Studies of Organ Transplantation in Animals and Man

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.

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.