Advertisement
Mayo Clinic Proceedings Home

Pancreas Transplantation for the Prevention of Diabetic Nephropathy

      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 of intensive 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 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.
      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)
      Type 1 diabetes mellitus affects more than 1 million people in the United States.
      • 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.
      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.
      • American Diabetes Association
      Standards of medical care for patients with diabetes mellitus.
      Historical data suggest that 20% to 30% 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
      • Andersen AR
      • Christiansen JS
      • Andersen JK
      • Kreiner S
      • Deckert T
      Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study.
      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.
      • Port FK
      • Wolfe RA
      • Mauger EA
      • Berling DP
      • Jiang K
      Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients.
      The economic cost is substantial. In the United States in 1991, the cost of treating diabetic patients with ESRD was more than $2 billion.
      • Nelson RG
      • Knowler WC
      • Pettitt DJ
      • Bennett PH
      Kidney diseases.
      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.
      • Basadonna G
      • Matas AJ
      • Gillingham K
      • et al.
      Kidney transplantation in patients with type I diabetes: 26-year experience at the University of Minnesota.
      Unfortunately, the waiting time for a cadaveric kidney is increasing constantly. Currently, there are more than 40,000 patients waiting, with only 8000 kidneys available annually, and the number of patients has grown while the supply of donor organs has remained stable.
      • Tilney NL
      A crisis in transplantation: too much demand for too few organs.
      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.
      • Bilous RW
      Can we prevent or delay diabetic nephropathy?.
      Figure thumbnail gr1
      Fig. 1Schematic representation of typical progression of albumin excretion 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
      • Molitch ME
      Management of early diabetic nephropathy.
      with permission). IDDM = insulin-dependent diabetes mellitus.
      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).
      • Bilous RW
      Can we prevent or delay diabetic nephropathy?.
      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),
      • Fioretlo P
      • Steffes MW
      • Mauer M
      Glomerular structure in non-protcinuric IDDM patients with various levels of albuminuria.
      while urinary albumin excretion (UAE) remains normal and the GFR is elevated (GFR, >100 mL/min per surface area [SA]). In stage III, which typically develops after more than 7 years of diabetes, UAB is elevated (UAE, 30–300 mg/24 h; referred to as microalbuminuria), but the dipstick for urinary protein remains negative. Measuring UAE in the micro albuminuria phase allows practitioners to detect early diabetic nephropathy. Although microalbuminuria may decrease with angiotensin-converting enzyme (ACE) inhibitor therapy,
      • Viberti G
      • Mogensen CE
      • Groop LC
      • Pauls JF
      • European Microalbuminuria Captopril Study Group
      Effect of caplopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.
      without intervention the UAE will increase at a rate of approximately 20
      • Borch-Johnsen K
      • Wenzel H
      • Viberti GC
      • Mogensen CE
      Is screening and intervention for microalbuminuria worthwhile in patients with insulin dependent diabetes? [published correction appears in BMJ. 1993;307:5437.
      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 10 years after the onset of diabetes. Stage IV is overt nephropathy. At this stage, a urinary dipstick will be positive for albumin (UAE, >300 mg/24 h; referred to as macroalbuminuria 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 10 mL/min per year.
      • Viberti GC
      • Bilous RW
      • Mackintosh D
      • Keen H
      Monitoring glomerular function in diabetic nephropathy : a prospective study.
      Because of hyperfiltration of early diabetic nephropathy, the GFR in this stage may first decrease into the reference range (GFR, 70–100 mL/min per SA). With no treatment, overt nephropathy will progress to uremia in 7 to 10 years (GFR, <20 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 20 to 30 years (Figure 1).
      Table 1Stages of Diabetic Nephropathy
      StageUrinary albumin (mg/24 h)Renal changesPathologic changesReversible
      I<30HyperfiltrationNoneYes
      II<30HyperfiltrationIncreased mesangial volumeYes
      III30-300HyperfiltrationIncreased mesangial matrix, sclerosis?
      IV>300Normal to decliningProgressive sclerosis?
      VVariableRenal failureFibrosis, sclerosisNo
      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 severe hypertension, very poor glycemic control, volume of urine, and the presence of urinary tract infections.
      • Kimmelstiel P
      • Wilson C
      Intercapillary lesions in the glomeruli of K kàney.
      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 30 to 300 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.
      • 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.
      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.
      • Bilous RW
      • Maucr SM
      • Sutherland DER
      • Najarian JS
      • Goetz FC
      • Steffes MW
      The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
      • Barbosa J
      • Steffes MW
      • Sutherland DER
      • Connett JE
      • Rao KV
      • Mauer SM
      Effect of glycémie control on early diabetic renal lesions: a 5-year randomized controlled clinical trial of insulin-dependent diabetic kidney transplant recipients.
      • Remuzzi G
      • Ruggenenti P
      • Benigni A
      Understanding the nature of renal disease progression.
      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.
      • Fioretlo P
      • Steffes MW
      • Mauer M
      Glomerular structure in non-protcinuric IDDM patients with various levels of albuminuria.
      Indeed, some patients with normal UAE have the morphologic changes of diabetes, whereas some with increased UAE G have normal morphology. In advanced disease, 2 pathologic changes predominate: diffuse glomerulosclerosis and nodular glomerulosclerosis (Kimmelstiel-Wilson bodies) (Figure 2).
      Figure thumbnail gr2
      Fig. 2Glomerulus in a patient with advanced diabetic nephropathy, showing the classic Kimmelstiel-Wilson bodies (arrow) (hematoxylin-eosin stain, original magnification x100).
      Physiologically, early diabetic kidney disease is associated with glomerular hyperfiltration, which is mediated by glomerular hyperperfusion and increased glomerular hydraulic pressure.
      • Mogensen CE
      Glomerular hyperfiltration in human diabetes.
      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, <40 mg/24 h).
      • Diabetes Control and Complications Trial Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellius.
      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. 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 7.0% (reference range, 4.0%-7.0%). 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.
      The absence of a glycémie threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial.
      Smoking cessation may decrease the risk of development of diabetic nephropathy.
      • Chase HP
      • Garg SK
      • Marshall G
      • et al.
      Cigarette smoking increases the risk of albumitturia among subjects with type 1 diabetes.
      The combination of smoking and poor glycemic control seems to be particularly damaging. Every attempt should be made to encourage patients with type 1 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.
      • Diabetes Control and Complications Trial Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellius.
      The absence of a glycémie threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial.
      In that trial, 73 patients had a baseline UAE of 40 to 200 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 of patients with a baseline UAE of 40 to 286 mg/24 h also failed to show any effect of improved glycemic control after 5 years.
      • Microalbuminuria Collaborative Study Group, United Kingdom
      Intensive therapy and progression to clinical albuminuria in patients with insulin dependent diabetes mellilus and microalbuminuria.
      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 micro albuminuria, while others had normal UAE. AE.
      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.
      • FeLcdt-Rasmussen B
      • Mathiesen ER
      • Jensen T
      • Laurizen T
      • Decken T
      Effect of improved metabolic control on loss of kidney function in type 1 (insulin-dependent) diabetic patients: an update of the Steno studies.
      These studies identified patients with high-range microalbuminuria (UAE, 100–300 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 10 of 10 patients, respectively).
      Several studies suggest that treatment with ACE inhibitors decreases the progression from microalbuminuria to clinical albuminuria.
      • Bilous RW
      Can we prevent or delay diabetic nephropathy?.
      • Viberti G
      • Mogensen CE
      • Groop LC
      • Pauls JF
      • European Microalbuminuria Captopril Study Group
      Effect of caplopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.
      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 II.
      • Wolf G
      Molecular mechanisms of angiotensin II in the kidney: emerging role in the progression of renal disease: beyond haemo-dynamics.
      A combined analysis of a European and a North American study of 2 years of ACE inhibitor therapy vs placebo (116 vs 119 “normotensive” patients with albuminuria) showed a 62.9% risk reduction (8 vs 25 patients) for the development of nephropathy.
      • Kalil RS
      • MaMa JZ
      • Liao M
      • Keane WF
      Effect of anlihypcrtcnsivc therapy on the kidney in patients with diabetes: a meta-rcgrcssion analysis.
      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 microalbuminuria to macroalbuminuria.
      • Ravid M
      • Lang R
      • Rachmani R
      • Lishncr M
      I-ong-tcrm rcno-protcctive effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mcllitus: a 7-ycar follow-up study.
      However, ACE inhibitors may only delay 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 20 years.
      • Krolewski AS
      • Warram JH
      Natural history of diabetic ncphrop-athy: how much can it be changed?.
      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.
      • 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.

      PREVENTION OF ESRD IN PATIENTS WITH CLINICAL ALBUMINURIA

      The development of clinical albuminuria (UAE, >300 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 function. In some patients, renal failure may occur in a few months, whereas others may have relatively 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 10% 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%,
      • Kalil RS
      • MaMa JZ
      • Liao M
      • Keane WF
      Effect of anlihypcrtcnsivc therapy on the kidney in patients with diabetes: a meta-rcgrcssion analysis.
      whereas it was 11.8% in a similar study involving patients with clinical albuminuria.
      • Lewis EJ
      • Hunsicker LG
      • Bain RP
      • Rohde RD
      • Collaborative Study Group
      The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy [published correction appears in N Engt J Med. 1993:330:152].
      Patients with more advanced nephropathy may have a higher incidence of smoking and noncompliance with treatment recommendations. Thus, these patients may represent a fundamentally different patient population than those with less advanced kidney disease.
      In light of the advanced state of the underlying renal lesions, it is not surprising that most studies of intensive insulin therapy in patients with clinical albuminuria have shown no effect on progression to ESRD. Again, these studies are small, and the glycemic control was not normal. However, other microvascular 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, patients with type 1 diabetes who had a UAE of 500 mg/24 h or greater and a serum creatinine of 2.5 mg/dL, or less were randomized to receive either captopril (n=207) or placebo (n=202).
      • Lewis EJ
      • Hunsicker LG
      • Bain RP
      • Rohde RD
      • Collaborative Study Group
      The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy [published correction appears in N Engt J Med. 1993:330:152].
      A total of 301 patients completed 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 doubling of the baseline serum creatinine concentration to at least 2.0 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=.007; Figure 3). The positive effect of captopril was dependent on the baseline serum creatinine level. In the 102 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 50%(40% vs 80%; P<.001). This subgroup of patients obviously 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 307 patients with a baseline serum creatinine <1.5 mg/dL). However, in the 3-year follow-up of the study, only 10% of 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.
      Figure thumbnail gr3
      Fig. 3Cumulative incidence of the doubling of baseline serum creatinine concentrations in patients with clinical diabetic nephropathy treated with either captopril or placebo.
      (from Lewis et
      • Lewis EJ
      • Hunsicker LG
      • Bain RP
      • Rohde RD
      • Collaborative Study Group
      The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy [published correction appears in N Engt J Med. 1993:330:152].
      with permission)
      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 (20 of 207 [10%] vs 31 of 202 [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 10 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.
      • Parving HH
      • Rossing P
      • Hommcl E
      • Smidt UM
      Angiotensin-converting enzyme inhibition in diabetic nephropathy: ten years' experience.
      • Mulee H
      • Johnsen SA
      • Bjorck S
      Long-term cnalapril treatment in diabetic nephropathy.
      • Parving HH
      • Andersen AR
      • Smidt UM
      • Hommel E
      • Mathiesen ER
      • Svendsen PA
      Effect of antihypcrtensive treatment on kidney function and diabetic nephropathy.
      • Bjorck S
      • Mulec H
      • Johnsen SA
      • Norden G
      • Aurell M
      Renal protective effect of enalapril in diabetic nephropathy.
      • Laffel LMB
      • McGill JB
      • Gans DJ
      • North American Microalbuminuria Study Group
      The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria.
      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.
      • Pedrini MT
      • Levey AS
      • La J
      • Chalmers TC
      • Wang PH
      The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis.
      The relative risk of progression among 108 dietary-restricted patients was almost 50% (relative risk, 0.56; 95% confidence interval, 0.40–0.77) 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.
      • Stcgall MD
      • Simon M
      • Wachs ME
      • Chan L
      • Nolan C
      • Kam I
      Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.
      This glycosylated hemoglobin level is within the reference range of 4.0% to 7.0% 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 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 900 pancreas transplantations are performed each year, 90% of which are performed in conjunction with a kidney transplantation in patients with type 1 diabetes and renal failure.
      • Grucssner AC
      • Sutherland DER
      Pancreas transplants for United States (US) and non-US cases as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS).
      With 1-year pancreas graft survival rates of almost 90% at some centers, simultaneous pancreas-kidney transplantation is now widely accepted as the treatment of choice for patients with type 1 diabetes and kidney failure.
      • Stcgall MD
      • Simon M
      • Wachs ME
      • Chan L
      • Nolan C
      • Kam I
      Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.
      • Grucssner AC
      • Sutherland DER
      Pancreas transplants for United States (US) and non-US cases as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS).
      • Bartlett ST
      • Kuo PC
      • Johnson LB
      • Lim JW
      • Schweitzer EJ
      Pancreas transplantation at the University of Maryland.
      • Gruessner RWG
      • Burke GW
      • Stratta R
      • et al.
      A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation.
      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 100 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 50% of the grafts functioning after 5 years.
      • Gruessner RWG
      • Sutherland DER
      • Najarian JS
      • Dunn DL
      • Gruessner AC
      Solitary pancreas transplantation for nonuremic patients with labile insulin-dependent diabetes mellitus.
      With the introduction of more effective immunosuppressive therapy, the 1-year graft survival rate of solitary pancreas transplantation has improved to 80%-almost equal to that of the simultaneous pancreas-kidney procedure.
      • Gruessner RWG
      • Sutherland DER
      • Najarian JS
      • Dunn DL
      • Gruessner AC
      Solitary pancreas transplantation for nonuremic patients with labile insulin-dependent diabetes mellitus.
      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 .
      • Bilous RW
      • Maucr SM
      • Sutherland DER
      • Najarian JS
      • Goetz FC
      • Steffes MW
      The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
      • Bohman SO
      • Tyden G
      • Wilczek H
      • et al.
      Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.
      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.
      • Fioretto P
      • Steffes MW
      • Sutherland DER
      • Goetz FC
      • Mauer M
      Reversal of lesions of diabetic nephropathy after pancreas transplantation.
      Eight patients with type 1 diabetes without uremia who had successful functioning pancreas transplants were followed up for 10 years. At 5 years, the UAE and the glomerular mesangial volume were unchanged. However, 10 years after successful transplantation, both the UAE and the glomerular mesangial volume had decreased substantially (Figure 4).
      Figure thumbnail gr4
      Fig. 4Thickness of the glomerular basement membrane, thickness of the tubular basement membrane, mesangial fractional volume, and mesangial-matrix fractional volume at baseline and 5 and 10 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
      • Fioretto P
      • Steffes MW
      • Sutherland DER
      • Goetz FC
      • Mauer M
      Reversal of lesions of diabetic nephropathy after pancreas transplantation.
      with permission)
      That study provides hope that pancreas transplantation can reverse or prevent the progression of diabetic 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 UAE varied greatly within the group, from 5 to 1200 mg/24 h. Of importance, the UAE was greater than 30 mg/24 h in 5 patients at the time of pancreas transplantation. At 10 years, the UAE was decreased in all 5 of these patients, and in 3 it was lower than 30 mg/24 h. In 1 patient, the UAE decreased from 278 to 20 mg/24 hover 10 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 of normoglycemia may be necessary. Although these results are promising, they do not clearly define which patients with diabetic nephropathy should receive a pancreas 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 PANCREAS 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, >9.0%), and established diabetic nephropathy (U >100 mg/24 100 mg/24 h) because the major benefit of pancreas transplantation is likely to be 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 100 mg/24 h might include patients who will not experience kidney failure for many years. A GFR between 60 and 100 mL/min per SA·would 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 10 years and now may be less than 10% over 10 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%.
      • Bilous RW
      • Maucr SM
      • Sutherland DER
      • Najarian JS
      • Goetz FC
      • Steffes MW
      The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
      Lymphoproliferative disease is generally treated with immunosuppressive therapy, with a mortality rate of less than 10%. Furthermore, many of the current immunosuppressive drugs are nephrotoxic. Therefore, these deleterious effects may outweigh potential effects of improved glycemic control. Previous data
      • Bilous RW
      • Maucr SM
      • Sutherland DER
      • Najarian JS
      • Goetz FC
      • Steffes MW
      The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
      suggest that patients with a GFR greater than 80 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 1500 patients with type 1 diabetes are placed on the cadaveric kidney transplant waiting list, and the numbers are increasing. At the same time, more than 3000 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 nephropathy, we believe that a randomized trial assessing the risks and benefits of pancreas transplantation vs intensive medical therapy in patients with established but not end-stage diabetic nenhronathv should be considered.

      REFERENCES

        • 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 J Kidney Dis. 1995; 25: 107-112
        • American Diabetes Association
        Standards of medical care for patients with diabetes mellitus.
        Diabetes Care. 1994; 17: 616-623
        • Andersen AR
        • Christiansen JS
        • Andersen JK
        • Kreiner S
        • Deckert T
        Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study.
        Diabetologia. 1983; 25: 496-501
        • Port FK
        • Wolfe RA
        • Mauger EA
        • Berling DP
        • Jiang K
        Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients.
        JAMA. 1993; 270: 1339-1343
        • Nelson RG
        • Knowler WC
        • Pettitt DJ
        • Bennett PH
        Kidney diseases.
        in: National Diabetes Group Diabetes in America. 2nd ed. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethcsda, Md1995: 349-400
        • Basadonna G
        • Matas AJ
        • Gillingham K
        • et al.
        Kidney transplantation in patients with type I diabetes: 26-year experience at the University of Minnesota.
        Clin Transpl. 1992; : 227-235
        • Tilney NL
        A crisis in transplantation: too much demand for too few organs.
        Transplant Rev. 1998; 12: 112-120
        • Molitch ME
        Management of early diabetic nephropathy.
        Am J Med. 1997; 102: 392-398
        • Bilous RW
        Can we prevent or delay diabetic nephropathy?.
        J R Coil Physicians Land. 1997; 31: 22-27
        • Fioretlo P
        • Steffes MW
        • Mauer M
        Glomerular structure in non-protcinuric IDDM patients with various levels of albuminuria.
        Diabetes. 1994; 43: 1358-1364
        • Viberti G
        • Mogensen CE
        • Groop LC
        • Pauls JF
        • European Microalbuminuria Captopril Study Group
        Effect of caplopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria.
        JAMA. 1994; 271: 275-279
        • Borch-Johnsen K
        • Wenzel H
        • Viberti GC
        • Mogensen CE
        Is screening and intervention for microalbuminuria worthwhile in patients with insulin dependent diabetes? [published correction appears in BMJ. 1993;307:5437.
        BMJ. 1993; 306: 1722-1725
        • Viberti GC
        • Bilous RW
        • Mackintosh D
        • Keen H
        Monitoring glomerular function in diabetic nephropathy : a prospective study.
        Am J Med. 1983; 74: 256-264
        • Kimmelstiel P
        • Wilson C
        Intercapillary lesions in the glomeruli of K kàney.
        Am J Pathul. 1936; 12: 83-97
        • Bilous RW
        • Maucr SM
        • Sutherland DER
        • Najarian JS
        • Goetz FC
        • Steffes MW
        The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.
        N Engl J Med. 1989; 321: 80-85
        • Barbosa J
        • Steffes MW
        • Sutherland DER
        • Connett JE
        • Rao KV
        • Mauer SM
        Effect of glycémie control on early diabetic renal lesions: a 5-year randomized controlled clinical trial of insulin-dependent diabetic kidney transplant recipients.
        JAMA. 1994; 272: 600-606
        • Remuzzi G
        • Ruggenenti P
        • Benigni A
        Understanding the nature of renal disease progression.
        Kidney Int. 1997; 51: 2-15
        • Mogensen CE
        Glomerular hyperfiltration in human diabetes.
        Diabetes Care. 1994; 17: 770-775
        • Diabetes Control and Complications Trial Research Group
        The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellius.
        N Engl J Med. 1993; 329: 977-986
      1. The absence of a glycémie threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial.
        Diabetes. 1996; 45: 1289-1298
        • Chase HP
        • Garg SK
        • Marshall G
        • et al.
        Cigarette smoking increases the risk of albumitturia among subjects with type 1 diabetes.
        JAMA. 1991; 265: 614-617
        • Microalbuminuria Collaborative Study Group, United Kingdom
        Intensive therapy and progression to clinical albuminuria in patients with insulin dependent diabetes mellilus and microalbuminuria.
        BMJ. 1995; 311: 973-977
        • FeLcdt-Rasmussen B
        • Mathiesen ER
        • Jensen T
        • Laurizen T
        • Decken T
        Effect of improved metabolic control on loss of kidney function in type 1 (insulin-dependent) diabetic patients: an update of the Steno studies.
        Diabelohgia. 1991; 34: 164-170
        • Wolf G
        Molecular mechanisms of angiotensin II in the kidney: emerging role in the progression of renal disease: beyond haemo-dynamics.
        Nephrol Dial Transplant. 1998; 13: 1131-1142
        • Kalil RS
        • MaMa JZ
        • Liao M
        • Keane WF
        Effect of anlihypcrtcnsivc therapy on the kidney in patients with diabetes: a meta-rcgrcssion analysis.
        Ann Intern Med. 1993; 118: 129-138
        • Ravid M
        • Lang R
        • Rachmani R
        • Lishncr M
        I-ong-tcrm rcno-protcctive effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mcllitus: a 7-ycar follow-up study.
        Arch Intern Med. 1996; 156: 286-289
        • Krolewski AS
        • Warram JH
        Natural history of diabetic ncphrop-athy: how much can it be changed?.
        Diabetes Rev. 1995; 3: 446-459
        • Lewis EJ
        • Hunsicker LG
        • Bain RP
        • Rohde RD
        • Collaborative Study Group
        The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy [published correction appears in N Engt J Med. 1993:330:152].
        N Engl J Med. 1993; 329: 1456-1462
        • Parving HH
        • Rossing P
        • Hommcl E
        • Smidt UM
        Angiotensin-converting enzyme inhibition in diabetic nephropathy: ten years' experience.
        Am J Kidney Dis. 1995; 26: 99-107
        • Mulee H
        • Johnsen SA
        • Bjorck S
        Long-term cnalapril treatment in diabetic nephropathy.
        Kidney Int Suppl. 1994; 45: S141-S144
        • Parving HH
        • Andersen AR
        • Smidt UM
        • Hommel E
        • Mathiesen ER
        • Svendsen PA
        Effect of antihypcrtensive treatment on kidney function and diabetic nephropathy.
        BMJ. 1987; 294: 1443-1447
        • Bjorck S
        • Mulec H
        • Johnsen SA
        • Norden G
        • Aurell M
        Renal protective effect of enalapril in diabetic nephropathy.
        BMJ. 1992; 304: 339-343
        • Laffel LMB
        • McGill JB
        • Gans DJ
        • North American Microalbuminuria Study Group
        The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria.
        Am J Med. 1995; 99: 497-504
        • Pedrini MT
        • Levey AS
        • La J
        • Chalmers TC
        • Wang PH
        The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis.
        Ann Intern Med. 1996; 124: 627-632
        • Stcgall MD
        • Simon M
        • Wachs ME
        • Chan L
        • Nolan C
        • Kam I
        Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine.
        Transplantation. 1997; 64: 1695-1700
        • Grucssner AC
        • Sutherland DER
        Pancreas transplants for United States (US) and non-US cases as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS).
        Clin Transpl. 1997; : 45-59
        • Bartlett ST
        • Kuo PC
        • Johnson LB
        • Lim JW
        • Schweitzer EJ
        Pancreas transplantation at the University of Maryland.
        Clin Transpl. 1996; : 271-280
        • Gruessner RWG
        • Burke GW
        • Stratta R
        • et al.
        A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation.
        Transplantation. 1996; 61: 261-273
        • Gruessner RWG
        • Sutherland DER
        • Najarian JS
        • Dunn DL
        • Gruessner AC
        Solitary pancreas transplantation for nonuremic patients with labile insulin-dependent diabetes mellitus.
        Transplantation. 1997; 64: 1572-1577
        • Bohman SO
        • Tyden G
        • Wilczek H
        • et al.
        Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.
        Diabetes. 1985; 34: 306-308
        • Fioretto P
        • Steffes MW
        • Sutherland DER
        • Goetz FC
        • Mauer M
        Reversal of lesions of diabetic nephropathy after pancreas transplantation.
        N Engl J Med. 1998; 339: 69-75