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Andrzej S. Krolewski, M.D., Ph.D.

Research Summary

Tracking Down Factors Leading to Complications in Diabetes

As Head of the Section on Genetics and Epidemiology, Andrzej S. Krolewski, M.D., Ph.D., has established a world-class research program on the genetics and epidemiology of diabetes and its complications. The overarching goal of his research is to understand the etiology and pathogenesis of late diabetic complications by studying human populations, concentrating on nephropathy in particular.

Drawing upon the large Joslin Clinic patient population, Dr. Krolewski created a modern population research laboratory, combining a very large database of clinical information captured from medical records with special examinations of patients attending the Joslin Clinic. Backing up this clinical data are banks of their DNA and biologic samples of plasma, serum, and urine collected over two decades of follow-up. His research uses epidemiologic, genetic and proteomic methods and is seen as a forerunner of the recently popularized translational medicine.

Dr. Krolewski’s current research encompasses four areas:

First, is a new model of early diabetic nephropathy.

In a large long-term prospective study of patients with type 1 diabetes and microalbuminuria, Dr. Krolewski documented its limited utility for predicting advanced nephropathy, demonstrating that only one third of these patients develop renal function decline. This decline begins at the time of onset of microalbuminuria when patients have normal renal function, and progresses to chronic kidney disease (CKD) and renal failure (ESRD). His findings were recently confirmed by DCCT/EDIC data. By documenting the low specificity of microalbuminuria and shifting attention to the occurrence of early and progressive decline in renal function, Dr. Krolewski has replaced the established paradigm of early diabetic nephropathy in Type 1 diabetes with a new model that has immediate implications. The first is that we must develop new diagnostic tools to identify patients at risk. The second is that we must develop clinical protocols to retard this early renal function loss while patients still have normal renal function.

Dr. Krolewski’s second area of research is the determinants of early renal function decline.

To unravel the mechanisms of initiation and progression of early renal function decline, he is conducting a series of follow-up studies that have yielded two important discoveries. One discovery is that a high serum uric acid concentration (even within the normal range) is a strong independent determinant of early renal function loss, suggesting the possibility that existing drugs for lowering it, such as Allopurinol, may retard the rate of renal function loss. This hypothesis will be tested in a clinical trial. The second discovery is that elevated serum concentrations of markers of the TNF pathway (TNFα, TNFR1 and TNFR2) and urine concentrations of several chemokines are very strong independent predictors of the development of early renal function decline. He is currently studying whether these are simply biomarkers or risk factors for early renal function loss that can be used as therapeutic targets.

Dr. Krolewski’s third area of focus is predictors of ESRD in patients with proteinuria and Type 1 diabetes.

He published the first comprehensive study of the development of ESRD in these patients at a time when almost all patients were treated with reno-protective drugs. Still, 50% developed ESRD within 15 years. These findings have now been replicated in a similar study in Finland. Dr. Krolewski is currently developing a diagnostic algorithm to estimate the time to the onset of ESRD so that patients at immediate risk of ESRD can be identified and enrolled into clinical trials to test aggressive clinical protocols, such as preemptive kidney transplant, pancreas transplantation or treatment with new anti-fibrotic drugs.

His fourth area of research is susceptibility and protective genes for nephropathy in diabetes.

Dr. Krolewski has searched for these genes using GWAS approaches as well as next generation sequencing. He has identified several novel loci. These loci have been replicated in other studies in humans as well as in mice. Dr. Krolewski’s laboratory is now studying the pathways through which these loci may contribute to DN susceptibility/protection.


 

Biography

Dr. Krolewski heads the Section on Genetics and Epidemiology and is a Professor of Medicine at Harvard Medical School. He received his medical degree and doctorate in Epidemiology from Warsaw Medical University in Poland. He obtained training in diabetes research at Joslin Diabetes Center and in molecular human genetics at the Center for Cancer Research at the Massachusetts Institute of Technology.

Page last updated: July 23, 2014