Studies of Organ Transplantation in Animals and Man

Michael Mauer, MD655 enrolled

Overview

A. To study the effects of pancreas transplantation (PT) on the structural abnormalities of diabetic nephropathy (DN) in patients with type 1 (insulin-dependent) diabetes mellitus (type 1 D). These studies will address the influence of long-term normoglycemia on two stages of diabetic renal disease. Due to the difficulties encountered for recruitment of patients to agree to undergo a GFR and a native kidney biopsy in conjunction with their clinical evaluation visit for transplant, we are now focusing efforts on obtaining skin biopsies previous to transplant, and then at regular intervals (3, 6, and 9 months, and yearly) following a successful transplantation. * Pancreas Transplantation Alone (PTA). To determine, at 5, 10, and 15 years after PTA, the effects of normoglycemia on the established lesions of DN in the long-term type 1 D patients' own kidneys. * Islet Transplantation Alone (ITA). To determine, at 5 years after ITA, the effects of normoglycemia on the early lesions of DN in type 1 D patients' own kidneys. * Pancreas Transplantation after Kidney Transplantation (PAK). To determine at 5-10 years the effects of normoglycemia on the early structural lesions of DN in kidneys transplanted some years earlier into type 1 D recipients. Hypothesis: The benefits of PT on the early glomerular lesions of DN will be demonstrable after 5 years in kidneys exposed to diabetes for a short duration, while in patients with long-standing type 1 D and more advanced glomerular DN lesions, longer exposure to euglycemia is necessary to demonstrate arrest or regression of the lesions.

These continuation studies focus on large pancreas (PTx) and kidney (KTx) transplant populations of type 1 diabetic (D) patients (pts) in order to better understand diabetic nephropathy (DN), the leading cause of renal failure. Objectives are: (a) to determine whether PTx can more readily arrest or reverse the early vs. the more established lesions of DN; (b) to continue studies of renal structural-functional relationships in DN, with emphasis on the multifaceted pathologic DN lesions, including glomerular, vascular, interstitial lesions and glomerular-tubular connections; (c) to continue studies of DN natural history and the role of renal biopsy in predicting outcome; (d) to quantitate and understand the basis of atubular glomeruli (AG) in DN; (e) to elucidate glomerular (glom) epithelial cell abnormalities in DN; (f) to study the glom extracellular matrix abnormalities of DN; (g) to study the recurrence of DN in the KTx; (h) to study the molecular/genetic basis of DN and develop cellular markers of DN risk; (i) to determine the long-term (10-15 yr) structural consequences of cyclosporine (CSA) on the native kidneys of PTx recipients; and (j) to determine the shorter-term (5 yr) consequences of Prograf on the native kidneys of PTx recipients and compare these with those seen after 5 years of CSA treatment. Together, these studies will help to elucidate the pathogenesis and natural history of DN, unravel some of the molecular and genetic aspects of this disease, describe the dynamics of DN reversal in PTx pts, and recurrence in KTx pts and expand our knowledge of the nephrotoxic effects of calcinosis inhibitors.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Pancreas Transplantation. The patients considered for recruitment are those being evaluated for pancreas transplant alone or pancreas transplant after kidney transplantation in IDDM patients at the University of Minnesota (U of M). The consent forms have been approved by the Institutional Review Board at the University of Minnesota and the transplant coordinators responsible for interacting with patients have continuously utilized these consent forms in the recruitment process. 2. Long-Term Post Kidney Transplant IDDM Patients. These patients are recruited by a study coordinator working directly with the PI and also use consent forms approved by the Institutional Review Board at the University of Minnesota. Exclusion Criteria: Pancreas Transplantation Alone 1. Serum creatinine \>1.5 mg/dl or CCr \<50 ml/min/1.73M2, as kidneys in such IDDM patients are approaching end stage renal disease and are not readily amenable to morphometric analysis. 2. Solitary kidneys or evidence of unilateral renal disease, based upon significant discrepancies in renal size by ultrasound. 3. Evidence of other important kidney disease by history, ultrasound, or baseline biopsy. 4. Other chronic diseases or conditions, in addition to IDDM, such as cystic fibrosis, serious mental illness, severe mental retardation, etc. 5. Pregnancy. Pregnancy tests will be performed on all eligible females of child-bearing age, and pregnant women will be excluded. Patients will again be eligible 3 months after completion of pregnancy. Pancreas Transplantation After Kidney Transplantation 1. Serum creatinine \>2 mg/dl; a higher value is accepted than for native kidney patients since patients have a single kidney and are receiving CSA or FK506. 2. Moderate to severe chronic rejection on baseline biopsy. 3. Evidence of other important kidney disease by history, ultrasound, or baseline biopsy. 4. Other chronic diseases or conditions, in addition to IDDM, such as cystic fibrosis, serious mental illness, severe mental retardation, etc. 5. Pregnancy. Pregnancy tests will be performed on all eligible females of child-bearing age, and pregnant women will be excluded. Patients will again be eligible 3 months after completion of pregnancy.

Outcomes

Primary Outcomes

Structural-functional relationships in diabetic nephropathy through detailed quantitative studies of Podocytes.

structural-functional relationships in diabetic nephropathy through detailed quantitative studies of podocytes, including cell number, shape and attachment using innovative approaches including quantitative immunoelectron microscopy and 3-dimensional high resolution electron microscopy. We will also study relationship between podocyte and glomerulotubular junction abnormalities.

Time frame: baseline through follow-up biopsy

Secondary Outcomes

We will continue our study the natural history of diabetic nephropathy.

We will study the structural parameters associated with urinary albumin excretion and determine which structural parameters are predictors of developing diabetic nephropathy.

Time frame: Baseline through follow up visits