is important in the development or maintenance of high blood pressure and the resultant damage to the brain, heart, and kidney. Drug development has focused on inhibiting steps in the biochemical pathway. ACE inhibitors block the formation of angiotensin II—the most biologically potent angiotensin peptide—and are among the most commonly used drugs to treat hypertension and concomitant conditions, such as renal insufficiency, proteinuria, and heart failure. Angiotensin receptor blockers (ARBs) interact with the angiotensin AT1 receptor and block most of its actions. They are approved by the US Food and Drug Administration (FDA) for the treatment of hypertension, and they help prevent left ventricular hypertrophy and mesangial sclerosis. Large studies have shown that ACE inhibitors and ARBs offer similar cardiovascular benefit.

The glomerulus has the only capillary bed with a blood supply that drains into an efferent arteriole instead of a venule, providing high resistance to aid filtration. Efferent arterioles are rich in AT1 receptors. In the presence of angiotensin II they constrict, increasing pressure in the glomerulus, which can lead to proteinuria and glomerulosclerosis. ACE inhibitors and ARBs relax the efferent arteriole, allowing increased blood flow through the glomerulus. This reduction in intraglomerular pressure is associated with less proteinuria and less glomerulosclerosis.

Diabetes promotes renal disease in many ways. Glucose and advanced glycation end products can lead to increased blood flow and increased pressure in the glomerulus. Through a variety of pathways, hyperglycemia, acting on angiotensin II, leads to NF-kapa beta production, profibrotic cytokines, increased matrix, and eventual fibrosis. ACE inhibitors and ARBs counteract many of these.

ACE inhibitors and ARBs slow nephropathy progression beyond blood pressure control

Several major clinical trials^27–32 examined the effects of either ACE inhibitors or ARBs in slowing the progression of diabetic nephropathy and have had consistently positive results.

The Collaborative Study Group³⁰ was a 3-year randomized trial in 419 patients with type 1 diabetes, using the ACE inhibitor captopril vs placebo. Captopril was associated with less decline in kidney function and a 50% reduction in the risk of the combined end points of death, dialysis, and transplantation that was independent of the small difference in blood pressures between the two groups.

The Irbesartan Diabetic Nephropathy Trial (IDNT)³¹ studied the effect of the ARB irbesartan vs the calcium channel blocker amlodipine vs placebo over 2.6 years in 1,715 patients with type 2 diabetes. Irbesartan was found to be significantly more effective in protecting against the progression of nephropathy, independent of reduction in blood pressure.

The RENAAL trial,³² published in 2001, was a 3-year, randomized, double-blind study comparing the ARB losartan at increasing dosages with placebo (both taken in addition to conventional antihypertensive treatment) in 1,513 patients with type 2 diabetes and nephropathy. The blood pressure goal was 140/90 mm Hg in both groups, but the losartan group had a lower rate of doubling of serum creatinine, end-stage renal disease, and combined end-stage renal disease or death.

‘Aldosterone escape’ motivates the search for new therapies

An important reason for developing more ways to block the renin-angiotensin-aldosterone system is because of “aldosterone escape,” the phenomenon of angiotensin II or aldosterone returning to pretreatment levels despite continued ACE inhibition.

Biollaz et al,³³ in a 1982 study of 19 patients with hypertension, showed that despite reducing blood pressure and keeping the blood level of ACE very low with twice-daily enalapril 20 mg, blood and urine levels of angiotensin II steadily rose back to baseline levels within a few months.

A growing body of evidence suggests that despite effective inhibition of angiotensin II activity, non-ACE synthetic pathways still permit angiotensin II generation via serine proteases such as chymase, cathepsin G, and tissue plasminogen activator.

Thus, efforts have been made to block the renin-angiotensin system in other places. In addition to ACE inhibitors and ARBs, two aldosterone receptor antagonists are available, spironolactone and eplerenone, both used to treat heart failure. A direct renin inhibitor, aliskiren, is also available.

A number of studies have shown that combination treatment with agents having different targets in the renin-angiotensin-aldosterone system leads to larger reductions in albuminuria than does single-agent therapy.

Mogensen et al³⁴ studied the effect of the ACE inhibitor lisinopril (20 mg per day) plus the ARB candesartan (16 mg per day) in subjects with microalbuminuria, hypertension, and type 2 diabetes. Combined treatment was more effective in reducing proteinuria.

Epstein et al³⁵ studied the effects of the ACE inhibitor enalapril (20 mg/day) combined with either of two doses of the selective aldosterone receptor antagonist eplerenone (50 or 100 mg/day) or placebo. Both eplerenone dosages, when added to the enalapril treatment, significantly reduced albuminuria from baseline as early as week 4 (P < .001), but placebo treatment added to the enalapril did not result in any significant decrease in urinary albumin excretion. Systolic blood pressure decreased significantly in all treatment groups and by about the same amount.

The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) trial³⁶ randomized more than 600 patients with type 2 diabetes and nephropathy to aliskiren (a renin inhibitor) or placebo added to the ARB losartan. Again, combination treatment was more renoprotective, independent of blood pressure lowering.

Worse outcomes with combination therapy?

More recent studies have indicated that although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal and cardiovascular outcomes. The multicenter Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET)³⁷ randomized more than 25,000 patients age 55 and older with established atherosclerotic vascular disease or with diabetes and end-organ damage to receive either the ARB telmisartan 80 mg daily, the ACE inhibitor ramipril 10 mg daily, or both. Mean follow-up was 56 months. The combination-treatment group had higher rates of death and renal disease than the single-therapy groups (which did not differ from one another).

Why the combination therapy had poorer outcomes is under debate. Patients may get sudden drops in blood pressure that are not detected with only periodic monitoring. Renal failure was mostly acute rather than chronic, and the estimated GFR declined more in the combined therapy group than in the single-therapy groups.

The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints (ALTITUDE) was designed to test the effect of the direct renin inhibitor aliskiren or placebo, both arms combined with either an ACE inhibitor or an ARB in patients with type 2 diabetes at high risk for cardiovascular and renal events. The trial was terminated early because of more strokes and deaths in the combination therapy arms. The results led the FDA to issue black box warnings against using aliskiren with these other classes of agents, and all studies testing similar combinations have been stopped. (In one study that was stopped and has not yet been published, 100 patients with proteinuria were treated with either aliskiren, the ARB losartan, or both, to evaluate the effects of aldosterone escape. Results showed no differences: about one-third of each group had this phenomenon.)

My personal recommendation is as follows: for younger patients with proteinuria, at lower risk for cardiovascular events and with disease due not to diabetes but to immunoglobulin A nephropathy or another proteinuric kidney disease, treat with both an ACE inhibitor and ARB. But the combination should not be used for patients at high risk of cardiovascular disease, which includes almost all patients with diabetes.

If more aggressive renin-angiotensin system blockade is needed against diabetic nephropathy, adding a diuretic increases the impact of blocking the renin-angiotensin-aldosterone system on both proteinuria and progression of renal disease. The aldosterone blocker spironolactone 25 mg can be added if potassium levels are carefully monitored.

ACE inhibitor plus calcium channel blocker is safer than ACE inhibitor plus diuretic

The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial³⁸ randomized more than 11,000 high-risk patients with hypertension to receive an ACE inhibitor (benazepril) plus either a calcium channel blocker (amlodipine) or thiazide diuretic (hydrochlorothiazide). Blood pressures were identical between the two groups, but the trial was terminated early, at 36 months, because of a higher risk of the combined end point of cardiovascular death, myocardial infarction, stroke, and other major cardiac events in the ACE inhibitor-thiazide group.

Although some experts believe this study is definitive and indicates that high blood pressure should never be treated with an ACE inhibitor-thiazide combination, I believe that caution is needed in interpreting these findings. This regimen should be avoided in older patients with diabetes at high risk for cardiovascular disease, but otherwise, getting blood pressure under control is critical, and this combination can be used if it works and the patient is tolerating it well.

In summary, the choice of blood pressure-lowering medications is based on reducing cardiovascular events and slowing the progression of kidney disease. Either an ACE inhibitor or an ARB is the first choice for patients with diabetes, hypertension, and any degree of proteinuria. Many experts recommend beginning one of these agents even if proteinuria is not present. However, the combination of an ACE inhibitor and ARB should not be used in diabetic patients, especially if they have cardiovascular disease, until further data clarify the results of the ONTARGET and ALTITUDE trials.

STRATEGY 4: METABOLIC MANIPULATION WITH NOVEL AGENTS

Several new agents have recently been studied for the treatment of diabetic nephropathy, including aminoguanidine, which reduces levels of advanced glycation end-products, and sulodexide, which blocks basement membrane permeability. Neither agent has been shown to be safe and effective in diabetic nephropathy. The newest agent is bardoxolone methyl. It induces the Keap1–Nrf2 pathway, which up-regulates cytoprotective factors, suppressing inflammatory and other cytokines that are major mediators of progression of chronic kidney disease.³⁹

Pergola et al,⁴⁰ in a phase 2, double-blind trial, randomized 227 adults with diabetic kidney disease and a low estimated GFR (20–45 mL/min/1.73 m²) to receive placebo or bardoxolone 25, 75, or 150 mg daily. Drug treatment was associated with improvement in the estimated GFR, a finding that persisted throughout the 52 weeks of treatment. Surprisingly, proteinuria did not decrease with drug treatment.

As of this writing, a large multicenter controlled randomized trial has been halted because of concerns by the data safety monitoring board, which found increased rates of death and fluid retention with the drug. A number of recent trials have shown a beneficial effect of sodium bicarbonate therapy in patients with late-stage chronic kidney disease. They have shown slowing of the progression of GFR decline in a number of renal diseases, including diabetes.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.

Prospective studies into transmission, molecular characteristics, and, most of all, treatment regimens are urgently needed. In addition, the development of new antimicrobials and nontraditional antimicrobial methods should have international priority.

The past 10 years have brought a formidable challenge to the clinical arena, as carbapenems, until now the most reliable antibiotics against Klebsiella species, Escherichia coli, and other Enterobacteriaceae, are becoming increasingly ineffective.

Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to hospitalized patients. Moreover, CRE often demonstrate resistance to many other classes of antibiotics, thus limiting our therapeutic options. Furthermore, few new antibiotics are in line to replace carbapenems. This public health crisis demands redefined and refocused efforts in the diagnosis, treatment, and control of infections in hospitalized patients.

Here, we present an overview of CRE and discuss avenues to escape a new era of untreatable infections.

INCREASED USE OF CARBAPENEMS AND EMERGENCE OF RESISTANCE

Developed in the 1980s, carbapenems are derivatives of thyanamycin. Imipenem and meropenem, the first members of the class, had a broad spectrum of antimicrobial activity that included coverage of Pseudomonas aeruginosa, adequately positioning them for the treatment of nosocomial infections. Back then, nearly all Enterobacteriaceae were susceptible to carbapenems.¹

In the 1990s, Enterobacteriaceae started to develop resistance to cephalosporins—till then, the first-line antibiotics for these organisms—by acquiring extended-spectrum betalactamases, which inactivate those agents. Consequently, the use of cephalosporins had to be restricted, while carbapenems, which remained impervious to these enzymes, had to be used more.² In pivotal international studies in the treatment of infections caused by strains of K pneumoniae that produced these inactivating enzymes, outcomes were better with carbapenems than with cephalosporins and fluoroquinolones.^3,4

Ertapenem, a carbapenem without antipseudomonal activity and highly bound to protein, was released in 2001. Its prolonged half-life permitted once-daily dosing, which positioned it as an option for treating infections in community dwellers.⁵ Doripenem is the newest member of the class of carbapenems, and its spectrum of activity is similar to that of imipenem and meropenem and includes P aeruginosa.⁶ The use of carbapenems, measured in a representative sample of 35 university hospitals in the United States, increased by 59% between 2002 and 2006.⁷

In the early 2000s, carbapenem resistance in K pneumoniae and other Enterobacteriaceae was rare in North America. But then, after initial outbreaks occurred in hospitals in the Northeast (especially New York City), CRE began to spread throughout the United States. By 2009–2010, the National Healthcare Safety Network from the Centers for Disease Control and Prevention (CDC) revealed that 12.8% of K pneumoniae isolates associated with bloodstream infections were resistant to carbapenems.⁸

In March 2013, the CDC disclosed that 3.9% of short-stay acute-care hospitals and 17.8% of long-term acute-care hospitals reported at least one CRE health care-associated infection in 2012. CRE had extended to 42 states, and the proportion of Enterobacteriaceae that are CRE had increased fourfold over the past 10 years.⁹

Coinciding with the increased use of carbapenems, multiple factors and modifiers likely contributed to the dramatic increase in CRE. These include use of other antibiotics in humans and animals, their relative penetration and selective effect on the gut microbiota, case-mix and infection control practices in different health care settings, and travel patterns.

POWERFUL ENZYMES THAT TRAVEL FAR

Bacterial acquisition of carbapenemases, enzymes that inactivate carbapenems, is crucial to the emergence of CRE. The enzyme in the sentinel carbapenem-resistant K pneumoniae isolate found in 1996 in North Carolina was designated K pneumoniae carbapenemase (KPC-1). This mechanism also conferred resistance to all cephalosporins, aztreonam, and beta-lactamase inhibitors such as clavulanic acid and tazobactam.¹⁰

KPC-2 (later determined to be identical to KPC-1) was found in K pneumoniae from Baltimore, and KPC-3 caused an early outbreak in New York City.^11,12 To date, 12 additional variants of bla_KPC, the gene encoding for the KPC enzyme, have been described.¹³

The genes encoding carbapenemases are usually found on plasmids or other common mobile genetic elements.¹⁴ These genetic elements allow the organism to acquire genes conferring resistance to other classes of antimicrobials, such as aminoglycoside-modifying enzymes and fluoroquinolone-resistance determinants, and beta-lactamases.^15,16 The result is that CRE isolates are increasingly multidrug-resistant (ie, resistant to three or more classes of antimicrobials), extensively drug-resistant (ie, resistant to all but one or two classes), or pandrug-resistant (ie, resistant to all available classes of antibiotics).¹⁷ Thus, up to 98% of KPC-producing K pneumoniae are resistant to trimethoprim-sulfamethoxazole, 90% are resistant to fluoroquinolones, and 60% are resistant to gentamicin or amikacin.¹⁵

The mobility of these genetic elements has also allowed for dispersion into diverse Enterobacteriaceae such as E coli, Klebsiella oxytoca, Enterobacter, Serratia, and Salmonella species. Furthermore, KPC has been described in non-Enterobacteriaceae such as Acinetobacter baumannii and P aeruginosa.

Extending globally, KPC is now endemic in the Mediterranean basin, including Israel, Greece, and Italy; in South America, especially Colombia, Argentina, and Brazil; and in China.¹⁸ Most interesting is the intercontinental transfer of these strains: it has been documented that the index patient with KPC-producing K pneumoniae in Medellin, Colombia, came from Israel to undergo liver transplantation.¹⁹ Likewise, KPC-producing K pneumoniae in France and Israel could be linked epidemiologically and genetically to the predominant US strain.^20,21

Even more explosive has been the surge of another carbapenemase, the Ambler Class B New Delhi metallo-beta-lactamase, or NDM-1. Initially reported in a urinary isolate of K pneumoniae from a Swedish patient who had been hospitalized in New Delhi in 2008, NDM-1 was soon found throughout India, in Pakistan, and in the United Kingdom.²² Interestingly, several of the UK patients with NDM-1-harboring bacteria had received organ transplants in the Indian subcontinent. Reports from elsewhere in Europe, Australia, and Africa followed suit, usually with a connection to the Indian subcontinent epicenter. In contrast, several other cases in Europe were traced to the Balkans, where there appears to be another focus of NDM-1.²³

Penetration of NDM-1 into North America has begun, with cases and outbreaks reported in several US and Canadian regions, and in a military medical facility in Afghanistan. In several of these instances, there has been a documented link with travel and hospitalizations overseas.^24–27 However, no such link with travel could be established in a recent outbreak in Ontario.²⁷

In addition, resistance to carbapenems may result from other enzymes (Table 1), or from combinations of changes in outer membrane porins and the production of extended spectrum beta-lactamases or other cephalosporinases.²⁸

DEADLY IMPACT ON THE MOST VULNERABLE

Regardless of the resistance pattern, Enterobacteriaceae are an important cause of health care-associated infections, including urinary and bloodstream infections in patients with indwelling catheters, pneumonia (often in association with mechanical ventilation), and, less frequently, infections of skin and soft tissues and the central nervous system.^29–31

Several studies have examined the clinical characteristics and outcomes of patients with CRE infections. Those typically affected are elderly and debilitated and have multiple comorbidities, including diabetes mellitus and immunosuppression. They are heavily exposed to health care with frequent antecedent hospitalizations and invasive procedures. Furthermore, they are often severely ill and require intensive care. Patients infected with carbapenem-resistant K pneumoniae, compared with those with carbapenem-susceptible strains, are more likely to have undergone organ or stem cell transplantation or mechanical ventilation, and to have had a longer hospital stay before infection.

They also experience a high mortality rate, which ranges from 30% in patients with nonbacteremic infections to 72% in series of patients with liver transplants or bloodstream infections.^32–37

More recently, CRE has been reported in other vulnerable populations, such as children with critical illness or cancer and in burn patients.^38–40

Elderly and critically ill patients with bacteremia originating from a high-risk source (eg, pneumonia) typically face the most adverse outcomes. With increasing drug resistance, inadequate initial antimicrobial therapy is more commonly seen and may account for some of these poor outcomes.^37,41

LONG-TERM CARE FACILITIES IN THE EYE OF THE STORM

A growing body of evidence suggests that long-term care facilities play a crucial role in the spread of CRE.

In an investigation into carbapenem-resistant A baumanii and K pneumoniae in a hospital system,³⁶ 75% of patients with carbapenem-resistant K pneumoniae were admitted from long-term care facilities, and only 1 of 13 patients was discharged home.

In a series of patients with carbapenem-resistant K pneumoniae bloodstream infections, 42% survived their index hospital stay. Of these patients, only 32% were discharged home, and readmissions were very common.³²

Admission from a long-term care facility or transfer from another hospital is significantly associated with carbapenem resistance in patients with Enterobacteriaceae.⁴² Similarly, in Israel, a large reservoir of CRE was found in postacute care facilities.⁴³

It is clear that long-term care residents are at increased risk of colonization and infection with CRE. However, further studies are needed to evaluate whether this simply refects an overlap in risk factors, or whether significant patient-to-patient transmission occurs in these settings.

INFECTION CONTROL TAKES CENTER STAGE

It is important to note that risk factors for CRE match those of various nosocomial infections, including other resistant gram-negative bacilli, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Candida species, and Clostridium difficile; in fact, CRE often coexist with other multidrug-resistant organisms.^44,45

Common risk factors include residence in a long-term care facility, an intensive care unit stay, use of lines and catheters, and antibiotic exposure. This commonality of risk factors implies that systematic infection-prevention measures will have an impact on the prevalence and incidence rates of multidrug-resistant organism infections across the board, CRE included. It should be emphasized that strict compliance with hand hygiene is still the foundation of any infection-prevention strategy.

Infection prevention and the control of transmission of CRE in long-term care facilities pose unique challenges. Guidelines from the Society for Healthcare Epidemiology and the Association for Professionals in Infection Control recommend the use of contact precautions for patients with multidrug-resistant organisms, including CRE, who are ill and totally dependent on health care workers for activities of daily living or whose secretions or drainage cannot be contained. These same guidelines advise against attempting to eradicate multidrug-resistant organism colonization status.⁴⁶

In acute care facilities, Best Infection Control Practices from the CDC and the Healthcare Infection Control Practices Advisory Committee encourage mechanisms for the rapid recognition and reporting of CRE cases to infection prevention personnel so that contact precautions can be implemented. Furthermore, facilities without CRE cases should carry out periodic laboratory reviews to identify cases, and patients exposed to CRE cases should be screened with surveillance cultures.⁴⁷

Outbreaks of CRE may require extraordinary infection control measures. An approach combining point-prevalence surveillance of colonization, detection of environmental and common-equipment contamination, with the implementation of a bundle consisting of chlorhexidine baths, cohorting of colonized patients and health care personnel, increased environmental cleaning, and staff education may be effective in controlling outbreaks of CRE.⁴⁸

Nevertheless, control of CRE may prove exceptionally difficult. A recent high-profile outbreak of carbapenem-resistant K pneumoniae at the National Institutes of Health Clinical Center in Maryland caused infections in 18 patients, 11 of whom died.⁴⁹ Of note, carbapenem-resistant K pneumoniae was detected in this outbreak in both respiratory equipment and sink drains. The outbreak was ultimately contained by detection through surveillance cultures and by strict cohorting of colonized patients, which minimized common medical equipment and personnel between affected patients and other patients in the hospital. Additionally, rooms were sanitized with hydrogen peroxide vapor, and sinks and drains where carbapenem-resistant K pneumoniae was detected were removed.

CHALLENGES IN THE MICROBIOLOGY LABORATORY

Adequate treatment and control of CRE infections is predicated upon their accurate and prompt diagnosis from patient samples in the clinical microbiology laboratory.⁵⁰

Traditional and current culture-based methods take several days to provide that information, delaying effective antibiotic therapy and permitting the transmission of undetected CRE. Furthermore, interpretative criteria of minimal inhibitory concentrations (MICs) of carbapenems recently required readjustment, as many KPC-producing strains of K pneumoniae had MICs below the previous breakpoint of resistance. In the past, this contributed to instances of “silent” dissemination of KPC-producing K pneumoniae.⁵¹

In contrast, using the new lower breakpoints of resistance for carbapenems without using a phenotypic test such as the modified Hodge test or the carbapenem-EDTA combination tests will result in a lack of differentiation between various mechanisms of carbapenem resistance.^28,52,53 This may be clinically relevant, as the clinical response to carbapenem therapy may vary depending on the mechanism of resistance.

GENERAL PRINCIPLES APPLY

In treating patients infected with CRE, clinicians need to strictly observe general principles of infectious disease management to ensure the best possible outcomes. These include:

Timely and accurate diagnosis, as discussed above.

Source control, which should include drainage of any infected collections, and removal of lines, devices, and urinary catheters.

Distinguishing between infection and colonization. CRE are often encountered as urinary isolates, and the distinction between asymptomatic bacteriuria and urinary tract infection may be extremely difficult, especially in residents of long-term care facilities with chronic indwelling catheters, who are thegroup at highest risk of CRE colonization and infection. Urinalysis may be helpful in the absence of pyuria, as this rules out an infection; however, it must be emphasized that the presence of pyuria is not a helpful feature, as pyuria is common in both asymptomatic bacteriuria and urinary tract infection.⁵⁴ Symptoms should be carefully evaluated in every patient with bacteriuria, and urinary tract infection should be a diagnosis of exclusion in patients with functional symptoms such as confusion or falls.

Selection of the most appropriate antibiotic regimen. While the emphasis is often on the antibiotic regimen, the above elements should not be neglected.

A DWINDLING THERAPEUTIC ARSENAL

Clinicians treating CRE infections are left with only a few antibiotic options. These options are generally limited by a lack of clinical data on efficacy, as well as by concerns about toxicity. These “drugs of last resort” include polymyxins (such as colistin), aminoglycosides, tigecycline, and fosfomycin. The role of carbapenem therapy, potentially in combination regimens, in a high-dose prolonged infusion, or even “double carbapenem therapy” remains to be determined.^37,55,56

Colistin

Colistin is one of the first-line agents for treating CRE infections. First introduced in the 1950s, its use was mostly abandoned in favor of aminoglycosides. A proportion of the data on safety and efficacy of colistin, therefore, is based on older, less rigorous studies.

Neurotoxicity and nephrotoxicity are the two main concerns with colistin, and while the incidence of these adverse events does appear to be lower with modern preparations, it is still substantial.⁵⁷ Dosing issues have not been completely clarified either, especially in relation to renal clearance and in patients on renal replacement therapy.^58,59 Unfortunately, there have been reports of outbreaks of CRE displaying resistance to colistin.⁶⁰

Tigecycline

Tigecycline is a newer antibiotic of the glycylcycline class. Like colistin, it has no oral preparation for systemic infections.

The main side effect of tigecycline is nausea.⁶¹ Other reported issues include pancreatitis and extreme alkaline phosphatase elevations.

The efficacy of tigecycline has come into question in view of meta-analyses of clinical trials, some of which have shown higher mortality rates in patients treated with tigecycline than with comparator agents.^62–65 Based on these data, the US Food and Drug Administration issued a warning in 2010 regarding the increased mortality risk. Although these meta-analyses did not include patients with CRE for whom available comparators would have been ineffective, it is an important safety signal.

The efficacy of tigecycline is further limited by increasing in vitro resistance in CRE. Serum and urinary levels of tigecycline are low, and most experts discourage the use of tigecycline as monotherapy for blood stream or urinary tract infections.

Aminoglycosides

CRE display variable in vitro susceptibility to different aminoglycosides. If the organism is susceptible, aminoglycosides may be very useful in the treatment of CRE infections, especially urinary tract infectons. In a study of carbapenem-resistant K pneumoniae urinary tract infections, patients who were treated with polymyxins or tigecycline were significantly less likely to have clearance of their urine as compared with patients treated with aminoglycosides.⁶⁶

Ototoxicity and nephrotoxicity are demonstrated adverse effects of aminoglycosides. Close monitoring of serum levels, interval audiology examinations at baseline and during therapy, and the use of extended-interval dosing may help to decrease the incidence of these toxicities.

Fosfomycin

Fosfomycin is only available as an oral formulation in the United States, although intravenous administration has been used in other countries. It is exclusively used to treat urinary tract infections.

CRE often retain susceptibility to fosfomycin, and clearance of urine in cystitis may be attempted with this agent to avoid the need for intravenous treatment.^29,67

Combination therapy, other topics to be explored

Recent observational reports from Greece, Italy, and the United States describe higher survival rates in patients with CRE infections treated with a combination regimen rather than monotherapy with colistin or tigecycline. This is despite reliable activity of colistin and tigecycline, and often in regimens containing carbapenems. Clinical experiments are needed to clarify the value of combination regimens that include carbapenems for the treatment of CRE infections.

Similarly, the role of carbapenems given as a high-dose prolonged infusion or as double carbapenem therapy needs to be explored further.^37,55,56,68

Also to be determined is the optimal duration of treatment. To date, there is no evidence that increasing the duration of treatment beyond that recommended for infections with more susceptible bacteria results in improved outcomes. Therefore, commonly used durations include 1 week for complicated urinary tract infections, 2 weeks for bacteremia (from the first day with negative blood cultures and source control), and 8 to 14 days for pneumonia.

A SERIOUS THREAT

The emergence of CRE is a serious threat to the safety of patients in our health care system. CRE are highly successful nosocomial pathogens selected by the use of antibiotics, which burden patients debilitated by advanced age, comorbidities, and medical interventions. Infections with CRE result in poor outcomes, and available treatments of last resort such as tigecycline and colistin are of unclear efficacy and safety.

Control of CRE transmission is hindered by the transit of patients through long-term care facilities, and detection of CRE is difficult because of the myriad mechanisms involved and the imperfect methods currently available. Clinicians are concerned and frustrated, especially given the paucity of antibiotics in development to address the therapeutic dilemma posed by CRE. The challenge of CRE and other multidrug-resistant organisms requires the concerted response of professionals in various disciplines, including pharmacists, microbiologists, infection control practitioners, and infectious disease clinicians (Table 2).

Control of transmission by infection prevention strategies and by antimicrobial stewardship is going to be crucial in the years to come, not only for limiting the spread of CRE, but also for preventing the next multidrug-resistant “superbug” from emerging. However, the current reality is that health care providers will be faced with increased numbers of patients infected with CRE.