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Kidney and Pancreas Transplantation

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The Division of Nephrology and the Department of Transplantation Medicine at NewYork Presbyterian-Weill Cornell has pioneered the development of gene based assays for the ascertainment of transplant status, and development of molecular parameters for personalized medicine.

Specific areas of research include:

  • Development of Molecular Diagnostics and Personalized Medicine. Transplant biopsies are the current gold standard test for the diagnosis of acute rejection of organ transplant. The invasive procedure of allograft biopsy, however, is associated with complications such as bleeding, and even grafts loss. In a land mark publication in the New England Journal of Medicine, our Gene Expression Monitoring (GEM) Laboratory demonstrated that measurement of messenger RNA (mRNA) for cytotoxic attack proteins granzyme B and perforin in urine offers a noninvasive means of diagnosing renal allograft rejection (Li et al. N Engl J Med. 2001 Mar 29; 344 (13):947-54).

    Histological features of transplant biopsies are currently required for the prediction of the outcome of an episode of acute rejection. In a recent publication in the New England Journal of Medicine, our Gene Expression Monitoring Laboratory resolved that levels of FoxP3 mRNA in urine are an accurate predictor of responsiveness to anti- rejection therapy and that graft outcome (graft failure vs. graft function) following an episode of acute rejection is also predicted by urinary cell FoxP3 mRNA levels (Muthukumar et al. (N Engl J Med. 2005 Dec 1; 353 (22):2342-51).
  • Click here to view a presentation on gene expression by Dr. Manikkam Suthanthiran

  • Validation by NIH sponsored Multi-Center Trials in Transplantation. The diagnostic and the prognostic utility of the molecular assays developed at NewYork Presbyterian/Weill Cornell have led to NIH sponsored national studies. In a multi-center Cooperative Clinical Trial in Transplantation comprised of 750 subjects, the molecular tests we have developed are being utilized to ascertain renal transplant status. Several major transplant centers including Weill Cornell and Columbia are participating in the largest to date molecular diagnostic study. Weill Cornell gene expression monitoring laboratory is functioning as the Molecular Core laboratory. This multi-center study should help translate the noninvasive molecular test we have developed for the diagnosis of acute rejection "from the bench to the bedside".
  • First Ever Induction of Tolerance to HLA-mismatched Renal Transplantation. Transplant recipients require life long use of immunosuppressive drugs to prevent the rejection of their transplanted organs. Dr. David Sachs and colleagues at Massachusetts General Hospital, Harvard Medical School have developed an innovative protocol that has resulted in the first ever induction tolerance to mismatched renal transplants. The protocol included using an antibody directed at a T cell surface protein CD2 antigen discovered at Weill Cornell to be important for blocking the adverse immune response directed at the transplant. Our studies of the tolerant patients have identified a unique molecular signature for tolerance. This land mark study was recently reported in the New England Journal of Medicine. In this regard, we have been selected by NIH-ITN to further develop and refine tolerance induction protocols, and investigate the mechanisms.
  • Post Transplantation Malignancy: New Causes and Potential Solutions. Malignancy is a dreaded complication of transplantation, and immunosuppressive drugs are an important cause for the increased incidence and severity of malignancy in the transplant recipients. Indeed, the 2007 U.S. News & World Report headlined this issue in its Kidney Disease section, and stated that "The rate of cancer after kidney transplant is high. Researchers are looking into the causes-and possible solutions."

    Our research studies have identified a new cause of cancer metastasis and a novel solution for the increased incidence of cancer. Our studies identified that the widely used immunosuppressive drugs cyclosporine and tacrolimus both stimulate the production of transforming growth factor beta, and that this factor promotes cancer metastasis (Hojo et al. Nature 1999, Maluccio et al. Transplantation 2003). Importantly, we identified that an immunosuppressive drug called rapamycin blocks tumor progression (Luan et al. Transplantation 2002, Luan et al. Kidney International 2003). The immediate implication of our observations is that transplant patients may benefit from switching from cyclosporine or tacrolimus to rapamycin. Indeed, emerging clinical data are consistent with our research findings.

Research in Type 1 Diabetes

There are two major challenges to wide spread use of islet transplantation in type 1 diabetic patients. The challenges are: (1) the need for life long immunosuppressive therapy; and (2) the need for a large islet mass (usually islets from 2 pancreata are required to make patient insulin independent).

Human Islet Transplantation

The Division of Nephrology and the Department of Transplantation Medicine at NewYork Presbyterian/Weill Cornell has successfully carried out six human islet cell transplants including the first successful islet transplantation in the Tri-State area. A highly successful human Islet Isolation laboratory has been established and our islet yield per pancreas (447194 x 103 islet equivalents [IE]) and islet cell purity (634%) are similar to the islet yield and purity reported by the stellar Edmonton group (Islet yield: 344103 x 103 IE; Purity: 6615%; Street et al. Diabetes 53:3107-3114, 2004). Also, the islet yield per gram of pancreas (IE/g) is similar between our islet isolations (4.7 1.7 x 103 IE/g) and that reported by the Edmonton group using optimally preserved pancreata (3.5 0.3 x 103 IE/g; Tsujimura et al. Transplantation 78:96-100, 2004). Very importantly, of the last 8 pancreata processed in our islet isolation laboratory, 6 yielded clinical grade islets (75% success rate) and were infused in to three consecutive type1 diabetic patients, with all three recipients becoming insulin independent.

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