A physiology-based approach to a patient with hyperkalemic renal tubular acidosis

Abstract

Hyperkalemic renal tubular acidosis is a non-anion gap metabolic acidosis that invariably indicates an abnormality in potassium, ammonium, and hydrogen ion secretion. In clinical practice, it is usually attributed to real or apparent hypoaldosteronism caused by diseases or drug toxicity. We describe a 54-year-old liver transplant patient that was admitted with flaccid muscle weakness associated with plasma potassium level of 9.25 mEq/L. Additional investigation revealed type 4 renal tubular acidosis and marked hypomagnesemia with high fractional excretion of magnesium. Relevant past medical history included a recent diagnosis of Paracoccidioidomycosis, a systemic fungal infection that is endemic in some parts of South America, and his outpatient medications contained trimethoprim-sulfamethoxazole, tacrolimus, and propranolol. In the present acid-base and electrolyte case study, we discuss a clinical approach for the diagnosis of hyperkalemic renal tubular acidosis and review the pathophysiology of this disorder.

Figure 1. (A) Pretreatment electrocardiogram with peaked T-waves, flattening of the P-wave, prolonged PR interval, and widening of the QRS complex. (B) Post-treatment electrocardiogram with normalization of T-waves, PR, and QRS intervals.

Figure 2. Interaction between potassium and proton excretion and ammoniagenesis. Sodium reabsorption by ENAC transporter in principal cells, driven by Na⁺/K⁺-ATPase, creates a lumen-negative transepithelial voltage that is critical for potassium (by ROMK) and proton (By H-ATPase) excretion in the collecting duct (CD). The excretion of H⁺ also requires the ammonia buffer that prevents a marked drop in urinary pH. Ammonia is produced in the proximal cells from glutamine and reaches tubular fluid as NH₄ ⁺. After, it is reabsorbed in the thick ascending limb to the interstitium and then is secreted as NH₃ into the CD by α-intercalated cells in parallel with the H⁺. Aldosterone (ALDO) is a pivot in these processes, stimulating both sodium reabsorption and ammoniagenesis. Impairment of the ENAC activity and/or Na⁺/K⁺-ATPase transporters, reduction of the amount of sodium delivered in CD, and the reduction in ammonia production are the main mechanisms involved in the pathogenesis of type 4 renal tubular acidosis. MR: mineralocorticoid receptor.

Figure 3. Pathophysiologic classification and etiologies of disorders associated with hyperkalemic hyperchloremic renal tubular acidosis. PHA: pseudohypoaldosteronism; CD: collecting duct; MR: mineralocorticoid receptor. ^a = The voltage defect causes a relative "resistance" to aldosterone in the CD, but does not interfere with its action on ammoniagenesis in the proximal cells; ^b = Others: Hyperkalemia due to these causes may be related to hyporeninemic hypoaldosteronism and/or a direct defect in voltage gradient generation in CD.

Figure 4. Clinical approach to the diagnosis of hyperkalemic RTA based on urine pH. Adapted from reference 1. *Antagonism, reduction or mutation in mineralocorticoid receptor.