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.

Keywords: aldosterone; angiotensin; chronic kidney disease; chronic metabolic acidosis; endothelin; progression of chronic renal failure.

Figure 1.

Adaptive and maladaptive responses to metabolic acidosis in CKD. The adaptive response to metabolic acidosis in CKD is centered on an increase in ammoniagenesis, ET-1 production, and intrakidney RAAS expression (angiotensin II and aldosterone), all of which are necessary to promote acid excretion. In the adaptive response, these components activate NHE3-mediated Na⁺/H⁺ exchange, along with H⁺-ATPase and H⁺/K⁺-ATPase expression, and increase ammonium excretion to effectively increase acid excretion per nephron, thereby decreasing acid retention. However, sustained expression of this adaptive response, as seen in chronic metabolic acidosis, can lead to damaging activation of the alternative complement pathway cascade due to increased ammoniagenesis, along with production of proinflammatory and profibrotic mediators. This maladaptive response injures tubule-interstitial tissue, leading to loss of nephron function and worsening CKD.

Figure 2.

Angiotensin II: benefits and consequences. Angiotensin II expression is increased in response to metabolic acidosis. Increased intrakidney angiotensin II stimulates NHE3-mediated Na⁺/H⁺ exchange by increasing the content of this transporter in tubule cells, thereby increasing acid excretion. This short-term response can become maladaptive with continual acid exposure, because sustained intrakidney angiotensinII production is linked with proteinuria, tubular atrophy, inflammation, and fibrosis, which together promote further tubule-interstitial injury and worsening CKD. ECM, extracellular matrix; ETS-1, transcription factor erythroblastosis virus E26 oncogen homolog-1; NF-κΒ, nuclear factor κ-light-chain-enhancer of activated B cells; TLR-4, Toll-like receptor 4.

Figure 3.

ET-1: benefits and consequences. ET-1 is activated in response to metabolic acidosis. Increased intrakidney ET-1 stimulates NHE3-mediated Na⁺-H⁺ exchange and increases aldosterone activity in the kidney which increases acid excretion. This short-term response can become maladaptive with continual acid exposure, because sustained intrakidney ET-1 production is linked with proteinuria, inflammation, and fibrosis, which together promote further tubule-interstitial injury and worsening CKD. CTGF, connective tissue growth factor (CCN2); ECM, extracellular matrix; HCO₃⁻, bicarbonate; MCP-1, monocyte chemoattractant protein-1; NF-κΒ, nuclear factor κ-light-chain-enhancer of activated B cells.

Figure 4.

Ammonia: benefits and consequences. Metabolic acidosis increases ammoniagenesis, leading to increased acid excretion. Increased ammoniagenesis can increase local ammonia concentration surrounding the nephron, triggering activation of complement C3 and C5b-9 and the alternative complement pathway. Damage from this maladaptive complement activation includes increased production of inflammatory and profibrotic mediators, which can promote proteinuria, inflammation, and fibrosis, thus worsening tubule-interstitial injury and CKD. NH₃, ammonia; NH₄⁺, ammonium.