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Nephrology

 

The Division and faculty members who are related closely to it perform ground-breaking research in a wide variety of areas related to renal physiology and kidney disease. For clarity, we have listed the research by category and investigator:

 

Human Genetics. Dr. Pollak's laboratory studies the genetic basis of proteinuric kidney disease. In addition, his lab has recently initiated studies to understand the genetic basis of kidney stone disease and developmental abnormalities of the kidney .

Ion and water transport
. The laboratories of Drs. Alper, Zeidel, Mathai and MacIver are active in this area, with studies on: the molecular physiology of bicarbonate transport in cell pH and volume regulation; potassium homeostasis in red cell hemoglobinopathies and in secretory epithelia; how water, protons and small non-electrolytes cross biological membranes; how intracellular signaling pathways modulate the secretion of chloride by rectal glands of elasmobranchs and many elements of the cell biology of mammalian bladder epithelium.

 

Vascular biology. Dr. Parikh is studying the role of the angiopoietin family of ligands in vascular leak syndromes in man. A translational focus has been on clinical trials of novel anti-angiogenesis drug combinations for cancer therapy ( Sukhatme). Karumanchi's research aims at understanding the pathophysiology of preeclampsia. A novel role for the orphan endothelial specific receptor Tie-1 in atherosclerosis has been elucidated (Chan and Sukhatme), as have downstream signaling pathways (Yuan, Karumanchi, Chan, and Sukhatme). Dr. Friedman's research focuses on the role of purinergic signaling (ectonucleotidases and purinergic receptors) in vascular disease. Using mouse models, he is investigating microvascular injury in diabetic nephropathy and large vessel disease in studies of arteriovenous fistula maturation and stenosis.

 

Proteinuria. Drs. Karumanchi and Mutter have generated microarray data from podocytes grown in high and normal glucose in studies aimed at deciphering novel targets and pathways. Transcriptional profiles of podocytes lacking nephrin (mutated in congenital Finnish nephrotic syndrome) and LMX-1b (mutated in nail-patella syndrome) are in progress. Urine proteomics data from diabetic patients with and without nephropathy are being analyzed in order to identify novel urine markers that predict worse renal outcomes. Dr. Mutter is investigating soluble mediators of proteinuria in Minimal Change Disease.

 

Acute renal failure. Dr. Parikh studies the biology of critical illness, focusing on endothelial molecular mechanisms that contribute to vascular leak. Additional studies in acute renal injury focus on a novel animal model of sepsis-induced ARF as well as a cohort study of acute renal failure patients at BIDMC.

Chronic kidney disease and kidney hypoxia. Dr. Friedman studies the role of purinergic signaling in renal microvascular disease, renal autoregulation, and venous arteriolization.

 

States of muscle atrophy. Dr. Lecker's research explores the molecular mechanisms behind the muscle wasting which occurs in uremia and other chronic illnesses such as cancer, sepsis and diabetes. Dr. Lecker's studies have identified a group of about 100 genes (termed "atrogenes") that are coordinately regulated during wasting. His work now focuses on the function of one of those genes, called atrogin-1. A recent collaboration with Hanai and Sukhatme has shed new light into the mechanisms of statin induced myopathy, which they have discovered is mediated by atrogin-1.

 

Cellular metabolism. Dr. Stanton's laboratory has focused on elucidating the regulation of glucose 6-phosphate dehydrogenase (G6PD), the main source of NADPH, the principal reductant in the cell. A key role of aldosterone in impairing vascular reactivity through diminishing G6PD has been recently elucidated.

 

Polycystic Kidney Disease. The Alper laboratory is studying the deficient shear/flow signaling phenotype of human PKD cyst cells of defined mutant genotype. Dr. Steinman is examining the role of ACE inhibitors/ARBs in effecting cyst growth and glomerular filtration rate in ADPKD patients. A second study in ADPKD examines the role of a V2 receptor antagonist in slowing progression of disease.

 

Renal Cancer. Drs. Seth and Sukhatme have defined novel targets for renal cancer via a whole genome RNAi screen. The metabolism of cancer cells is also a focus of new studies.

 

Renal function. One of Dr. Mandelbrot's research efforts is on novel technologies for measuring renal function. He has described the use of neutron activation to measure glomerular filtration rate and future studies will use this method to measure renal blood flow.

 

Diabetic nephropathy/ESRD clinical studies. Ongoing trials include: the efficacy and safety of sulodexide on type 2 diabetics with overt proteinuria and renal insufficiency ( Cohen and Williams), and an antibody to connective tissue growth factor in early diabetic nephropathy (Williams).

 

Tolerance and rejection. An understanding and clinical application of immune tolerance is the primary goal of the Strom laboratory. The balance of activated effector to regulatory cells can be manipulated through signals that are triggered by specially designed cytokine related Ig fusion proteins crafted in the Strom laboratory or through activation of select members of the T cell immunoglobulin family of proteins.

 

Drug trials in renal transplantation. Drs. Pavlakis and Mandelbrot, remain active in this area. Strategies to reduce calcineurin nephrotoxicity in renal transplant patients, the optimal management of hepato-renal patients, including liver transplantation, and IL-2 receptor blockade to prevent rejection of renal transplants are under investigation.

 

Islet Transplantation. Islet Transplantation is at BIDMC as part of the center for Islet Transplantation at Harvard Medical School. Dr. Pavlakis and colleagues are currently enrolling patients with diabetes who have received a kidney transplant.

 

Anemia in Renal Failure. - Dr. Mutter is investigating the role of soluble erythropoietin receptor in the anemia of chronic kidney disease.

 

Vitamin K dependent proteins: Dr. John Danziger is interested in the vitamin K dependent proteins (VKDPs), a family of proteins which require vitamin K as a cofactor in order to become biologically active. Specific interests include the importance of VKDPs in patients with chronic kidney disease and malabsorptive gastrointestinal illnesses, specifically looking at their role in vascular calcification and osteoperosis.

Disparity in Living Kidney Transplantation rates among African Americans - Drs. Mandelbrot and Pavlakis are involved in an NIH sponsored trial to reduce the rates of disparity in African Americans.

 

Voiding Dysfunction in the Urinary Bladder - Drs. Hill and Yu are investigating mechanisms of mechanosensation and purinergic regulation of bladder contractility. Their studies aim to elucidate mechanisms involved in bladder disease such as incontinence, overactive bladder and neurogenic bladder.

 

An NIH research training grant supports several basic and clinical science research fellowship positions. Several renal faculty are also members of other NIH training programs, including Hematology-Oncology, ObGyn, Gastroenterology, Pediatric Gastroenterology and Nutrition. Renal fellows in their research years may conduct studies in laboratories both within and outside of the Beth Israel Deaconess Medical Center.