Changing Protein Permeability with Nephron Loss: Evidence for a Human Remnant Nephron Effect

Background: If loss of functioning nephrons predisposes to glomerular barotrauma (a “remnant nephron” effect), then glomerular permeability should increase as glomerular filtration rate (GFR) falls, as is observed in animal models of nephron loss. Methods: Changes in net renal protein permeability, defined as proteinuria or albuminuria per mL/min of GFR, were measured in the setting of nephron loss due to kidney donation (Assessing Long Term Outcomes in Living Kidney Donors cohort) or progressive chronic kidney disease (CKD; Modification of Diet in Renal Disease [MDRD], African American Study of Kidney Disease [AASK], and Chronic Renal insufficiency Cohort [CRIC] studies). Results: Following kidney donation, renal albumin permeability increased by 31% from predonation levels (p < 0.001). With progression of CKD, a 50% loss of residual GFR was accompanied by increases in proteinuria per mL/min GFR of 1.8-, 2.1-, and 1.6-fold in the MDRD, AASK, and CRIC cohorts, respectively (p < 0.001 for all), independent of changes in systolic blood pressure and ACEi/ARB use. A 70% reduction in GFR was associated with permeability increases of 3.1-, 4.4-, and 2.6-fold in the same cohorts. Among MDRD participants with progression of nonglomerular primary disease, the 75th percentile of final permeability was 141 mg/24 h proteinuria per mL/min GFR. This degree of permeability would have resulted in nephrotic range proteinuria had it been present at the baseline mean GFR of 40 mL/min, implying the development of de novo glomerular pathology as GFR fell. Increasing permeability also accompanied CKD progression in participants with nephrotic syndrome at baseline. Consequently, these participants had little improvement in 24 h proteinuria or serum albumin, despite substantial loss of functioning nephron mass across which the protein leak occurred. In the absence of a fall in GFR, there was no increase in permeability in any cohort. Conclusion: Nephron loss is accompanied by an increase in renal protein permeability, even in the absence of a primary glomerular disease. This is consistent with a remnant nephron effect in human CKD.