This project, in part, represents an extension of work previously reported as Project Number Z01 DK69037. Glomerular function was measured initially over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Eighty-six of these subjects had type 2 diabetes and micro- or macroalbuminuria. Subjects underwent serial determinations of albuminuria and GFR. Many of these subjects continue to be followed and we have accumulated over 19 years of data on glomerular hemodynamic function in these patients. We also follow a population-based cohort of Pima Indians who are invited every two years to participate in a research examinination. The methods for this longitudinal study are described in detail in Project Numbers Z01 DK069097 and Z01 DK069000. Urinary albumin-to-creatinine ratios (ACRs) and serum creatinine concentration are measured at each of these examinations, and participants who progress to kidney failure are identified. In the last year, we examined the frequency distribution of albuminuria and estimated GFR (eGFR) in Pima Indians with type 2 diabetes in two time periods characterized by different therapeutic management of diabetic kidney disease to determine if a change in the distribution occurred and if this change was related to changes in diabetes management. We found that the frequency distribution changed significantly over the past 20 years. The redistribution of ACR towards lower values without a concomitant change in eGFR led to an increase in the proportion of those with chronic kidney disease characterized by low eGFR and normoalbuminuria, a condition virtually non-existent in diabetic Pima Indians in the 1980s. The doubling in the prevalence of this condition over the past two decades coincides with the introduction and widespread use of more effective medicines to manage hyperglycemia and blood pressure in the community and elsewhere. Although a causal relationship cannot be determined from an observational study, our results suggest that the finding of low eGFR and normal urinary albumin excretion in patients with type 2 diabetes is due, at least in part, to recent improvements in therapeutic management of diabetes and diabetic kidney disease rather than the emergence of an atypical form of diabetic kidney disease. We also examined the prognostic significance of elevated albuminuria in Pima Indian children to determine whether screening for kidney disease in youth predicts progressive kidney disease as it does in adults. We found that elevated ACR, using adult cut-points, was infrequent and largely transient in youth without diabetes, but in those with diabetes, elevated ACR was relatively frequent, largely persistent, and highly predictive of progression to more severe kidney disease. This observation supports the use of annual ACR screening in diabetic youth. Intrauterine exposure to diabetes is widely recognized to increase the risk of obesity and early-onset type 2 diabetes in the offspring, but the effect of this exposure on diabetic kidney disease is less well understood. We found that intrauterine exposure to diabetes was associated with a 4-fold increase in the incidence of end-stage renal disease in the young adult offspring with type 2 diabetes. This effect was explained largely by the earlier onset of diabetes associated with this exposure. In the coming year, changes in glomerular hemodynamics will be examined relative to structural damage identified by morphometric evaluation of kidney biopsies as reported in Project Number Z01 DK069100. We will also report on the predictive value of low estimated glomerular filtration rate and elevated albuminuria for kidney outcomes in a meta-analysis that includes 16 other cohorts. This project continues to yield new insights into the pathogenesis, course, and management of kidney disease in type 2 diabetes. Characterization of hemodynamic function over prolonged periods, combined with detailed clinical information derived from ongoing epidemiologic evaluation have greatly enriched the value of thhis data resource for studying diabetic kidney disease.
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