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A New Perspective on Iga Nephropathy Pioneering Three ADVANCES IN NEPHROLOGY Affiliated with Columbia University College of Physicians and Surgeons and Weill Cornell Medical College Pioneering Three-Gene Signature Test for Predicting NOVEMBER/DECEMBER 2014 Kidney Transplant Rejection Receives Top Research Honors Ali G. Gharavi, MD In July 2013, The New England Journal recognizes outstanding research in Chief, Division of Nephrology of Medicine published a study by nephrology with a clinical emphasis. NewYork-Presbyterian/ Manikkam Suthanthiran, MD, Chief The recognition bestowed upon Columbia University Medical Center of Nephrology and Hypertension at Dr. Suthanthiran and his team is [email protected] NewYork-Presbyterian/Weill Cornell, clearly well deserved. For more than Manikkam Suthanthiran, MD and his research team on a break- a decade, they have pursued an Chief, Division of Nephrology through noninvasive test that can alternative method to the invasive and Hypertension detect whether transplanted kidneys percutaneous needle core biopsy NewYork-Presbyterian/ are in the process of being rejected, as procedure traditionally used to Weill Cornell Medical Center well as identify patients at risk for determine kidney allograft status. [email protected] rejection weeks to months before they The solution came in the form of a show symptoms. The innovative dis- urine-based test. “By measuring just Dr. Manikkam Suthanthiran covery was recognized by the National three genetic molecules in a urine Institute of Allergy and Infectious Diseases as one of sample, the test accurately diagnoses acute rejec- its top 20 research advances for 2013, and in April tion of kidney transplants, the most frequent and CONTINUING 2014, the Clinical Research Forum selected the serious complication of kidney transplants,” says MEDICAL EDUCATION work as one of the Top 10 Outstanding Clinical Dr. Suthanthiran. “We were told we would never be For all upcoming Research Achievements in the United States. able to isolate good quality mRNA from urine.” education events through Most recently, Dr. Suthanthiran was selected to Since his earliest days of training at Harvard, NewYork-Presbyterian Hospital, receive the prestigious Jean Hamburger Award of Dr. Suthanthiran has always followed the maxim, visit www.nyp.org/pro. the International Society of Nephrology, which (continued on page 2) A New Perspective on IgA Nephropathy Immunoglobin A nephropathy (IgAN) is the most “When I was in medical school, the explanation common form of primary glomerulonephritis. It for the higher prevalence of IgA nephropathy in is characterized by the deposition of the antibody East Asians was attributed to a higher rate of immunoglobulin A in the filtering unit of the kidney biopsies performed by physicians in China kidney, resulting in glomerulonephritis, glomerular and Japan,” notes Dr. Gharavi. “Conversely, it sclerosis, and progressive loss of kidney function. In was thought that IgAN was uncommon in Africa fact, IgAN is a significant cause of end-stage renal because of the few number of kidney specialists disease worldwide, and the most common cause of available, so the disease went undiagnosed. We kidney failure in China and Japan. More than 20% now know that this is not necessarily the case. of patients eventually require a transplant. For example, if you look at Asian populations A better understanding of the etiology of IgA who have immigrated to America, there’s a higher NewYork-Presbyterian Nephrology nephropathy and its complex genetic structure has prevalence of IgAN, suggesting an inherited ranks #3 in the nation. been a major focus of Ali G. Gharavi, MD, Chief factor, as well as an ethnic variation.” of Nephrology at NewYork-Presbyterian/Columbia, Dr. Gharavi, along with Columbia nephrologist and his research team. Their work has produced Krzysztof Kiryluk, MD, and collaborators at some important findings, including the identification of 35 medical centers around the world, undertook a multiple regions of the genome that confer risk of genome-wide association study of more than 20,000 IgAN and novel insight into the mechanisms of individuals to determine the validity of this theory. kidney injury underlying the condition. (continued on page 3) Advances in Nephrology Pioneering Three-Gene Signature Test (continued from page 1) “never say never.” And while a number of researchers had tried to when this happens we then need to do a highly invasive needle- develop blood or urine-based tests to measure genes or proteins stick biopsy to look at the kidney and determine the cause.” that signify kidney organ rejection, Dr. Suthanthiran and his “The three-gene signature test is about 85% accurate, much research team were the first to create a gene expression profile higher than the creatinine test,” adds Dr. Suthanthiran. “To urine test – an advance that was reported in The New England achieve 100% success following transplantation, to achieve toler- Journal of Medicine in 2001, with an update in 2005. ance of the transplanted organ, that is our primary goal – because The research team – using a number of sophisticated tools when tolerance is achieved, a transplanted organ truly brings the they developed – measured the absolute levels of 13 prespecified gift of life. messenger RNA (mRNA) molecules in urine samples collected “The three-gene signature test has moved us from the one- from kidney graft recipients at the time of for-cause biopsy for size-fits-all drug treatment model to a much more personalized acute allograft dysfunction, investigating whether differential treatment plan,” says Dr. Suthanthiran. “We have also developed diagnosis is feasible using urinary cell mRNA profiles. They found additional biomarkers to detect fibrosis, a common feature of that increased expression of three mRNAs could determine if an kidney transplants destined to fail, to diagnose BKV viral disease, organ will be, or is being, rejected. The mRNAs indicated that a common viral disease in kidney transplant recipients, and to killer T immune cells are being recruited to the kidney in order determine why kidney transplants are not functioning well. The to destroy what the body has come to recognize as alien tissue. noninvasive tests we have developed, together, provide us with an The signature test consists of adding levels of the three opportunity to manage transplant patients in a more precise, mRNAs in urine into a composite score. “Tracked over time, a individualized fashion. The progress we have made with these tests rising score can indicate heightened immune system activity transcend transplantation and have broader implications for design- against a transplanted kidney,” says Dr. Suthanthiran. “A score ing therapies to prevent the progression of native kidney disease.” that stays the same suggests that the patient is not at risk for rejection. This allows us to monitor kidney transplant patients Reference Articles using urine samples rather than an invasive biopsy. You cannot Matignon M, Ding R, Dadhania DM, Mueller FB, Hartono C, carry out invasive biopsies monthly to see what’s going on with a Snopkowski C, Li C, Lee JR, Sjoberg D, Seshan SV, Sharma VK, Yang H, kidney. With urine, we can test monthly, or even weekly, making Nour B, Vickers AJ, Suthanthiran M, Muthukumar T. Urinary cell mRNA the monitoring process much easier for the patient.” profiles and differential diagnosis of acute kidney graft dysfunction. The composite score also enables physicians to tailor a patient’s Journal of the American Society of Nephrology. 2014 Jul;25(7):1586-97. use of multiple immunosuppressive drugs over time. Any increase Muthukumar T, Lee JR, Dadhania DM, Ding R, Sharma VK, Schwartz would suggest a somewhat higher dose of therapy is needed to JE, Suthanthiran M. Allograft rejection and tubulointerstitial fibrosis in keep the organ safe. “This is akin to monitoring blood glucose in human kidney allografts: interrogation by urinary cell mRNA profiling. Transplantation Reviews (Orlando, FL). 2014 Jul;28(3):145-54. a patient with diabetes,” says Dr. Suthanthiran. “Because different Lee JR, Muthukumar T, Dadhania D, Ding R, Sharma VK, Schwartz JE, people have different sensitivity to the two-to-four immunosup- Suthanthiran M. Urinary cell mRNA profiles predictive of human kidney pressive drugs they have to take, this test offers us a very allograft status. Immunological Reviews. 2014 Mar;258(1):218-40. personalized approach to managing transplantations.” Suthanthiran M, Schwartz JE, Ding R, Abecassis M, Dadhania D, The promise of the test first developed in Dr. Suthanthiran’s Samstein B, Knechtle SJ, Friedewald J, Becker YT, Sharma VK, Williams laboratory at Weill Cornell and previously reported more than a NM, Chang CS, Hoang C, Muthukumar T, August P, Keslar KS, Fairchild decade ago in The New England Journal of Medicine, led to an NIH- RL, Hricik DE, Heeger PS, Han L, Liu J, Riggs M, Iklé DN, Bridges sponsored multicenter clinical trial in 2006 that would include ND, Shaked A; Clinical Trials in Organ Transplantation 04 (CTOT-04) nearly 500 kidney transplant patients at five major transplant Study Investigators. Urinary-cell mRNA profile and acute cellular rejection The New England Journal of Medicine centers in the country. In this first-of-its-kind blinded study, in kidney allografts. 2013 Jul 4;369(1):20-31. researchers collected 4,300 urine specimens during the first year Dadhania D, Snopkowski C, Muthukumar T, Lee J, Ding R, Sharma VK, of transplantation, starting at day three post-transplantation. Christos P, Bang H, Kapur S, Seshan SV, Suthanthiran M. Noninvasive Dr. Suthanthiran’s laboratory processed and measured the samples prognostication of polyomavirus BK virus-associated nephropathy. for 13 different genes, using the assay they developed in their lab. Transplantation. 2013 Jul 27;96(2):131-38. Their results were sent to the NIH statistical core for further Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, analysis. The three-gene-based biomarkers signature was used to Hartono C, Li B, Sharma VK, Seshan SV, Kapur S, Hancock WW, derive a composite score and identify a threshold value indicative Schwartz JE, Suthanthiran M.
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