Sizzling Issues in Clinical Renal Transplantation

Abstract

The most common cause of renal allograft loss among patients who return to dialysis or undergo retransplantation is chronic allograft injury, which is morphologically characterized by interstitial fibrosis and tubular atrophy (IF/TA). The severity of the sclerosing kidney graft injury is primarily graded by the extent of tubulointerstitial damage. Clinically relevant Banff scores for interstitial fibrosis and tubular atrophy of ≥2 (representing ≥25% of the cortical area involved) are said to be clinically relevant. It has been suggested that this chronic allograft injury is the result of two different types of injury. An early phase (<1 year), which is characterized by mild tubulointerstitial damage, is the result of ischemic-reperfusion injury and subclinical and clinical allograft rejection. A late phase (>1 year), characterized by arteriolar hyalinosis, glomerulosclerosis, and additional tubulointerstitial damage, is the result of hypertension, calcineurin inhibitor (CNI) nephrotoxicity, and chronic humoral rejection (1). The acceptance of this framework implies that we should closely monitor the renal allograft compartment for markers of subclinical rejection, use potent immunosuppression in the early posttransplantation period (<6 months), and, later (>6 months), we should consider minimizing not only the dosage of immunosuppression but also the use of less nephrotoxic immunosuppressive agents. Addressing these goals has been the subject of multiple single-center and multicenter trials, but, so far, the identification of a safe and beneficial method has remained elusive. It must be kept in mind that once the “fibrotic process” begins, it inexorably leads to allograft loss. Over the years, many antifibrogenic strategies have been proposed (avoidance or dosage reduction of CNIs, use of mycophenolate mofetil, use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), blockade of endothelin or anti–TGF-β), but, unfortunately, none of them has consistently provided beneficial results. The authors of this study reported in a previous open-label, multicenter, randomized trial a very low (<5%) incidence of subclinical rejection during the first 6 months after transplantation (2). The study cohort (n = 218) consisted of patients who had low immunologic risk (white race, panel-reactive antibody <5%); received no induction therapy; and were treated with tacrolimus, mycophenolate mofetil, and prednisone. The study patients were randomly assigned to undergo protocol biopsies at engraftment and 1, 2, 3, 6, and 24 months (n = 111; biopsy group) or a biopsy at engraftment and at 6 and 24 months (n = 107; control group). The primary aim was to determine the prevalence of IF/TA (≥2). An additional goal was to determine the clinical value of protocol biopsies in the treatment of this selected group of patients. No statistical difference (P = 0.28) was found between the two groups, leading the authors to conclude that protocol biopsies are of no value in the treatment of these type of patients in the early posttransplantation period (2). Findings. This report is an extension (6 to 24 months) of the biopsy findings (25% of the original patients were discontinued from the study for various reasons) described already. By 24 months and despite the presence of preserved renal function (calculated creatinine clearance approximately 74 ml/min) and low-grade proteinuria (<500 mg/d), 40 to 50% of the patients had developed IF/TA ≥2. A logistic regression analysis identified deceased-donor status (did poorer) and the use of ACEIs and/or ARBs (did better) as the only two independent predictors of this outcome. Of note, the use of ACEIs and ARBs was identified by a post hoc analysis and was found to reduce the odds of IF/TA by four-fold. Commentary. The recruitment of profibrogenic cytokines (IL-1, IL-6, TGF-β, TNF-α, and adhesion molecules) by early intragraft events (e.g., ischemia-reperfusion injury, subclinical rejection) triggers a cascade of events that result in augmentation of collagen synthesis and ultimately lead to the demise of the allograft. Clearly, the sole reliance on the change of clinical markers such as creatinine, proteinuria, and estimated GFR is not adequate. A pragmatic, clinically applicable method to identify molecular markers of subclinical rejection has not yet been systematically demonstrated in controlled trials. Until this happens, the selective use of protocol biopsies remains a clinically useful tool. There is experimental and clinical evidence that the use of CNIs is associated with a profibrotic cytokine profile (TGF-β1 and tissue inhibitor of metalloproteinases) that leads to interstitial fibrosis as well as its abrogation by angiotensin II blockade (3). Even though the use of ACEIs and/or ARBs has not gained wide acceptance in the treatment of renal transplant recipients who are treated with CNIs (because of a potential for decreased renal blood flow and GFR associated with a single kidney), the findings by Rush et al. call for the execution of randomized, controlled clinical trials using this type of pharmacologic agent.