The balance of RA and RE, a major determinant of intraglomerular pressure (P<glo), may be important in the initiation and progression of diabetic kidney disease (DKD). Although RA and RE are not directly measurable in humans these parameters can be estimated by the Gomez equation using measures of whole-kidney GFR and renal plasma flow (RPF), mean arterial pressure (MAP), hematocrit, and plasma oncotic pressure. We examined the association of the RA/RE ratio with ESKD incidence in 212 Pima Indians with T2D who underwent measures of GFR (iothalamate) and RPF (p-aminohippurate). RA/RE ratio’s association with kidney structural lesions was also examined in a subset of 111 participants. Of the 212 subjects (29% men; mean age 52 years, diabetes duration 22 years, MAP 92 mmHg, HbA1c 10.1%, GFR 111 ml/min; median ACR 99 mg/g), 57 progressed to ESKD during median follow-up of 18.4 years. Cox regression, adjusting for sex, baseline age, diabetes duration, HbA1c, renin-angiotensin system blocker use and GFR, indicated that each 1 SD increment in the RA/RE ratio conferred higher risk of ESKD (4.19; 95%CI 2.18-8.04). In addition, the correlation between the RA/RE ratio and mesangial fractional volume, a key predictor of DKD progression (R2=15%, P<0.0001), was stronger than the correlation between GFR and mesangial fractional volume (R2=7%, P=0.004). Elevated RA/RE ratio, reflective of low P<glo, strongly associates with incident ESKD, independent of GFR, and with the glomerular structural lesion that best predicts this ESKD progression. These data, directly challenging the hypothesis that intraglomerular hypertension drives DKD, are derived from whole-kidney GFR and RPF, and therefore do not necessarily reflect single-nephron function. Nevertheless, identifying the mechanisms underlying this hemodynamic imbalance and its potential ischemic influences may provide new therapeutic targets.
P. Saulnier: None. H.C. Looker: None. M. Mauer: None. R.G. Nelson: None. P. Bjornstad: Advisory Panel; Self; XORTX Therapeutics Inc. Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Novo Nordisk Foundation. Research Support; Self; Horizon Pharma.
American Diabetes Association (1-08-CR-42 to R.G.N.); National Institute of Diabetes and Digestive and Kidney Diseases