A Mechanism for Pentamidine-Induced Hyperkalemia: Inhibition of Distal Nephron Sodium Transport

15 January 1995 | Volume 122 Issue 2 | Pages 103-106

Objectives: To determine whether pentamidine directly affects the transport of renal ions and thus provides a mechanism for hyperkalemia, which develops in as many as 100% of patients with the acquired immunodeficiency syndrome (AIDS) who receive pentamidine for more than 6 days.

Design: Transepithelial and single-channel electrical measurements were made on two models of distal-nephron ion transport: an amphibian distal-nephron cell line (A6) and primary cultures of rabbit cortical collecting tubules.

Results: Luminal bath application of pentamidine to A6 monolayers inhibited the amiloride-sensitive, short-circuit current with a 50% inhibitory concentration of 700 µmolars (five experiments). In the principal cell apical membranes of cortical collecting tubule primary cultures, amiloride-sensitive, 4-picosiemen Na⁺ channels in cell-attached patches were also identified. When the luminal membrane was directly exposed to 1.0 µmolars of pentamidine in the patch pipette solution, channel activity decreased by 40% (11 experiments). Channel inhibition rapidly reversed with washout of intrapipette pentamidine (four experiments). In contrast, replacement of either the luminal bath outside the patch pipette (four experiments) or the serosal bath (five experiments) with pentamidine did not significantly affect Na⁺ channel activity in the patches.

Conclusions: Luminal or "urinary" pentamidine inhibits distal nephron reabsorption of Na⁺ by blocking apical Na⁺ channels in a manner similar to "potassium-sparing" diuretics (for example, amiloride and triamterene). This results in a decrease in the electrochemical gradients that drive secretion of distal nephron K⁺. Because pentamidine is eliminated through urinary excretion, this renal tubular effect provides a mechanism for pentamidine-induced hyperkalemia.

Author and Article Information

From the University of Pennsylvania School of Medicine and Veterans Affairs Medical Center, Philadelphia, Pennsylvania, and Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, Georgia.
Requests for Reprints: Brian N. Ling, MD, Emory University School of Medicine, Renal Division, 1364 Clifton Road Northeast, Atlanta, GA 30322.
Acknowledgments: The authors thank Allyson Morrison and Elisabeth E. Seal for their technical assistance in preparing and maintaining the A6 cell cultures and rabbit cortical collecting tubule primary cultures.
Grant Support: By a Veterans Affairs Merit Review Award, an American Heart Association Established Investigator Award, a Grant-in-Aid Award, a grant from the Center for Excellence Program, a National Institutes of Health Clinical Investigator Award (K08-DK02111), and an Emory University Research Committee Award.