Brief Early Life Angiotensin-Converting Enzyme Inhibition Offers Renoprotection in Sheep with a Solitary Functioning Kidney at 8 Months of Age

Zoe McArdle; Reetu R. Singh; Helle Bielefeldt-Ohmann; Karen M. Moritz; Michiel F. Schreuder; Kate M. Denton

doi:10.1681/ASN.2021111534

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Visual Abstract

Significance Statement

Children born with a solitary functioning kidney (SFK) can develop kidney injury as a consequence of glomerular hyperfiltration. Angiotensin-converting enzyme inhibitors (ACEis) reduce BP and are renoprotective in adults. Our study demonstrates that treatment with ACEi early in life (between weeks 4 and 8 after birth) in sheep born with a SFK prevents albuminuria and reduces glomerular hyperfiltration, thus maintaining renal functional reserve, 6 months after treatment withdrawal. Further, improvements in kidney function were associated with increased nitric oxide bioavailability. This study suggests ACEi for 1 month early in life may improve the trajectory for the development of kidney disease in individuals born with SFK.

Abstract

Background Children born with a solitary functioning kidney (SFK) are predisposed to develop hypertension and kidney injury. Glomerular hyperfiltration and hypertrophy contribute to the pathophysiology of kidney injury. Angiotensin-converting enzyme inhibition (ACEi) can mitigate hyperfiltration and may be therapeutically beneficial in reducing progression of kidney injury in those with an SFK.

Methods SFK was induced in male sheep fetuses at 100 days gestation (term=150 days). Between 4 and 8 weeks of age, SFK lambs received enalapril (SFK+ACEi; 0.5mg/kg per day, once daily, orally) or vehicle (SFK). At 8 months, we examined BP, basal kidney function, renal functional reserve (RFR; GFR response to combined amino acid and dopamine infusion), GFR response to nitric oxide synthase (NOS) inhibition, and basal nitric oxide (NO) bioavailability (basal urinary total nitrate and nitrite [NOx]).

Results SFK+ACEi prevented albuminuria and resulted in lower basal GFR (16%), higher renal blood flow (approximately 22%), and lower filtration fraction (approximately 35%), but similar BP, compared with vehicle-treated SFK sheep. Together with greater recruitment of RFR (approximately 14%) in SFK+ACEi than SFK animals, this indicates a reduction in glomerular hyperfiltration–mediated kidney dysfunction. During NOS inhibition, the decrease in GFR (approximately 14%) was greater among SFK+ACEi than among SFK animals. Increased (approximately 85%) basal urinary total NOx in SFK+ACEi compared with SFK animals indicates elevated NO bioavailability likely contributed to improvements in kidney function and prevention of albuminuria.

Conclusions Brief and early ACEi in SFK is associated with reduced glomerular hyperfiltration–mediated kidney disease up to 8 months of age in a sheep model.

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