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. In the last year, we demonstrated that kidney failure risk equations developed in a Canadian population showed high discrimination when validated in 31 multinational cohorts that included 721,357 individuals. In non-North American cohorts, a calibration factor was necessary. This equation can be incorporated into health care systems to assist clinicians in managing their patients by providing an estimate of their level of risk for kidney disease progression. We published several papers with the CKD Prognosis Consortium in the past year, including one which examined the predictive value of current estimated GFR versus past estimated GFR for future risk of end-stage renal disease or mortality. We found that both past and current estimated GFR were useful predictors that contributed substantially to the risk of these major adverse health outcomes. These papers were meta-analyses of multiple cohorts worldwide, and each study included over 1 million participants. We reported findings from community-based participatory research in which patient perspectives on the germane research questions were incorporated into the studies. We described how this approach to organizing health outcomes research was beneficial in acquiring community buy-in to management of diabetic kidney disease. This work sets the stage for much larger diabetic kidney disease management efforts in remote high-risk communities. Our systems biology efforts continue to yield interesting findings. By integrating publicly available human protein-to-protein interaction networks with global metabolic networks using metabolomic data from patients with diabetic nephropathy, we identified an important functional role for MDM2 in the development of diabetic kidney disease. Significant downregulation of MDM2 gene expression was found in both the glomerular and tubulointerstitial compartments of kidney biopsy tissue from two independent cohorts, including the Pima Indians. We ultimately linked MDM2 to a reduction in 2 key metabolite biomarkers. In biomarker work, we reported that several advanced glycation end-products in Pima Indians with type 2 diabetes and early diabetic kidney disease are associated with specific lesions of diabetic kidney disease and with the loss of renal function that occurs in the presence of those lesions. We also found that a routine WBC count and differential provide clinically relevant information about diabetic kidney disease risk in Pima Indians and Caucasians with type 2 diabetes. Lymphocytes and neutrophils, which together represent >90% of WBCs, had the strongest associations with structural lesions of diabetic kidney disease in the Pimas and with renal function loss in French Caucasians from the SURDIAGENE study. Lastly, we found that in a type 1 diabetes cohort, higher plasma bradykinin and related peptide concentrations measured before the clinical onset of diabetic kidney disease were associated with preservation of glomerular structures, suggesting that elevations of these kinin concentrations may reflect adaptive responses to early renal structural changes in diabetic kidney disease.
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