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Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor

Srivastava, Tarak, MD1,2; Hariharan, Sundaram, MD3; Alon, Uri S., MD1; McCarthy, Ellen T., MD4; Sharma, Ram, PhD2; El-Meanawy, Ashraf, MD, PhD5; Savin, Virginia J., MD2,4; Sharma, Mukut, PhD2,4,6

doi: 10.1097/TP.0000000000002304
Reviews

Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and comorbidities exacerbate the hyperfiltration-induced loss of kidney function in the years after donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single-nephron glomerular filtration rate elevates FFSS on the podocyte cell body. Although tensile stress invokes the RAAS, FFSS predominantly activates the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.

A better understanding of the biomechanical forces of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration after kidney donation can lead to novel therapeutic agents to target FFSS through the COX2-PGE2-EP2 axis in hyperfiltration-mediated injury.

1 Section of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO.

2 Renal Research, Research and Development, Kansas City VA Medical Center, Kansas City, MO.

3 Department of Medicine and Surgery, Thomas E Starzl Transplant Institute, Pittsburgh, PA.

4 Kidney Institute, University of Kansas Medical Center, Kansas City, KS.

5 Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI.

6 Midwest Biomedical Research Foundation, KCVA Medical Center, Kansas City, MO.

Received 22 December 2017. Revision received 11 May 2018.

Accepted 15 May 2018.

This work was supported by NIDDK R01DK107490 (Srivastava, Sharma), the Department of Veterans Affairs, the Veterans Health Administration, Office of Research and Development, VA BX001037 (Savin, Sharma), DK 1RO1 DK064969 (McCarthy, Sharma), the Sam and Helen Kaplan Research Fund in Pediatric Nephrology (Alon, Srivastava), and the Midwest Biomedical Research Foundation (Savin, Sharma).

The authors declare no conflicts of interest.

T.S., S.H., U.S.A., E.T.MC., R.S., A.E.-M., V.J.S., and M.S. have worked closely together for many years. This overview is based on our earlier work and ongoing discussions within the group. All authors have been part of the conceptualization, design, review, revision, and approval of the final article as submitted. T.S. and M.S. drafted the initial and completed the final versions of the article for the group.

Correspondence: Tarak Srivastava, MD, Division of Nephrology Children's Mercy Hospital 2401 Gillham Road, Kansas City, MO 64108. (tsrivastava@cmh.edu).

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