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]