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

Thomas R. Kleyman, MD; Camille Roberts; and Brian N. Ling, MD
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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.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;122(2):103-106. doi:10.7326/0003-4819-122-2-199501150-00004
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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 µM (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 µM 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.

Figures

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Figure 1.
Structures of pentamidine and “potassium-sparing” diuretics such as amiloride, triamterene, and trimethoprim.
Grahic Jump Location
Grahic Jump Location
Figure 2.
Effect of pentamidine on short-circuit current (Isc) in A6 distal nephron cells.

The amiloride-sensitive component of the short-circuit current is expressed as a percentage of the control values. For pentamidine applied to the luminal surface, data are presented as the mean ± SE (five experiments).

Grahic Jump Location
Grahic Jump Location
Figure 3.
Effect of intrapipette pentamidine on Na+ channel activity in rabbit cortical collecting tubule primary cultures.Top.Bottom.

Open probability was measured from apical, cell-attached patches containing only one Na+ channel. Open probability was calculated from 3 minutes of continuous recording at the resting principal cell membrane potential. Lines connect data from the same patch experiment. Actual single-channel traces from the patch represented by open circles in the top panel. Downward channel transitions represent inward current (pipette to cell) or Na+ reabsorption at resting membrane potential. Original corner frequency was done at 1 KHz, sampling at 2 KHz, and additional software filtering at 200 Hz. C = zero current level (closed state); O = open state; pA = picoamperes.

Grahic Jump Location

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