Epidemiology, Pathophysiology and Treatment of Diabetic Nephropathy

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

This project, in part, represents an extension of work previously reported as Project Numbers Z01 DK69037, Z01 DK069097 and Z01 DK069000. It also reports on continuation of work previously reported under Project Numbers DK069036-23, DK069063-17, and DK069100-06. All work related to diabetic kidney disease, except for the genetics of diabetic kidney disease, is now reported under this single project. Below are described some representative studies that were published in the past year. A study in collaboration with the University of Colorado, the University of Minnesota, the University of Washington, and the University of Poitiers demonstrated for the first time that younger age at onset of type 2 diabetes associates strongly with more severe kidney structural lesions. The structural lesions most prominently associated with youth-onset type 2 diabetes were greater mesangial expansion and thickened glomerular basement membrane than in those of later onset. These are key early structural predictors of declining kidney function. These findings support previous observations in other studies of a more severe clinical phenotype of diabetic kidney disease in youth-onset type 2 diabetes and provide the structural framework for this observation. For the past two decades, equations for estimating the glomerular filtration rate based on the serum creatinine concentration have been widespread in clinical laboratory reporting as a means of identifying cases of chronic kidney disease. Current guidelines recommend an equation that includes a race term (Black vs. non-Black) in the equation, because previous studies indicated a higher average serum creatinine concentration for the same level of measured glomerular filtration rate in Blacks than in non-Blacks. Inclusion of race in glomerular filtration rate estimating equations, however, is facing increased scrutiny because race is a social and not a biological construct and its use in medical algorithms may contribute to systemic racism in medicine. For this reason, the Chronic Kidney Disease Epidemiology Collaboration used measured glomerular filtration rate data from over 5000 individuals, including American Indians with whom we work, to develop new estimating equations that do not include a race term. We then compared their ability to correctly identify cases of chronic kidney disease relative to the older race-based equations. We demonstrated that the new estimating equations without race are sufficiently accurate in many circumstances to be useful clinically, and laboratories worldwide are now adopting these new equations for estimating glomerular filtration rate in the clinical setting. In collaboration with the University of Poitiers, the University of Colorado, the University of Minnesota, and the University of Washington, we examined the role of intraglomerular hemodynamic function in the progression to kidney failure in an American Indian cohort. We demonstrated that trajectories of afferent to efferent arteriolar resistance in the glomerulus and intraglomerular hydraulic pressure, two parameters which cannot be measured directly in humans but can be estimated from equations developed by Gomez, were independently predictive of progression to kidney failure and were strongly associated with the early structural determinants of that progression that were measured in kidney tissue obtained at kidney biopsy. The predominant structural lesions associated with these intraglomerular hemodynamic parameters included loss of glomerular filtration surface density, loss of endothelial fenestrations, increased width of the glomerular basement membrane, and increased mesangial and cortical interstitial fractional volumes. All of these are early structural lesions previously associated with progressive diabetic kidney disease. Interestingly, individuals with progressive diabetic kidney disease exhibited either changes in arteriolar resistance or changes in intraglomerular hydraulic pressure, but not both, suggesting that each of these trajectories associated with kidney failure represents a distinct phenotype and may reflect different mechanisms of diabetic kidney disease progression. In collaboration with the Joslin Diabetes Center, we published several papers examining circulating markers of progressive diabetic kidney disease that may reflect novel mechanisms of diabetic kidney disease that can be targeted with new renoprotective therapies. Specifically, unbiased, global miRNome and targeted proteomic approaches identified novel circulating miRNAs and circulating axon guidance proteins that strongly associated with the 10-year risk of kidney failure in both type 1 and type 2 diabetes and in both early and late kidney disease in different racial groups. The circulating proteins were also strongly associated with the early structural lesions identified on kidney biopsy. In a separate study we used an untargeted approach to examine 795 circulating proteins to identify those associated with progression of diabetic kidney disease to kidney failure. We identified 11 proteins associated with neuron development or with development of kidney fibrosis that strongly predicted kidney disease progression in both types of diabetes and in different racial groups. Since fibrosis is a major driver of chronic kidney disease, we collaborated with the MD Anderson Cancer Center at the University of Texas, the University of Michigan, the University of Minnesota, and the University of Washington to examine the role of a polyubiquitinated form of phosphatase and tensin homolog (PTEN) in progressive diabetic kidney disease. PTEN is known to promote epithelial-mesenchymal transition in vitro, which is a driver of kidney fibrosis. We demonstrated for the first time that higher serum PTEN was associated with increased risk of decline in the glomerular filtration rate and with an increased risk of kidney failure in American Indians with type 2 diabetes.