Brian J. Nankivell

Banff '05 Meeting Report: Differential Diagnosis of Chronic Allograft Injury and Elimination of Chronic Allograft Nephropathy (‘CAN’)

The 8th Banff Conference on Allograft Pathology was held in Edmonton, Canada, 15–21 July 2005. Major outcomes included the elimination of the non‐specific term ‘chronic allograft nephropathy’ (CAN) from the Banff classification for kidney allograft pathology, and the recognition of the entity of chronic antibody‐mediated rejection. Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference.

Rejection of the Kidney Allograft

This review gives an account of our current understanding of the mechanisms of rejection of renal allografts. New immunosuppressive agents show promise, but graft survival beyond 5 years has not improved substantially.

Chronic allograft nephropathy: current concepts and future directions.

The paradigm that chronic rejection causes all progressive late allograft failure has been replaced by a hypothesis of cumulative damage, where a series of time-dependent immune and nonimmune mechanisms injure the kidney and lead to chronic interstitial fibrosis and tubular atrophy, representing a final common pathway of injury and its consequent fibrotic healing response. Allograft damage is common, progressive, time-dependent, clinically important and modified by immunosuppression. Early after transplantation, tubulointerstitial damage is predominantly related to ischemia reperfusion injury, acute tubular necrosis, acute and subclinical rejection and/or calcineurin inhibitor nephrotoxicity, superimposed on preexisting donor disease. Later, cellular inflammation lessens and is replaced by microvascular and glomerular injury from calcineurin inhibitor nephrotoxicity, hypertension, immune-mediated fibrointimal vascular hyperplasia, transplant glomerulopathy and capillary injury, polyoma virus and/or recurrent glomerulonephritis. Additional mechanisms of injury include internal architectural disruption of the kidney, cortical ischemia, persistent chronic inflammation, replicative senescence, cytokine excess and fibrosis induced by epithelial-to-mesenchymal transition. Current understanding of the etiology, pathophysiology and evolution of pathological changes are detailed. An approach to histological assessment of the individual failing graft are presented and a series of postulates are defined for future studies of chronic allograft nephropathy.

PREDICTING GLOMERULAR FILTRATION RATE AFTER KIDNEY TRANSPLANTATION

Serum creatinine is an important clinical measure of impairment of glomerular filtration rate (GFR) after kidney transplantation. The use of formulas that predict GFR (such as the Cockcroft-Gault) derived from patients with chronic renal failure and standardized against measured creatinine clearance may not be accurate when applied to kidney transplant recipients. The purpose of this study, was to investigate the level of inaccuracy and its causes and then to derive predictive GFR formulas that are appropriate to renal transplantation. Determinants of isotopic GFR, serum creatinine, and muscle mass were evaluated in consecutive kidney recipients (n = 146) using 99mTc DTPA GFR (n = 751) as a reference method. Factors that predicted GFR apart from serum creatinine included sex, height, body weight, serum urea, years on dialysis, numbers of rejections and infective episodes, and prednisolone dose. The relationship between serum creatinine and GFR was highly variable and dependent on factors that alter muscle mass and muscle catabolic rate. The relationship was further altered by ATN and chronic rejection when tubular secretion of creatinine was reduced. Three alternative GFR formulas (which can be applied to renal transplant patients according to the availability of clinical parameters) were derived and tested against six published methods of GFR estimation. Our derived formulas had the highest correlation, no overall bias, least scatter of sum of squares, and least error at low levels of GFR. They represent a better estimation of GFR in kidney transplantation than published formulas, and would allow a standardized approach to the study of long-term renal dysfunction.

Effect of histological damage on long-term kidney transplant outcome

Background. Chronic renal allograft failure remains a major challenge to overcome. Factors such as donor quality, delayed graft function (DGF), acute rejection, and immunosuppression are known to affect long-term outcome, but their relationship to histological damage to graft outcome is unclear. Methods. Protocol kidney biopsies (n=112) obtained at 3 months after transplantation yielded 102 with adequate tissue. Histology was scored by the Banff schema, and compared with implantation biopsies (n=91), repeat 12-month histology (n=39), decline in serum creatinine and serial isotopic glomerular filtration rate, onset of chronic allograft nephropathy (CAN), and actuarial graft survival censored for death with a functioning graft. Results. At a median follow-up of 9.3 years, 20 patients had graft failure and 26 died with a functioning graft. Banff chronic nephropathy was present in 24% of 3-month biopsies, and was predicted by microvascular disease in the donor, cold ischemia, DGF, and acute vascular rejection (P <0.001). Acute glomerulitis at 3 months correlated with segmental glomerulosclerosis at 12 months, subsequent recurrent glomerulonephritis, and graft failure (P <0.01). Subclinical rejection at 3 months occurred in 29% of biopsies, correlated with prior acute rejection and HLA mismatch, and led to chronic histological damage by 12 months (r =0.25–0.67, P <0.05–0.001). Subclinical rejection, arteriolar hyalinosis, and tubulitis present at 3 months had resolved by 12 months. The 10-year survival rates for Banff chronic nephropathy were 90.4% for grade 0, 81.0% grade 1, and 57.9% for grades 2 or greater (P <0.01). Early tubulointerstitial damage at 3 months profoundly influenced graft survival beyond 10 years. CAN was predicted by kidney ischemia, 3-month chronic intimal vascular thickening, tubular injury, proteinuria, and late rejection. Chronic fibrointimal thickening of the small arteries and chronic interstitial fibrosis at 3 months independently predicted graft loss and decline in renal function (P <0.05-0.001). Conclusions. Early transplant damage occurs in the tubulointerstitial compartment from preexisting donor kidney injury and discrete events such as vascular rejection and DGF. Subsequent chronic damage and graft failure reflect accumulated previous injury and chronic interstitial fibrosis, vascular impairment, subclinical rejection, and injury from late rejection. CAN may be conceptualized as the sequelae of incremental and cumulative damage to the transplanted kidney. The duration of graft survival is dependent and predicted by the quality of the transplanted donor kidney combined with the intensity, frequency, and irreversibility of these damaging insults.

Diagnosis and prevention of chronic kidney allograft loss

Kidney transplantation is the best possible treatment for many patients with end-stage renal failure, but progressive dysfunction and eventual allograft loss with return to dialysis is associated with increased mortality and morbidity. Immune injury from acute or chronic rejection and non-immune causes, such as nephrotoxicity from calcineurin inhibitors, ischaemia-reperfusion injury, recurrent glomerular disease, and allograft BK viral infection, are potential threats. Serial monitoring of renal function enables early recognition of chronic allograft dysfunction, and investigations such as therapeutic drug concentrations, urinalysis, imaging, and a diagnostic biopsy should be undertaken before irreversible nephron loss has occurred. Specific interventions targeting the pathophysiological cause of dysfunction include strengthening of immunosuppression for chronic rejection, or calcineurin inhibitor minimisation, substitution, or elimination if nephrotoxicity dominates. Recommended proactive preventive measures are control of hypertension, proteinuria, dyslipidaemia, diabetes, smoking, and other comorbidities. Strategies to maintain transplant function and improve long-term graft survival are important goals of translational research.

The significance of subclinical rejection and the value of protocol biopsies.

Subclinical rejection (SCR) is diagnosed by protocol histology with a maximal prevalence occurring early after transplantation, falling to low levels by 1 year. Needle‐core biopsy is safe, and the histology obtained fairly reflects subclinical immune activity. Several studies have consistently shown that SCR is associated with chronic tubulointerstitial damage, subsequent renal dysfunction and reduced graft survival. SCR is effectively treated by pulse corticosteroid therapy, although increased baseline immunosuppression may be necessary. A single randomized clinical trial of biopsy and corticosteroid therapy demonstrated significantly improved early structural and functional outcomes, and a (nonsignificant) 17% risk reduction in 4‐year graft survival. Three possible approaches include: no protocol biopsies (usually accompanied by powerful immunosuppression); biopsies only in high‐risk recipients (who may be difficult to reliably predict) or universal screening protocol biopsy (comprehensive but limited by cost and resource utilization). The appropriate screening methodology for a transplant unit is both a clinical and an economic decision; influenced by the SCR prevalence and potential gains of treatment, against costs and resource utilization. Further trials to quantify the cost‐benefit balance in a typical, heterogeneous recipient population using modern immunosuppression are required.

Predictors of renal transplant histology at three months.

BACKGROUND The quality of a damaged kidney, the complexity of the surgery, and the events in the first weeks after transplantation, such as delayed graft function (DGF) and acute rejection, may influence its histological appearance and long-term survival. The aim of this study was to evaluate the importance of these factors in predicting renal allograft histology at 3 months. METHODS Prospective, protocol kidney biopsy specimens (n=112), obtained 3 months after transplantation, were scored for chronic damage by the Banff schema and evaluated by multivariate analysis against donor factors, implantation histology, prior recipient sensitization, ischemia, perioperative factors, and subsequent clinical events, such as DGF and acute rejection. RESULTS Adequate samples were obtained in 102 of 112 biopsies and classified as chronic Banff grade 0 (n=22), grade I (n=56), grade II (n=23), or grade III (n=1). Acute Banff scores were minimal. DGF occurred in 49% and was the strongest predictor of tubulointerstitial damage at 3 months. DGF correlated with acute tubular necrosis on the implantation biopsy specimen and with the number of acute rejection episodes; DGF also correlated with the Banff grades of chronic glomerulitis, chronic interstitial fibrosis, and tubular atrophy scores (P<0.05-0.001) in the 3-month biopsy specimen. By multivariate analysis, chronic tubular atrophy was independently predicted by the presence of vascular disease in the donor biopsy specimen, DGF, and vascular rejection occurring within the first 3 months (P<0.05-0.001). Chronic interstitial fibrosis was unrelated to fibrosis in the donor biopsy specimen but was independently predicted by DGF, donor age, and vascular rejection (P<0.05-0.001). Vascular disease in the donor biopsy specimen correlated with chronic intimal thickening (r=0.36, P<0.01) and arteriolar hyalinosis score (r=0.54, P<0.001) on the 3-month biopsy specimen. Banff chronic intimal vascular thickening was independently predicted by donor biopsy specimen vascular grade, prior vascular rejection episodes, and renal cold ischemia time (P<0.05-0.01). There were no correlates with the mean cyclosporine (CsA) dose, blood levels, diagnosis of CsA toxicity, or cellular rejection within the first 3 months. CONCLUSIONS This study has demonstrated that the quality of the donor organ at implantation was strongly predictive of subsequent renal histology in grafts functioning at 3 months. Vascular rejection and DGF had a significant long-term effect on graft damage, but cellular rejection and simple measures of CsA exposure did not.

Banff Schema for Grading Pancreas Allograft Rejection: Working Proposal by a Multi-Disciplinary International Consensus Panel

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi‐disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell‐mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better‐ or worse‐graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody‐mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined.

Diabetic neuropathy after pancreas transplantation: determinants of recovery.

Although simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia and correction of uremia in type I diabetic patients with renal failure, little data are available on long-term outcome and clinical determinants of recovery of peripheral neuropathy. In this prospective study, 219 electrophysiological studies using a standardized protocol were performed before and up to 8 years after SPK in 44 patients. Nine control diabetic recipients with functioning kidney but nonfunctioning pancreas transplants were studied on 35 occasions. Patients were 38.5+/-7.9 years old (mean+/-SD) with pretransplant diabetes present for 25.2+/-7.6 years. Significant polyneuropathy (total nerve conduction scores [NCS] <-1.0) was present in 89% before transplantation, which correlated with body weight (r=0.628, P<0.001). Two distinct patterns of neurological recovery were observed after SPK. Conduction velocity (CV) improved in a biphasic pattern, with a rapid initial recovery followed by subsequent stabilization. In contrast, the recovery of nerve amplitude was monophasic, and continued to improve for up to 8 years. Initial improvement in NCS was primarily due to an increase in CV (P=0.002 vs. baseline), and was best in shorter and younger patients. Recovery of total NCS at 6 months after SPK, assessed by multivariate analysis, was least in obese recipients and when performed in patients who had started dialysis before SPK, and was associated with lower transplant kidney isotopic glomerular filtration rate and HLA mismatch (P<0.05 to 0.001). Subsequent improvement was associated with less severe initial neuropathy, smaller body weight, and longer duration of diabetes (P<0.01 to 0.001). Fasting hyperinsulinemia was associated with impairment of initial recovery and subsequent NCS after SPK, but was worse in the control group. Recovery of nerve action potential amplitudes was predicted by better initial amplitudes and HLA mismatch, lower body weight, and the use of nifedipine (P<0.05 to 0.001). Nifedipine was used for hypertension in 33% of SPK and was associated with better CV and amplitudes, particularly in the upper limbs, where there was less neuropathy. The use of angiotensin-converting enzyme inhibitors also appeared beneficial, but this was confined to the lower limbs. SPK resulted in a gradual, sustained, and late improvement in nerve action potential amplitudes, consistent with axonal regeneration and partial reversal of diabetic neuropathy. These data suggest that early transplantation of uremic diabetic patients before onset of severe neuropathy, minimizing obesity and optimizing renal transplant function, maximizes neurological recovery after SPK. Furthermore, the preliminary data support randomized clinical trials for evaluation of nifedipine and angiotensin-converting enzyme inhibitors in diabetic neuropathy.