How does Acute Kidney Injury (AKI) cause metabolic acidosis?

How Acute Kidney Injury Causes Metabolic Acidosis

AKI causes metabolic acidosis primarily through impaired renal acid excretion—specifically reduced ammonia production and excretion by damaged tubules—combined with retention of organic acids and sulfates from protein metabolism that the failing kidneys cannot eliminate. 1, 2

Primary Mechanisms of Acid Accumulation

Impaired Renal Acid Excretion

• The kidneys normally excrete 50-100 mEq of acid daily through two mechanisms: titratable acid excretion and ammonia (NH3) production, with ammonia accounting for the majority of acid elimination 3
• In AKI, damaged proximal and distal tubular cells lose their ability to generate and excrete ammonia, which is the most critical defect leading to acid retention 2, 3
• Titratable acid excretion (primarily phosphate buffering) is relatively preserved until kidney function is severely impaired, making ammonia dysfunction the dominant early problem 3
• The inability to reabsorb filtered bicarbonate can occur but is less prominent than the failure to excrete acid 3

Retention of Metabolic Acids

• Protein catabolism—the metabolic hallmark of AKI—generates sulfuric and phosphoric acids from amino acid breakdown that accumulate when GFR falls 4, 1
• Organic acids (lactate, ketoacids) accumulate both from tissue hypoperfusion and from impaired renal clearance 1, 5
• In sepsis-associated AKI specifically, tissue hypoperfusion produces lactic acidosis while simultaneously the damaged kidneys cannot excrete the accumulated lactate 1

Type of Acidosis Produced

• AKI typically produces a high anion gap metabolic acidosis due to retention of unmeasured anions (sulfate, phosphate, organic acids) 2, 5
• Non-anion gap (hyperchloremic) acidosis can also occur, particularly when bicarbonate losses exceed acid retention or with certain tubular injury patterns 5
• The anion gap reflects the accumulation of unmeasured anions that the failing kidneys cannot eliminate 5

Contributing Metabolic Derangements

Systemic Metabolic Changes

• Peripheral insulin resistance and activation of hepatic gluconeogenesis occur in AKI, contributing to altered cellular metabolism and acid production 4
• Impaired lipid clearance with hypertriglyceridemia results from inhibition of lipolysis 4
• Depletion of antioxidant systems and pro-inflammatory state amplify cellular metabolic dysfunction 4

Inflammatory Mediators

• In sepsis-associated AKI, inflammatory mediators directly affect cellular metabolism, leading to metabolic derangements that worsen acidosis beyond simple retention 1

Clinical Context Variations

Severity Correlation

• The degree of metabolic acidosis generally correlates with AKI severity (KDIGO stages 1-3), as more extensive tubular damage produces greater impairment in acid excretion 4, 2
• Serum bicarbonate typically falls below 22 mEq/L, with proportional decreases in arterial pH 6, 3

Dialysis Considerations

• KDIGO guidelines specifically address sodium bicarbonate use in patients with AKI and metabolic acidosis, acknowledging this as a common complication requiring management 4
• Renal replacement therapy efficiently treats metabolic acidosis by removing accumulated acids and providing bicarbonate replacement 2

Important Clinical Pitfalls

• Do not assume normal serum bicarbonate excludes acid retention in early AKI—acid can accumulate before bicarbonate levels fall, particularly with ongoing dietary acid loads 3
• Inappropriately low urinary ammonia excretion (when measurable) confirms that impaired renal acid excretion is the pathogenic mechanism rather than excessive acid production alone 3
• The Surviving Sepsis Campaign specifically recommends against sodium bicarbonate therapy for lactic acidemia with pH ≥7.15, as treating the underlying sepsis and perfusion is more important than bicarbonate administration 1
• Concurrent medications (ACE inhibitors, ARBs, NSAIDs) can worsen both AKI and associated metabolic acidosis through hemodynamic effects 4, 7