Nephrology

To the Editor: I read with interest the exchange of letters between Drs. Norenberg and Graves in the December 2007 issue,^1,2 which followed Dr. Graves’ article in the October 2007 issue.³ Dr. Norenberg suggests that it is not always prudent to try to push systolic pressures below 140 mm Hg in the elderly, and Dr. Graves takes the position that physicians like Dr. Norenberg have been “too slow to adapt to evidence-based guidelines for quality of care.” I would like to focus on Dr. Graves’ reference to evidence-based guidelines for the treatment of systolic hypertension in the elderly.

Although there have been multiple published studies of the treatment of this disorder, none has achieved an average systolic blood pressure lower than 140. The Systolic Hypertension in the Elderly Program (SHEP)⁴ came closest with a final systolic blood pressure of 144. No study has ever documented the efficacy and safety of achieving systolic blood pressures less than 140 in a cohort of elderly patients, and there is substantial evidence that excessive lowering of diastolic blood pressure can be harmful.^5,6

Many elderly patients can achieve the target referenced by Dr. Graves, and it is reasonable to expect physicians to continue to strive for that goal, but it would be unwise to push all seniors below 140 systolic. Consider the elderly patient with systolic hypertension who is on a robust three-drug regimen including a diuretic, with a blood pressure of 144/60 and with persistent but tolerable drug side effects. I am aware of no clinical trials that demonstrate that further lowering of this patient’s blood pressure would provide incremental benefit to outweigh the potential risks and costs of additional medications.

We need to be careful not to confuse evidence-based medicine with high-placed opinions, which can result in rigid approaches to treatment that are not in the best interest of our patients.

To the Editor: I read with interest the exchange of letters between Drs. Norenberg and Graves in the December 2007 issue,^1,2 which followed Dr. Graves’ article in the October 2007 issue.³ Dr. Norenberg suggests that it is not always prudent to try to push systolic pressures below 140 mm Hg in the elderly, and Dr. Graves takes the position that physicians like Dr. Norenberg have been “too slow to adapt to evidence-based guidelines for quality of care.” I would like to focus on Dr. Graves’ reference to evidence-based guidelines for the treatment of systolic hypertension in the elderly.

Although there have been multiple published studies of the treatment of this disorder, none has achieved an average systolic blood pressure lower than 140. The Systolic Hypertension in the Elderly Program (SHEP)⁴ came closest with a final systolic blood pressure of 144. No study has ever documented the efficacy and safety of achieving systolic blood pressures less than 140 in a cohort of elderly patients, and there is substantial evidence that excessive lowering of diastolic blood pressure can be harmful.^5,6

Many elderly patients can achieve the target referenced by Dr. Graves, and it is reasonable to expect physicians to continue to strive for that goal, but it would be unwise to push all seniors below 140 systolic. Consider the elderly patient with systolic hypertension who is on a robust three-drug regimen including a diuretic, with a blood pressure of 144/60 and with persistent but tolerable drug side effects. I am aware of no clinical trials that demonstrate that further lowering of this patient’s blood pressure would provide incremental benefit to outweigh the potential risks and costs of additional medications.

We need to be careful not to confuse evidence-based medicine with high-placed opinions, which can result in rigid approaches to treatment that are not in the best interest of our patients.

To the Editor: I read with interest the exchange of letters between Drs. Norenberg and Graves in the December 2007 issue,^1,2 which followed Dr. Graves’ article in the October 2007 issue.³ Dr. Norenberg suggests that it is not always prudent to try to push systolic pressures below 140 mm Hg in the elderly, and Dr. Graves takes the position that physicians like Dr. Norenberg have been “too slow to adapt to evidence-based guidelines for quality of care.” I would like to focus on Dr. Graves’ reference to evidence-based guidelines for the treatment of systolic hypertension in the elderly.

Although there have been multiple published studies of the treatment of this disorder, none has achieved an average systolic blood pressure lower than 140. The Systolic Hypertension in the Elderly Program (SHEP)⁴ came closest with a final systolic blood pressure of 144. No study has ever documented the efficacy and safety of achieving systolic blood pressures less than 140 in a cohort of elderly patients, and there is substantial evidence that excessive lowering of diastolic blood pressure can be harmful.^5,6

Many elderly patients can achieve the target referenced by Dr. Graves, and it is reasonable to expect physicians to continue to strive for that goal, but it would be unwise to push all seniors below 140 systolic. Consider the elderly patient with systolic hypertension who is on a robust three-drug regimen including a diuretic, with a blood pressure of 144/60 and with persistent but tolerable drug side effects. I am aware of no clinical trials that demonstrate that further lowering of this patient’s blood pressure would provide incremental benefit to outweigh the potential risks and costs of additional medications.

We need to be careful not to confuse evidence-based medicine with high-placed opinions, which can result in rigid approaches to treatment that are not in the best interest of our patients.

In Reply: First, I am gratified by the tremendous interest in the care of the hypertensive patient that my article has generated. Dr. Norenberg and Dr. Kelleher are insightful clinicians, as evidenced by the issues that their letters raise. Secondly, as I am now 54 years old, SHEP’s definition of “elderly” as 60 years old and older appears less accurate to me! However, I think we might all agree that to date there has not been a trial with people 65 years old and younger that has not shown benefit to treatment of the blood pressure to less than 140/90 mm Hg.

I believe that Dr. Kelleher’s quest for more “evidence-based” data refers to treatment data in patients above that age. Hopefully, this quest will be answered by the results of the Hypertension in the Very Elderly Trial (HYVET).¹ In this trial, 3,845 patients older than 80 years were treated to less than 140/90 mm Hg. On July 12, 2007, the trial was stopped by the data safety and monitoring board, with the expectation of published results at the European Society of Hypertension and International Society of Hypertension joint meeting in Berlin in 2008.

Third, I must remind the reader that in practicing evidence-based medicine, we clinicians always must interpret the results of double-blind placebo-controlled trials, which tell us the mean effect of a treatment, but apply this information to the individual patient seated in front of us. A recent study² of individual blood pressure response to four forms of monotherapy showed that, in some patients, the blood pressure rose with hydrochlorothiazide instead of falling!

Fourth, Dr. Kelleher implies, correctly, that not all patients can reach the target of less than 140/90. In this regard I think the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)³ is very instructive. ALLHAT is the first trial ever to show improvement in the percent of people reaching goal blood pressure, rising from 52% to 63% during the 5-year study. ALLHAT shows us how good we can be and that we should not accept the failure to reach goal blood pressure in at least two-thirds of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

In Reply: First, I am gratified by the tremendous interest in the care of the hypertensive patient that my article has generated. Dr. Norenberg and Dr. Kelleher are insightful clinicians, as evidenced by the issues that their letters raise. Secondly, as I am now 54 years old, SHEP’s definition of “elderly” as 60 years old and older appears less accurate to me! However, I think we might all agree that to date there has not been a trial with people 65 years old and younger that has not shown benefit to treatment of the blood pressure to less than 140/90 mm Hg.

I believe that Dr. Kelleher’s quest for more “evidence-based” data refers to treatment data in patients above that age. Hopefully, this quest will be answered by the results of the Hypertension in the Very Elderly Trial (HYVET).¹ In this trial, 3,845 patients older than 80 years were treated to less than 140/90 mm Hg. On July 12, 2007, the trial was stopped by the data safety and monitoring board, with the expectation of published results at the European Society of Hypertension and International Society of Hypertension joint meeting in Berlin in 2008.

Third, I must remind the reader that in practicing evidence-based medicine, we clinicians always must interpret the results of double-blind placebo-controlled trials, which tell us the mean effect of a treatment, but apply this information to the individual patient seated in front of us. A recent study² of individual blood pressure response to four forms of monotherapy showed that, in some patients, the blood pressure rose with hydrochlorothiazide instead of falling!

Fourth, Dr. Kelleher implies, correctly, that not all patients can reach the target of less than 140/90. In this regard I think the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)³ is very instructive. ALLHAT is the first trial ever to show improvement in the percent of people reaching goal blood pressure, rising from 52% to 63% during the 5-year study. ALLHAT shows us how good we can be and that we should not accept the failure to reach goal blood pressure in at least two-thirds of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

In Reply: First, I am gratified by the tremendous interest in the care of the hypertensive patient that my article has generated. Dr. Norenberg and Dr. Kelleher are insightful clinicians, as evidenced by the issues that their letters raise. Secondly, as I am now 54 years old, SHEP’s definition of “elderly” as 60 years old and older appears less accurate to me! However, I think we might all agree that to date there has not been a trial with people 65 years old and younger that has not shown benefit to treatment of the blood pressure to less than 140/90 mm Hg.

I believe that Dr. Kelleher’s quest for more “evidence-based” data refers to treatment data in patients above that age. Hopefully, this quest will be answered by the results of the Hypertension in the Very Elderly Trial (HYVET).¹ In this trial, 3,845 patients older than 80 years were treated to less than 140/90 mm Hg. On July 12, 2007, the trial was stopped by the data safety and monitoring board, with the expectation of published results at the European Society of Hypertension and International Society of Hypertension joint meeting in Berlin in 2008.

Third, I must remind the reader that in practicing evidence-based medicine, we clinicians always must interpret the results of double-blind placebo-controlled trials, which tell us the mean effect of a treatment, but apply this information to the individual patient seated in front of us. A recent study² of individual blood pressure response to four forms of monotherapy showed that, in some patients, the blood pressure rose with hydrochlorothiazide instead of falling!

Fourth, Dr. Kelleher implies, correctly, that not all patients can reach the target of less than 140/90. In this regard I think the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)³ is very instructive. ALLHAT is the first trial ever to show improvement in the percent of people reaching goal blood pressure, rising from 52% to 63% during the 5-year study. ALLHAT shows us how good we can be and that we should not accept the failure to reach goal blood pressure in at least two-thirds of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

The final and most important point is that the time for arguing the guideline recommendations^4–6 based on our own opinion is past. Third-party payers and patients are demanding we meet those guidelines until new information suggests that they need to be altered. HYVET may force such an alteration, but until then Dr. Norenberg, Dr. Kelleher, and I must attempt to reach the target of less than 140/90 in the majority of our patients.

Many people have some amount of blood in their urine, but relatively few have a serious problem.

In a population-based study in Rochester, Minnesota, red blood cells were found in the urine of 13% of symptom-free adults.¹ In other studies, the figure ranged from 9% to 18%.²

Hematuria is sometimes detected during investigation of symptoms such as dysuria, urinary frequency, or flank pain. However, many referrals to urologists are made purely on the basis of the results of a dipstick urinalysis screening test in a patient without symptoms.

The United States Preventive Task Force³ discourages routine testing for hematuria to screen for bladder cancer in patients without symptoms, and the Canadian Task Force on the Periodic Health Examination⁴ and the American Urological Association (AUA)^2,5 do not recommend it either. Nevertheless, approximately 40% of primary care physicians believe in it,⁶ although the number seems to be declining.⁷ A reason that dipstick testing is so popular is that it is an inexpensive and simple way to detect glucosuria and medical renal disease.^8–11

The risk of significant disease in a patient with microhematuria but without symptoms is low, and the evaluation for hematuria can be costly and invasive. For an individual patient with a hemoglobin-positive dipstick test, the finding should not be ignored, but the patient does not necessarily need a complete evaluation. It is important to determine which patients require urologic studies and consultation, nephrologic evaluation, or no intervention at all.

This review addresses issues related to hematuria for the primary care physician, clarifies some of the important definitions, builds on these terms to delineate which patients should be referred to a urologist, and provides simple recommendations about ancillary studies and their potential role before urologic consultation. Understanding this information will ultimately assure appropriate management of patients without symptoms who have positive dipstick screening tests, leading to decreased use of costly and invasive tests and more appropriate long-term follow-up.

BASIC DEFINITIONS

Gross (macroscopic) hematuria is blood in the urine that is visible without microscopy. This condition almost always warrants urologic evaluation.^2,5

Microscopic hematuria, or microhematuria, is the finding of red blood cells in the urine on microscopy. (In contrast, in dipstick hematuria—see below—blood cells may or may not be present in the urine.)

“Dipstick hematuria” and “dipstick microhematuria” are potential misnomers. The dip-stick test for hematuria is a nondiagnostic screening test. A positive result is simply a color change due to oxidation of a test-strip reagent; it does not confirm that blood cells are present. Factors that can cause a false-positive result on a dipstick test include hemoglobinuria, myoglobinuria, concentrated urine, menstrual blood in the urine sample, and rigorous exercise.¹² Thus, the diagnosis of hematuria cannot be made by dipstick alone. Unless red blood cells are seen microscopically, the term microhematuria is inappropriate.

Of note, if the specific gravity of the urine is very low (< 1.007), microscopy can fail to detect urinary red blood cells, owing to cell lysis.² This limitation can be overcome by restricting the patient’s fluid intake and then repeating the urinalysis.

Many patients with a positive dipstick oxidation reaction are labeled as having dip-stick hematuria although microscopic analysis would show that red blood cells are absent. Perhaps the term dipstick pseudohematuria would be more accurate. These patients will not benefit from a costly and invasive urologic workup, so it is crucial to distinguish them from patients with true microhematuria.

SIGNIFICANT HEMATURIA: ≥ 3 RBCs/HPF

Microhematuria is often intermittent, and many healthy patients occasionally have a few red blood cells in the urine.¹³ However, no cutoff point for the amount of hematuria can be used to rule out the possibility of cancer.¹⁴ To account for these complicating factors, the AUA Best Practice Policy Panel on Asymptomatic Hematuria considered the literature and expert opinions to define the amount of microhematuria warranting evaluation in patients with risk factors for significant urologic disease.^2,5

The AUA panel defined microhematuria as an average of three or more red blood cells per high-power microscopic field (RBCs/HPF) in two out of three properly collected and prepared specimens. Urine should be collected midstream after wiping the urethral meatus with a disinfectant and voiding the initial portion of urine into the toilet. For proper preparation of the urine sample, 10 mL of urine should be centrifuged at 2,000 rpm for 5 minutes and the supernatant discarded. The sediment should then be resuspended in 0.5 to 1.0 mL of remaining urine, and a drop of this suspension should be examined microscopically. If contamination is suggested (ie, if squamous epithelial cells, bacteria, or both are present), one should consider collecting a specimen through catheterization.^2,5

The AUA guidelines do not specify some of the details of management, such as the timing of subsequent microscopic urinalyses, but we recommend that all urinalyses to establish whether significant hematuria is present be done within 3 to 6 months of the screening dip-stick test. If a patient has no risk factors for cancer and has a negative result on the first microscopic urinalysis, the follow-up test can be performed in 1 year. Table 1 shows risk factors for significant urologic disease that warrant evaluation in patients with asymptomatic hematuria.⁵

Isolated urinary findings that might warrant evaluation by a nephrologist rather than a urologist include proteinuria, red cell casts, and dysmorphic red blood cells, especially if the serum creatinine level is elevated.^2,5 Many medical renal conditions (eg, glomerulonephritis) and hemoglobinopathies (eg, sickle cell trait) can cause blood in the urine; when these conditions are accompanied by risk factors for urologic disease, urologic evaluation is indicated as well.

CLINICAL RELEVANCE OF HEMATURIA

Approximately 25% of cases of macroscopic hematuria are due to urologic cancers,^14,15 and another 34% are due to other significant urologic diseases¹⁴—thus, the recommendation that patients with macroscopic hematuria be evaluated by a urologist. In contrast, in microhematuria, the rates of cancer are much lower, ranging between 1% and 10% in large studies.^2,5

The urine dipstick test has been found to be 65% to 99% specific for the presence of blood cells, free hemoglobin, or myoglobin.^2,5 If the true specificity is closer to the lower figure and all patients with a positive dipstick test were referred to a urologist, this would mean the urologic workup would be unnecessary in up to 35% of them, because the dipstick result would be falsely positive.

But that is not all. Most causes of hemoglobinuria or myoglobinuria are of limited clinical significance, except for rare conditions that are usually clinically obvious, such as severe burn injury. Further, remember that from 9% to 18% of patients without symptoms have red blood cells in the urine.^2,5 In theory, if everyone in the United States had a dipstick test, this would be positive in patients with hematuria as well as in those with hemoglobinuria, myoglobinuria, and other false-positives; if everyone with a positive dipstick result were then referred to a urologist, a substantial portion of the population would receive an unnecessary urologic referral.

Urologic referral and evaluation in these patients not only wastes money: if they undergo imaging studies, they are exposed to radiation and contrast media, with their associated risks, and if they undergo cystoscopy, they face its attendant discomfort and risk of infection.

WHICH PATIENTS WITH HEMATURIA TO REFER TO A UROLOGIST

Gross hematuria

Red or tea-colored urine usually indicates gross hematuria. When there is any doubt—such as in the case of a color-blind patient—the presence of red blood cells can be confirmed or ruled out by a microscopic urinalysis.

Nearly all patients with an episode of gross hematuria should be referred to a urologist. The sole exception to this rule can be made when a woman younger than 40 years experiences gross hematuria in the classic setting of a culture-proven, symptomatic urinary tract infection (UTI) and her infection, symptoms, and hematuria all resolve completely with appropriate antibiotics.^2,5 However, bleeding from cancer is classically intermittent. Therefore, one should not skip the urine culture and just prescribe antibiotics empirically: the patient might actually have cancer, but the supposed UTI may appear to resolve with antibiotic therapy. For the same reason, resolution of hematuria in any other setting does not obviate the need for referral.

Another scenario usually associated with a benign cause is bleeding after extreme physical activity—also known as “runner’s hematuria” or “march hematuria” (so named because it sometimes occurs in soldiers after a particularly grueling training march). Importantly, even in this situation, one should still be suspicious and probably refer the patient to a urologist: just because the patient has just run a marathon, it does not mean that he or she does not have cancer.

Depending on the character, timing, location, and many other characteristics of the patient’s bleeding, a variety of studies may or may not be necessary. For example, blood-spotting of the underpants might signify urethral bleeding, and imaging and cytologic studies might not be indicated. In view of the variability in presentation and workup, we recommend that the proper workup for these patients be determined by a urologist.

Symptomatic microhematuria

Patients with true microhematuria (three or more RBCs/HPF) accompanied by bothersome or worrisome symptoms should be referred to a urologist. In a study in Scotland, Sultana et al¹⁶ found that cancer was present in 6 (5%) of 126 patients with microhematuria without symptoms compared with 13 (10.5%) of 124 patients with microhematuria and irritative voiding symptoms; the difference, however, was not statistically significant.

Microscopic urinalysis should be part of the evaluation for flank pain or certain urinary symptoms such as frequency, urgency, retention, or dysuria; results of this test at the time of symptoms can later help the urologist distinguish the cause of the symptoms or hematuria. In addition, in combination with dipstick analysis, microscopic analysis can help distinguish patients with UTI or medical renal disease. If the evaluation suggests that the hematuria and symptoms are due to a UTI, then the findings on a repeat microscopic analysis, performed after the infection has cleared, should be normal. If hematuria, defined as three or more RBCs/HPF, persists in two of three subsequent urinalyses, then the guidelines mandate diagnostic evaluation even if the urinalysis subsequently becomes negative.

Asymptomatic hematuria

In symptom-free patients with dipstick hematuria found on a screening examination, it is crucial to confirm and document true microhematuria. Per the AUA guidelines, microhematuria worthy of urologic workup is the presence of three or more RBCs/HPF on at least two out of three microscopic urinalyses.^2,5 Patients with dipstick pseudohematuria do not meet this criterion and will not benefit from a costly and invasive evaluation. Conversely, patients with higher levels of microhematuria, who have any risk factors for cancer, or who are anxious about the test results might benefit from urologic consultation before a second urinalysis to confirm the first, positive finding.

Many patients younger than age 40 with asymptomatic microhematuria but no other risk factors for urinary tract cancer can be followed conservatively. Khadra et al¹⁴ reported that only 1 of 143 patients younger than 40 years with microhematuria had cancer. Similarly, Jones et al¹⁷ found, in a prospective study, that no man younger than 40 years with microscopic hematuria had cancer.

Of note: gross or microscopic blood in the urine, even in the setting of anticoagulation, is a marker of urinary tract pathology such as cancer, stones, or infection. Just as patients on anticoagulation therapy who develop gastrointestinal bleeding need a gastrointestinal evaluation, those with hematuria require a urologic evaluation.^2,5

STUDIES TO CONSIDER BEFORE CONSULTATION

In symptom-free patients, it is inappropriate to order laboratory or imaging tests on the basis of a dipstick test alone, without confirming that they actually have hematuria. When the blood is confirmed to be present by microscopic examination of centrifuged urine (as described above), benign causes such as UTI should be considered. If a patient does have a UTI with hematuria, urinalysis should be repeated once the infection has cleared up.

Imaging studies

For symptomatic microhematuria. Patients with acute symptoms of renal colic should undergo computed tomography (CT) in a “stone protocol” (without contrast, with 3- to 5-mm cuts of the abdomen and pelvis) to assess for urinary lithiasis. Pregnancy should always be ruled out before radiation exposure; renal ultrasonography is generally the first-choice imaging study for pregnant patients.

For asymptomatic microhematuria. Patients without the classic flank pain of urolithiasis should undergo more extensive studies. For patients at increased risk of cancer, such as heavy smokers, CT urography is the optimal imaging study and is the test least likely to necessitate other follow-up studies.^18–20 Other imaging options, including ultrasonography and intravenous pyelography, incompletely assess the upper urinary tracts including both renal parenchyma and urothelial surfaces. CT urography has been shown to find more than 40% of hematuria-causing lesions missed by other studies.¹⁸ Because ordering alternative imaging first will often result in redundant studies, CT urography is the preferred initial imaging study in the evaluation of hematuria.

Before exposing a patient to contrast media, one should ascertain that he or she is not allergic to it. In addition, in patients at risk of contrast nephropathy (ie, those older than 60 years, with diabetes, or with preexisting medical renal disease), one should check the serum creatinine concentration. Magnetic resonance urography, a more expensive study, is as accurate as CT for diagnosing many urologic conditions, so it can be performed in lieu of CT urography in patients with renal insufficiency, iodine allergy, or any reason to avoid ionizing radiation. Some clinicians perform plain radiography of the kidneys, ureters, and bladder as well as ultrasonography in this setting, but determination of the appropriate alternative to CT urography, if required, is best left to the urologist.

Other tests

Cytologic testing of the urine can be valuable in patients with gross hematuria and in those with microhematuria who have risk factors for urinary tract cancer. Although its reported median sensitivity for malignancy is only 48%, a positive cytologic test is approximately 94% specific for malignancy.²¹ Other studies, such as the fluorescence in situ hybridization assay, and the nuclear matrix protein 22 test do not yet have a clear role in the diagnosis of urinary tract disease.²²

However, in general, we caution non-urologists not to order special tumor marker or cytologic tests, or to do so only with careful forethought. Although these studies occasionally detect occult cancer in patients at high risk, an “atypical” finding on cytology or a positive tumor marker test can lead to inappropriate referral and unnecessary biopsy or other tests.

WHEN NOT TO REFER A PATIENT WITH HEMATURIA TO A UROLOGIST

Symptom-free patients with a positive dipstick hemoglobin test should not immediately be referred to a urologist: they should have a microscopic urinalysis first to determine whether they actually have microhematuria, unless microscopic laboratory services are unavailable. Only patients with documented true hematuria, as defined by the AUA guidelines, should be referred for urologic evaluation and diagnostic testing. Once a patient is referred for evaluation, the consultant is under clear pressure to perform a complete investigation to fulfill the expectations of the referring physician. Avoiding expensive unnecessary testing and referral in those without hematuria allows appropriate utilization of resources.

Patients with microhematuria associated with a UTI should have a repeat urinalysis after the UTI is successfully treated; if the hematuria clears with the infection, then the patient needs no further evaluation. Patients with dipstick pseudohematuria and significant proteinuria or a predominance of dysmorphic urinary blood cells might benefit from an evaluation by a nephrologist rather than a urologist.² This is especially true if the patient has an elevated serum creatinine level.

ECONOMIC RELEVANCE

In our tertiary care urology clinic, approximately 75% of patients who are referred to us because of microhematuria have not had a microscopic urinalysis before coming here. On further evaluation, up to 75% of these patients are found to have dipstick pseudohematuria that did not actually require consultation or evaluation.²³ It is possible that this occurs even more frequently in the general practice setting.

A Medicare level-4 urologic consultation for hematuria costs $170; the cumulative cost of unwarranted referrals is undoubtedly substantial. Even more money is wasted on CT urography, cytology, and other testing performed before urologic consultation in patients ultimately found not to have true hematuria. The economic and iatrogenic risks of evaluation cannot be justified in patients who do not exhibit findings that can be considered abnormal as defined in this article.

CONCLUSION

It is important to distinguish whether hematuria is microscopic or macroscopic, whether there are associated symptoms, and whether a patient has risk factors for significant urologic disease. While dipstick tests are sensitive, they do not reliably diagnose microhematuria, which is the microscopically proven presence of urinary red blood cells. Positive dipstick tests should always be followed by microscopic urinalysis; failure to do so can result in the unfortunate and unnecessary evaluation of dipstick pseudohematuria, a normal condition.

The AUA defines significant hematuria as three or more RBCs/HPF in two of three properly prepared specimens.² This should determine whether a symptom-free patient needs urologic referral and evaluation for hematuria.

By following these principles, primary care physicians have a valuable opportunity to direct medical care, increase the efficiency of our health care system, and protect patients from the anxiety, costs, and risks of an unnecessary urologic workup.

Many people have some amount of blood in their urine, but relatively few have a serious problem.

In a population-based study in Rochester, Minnesota, red blood cells were found in the urine of 13% of symptom-free adults.¹ In other studies, the figure ranged from 9% to 18%.²

Hematuria is sometimes detected during investigation of symptoms such as dysuria, urinary frequency, or flank pain. However, many referrals to urologists are made purely on the basis of the results of a dipstick urinalysis screening test in a patient without symptoms.

The United States Preventive Task Force³ discourages routine testing for hematuria to screen for bladder cancer in patients without symptoms, and the Canadian Task Force on the Periodic Health Examination⁴ and the American Urological Association (AUA)^2,5 do not recommend it either. Nevertheless, approximately 40% of primary care physicians believe in it,⁶ although the number seems to be declining.⁷ A reason that dipstick testing is so popular is that it is an inexpensive and simple way to detect glucosuria and medical renal disease.^8–11

The risk of significant disease in a patient with microhematuria but without symptoms is low, and the evaluation for hematuria can be costly and invasive. For an individual patient with a hemoglobin-positive dipstick test, the finding should not be ignored, but the patient does not necessarily need a complete evaluation. It is important to determine which patients require urologic studies and consultation, nephrologic evaluation, or no intervention at all.

This review addresses issues related to hematuria for the primary care physician, clarifies some of the important definitions, builds on these terms to delineate which patients should be referred to a urologist, and provides simple recommendations about ancillary studies and their potential role before urologic consultation. Understanding this information will ultimately assure appropriate management of patients without symptoms who have positive dipstick screening tests, leading to decreased use of costly and invasive tests and more appropriate long-term follow-up.

BASIC DEFINITIONS

Gross (macroscopic) hematuria is blood in the urine that is visible without microscopy. This condition almost always warrants urologic evaluation.^2,5

Microscopic hematuria, or microhematuria, is the finding of red blood cells in the urine on microscopy. (In contrast, in dipstick hematuria—see below—blood cells may or may not be present in the urine.)

“Dipstick hematuria” and “dipstick microhematuria” are potential misnomers. The dip-stick test for hematuria is a nondiagnostic screening test. A positive result is simply a color change due to oxidation of a test-strip reagent; it does not confirm that blood cells are present. Factors that can cause a false-positive result on a dipstick test include hemoglobinuria, myoglobinuria, concentrated urine, menstrual blood in the urine sample, and rigorous exercise.¹² Thus, the diagnosis of hematuria cannot be made by dipstick alone. Unless red blood cells are seen microscopically, the term microhematuria is inappropriate.

Of note, if the specific gravity of the urine is very low (< 1.007), microscopy can fail to detect urinary red blood cells, owing to cell lysis.² This limitation can be overcome by restricting the patient’s fluid intake and then repeating the urinalysis.

Many patients with a positive dipstick oxidation reaction are labeled as having dip-stick hematuria although microscopic analysis would show that red blood cells are absent. Perhaps the term dipstick pseudohematuria would be more accurate. These patients will not benefit from a costly and invasive urologic workup, so it is crucial to distinguish them from patients with true microhematuria.

SIGNIFICANT HEMATURIA: ≥ 3 RBCs/HPF

Microhematuria is often intermittent, and many healthy patients occasionally have a few red blood cells in the urine.¹³ However, no cutoff point for the amount of hematuria can be used to rule out the possibility of cancer.¹⁴ To account for these complicating factors, the AUA Best Practice Policy Panel on Asymptomatic Hematuria considered the literature and expert opinions to define the amount of microhematuria warranting evaluation in patients with risk factors for significant urologic disease.^2,5

The AUA panel defined microhematuria as an average of three or more red blood cells per high-power microscopic field (RBCs/HPF) in two out of three properly collected and prepared specimens. Urine should be collected midstream after wiping the urethral meatus with a disinfectant and voiding the initial portion of urine into the toilet. For proper preparation of the urine sample, 10 mL of urine should be centrifuged at 2,000 rpm for 5 minutes and the supernatant discarded. The sediment should then be resuspended in 0.5 to 1.0 mL of remaining urine, and a drop of this suspension should be examined microscopically. If contamination is suggested (ie, if squamous epithelial cells, bacteria, or both are present), one should consider collecting a specimen through catheterization.^2,5

The AUA guidelines do not specify some of the details of management, such as the timing of subsequent microscopic urinalyses, but we recommend that all urinalyses to establish whether significant hematuria is present be done within 3 to 6 months of the screening dip-stick test. If a patient has no risk factors for cancer and has a negative result on the first microscopic urinalysis, the follow-up test can be performed in 1 year. Table 1 shows risk factors for significant urologic disease that warrant evaluation in patients with asymptomatic hematuria.⁵

Isolated urinary findings that might warrant evaluation by a nephrologist rather than a urologist include proteinuria, red cell casts, and dysmorphic red blood cells, especially if the serum creatinine level is elevated.^2,5 Many medical renal conditions (eg, glomerulonephritis) and hemoglobinopathies (eg, sickle cell trait) can cause blood in the urine; when these conditions are accompanied by risk factors for urologic disease, urologic evaluation is indicated as well.

CLINICAL RELEVANCE OF HEMATURIA

Approximately 25% of cases of macroscopic hematuria are due to urologic cancers,^14,15 and another 34% are due to other significant urologic diseases¹⁴—thus, the recommendation that patients with macroscopic hematuria be evaluated by a urologist. In contrast, in microhematuria, the rates of cancer are much lower, ranging between 1% and 10% in large studies.^2,5

The urine dipstick test has been found to be 65% to 99% specific for the presence of blood cells, free hemoglobin, or myoglobin.^2,5 If the true specificity is closer to the lower figure and all patients with a positive dipstick test were referred to a urologist, this would mean the urologic workup would be unnecessary in up to 35% of them, because the dipstick result would be falsely positive.

But that is not all. Most causes of hemoglobinuria or myoglobinuria are of limited clinical significance, except for rare conditions that are usually clinically obvious, such as severe burn injury. Further, remember that from 9% to 18% of patients without symptoms have red blood cells in the urine.^2,5 In theory, if everyone in the United States had a dipstick test, this would be positive in patients with hematuria as well as in those with hemoglobinuria, myoglobinuria, and other false-positives; if everyone with a positive dipstick result were then referred to a urologist, a substantial portion of the population would receive an unnecessary urologic referral.

Urologic referral and evaluation in these patients not only wastes money: if they undergo imaging studies, they are exposed to radiation and contrast media, with their associated risks, and if they undergo cystoscopy, they face its attendant discomfort and risk of infection.

WHICH PATIENTS WITH HEMATURIA TO REFER TO A UROLOGIST

Gross hematuria

Red or tea-colored urine usually indicates gross hematuria. When there is any doubt—such as in the case of a color-blind patient—the presence of red blood cells can be confirmed or ruled out by a microscopic urinalysis.

Nearly all patients with an episode of gross hematuria should be referred to a urologist. The sole exception to this rule can be made when a woman younger than 40 years experiences gross hematuria in the classic setting of a culture-proven, symptomatic urinary tract infection (UTI) and her infection, symptoms, and hematuria all resolve completely with appropriate antibiotics.^2,5 However, bleeding from cancer is classically intermittent. Therefore, one should not skip the urine culture and just prescribe antibiotics empirically: the patient might actually have cancer, but the supposed UTI may appear to resolve with antibiotic therapy. For the same reason, resolution of hematuria in any other setting does not obviate the need for referral.

Another scenario usually associated with a benign cause is bleeding after extreme physical activity—also known as “runner’s hematuria” or “march hematuria” (so named because it sometimes occurs in soldiers after a particularly grueling training march). Importantly, even in this situation, one should still be suspicious and probably refer the patient to a urologist: just because the patient has just run a marathon, it does not mean that he or she does not have cancer.

Depending on the character, timing, location, and many other characteristics of the patient’s bleeding, a variety of studies may or may not be necessary. For example, blood-spotting of the underpants might signify urethral bleeding, and imaging and cytologic studies might not be indicated. In view of the variability in presentation and workup, we recommend that the proper workup for these patients be determined by a urologist.

Symptomatic microhematuria

Patients with true microhematuria (three or more RBCs/HPF) accompanied by bothersome or worrisome symptoms should be referred to a urologist. In a study in Scotland, Sultana et al¹⁶ found that cancer was present in 6 (5%) of 126 patients with microhematuria without symptoms compared with 13 (10.5%) of 124 patients with microhematuria and irritative voiding symptoms; the difference, however, was not statistically significant.

Microscopic urinalysis should be part of the evaluation for flank pain or certain urinary symptoms such as frequency, urgency, retention, or dysuria; results of this test at the time of symptoms can later help the urologist distinguish the cause of the symptoms or hematuria. In addition, in combination with dipstick analysis, microscopic analysis can help distinguish patients with UTI or medical renal disease. If the evaluation suggests that the hematuria and symptoms are due to a UTI, then the findings on a repeat microscopic analysis, performed after the infection has cleared, should be normal. If hematuria, defined as three or more RBCs/HPF, persists in two of three subsequent urinalyses, then the guidelines mandate diagnostic evaluation even if the urinalysis subsequently becomes negative.

Asymptomatic hematuria

In symptom-free patients with dipstick hematuria found on a screening examination, it is crucial to confirm and document true microhematuria. Per the AUA guidelines, microhematuria worthy of urologic workup is the presence of three or more RBCs/HPF on at least two out of three microscopic urinalyses.^2,5 Patients with dipstick pseudohematuria do not meet this criterion and will not benefit from a costly and invasive evaluation. Conversely, patients with higher levels of microhematuria, who have any risk factors for cancer, or who are anxious about the test results might benefit from urologic consultation before a second urinalysis to confirm the first, positive finding.

Many patients younger than age 40 with asymptomatic microhematuria but no other risk factors for urinary tract cancer can be followed conservatively. Khadra et al¹⁴ reported that only 1 of 143 patients younger than 40 years with microhematuria had cancer. Similarly, Jones et al¹⁷ found, in a prospective study, that no man younger than 40 years with microscopic hematuria had cancer.

Of note: gross or microscopic blood in the urine, even in the setting of anticoagulation, is a marker of urinary tract pathology such as cancer, stones, or infection. Just as patients on anticoagulation therapy who develop gastrointestinal bleeding need a gastrointestinal evaluation, those with hematuria require a urologic evaluation.^2,5

STUDIES TO CONSIDER BEFORE CONSULTATION

In symptom-free patients, it is inappropriate to order laboratory or imaging tests on the basis of a dipstick test alone, without confirming that they actually have hematuria. When the blood is confirmed to be present by microscopic examination of centrifuged urine (as described above), benign causes such as UTI should be considered. If a patient does have a UTI with hematuria, urinalysis should be repeated once the infection has cleared up.

Imaging studies

For symptomatic microhematuria. Patients with acute symptoms of renal colic should undergo computed tomography (CT) in a “stone protocol” (without contrast, with 3- to 5-mm cuts of the abdomen and pelvis) to assess for urinary lithiasis. Pregnancy should always be ruled out before radiation exposure; renal ultrasonography is generally the first-choice imaging study for pregnant patients.

For asymptomatic microhematuria. Patients without the classic flank pain of urolithiasis should undergo more extensive studies. For patients at increased risk of cancer, such as heavy smokers, CT urography is the optimal imaging study and is the test least likely to necessitate other follow-up studies.^18–20 Other imaging options, including ultrasonography and intravenous pyelography, incompletely assess the upper urinary tracts including both renal parenchyma and urothelial surfaces. CT urography has been shown to find more than 40% of hematuria-causing lesions missed by other studies.¹⁸ Because ordering alternative imaging first will often result in redundant studies, CT urography is the preferred initial imaging study in the evaluation of hematuria.

Before exposing a patient to contrast media, one should ascertain that he or she is not allergic to it. In addition, in patients at risk of contrast nephropathy (ie, those older than 60 years, with diabetes, or with preexisting medical renal disease), one should check the serum creatinine concentration. Magnetic resonance urography, a more expensive study, is as accurate as CT for diagnosing many urologic conditions, so it can be performed in lieu of CT urography in patients with renal insufficiency, iodine allergy, or any reason to avoid ionizing radiation. Some clinicians perform plain radiography of the kidneys, ureters, and bladder as well as ultrasonography in this setting, but determination of the appropriate alternative to CT urography, if required, is best left to the urologist.

Other tests

Cytologic testing of the urine can be valuable in patients with gross hematuria and in those with microhematuria who have risk factors for urinary tract cancer. Although its reported median sensitivity for malignancy is only 48%, a positive cytologic test is approximately 94% specific for malignancy.²¹ Other studies, such as the fluorescence in situ hybridization assay, and the nuclear matrix protein 22 test do not yet have a clear role in the diagnosis of urinary tract disease.²²

However, in general, we caution non-urologists not to order special tumor marker or cytologic tests, or to do so only with careful forethought. Although these studies occasionally detect occult cancer in patients at high risk, an “atypical” finding on cytology or a positive tumor marker test can lead to inappropriate referral and unnecessary biopsy or other tests.

WHEN NOT TO REFER A PATIENT WITH HEMATURIA TO A UROLOGIST

Symptom-free patients with a positive dipstick hemoglobin test should not immediately be referred to a urologist: they should have a microscopic urinalysis first to determine whether they actually have microhematuria, unless microscopic laboratory services are unavailable. Only patients with documented true hematuria, as defined by the AUA guidelines, should be referred for urologic evaluation and diagnostic testing. Once a patient is referred for evaluation, the consultant is under clear pressure to perform a complete investigation to fulfill the expectations of the referring physician. Avoiding expensive unnecessary testing and referral in those without hematuria allows appropriate utilization of resources.

Patients with microhematuria associated with a UTI should have a repeat urinalysis after the UTI is successfully treated; if the hematuria clears with the infection, then the patient needs no further evaluation. Patients with dipstick pseudohematuria and significant proteinuria or a predominance of dysmorphic urinary blood cells might benefit from an evaluation by a nephrologist rather than a urologist.² This is especially true if the patient has an elevated serum creatinine level.

ECONOMIC RELEVANCE

In our tertiary care urology clinic, approximately 75% of patients who are referred to us because of microhematuria have not had a microscopic urinalysis before coming here. On further evaluation, up to 75% of these patients are found to have dipstick pseudohematuria that did not actually require consultation or evaluation.²³ It is possible that this occurs even more frequently in the general practice setting.

A Medicare level-4 urologic consultation for hematuria costs $170; the cumulative cost of unwarranted referrals is undoubtedly substantial. Even more money is wasted on CT urography, cytology, and other testing performed before urologic consultation in patients ultimately found not to have true hematuria. The economic and iatrogenic risks of evaluation cannot be justified in patients who do not exhibit findings that can be considered abnormal as defined in this article.

CONCLUSION

It is important to distinguish whether hematuria is microscopic or macroscopic, whether there are associated symptoms, and whether a patient has risk factors for significant urologic disease. While dipstick tests are sensitive, they do not reliably diagnose microhematuria, which is the microscopically proven presence of urinary red blood cells. Positive dipstick tests should always be followed by microscopic urinalysis; failure to do so can result in the unfortunate and unnecessary evaluation of dipstick pseudohematuria, a normal condition.

The AUA defines significant hematuria as three or more RBCs/HPF in two of three properly prepared specimens.² This should determine whether a symptom-free patient needs urologic referral and evaluation for hematuria.

By following these principles, primary care physicians have a valuable opportunity to direct medical care, increase the efficiency of our health care system, and protect patients from the anxiety, costs, and risks of an unnecessary urologic workup.

Many people have some amount of blood in their urine, but relatively few have a serious problem.

In a population-based study in Rochester, Minnesota, red blood cells were found in the urine of 13% of symptom-free adults.¹ In other studies, the figure ranged from 9% to 18%.²

Hematuria is sometimes detected during investigation of symptoms such as dysuria, urinary frequency, or flank pain. However, many referrals to urologists are made purely on the basis of the results of a dipstick urinalysis screening test in a patient without symptoms.

The United States Preventive Task Force³ discourages routine testing for hematuria to screen for bladder cancer in patients without symptoms, and the Canadian Task Force on the Periodic Health Examination⁴ and the American Urological Association (AUA)^2,5 do not recommend it either. Nevertheless, approximately 40% of primary care physicians believe in it,⁶ although the number seems to be declining.⁷ A reason that dipstick testing is so popular is that it is an inexpensive and simple way to detect glucosuria and medical renal disease.^8–11

The risk of significant disease in a patient with microhematuria but without symptoms is low, and the evaluation for hematuria can be costly and invasive. For an individual patient with a hemoglobin-positive dipstick test, the finding should not be ignored, but the patient does not necessarily need a complete evaluation. It is important to determine which patients require urologic studies and consultation, nephrologic evaluation, or no intervention at all.

This review addresses issues related to hematuria for the primary care physician, clarifies some of the important definitions, builds on these terms to delineate which patients should be referred to a urologist, and provides simple recommendations about ancillary studies and their potential role before urologic consultation. Understanding this information will ultimately assure appropriate management of patients without symptoms who have positive dipstick screening tests, leading to decreased use of costly and invasive tests and more appropriate long-term follow-up.

BASIC DEFINITIONS

Gross (macroscopic) hematuria is blood in the urine that is visible without microscopy. This condition almost always warrants urologic evaluation.^2,5

Microscopic hematuria, or microhematuria, is the finding of red blood cells in the urine on microscopy. (In contrast, in dipstick hematuria—see below—blood cells may or may not be present in the urine.)

“Dipstick hematuria” and “dipstick microhematuria” are potential misnomers. The dip-stick test for hematuria is a nondiagnostic screening test. A positive result is simply a color change due to oxidation of a test-strip reagent; it does not confirm that blood cells are present. Factors that can cause a false-positive result on a dipstick test include hemoglobinuria, myoglobinuria, concentrated urine, menstrual blood in the urine sample, and rigorous exercise.¹² Thus, the diagnosis of hematuria cannot be made by dipstick alone. Unless red blood cells are seen microscopically, the term microhematuria is inappropriate.

Of note, if the specific gravity of the urine is very low (< 1.007), microscopy can fail to detect urinary red blood cells, owing to cell lysis.² This limitation can be overcome by restricting the patient’s fluid intake and then repeating the urinalysis.

Many patients with a positive dipstick oxidation reaction are labeled as having dip-stick hematuria although microscopic analysis would show that red blood cells are absent. Perhaps the term dipstick pseudohematuria would be more accurate. These patients will not benefit from a costly and invasive urologic workup, so it is crucial to distinguish them from patients with true microhematuria.

SIGNIFICANT HEMATURIA: ≥ 3 RBCs/HPF

Microhematuria is often intermittent, and many healthy patients occasionally have a few red blood cells in the urine.¹³ However, no cutoff point for the amount of hematuria can be used to rule out the possibility of cancer.¹⁴ To account for these complicating factors, the AUA Best Practice Policy Panel on Asymptomatic Hematuria considered the literature and expert opinions to define the amount of microhematuria warranting evaluation in patients with risk factors for significant urologic disease.^2,5

The AUA panel defined microhematuria as an average of three or more red blood cells per high-power microscopic field (RBCs/HPF) in two out of three properly collected and prepared specimens. Urine should be collected midstream after wiping the urethral meatus with a disinfectant and voiding the initial portion of urine into the toilet. For proper preparation of the urine sample, 10 mL of urine should be centrifuged at 2,000 rpm for 5 minutes and the supernatant discarded. The sediment should then be resuspended in 0.5 to 1.0 mL of remaining urine, and a drop of this suspension should be examined microscopically. If contamination is suggested (ie, if squamous epithelial cells, bacteria, or both are present), one should consider collecting a specimen through catheterization.^2,5

The AUA guidelines do not specify some of the details of management, such as the timing of subsequent microscopic urinalyses, but we recommend that all urinalyses to establish whether significant hematuria is present be done within 3 to 6 months of the screening dip-stick test. If a patient has no risk factors for cancer and has a negative result on the first microscopic urinalysis, the follow-up test can be performed in 1 year. Table 1 shows risk factors for significant urologic disease that warrant evaluation in patients with asymptomatic hematuria.⁵

Isolated urinary findings that might warrant evaluation by a nephrologist rather than a urologist include proteinuria, red cell casts, and dysmorphic red blood cells, especially if the serum creatinine level is elevated.^2,5 Many medical renal conditions (eg, glomerulonephritis) and hemoglobinopathies (eg, sickle cell trait) can cause blood in the urine; when these conditions are accompanied by risk factors for urologic disease, urologic evaluation is indicated as well.

CLINICAL RELEVANCE OF HEMATURIA

Approximately 25% of cases of macroscopic hematuria are due to urologic cancers,^14,15 and another 34% are due to other significant urologic diseases¹⁴—thus, the recommendation that patients with macroscopic hematuria be evaluated by a urologist. In contrast, in microhematuria, the rates of cancer are much lower, ranging between 1% and 10% in large studies.^2,5

The urine dipstick test has been found to be 65% to 99% specific for the presence of blood cells, free hemoglobin, or myoglobin.^2,5 If the true specificity is closer to the lower figure and all patients with a positive dipstick test were referred to a urologist, this would mean the urologic workup would be unnecessary in up to 35% of them, because the dipstick result would be falsely positive.

But that is not all. Most causes of hemoglobinuria or myoglobinuria are of limited clinical significance, except for rare conditions that are usually clinically obvious, such as severe burn injury. Further, remember that from 9% to 18% of patients without symptoms have red blood cells in the urine.^2,5 In theory, if everyone in the United States had a dipstick test, this would be positive in patients with hematuria as well as in those with hemoglobinuria, myoglobinuria, and other false-positives; if everyone with a positive dipstick result were then referred to a urologist, a substantial portion of the population would receive an unnecessary urologic referral.

Urologic referral and evaluation in these patients not only wastes money: if they undergo imaging studies, they are exposed to radiation and contrast media, with their associated risks, and if they undergo cystoscopy, they face its attendant discomfort and risk of infection.

WHICH PATIENTS WITH HEMATURIA TO REFER TO A UROLOGIST

Gross hematuria

Red or tea-colored urine usually indicates gross hematuria. When there is any doubt—such as in the case of a color-blind patient—the presence of red blood cells can be confirmed or ruled out by a microscopic urinalysis.

Nearly all patients with an episode of gross hematuria should be referred to a urologist. The sole exception to this rule can be made when a woman younger than 40 years experiences gross hematuria in the classic setting of a culture-proven, symptomatic urinary tract infection (UTI) and her infection, symptoms, and hematuria all resolve completely with appropriate antibiotics.^2,5 However, bleeding from cancer is classically intermittent. Therefore, one should not skip the urine culture and just prescribe antibiotics empirically: the patient might actually have cancer, but the supposed UTI may appear to resolve with antibiotic therapy. For the same reason, resolution of hematuria in any other setting does not obviate the need for referral.

Another scenario usually associated with a benign cause is bleeding after extreme physical activity—also known as “runner’s hematuria” or “march hematuria” (so named because it sometimes occurs in soldiers after a particularly grueling training march). Importantly, even in this situation, one should still be suspicious and probably refer the patient to a urologist: just because the patient has just run a marathon, it does not mean that he or she does not have cancer.

Depending on the character, timing, location, and many other characteristics of the patient’s bleeding, a variety of studies may or may not be necessary. For example, blood-spotting of the underpants might signify urethral bleeding, and imaging and cytologic studies might not be indicated. In view of the variability in presentation and workup, we recommend that the proper workup for these patients be determined by a urologist.

Symptomatic microhematuria

Patients with true microhematuria (three or more RBCs/HPF) accompanied by bothersome or worrisome symptoms should be referred to a urologist. In a study in Scotland, Sultana et al¹⁶ found that cancer was present in 6 (5%) of 126 patients with microhematuria without symptoms compared with 13 (10.5%) of 124 patients with microhematuria and irritative voiding symptoms; the difference, however, was not statistically significant.

Microscopic urinalysis should be part of the evaluation for flank pain or certain urinary symptoms such as frequency, urgency, retention, or dysuria; results of this test at the time of symptoms can later help the urologist distinguish the cause of the symptoms or hematuria. In addition, in combination with dipstick analysis, microscopic analysis can help distinguish patients with UTI or medical renal disease. If the evaluation suggests that the hematuria and symptoms are due to a UTI, then the findings on a repeat microscopic analysis, performed after the infection has cleared, should be normal. If hematuria, defined as three or more RBCs/HPF, persists in two of three subsequent urinalyses, then the guidelines mandate diagnostic evaluation even if the urinalysis subsequently becomes negative.

Asymptomatic hematuria

In symptom-free patients with dipstick hematuria found on a screening examination, it is crucial to confirm and document true microhematuria. Per the AUA guidelines, microhematuria worthy of urologic workup is the presence of three or more RBCs/HPF on at least two out of three microscopic urinalyses.^2,5 Patients with dipstick pseudohematuria do not meet this criterion and will not benefit from a costly and invasive evaluation. Conversely, patients with higher levels of microhematuria, who have any risk factors for cancer, or who are anxious about the test results might benefit from urologic consultation before a second urinalysis to confirm the first, positive finding.

Many patients younger than age 40 with asymptomatic microhematuria but no other risk factors for urinary tract cancer can be followed conservatively. Khadra et al¹⁴ reported that only 1 of 143 patients younger than 40 years with microhematuria had cancer. Similarly, Jones et al¹⁷ found, in a prospective study, that no man younger than 40 years with microscopic hematuria had cancer.

Of note: gross or microscopic blood in the urine, even in the setting of anticoagulation, is a marker of urinary tract pathology such as cancer, stones, or infection. Just as patients on anticoagulation therapy who develop gastrointestinal bleeding need a gastrointestinal evaluation, those with hematuria require a urologic evaluation.^2,5

STUDIES TO CONSIDER BEFORE CONSULTATION

In symptom-free patients, it is inappropriate to order laboratory or imaging tests on the basis of a dipstick test alone, without confirming that they actually have hematuria. When the blood is confirmed to be present by microscopic examination of centrifuged urine (as described above), benign causes such as UTI should be considered. If a patient does have a UTI with hematuria, urinalysis should be repeated once the infection has cleared up.

Imaging studies

For symptomatic microhematuria. Patients with acute symptoms of renal colic should undergo computed tomography (CT) in a “stone protocol” (without contrast, with 3- to 5-mm cuts of the abdomen and pelvis) to assess for urinary lithiasis. Pregnancy should always be ruled out before radiation exposure; renal ultrasonography is generally the first-choice imaging study for pregnant patients.

For asymptomatic microhematuria. Patients without the classic flank pain of urolithiasis should undergo more extensive studies. For patients at increased risk of cancer, such as heavy smokers, CT urography is the optimal imaging study and is the test least likely to necessitate other follow-up studies.^18–20 Other imaging options, including ultrasonography and intravenous pyelography, incompletely assess the upper urinary tracts including both renal parenchyma and urothelial surfaces. CT urography has been shown to find more than 40% of hematuria-causing lesions missed by other studies.¹⁸ Because ordering alternative imaging first will often result in redundant studies, CT urography is the preferred initial imaging study in the evaluation of hematuria.

Before exposing a patient to contrast media, one should ascertain that he or she is not allergic to it. In addition, in patients at risk of contrast nephropathy (ie, those older than 60 years, with diabetes, or with preexisting medical renal disease), one should check the serum creatinine concentration. Magnetic resonance urography, a more expensive study, is as accurate as CT for diagnosing many urologic conditions, so it can be performed in lieu of CT urography in patients with renal insufficiency, iodine allergy, or any reason to avoid ionizing radiation. Some clinicians perform plain radiography of the kidneys, ureters, and bladder as well as ultrasonography in this setting, but determination of the appropriate alternative to CT urography, if required, is best left to the urologist.

Other tests

Cytologic testing of the urine can be valuable in patients with gross hematuria and in those with microhematuria who have risk factors for urinary tract cancer. Although its reported median sensitivity for malignancy is only 48%, a positive cytologic test is approximately 94% specific for malignancy.²¹ Other studies, such as the fluorescence in situ hybridization assay, and the nuclear matrix protein 22 test do not yet have a clear role in the diagnosis of urinary tract disease.²²

However, in general, we caution non-urologists not to order special tumor marker or cytologic tests, or to do so only with careful forethought. Although these studies occasionally detect occult cancer in patients at high risk, an “atypical” finding on cytology or a positive tumor marker test can lead to inappropriate referral and unnecessary biopsy or other tests.

WHEN NOT TO REFER A PATIENT WITH HEMATURIA TO A UROLOGIST

Symptom-free patients with a positive dipstick hemoglobin test should not immediately be referred to a urologist: they should have a microscopic urinalysis first to determine whether they actually have microhematuria, unless microscopic laboratory services are unavailable. Only patients with documented true hematuria, as defined by the AUA guidelines, should be referred for urologic evaluation and diagnostic testing. Once a patient is referred for evaluation, the consultant is under clear pressure to perform a complete investigation to fulfill the expectations of the referring physician. Avoiding expensive unnecessary testing and referral in those without hematuria allows appropriate utilization of resources.

Patients with microhematuria associated with a UTI should have a repeat urinalysis after the UTI is successfully treated; if the hematuria clears with the infection, then the patient needs no further evaluation. Patients with dipstick pseudohematuria and significant proteinuria or a predominance of dysmorphic urinary blood cells might benefit from an evaluation by a nephrologist rather than a urologist.² This is especially true if the patient has an elevated serum creatinine level.

ECONOMIC RELEVANCE

In our tertiary care urology clinic, approximately 75% of patients who are referred to us because of microhematuria have not had a microscopic urinalysis before coming here. On further evaluation, up to 75% of these patients are found to have dipstick pseudohematuria that did not actually require consultation or evaluation.²³ It is possible that this occurs even more frequently in the general practice setting.

A Medicare level-4 urologic consultation for hematuria costs $170; the cumulative cost of unwarranted referrals is undoubtedly substantial. Even more money is wasted on CT urography, cytology, and other testing performed before urologic consultation in patients ultimately found not to have true hematuria. The economic and iatrogenic risks of evaluation cannot be justified in patients who do not exhibit findings that can be considered abnormal as defined in this article.

CONCLUSION

It is important to distinguish whether hematuria is microscopic or macroscopic, whether there are associated symptoms, and whether a patient has risk factors for significant urologic disease. While dipstick tests are sensitive, they do not reliably diagnose microhematuria, which is the microscopically proven presence of urinary red blood cells. Positive dipstick tests should always be followed by microscopic urinalysis; failure to do so can result in the unfortunate and unnecessary evaluation of dipstick pseudohematuria, a normal condition.

The AUA defines significant hematuria as three or more RBCs/HPF in two of three properly prepared specimens.² This should determine whether a symptom-free patient needs urologic referral and evaluation for hematuria.

By following these principles, primary care physicians have a valuable opportunity to direct medical care, increase the efficiency of our health care system, and protect patients from the anxiety, costs, and risks of an unnecessary urologic workup.

Reprinted with permission from Medical Malpractice Verdicts, Settlements and Experts, Lewis Laska, Editor, (800) 298-6288.

Radiation Error After Surgery for Acinic Cancer
A woman in her 50s discovered a growth in her left parotid gland. Although the mass was not thought to be malignant, she elected to have it removed. Biopsy results led to a diagnosis of acinic cancer.

The patient underwent 13 radiation treatments with the defendant, a radiation oncologist, before it was discovered that the defendant had been radiating the right parotid gland instead of the surgical site at the left parotid gland.

The plaintiff claimed that radiation to the right parotid gland destroyed its ability to function, leaving her with a permanent dry mouth and diminished sense of taste. She also claimed that loss of the gland has caused oral and digestive health problems. The defendant admitted negligence in treating the wrong side of the patient’s face but disputed the damages in question.

According to a published report, a $250,000 verdict was returned.

Link Overlooked Between MSSA and Osteomyelitis
A teenage boy, born with sickle cell anemia, experienced vaso-occlusive crises once or twice each year. During these episodes, he would be treated with morphine, oxycodone with acetaminophen, and/or acetaminophen with codeine, along with IV hydration.

At age 16, the boy was admitted to the defendant hospital with a fever; he received a diagnosis of pneumonia, based on a chest x-ray. Of three blood cultures that were performed, one yielded positive results for methicillin-sensitive Staphylococcus aureus (MSSA). The patient underwent four days’ IV therapy with triple antibiotics, followed by a 10-day supply of oral antibiotics to be taken following discharge.

The next month, the patient was readmitted for three days at the defendant hospital with a three-week history of back pain. Six days after his second discharge, the boy returned to the defendant hospital, complaining once again of back pain. He was hospitalized for eight days. During both hospitalizations, the plaintiff was treated with pain medications and IV hydration.

A week after his return home, the patient developed excruciating pain; he was unable to walk and became short of breath. He was taken to a different hospital, where x-rays and MRI revealed a fracture and collapse of the T7 vertebra. He underwent surgical repair with insertion of a plate and screws. Following a needle biopsy performed on day 8 of this hospitalization, a diagnosis was made of osteomyelitis of the spine. A biopsy revealed MSSA of the same type found in the boy’s blood culture during the initial admission. He was hospitalized for six weeks.

The plaintiff alleged negligence in the defendant’s failure to make a timely diagnosis of osteomyelitis. He claimed that osteomyelitis should have been considered when the blood culture was reported, and that his last discharge from the defendant hospital should not have occurred because he was unable to walk. The plaintiff claimed that he will develop arthritis as he grows older and will be at higher risk for lung and heart problems.

According to the defendant, the plaintiff reported that his pain had continued to decrease before his third discharge, that he was walking in the hallways of the defendant hospital before that discharge, and that he was able to walk into the nondefendant hospital. The defendant further claimed that the plaintiff’s discharge instructions after each hospitalization included follow-up at a hematology clinic, but he did not comply. The defendant also claimed that the plaintiff had severe osteoporosis secondary to sickle cell anemia, that his chronic illness was associated with a reduced life expectancy, and that any lung or heart problems that might develop would be the result of sickle cell anemia, not osteomyelitis.

A settlement of $925,000 was negotiated.

Long Wait for Diagnostic Testing
In May 2001, a 38-year-old Arizona man developed fever, chills, muscle aches, and cough. His family physician made a diagnosis of pneumonia. Late that summer, the patient developed headaches and a variety of other symptoms, including pain in the cervical spine, weight loss, and intermittent fevers. By October, the man was also complaining of fatigue, headaches, fever, and an unintended 20-lb weight loss. He was seen by a neurologist in November.

In early 2002, the patient was experiencing persistent headaches and vomiting and additional weight loss. One day in February, when the man was unable to find his way home, he went to a hospital. After being triaged, he was taken to his family physician by his wife. The plaintiff was seen by an internist two weeks later.

In March, the plaintiff went to a large, not-for-profit teaching hospital, where he was seen by a physician assistant. He was then seen by a rheumatologist in April.

In June 2002, the patient’s family physician ordered a spinal tap. A diagnosis of coccidioidomycosis (“valley fever meningitis”) was made. The man was treated and discharged from the hospital.

In July, he was readmitted, then transferred to another hospital, where he was treated until November. He then received home health care visits until June 2003, when a brain shunt was inserted to treat hydrocephalus. Later that year, the man had a recurrence of severe headaches. These were attributed to shunt malfunction, which necessitated insertion of a new shunt.

The plaintiff claimed that he had sustained extensive and debilitating neurologic injuries and brain damage. He has right-side facial paralysis, vision problems that require an eye patch, and vestibular dysfunction. He is unable to grip items and requires several prescription medications.

According to a published report, the plaintiff’s insurer, the family physician, and the hospitals involved settled prior to trial for confidential amounts. At trial, the plaintiff alleged negligence in his having been seen by a PA instead of a physician, in the PA’s failure to consult with his supervising physician, and in his failure to order proper testing or to obtain consultations.

The remaining defendants argued that the plaintiff was instructed to return for follow-up in order for a treatment plan to be formulated. The defendants also claimed that the plaintiff’s insurer denied authorization for testing and the plaintiff declined to self-pay. The defendants argued that if the plaintiff had followed up, abnormal findings on his subsequent examination would have prompted additional testing. The defendants also claimed that even if the patient’s condition had been diagnosed in March or April 2002, he still would have developed hydrocephalus and required a shunt.

A defense verdict was returned for the remaining defendants.

Renal Failure After Histoplasmosis Is Misdiagnosed
Eight years after undergoing transplantation with one of her father’s kidneys, a 29-year-old woman in relatively good health developed a mass in her right armpit. Her nephrologist (also her primary care provider) prescribed antibiotics in October 2001.

In November, when the lesion had not improved, the patient was referred to a surgeon, who removed the mass and sent it to the defendant pathologist for evaluation. The pathologist made a diagnosis of hidradenitis suppurative, an inflammation of the sweat glands.

The patient’s condition worsened. In January, she was admitted to the ICU, where she was diagnosed with histoplasmosis. Systemic complications, combined with the effects of the medications she needed, caused her kidney to fail. She recovered from histoplasmosis, but in April 2002, she needed to begin dialysis. By December, she was strong enough to undergo a second kidney transplant; this time, her mother was the donor. Complications arose, however, which resulted in the patient’s death in March 2003.

The plaintiff alleged negligence in the pathologist’s failure to diagnose histoplasmosis in a timely fashion. The defendant pathologist maintained that the tissue samples did not require him to conduct special stains to look for histoplasmosis. He also claimed that the decedent was already in renal failure and that the first transplanted kidney would have failed in any event.

According to a published report, a $5,924,141 verdict was returned, after which the parties involved reached a confidential settlement.       

Reprinted with permission from Medical Malpractice Verdicts, Settlements and Experts, Lewis Laska, Editor, (800) 298-6288.

Radiation Error After Surgery for Acinic Cancer
A woman in her 50s discovered a growth in her left parotid gland. Although the mass was not thought to be malignant, she elected to have it removed. Biopsy results led to a diagnosis of acinic cancer.

The patient underwent 13 radiation treatments with the defendant, a radiation oncologist, before it was discovered that the defendant had been radiating the right parotid gland instead of the surgical site at the left parotid gland.

The plaintiff claimed that radiation to the right parotid gland destroyed its ability to function, leaving her with a permanent dry mouth and diminished sense of taste. She also claimed that loss of the gland has caused oral and digestive health problems. The defendant admitted negligence in treating the wrong side of the patient’s face but disputed the damages in question.

According to a published report, a $250,000 verdict was returned.

Link Overlooked Between MSSA and Osteomyelitis
A teenage boy, born with sickle cell anemia, experienced vaso-occlusive crises once or twice each year. During these episodes, he would be treated with morphine, oxycodone with acetaminophen, and/or acetaminophen with codeine, along with IV hydration.

At age 16, the boy was admitted to the defendant hospital with a fever; he received a diagnosis of pneumonia, based on a chest x-ray. Of three blood cultures that were performed, one yielded positive results for methicillin-sensitive Staphylococcus aureus (MSSA). The patient underwent four days’ IV therapy with triple antibiotics, followed by a 10-day supply of oral antibiotics to be taken following discharge.

The next month, the patient was readmitted for three days at the defendant hospital with a three-week history of back pain. Six days after his second discharge, the boy returned to the defendant hospital, complaining once again of back pain. He was hospitalized for eight days. During both hospitalizations, the plaintiff was treated with pain medications and IV hydration.

A week after his return home, the patient developed excruciating pain; he was unable to walk and became short of breath. He was taken to a different hospital, where x-rays and MRI revealed a fracture and collapse of the T7 vertebra. He underwent surgical repair with insertion of a plate and screws. Following a needle biopsy performed on day 8 of this hospitalization, a diagnosis was made of osteomyelitis of the spine. A biopsy revealed MSSA of the same type found in the boy’s blood culture during the initial admission. He was hospitalized for six weeks.

The plaintiff alleged negligence in the defendant’s failure to make a timely diagnosis of osteomyelitis. He claimed that osteomyelitis should have been considered when the blood culture was reported, and that his last discharge from the defendant hospital should not have occurred because he was unable to walk. The plaintiff claimed that he will develop arthritis as he grows older and will be at higher risk for lung and heart problems.

According to the defendant, the plaintiff reported that his pain had continued to decrease before his third discharge, that he was walking in the hallways of the defendant hospital before that discharge, and that he was able to walk into the nondefendant hospital. The defendant further claimed that the plaintiff’s discharge instructions after each hospitalization included follow-up at a hematology clinic, but he did not comply. The defendant also claimed that the plaintiff had severe osteoporosis secondary to sickle cell anemia, that his chronic illness was associated with a reduced life expectancy, and that any lung or heart problems that might develop would be the result of sickle cell anemia, not osteomyelitis.

A settlement of $925,000 was negotiated.

Long Wait for Diagnostic Testing
In May 2001, a 38-year-old Arizona man developed fever, chills, muscle aches, and cough. His family physician made a diagnosis of pneumonia. Late that summer, the patient developed headaches and a variety of other symptoms, including pain in the cervical spine, weight loss, and intermittent fevers. By October, the man was also complaining of fatigue, headaches, fever, and an unintended 20-lb weight loss. He was seen by a neurologist in November.

In early 2002, the patient was experiencing persistent headaches and vomiting and additional weight loss. One day in February, when the man was unable to find his way home, he went to a hospital. After being triaged, he was taken to his family physician by his wife. The plaintiff was seen by an internist two weeks later.

In March, the plaintiff went to a large, not-for-profit teaching hospital, where he was seen by a physician assistant. He was then seen by a rheumatologist in April.

In June 2002, the patient’s family physician ordered a spinal tap. A diagnosis of coccidioidomycosis (“valley fever meningitis”) was made. The man was treated and discharged from the hospital.

In July, he was readmitted, then transferred to another hospital, where he was treated until November. He then received home health care visits until June 2003, when a brain shunt was inserted to treat hydrocephalus. Later that year, the man had a recurrence of severe headaches. These were attributed to shunt malfunction, which necessitated insertion of a new shunt.

The plaintiff claimed that he had sustained extensive and debilitating neurologic injuries and brain damage. He has right-side facial paralysis, vision problems that require an eye patch, and vestibular dysfunction. He is unable to grip items and requires several prescription medications.

According to a published report, the plaintiff’s insurer, the family physician, and the hospitals involved settled prior to trial for confidential amounts. At trial, the plaintiff alleged negligence in his having been seen by a PA instead of a physician, in the PA’s failure to consult with his supervising physician, and in his failure to order proper testing or to obtain consultations.

The remaining defendants argued that the plaintiff was instructed to return for follow-up in order for a treatment plan to be formulated. The defendants also claimed that the plaintiff’s insurer denied authorization for testing and the plaintiff declined to self-pay. The defendants argued that if the plaintiff had followed up, abnormal findings on his subsequent examination would have prompted additional testing. The defendants also claimed that even if the patient’s condition had been diagnosed in March or April 2002, he still would have developed hydrocephalus and required a shunt.

A defense verdict was returned for the remaining defendants.

Renal Failure After Histoplasmosis Is Misdiagnosed
Eight years after undergoing transplantation with one of her father’s kidneys, a 29-year-old woman in relatively good health developed a mass in her right armpit. Her nephrologist (also her primary care provider) prescribed antibiotics in October 2001.

In November, when the lesion had not improved, the patient was referred to a surgeon, who removed the mass and sent it to the defendant pathologist for evaluation. The pathologist made a diagnosis of hidradenitis suppurative, an inflammation of the sweat glands.

The patient’s condition worsened. In January, she was admitted to the ICU, where she was diagnosed with histoplasmosis. Systemic complications, combined with the effects of the medications she needed, caused her kidney to fail. She recovered from histoplasmosis, but in April 2002, she needed to begin dialysis. By December, she was strong enough to undergo a second kidney transplant; this time, her mother was the donor. Complications arose, however, which resulted in the patient’s death in March 2003.

The plaintiff alleged negligence in the pathologist’s failure to diagnose histoplasmosis in a timely fashion. The defendant pathologist maintained that the tissue samples did not require him to conduct special stains to look for histoplasmosis. He also claimed that the decedent was already in renal failure and that the first transplanted kidney would have failed in any event.

According to a published report, a $5,924,141 verdict was returned, after which the parties involved reached a confidential settlement.       

Reprinted with permission from Medical Malpractice Verdicts, Settlements and Experts, Lewis Laska, Editor, (800) 298-6288.

Radiation Error After Surgery for Acinic Cancer
A woman in her 50s discovered a growth in her left parotid gland. Although the mass was not thought to be malignant, she elected to have it removed. Biopsy results led to a diagnosis of acinic cancer.

The patient underwent 13 radiation treatments with the defendant, a radiation oncologist, before it was discovered that the defendant had been radiating the right parotid gland instead of the surgical site at the left parotid gland.

The plaintiff claimed that radiation to the right parotid gland destroyed its ability to function, leaving her with a permanent dry mouth and diminished sense of taste. She also claimed that loss of the gland has caused oral and digestive health problems. The defendant admitted negligence in treating the wrong side of the patient’s face but disputed the damages in question.

According to a published report, a $250,000 verdict was returned.

Link Overlooked Between MSSA and Osteomyelitis
A teenage boy, born with sickle cell anemia, experienced vaso-occlusive crises once or twice each year. During these episodes, he would be treated with morphine, oxycodone with acetaminophen, and/or acetaminophen with codeine, along with IV hydration.

At age 16, the boy was admitted to the defendant hospital with a fever; he received a diagnosis of pneumonia, based on a chest x-ray. Of three blood cultures that were performed, one yielded positive results for methicillin-sensitive Staphylococcus aureus (MSSA). The patient underwent four days’ IV therapy with triple antibiotics, followed by a 10-day supply of oral antibiotics to be taken following discharge.

The next month, the patient was readmitted for three days at the defendant hospital with a three-week history of back pain. Six days after his second discharge, the boy returned to the defendant hospital, complaining once again of back pain. He was hospitalized for eight days. During both hospitalizations, the plaintiff was treated with pain medications and IV hydration.

A week after his return home, the patient developed excruciating pain; he was unable to walk and became short of breath. He was taken to a different hospital, where x-rays and MRI revealed a fracture and collapse of the T7 vertebra. He underwent surgical repair with insertion of a plate and screws. Following a needle biopsy performed on day 8 of this hospitalization, a diagnosis was made of osteomyelitis of the spine. A biopsy revealed MSSA of the same type found in the boy’s blood culture during the initial admission. He was hospitalized for six weeks.

The plaintiff alleged negligence in the defendant’s failure to make a timely diagnosis of osteomyelitis. He claimed that osteomyelitis should have been considered when the blood culture was reported, and that his last discharge from the defendant hospital should not have occurred because he was unable to walk. The plaintiff claimed that he will develop arthritis as he grows older and will be at higher risk for lung and heart problems.

According to the defendant, the plaintiff reported that his pain had continued to decrease before his third discharge, that he was walking in the hallways of the defendant hospital before that discharge, and that he was able to walk into the nondefendant hospital. The defendant further claimed that the plaintiff’s discharge instructions after each hospitalization included follow-up at a hematology clinic, but he did not comply. The defendant also claimed that the plaintiff had severe osteoporosis secondary to sickle cell anemia, that his chronic illness was associated with a reduced life expectancy, and that any lung or heart problems that might develop would be the result of sickle cell anemia, not osteomyelitis.

A settlement of $925,000 was negotiated.

Long Wait for Diagnostic Testing
In May 2001, a 38-year-old Arizona man developed fever, chills, muscle aches, and cough. His family physician made a diagnosis of pneumonia. Late that summer, the patient developed headaches and a variety of other symptoms, including pain in the cervical spine, weight loss, and intermittent fevers. By October, the man was also complaining of fatigue, headaches, fever, and an unintended 20-lb weight loss. He was seen by a neurologist in November.

In early 2002, the patient was experiencing persistent headaches and vomiting and additional weight loss. One day in February, when the man was unable to find his way home, he went to a hospital. After being triaged, he was taken to his family physician by his wife. The plaintiff was seen by an internist two weeks later.

In March, the plaintiff went to a large, not-for-profit teaching hospital, where he was seen by a physician assistant. He was then seen by a rheumatologist in April.

In June 2002, the patient’s family physician ordered a spinal tap. A diagnosis of coccidioidomycosis (“valley fever meningitis”) was made. The man was treated and discharged from the hospital.

In July, he was readmitted, then transferred to another hospital, where he was treated until November. He then received home health care visits until June 2003, when a brain shunt was inserted to treat hydrocephalus. Later that year, the man had a recurrence of severe headaches. These were attributed to shunt malfunction, which necessitated insertion of a new shunt.

The plaintiff claimed that he had sustained extensive and debilitating neurologic injuries and brain damage. He has right-side facial paralysis, vision problems that require an eye patch, and vestibular dysfunction. He is unable to grip items and requires several prescription medications.

According to a published report, the plaintiff’s insurer, the family physician, and the hospitals involved settled prior to trial for confidential amounts. At trial, the plaintiff alleged negligence in his having been seen by a PA instead of a physician, in the PA’s failure to consult with his supervising physician, and in his failure to order proper testing or to obtain consultations.

The remaining defendants argued that the plaintiff was instructed to return for follow-up in order for a treatment plan to be formulated. The defendants also claimed that the plaintiff’s insurer denied authorization for testing and the plaintiff declined to self-pay. The defendants argued that if the plaintiff had followed up, abnormal findings on his subsequent examination would have prompted additional testing. The defendants also claimed that even if the patient’s condition had been diagnosed in March or April 2002, he still would have developed hydrocephalus and required a shunt.

A defense verdict was returned for the remaining defendants.

Renal Failure After Histoplasmosis Is Misdiagnosed
Eight years after undergoing transplantation with one of her father’s kidneys, a 29-year-old woman in relatively good health developed a mass in her right armpit. Her nephrologist (also her primary care provider) prescribed antibiotics in October 2001.

In November, when the lesion had not improved, the patient was referred to a surgeon, who removed the mass and sent it to the defendant pathologist for evaluation. The pathologist made a diagnosis of hidradenitis suppurative, an inflammation of the sweat glands.

The patient’s condition worsened. In January, she was admitted to the ICU, where she was diagnosed with histoplasmosis. Systemic complications, combined with the effects of the medications she needed, caused her kidney to fail. She recovered from histoplasmosis, but in April 2002, she needed to begin dialysis. By December, she was strong enough to undergo a second kidney transplant; this time, her mother was the donor. Complications arose, however, which resulted in the patient’s death in March 2003.

The plaintiff alleged negligence in the pathologist’s failure to diagnose histoplasmosis in a timely fashion. The defendant pathologist maintained that the tissue samples did not require him to conduct special stains to look for histoplasmosis. He also claimed that the decedent was already in renal failure and that the first transplanted kidney would have failed in any event.

According to a published report, a $5,924,141 verdict was returned, after which the parties involved reached a confidential settlement.       

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

As reviewed by Dr. Naim Issa and colleagues in this issue of the Journal, practices are changing with regard to choice of imaging techniques and contrast materials in patients with renal insufficiency. In 1 week, while on our inpatient rheumatology consultation service, I specifically commented in two patients’ charts that I would prefer to avoid the use of gadolinium because the patients had significant renal dysfunction. Since the patients did not yet need dialysis, standard contrast dye was also relatively contraindicated. It was a bit of a dilemma.

In an accompanying editorial, Dr. Jonathan Kay proposes that this pseudoscleroderma syndrome be called “gadolinium-associated systemic fibrosis (GASF).” Dr. Kay and colleagues have recently published an important study (Arthritis Rheum 2007; 56:3433–3441) in which they report that, with a focused physical examination, this often-unrecognized clinical syndrome can be diagnosed in 13% of patients undergoing chronic hemodialysis and that the diagnosis indicates a significant risk of death. They confirm the suggestion of earlier authors that exposure to gadolinium is a significant predisposing factor for the syndrome.

Gadolinium is not the first exogenous chemical trigger of a fibrosing syndrome to be identified: eg, bleomycin (Blenoxane) is a well-known trigger of pulmonary fibrosis. Pseudoscleroderma syndromes have been described after exposure to certain rapeseed oils and to impure preparations of tryptophan (the “eosinophilic-mayalgia syndrome”). The mechanisms of these reactions are not fully understood, and other than the accumulation of gadolinium in tissues in the setting of chronic renal disease, not much is known about the pathophysiology of GASF.

Guidelines will be proposed to try to limit the occurrence of this devastating syndrome. But we can only guess as to the glomerular filtration rate cutoff at which we should be most concerned, and we can only hope that acute dialysis after gadolinium exposure will be protective. In the meantime, we will need to revise our view that “MRI with contrast” is a benign test.

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

Now faith is the substance of things hoped for, the evidence of things not seen.
—HEBREWS 11:1

Since the first case appeared in 1997,¹ nephrogenic systemic fibrosis (NSF) has been detected with increasing frequency in patients with chronic kidney disease. Recognition that this condition affects more than just the skin led to the change in its name from “nephrogenic fibrosing dermopathy” to “nephrogenic systemic fibrosis.”

In this issue, Issa and colleagues² review this devastating new disease and discuss its association with gadolinium exposure.

See related article

NSF RESEMBLES OTHER FIBROSING DISORDERS

The clinical presentation of NSF most closely resembles that of scleromyxedema or scleroderma.¹ However, the face is spared in patients with NSF except for yellow plaques on the sclerae, a frequent finding. Monoclonal gammopathy (which may be associated with scleromyxedema) and Raynaud’s phenomenon (which often is associated with scleroderma) usually are absent in NSF.³

A set of histologic findings differentiates NSF from other fibrosing disorders. Skin biopsy reveals fibrosis and elastosis, often with mucin deposition. If NSF is suspected, immunohistochemical stains for CD34, CD45RO, and type I procollagen should be performed to look for dermal spindle cells (presumably “circulating fibrocytes”) coexpressing these markers. Histiocytic cells and dermal dendrocytes expressing CD68 and factor XIIIa have also been described in NSF skin lesions, but other inflammatory cells usually are absent.⁴ However, the histologic changes of NSF are difficult to distinguish from those of scleromyxedema.⁵

Thus, as with scleroderma, the diagnosis of NSF remains clinical. Skin biopsy, even of an affected area, occasionally may yield non-diagnostic findings. Histologic findings serve to confirm the diagnosis of NSF in the appropriate clinical setting.

RISK FACTORS FOR NSF: POSSIBLE ASCERTAINMENT BIAS

Renal dysfunction

Because cases of NSF have been searched for only in patients with chronic kidney disease, reported cases have been found only in this patient population. A major limitation of most published case series is that cases have been gathered from among those with histologic confirmation of NSF, and “controls” have been gathered from the remainder of the population receiving dialysis treatment without confirmation by physical examination of the absence of cutaneous changes of NSF.

Most cases have been found in those with stage 5 chronic kidney disease (creatinine clearance < 15 mL/min or requiring dialysis). However, cases have been described in patients with stage 4 chronic kidney disease (creatinine clearance 15–29 mL/min) and, occasionally, in those with lesser degrees of impaired renal function.

Despite the ascertainment bias in identifying cases, this greater prevalence of NSF with lesser renal function suggests a role for renal dysfunction in the pathogenesis of NSF.

To date, nearly all patients who have developed NSF have had known exposure to gadolinium-containing contrast agents. Gadolinium has been found in tissue of patients with NSF,^6,7 yielding the postulate that gadolinium drives tissue fibrosis.

More patients with chronic kidney disease who developed NSF had been exposed to gadodiamide (Omniscan) than to other gadolinium-containing contrast agents, leading to the hypothesis that less-stable gadolinium-chelate complexes release greater amounts of free gadolinium, which then deposits in tissue and triggers fibrosis. However, it has not yet been determined that the gadolinium deposited in tissue is in the free form and not bound to chelate. Furthermore, this attractive hypothesis must be tempered by the recognition that NSF also has developed after exposure to gadopentetate dimeglumine (Magnevist), a more stable gadolinium-chelate complex than gadodiamide.⁸ The greater number of patients who have developed NSF after gadodiamide exposure may reflect the relative use of these contrast agents in radiology practice.

It is important to be aware that gadolinium-containing contrast agents are used in more than just magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Because gadolinium also blocks transmission of x-rays, radiologists occasionally have used gadolinium-containing contrast agents for angiography, venography, fistulography, and computed tomography in patients for whom use of iodinated contrast agents is contraindicated. Thus, a patient with chronic kidney disease may have received a gadolinium-containing contrast agent even if no magnetic resonance study had been performed.

Assessment of tissue gadolinium content may confirm prior exposure to a gadolinium-containing contrast agent if the patient does not recall having undergone an imaging study. In the one report that claims the development of NSF in two patients without prior gadolinium exposure, tissue was not assessed for gadolinium content.⁹

No study has yet been performed to assess the relative prevalence of NSF among patients with different stages of chronic kidney disease who have been exposed to gadolinium-containing contrast agents. Thus, it is impossible to ascertain a threshold of renal dysfunction above which the use of gadolinium-containing contrast agents might be safe.

In 90 patients with stage 5 chronic kidney disease, we found that 30% of those who previously had undergone gadolinium-enhanced imaging studies developed cutaneous changes of NSF; the relative risk of developing these skin changes after exposure to a gadolinium-containing contrast agent was 10.7 (95% confidence interval 1.5–6.9).⁸

Thus, it is essential that guidelines for the use of these contrast agents be formulated and implemented. Caution must be observed when administering a gadolinium-containing contrast agent to a patient with any degree of renal dysfunction. These patients must be informed of the possible risk of developing NSF, and appropriate follow-up must be conducted to assess for potential changes of NSF.

Other possible risk factors

Not all patients with chronic kidney disease who are exposed to gadolinium-containing contrast agents develop NSF: factors other than the degree of renal dysfunction must be involved in the pathogenesis of this condition.

Exposure to medications commonly taken by patients with chronic kidney disease, such as erythropoietin¹⁰ and iron supplements,¹¹ has been suggested as a contributing factor. However, these medications are so widely used that this exposure is unlikely to explain why some patients develop NSF after receiving gadolinium-containing contrast agents and others do not.

Interestingly, lanthanum carbonate (Fosrenol) was approved by the US Food and Drug Administration in 2004 for use as a phosphate binder in patients with stage 5 chronic kidney disease. Since lanthanum and gadolinium both are rare earth metals of the lanthanide series, one might speculate that lanthanum deposition in tissue could produce similar changes or could potentiate those induced by gadolinium.

Future prospective case-control studies need to address risk factors for the development of NSF.

EFFECTIVE TREATMENT NEEDED

Because NSF imposes a markedly increased rate of death and devastating morbidity,⁸ efforts must be directed toward preventing its development and treating those who already are affected. So far, no treatment has been universally effective in reversing the fibrotic changes of NSF. Potentially effective therapeutic agents must be identified and studied in these patients.

Although performing hemodialysis promptly after the use of a gadolinium-containing contrast agent would appear to be a prudent clinical practice, there are no data to suggest that it is effective in preventing NSF. If free gadolinium disassociates from its chelate and deposits rapidly in tissue, it is unclear that hemodialysis could be performed soon enough to prevent this deposition. Furthermore, hemodialysis is not without associated potential risks and morbidity, especially in people with chronic kidney disease who are not already receiving hemodialysis. Thus, at present, avoiding the use of gadolinium-containing contrast agents in patients with chronic kidney disease appears to be the best preventive strategy.

A NAME CHANGE

Over the past decade, much has been learned about the clinical manifestations, course, and pathogenesis of NSF. However, the term “nephrogenic” in the name of this disease is misleading, in that this fibrosing disorder is not caused by the kidneys. Although some degree of renal dysfunction appears to be necessary for NSF to develop, the presence of gadolinium in tissue seems to drive fibrosis. Thus, it is time that “nephrogenic systemic fibrosis” be renamed more precisely as “gadolinium-associated systemic fibrosis” or “GASF.”

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.

The use of gadolinium as a contrast agent in magnetic resonance imaging (MRI) in patients with impaired kidney function has come under scrutiny because of recent reports of a potential association between its use and nephrogenic systemic fibrosis (NSF).

See related editorial

This entity was first identified in the United States in 1997. Cowper et al¹ in 2000 described 15 hemodialysis patients who developed thickening and hardening of the skin with brawny hyperpigmentation, papules, and subcutaneous nodules on the extremities.

This “new disease” was initially called “nephrogenic fibrosing dermopathy,” as it was exclusively seen in patients with renal impairment and was thought to affect only the skin and subcutaneous tissue. With growing evidence of the extent and pathogenicity of the fibrosis in visceral organs, the nomenclature was changed to NSF, to better reflect the systemic nature of the disease.

PRESENTATION: MILD TO DEVASTATING

NSF has thus far been reported only in patients with renal impairment, most of whom were dialysis-dependent. It does not seem to be more common in one sex or the other, in any age range, or in any ethnic group. It can range in severity from mild to a devastating scleroderma-like systemic fibrosing disorder.

The heart, lungs, skeletal muscle, and diaphragm can also be involved, sometimes leading to serious complications and death.^4–6

The disease is usually progressive and unremitting. Mendoza et al,⁷ in a review of 12 cases of NSF, reported that the disease had a progressive course in 6 patients, of whom 3 died within 2 years and 3 were ultimately confined to a wheelchair. More severe findings and rapid progression of the skin disease are associated with a poor prognosis.

Todd et al⁸ prospectively examined 186 dialysis patients to look for possible NSF. Of those with skin changes consistent with NSF, 48% died within 2 years, compared with 20% of those without these skin changes. Cardiovascular causes accounted for 58% of the deaths in patients with cutaneous changes of NSF and for 48% of the deaths in patients without these changes. Most of the excess deaths occurred within 6 months after the skin examination, suggesting an increased risk for early death in patients with skin changes suggestive of NSF.

DIAGNOSIS OF NSF IS CLINICAL

At presentation, NSF is frequently misdiagnosed and treated as cellulitis or edema. However, now that subspecialists—especially dermatologists, rheumatologists, and nephrologists—are becoming more aware of it, the correct diagnosis is being made earlier.

NSF should be suspected in any patient with underlying renal dysfunction—especially if on dialysis and if he or she has received a gadolinium contrast agent during MRI—who develops scleroderma-like cutaneous lesions affecting the distal extremities. Because most health care providers are still unfamiliar with this emerging disease, patients with renal impairment and suspected NSF should be referred to a rheumatologist or dermatologist to confirm the diagnosis, which is mainly entertained on a clinical basis. There is no laboratory biomarker for NSF.

A deep incisional skin biopsy may aid in the diagnosis. Due to the regional distribution of the disease, sampling error may occur, and repeat biopsy is warranted if the initial biopsy is nondiagnostic but the clinical picture suggests NSF.

Histopathologic examination typically shows lesions containing proliferation of dermal spindle cells, thick collagen bundles with surrounding clefts, and a variable amount of mucin and elastic fibers.² A characteristic and almost pathognomonic staining profile is the immunohistochemical identification of CD34 reactivity in the fibroblast-like cells (Figure 3). Cells expressing CD34 are normally found in the umbilical cord, the bone marrow (as pluripotential hematopoietic stem cells), and in the vascular endothelium. How they come to be in the skin is still speculative, but their presence suggests that circulating fibrocytes migrate from the bone marrow and deposit in the skin and other organs.^9,10

Pulmonary function testing can be done to rule out lung involvement and transthoracic two-dimensional echocardiography can be done to rule out possible cardiomyopathy if these conditions are suggested by examination at the time of diagnosis.⁷ Muscle biopsy is not necessary to determine the extent of systemic involvement, since the findings do not necessarily correlate with other systemic involvement.

DIFFERENTIAL DIAGNOSIS

An important diagnostic feature of NSF is that it spares the face, a finding derived from all reported and confirmed cases of NSF (Figure 2). In contrast, scleromyxedema, systemic scleroderma, and morphea often involve the face.

Scleromyxedema is often associated with monoclonal gammopathy (usually an immunoglobulin G lambda paraproteinemia) whereas NSF is not.

Scleroderma is supported by the findings of Raynaud’s phenomenon, antinuclear antibodies, and either anticentromere or anti-DNA topoisomerase I (Scl-70) antibodies, but the absence of these antibodies does not necessarily rule it out.

Eosinophilic fasciitis is diagnosed on the basis of histologic examination of a deep wedge skin biopsy specimen that includes fascia.

Other diagnoses that should be considered include amyloidosis and calciphylaxis.

ASSOCIATION WITH GADOLINIUM: WHAT IS THE EVIDENCE?

Case series

The association of gadolinium use with NSF has been described in several case reports and case series.

Grobner¹¹ reported that administration of gadodiamide (Omniscan, a gadolinium compound) for MRI was associated with NSF in five patients on chronic hemodialysis who had end-stage renal disease. Their ages ranged from 43 to 74 years, and they had been on dialysis from 10 to 58 months. The time of onset of NSF ranged from 2 to 4 weeks after exposure to gadodiamide.

Marckmann et al¹² reported that NSF developed in 13 (3.5%) of 370 patients with severe kidney disease who received gadodiamide. Five of the 13 patients had stage 5 (advanced) chronic kidney disease and were not yet on renal replacement therapy, 7 were on hemodialysis, and 1 was on peritoneal dialysis. The time of onset ranged from 2 to 75 days (median 25 days) after exposure.

Kuo et al¹³ similarly estimated the incidence of NSF at approximately 3% in patients with severe renal failure who receive intravenous gadolinium-based contrast material for MRI.

Broome et al¹⁴ reported that 12 patients developed NSF within 2 to 11 weeks after receiving gadodiamide. Eight of the 12 patients had end-stage renal disease and were on hemodialysis; the other 4 patients had acute kidney injury attributed to hepatorenal syndrome, and 3 of these 4 patients were on hemodialysis.

Khurana et al¹⁵ reported that 6 patients on hemodialysis developed NSF from 2 weeks to 2 months after receiving a dose of gadodiamide of between 0.11 and 0.36 mmol/kg. These doses are high, and the findings suggest an association between the gadolinium dose and NSF. The dose approved by the US Food and Drug Administration (FDA) is only 0.1 mmol/kg, and the use of gadolinium is approved only in MRI. However, higher doses (0.3–0.4 mmol/kg) are widely used in practice for better imaging quality in magnetic resonance angiography (MRA).

Deo et al¹⁶ reported 3 cases of NSF in 87 patients with end-stage renal disease who underwent 123 radiologic studies with gadolinium. No patient with end-stage renal disease who was not exposed to gadolinium developed NSF, and the association between exposure to gadolinium and the subsequent development of NSF was statistically significant (P = .006). The authors concluded that each gadolinium study presented a 2.4% risk of NSF in end-stage renal disease patients.

This retrospective study is flawed by not having been cross-sectional or case-controlled, since the other 84 patients who received gadolinium were not examined at all to establish the absence of NSF.

Case-control studies

More evidence of association of NSF with gadolinium exposure comes from other reports.

Physicians in St. Louis, MO,¹⁷ identified 33 cases of NSF and performed a case-control study, matching each of 19 of the patients (for whom data were available and who met their entry criteria) with 3 controls. They found that exposure to gadolinium was independently associated with the development of NSF.

Sadowski et al¹⁸ reported that 13 patients with biopsy-confirmed NSF all had been exposed to gadodiamide and one had been exposed to gadobenate (MultiHANCE) in addition to gadodiamide. All 13 patients had renal insufficiency, with an estimated glomerular filtration rate (GFR) less than 60 mL/minute/1.73 m². The investigators compared this group with a control group of patients with renal insufficiency who did not develop NSF. The NSF group had more proinflammatory events (P < .001) and more gadolinium-contrast-enhanced MRI examinations per patient (P = .002) than the control group.

Marckmann et al¹⁹ compared 19 patients who had histologically proven cases of NSF and 19 sex- and age-matched controls; all 38 patients had chronic kidney disease and had been exposed to gadolinium. Patients with NSF had received higher cumulative doses of gadodiamide and higher doses of erythropoietin and had higher serum concentrations of ionized calcium and phosphate than did their controls, as did patients with severe NSF compared with those with nonsevere NSF.

Comment. All the above reports are limited by their study design and suffer from recognition bias because not all of the patients with severe renal insufficiency who were exposed to gadolinium were examined for possible asymptomatic skin changes that might be characteristic of NSF. Therefore, it is impossible to be certain that all of the patients classified as not having NSF truly did not have it or did not subsequently develop it. Furthermore, the reports lacked standardized diagnostic criteria. Hence, the real prevalence and incidence of NSF are difficult to determine.

As mentioned above, Todd et al⁸ examined 186 dialysis patients for cutaneous changes of NSF (using a scoring system based on hyper-pigmentation, hardening, and tethering of skin on the extremities). Patients who had been exposed to gadolinium had a higher risk of developing these skin changes than did nonexposed patients (odds ratio 14.7, 95% confidence interval 1.9–117.0). More importantly, the investigators found cutaneous changes of NSF in 25 (13%) of the 186 patients, 4 of whom had prior skin biopsies available for review, each revealing the histologic changes of NSF. This study suggests that NSF may be more prevalent than previously thought.

Is kidney dysfunction always present?

All the reported patients with NSF had underlying renal impairment. The renal dysfunction ranged from acute kidney injury to advanced chronic kidney disease (estimated GFR < 30 mL/minute/1.73 m²) and end-stage renal disease on renal replacement therapy, ie, hemodialysis or peritoneal dialysis. The incidence of NSF does not seem to be related to the cause of the underlying kidney disease.

What other diseases or comorbidities can be associated with NSF?

It is still unclear why not every patient with advanced renal failure develops NSF after exposure to gadolinium.

A variety of complex diseases and conditions have been reported to be associated with NSF, with no clear-cut evidence of causality or trigger. These include hypercoagulability states, thrombotic events, surgical procedures (especially those with reconstructive vascular components), calciphylaxis, kidney transplantation, hepatic disease (hepatorenal syndrome, liver transplantation, and hepatitis B and C), idiopathic pulmonary fibrosis, systemic lupus erythematosus, hypothyroidism, elevated serum ionized calcium or serum phosphate, hyperparathyroidism, and metabolic acidosis. A possible explanation is that most of these conditions are associated with an increased use of MRI or MRA testing (eg, in the workup for kidney or liver transplantation).

Many drugs have also been reported to be associated with NSF, including high-dose erythropoietin,²⁰ sevelamer (Renagel),²¹ and, conversely, lack of angiotensin-converting enzyme inhibitor therapy,²² but none of these findings has been reproduced to date.

GADOLINIUM CHARACTERISTICS AND PHARMACOKINETICS

Gadolinium is a rare-earth lanthanide metallic element (atomic number 64) that is used in MRI and MRA because of its paramagnetic properties that enhance the quality of imaging. Its ionic form (Gd³⁺) is highly toxic if injected intravenously, so it is typically bound to a “chelate” to decrease its toxicity.²³ The chelate stabilizes Gd³⁺ and thereby prevents its dissociation in vivo. These Gd-chelates can be classified (Table 2) according to their charge (ionic vs nonionic) and their structure (linear vs cyclic).

Most of the reported cases of NSF have been in patients who received gadodiamide, a nonionic, linear agent. Why gadodiamide has the highest rates of association with NSF is still unclear; perhaps it is simply the most widely used agent. Also, linear Gd compounds may be less stable and more likely to dissociate in vivo. The updated FDA Public Health Advisory in May 2007 warned against the use of all gadolinium-containing contrast agents for MRI, not just gadodiamide.

After intravenous injection, Gd-chelate equilibrates rapidly (within 2 hours) in the extracellular space. Very little of it enters into cells or binds to proteins. It is eliminated unchanged in the glomerular filtrate with no tubular secretion. In a study by Joffe et al,²⁴ the elimination half-life of gadodiamide in patients with severely reduced renal function was considerably longer than in healthy volunteers (34.3 hours ± 22.9 vs 1.3 hours ± 0.25).

Since gadolinium compounds are not protein-bound and have a limited volume of distribution, they are typically removed by hemodialysis. Joffe et al found that an average of 65% of the gadodiamide was removed in a single hemodialysis session. However, they did not describe the specific features of the hemodialysis session, and it took four hemodialysis treatments to remove 99% of a single dose of gadolinium.²⁴ A dialysis membrane with high permeability (large pores) seems to increase the clearance of the Gd-chelate during hemodialysis.²⁵

Peritoneal dialysis may not remove gadolinium as effectively: Joffe et al²⁴ reported that after 22 days of continuous ambulatory peritoneal dialysis, only 69% of the total amount of gadodiamide had been excreted, suggesting a very low peritoneal clearance.

SPECULATIVE PATHOGENESIS

Although a causal relationship between gadolinium use in patients with renal dysfunction and NSF has not been definitively established, the data derived from case reports assuredly raise this suspicion. Furthermore, on biopsy, gadolinium can be found in the skin of patients with NSF, adding evidence of causality.^26–28

The mechanism by which Gd³⁺ might trigger NSF is still not understood. A plausible speculation is that if renal function is reduced, the half-life of the Gd-chelate molecule is significantly increased, as is the chance of Gd³⁺ dissociating from its chelate, leading to increased tissue exposure. Vascular trauma and endothelial dysfunction may allow free Gd³⁺ to enter tissues more easily, where macrophages phagocytose the metal, produce local profibrotic cytokines, and send out signals that recruit circulating fibrocytes to the tissues. Once in tissues, circulating fibrocytes induce a fibrosing process that is indistinguishable from normal scar formation.²⁹

TREATMENTS LACK DATA

There is no consistently successful treatment for NSF.

In isolated reports, successful kidney transplantation slowed the skin fibrosis, but these findings need to be confirmed.^30,31 Data from case reports should be interpreted very cautiously, as they are by nature sporadic and anecdotal. Moreover most of the reports of NSF were published on Web sites or as editorials and did not undergo exhaustive peer review. Because the evidence is weak, kidney transplantation should not be recommended as a treatment for NSF.

Oral steroids, plasmapheresis, extracorporeal photopheresis, thalidomide, topical ultraviolet-A therapy, and other treatments have yielded very conflicting results, with only anecdotal improvement of symptoms. In a recent case report,³² the use of intravenous sodium thiosulfate in addition to aggressive physical therapy provided some benefit by reducing the pain and improving the skin lesions.

Because of the lack of strong evidence of efficacy, we cannot advocate the use of any of these treatments until larger clinical trial results are available. Aggressive physical therapy along with appropriate pain control may have benefits and should be offered to all patients suffering from NSF.

Avoid gadolinium exposure in patients with renal insufficiency

The FDA³³ recently asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, Opti-MARK, ProHance), due to risk of NSF in patients with acute or chronic severe renal insufficiency (GFR < 30 mL/minute/1.73 m²) and in patients with acute renal insufficiency of any severity due to hepatorenal syndrome or in the perioperative liver transplantation period.

For the time being, gadolinium should be contraindicated in patients with acute kidney injury and chronic kidney disease stages 4 and 5 and in those who are on renal replacement therapy (either hemodialysis or peritoneal dialysis). If an MRI study with gadolinium-based contrast is absolutely required in a patient with end-stage renal disease or advanced chronic kidney disease, an agent other than gadodiamide should be used in the lowest possible dose.

Will hemodialysis prevent NSF?

In a patient who is already on hemodialysis, it seems prudent to perform hemodialysis soon after gadolinium exposure and again the day after exposure to increase gadolinium elimination. However, to date, there are no data to support the theory that doing this will prevent NSF.

Because peritoneal dialysis has been reported to clear gadolinium poorly, use of gadolinium is contraindicated. If gadolinium is absolutely needed, either more-aggressive peritoneal dialysis (keeping the abdomen “wet”) or temporary hemodialysis may be considered.

For patients with advanced chronic kidney disease who are not yet on renal replacement therapy, the use of gadolinium is contraindicated, and hemodialysis should not be empirically recommended after gadolinium exposure because we have no evidence to support its utility and because hemodialysis may cause harm.

Nephrology consultation should be considered before any gadolinium use in a patient with impaired renal function, whether acute or chronic.