Nephrology Clinical and Translational Program

Genomics of Chronic Allograft Rejection

We are using microarray technology to help understand mechanisms of transplant rejection. GeneChip technology allows simultaneous detection of thousands of genes. This broad spectrum approach to the molecular analysis of a complex disease, such as chronic rejection, will allow us to better understand the pathogenic mechanisms and help refine diagnosis and treatment. In a related line of investigation, we are focusing on kidney transplantation recipients that develop antibodies to their donor following transplant, in order to determine if the development of donor specific antibodies leads to the development of transplant glomerulopathy and examine whether theses patients can be identified before they become sensitized.

Delayed graft function (DGF) is a form of acute renal failure resulting in post-transplantation oliguria, increased allograft immunogenicity, and decreased long-term survival. Our ongoing research is based on the following two hypothesis: (1) The susceptibility to DGF is modified by inherited genetic polymorphisms that alter the level of response in genes that are known to modify the response to tissue injury; (2) Distinct gene expression patterns can be identified in the transplanted allograft that can predict DGF and that can reliably discriminate complex mechanisms of DGF.

The role of innate immune response in islet transplantation

A major challenge of pancreatic islet transplantation is the protection of the already putatively marginal islet cell mass. Our data demonstrate that islets have the capacity to behave in a similar manner to cells of the immune system, recruiting leukocytes from the blood stream. The hypothesis is that islet-derived mediators directly or indirectly affect islet engraftment, function and viability, and serve to further amplify the adaptive immune response. The goals are to characterize the innate immune response to specific stimuli in islet transplantation and to identify therapeutic strategies to improve islet transplant engraftment and survival.

Clarification of frailty and functional decline is important in the elderly with chronic kidney disease (CKD), especially those with end stage renal disease (ESRD) on dialysis, a rapidly growing population. CKD has become a geriatric disease and is a predictor for cardiovascular events, hospitalizations, and all-cause mortality. Intervening health events represent trigger points of entry and activation of a cycle of frailty with ensuing repetitive disability/adverse outcomes. CKD can be viewed as a "silent co-morbidity" interacting with the biology of frailty to affect functional outcomes.

The focus of this research is to identify novel mediators of renal epithelial apoptosis in HIV-associated nephropathy and other renal diseases. We employ a variety of molecular techniques to perform studies using tissue and cell lines derived from patients to advance our understanding of the pathogenesis of renal disease.

The Genetics and Proteomics of Hypertension and Kidney Disease

A number of clinical trials have demonstrated that it is possible o slow the progression of kidney disease, for example by using converting enzyme inhibitors. What is also clear from these trials is that the rate of progression remains significant despite the optimal therapy currently available. We are currently employing genetics, pharmacogenetic, and mass spectrometry-based proteomic techniques to identify genetic polymorphisms and proteomic patterns that predict the progression of kidney disease and effectiveness of therapy in subjects from the African American Study of Kidney Disease and Hypertension (AASK) Study. Using these techniques we hope to identify patients a risk for progressive renal disease, and new targets for therapeutic interventions.

Chronic kidney disease is a complex medical condition, affecting eleven million people and associated with high rates of cardiovascular events, hospitalizations, and mortality. We are performing prospective observational cohort studies and case-control studies in special populations, such as diabetics, the elderly, patients with HIV-1 infection, and patients in medically underserved areas of New York City. Our work focuses on ways to better identify patients with CKD and improve the quality of care they receive. This will lead to clinical trials that test novel therapies that may reduce cardiovascular morbidity and slow the rate of progression of kidney disease.

• The role of innate immune response in islet transplantation
• Management of the highly sensitized renal transplant recipient
• Investigation of new immunosuppressants
• Renal failure in the non-renal transplant patient
• Diabetic Nephropathy
• Oxidative Stress in End Stage Renal Disease
• Frequent Hemodialysis
• Glomerular Disease