Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR

Abstract

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.

Inflammation: A Key Contributor to the Genesis and Progression of Chronic Kidney Disease

“…Indeed, metabolic acidosis in CKD is associated with more rapid CKD progression [30,31] and increased mortality [32] . Consistently maintaining normal ranges of serum HCO 3 -and correcting acidosis have been associated with favorable clinical outcomes [33][34][35][36][37][38] . Taken together, in early stages of CKD, serum total CO 2 can be normal at the cost of active compensation by individual nephrons.…”

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

“…Recently, alkali supplementation has been reported to attenuate the deterioration of kidney function in CKD patients with metabolic acidosis. 13,14 These data suggest a pathogenic role of an acidic environment for CKD progression, as well as the potential of therapeutic intervention targeting luminal acidity for CKD treatment. However, there has been only limited information as to how the physiologic low pH level may contribute to, or exacerbate, ROS accumulation in proteinuric kidney disease.…”

The Role of Bicarbonate in CKD

“…Multiple other mechanisms, including those involving angiotensin II and aldosterone, are probably involved as well (6). Wesson et al have shown that endothelin levels are increased (7,8). Other studies have suggested that tubule fluid pH may be an important factor in promoting tubule injury in the presence of proteinuria, with alkalinization, at least in vitro, ameliorating tubule cell injury (9).…”

“…From a clinical treatment perspective, at this point several studies in the last few years have suggested that the administration of sodium bicarbonate (or other alkali sources, such as citrate or fruits and vegetables) in patients with CKD, even with minimally decreased or even normal serum bicarbonate concentrations, may slow progression (8,(12)(13)(14)(15). Although all of these studies have been relatively small, they all point to a beneficial effect of alkali administration on progression of CKD.…”

“…This was accomplished with no increase in gastrointestinal adverse effects, which is another concern in giving sodium bicarbonate. Sodium citrate has been used effectively by others (8) to correct the acidosis of CKD, but it is more expensive and promotes aluminum absorption from the gut when given with aluminum-containing antacids; citrate would be an alternative if sodium bicarbonate was unacceptable.…”