Development of cardiovascular disease due to renal insufficiency in male sheep following fetal unilateral nephrectomy.
BACKGROUND
Renal insufficiency is associated with the development of cardiovascular disease.


OBJECTIVE
This study investigated whether reduced fetal renal mass resulted in renal insufficiency, hypertension, cardiac dysfunction and whether these changes progressed with age.


RESULTS
Fetal uninephrectomy was performed at 100-day gestation (term, 150 days) and studies performed in male sheep from 6 weeks to 24 months of age. Renal function declined with age in sham animals as demonstrated by increasing plasma creatinine levels and urinary excretion of albumin. The age-related decline in renal function was exacerbated in animals that had undergone fetal uninephrectomy. Evidence of renal insufficiency was indicated from as early as 6 weeks of age with elevations in plasma creatinine (Ptreatment < 0.001), urea (Ptreatment < 0.001) and sodium (Ptreatment < 0.05) levels in uninephrectomized lambs as compared with sham animals. At 6 months, urinary albumin excretion (P < 0.001) was increased and urinary sodium excretion (P < 0.001) decreased in the uninephrectomized animals. By 24 months, renal function had deteriorated further with significant progression of albuminuria (P(treatment x age) < 0.001). Elevation of mean arterial pressure (approximately 15 mmHg) was associated with significantly increased cardiac output, stroke volume and plasma volume at 6 months; arterial pressure (approximately 27 mmHg) had increased further in uninephrectomized animals at 24 months and was driven by increased total peripheral resistance. Cardiac functional reserve (dobutamine challenge) was reduced in uninephrectomized animals at 6 and 24 months of age (Ptreatment < 0.001), and this was associated with left ventricular enlargement (P < 0.001) and reduced fractional shortening (P < 0.01).


CONCLUSIONS
Fetal uninephrectomy causing a reduction in nephron endowment results in an accelerated age-related decline in renal function. This is associated with an early onset of elevated blood pressure and impairments in cardiac structure and function.
Singh
Reetu R
RR
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
Denton
Kate M
KM
Bertram
John F
JF
Jefferies
Andrew J
AJ
Head
Geoffrey A
GA
Lombardo
Paul
P
Schneider-Kolsky
Michal
M
Moritz
Karen M
KM
D000818:Animals; D017704:Baroreflex; D001724:Birth Weight; D001794:Blood Pressure; D002316:Cardiotonic Agents; D002318:Cardiovascular Diseases / Q000209:etiology*; D004280:Dobutamine; D004452:Echocardiography; D045604:Extracellular Fluid / Q000378:metabolism; D005333:Fetus / Q000601:surgery; D006339:Heart Rate; D006706:Homeostasis; D007677:Kidney Function Tests; D008297:Male; D009392:Nephrectomy; D010953:Plasma Volume; D051437:Renal Insufficiency / Q000150:complications* / Q000151:congenital / Q000378:metabolism; D012756:Sheep
D002316:Cardiotonic Agents; D004280:Dobutamine