Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Dietary casein promotes a progressive decline in the glomerular filtration rate (GFR) of remnant kidneys associated with metabolic acidosis and an endothelin-mediated increase in renal acidification. We tested whether diets that affect the acid-base status contributes to the decline of GFR through endothelin receptors in rats with a remnant kidney. Rats on a casein diet had metabolic acidosis at baseline and developed a progressive decline in GFR after renal mass reduction. Dietary sodium bicarbonate but not sodium chloride ameliorated metabolic acidosis and prevented the decrease in GFR but only after the sodium bicarbonate-induced increase in blood pressure was treated. Dietary soy protein did not induce baseline metabolic acidosis and rats with remnant kidney on a soy diet had no decrease in their GFR. By contrast, rats with a remnant kidney on soy protein given dietary acid developed metabolic acidosis and a decreased GFR. This decline in GFR was prevented in either case by endothelin A but not endothelin A/B receptor antagonism. Our study suggests that the casein-induced decline in GFR of the remnant kidney is mediated by metabolic acidosis through endothelin A receptors.

Reduction in blood pressure can be achieved by inducing immunity against targets in the RAAS. The target antigen and selection of adjuvant are crucial factors determining effectiveness and safety of the vaccine. CYT006-AngQb (angiotensin II vaccine) reduced blood pressure in humans but the results were not reproducible with more frequent dosing. Vaccines for hypertension are still in the early phase. We hope for an effective vaccine for hypertension in the years to come.