Critical timing of ACEi initiation prevents compensatory glomerular hypertrophy in the remaining single kidney

Abhijit S Naik,Christopher L O'Connor,Jocelyn E Wiggins,Jawad Aqeel,Markus Bitzer,Su Q Wang,Roger C Wiggins,Mahboob Chowdhury

doi:10.1038/s41598-021-99124-z

Abstract

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. Modeling shows that post-nephrectomy compensatory glomerular volume (GV) increase drives podocyte depletion and hypertrophic stress resulting in proteinuria and glomerulosclerosis, implying that GV increase could serve as a therapeutic target to prevent progression. In this report we examine how Angiotensin Converting Enzyme inhibition (ACEi), started before uninephrectomy can reduce compensatory GV increase in wild-type Fischer344 rats. An unbiased computer-assisted method was used for morphometric analysis. Urine Insulin-like growth factor-1 (IGF-1), the major diver of body and kidney growth, was used as a readout. In long-term (40-week) studies of uni-nephrectomized versus sham-nephrectomized rats a 2.2-fold increase in GV was associated with reduced podocyte density, increased proteinuria and glomerulosclerosis. Compensatory GV increase was largely prevented by ACEi started a week before but not after uni-nephrectomy with no measurable impact on long-term eGFR. Similarly, in short-term (14-day) studies, ACEi started a week before uni-nephrectomy reduced both GV increase and urine IGF-1 excretion. Thus, timing of ACEi in relation to uni-nephrectomy had significant impact on post-nephrectomy “compensatory” glomerular growth and outcomes that could potentially be used to improve kidney transplantation and live kidney donation outcomes.

Highlights

Increasing evidence suggests that single in kidney states progressive glomerulosclerosis limits kidney lifespan
These data indicate that hypertrophic stresses incurred at transplantation could result in increased podocyte stress and detachment leading to progressive glomerulosclerosis and contributing to shortened allograft lifespan
Following uni-Nx rats remained relatively stable for about 15 weeks, albeit with increased urine volume and higher protein excretion compared to sham-Nx rats

Summary

Introduction

Increasing evidence suggests that single in kidney states (e.g., kidney transplantation and living donation) progressive glomerulosclerosis limits kidney lifespan. In uni-nephrectomized humans larger nephron size is associated with worse long-term outcomes[4] This raises the question of whether single kidney states should be viewed as metastable and at risk of reduced kidney lifespan absent hypertrophic stress prevention. A large meta-analysis of living donors shows higher urine protein excretion rates compared to controls that increases with time after donation suggesting ongoing progressive glomerular stresses[10]. A recent report suggests a significant benefit of angiotensin II blockade in allografts if initiated early after transplantation, a finding supported by a large systematic review[20,21] These data indicate that hypertrophic stresses incurred at transplantation could result in increased podocyte stress and detachment leading to progressive glomerulosclerosis and contributing to shortened allograft lifespan

Methods

Results

Conclusion