Course Authors
Eli A. Friedman, M.D.
Dr. Friedman has received grant/research support from Alteon within the past three years.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Place whole organ pancreas transplantation in perspective for management of individuals with type 1 diabetes and kidney failure
List the technical (surgical) problems confronting the surgeon intending to perform a pancreas transplant in a type 1 diabetic individual
Discuss the most recent results of pancreas transplantation in diabetic recipients.
Introduction and Perspective
In this final year of the twentieth century, diabetes mellitus is universally recognized as the leading cause of irreversible renal failure - unfortunately termed end-stage renal disease (ESRD) - in industrialized (i.e., well-fed) nations. Trends in both the incidence and prevalence of ESRD attributed to diabetes indicate an annual growth rate over the past decade in excess of nine percent. According to the 1998 report of the United States Renal Data System (USRDS), in 1996, of 283,932 U.S. patients who received either dialytic therapy or a kidney transplant, 92,211 had diabetes, a prevalence rate of 32.4%. The full impact of diabetes-related kidney disease is shown by the incidence rate of 43% in 1996, during which 30,393 of 72,000 new (incident) cases of ESRD were attributed to diabetes. Dissatisfaction with contemporary approaches to forestalling diabetic complications, such as nephropathy, stimulated unremitting interest in a diabetes "cure," such as surgical transplantation of a pancreas.
Diabetes mellitus is the disorder most often linked to the development of end-stage renal disease (ESRD), limb amputation and blindness in the USA, Europe, South America, Japan, India and Africa. While kidney disease is as likely to develop in long-duration, non-insulin dependent diabetes (type 2) as in insulin-dependent diabetes mellitus (type 1), the tragic debility induced in children and young adults attracts both professional and media attention to the patient with type 1 diabetes. Yet, nephropathy is equally likely in both types of diabetes - and when managed by usual treatment - follows a predictable course that starts with microalbuminuria, progresses to proteinuria, azotemia and culminates in ESRD.
Current regimens for regulation of diabetes focus on slowing the course of nephropathy and retinopathy by normalizing hypertensive blood pressure, establishment of euglycemia and reducing dietary protein intake. Despite rigid adherence to physician imposed life-restricting rules and compliance with ordered multiple fingerstick blood glucose measurements, the type 1 diabetic patient still experiences a shortened life expectancy with extensive comorbidity. When compared with individuals who have other causes of progressive nephropathy, the type 1 diabetic patient sustains greater mortality and morbidity due to concomitant systemic disorders, especially coronary artery, peripheral vascular and cerebrovascular disease.
Although a functioning kidney transplant provides the uremic type 1 diabetic patient better survival with superior rehabilitation than does either cutaneous ambulatory peritoneal dialysis (CAPD) or maintenance hemodialysis, both macrovasculopathy and microvasculopathy continue to worsen despite satisfactory renal allograft function.
Since the 1921 experiments by Banting and Best in pancrectomized dogs, the dream of surgical replacement of failed islet function has been a continuing obsession for the type 1 diabetic individual and his physicians. Over the past decade, this hope has been transformed into a workable, though arduous, treatment in which performance of a combined pancreas and kidney transplant may actually cure diabetes and permit full rehabilitation.
Pancreas Transplantation
Starting in the late 1960s, increasingly successful results document the curative effect of pancreatic transplants inserted concurrently with a renal allograft.(1),(2) Admittedly, combined pancreas and kidney transplants do raise immediate perioperative mortality over that of kidney transplants alone. Because of early statistics which showed that survival, at one year, of recipients of combined pancreas kidney transplants was 10-20% inferior to that of kidney transplant recipients, critiques of pancreas transplantation categorized the procedure as still experimental, inordinately dangerous and of short-lived benefit to the recipient. Gradually, yet convincingly, the outcome of pancreas transplantation has improved to the extent that it must be seriously considered (and offered) to every type 1 diabetic person younger than age 45 with diabetic nephropathy.
Surgical Technique of Pancreas Transplantation
Improvements in surgical technique, however, have narrowed the risk of excess mortality attributed to coupling a pancreas allograft with a renal transplant. Determining how and where to drain the proteolytic digestive juices from the exocrine pancreas was the most troublesome aspect of deciding upon operative strategy. Neither obstructing the pancreatic duct with injected silicone elastic nor permitting the free drainage of pancreatic juices into the peritoneum proved practical - both methods resulted in abdominal pain and serosal injury due to leaked proteases.
The most commonly employed operative method today is insertion of the pancreatic duct into the bladder via a bladder wall tunnel and a neocystotomy. Repetitive hospitalizations of pancreas transplant recipients during the first year are caused by bladder pain, hemorrhage and infection, which result from the enzyme-rich pancreas secretions passing directly into the unprotected bladder. Patients accept the trade off of freedom from insulin injections and enhanced quality of life afforded by a functioning pancreas transplant.
A functional pancreas allograft will normalize glycosylated hemoglobin, fasting blood glucose and other 24-h metabolic profiles. The International Pancreas Transplant Registry reported in 1998 that, by the end of 1996, 9,000 pancreas transplants had been reported to the Registry. For those performed between 1994-1996, one-year pancreas survival rates were 81% for simultaneous pancreas and kidney transplantation (n = 1,516), 71% for pancreas after kidney (n = 141) and 64% for pancreas alone (n = 64).(3)
Whether another desired objective of pancreatic transplantation, the prevention of progression of diabetic microvascular and macrovascular extrarenal complications, will be reached is not yet known. Preliminary study of renal biopsies in patients, who have received sequential kidney and, later, pancreas allografts, indicates that the presence of a functioning pancreas slows the progression of and even reverses established diabetic glomerulopathy.
Hope that a pancreas transplant would end the siege of diabetic complications was gleaned from first observations of the course of diabetic neuropathy following combined pancreas and kidney transplantation in which some patients had stabilization(4) and improvement(5) in diabetic motor neuropathy. Unfortunately, when pancreas transplantation was performed in patients with extensive extrarenal disease, there has been neither cessation of further injury nor reversal of established diabetic retinopathy, diabetic cardiomyopathy or extensive peripheral vascular disease.(6) Importantly, a functioning pancreas transplant has been enthusiastically welcomed by patients with type 1 diabetes who become emancipated from the daily burden of balancing diet, exercise and insulin dosage.(7),(8)
The report by Sollinger et al., which recounts the remarkable experience at the University of Wisconsin from 1985 to 1997 during which 500 simultaneous pancreas-kidney transplants were performed, epitomizes the potential of a pancreas transplant program. The Wisconsin group attained remarkable patient survival at one, five and 10 years of 96.4%, 88.6%, and 76.3% with intact kidney function over this interval of 88.6%, 80.3%, and 66.6%; and pancreas function of 87.5%, 78.1%, and 67.2%.(9) Surprisingly and counterintuitively, evidence that pancreas transplantation may be applicable in type 2 diabetes is now being accumulated.(10)
Conclusion
In 1999, the ESRD patient with type 1 diabetes should view a simultaneous kidney and pancreas transplant as the preferred therapy, for it permits complete escape, for the duration of pancreas graft function, from the burden and life constraints produced by an inexorable disease.(11)