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

Abstract

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.

Figure 1

The large podocyte cell body (CB) localizes in the glomerular urinary space anchored to the capillary surface through major processes (MP) that branch into foot processes (FP) to cover the glomerular basement membrane (GBM) of the capillary wall (shown by black dashed circle). Foot processes experience the stretch caused by glomerular capillary pressure (P_GC, straight line arrows), resulting in tensile stress on the podocyte. The ultrafiltrate flowing over the cell body and major processes of the podocyte exerts fluid flow shear stress (FFSS) on podocytes (shown by blue curved arrows). Early hyperfiltration in the remaining kidney of donors results in increased FFSS on podocytes from increased single nephron glomerular filtration rate. These changes are later exacerbated by increased tensile stress on podocytes from a rise in glomerular capillary pressure (P_GC).

Figure 2

Hyperfiltration-mediated hemodynamic changes may be conceptualized as a continuum. In most kidney diseases, a gradual loss of functional nephrons over time leads to hyperfiltration in the remaining glomeruli. Adaptive changes initially appear in the form of increased single nephron glomerular filtration rate (SNGFR) from changes in renal blood flow and ultrafiltration coefficient (K_f). Over time, progressive loss of functional nephrons results in glomerular hypertension from increased glomerular capillary pressure (P_GC). We theorize that in the later stages of CKD with continuing loss of functional nephrons there will be a more rapid decline in GFR from acceleration in hyperfiltration-mediated injury. We propose that the cyclooxygenase 2 enzyme - prostaglandin E₂ - prostanoid receptor EP₂ (COX2-PGE₂-EP₂) axis and components of the renin-angiotensin-aldosterone system (RAAS) are relevant in the early and late stages of the hyperfiltration continuum, respectively (see text for details). The red arrow marks the average reported GFR in the early period following kidney donation. Early molecular, biochemical, and signaling changes in the podocyte prior to an elevation of P_GC are not known. Slow progression of the disease provides an opportunity for innovative intervention to protect the remaining kidney of donors.

Figure 3

Outline of a conceptual model of hyperfiltration-mediated injury in the remaining kidney in transplant donors. The 2 biomechanical forces, namely fluid flow shear stress (FFSS) caused by single nephron glomerular filtration rate (SNGFR) and tensile stress caused by glomerular capillary pressure (P_GC), mediate different pathways that can be potentially targeted by drug therapy (shown by lightning arrow). These forces have been shown to cause damage to the glomerular filtration barrier, leading to proteinuria and nephron loss. This begets additional nephron loss through further increasing the biomechanical forces, thus setting up a spiraling cascade.