Kidney donors face a small but definite risk of end-stage renal disease 15-30 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 co-morbidities exacerbate the hyperfiltration-induced loss of kidney function in the years following 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. While tensile stress invokes the RAAS, FFSS predominantly activates the COX2-PGE2-EP2 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 COX2-PGE2-EP2 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. Address for Correspondence: Tarak Srivastava, M.D., Associate Professor in Pediatrics, Division of Nephrology, Children's Mercy Hospital, 2401 Gillham Road,, Kansas City, MO 64108. Tel: 1-816-234-3010. Fax: 1-816-302-9919. Email: tsrivastava@cmh.edu AUTHORSHIP PAGE Contribution Drs. Srivastava, Hariharan, Alon, McCarthy, R. Sharma, El-Meanawy, Savin, and M. Sharma 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 manuscript as submitted. Drs. Srivastava and M. Sharma drafted the initial and completed the final versions of the manuscript for the group. Disclosure The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States Government. The authors declare no conflicts of interest. Funding 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). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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