Nephron endowment and the pathogenesis of chronic renal failure

Abstract

When glomerular filtration rate (GFR) in humans falls below about half of normal, a relentless progressive loss of function ensues, even when the original disease becomes inactive [1], This clinical phenomenon is modelled by partial ablation of renal mass in rats which leads to progressive proteinuria, systemic hypertension and glomerulosclerosis [2]. Study of rats subjected to extensive renal mass ablation has provided major insights into the progressive nature of kidney disease. As a compensatory response to reduced renal mass, surviving nephrons undergo adaptations in structure and function, including nephron hypertrophy and increases in single-nephron GFR to meet excretory demands [3] Brenner and colleagues proposed that maladaptive glomerular hemodynamic changes associated with increased single-nephron GFR initiate and perpetuate glomerular injury following renal mass ablation and suggested that similar events occur when nephrons are lost through disease [3, 4]. In response to reduced total GFR, increased single-nephron GFR was observed, mediated by elevated glomerular flows and pressures. Raised glomerular hydraulic pressure (glomerular hypertension) appears to be the major effector of glomerular injury following renal mass reduction [5–8]. In addition to the detrimental effects of acquired nephron loss, severe inborn deficits in total nephron supply also lead to progressive glomerular injury.