Beneficial effects of brief early life angiotensin-converting enzyme inhibition wane with time in sheep with solitary functioning kidney

Abstract

A child with a congenital solitary functioning kidney (SFK) may develop kidney disease from early in life due to hyperfiltration injury. Previously, we showed in a sheep model of SFK that brief angiotensin converting enzyme inhibition (ACEi) early in life is reno-protective and increases renal functional reserve (RFR) at 8 months of age. Here we investigated the long-term effects of brief early ACEi in SFK sheep out to 20 months of age. At 100 days gestation (term=150 days) SFK was induced by fetal unilateral nephrectomy, or sham surgery was performed (controls). SFK lambs received enalapril (SFK+ACEi; 0.5mg/kg, once daily, orally) or vehicle (SFK) from 4 to 8 weeks of age. At 8, 14 and 20 months of age urinary albumin excretion was measured. At 20 months of age, we examined basal kidney function and RFR via infusion of combined amino acid and dopamine (AA+D). SFK+ACEi resulted in lower albuminuria (40%) at 8 months, but not at 14 or 20 months of age compared with vehicle-SFK. At 20 months, basal GFR (13%) was lower in SFK+ACEi compared with SFK, but renal blood flow (RBF), renal vascular resistance (RVR) and filtration fraction were similar to SFK. During AA+D, the increase in GFR was similar in SFK+ACEi and SFK animals, but the increase in RBF was greater (46%) in SFK+ACEi than SFK animals. Brief ACEi in SFK delayed kidney disease in the short-term but these effects were not sustained long-term.

Brief early life angiotensin-converting enzyme inhibition attenuates the diuretic response to saline loading in sheep with solitary functioning kidney

“…Only males were used in this study. Following recovery (∼10 days), the ewes were returned to the farm to lamb down, with birth weights previously reported [ 24 ]. Lambs from the SFK group ( n =19) were randomly assigned to undergo ACEi treatment at 4 weeks of age, via administration of enalapril (maleate salt, E6888) once daily orally ( n =10, 0.5 mg/kg/day, SFK+ACEi group), which was stopped at 8 weeks of age.…”

“…In addition, a polyethylene catheter was introduced into the jugular vein (PE tubing, 1.2 × 1.0, Microtube Extrusions, Australia) for infusion purposes. At 20 months of age each sheep underwent three separate studies: (1) vehicle infusion (time control study), previously reported as a singular average [ 24 ], (2) renal functional reserve study previously reported [ 24 ], and (3) isotonic saline load. Due to COVID-19 restrictions at the time of experimentation, we were unable to perform the saline experiment in n =3 animals (sham, n =1; SFK+ACEi, n =2); for continuity, all results are presented excluding these animals.…”

“…A limitation of the present study is that a sheep model of SFK, generated by the surgical removal of one kidney at 100 days gestation, cannot recapitulate the variation in the cause or timing of a kidney loss that occurs in humans that are born with a single kidney. In addition, the saline loading study was only performed at 20 months of age, which was 18 months after the withdrawal of ACEi treatment, when most physiological changes with this treatment had waned [ 24 ]. Examination of the responses to saline loading, when the responses to early life ACEi were more robust [ 23 ], would have strengthened the conclusions that could be drawn.…”

“…We have recently shown that a short period of ACEi early in the postnatal period (4–8 weeks of age) in SFK sheep reduces albuminuria independent of blood pressure lowering, improves kidney hemodynamics, renal functional reserve and nitric oxide bioavailability at 8 months of age [ 23 ]. Although these reno-protective benefits waned with age, with albuminuria similar to untreated SFK levels at 20 months, there were residual kidney functional changes still present 18 months after the withdrawal of ACEi [ 24 ].…”