Pathophysiology of hyperkalemia in kidney transplant
With an intracellular concentration of 150 mmol/L compared to 4 mmol/L in the extracellular compartment, potassium is the most abundant intracellular cation. Potassium intake, distribution between intracellular and extracellular compartments, and renal excretion help determine serum potassium concentration. In the distal nephron segments and mediated by aldosterone, potassium secretion takes place in response to distal sodium delivery which triggers sodium reabsorption via the epithelial sodium channel (ENaC). This action creates an electrical gradient that favors potassium secretion. [10] Medications used in KT are considered to be the major cause of hyperkalemia in a functioning graft.[7]
CNIs such as tacrolimus and cyclosporine are the core maintenance immunosuppressants in KT due to superior graft survival. They can, however, induce hyperkalemia by various mechanisms, with tacrolimus posing a significantly higher risk than cyclosporine.[11] These mechanisms include impaired function of the sodium-chloride cotransporter (NCC) in the distal convoluted tubule as well as downregulation of mineralocorticoid expression via RAAS suppression leading to hyperkalemic type 4 renal tubular acidosis. [12] In addition, supratherapeutic CNI concentrations can result in afferent renal arteriolar vasoconstriction and acute kidney injury resulting in impaired potassium elimination. [13-15] These mechanisms offer insight into unique treatment options for hyperkalemia.
Trimethoprim/Sulfamethoxazole (TMP/SMX) is an antimicrobial that is commonly used post-transplant to prevent pneumocystis pneumonia and urinary tract infections. Trimethoprim can cause hyperkalemia by blocking the epithelial sodium channel (ENaC) in the distal nephron, thereby impairing potassium elimination. [16] Of note, the incidence of hyperkalemia is relatively lower with a regimen consisting of one single strength tablet three times weekly compared to full dose (1-2 double strength tablets twice daily) regimens. [7]
Finally, the Renin-Angiotensin-Aldosterone-System (RAAS) inhibitors appeal for the management of hypertension as they have been shown to decrease proteinuria and decrease mortality in patients with CKD. However, RAAS inhibitor use post-transplant has been associated with a 2.2-fold increased risk for life-threatening hyperkalemia (defined as a K >6mmol/L), limiting their routine use. [17] Nevertheless, the introduction of the new potassium binders (patiromer and sodium zirconium cyclosilicate) may allow for the continuation of RAAS inhibitors in patients with compelling indications. [18]