Mathematical Model‐based Analysis of the Acute and Chronic Mechanisms of Diabetic Hyperfiltration
Authors: Hallow Melissa , Vallon Volker 
Published: November 2023

An increase in glomerular filtration rate (GFR) in early diabetes has been associated with development and progression of diabetic kidney disease. Our understanding of the mechanisms responsible for hyperfiltration and subsequent renal injury is incomplete, but may be critical for developing new approaches to prevent diabetic kidney disease. The tubular hypothesis of hyperfiltration proposes that hyperfiltration is initiated by a primary increase in sodium (Na) reabsorption in the proximal tubule (PT), due to tubular growth and increased Na‐glucose cotransport.

The renal response to a primary increase in PT Na reabsorption likely involves multiple mechanisms over both the acute and chronic timescales. A more complete understanding of the relative contributions of the driving mechanisms, as well as the relationship between the acute and chronic response, is needed to better understand how diabetic hyperfiltration is initiated and maintained. In this study, we utilized an integrated mathematical model of the renal vasculature, tubular Na and fluid handling, and systemic blood volume regulation to investigate the mechanisms responsible for the hyperfiltration response to increased Na reabsorption in the PT.

We find that both tubuloglomerular feedback (TGF) and decreased PT pressure likely contribute to the acute GFR response to increased PT reabsorption. However, these mechanisms and the acute GFR rise appear insufficient to fully return Na balance. Additional adaptations must occur chronically to restore Na balance – either distal Na reabsorption must be reduced to compensate for the increased PT reabsorption, or GFR must be further augmented to match Na excretion to intake. We find that when preglomerular autoregulation is intact, modest distal reductions in Na reabsorption can fully compensate, with no further increase in GFR needed. The distal effect is driven by true pressure‐natriuresis, but regulation by renal sympathetic nerve activity and the renin angiotensin aldosterone system moderate this effect and allow Na homeostasis with minimal increases in blood pressure. However, when preglomerular autoregulation or downregulation of distal Na reabsorption is impaired (as has been proposed in diabetes), Na balance is returned through a further increase in glomerular pressure/GFR.

In summary, these results suggest that the hyperfiltration response to a primary increase in PT Na reabsorption is multifactorial. While the acute response is likely dominated by TGF and tubular pressure changes, impaired renal autoregulation and impaired pressure natriuresis/ neurohumoral distal Na transport regulation contribute to the magnitude of the chronic hyperfiltration response and the associated increase in glomerular pressure. In other words, improving preglomerular autoregulation and/or restoring renal Na transport regulation may attenuate hyperfiltration/glomerular hypertension and thereby the drive to renal damage long‐term. An interactive interface to the model is available at qsp.engr.uga.edu:3838/Hyperfiltration_EB.