Nephrology

Q) I’ve heard a lot of references to “renal denervation” and its use for resistant hypertension. What is it? Does it work? Is it common in the US?

Renal denervation is a minimally invasive endovascular procedure that ablates (or disrupts) the renal nerves in and around the renal arteries with radiofrequency energy.⁵ Renal denervation has been approved in the US and other countries and is being used clinically in Europe, Canada, and Australia.⁶

It is thought that renal denervation interrupts the efferent and afferent signals that stimulate the renin-angiotensin-aldosterone system (RAAS) and regulate whole-body sympathetic nervous system activity.⁵ Similar to surgical sympathectomy, renal denervation should theoretically lower blood pressure. However, Ezzahti et al found that renin levels did not decrease in patients following renal denervation.⁷

Drug-resistant hypertension is defined as blood pressure that remains greater than 140/90 mm Hg despite treatment with three or more antihypertensive medications, including a diuretic.⁸ Patients with resistant hypertension have increased cardiovascular risk.⁹ Clinical trials of renal denervation have focused on treatment of resistant hypertension, in the hope of reducing the associated morbidity and mortality.

Results of the Symplicity HTN-3 trial, which assessed the safety and efficacy of renal denervation, were anxiously awaited, since prior trials yielded mixed results. Although the Symplicity HTN-1 and Symplicity HTN-2 studies demonstrated a possible benefit of renal denervation to lower office measured blood pressure, other studies did not show a decrease in BP in patients who had undergone renal denervation.^6,7 These early trials, however, were small and did not randomize patients to a sham procedure.¹⁰

The Symplicity HTN-3 trial included 535 patients at 88 centers in the US. Patients were randomly assigned to receive either renal denervation plus baseline antihypertensive medications or a sham procedure plus baseline antihypertensive medications.

The researchers found that the sham procedure was just as effective as the “true” renal denervation in decreasing systolic blood pressure in patients with resistant hypertension.¹⁰ In other words, renal denervation did not demonstrate efficacy for this purpose.

In response to the results of this well-designed trial, the FDA has halted approval to perform renal denervation in patients with resistant hypertension in the US. However, clinical investigation will continue among subgroups of hypertensive patients or separate populations.

Despite a lack of efficacy, renal denervation does appear to be well tolerated, as evidenced by safety data from Symplicity HTN-3. —JK

Jessica Knight, ACNP
University of New Mexico Hospital, Albuquerque

REFERENCES
5. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for the treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-2982.
6. Thukkani AK, Bhatt LD. Renal denervation therapy for hypertension. Circulation. 2013;128:2251-2254.
7. Ezzahti M, Moelker A, Friesema E, et al. Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension. J Hypertens. 2014;32(1):135-141.
8. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
9. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635-1642.
10. Bhatt DL, Kandzari DE, O’Neill WW, et al; Symplicity HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Q) I’ve heard a lot of references to “renal denervation” and its use for resistant hypertension. What is it? Does it work? Is it common in the US?

Renal denervation is a minimally invasive endovascular procedure that ablates (or disrupts) the renal nerves in and around the renal arteries with radiofrequency energy.⁵ Renal denervation has been approved in the US and other countries and is being used clinically in Europe, Canada, and Australia.⁶

It is thought that renal denervation interrupts the efferent and afferent signals that stimulate the renin-angiotensin-aldosterone system (RAAS) and regulate whole-body sympathetic nervous system activity.⁵ Similar to surgical sympathectomy, renal denervation should theoretically lower blood pressure. However, Ezzahti et al found that renin levels did not decrease in patients following renal denervation.⁷

Drug-resistant hypertension is defined as blood pressure that remains greater than 140/90 mm Hg despite treatment with three or more antihypertensive medications, including a diuretic.⁸ Patients with resistant hypertension have increased cardiovascular risk.⁹ Clinical trials of renal denervation have focused on treatment of resistant hypertension, in the hope of reducing the associated morbidity and mortality.

Results of the Symplicity HTN-3 trial, which assessed the safety and efficacy of renal denervation, were anxiously awaited, since prior trials yielded mixed results. Although the Symplicity HTN-1 and Symplicity HTN-2 studies demonstrated a possible benefit of renal denervation to lower office measured blood pressure, other studies did not show a decrease in BP in patients who had undergone renal denervation.^6,7 These early trials, however, were small and did not randomize patients to a sham procedure.¹⁰

The Symplicity HTN-3 trial included 535 patients at 88 centers in the US. Patients were randomly assigned to receive either renal denervation plus baseline antihypertensive medications or a sham procedure plus baseline antihypertensive medications.

The researchers found that the sham procedure was just as effective as the “true” renal denervation in decreasing systolic blood pressure in patients with resistant hypertension.¹⁰ In other words, renal denervation did not demonstrate efficacy for this purpose.

In response to the results of this well-designed trial, the FDA has halted approval to perform renal denervation in patients with resistant hypertension in the US. However, clinical investigation will continue among subgroups of hypertensive patients or separate populations.

Despite a lack of efficacy, renal denervation does appear to be well tolerated, as evidenced by safety data from Symplicity HTN-3. —JK

Jessica Knight, ACNP
University of New Mexico Hospital, Albuquerque

REFERENCES
5. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for the treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-2982.
6. Thukkani AK, Bhatt LD. Renal denervation therapy for hypertension. Circulation. 2013;128:2251-2254.
7. Ezzahti M, Moelker A, Friesema E, et al. Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension. J Hypertens. 2014;32(1):135-141.
8. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
9. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635-1642.
10. Bhatt DL, Kandzari DE, O’Neill WW, et al; Symplicity HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Q) I’ve heard a lot of references to “renal denervation” and its use for resistant hypertension. What is it? Does it work? Is it common in the US?

Renal denervation is a minimally invasive endovascular procedure that ablates (or disrupts) the renal nerves in and around the renal arteries with radiofrequency energy.⁵ Renal denervation has been approved in the US and other countries and is being used clinically in Europe, Canada, and Australia.⁶

It is thought that renal denervation interrupts the efferent and afferent signals that stimulate the renin-angiotensin-aldosterone system (RAAS) and regulate whole-body sympathetic nervous system activity.⁵ Similar to surgical sympathectomy, renal denervation should theoretically lower blood pressure. However, Ezzahti et al found that renin levels did not decrease in patients following renal denervation.⁷

Drug-resistant hypertension is defined as blood pressure that remains greater than 140/90 mm Hg despite treatment with three or more antihypertensive medications, including a diuretic.⁸ Patients with resistant hypertension have increased cardiovascular risk.⁹ Clinical trials of renal denervation have focused on treatment of resistant hypertension, in the hope of reducing the associated morbidity and mortality.

Results of the Symplicity HTN-3 trial, which assessed the safety and efficacy of renal denervation, were anxiously awaited, since prior trials yielded mixed results. Although the Symplicity HTN-1 and Symplicity HTN-2 studies demonstrated a possible benefit of renal denervation to lower office measured blood pressure, other studies did not show a decrease in BP in patients who had undergone renal denervation.^6,7 These early trials, however, were small and did not randomize patients to a sham procedure.¹⁰

The Symplicity HTN-3 trial included 535 patients at 88 centers in the US. Patients were randomly assigned to receive either renal denervation plus baseline antihypertensive medications or a sham procedure plus baseline antihypertensive medications.

The researchers found that the sham procedure was just as effective as the “true” renal denervation in decreasing systolic blood pressure in patients with resistant hypertension.¹⁰ In other words, renal denervation did not demonstrate efficacy for this purpose.

In response to the results of this well-designed trial, the FDA has halted approval to perform renal denervation in patients with resistant hypertension in the US. However, clinical investigation will continue among subgroups of hypertensive patients or separate populations.

Despite a lack of efficacy, renal denervation does appear to be well tolerated, as evidenced by safety data from Symplicity HTN-3. —JK

Jessica Knight, ACNP
University of New Mexico Hospital, Albuquerque

REFERENCES
5. Esler MD, Krum H, Schlaich M, et al. Renal sympathetic denervation for the treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation. 2012;126(25):2976-2982.
6. Thukkani AK, Bhatt LD. Renal denervation therapy for hypertension. Circulation. 2013;128:2251-2254.
7. Ezzahti M, Moelker A, Friesema E, et al. Blood pressure and neurohormonal responses to renal nerve ablation in treatment-resistant hypertension. J Hypertens. 2014;32(1):135-141.
8. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51(6):1403-1419.
9. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13):1635-1642.
10. Bhatt DL, Kandzari DE, O’Neill WW, et al; Symplicity HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Q) Quite a few of my teenage patients are overweight. I know they are at risk for diabetes, but does their weight also affect their kidneys? Isn’t diabetes the main cause of kidney failure?

The number one cause of chronic kidney disease (CKD) in the United States and worldwide is diabetes, but it is certainly not the only risk factor. Studies have shown a link between obesity and CKD; even in the absence of kidney disease, obesity may cause glomerular dysfunction and an increase in glomerular size.¹

Obesity during adolescence has been identified as a strong predictor of CKD in adulthood. Other diseases and conditions that, if present in adolescence, indicate future risk for kidney ­disease include diabetes, hypertension, inflammation, and proteinuria.

A recent Swedish study followed patients from adolescence to adulthood to identify markers that would predict later kidney disease. In this study, the most predictive factor of kidney failure in adulthood was proteinuria in adolescence (odds ratio, 7.72). These results may be limited by the homogeneity of the predominantly white, male study population, but the extensive follow-up period, which “highlights the long natural history” of kidney disease, is one strength of this study.²

Based on these and other findings, you know that if your teenage patients have proteinuria, they are much more likely to develop kidney failure as an adult. Yet, in the US, the American Academy of Pediatrics and the US Preventive Services Task Force do not recommend urine screening for asymptomatic children.³

Interestingly, however, a survey of pediatric practices revealed that 58% of pediatricians screen adolescents with urinalysis, even if they are asymptomatic.⁴ In other words, they ignore the guidelines. If they did not, we would likely miss what is possibly the most important predictive factor for kidney failure in adults. —TAH

Tia Austin Hayes, FNP-C
UMMC/JMM Outpatient Dialysis/Renal Clinic, Jackson, Mississippi

REFERENCES
1. Rocchini A. Childhood obesity and a diabetes epidemic. N Engl J Med. 2002;346(11):854-855.
2. Sundin PO, Udumyan R, Sjöström P, Montgomery S. Predictors in adolescence of ESRD in middle-aged men. Am J Kidney Dis. 2014;64(5):723-729.
3. Kaplan RE, Springate JE, Feld LG. Screening dipstick urinalysis: a time to change. Pediatrics. 1997;100(6):919-921.
4. Sox CM, Christakis DA. Pediatricians’ screening urinalysis practices. J Pediatr. 2005; 147(3):362-365.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Q) Quite a few of my teenage patients are overweight. I know they are at risk for diabetes, but does their weight also affect their kidneys? Isn’t diabetes the main cause of kidney failure?

The number one cause of chronic kidney disease (CKD) in the United States and worldwide is diabetes, but it is certainly not the only risk factor. Studies have shown a link between obesity and CKD; even in the absence of kidney disease, obesity may cause glomerular dysfunction and an increase in glomerular size.¹

Obesity during adolescence has been identified as a strong predictor of CKD in adulthood. Other diseases and conditions that, if present in adolescence, indicate future risk for kidney ­disease include diabetes, hypertension, inflammation, and proteinuria.

A recent Swedish study followed patients from adolescence to adulthood to identify markers that would predict later kidney disease. In this study, the most predictive factor of kidney failure in adulthood was proteinuria in adolescence (odds ratio, 7.72). These results may be limited by the homogeneity of the predominantly white, male study population, but the extensive follow-up period, which “highlights the long natural history” of kidney disease, is one strength of this study.²

Based on these and other findings, you know that if your teenage patients have proteinuria, they are much more likely to develop kidney failure as an adult. Yet, in the US, the American Academy of Pediatrics and the US Preventive Services Task Force do not recommend urine screening for asymptomatic children.³

Interestingly, however, a survey of pediatric practices revealed that 58% of pediatricians screen adolescents with urinalysis, even if they are asymptomatic.⁴ In other words, they ignore the guidelines. If they did not, we would likely miss what is possibly the most important predictive factor for kidney failure in adults. —TAH

Tia Austin Hayes, FNP-C
UMMC/JMM Outpatient Dialysis/Renal Clinic, Jackson, Mississippi

REFERENCES
1. Rocchini A. Childhood obesity and a diabetes epidemic. N Engl J Med. 2002;346(11):854-855.
2. Sundin PO, Udumyan R, Sjöström P, Montgomery S. Predictors in adolescence of ESRD in middle-aged men. Am J Kidney Dis. 2014;64(5):723-729.
3. Kaplan RE, Springate JE, Feld LG. Screening dipstick urinalysis: a time to change. Pediatrics. 1997;100(6):919-921.
4. Sox CM, Christakis DA. Pediatricians’ screening urinalysis practices. J Pediatr. 2005; 147(3):362-365.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Q) Quite a few of my teenage patients are overweight. I know they are at risk for diabetes, but does their weight also affect their kidneys? Isn’t diabetes the main cause of kidney failure?

The number one cause of chronic kidney disease (CKD) in the United States and worldwide is diabetes, but it is certainly not the only risk factor. Studies have shown a link between obesity and CKD; even in the absence of kidney disease, obesity may cause glomerular dysfunction and an increase in glomerular size.¹

Obesity during adolescence has been identified as a strong predictor of CKD in adulthood. Other diseases and conditions that, if present in adolescence, indicate future risk for kidney ­disease include diabetes, hypertension, inflammation, and proteinuria.

A recent Swedish study followed patients from adolescence to adulthood to identify markers that would predict later kidney disease. In this study, the most predictive factor of kidney failure in adulthood was proteinuria in adolescence (odds ratio, 7.72). These results may be limited by the homogeneity of the predominantly white, male study population, but the extensive follow-up period, which “highlights the long natural history” of kidney disease, is one strength of this study.²

Based on these and other findings, you know that if your teenage patients have proteinuria, they are much more likely to develop kidney failure as an adult. Yet, in the US, the American Academy of Pediatrics and the US Preventive Services Task Force do not recommend urine screening for asymptomatic children.³

Interestingly, however, a survey of pediatric practices revealed that 58% of pediatricians screen adolescents with urinalysis, even if they are asymptomatic.⁴ In other words, they ignore the guidelines. If they did not, we would likely miss what is possibly the most important predictive factor for kidney failure in adults. —TAH

Tia Austin Hayes, FNP-C
UMMC/JMM Outpatient Dialysis/Renal Clinic, Jackson, Mississippi

REFERENCES
1. Rocchini A. Childhood obesity and a diabetes epidemic. N Engl J Med. 2002;346(11):854-855.
2. Sundin PO, Udumyan R, Sjöström P, Montgomery S. Predictors in adolescence of ESRD in middle-aged men. Am J Kidney Dis. 2014;64(5):723-729.
3. Kaplan RE, Springate JE, Feld LG. Screening dipstick urinalysis: a time to change. Pediatrics. 1997;100(6):919-921.
4. Sox CM, Christakis DA. Pediatricians’ screening urinalysis practices. J Pediatr. 2005; 147(3):362-365.

The author would like to thank Eric Judd, MD, of the University of Alabama at Birmingham, for his advice on the preparation of this response.

Pancreas transplant is the only long-term diabetes treatment that consistently results in normal hemoglobin A_1c levels without the risk of severe hypoglycemia. Additionally, pancreas transplant may prevent, halt, or even reverse the complications of diabetes.

Here, we explore the indications, options, and outcomes of pancreas transplant as a treatment for diabetes mellitus.

DIABETES IS COMMON, AND OFTEN NOT WELL CONTROLLED

Diabetes mellitus affects more than 25 million people in the United States (8.3% of the population) and is the leading cause of kidney failure, nontraumatic lower-limb amputation, and adult-onset blindness. In 2007, nearly $116 billion was spent on diabetes treatment, not counting another $58 billion in indirect costs such as disability, work loss, and premature death.¹

Only about half of patients achieve hemoglobin A_1c < 7% with medical therapy

Despite the tremendous expenditure in human, material, and financial resources, only about 50% of patients achieve their diabetes treatment goals. In 2013, a large US population-based study­² reported that 52.2% of patients were achieving the American Diabetes Association treatment goal of hemoglobin A_1c lower than 7%. A similar study in South Korea³ found that 45.6% were at this goal.

Most of the patients in these studies had type 2 diabetes, and the data suggested that attaining glycemic goals is more difficult in insulin-treated patients. Studies of patients with type 1 diabetes found hemoglobin A_1c levels lower than 7% in only 8.1% of hospitalized patients with type 1 diabetes, and in only 13% in an outpatient diabetes clinic.^4,5

YET RATES OF PANCREAS TRANSPLANT ARE DECLINING

Pancreas transplant was first performed more than 40 years ago at the University of Minnesota.⁶ Since then, dramatic changes in immunosuppression, organ preservation, surgical technique, and donor and recipient selection have brought about significant progress.

Currently, more than 13,000 patients are alive with a functioning pancreas allograft. After reaching a peak in 2004, the annual number of pancreas transplants performed in the United States has declined steadily, whereas the procedure continues to increase in popularity outside North America.⁷ The primary reason for the decline is recognition of donor factors that lead to success—surgeons are refusing to transplant organs they might have accepted previously, because experience suggests they would yield poor results. In the United States, 1,043 pancreas transplants were performed in 2012, and more than 3,100 patients were on the waiting list.⁸

Islet cell transplant—a different procedure involving harvesting, encapsulating, and implanting insulin-producing beta cells—has not gained widespread application due to very low long-term success rates.

THREE CATEGORIES OF PANCREAS TRANSPLANT

Pancreas transplant can be categorized according to whether the patient is also receiving or has already received a kidney graft (Table 1).

Simultaneous kidney and pancreas transplant is performed in patients who have type 1 diabetes with advanced chronic kidney disease due to diabetic nephropathy. This remains the most commonly performed type, accounting for 79% of all pancreas transplants in 2012.⁸

Pancreas-after-kidney transplant is most often done after a living-donor kidney transplant. This procedure accounted for most of the increase in pancreas transplants during the first decade of the 2000s. However, the number of these procedures has steadily decreased since 2004, and in 2012 accounted for only 12% of pancreas transplants.⁸

Pancreas transplant alone is performed in nonuremic diabetic patients who have labile blood sugar control. Performed in patients with preserved renal function but severe complications of “brittle” diabetes, such as hypoglycemic unawareness, this type accounts for 8% of pancreas transplants.⁹

Indications for pancreas transplant

A small number of these procedures are done for indications unrelated to diabetes mellitus. In most of these cases, the pancreas is transplanted as part of a multivisceral transplant to facilitate the technical (surgical) aspect of the procedure—the pancreas, liver, stomach, gallbladder, and part of the intestines are transplanted en bloc to maintain the native vasculature. Very infrequently, pancreas transplant is done to replace exocrine pancreatic function.

A small, select group of patients with type 2 diabetes and low body mass index (BMI) may be eligible for pancreas transplant, and they accounted for 8.2% of active candidates in 2012.⁸ However, most pancreas transplants are performed in patients with type 1 diabetes.

WHAT MAKES A GOOD ALLOGRAFT?

Pancreas allografts are procured as whole organs from brain-dead organ donors. Relatively few pancreas allografts (3.1% in 2012) are from cardiac-death donors, because of concern about warm ischemic injury during the period of circulatory arrest.⁸

Proper donor selection is critical to the success of pancreas transplant, as donor factors including medical history, age, BMI, and cause of death can significantly affect the outcome. In general, transplant of a pancreas allograft from a young donor (age < 30) with excellent organ function, low BMI, and traumatic cause of death provides the best chance of success.

The Pancreas Donor Risk Index (PDRI)¹⁰ was developed after analysis of objective donor criteria, transplant type, and ischemic time in grafts transplanted between 2000 and 2006. One-year graft survival was directly related to the PDRI and ranged between 77% and 87% in recipients of “standard” pancreas allografts (PDRI score of 1.0). Use of grafts from the highest (worst) three quintiles of PDRI (PDRI score > 1.16) was associated with 1-year graft survival rates of 67% to 82%, significantly inferior to that seen with “higher- quality” grafts, again emphasizing the need for rigorous donor selection.¹⁰

In addition to these objective measures, visual assessment of pancreas quality at the time of procurement remains an equally important predictor of success. Determination of subjective features, such as fatty infiltration and glandular fibrosis, requires surgical experience developed over several years. In a 2010 analysis, dissatisfaction with the quality of the donor graft on inspection accounted for more than 80% of refusals of potential pancreas donors.¹¹ These studies illustrate an ill-defined aspect of pancreas transplant, ie, even when the pancreas donor is perceived to be suitable, the outcome may be markedly different.

SURGICAL COMPLICATIONS

Surgical complications have long been considered a limiting factor in the growth of pancreas transplant. Technical failure or loss of the graft within 90 days is most commonly due to graft thrombosis, leakage of the enteric anastomosis, or severe peripancreatic infection. The rate of technical failure has declined across all recipient categories and is currently about 9%.⁸

DO RECIPIENT FACTORS AFFECT OUTCOMES?

As mentioned above, the PDRI identifies donor factors that influence the 1-year graft survival rate. Recipient factors are also thought to play a role, although the influence of these factors has not been consistently demonstrated.

Humar et al¹⁵ found that recipient obesity (defined in this study as BMI > 25 kg/m²) and donor age over 40 were risk factors for early laparotomy after pancreas transplant.¹⁵ Moreover, patients undergoing early laparotomy had poorer graft survival outcomes.

This finding was reinforced by an analysis of 5,725 primary simultaneous pancreas-kidney recipients between 2000 and 2007. Obesity (BMI 30 ≥ kg/m²) was associated with increased rates of patient death, pancreas graft loss, and kidney graft loss at 3 years.¹⁶

More recently, Finger et al¹⁷ did not find a statistically significant association between recipient BMI and technical failure, but they did notice a trend toward increased graft loss with a BMI greater than 25 kg/m². Similarly, others have not found a clear adverse association between recipient BMI and pancreas graft survival.

Intuitively, obesity and other recipient factors such as age, vascular disease, duration of diabetes, and dialysis should influence pancreas graft survival but have not been shown in analyses to carry an adverse effect.¹⁸ The inability to consistently find adverse effects of recipient characteristics is most likely due to the relative similarity between the vast majority of pancreas transplant recipients and the relatively small numbers of adverse events. In 98 consecutive pancreas transplants at our center between 2009 and 2014, the technical loss rate was 1.8% (unpublished data).

Acute rejection most commonly occurs during the first year and is usually reversible. More than 1 year after transplant, graft loss is due to chronic rejection, and death is usually from underlying cardiovascular disease.

The immunosuppressive regimens used in pancreas transplant are similar to those in kidney transplant. Since the pancreas is considered to be more immunogenic than other organs, most centers employ a strategy of induction immunosuppression with T-cell–depleting or interleukin 2-receptor antibodies. Maintenance immunosuppression consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate), and a corticosteroid.⁸

Immunosuppressive complications occur at a rate similar to that seen in other solid-organ transplants and include an increased risk of opportunistic infection and malignancy. The risk of these complications must be balanced against the patient’s risk of health decline with dialysis and insulin-based therapies.

OVERALL OUTCOMES ARE GOOD

The success rate of pancreas transplant is currently at its highest since the inception of the procedure. The unadjusted patient survival rate for all groups is over 96% at 1 year, and over 80% at 5 years.⁸ One-year patient survival after pancreas transplant alone, at better than 96%, is the highest of all organ transplant procedures.⁹

Patient survival 1 year after pancreas-alone transplant is > 96%

Several recently published single-center reviews of pancreas transplant since 2000 report patient survival rates of 96% to 100% at 1 year and 88% to 100% at 5 years.^19–22 This variability is likely closely linked to donor and recipient selection, as centers performing smaller numbers of transplants tend to be more selective and, in turn, report higher patient survival rates.^19,21

Long-term patient survival outcomes can be gathered from larger, registry-based reviews, accepting limitations in assessing causes of patient death. Siskind et al²³ analyzed the outcomes of 20,854 US pancreas transplants done between 1996 and 2012 and found the 10-year patient survival rate ranged from 43% to 77% and was highly dependent on patient age at the time of the procedure.²³ Patient survival after transplant must be balanced against the generally poor long-term survival prospects of diabetic patients on dialysis.

By type of transplant, pancreas graft survival rates at 1 year are 89% for simultaneous pancreas-kidney transplant, 86% for pancreas-after-kidney transplant, and 84% for pancreas-alone transplant. Graft survival rates at 5 years are 71% for simultaneous pancreas-kidney transplant, 65% for pancreas-after-kidney transplant, and 58% for pancreas-alone transplant.^8,9

Simultaneous pancreas-kidney transplant has been shown to improve the survival rate compared with cadaveric kidney transplant alone in patients with type 1 diabetes and chronic kidney disease.^24,25 The survival benefit of isolated pancreas transplant (after kidney transplant and alone) is not evident at 4-year follow-up compared with patients on the waiting list. However, the benefit for the individual patient must be considered by weighing the incapacities experienced with insulin-based treatments against the risks of surgery and immunosuppression.^26,27 For patients who have experienced frequent and significant hypoglycemic episodes, particularly those requiring third-party assistance, pancreas transplant can be a lifesaving procedure.

Effects on secondary diabetic complications

Notwithstanding the effect on the patient’s life span, data from several studies of long-term pancreas transplant recipients suggest that secondary diabetic complications can be halted or even improved. Most of these studies examined the effect of restoring euglycemia in nephropathy and the subsequent influence on renal function.

Effect on renal function. Kleinclauss et al²⁸ examined renal allograft function in type 1 diabetic recipients of living-donor kidney transplants. Comparing kidney allograft survival and function in patients who received a subsequent pancreas-after-kidney transplant vs those who did not, graft survival was superior after 5 years, and the estimated glomerular filtration rate was 10 mL/min higher in pancreas-after-kidney recipients.²⁸ This improvement in renal function was not seen immediately after the pancreas transplant but became evident more than 4 years after establishment of normoglycemia. Somewhat similarly, reversal of diabetic changes in native kidney biopsies has been seen 10 years after pancreas transplant.²⁹

Effect on neuropathy. In other studies, reversal of autonomic neuropathy and hypoglycemic unawareness and improvements in peripheral sensory-motor neuropathy have also been observed.^30–32

Effect on retinopathy. Improvements in early-stage nonproliferative diabetic retinopathy and laser-treated proliferative lesions have been seen, even within short periods of follow-up.³³ Other groups have shown a significantly higher proportion of improvement or stability of advanced diabetic retinopathy at 3 years after simultaneous pancreas-kidney transplant, compared with kidney transplant alone in patients with type 1 diabetes.³⁴

Effect on heart disease. Salutary effects on cardiovascular risk factors and amelioration of cardiac morphology and functional cardiac indices have been seen within the first posttransplant year.³⁵ Moreover, with longer follow-up (nearly 4 years), simultaneous pancreas-kidney recipients with functioning pancreas grafts were found to have less progression of coronary atherosclerosis than simultaneous pancreas-kidney recipients with early pancreas graft loss.³⁶ These data provide a potential pathophysiologic mechanism for the long-term survival advantage seen in uremic type 1 diabetic patients undergoing simultaneous pancreas-kidney transplant.

In the aggregate, these findings suggest that, in the absence of surgical and immunosuppression-related complications, a functioning pancreas allograft can alter the progress of diabetic complications. As an extension of these results, pancreas transplant done earlier in the course of diabetes may have an even greater impact.

Pancreas transplant is the only long-term diabetes treatment that consistently results in normal hemoglobin A_1c levels without the risk of severe hypoglycemia. Additionally, pancreas transplant may prevent, halt, or even reverse the complications of diabetes.

Here, we explore the indications, options, and outcomes of pancreas transplant as a treatment for diabetes mellitus.

DIABETES IS COMMON, AND OFTEN NOT WELL CONTROLLED

Diabetes mellitus affects more than 25 million people in the United States (8.3% of the population) and is the leading cause of kidney failure, nontraumatic lower-limb amputation, and adult-onset blindness. In 2007, nearly $116 billion was spent on diabetes treatment, not counting another $58 billion in indirect costs such as disability, work loss, and premature death.¹

Only about half of patients achieve hemoglobin A_1c < 7% with medical therapy

Despite the tremendous expenditure in human, material, and financial resources, only about 50% of patients achieve their diabetes treatment goals. In 2013, a large US population-based study­² reported that 52.2% of patients were achieving the American Diabetes Association treatment goal of hemoglobin A_1c lower than 7%. A similar study in South Korea³ found that 45.6% were at this goal.

Most of the patients in these studies had type 2 diabetes, and the data suggested that attaining glycemic goals is more difficult in insulin-treated patients. Studies of patients with type 1 diabetes found hemoglobin A_1c levels lower than 7% in only 8.1% of hospitalized patients with type 1 diabetes, and in only 13% in an outpatient diabetes clinic.^4,5

YET RATES OF PANCREAS TRANSPLANT ARE DECLINING

Pancreas transplant was first performed more than 40 years ago at the University of Minnesota.⁶ Since then, dramatic changes in immunosuppression, organ preservation, surgical technique, and donor and recipient selection have brought about significant progress.

Currently, more than 13,000 patients are alive with a functioning pancreas allograft. After reaching a peak in 2004, the annual number of pancreas transplants performed in the United States has declined steadily, whereas the procedure continues to increase in popularity outside North America.⁷ The primary reason for the decline is recognition of donor factors that lead to success—surgeons are refusing to transplant organs they might have accepted previously, because experience suggests they would yield poor results. In the United States, 1,043 pancreas transplants were performed in 2012, and more than 3,100 patients were on the waiting list.⁸

Islet cell transplant—a different procedure involving harvesting, encapsulating, and implanting insulin-producing beta cells—has not gained widespread application due to very low long-term success rates.

THREE CATEGORIES OF PANCREAS TRANSPLANT

Pancreas transplant can be categorized according to whether the patient is also receiving or has already received a kidney graft (Table 1).

Simultaneous kidney and pancreas transplant is performed in patients who have type 1 diabetes with advanced chronic kidney disease due to diabetic nephropathy. This remains the most commonly performed type, accounting for 79% of all pancreas transplants in 2012.⁸

Pancreas-after-kidney transplant is most often done after a living-donor kidney transplant. This procedure accounted for most of the increase in pancreas transplants during the first decade of the 2000s. However, the number of these procedures has steadily decreased since 2004, and in 2012 accounted for only 12% of pancreas transplants.⁸

Pancreas transplant alone is performed in nonuremic diabetic patients who have labile blood sugar control. Performed in patients with preserved renal function but severe complications of “brittle” diabetes, such as hypoglycemic unawareness, this type accounts for 8% of pancreas transplants.⁹

Indications for pancreas transplant

A small number of these procedures are done for indications unrelated to diabetes mellitus. In most of these cases, the pancreas is transplanted as part of a multivisceral transplant to facilitate the technical (surgical) aspect of the procedure—the pancreas, liver, stomach, gallbladder, and part of the intestines are transplanted en bloc to maintain the native vasculature. Very infrequently, pancreas transplant is done to replace exocrine pancreatic function.

A small, select group of patients with type 2 diabetes and low body mass index (BMI) may be eligible for pancreas transplant, and they accounted for 8.2% of active candidates in 2012.⁸ However, most pancreas transplants are performed in patients with type 1 diabetes.

WHAT MAKES A GOOD ALLOGRAFT?

Pancreas allografts are procured as whole organs from brain-dead organ donors. Relatively few pancreas allografts (3.1% in 2012) are from cardiac-death donors, because of concern about warm ischemic injury during the period of circulatory arrest.⁸

Proper donor selection is critical to the success of pancreas transplant, as donor factors including medical history, age, BMI, and cause of death can significantly affect the outcome. In general, transplant of a pancreas allograft from a young donor (age < 30) with excellent organ function, low BMI, and traumatic cause of death provides the best chance of success.

The Pancreas Donor Risk Index (PDRI)¹⁰ was developed after analysis of objective donor criteria, transplant type, and ischemic time in grafts transplanted between 2000 and 2006. One-year graft survival was directly related to the PDRI and ranged between 77% and 87% in recipients of “standard” pancreas allografts (PDRI score of 1.0). Use of grafts from the highest (worst) three quintiles of PDRI (PDRI score > 1.16) was associated with 1-year graft survival rates of 67% to 82%, significantly inferior to that seen with “higher- quality” grafts, again emphasizing the need for rigorous donor selection.¹⁰

In addition to these objective measures, visual assessment of pancreas quality at the time of procurement remains an equally important predictor of success. Determination of subjective features, such as fatty infiltration and glandular fibrosis, requires surgical experience developed over several years. In a 2010 analysis, dissatisfaction with the quality of the donor graft on inspection accounted for more than 80% of refusals of potential pancreas donors.¹¹ These studies illustrate an ill-defined aspect of pancreas transplant, ie, even when the pancreas donor is perceived to be suitable, the outcome may be markedly different.

SURGICAL COMPLICATIONS

Surgical complications have long been considered a limiting factor in the growth of pancreas transplant. Technical failure or loss of the graft within 90 days is most commonly due to graft thrombosis, leakage of the enteric anastomosis, or severe peripancreatic infection. The rate of technical failure has declined across all recipient categories and is currently about 9%.⁸

DO RECIPIENT FACTORS AFFECT OUTCOMES?

As mentioned above, the PDRI identifies donor factors that influence the 1-year graft survival rate. Recipient factors are also thought to play a role, although the influence of these factors has not been consistently demonstrated.

Humar et al¹⁵ found that recipient obesity (defined in this study as BMI > 25 kg/m²) and donor age over 40 were risk factors for early laparotomy after pancreas transplant.¹⁵ Moreover, patients undergoing early laparotomy had poorer graft survival outcomes.

This finding was reinforced by an analysis of 5,725 primary simultaneous pancreas-kidney recipients between 2000 and 2007. Obesity (BMI 30 ≥ kg/m²) was associated with increased rates of patient death, pancreas graft loss, and kidney graft loss at 3 years.¹⁶

More recently, Finger et al¹⁷ did not find a statistically significant association between recipient BMI and technical failure, but they did notice a trend toward increased graft loss with a BMI greater than 25 kg/m². Similarly, others have not found a clear adverse association between recipient BMI and pancreas graft survival.

Intuitively, obesity and other recipient factors such as age, vascular disease, duration of diabetes, and dialysis should influence pancreas graft survival but have not been shown in analyses to carry an adverse effect.¹⁸ The inability to consistently find adverse effects of recipient characteristics is most likely due to the relative similarity between the vast majority of pancreas transplant recipients and the relatively small numbers of adverse events. In 98 consecutive pancreas transplants at our center between 2009 and 2014, the technical loss rate was 1.8% (unpublished data).

Acute rejection most commonly occurs during the first year and is usually reversible. More than 1 year after transplant, graft loss is due to chronic rejection, and death is usually from underlying cardiovascular disease.

The immunosuppressive regimens used in pancreas transplant are similar to those in kidney transplant. Since the pancreas is considered to be more immunogenic than other organs, most centers employ a strategy of induction immunosuppression with T-cell–depleting or interleukin 2-receptor antibodies. Maintenance immunosuppression consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate), and a corticosteroid.⁸

Immunosuppressive complications occur at a rate similar to that seen in other solid-organ transplants and include an increased risk of opportunistic infection and malignancy. The risk of these complications must be balanced against the patient’s risk of health decline with dialysis and insulin-based therapies.

OVERALL OUTCOMES ARE GOOD

The success rate of pancreas transplant is currently at its highest since the inception of the procedure. The unadjusted patient survival rate for all groups is over 96% at 1 year, and over 80% at 5 years.⁸ One-year patient survival after pancreas transplant alone, at better than 96%, is the highest of all organ transplant procedures.⁹

Patient survival 1 year after pancreas-alone transplant is > 96%

Several recently published single-center reviews of pancreas transplant since 2000 report patient survival rates of 96% to 100% at 1 year and 88% to 100% at 5 years.^19–22 This variability is likely closely linked to donor and recipient selection, as centers performing smaller numbers of transplants tend to be more selective and, in turn, report higher patient survival rates.^19,21

Long-term patient survival outcomes can be gathered from larger, registry-based reviews, accepting limitations in assessing causes of patient death. Siskind et al²³ analyzed the outcomes of 20,854 US pancreas transplants done between 1996 and 2012 and found the 10-year patient survival rate ranged from 43% to 77% and was highly dependent on patient age at the time of the procedure.²³ Patient survival after transplant must be balanced against the generally poor long-term survival prospects of diabetic patients on dialysis.

By type of transplant, pancreas graft survival rates at 1 year are 89% for simultaneous pancreas-kidney transplant, 86% for pancreas-after-kidney transplant, and 84% for pancreas-alone transplant. Graft survival rates at 5 years are 71% for simultaneous pancreas-kidney transplant, 65% for pancreas-after-kidney transplant, and 58% for pancreas-alone transplant.^8,9

Simultaneous pancreas-kidney transplant has been shown to improve the survival rate compared with cadaveric kidney transplant alone in patients with type 1 diabetes and chronic kidney disease.^24,25 The survival benefit of isolated pancreas transplant (after kidney transplant and alone) is not evident at 4-year follow-up compared with patients on the waiting list. However, the benefit for the individual patient must be considered by weighing the incapacities experienced with insulin-based treatments against the risks of surgery and immunosuppression.^26,27 For patients who have experienced frequent and significant hypoglycemic episodes, particularly those requiring third-party assistance, pancreas transplant can be a lifesaving procedure.

Effects on secondary diabetic complications

Notwithstanding the effect on the patient’s life span, data from several studies of long-term pancreas transplant recipients suggest that secondary diabetic complications can be halted or even improved. Most of these studies examined the effect of restoring euglycemia in nephropathy and the subsequent influence on renal function.

Effect on renal function. Kleinclauss et al²⁸ examined renal allograft function in type 1 diabetic recipients of living-donor kidney transplants. Comparing kidney allograft survival and function in patients who received a subsequent pancreas-after-kidney transplant vs those who did not, graft survival was superior after 5 years, and the estimated glomerular filtration rate was 10 mL/min higher in pancreas-after-kidney recipients.²⁸ This improvement in renal function was not seen immediately after the pancreas transplant but became evident more than 4 years after establishment of normoglycemia. Somewhat similarly, reversal of diabetic changes in native kidney biopsies has been seen 10 years after pancreas transplant.²⁹

Effect on neuropathy. In other studies, reversal of autonomic neuropathy and hypoglycemic unawareness and improvements in peripheral sensory-motor neuropathy have also been observed.^30–32

Effect on retinopathy. Improvements in early-stage nonproliferative diabetic retinopathy and laser-treated proliferative lesions have been seen, even within short periods of follow-up.³³ Other groups have shown a significantly higher proportion of improvement or stability of advanced diabetic retinopathy at 3 years after simultaneous pancreas-kidney transplant, compared with kidney transplant alone in patients with type 1 diabetes.³⁴

Effect on heart disease. Salutary effects on cardiovascular risk factors and amelioration of cardiac morphology and functional cardiac indices have been seen within the first posttransplant year.³⁵ Moreover, with longer follow-up (nearly 4 years), simultaneous pancreas-kidney recipients with functioning pancreas grafts were found to have less progression of coronary atherosclerosis than simultaneous pancreas-kidney recipients with early pancreas graft loss.³⁶ These data provide a potential pathophysiologic mechanism for the long-term survival advantage seen in uremic type 1 diabetic patients undergoing simultaneous pancreas-kidney transplant.

In the aggregate, these findings suggest that, in the absence of surgical and immunosuppression-related complications, a functioning pancreas allograft can alter the progress of diabetic complications. As an extension of these results, pancreas transplant done earlier in the course of diabetes may have an even greater impact.

Pancreas transplant is the only long-term diabetes treatment that consistently results in normal hemoglobin A_1c levels without the risk of severe hypoglycemia. Additionally, pancreas transplant may prevent, halt, or even reverse the complications of diabetes.

Here, we explore the indications, options, and outcomes of pancreas transplant as a treatment for diabetes mellitus.

DIABETES IS COMMON, AND OFTEN NOT WELL CONTROLLED

Diabetes mellitus affects more than 25 million people in the United States (8.3% of the population) and is the leading cause of kidney failure, nontraumatic lower-limb amputation, and adult-onset blindness. In 2007, nearly $116 billion was spent on diabetes treatment, not counting another $58 billion in indirect costs such as disability, work loss, and premature death.¹

Only about half of patients achieve hemoglobin A_1c < 7% with medical therapy

Despite the tremendous expenditure in human, material, and financial resources, only about 50% of patients achieve their diabetes treatment goals. In 2013, a large US population-based study­² reported that 52.2% of patients were achieving the American Diabetes Association treatment goal of hemoglobin A_1c lower than 7%. A similar study in South Korea³ found that 45.6% were at this goal.

Most of the patients in these studies had type 2 diabetes, and the data suggested that attaining glycemic goals is more difficult in insulin-treated patients. Studies of patients with type 1 diabetes found hemoglobin A_1c levels lower than 7% in only 8.1% of hospitalized patients with type 1 diabetes, and in only 13% in an outpatient diabetes clinic.^4,5

YET RATES OF PANCREAS TRANSPLANT ARE DECLINING

Pancreas transplant was first performed more than 40 years ago at the University of Minnesota.⁶ Since then, dramatic changes in immunosuppression, organ preservation, surgical technique, and donor and recipient selection have brought about significant progress.

Currently, more than 13,000 patients are alive with a functioning pancreas allograft. After reaching a peak in 2004, the annual number of pancreas transplants performed in the United States has declined steadily, whereas the procedure continues to increase in popularity outside North America.⁷ The primary reason for the decline is recognition of donor factors that lead to success—surgeons are refusing to transplant organs they might have accepted previously, because experience suggests they would yield poor results. In the United States, 1,043 pancreas transplants were performed in 2012, and more than 3,100 patients were on the waiting list.⁸

Islet cell transplant—a different procedure involving harvesting, encapsulating, and implanting insulin-producing beta cells—has not gained widespread application due to very low long-term success rates.

THREE CATEGORIES OF PANCREAS TRANSPLANT

Pancreas transplant can be categorized according to whether the patient is also receiving or has already received a kidney graft (Table 1).

Simultaneous kidney and pancreas transplant is performed in patients who have type 1 diabetes with advanced chronic kidney disease due to diabetic nephropathy. This remains the most commonly performed type, accounting for 79% of all pancreas transplants in 2012.⁸

Pancreas-after-kidney transplant is most often done after a living-donor kidney transplant. This procedure accounted for most of the increase in pancreas transplants during the first decade of the 2000s. However, the number of these procedures has steadily decreased since 2004, and in 2012 accounted for only 12% of pancreas transplants.⁸

Pancreas transplant alone is performed in nonuremic diabetic patients who have labile blood sugar control. Performed in patients with preserved renal function but severe complications of “brittle” diabetes, such as hypoglycemic unawareness, this type accounts for 8% of pancreas transplants.⁹

Indications for pancreas transplant

A small number of these procedures are done for indications unrelated to diabetes mellitus. In most of these cases, the pancreas is transplanted as part of a multivisceral transplant to facilitate the technical (surgical) aspect of the procedure—the pancreas, liver, stomach, gallbladder, and part of the intestines are transplanted en bloc to maintain the native vasculature. Very infrequently, pancreas transplant is done to replace exocrine pancreatic function.

A small, select group of patients with type 2 diabetes and low body mass index (BMI) may be eligible for pancreas transplant, and they accounted for 8.2% of active candidates in 2012.⁸ However, most pancreas transplants are performed in patients with type 1 diabetes.

WHAT MAKES A GOOD ALLOGRAFT?

Pancreas allografts are procured as whole organs from brain-dead organ donors. Relatively few pancreas allografts (3.1% in 2012) are from cardiac-death donors, because of concern about warm ischemic injury during the period of circulatory arrest.⁸

Proper donor selection is critical to the success of pancreas transplant, as donor factors including medical history, age, BMI, and cause of death can significantly affect the outcome. In general, transplant of a pancreas allograft from a young donor (age < 30) with excellent organ function, low BMI, and traumatic cause of death provides the best chance of success.

The Pancreas Donor Risk Index (PDRI)¹⁰ was developed after analysis of objective donor criteria, transplant type, and ischemic time in grafts transplanted between 2000 and 2006. One-year graft survival was directly related to the PDRI and ranged between 77% and 87% in recipients of “standard” pancreas allografts (PDRI score of 1.0). Use of grafts from the highest (worst) three quintiles of PDRI (PDRI score > 1.16) was associated with 1-year graft survival rates of 67% to 82%, significantly inferior to that seen with “higher- quality” grafts, again emphasizing the need for rigorous donor selection.¹⁰

In addition to these objective measures, visual assessment of pancreas quality at the time of procurement remains an equally important predictor of success. Determination of subjective features, such as fatty infiltration and glandular fibrosis, requires surgical experience developed over several years. In a 2010 analysis, dissatisfaction with the quality of the donor graft on inspection accounted for more than 80% of refusals of potential pancreas donors.¹¹ These studies illustrate an ill-defined aspect of pancreas transplant, ie, even when the pancreas donor is perceived to be suitable, the outcome may be markedly different.

SURGICAL COMPLICATIONS

Surgical complications have long been considered a limiting factor in the growth of pancreas transplant. Technical failure or loss of the graft within 90 days is most commonly due to graft thrombosis, leakage of the enteric anastomosis, or severe peripancreatic infection. The rate of technical failure has declined across all recipient categories and is currently about 9%.⁸

DO RECIPIENT FACTORS AFFECT OUTCOMES?

As mentioned above, the PDRI identifies donor factors that influence the 1-year graft survival rate. Recipient factors are also thought to play a role, although the influence of these factors has not been consistently demonstrated.

Humar et al¹⁵ found that recipient obesity (defined in this study as BMI > 25 kg/m²) and donor age over 40 were risk factors for early laparotomy after pancreas transplant.¹⁵ Moreover, patients undergoing early laparotomy had poorer graft survival outcomes.

This finding was reinforced by an analysis of 5,725 primary simultaneous pancreas-kidney recipients between 2000 and 2007. Obesity (BMI 30 ≥ kg/m²) was associated with increased rates of patient death, pancreas graft loss, and kidney graft loss at 3 years.¹⁶

More recently, Finger et al¹⁷ did not find a statistically significant association between recipient BMI and technical failure, but they did notice a trend toward increased graft loss with a BMI greater than 25 kg/m². Similarly, others have not found a clear adverse association between recipient BMI and pancreas graft survival.

Intuitively, obesity and other recipient factors such as age, vascular disease, duration of diabetes, and dialysis should influence pancreas graft survival but have not been shown in analyses to carry an adverse effect.¹⁸ The inability to consistently find adverse effects of recipient characteristics is most likely due to the relative similarity between the vast majority of pancreas transplant recipients and the relatively small numbers of adverse events. In 98 consecutive pancreas transplants at our center between 2009 and 2014, the technical loss rate was 1.8% (unpublished data).

Acute rejection most commonly occurs during the first year and is usually reversible. More than 1 year after transplant, graft loss is due to chronic rejection, and death is usually from underlying cardiovascular disease.

The immunosuppressive regimens used in pancreas transplant are similar to those in kidney transplant. Since the pancreas is considered to be more immunogenic than other organs, most centers employ a strategy of induction immunosuppression with T-cell–depleting or interleukin 2-receptor antibodies. Maintenance immunosuppression consists of a calcineurin inhibitor (tacrolimus or cyclosporine), an antimetabolite (mycophenolate), and a corticosteroid.⁸

Immunosuppressive complications occur at a rate similar to that seen in other solid-organ transplants and include an increased risk of opportunistic infection and malignancy. The risk of these complications must be balanced against the patient’s risk of health decline with dialysis and insulin-based therapies.

OVERALL OUTCOMES ARE GOOD

The success rate of pancreas transplant is currently at its highest since the inception of the procedure. The unadjusted patient survival rate for all groups is over 96% at 1 year, and over 80% at 5 years.⁸ One-year patient survival after pancreas transplant alone, at better than 96%, is the highest of all organ transplant procedures.⁹

Patient survival 1 year after pancreas-alone transplant is > 96%

Several recently published single-center reviews of pancreas transplant since 2000 report patient survival rates of 96% to 100% at 1 year and 88% to 100% at 5 years.^19–22 This variability is likely closely linked to donor and recipient selection, as centers performing smaller numbers of transplants tend to be more selective and, in turn, report higher patient survival rates.^19,21

Long-term patient survival outcomes can be gathered from larger, registry-based reviews, accepting limitations in assessing causes of patient death. Siskind et al²³ analyzed the outcomes of 20,854 US pancreas transplants done between 1996 and 2012 and found the 10-year patient survival rate ranged from 43% to 77% and was highly dependent on patient age at the time of the procedure.²³ Patient survival after transplant must be balanced against the generally poor long-term survival prospects of diabetic patients on dialysis.

By type of transplant, pancreas graft survival rates at 1 year are 89% for simultaneous pancreas-kidney transplant, 86% for pancreas-after-kidney transplant, and 84% for pancreas-alone transplant. Graft survival rates at 5 years are 71% for simultaneous pancreas-kidney transplant, 65% for pancreas-after-kidney transplant, and 58% for pancreas-alone transplant.^8,9

Simultaneous pancreas-kidney transplant has been shown to improve the survival rate compared with cadaveric kidney transplant alone in patients with type 1 diabetes and chronic kidney disease.^24,25 The survival benefit of isolated pancreas transplant (after kidney transplant and alone) is not evident at 4-year follow-up compared with patients on the waiting list. However, the benefit for the individual patient must be considered by weighing the incapacities experienced with insulin-based treatments against the risks of surgery and immunosuppression.^26,27 For patients who have experienced frequent and significant hypoglycemic episodes, particularly those requiring third-party assistance, pancreas transplant can be a lifesaving procedure.

Effects on secondary diabetic complications

Notwithstanding the effect on the patient’s life span, data from several studies of long-term pancreas transplant recipients suggest that secondary diabetic complications can be halted or even improved. Most of these studies examined the effect of restoring euglycemia in nephropathy and the subsequent influence on renal function.

Effect on renal function. Kleinclauss et al²⁸ examined renal allograft function in type 1 diabetic recipients of living-donor kidney transplants. Comparing kidney allograft survival and function in patients who received a subsequent pancreas-after-kidney transplant vs those who did not, graft survival was superior after 5 years, and the estimated glomerular filtration rate was 10 mL/min higher in pancreas-after-kidney recipients.²⁸ This improvement in renal function was not seen immediately after the pancreas transplant but became evident more than 4 years after establishment of normoglycemia. Somewhat similarly, reversal of diabetic changes in native kidney biopsies has been seen 10 years after pancreas transplant.²⁹

Effect on neuropathy. In other studies, reversal of autonomic neuropathy and hypoglycemic unawareness and improvements in peripheral sensory-motor neuropathy have also been observed.^30–32

Effect on retinopathy. Improvements in early-stage nonproliferative diabetic retinopathy and laser-treated proliferative lesions have been seen, even within short periods of follow-up.³³ Other groups have shown a significantly higher proportion of improvement or stability of advanced diabetic retinopathy at 3 years after simultaneous pancreas-kidney transplant, compared with kidney transplant alone in patients with type 1 diabetes.³⁴

Effect on heart disease. Salutary effects on cardiovascular risk factors and amelioration of cardiac morphology and functional cardiac indices have been seen within the first posttransplant year.³⁵ Moreover, with longer follow-up (nearly 4 years), simultaneous pancreas-kidney recipients with functioning pancreas grafts were found to have less progression of coronary atherosclerosis than simultaneous pancreas-kidney recipients with early pancreas graft loss.³⁶ These data provide a potential pathophysiologic mechanism for the long-term survival advantage seen in uremic type 1 diabetic patients undergoing simultaneous pancreas-kidney transplant.

In the aggregate, these findings suggest that, in the absence of surgical and immunosuppression-related complications, a functioning pancreas allograft can alter the progress of diabetic complications. As an extension of these results, pancreas transplant done earlier in the course of diabetes may have an even greater impact.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 58-year-old man with a history of cystoprostatectomy for prostate cancer, end-stage renal disease on hemodialysis, and distal ureteral obstruction requiring bilateral nephrostomy tubes noticed that one of the nephrostomy bags looked “purple” (Figure 1). A specimen collected from one bag was reddish purple (Figure 2). The urine in the other bag was normal. The condition was diagnosed as purple urine bag syndrome.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome, a relatively rare condition that appears after 2 to 3 months of indwelling urinary catheterization, is usually asymptomatic, the only signs being the purplish urine and staining of the urinary bags and catheters. However, it should be considered a sign of underlying urinary tract infection, which can disseminate causing local complications (Fournier gangrene), systemic complications (septicemia), and death.^1–3

The syndrome, first described in 1978 in children with spina bifida and urinary diversion,⁴ is more prevalent in women than in men, possibly because of the shorter urethra and closer proximity to the anus, which predispose women to bacterial colonization of the urinary tract. Predisposing conditions include dementia,⁵ female sex, increased dietary tryptophan, bacteriuria, urinary tract infection, constipation, older age, immobility, and alkaline urine.^6–8

The cause of the discoloration

The purple color is from indigo and indirubin compounds in the urine, the result of the breakdown of dietary tryptophan. The color varies depending on the proportions of the two pigments.

Dietary tryptophan is broken down into indole by colonic bacteria. After reaching the portal circulation, it is excreted into the urine as indoxyl sulfate, which is broken down to indoxyl by sulfatase-producing bacteria (eg, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Providencia species, Morganella morganii). Indoxyl is then oxidized to indigo and indirubin.

These compounds do not discolor the urine directly, but rather precipitate after interacting with the lining of the urinary catheter and bags, thereby imparting a purple color.^1,9–13

Management

Effective initial measures are improved urinary hygiene (eg, frequent, careful changing of the urinary catheter) and management of constipation, as constipation leads to increased colonization of the intestine by bacteria that metabolize dietary tryptophan into indoxyl. Antibiotics should be given for symptomatic urinary tract infection (fever, increased urinary frequency, dysuria, abdominal pain) but not for color change alone. Coverage should be for gram-negative bacilli, although methicillin-resistant Staphylococcus aureus, which is gram-positive, has also been reported to cause purple urine bag syndrome.

In most cases, purple urine bag syndrome is benign and requires no therapy other than that mentioned above.^3,13–15 However, in rare cases, immunocompromised patients (eg, people with diabetes) can develop local complications and sepsis from dissemination of bacterial infection, requiring aggressive therapy.¹⁴ Therefore, purple urine bag syndrome should be recognized as an indicator of an underlying urinary tract infection and should be treated if symptomatic. Nevertheless, the long-term prognosis is generally good.

OUR PATIENT’S MANAGEMENT

Our patient was confirmed to have urinary colonization with P aeruginosa and E coli, and alkaline urine. He underwent replacement of the nephrostomy tubes and urinary bag during his hospital stay (he was already in the hospital for another indication), but he continued to produce purple-colored urine from his right side and normal-colored urine from his left side. The unilateral involvement was likely from selective colonization of the right-sided nephrostomy tube with gram-negative bacteria.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

A 64-year-old man was admitted for extensive painful ulceration of the left lower leg (Figure 1) that occurred after a fall and that had worsened over the last 4 months.

His medical history included hyperuricemia, hypertension, and type 2 diabetes mellitus. He had no known cardiac or renal disease.

Results of initial laboratory testing showed the following:

• Hemoglobin 10.9 g/dL (reference range 13.5–17.5); red blood cells were normocytic and normochromic
• White blood cell count 10.2 × 10⁹/L (4.5–11.0)
• Neutrophil count 9.11 × 10⁹/L (2.0–8.5)
• C-reactive protein 259 mg/L (< 5)
• Creatinine, urea, sodium, potassium, calcium, and phosphate were within normal limits.

Doppler ultrasonography of the legs showed mild diffuse atheromatous arterial disease without significant blockage of blood flow, in addition to mild bilateral venous insufficiency.

Cutaneous biopsy showed intravascular calcium deposition in the hypodermis (Figure 2) and reticular dermis, erythrocyte extravasation in the superficial dermis, and epidermal necrosis, thus establishing the diagnosis of nonuremic calciphylaxis. The vascular occlusion with spreading necrosis gave the characteristic stellate appearance.

Aside from diabetes, our patient had none of the conditions usually associated with nonuremic calciphylaxis—namely, hyperparathyroidism, previous corticosteroid therapy, warfarin use, connective tissue disease, or malignancy.

A POORLY UNDERSTOOD SMALL-VESSEL VASCULOPATHY

Calciphylaxis is a poorly understood small-vessel vasculopathy, most often associated with end-stage renal disease, with a prevalence of 1% to 4% in patients on dialysis.¹ It carries a high risk of death, most often from sepsis.

The cause is still unclear, but several conditions have been implicated, including primary hyperparathyroidism, malignancies, alcoholic liver disease, connective tissue disease, and diabetes.²

Making the diagnosis may be challenging, especially in nonuremic patients. It is a rare condition, the presentation is not always typical, and it can occur with fully normal kidney function and normal indicators of calcium and phosphate metabolism.

The differential diagnosis includes:

• Vasculitis, either primary or secondary to an autoimmune disorder such as rheumatoid arthritis, systemic lupus erythematosus, or cryoglobulinemia
• Peripheral vascular disease
• Other inflammatory conditions such as pyoderma gangrenosum and panniculitis
• Infections such as cellulitis and necrotizing fasciitis
• Iatrogenic disorders such as warfarin necrosis and early-stage nephrogenic systemic fibrosis.^3,4

The current approach to treatment is multidisciplinary and is based only on case reports and small case series, since no randomized prospective trial has been done. The goal is optimal control of calcium and phosphate homeostasis and correction of hypercoagulability.⁵ Available data^4,5 support appropriate wound care and surgical debridement.^4,5 Intravenous sodium thiosulfate is the most widely used medical treatment and can be given regardless of the level of renal function. Resolution rates have been greater than 90% in patients with normal renal function, whereas improvement in cutaneous ulcers and pain has been observed in 70% of hemodialysis patients.⁴ However, it does not reduce the associated mortality rate.⁴

Awareness of nonuremic calciphylaxis and a high index of suspicion are needed when any patient presents with a leg ulcer and no clear cause. It should be considered in the differential diagnosis of leg ulcer in patients with chronic renal failure even if they have risk factors for more common causes of ulcers, and even occasionally in patients such as ours without chronic kidney disease or other risk factors for this condition.

OUR PATIENT’S MANAGEMENT

The patient developed profuse diarrhea, and infection with Clostridium difficile was confirmed. Despite treatment with metronidazole and vancomycin, he died several days later. No treatment directed to calciphylaxis was ever started because of the patient’s unstable condition during the entire hospitalization.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

Most patients with proteinuria benefit from a renin-angiotensin-aldosterone system (RAAS) inhibitor. Exceptions due to adverse effects are discussed below.

WHY RAAS INHIBITORS?

RAAS inhibitors—particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—reduce proteinuria and slow the progression of chronic kidney disease by improving glomerular hemodynamics, restoring the altered glomerular barrier function, and limiting the nonhemodynamic effects of angiotensin II and aldosterone, such as fibrosis and vascular endothelial dysfunction.¹ Studies have shown that these protective effects are, at least in part, independent of the reduction in systemic blood pressure.^2,3

EVIDENCE FOR USING RAAS INHIBITORS IN PATIENTS WITH PROTEINURIA

In nondiabetic kidney disease, there is strong evidence from the REIN and AASK trials that treatment with ACE inhibitors results in slower decline in glomerular filtration rate (GFR), and this risk reduction is more pronounced in patients with a higher degree of proteinuria.^4–6

In type 1 diabetes, treatment with an ACE inhibitor in patients with overt proteinuria was associated with a 50% decrease in the risk of the combined end point of death, dialysis, or renal transplant.⁷ Patients with moderately increased albuminuria who were treated with an ACE inhibitor also had a reduced incidence of progression to overt proteinuria.⁸ Angiotensin inhibition may be beneficial even in normotensive patients with type 1 diabetes and persistent moderately increased albuminuria.^9,10

In type 2 diabetes, the IDNT and RENAAL trials showed that treatment with an ARB in patients with overt nephropathy was associated with a statistically significant decrease (20% in IDNT, 16% in RENAAL) in the risk of the combined end point of death, end-stage renal disease, or doubling of serum creatinine.^11,12 While there are more data for ARBs than for ACE inhibitors in type 2 diabetes, the DETAIL study showed that an ACE inhibitor was at least as effective as an ARB in providing long-term renal protection in type 2 diabetes and moderately increased albuminuria.¹³

Data are limited on the role of angiotensin inhibition in normotensive patients with type 2 diabetes and persistent moderately increased albuminuria, but consensus opinion suggests treatment with an ACE inhibitor or ARB in these patients if there are no contraindications.

LIMITATIONS

Adverse effects of ACE inhibitors and ARBs include cough (more with ACE inhibitors), angioedema (more with ACE inhibitors), and hyperkalemia.

The use of ARBs in patients with a history of ACE inhibitor-related angioedema has been previously discussed in this Journal.¹⁴ Guidelines advocate caution when prescribing ARBs for patients who will benefit from RAAS inhibition and have had ACE inhibitor-related angioedema.¹⁵

These drugs should be instituted and continued in patients with proteinuria who can tolerate them without adverse effects.

RAAS inhibitor therapy can cause a modest rise in creatinine due to reduction in intraglomerular pressure. An elevation in creatinine of up to 30% that stabilizes in the first 2 months is not necessarily a reason to discontinue therapy. However, a continued rise in creatinine should prompt evaluation for excessive fall in blood pressure (especially with volume depletion from concomitant diuretic use), possible bilateral renal artery stenosis, or both. There is no level of GFR or serum creatinine at which an ACE inhibitor or ARB is absolutely contraindicated, and this decision should be made on an individual basis in conjunction with a nephrologist.

Risks for hyperkalemia should always be kept in mind at lower GFR levels. It would be prudent to check serum creatinine and potassium levels within the first week or two after starting or intensifying RAAS inhibition in these patients.

CAUTION

Combination therapy with an ACE inhibitor and an ARB was hypothesized to provide more complete RAAS blockade, with the hope of better clinical outcomes. However, this strategy has been questioned with results from three studies—ONTARGET, ALTITUDE, and the VA NEPHRON-D study—all of which showed worse renal outcomes, hypertension, and hyperkalemia with use of dual RAAS blockade.^16–20 The combined evidence so far suggests that dual RAAS blockade should not be routinely prescribed.

RAAS INHIBITION IN PRACTICE

RAAS inhibition should be instituted and continued in patients with proteinuria who are able to tolerate the therapy and do not experience adverse effects as discussed above. Although there is no specific consensus guideline on the frequency of assessment of albumin excretion after diagnosis of albuminuria and institution of RAAS inhibition and blood pressure control in patients with diabetes, periodic surveillance at least once a year is reasonable to assess response to therapy and possible disease progression.²¹ If there is significant proteinuria or possibility of nondiabetic kidney disease, the patient should be referred to a nephrologist.

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.

What Matters prides itself on reviewing the literature and presenting thoughtful commentary on articles that are relevant and applicable to the practicing clinician. We separate the wheat from the chaff. We are not, however, above taking on attention-grabbing articles.

Over the years, this column has reported on various methods to facilitate the expulsion of kidney stones, including tamsulosin, phosphodiesterase type 5 (PDE5) inhibitors, and steroids. But this one called out for our assessment: sex to expel kidney stones. Erroneously perceived prurient interests must be forgiven.

Dr. Omer Gokhan Doluoglu of the Clinic of Ankara (Turkey) Training and Research Hospital and colleagues conducted a randomized trial evaluating the effectiveness of sexual intercourse, tamsulosin, or standard medical therapy for kidney stone expulsion (Urology. 2015;86[1]:19-24). Potential subjects were eligible for inclusion if they had radiopaque distal ureteral stones. Subjects were excluded if the stones were larger than 6 mm.

Subjects were randomized to encouragement to have sexual intercourse at least three times per week, tamsulosin 0.4 mg/day, or symptomatic therapy alone. All patients received an antispasmodic and an anti-inflammatory, and were told to drink 2 L of water per day. Sexual intercourse and masturbation were prohibited in groups 2 and 3 during the treatment period, which lasted 4 weeks.

Ninety patients were randomized to the three groups. The mean stone size was 4.7-5.0 mm and not significantly different between the groups.

At 2 weeks, 83.9% (26 of 31) of the patients in the intercourse group, 47.6% (10 of 21) in the tamsulosin group, and 34.8% (8 of 23) passed the stones (P = .001). There was no difference between the groups at 4 weeks. Mean expulsion times were 10 days, 16.6 days, and 18 days, respectively (P = .0001).

The study’s authors propose that nitrous oxide is operant here by causing ureteric relaxation when released to create penile tumescence and during sexual activity. Because masturbation could achieve the same effect, patients in the other groups were told they could not. How effective this instruction was in the current study is unknown, because only “sexual intercourses” were collected on follow-up.

The random-envelope method used is less than ideal, and no data were reported on differences in the number of sexual experiences between groups. If we assume for a moment that a real effect exists, one is left wondering if more would be better. Does the requirement of a partner decrease the likelihood of more frequent stone-expelling sexual experiences? If our patients do not have sexual partners, do we not share these data with them?

And if we use PDE5 inhibitors and encourage sexual activity, do we … kill two birds with one stone?

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no relevant financial disclosures about this article. Follow him on Twitter @jonebbert.