Pancreas Transplantation for the Prevention of Diabetic Nephropathy

Pancreas Transplantation for the Prevention of Diabetic Nephropathy MARK D. STEGALL, MD; TIMOTHY S. LARSON, MD; YOGISH SCOTT L. NYBERG, MD, PHD; MIKEL PRIETO, MD; JORGE Diabetic nephropathy is the leading cause of kidney failure in the United States. Poor glycemic control, hypertension, and smoking have been implicated as risk factors for the development and progression of diabetic nephropathy in patients with type 1 diabetes mellitus. Improved medical therapy including angiotensin-converting enzyme inhibitors and tight glycemic control with use ofintensive insulin therapy have been shown to reduce the progression of diabetic nephropathy substantially based on albumin excretion rates. Despite these improvements in medical management, many patients still experience progression from early diabetic nephropathy to end-stage renal disease. Successful pancreas transplantation leads to normal glycemic A. VELOSA, MD; JOSEPH P. GRANDE, MD, PHD; MD; AND ROBERT A. RIZZA, MD control in patients with type 1 diabetes, but historically it has generally been limited to patients with both kidney failure and diabetes. In this review of the current treatment of diabetic nephropathy, we examine the potential role of preemptive pancreas transplantation in patients with diabetic nephropathy. Mayo Clin Proc. 2;75:49-56 ACE = angiotensin-converting enzyme; DCCT = Diabetes Control and Complications Trial; ESRD = end-stage renal disease; GFR =glomerular filtration rate; SA =surface area; UAE = urinary albumin excretion T ype 1 diabetes mellitus affects more than 1 million people in the United States. 1 Diabetic patients are at increased risk for developing blindness due to proliferative retinopathy, heart disease, stroke, peripheral vascular disease, debilitating neuropathies (autonomic and peripheral), infections, and kidney failure," Historical data suggest that 2% to 3% of diabetic patients will develop kidney disease over their lifetime, making it the most common cause of end-stage renal disease (ESRD) in the United States? The development of ESRD is a major source of not only morbidity but also mortality because patients with diabetes undergoing dialysis have a lower survival rate compared with nondiabetic patients." The economic cost is substantial. In the United States in 1991, the cost of treating diabetic patients with ESRD was more than $2 billion.' Because kidney transplantation seems to improve patient survival and is less costly than maintenance dialysis, kidney transplantation has been the treatment of choice for patients with ESRD due to diabetes." Unfortunately, the waiting time for a cadaveric kidney is increasing constantly. Currently, there are more than 4, patients waiting, with only 8 kidneys available annually, and the number of patients has grown while the supply of donor organs has remained stable.' Clearly, the current interest in therapies that prevent or at least slow the progression of diabetic nephropathy in patients with type 1 diabetes is warranted. The focus of this review is the current state of treatment of diabetic nephropathy, with special emphasis on the possible role of pancreas transplantation. DIABETIC NEPHROPATHY-DEFINITIONS, STAGES, AND PATHOLOGY In diabetic nephropathy, the causative agent, hyperglycemia, is identified almost from the beginning, an outcome facilitating a more complete characterization of the natural history of the disease over time (Figure 1). Classically, diabetic nephropathy has been categorized into 5 stages." Stage I is the onset of diabetic kidney disease. Renal function changes at this stage consist of an increased glomerular filtration rate (GFR) and kidney hypertrophy (Table 1).9 These changes are not clinically evident and may be reversible with good glycemic control. In stage II, renal morphologic changes begin to develop (eg, increases in glomerular basement membrane thickness and mesangial matrix volume), 1 while urinary albumin excretion (UAE) remains normal and the GFR is elevated (GFR, >1 ml/min per surface area [SA]). In stage III, which typically develops after more than 7 years of diabetes, UAE is elevated (UAE, 3-3 mg/24 h; referred to as microalbuminuria), but the dipstick for urinary protein remains negative. Measuring UAE in the microalbuminuria phase From the Division of Transplantation Surgery (M.D.S., S.L.N., M.P.), Division of Nephrology and Internal Medicine (T.S.L., JAV.), Division of Endocrinology, Metabolism, Nutrition and Internal Medicine (Y.C.K., R.A.R.), and Department of Laboratory Medicine and Pathology (J.P.G.), Mayo Clinic Rochester, Rochester, Minn. Address reprint requests and correspondence to Mark D. Stegall, MD, Division of Transplantation Surgery, Mayo Clinic Rochester, 2 First St SW, Rochester, MN 5595. Mayo Clin Proc. 2;75:49-56 C. KUDVA, 49 2 Mayo Foundation for Medical Education and Research

Mayo Clin Proc, January 2, Vol 75 Pancreas Transplantation 5 't:' s: 1 16 Glomerular filtration rate 14 g Ql! t: 3".1 8 8 Ql e 'E.Q1 4.1 :::> C 3 c.> j 2. «Ii> "T1 ::D 2 4 6 8 1 12 14 16 18 2 22 24 26 28 Duration of IDDM (yr) Figure 1.Schematic representation of typical progression of albuminexcretion rate and glomerular filtration rate (GFR) over time in a patient with diabetic nephropathy. Note that albuminuria exists for many years before GFR declines (from Molitch" with permission). IDDM = insulin-dependent diabetes mellitus. allows practitioners to detect early diabetic nephropathy. Although microalbuminuria may decrease with angiotensin-converting enzyme (ACE) inhibitor therapy, II without intervention the UAE will increase at a rate of approximately 2% per year." An increase in blood pressure is usually detectable once microalbuminuria exists. As shown schematically in Figure 1, this stage of nephropathy does not usually occur until at least 1 years after the onset of diabetes. Stage IV is overt nephropathy. At this stage, a urinary dipstick will be positive for albumin (UAE, >3 mg/24 h; referred to as macro albuminuria or clinical albuminuria). Kidney damage may be irreversible at this stage, and renal function starts to decline based on a gradual decrease of the GFR of 1 ml/min per year." Because of hyperfiltration of early diabetic nephropathy, the GFR in this stage may first decrease into the reference range (GFR, 7-1 ml/min per SA). With no treatment, overt nephropathy will progress to uremia in 7 to 1 years (GFR, <2 ml/min per SA). Stage V is ESRD that is characterized by minimal residual renal function requiring either dialysis or kidney transplantation. The usual time between diabetes onset and ESRD is 2 to 3 years (Figure 1). Clinically, a patient's classification is usually based on the degree of UAE. However, this approach has some limitations. The extent of albuminuria varies with many factors, including exercise, congestive heart failure, severe hypertension, very poor glycemic control, volume of urine, and the presence of urinary tract infections." Accurate serial 24-hour collections of urine can be difficult to obtain. Thus, many clinicians rely on the ratio of the urinary albumin to urinary creatinine in the first voided specimen of the morning as an index of UAE. A ratio of 3 to 3 mg of albumin to 1 g of creatinine is the microalbuminuria stage. A timed overnight urine collection can also be used instead of a 24-hour collection. The current recommendation is that tests for the determination of microalbuminuria be performed annually in postpubertal patients who have had diabetes for at least 5 years and in patients with onset of diabetes after age 18 years.' Testing is important because microalbuminuria is a strong predictor of progression to overt nephropathy, and early intervention with ACE inhibitors may delay or prevent progression. Pathologically, diabetic nephropathy is characterized by the accumulation of extracellular matrix in the glomerulus of a kidney.'>" This accumulation leads to increased glomerular mesangial volume and increased thickness of the glomerular capillary basement membrane. These changes can occur in the earliest stages of diabetic nephropathy, although they do not always correlate with the stages of albuminuria. to Indeed, some patients with normal UAE have the morphologic changes of diabetes, whereas some with increased UAE have normal morphology. In advanced disease, 2 pathologic changes predominate: diffuse glomerulosclerosis and nodular glomerulosclerosis (Kimmelstiel-Wilson bodies) (Figure 2). Physiologically, early diabetic kidney disease is associated with glomerular hyperfiltration, which is mediated by glomerular hyperperfusion and increased glomerular hydraulic pressure." Glomerular hypertension associated with hyperfiltration precedes albuminuria and is thought to have a role in the pathogenesis of glomerulosclerosis and subsequent decline in the GFR. Renal function as measured by the GFR or iothalamate clearance is usually well preserved until relatively late in the course of diabetic nephropathy (Figure 1). PREVENTION OF DIABETIC NEPHROPATHY IN PATIENTS WITHOUT ALBUMINURIA The causative event in diabetic nephropathy is prolonged hyperglycemia. Thus, the ideal treatment should be normal glucose control. The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive glycemic control can reduce the development of nephropathy by about 33% in patients with type 1 diabetes who have a brief duration of disease «5 years) and no evidence of nephropathy (UAE, <4 mg/24 h).19 However, there are several additional observations that should be mentioned concerning the intensive insulin therapy used in that study. First, the number of patients receiving intensive therapy who had episodes of severe hypoglycemia (coma or need for medical assistance) increased 4-fold. Second, most patients in the study gained weight (mean, 4.6 kg after 5 years). Third, glycosylated hemoglobin levels were not normal even with intensive insulin therapy, but were a mean of 7.% (refer-

Mayo Clin Proc, January 2, Vol 75 Pancreas Transplantation 51 Table 1. Stages of Diabetic Nephropathy Urinary albumin Stage (mg/24 h) Renal changes Pathologic changes Reversible I <3 Hyperfiltration None Yes II <3 Hyperfiltration Increased mesangial Yes volume III 3-3 Hyperfiltration Increased mesangial? matrix, sclerosis IV >3 Normal to declining Progressive sclerosis? V Variable Renal failure Fibrosis, sclerosis No ence range, 4.%-7.%). The DCCT Research Group concluded that there was no minimal glycemic threshold below which complications would not occur and thus recommended that patients attempt to achieve as tight glucose control as possible." Smoking cessation may decrease the risk of development of diabetic nephropathy." The combination of smoking and poor glycemic control seems to be particularly damaging. Every attempt should be made to encourage patients with type I diabetes to stop smoking. PREVENTION OF PROGRESSION FROM MICROALBUMINURIA TO CLINICAL NEPHROPATHY Microalbuminuria is usually the first clinical sign that diabetic nephropathy is present. During this stage, the GFR is usually normal or above normal (ie, hyperfiltration). Therapeutic aims are either the reversal of microalbuminuria or the prevention of progression to clinical albuminuria. Using these end points, data from several studies suggest that, at this early stage, diabetic nephropathy may be reversible. Attempts at improved glycemic control have shown variable results on the progression of microalbuminuria to macroalbuminuria. In the DCCT, intensive insulin therapy in patients with microalbuminuria at baseline did not significantly decrease the risk of progression to clinical albuminuria.p-" In that trial, 73 patients had a baseline UAE of 4 to 2 mg/24 h and were monitored for a mean of 6.5 years. There was no difference in progression to nephropathy between the intensively and conventionally treated groups. A subsequent United Kingdom study ono patients with a baseline UAE of 4 to 286 mg/24 h also failed to show any effect of improved glycemic control after 5 years." Part of the reason for this finding may be a function of statistical power. Another reason may be the length of follow-up; the duration of most of the earlier studies was brief. In addition, the patients were heterogeneous with respect to albuminuria-some had microalbuminuria, while others had normal UAE. In contrast, improved metabolic control with use of continuous insulin infusion pumps in the Steno studies resulted in a decrease in the number of patients who had progression of microalbuminuria to clinical albuminuria." These studies identified patients with high-range microalbuminuria (UAE, 1-3 mg/24 h) as the group with the greatest risk of progression at 5- and 8-year follow-up. Continuous subcutaneous insulin infusion in this highrange microalbuminuria group improved metabolic control and substantially decreased progression to nephropathy compared with conventional insulin treatment (2 of 9 patients vs 1 of 1 patients, respectively). Several studies suggest that treatment with ACE inhibitors decreases the progression from microalbuminuria to clinical albuminuria.v" This effect seems to be independent of the decrease in systemic blood pressure and is probably at least in part via reduction of glomerular capillary hypertension. Recent experimental evidence showing that angiotensin II promotes glomerular fibrosis suggests that ACE inhibitors also may have beneficial effects via direct blockade of angiotensin 11. 24 Figure 2. Glomerulus in a patient with advanced diabetic nephropathy, showing the classic Kimmelstiel-Wilson bodies (arrow) (hematoxylin-eosin stain, original magnification x 1).

Ma yo C1in Proc, January 2, Vol 75 Pancreas Transplantation 52 5 15 Cl. - 4 ::IC '"' "'".r:e 3 ;=.,. ).,., ) 2 -Ul Cas.,.n 1 Q...5 1. 1.5 2. 2.5 3. 3.5 4. 75 82 45 5 22 Yearsof follow-up Placebo Captopril 22 27 184 199 173 19 16 1 16 142 167 99 12 24 Figure 3. Cumulative incidence of the doubling of baseline serum crea tinine concentrations in pati ent s with clinical diabetic nephropath y treated with either captopril or placebo (from Lewis et af8with permission). A combined analysi s of a European and a North American study of 2 years of ACE inhibitor therap y vs placebo (116 vs 119 "normotensive" patients with albuminuria) showed a 62.9% risk reducti on (8 vs 25 patients ) for the development of nephropathy.25 Again, the brief duration of the study is a major drawback. A similar study of patients with type 2 diabetes showed that treatment with ACE inhibitors for 7 years substantially decreased progression from microal buminuria to macroalbuminuria." However, ACE inhibitors may on ly de lay the progression of nephropathy. The mean time from onset of albuminuria to progression to clinical nephropathy is approximately 7 years, while the interval from microalbuminuria to renal failure may be 2 years." Thus, long-term studies are needed to show that initiation of ACE inhibitors at the microalbuminuria stage prevents the development of renal failure. Despite these limitations, the use of ACE inhibitors in patients with microalbuminuria is becoming standard treatment. 1 PREVENTION OF ESRD IN PATIENTS WITH CLINICAL ALBUMINURIA The development of clinical albumin uria (UAE, >3 mg! 24 h) is believed to be the beginning of an inexorable slide to ESRD. The GFR is usually normal or higher than normal at the beginning of this stage, but it may begin to decline in the first few years after clinical albuminuria has developed. The major therapeutic aims at this stage are to stabilize UAE and to prevent progression to renal failure. When evaluating studies of this stage of diabetic nephropathy, it is important to note that patients may be heterogeneous with respect to renal functio n. In some patien ts, renal fail- ure may occur in a few month s, wherea s other s may have relati vely normal renal function for years. If diabetic nephropathy is left untreated at the clinical albuminuria stage, the GFR will eventually begin to decline at the rate of 5% to 1% per year until renal failure occurs. Patients with advanced diabetic nephropathy seem to have much poorer glycemic control than those with less severe kidney disease. For example, in 2 studies with captopril, the mean glycosylated hemoglobin level in patients with microalbuminuria was 8.1%,25 whereas it was 11.8% in a similar study involving patients with clinical albuminuria." Patients with more advanced nephropathy may have a higher incidence of smoking and noncompliance with treatment recommendations. Thus, these patient s may represent a fundamentally different patient population than those with less advanced kidney disease. In light of the advanced state of the underl ying renal lesions, it is not surprising that most studies of intensive insulin therapy in patients with clinical albuminuria have shown no effect on progre ssion to ESRD. Again, these studies are small, and the glycemic control was not normal. However, other micro vascular complications may respond differently even at this stage of albuminuria, and therefore tight glycemic control is still recommended in these patients. Treatment with ACE inhibitors seems to slow the progression from clinical albuminuria to renal failure. In a large prospective, double-blind multicenter study, patient s with type I diabetes who had a UAE of 5 mg/24 h or greater and a serum creatinine of 2.5 mg/dl or less were randomized to receive either captopril (n=27) or placebo (n=22).28 A total of 31 patients comp leted their final scheduled visit (median follow-up, 3 years; range, 1.8 to 4.8 years ). The primary end point of that study was a doubl ing of the baseline serum creat inine concentration to at least 2. mg!dl. The number of patients who reached each time point is shown in Figure 3 (two thirds were followed up for at least 2 years). In 25 patients in the captopril group and in 43 in the placebo group, serum creatinine concentrations doubled (P=.7; Figure 3). The positive effect of captopril was dependent on the baseline serum creatinine level. In the 12 patients with a baseline serum creatinine concentration of 1.5 mg!dl or greater, captopril decreased the rate of doubling of the serum creatinine by almost 5% (4% vs 8%; P<.OOl). This subgroup of patients obviousl y had advanced nephropathy, and thus a large percentage in both treatment groups had progression to kidney failure. In that same study, ACE inhibitors had no significant effect on the creatinine concentration in patients with less advanced nephropathy (P =.31 in 37 patients with a baseline serum creati nine <1.5 mg/dl). However, in the 3-year follow-up of the study, only 1% of

Mayo Clin Proc, January 2, Vol 75 patients in each treatment group with a baseline creatinine lower than 1.5 mg/dl had a doubling of the serum creatinine concentration. A longer follow-up might have shown an effect. In that same study, other end points were substantially improved in the ACE inhibitor group. The serum creatinine concentration and the UAE were appreciably lower in the captopril-treated group at the end of 3 years. In the captopril group, fewer patients had progression to dialysis or transplantation compared with those in the placebo group (2 of 27 [1%] vs 31 of 22 [15%]). When death was included, the differences were even more pronounced. Based on this relatively brief follow-up, captopril seems to be able to slow the progression to renal failure at least in patients with advanced nephropathy. The finding that captopril is more effective than placebo is important, but the continued progression in treated patients even during a relatively brief follow-up period suggests that captopril does not completely prevent renal failure in those with advanced nephropathy. It may only slow the progression to eventual renal failure. Extrapolation of data from these studies suggests that ACE inhibitors may slow the rate of decline of GFR in patients with clinical albuminuria, from the untreated rate of 1 to 14 ml/min per 1.73 m2 a year to a rate of 2 to 5 ml/min per 1.73 m2 a year.29-33 Most patients in the ACE inhibitor studies continued to have poor glycemic control, which might contribute to the continued deterioration of renal function. The combination of ACE inhibitors and improved glycemic control might have a greater effect on the progression of diabetic nephropathy than either strategy alone. The results of comparatively few published studies of protein restriction in diabetic patients can be summarized by the meta-analysis of 5 small studies." The relative risk of progression among 18 dietary-restricted patients was almost 5% (relative risk,.56; 95% confidence interval,.4-.77) compared with those who had a more liberal protein intake. POTENTIAL ROLE OF EARLY PANCREAS TRANSPLANTATION FOR DIABETIC NEPHROPATHY Successful vascularized pancreas transplantation provides essentially normal glycemic control for patients with type 1 diabetes. The glycosylated hemoglobin levels average 5.5% with almost no hypoglycemic episodes." This glycosylated hemoglobin level is within the reference range of 4.% to 7.% observed in patients without diabetes. Conversely, the glycosylated hemoglobin levels achieved in the best "tight control" studies such as the DCCT were only 7%. This near-normal glycosylated hemoglobin level resulted in only a one-third reduction in the Pancreas Transplantation 53 progression of diabetic nephropathy. Thus, two thirds of patients treated with intensive insulin regimens had progression of diabetic nephropathy. The degree of glycemic control achievable with pancreas transplantation may be necessary if a lower "glycemic threshold" is needed to prevent or reverse diabetic nephropathy. In the United States, more than 9 pancreas transplantations are performed each year, 9% of which are performed in conjunction with a kidney transplantation in patients with type 1 diabetes and renal failure." With 1year pancreas graft survival rates of almost 9% at some centers, simultaneous pancreas-kidney transplantation is now widely accepted as the treatment of choice for patients with type I diabetes and kidney failure.v" Pancreas transplantation in patients without kidney failure is more limited. The major indication for solitary pancreas transplantation in nonuremic patients has been "complicated" diabetes, especially hypoglycemic unawareness. In 1997, fewer than 1 pancreas transplantations were performed in diabetic patients without kidney failure. Historically, 1 reason for the limited application of solitary pancreas transplantation has been its poor success rate, with only 5% of the grafts functioning after 5 years." With the introduction of more effective immunosuppressive therapy, the I-year graft survival rate of solitary pancreas transplantation has improved to 8%-almost equal to that of the simultaneous pancreas-kidney procedure.'? The increasing success of pancreas transplantation is due to many factors, including improved immunosuppressive regimens, lower infection rates, and fewer surgical complications. Thus, the deleterious consequences of pancreas transplantation no longer seem to outweigh the positive effects of improved glycemic control. This improved success has led our group to consider expanding the indications for pancreas transplantation to include patients without kidney failure. Few studies have focused on the effect of pancreas transplantation on diabetic nephropathy. In studies of transplanted kidneys, successful pancreas transplantation has been shown to prevent or reverse the development of diabetic nephropathy.15,4 However, almost no data exist on the effect of pancreas transplantation on diabetic nephropathy in the native kidneys of nonuremic patients. Recently, a study suggested that successful pancreas transplantation can reverse diabetic nephropathy in native kidneys." Eight patients with type 1 diabetes without uremia who had successful functioning pancreas transplants were followed up for 1 years. At 5 years, the UAE and the glomerular mesangial volume were unchanged. However, 1 years after successful transplantation, both the UAE and the glomerular mesangial volume had decreased substantially (Figure 4).

54 Pancreas Transplantation Mayo Clin Proc, January 2, Vol 75... c CI) 8 'E _ 1,3 E- CI) E 7 CI) E lil.e..e. 1,1 ell CI) 6..o c III CI)... ell ". ell 5 c 9 ell....--=::::::::::::.. ell -........ ;: E : : 4 ell..o 7 CI) CI) - E :::::J CI) i E E 3.g E 5.!2 l- o o " " Baseline 5 years 1 years Baseline 5 years 1 years '.L.7 CI) x CI) E.35 _ :::::J 'i: E.55 /.... :::::J ell- Ill_.- 1> c _ E 's:i 2. >.25 ell ell.4 ell- III C.- ell Q) Olc :2:.. c i : - ell.-.25.15 <J lil- III CI) U... :2: Of Of Baseline 5 years 1 years Baseline 5 years 1 years Figure 4. Thickness of the glomerular basement membrane, thickness of the tubular basement membrane, mesangial fractional volume, and mesangial-matrix fractional volume at baseline and 5 and 1 years after pancreas transplantation. The mesangial fractional volume is the proportion of the glomerulus occupied by the mesangium; the mesangial-matrix fractional volume is the proportion of the glomerulus occupied by the mesangial matrix. The shaded areas represent the normal ranges obtained in 66 age- and sex-matched normal controls (mean ± 2 SD). Data for individual patients are connected by lines (from Fioretto et al" with permission). That study prov ides hope that pancreas transplantation can reverse or prevent the progression ofdiabetic nephropathy in native kidneys. The lack of an effect at 5 years underscores the importance of long-term follow-up. One limitation of that study is that patients were not prospectively selected because of diabetic nephropathy, but rather because of other diabetic complications. Indeed, the baseline DAE varied greatly within the group, from 5 to 12 mg/24 h. Ofimportance, the DAE was greater than 3 mg/24 h in 5 patients at the time of pancreas transplantation. At 1 years, the DAE was decreased in all 5 of these patients, and in 3 it was lower than 3 mg/24 h. In 1 patient, the DAE decreased from 278 to 2 mg/24 hover 1 years, whereas in another, it decreased from 1276 to 176 mg/24 h; in both patients, the creatinine clearance remained higher than 65 ml/min. These data suggest that pancreas transplantation may be effective even in advanced nephropathy, although many years ofnormoglycemia may be necessary. Although these results are prom ising, they do not clearly define which patients with diabetic nephropathy should receive a pan - creas transplant. Pancreas transplantation should not be used as treatment in all stages of diabetic nephropathy. Improvements in medical therapy, especially ACE inhibitors, suggest that pancreas transplantation is unnecessary for the treatment of early diabetic nephropathy. In contrast, pancreas transplantation in patients with far-advanced nephropathy may be ineffective because the kidney disease may be irreversible. Patients with advanced but not endstage nephropathy might benefit from the near-normal glycemic control that occurs with pancreas transplantation. IS IT TIME TO TEST THE HYPOTHESIS THAT THE BENEFITS OF PANC REAS TRANSPLANTATION OUTWEIGH THE RISKS IN CERTAIN PATIENTS? In the absence of a kidney biopsy, it is currently difficult to identify which patients have advanced but potentially reversible kidney disease. One such group may be patients with both persistent poor glycemic control, despite diabetes therapy (glycosylated hemoglobin, >9.%), and established diabetic nephropathy (UAE, >1 mg/24 h) because the major benefit of pancreas transplantation is likely to be

Mayo Clin Proc, January 2, Vol 75 due to improved glucose control. Therefore, patients with almost normal glycosylated hemoglobin levels presumably would be less likely to benefit from transplantation than those with poor glycemic control. Urinary albumin excretion of more than 1 mg/24 h might include patients who will not experience kidney failure for many years. A GFR between 6 and 1 ml/min per SAwould likely identify patients with substantial residual renal function who might benefit from a delay in the progression of diabetic nephropathy if improved glycemic control can produce such an effect. However, any potential benefits of pancreas transplantation must be weighed against the risks of surgery and immunosuppression. Transplant-related mortality has decreased over the past 1 years and now may be less than 1% over 1 years. The risk of the development of certain types of cancer with long-term immunosuppression has increased. Studies of solitary pancreas transplantation have suggested that the 5-year risk of posttransplantation lymphoproliferative disease developing is less than 1%.15 Lymphoproliferative disease is generally treated with immunosuppressive therapy, with a mortality rate of less than 1%. Furthermore, many of the current immunosuppressive drugs are nephrotoxic. Therefore, these deleterious effects may outweigh potential effects of improved glycemic control. Previous data's suggest that patients with a GFR greater than 8 ml/min per SA tolerate these drugs relatively well despite an early decrement in renal function. If pancreas transplantation can prevent the progression of diabetic nephropathy and if the benefits outweigh the risks, the implications for patients could be important. Each year, more than 15 patients with type I diabetes are placed on the cadaveric kidney transplant waiting list, and the numbers are increasing. At the same time, more than 3 cadaveric pancreas organs are discarded each year. Thus, it is theoretically possible to perform a pancreas transplantation in every patient with type 1 diabetes that will progress to ESRD. By performing transplantation in patients with earlier stages of nephropathy when they are healthier, both patient survival and pancreas graft survival might increase. In addition, the patient's quality of life might be better preserved, and progression of diabetic nephropathy to renal failure may occur in fewer patients. CONCLUSIONS Despite improvements in medical therapy for patients with diabetic nephropathy, increasing numbers of patients with type 1 diabetes develop ESRD each year. In light of the improved graft survival of solitary pancreas transplants and recent data showing that a successful pancreas transplantation can reverse the pathologic lesions of diabetic Pancreas Transplantation 55 nephropathy, we believe that a randomized trial assessing the risks and benefits of pancreas transplantation vs intensive medical therapy inpatients with established but not end-stage diabetic nephropathy should be considered. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 1. II. 12. 13. 14. 15. 16. 17. 18. 19. Bennett PH, Haffner S, Kasiske BL, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation. Am 1 Kidney Dis.1995;25:17-112. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 1994;17:616-623. 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