Studies of Organ Transplantation in Animals and Man

Condition(s) targeted: Diabetes Mellitus

Phase: N/A

Status: Recruiting

Sponsored by: Michael Mauer, MD

Official(s) and/or principal investigator(s):
Michael S Mauer, MD, Principal Investigator, Affiliation: Pediatric Nephrology, University of Minnesota
Arthur J Matas, MD, Study Director, Affiliation: University of MN, School of Medicine, Dept of Surgery

Overall contact:
Cathy A Bagne, BS, Phone: 612-624-4688, Email: pinth001@umn.edu

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.

- 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.

Official title: "Ii-Pancreas Transplantation in Man", "Long Term Effects of Cyclosporine (CSA) and Tacrolimus (FK506) on Renal Structure and Function", "Studies of the Renal Interstitium Type I Diabetic Patients",

Study design: Cohort, Prospective

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Both.

Criteria:

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.

Cathy A Bagne, BS, Phone: 612-624-4688, Email: pinth001@umn.edu

Universtity of Minnesota, Department of Pediatric Nephrology, Minneapolis, Minnesota 55455, United States; Recruiting

Related publications:

Moriya T, Groppoli TJ, Kim Y, Mauer M. Quantitative immunoelectron microscopy of type VI collagen in glomeruli in type I diabetic patients. Kidney Int. 2001 Jan;59(1):317-23.

Sutherland DE, Gruessner RW, Dunn DL, Matas AJ, Humar A, Kandaswamy R, Mauer SM, Kennedy WR, Goetz FC, Robertson RP, Gruessner AC, Najarian JS. Lessons learned from more than 1,000 pancreas transplants at a single institution. Ann Surg. 2001 Apr;233(4):463-501. Review.

Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME, Russell G, Mauer M. Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. Diabetes. 2002 Feb;51(2):506-13. Erratum in: Diabetes 2002 Apr;51(4):1294.

Katz A, Caramori ML, Sisson-Ross S, Groppoli T, Basgen JM, Mauer M. An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients. Kidney Int. 2002 Jun;61(6):2058-66.

Suzuki D, Yagame M, Kim Y, Sakai H, Mauer M. Renal in situ hybridization studies of extracellular matrix related molecules in type 1 diabetes mellitus. Nephron. 2002;92(3):564-72.

Huang C, Kim Y, Caramori ML, Fish AJ, Rich SS, Miller ME, Russell GB, Mauer M. Cellular basis of diabetic nephropathy: II. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes. Diabetes. 2002 Dec;51(12):3577-81.

Najafian B, Kim Y, Crosson JT, Mauer M. Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy. J Am Soc Nephrol. 2003 Apr;14(4):908-17.

Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes. 2003 Apr;52(4):1036-40.

Huang C, Kim Y, Caramori ML, Fish AJ, Rich SS, Miller ME, Russell GB, Mauer M. Cellular basis of diabetic nephropathy: III. In vitro GLUT1 mRNA expression and risk of diabetic nephropathy in type 1 diabetic patients. Diabetologia. 2004 Oct;47(10):1789-94. Epub 2004 Oct 22.

Starting date: January 1981
Ending date: April 2009
Last updated: September 12, 2008