Delayed graft function in the kidney transplant

Abstract

Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories that continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process.

Conflict of interest statement

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1. Mechanism of Injury in the Kidney Transplant Process

(A) Ischemia. Microvascular tone increases in response to a decrease in blood pressure. Ischemia initiates signaling events on the vascular endothelial cell surface. Heat shock proteins and High-mobility-group B-1 activate Toll-like receptors which stimulate synthesis of MHC-1 molecules. Reactive oxygen species and an acidotic milieu result in phospholipolysis, endothelial membrane injury and thrombin-mediated fibrin deposition. In the tubular epithelial cell oxygen supply is depleted. ATP degrades forming superoxide among its byproducts. Excess adenosine nucleotides signal AMPK activation which limits the cell’s metabolic rate. Oxygen-carrying metalloproteins are degraded via heme oxygenase-1 (HO-1). Without ATP, Na/K ATPase exchangers cannot function leading to intracellular K+ and extracellular Na+ retention. (B) Reperfusion. Injury begins with complement activation, C5b binding to the membrane attack complex, and C5a to the C5a anaphylotoxin receptor. In response to ROS-mediated signaling leukocytes localize to the endothelial cell. Cell stress upregulates P-selectin surface receptor, β-integrins and chemokines such as monocyte chemoattractant protein-1. Dendritic cells present exogenous antigens to recipient secondary lymphoid tissue which transform T-cells from a naïve to a competent phenotype. Excess oxygen can not be utilized efficiently in mitochondria deficient of nucleoside precursors. NADPH oxidase is upregulated instead forming superoxide. In combination with an excess in nitric oxide, peroxynitrate leads to DNA strand rupture, lipid peroxidation, programmed cell death (apoptosis) and unprogrammed cell death (necrosis).

Figure 2. Gradations of Cellular Damage in the Kidney from Ischemia-reperfusion Injury 48–72hrs post-implantation

(A,B) Allograft, living donor (LD) (Periodic acid-Schiff). (A) Apical membrane of the proximal tubules is breached in isolated sections (black arrow) while the basement membrane remains adherent. Interstitial infiltrates are mild with few inflammatory cells (black triangle). Bowman’s space is present with little compression of the glomerulus (asterisk) (100x). (B) Mild cellular edema is present in the proximal tubule (arrow) with none in the thin segment of the loop of Henle (asterisk) (300x). (C,D) Allograft, donation after cardiac death (DCD) (Periodic acid-Schiff). (C) Proximal and distal tubule cell damage is evident with basement membrane separation (black arrow). (D) Rich interstitial leukocyte infiltration is present with little invasion of the tubular basement membrane (triangles). Tubular cells in the thin (T) and thick (Th) segments of the loop of Henle have separated from the basement membrane. Cellular edema is present (asterisk). (E,F) Native kidney ATN (Periodic acid-Schiff). (E) Proximal and distal segments of the tubule are damaged with extensive denudation of the basement membrane (black arrow). The Bowman’s capsule is expanded with debris in the urinary space (asterisk) and breakdown of basement membrane but (F) relatively less transmigration of leukocytes into the interstitium (black outline).

Figure 3. Delayed Graft Function risk calculator

Donor, recipient, and surgical factors are included in a functional nomogram. The information includes (A) continuous and categorical variables that have the highest likelihood of contributing to the development of DGF. (B) Patient characteristics are additive and correlate with a risk of DGF between 10–90%.

Figure 4. Treatment of Early Transplant Kidney Injury

(A) On endothelial cells the thrombin inhibitors (melagatran) prevent fibrinogen conversion to fibrin deposit. Anti-complement factor 5 antibody (eculizumab) prevents MAC formation and anaphylotoxin signaling. Inflammatory cell signaling is targeted by biologic agents that bind to α-P-glycoprotein ligand (YSPSL), CD-25 receptor (basiliximab) and CD-52 receptor (alemtuzumab). Multiple receptors are targeted with anti-thymocyte globulin including CD-8. Dopamine and carbon monoxide upregulate heme oxygenase-1 activity to convert metalloproteins to the more inert byproducts of biliverdin, Fe2+, and carbon monoxide.(B) In vascular smooth muscle cells vasospasm is relieved by inhibition of calcium binding to the actin myofilament. Endothelin-1A (bosentan) and adenosine receptor-1A antagonists (rolofylline) inhibit G protein coupled receptors which open inositol triphosphate-dependent calcium channels. Calcium channel blockers prevent calcium release through voltage-dependent channels.

Figure 4. Treatment of Early Transplant Kidney Injury

(A) On endothelial cells the thrombin inhibitors (melagatran) prevent fibrinogen conversion to fibrin deposit. Anti-complement factor 5 antibody (eculizumab) prevents MAC formation and anaphylotoxin signaling. Inflammatory cell signaling is targeted by biologic agents that bind to α-P-glycoprotein ligand (YSPSL), CD-25 receptor (basiliximab) and CD-52 receptor (alemtuzumab). Multiple receptors are targeted with anti-thymocyte globulin including CD-8. Dopamine and carbon monoxide upregulate heme oxygenase-1 activity to convert metalloproteins to the more inert byproducts of biliverdin, Fe2+, and carbon monoxide.(B) In vascular smooth muscle cells vasospasm is relieved by inhibition of calcium binding to the actin myofilament. Endothelin-1A (bosentan) and adenosine receptor-1A antagonists (rolofylline) inhibit G protein coupled receptors which open inositol triphosphate-dependent calcium channels. Calcium channel blockers prevent calcium release through voltage-dependent channels.