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Paper of the Month: Anti-rejection drugs and hypertension Share This OHSU Content

nature medicine 150This month's featured paper is titled “The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension.” 

The research in this paper was conducted as part of an investigative collaboration at OHSU.*

The calcineurin inhibiting drugs (CNIs) cyclosporine and tacrolimus revolutionized organ transplantation, and are now standard components of nearly all anti-rejection regimens. Unfortunately, these drugs have substantial complications, including kidney failure, that complicate their use. One of the most important side effects is hypertension, often associated with hyperkalemia. This side effect resembles a genetic disease, familial hyperkalemic hypertension, which has been studied by the Ellison laboratory at OHSU and the Portland VA Medical Center for the last 10 years. This disease is caused by over-activity of the renal sodium chloride cotransporter (NCC).

“In 2008, I was approached by Ewout Hoorn, a third year resident from Erasmus University in the Netherlands, about the possibility that he could spend 6 months in my laboratory,” said David Ellison, MD, Professor, Department of Medicine and Head of the Division of Nephrology & Hypertension. “As a clinician, Ewout was interested in examining a medically relevant question, so we decided to test the hypothesis that CNIs cause hypertension by stimulating NCC in the kidney.” The results, published in the October issue of the journal Nature Medicine, confirm that hypothesis.

Dr. Stenzel-Poore:

This paper was selected because it provides important insight into how common anti-rejection medication causes the deleterious side effect of hypertension. This knowledge offers great promise for the development of new drugs that will limit the unwanted side effects of anti-rejection therapy and improve patient care.

Working at OHSU, Ewout Hoorn, MD, PhD, showed that the CNI tacrolimus caused salt-sensitive hypertension and potassium retention in mice; this was associated with an increase in the abundance of phosphorylated (activated) NCC. Colleagues from Berlin, Germany showed that NCC-expressing cells in kidney also contain the molecular target of tacrolimus, and Chao-Ling Yang, MD, Research Assistant Professor, Department of Medicine, in the Ellison laboratory, demonstrated that tacrolimus increases the abundance of phosphorylated NCC in cultured kidney cells. 

Although these results show that tacrolimus stimulates NCC activity in vivo and in vitro, they do not indicate whether stimulation of NCC causes the hypertension. To address this issue, Dr. Hoorn and colleagues analyzed effects of tacrolimus on blood pressure in mice that lack NCC. Strikingly, tacrolimus did not increase blood pressure in NCC-knockout mice at all. Because NCC-knockout mice lack NCC throughout life, however, developmental effects may have contributed to the tacrolimus resistance. To exclude this, the group showed that tacrolimus-induced hypertension could be reversed by treatment with a small molecule inhibitor of NCC (a thiazide diuretic). Further, the thiazide increased urine chloride excretion in tacrolimus-treated mice more than in controls, supporting the conclusion that tacrolimus causes hypertension by activating NCC.

Inasmuch as NCC-knockout mice were resistant to hypertension, the group next tested the effects of tacrolimus on transgenic mice overexpressing NCC (generated recently by Jim McCormick, PhD, in the McCormick laboratory). When treated with tacrolimus, mice overexpressing NCC developed more severe hypertension than did their wild-type counterparts.

As these studies were being conducted at OHSU, a group in London, headed by Robert Unwin, PhD, was studying the same phenomenon in humans. After initiating a transatlantic collaboration, the two groups showed that, just like in mice, thiazide had a larger effect in patients treated with CNIs than in controls. Further, the abundance of NCC was strikingly greater in the kidneys of CNI-treated patients than in patients treated with other immunosuppressive drugs.

Dr. Hoorn commented that, “our findings have implications for patient care today, and for drug development tomorrow. Today, they suggest that thiazide diuretics, which block NCC in the kidney, should be used to treat CNI-induced hypertension. For tomorrow, they suggest that it may be possible to develop drugs that suppress the immune system, without causing hypertension and kidney damage.”

 

Ellison lab





















Pictured above: (from left to right) James Conley, MD; Chao-Ling Yang, MD;  David Ellison, MD; Jim McCormick, PhD; Ewout Hoorn, MD, PhD; Shaunessy Rogers, and Tom Roeschel, all of whom contributed to the paper. The investigators from London and Berlin are not shown.

 

Paper Authors

Ewout J Hoorn MD, PhD, 1; Stephen B Walsh, 1, 2; James A McCormick, PhD, 1; Antje Fürstenberg, 2; Chao-Ling Yang, MD, 1; Tom Roeschel, 3; Alexander Paliege, 3; Alexander J Howie, 4; James Conley, MD, 1; Sebastian Bachmann, 3; Robert J Unwin, 2; David H Ellison, MD, 1, 5

Author Information

1 Division of Nephrology & Hypertension, OHSU    
2 UCL Centre for Nephrology, University College London, London, UK         
3 Department of Anatomy, Charité, Berlin, Germany
4 Department of Pathology, University College London, London, UK         
5 Veterans Affairs Medical Center, Portland, Oregon

ABOUT THE PAPER OF THE MONTH

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Associate Dean for Basic Science Mary Stenzel-Poore, PhD.

This paper was selected because it provides important insight into how common anti-rejection medication causes the deleterious side effect of hypertension. This knowledge offers great promise for the development of new drugs that will limit the unwanted side effects of anti-rejection therapy and improve patient care.