Mechanisms of Metabolic Acidosis–Induced Kidney Injury in Chronic Kidney Disease

Abstract

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.Published online ahead of print. Publication date available at www.jasn.org.

Mechanism of Action of Veverimer: A Novel, Orally Administered, Nonabsorbed, Counterion-Free, Hydrochloric Acid Binder under Development for the Treatment of Metabolic Acidosis in Chronic Kidney Disease

“…HCl removal in this manner results in an elevation of serum bicarbonate (Figure 5 and Figure 6). In patients with CKD and metabolic acidosis, where kidney-mediated acid excretion is reduced resulting in acid retention (Wesson et al, 2020), veverimer can restore an important acid excretion capacity, and so is distinguished from other metabolic acidosis interventions that either reduce acid intake or neutralize systemic acidity.…”

“…Metabolic acidosis is a common disorder in patients with non-dialysis-dependent, stage 3 -5 chronic kidney disease (CKD) and is caused by the inability of the diseased kidney to quantitatively remove daily endogenous acid production (Alpern and Sakhaee, 1997;Hamm et al, 2015;Kraut and Madias, 2016). The result of this imbalance is that acid accumulates in the body and serum bicarbonate, the major extracellular acid buffer, and pH both fall from their normal ranges of 22 -29 mEq/L and 7.36 -7.44, respectively (Wesson et al, 2020). Chronic metabolic acidosis is recognized clinically as a persistent reduction of serum bicarbonate to less than the lower limit of normal, which is generally 22 mEq/L, in a patient with CKD and normal pulmonary function (Kraut and Madias, 2018;Raphael, 2018).…”

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

“…Protein catabolism generates acidic products, contributing to acidosis in the course of CKD and ESRD. Collectively, these abnormalities lead to a state of protein catabolism, resulting in a persistent negative nitrogen balance, leading to muscle wasting [120].…”

Assessing Acid-Base Status in Patients With CKD: Does Measurement of Blood pH Matter?

“…Stimulation of endothelin, aldosterone, the renin-angiotensin system, and ammonia production play a prominent role. 5 Importantly, the signal to increase production and secretion of these molecules appears to be alterations in the pH of the renal interstitial tissue or cells of various nephron segments. 6 The finding that hypobicarbonatemia with acidemia was associated with KFRT over 3 years in the present study emphasizes the importance of an acidic renal environment in mediating loss of kidney function over a relatively short duration.…”