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• W2127001878 abstract "We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell–mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell–mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence. We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell–mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell–mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence. Late failure of kidney transplants remains an important clinical problem (1Meier-Kriesche HU Schold JD Kaplan B Long-term renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies?.Am J Transplant. 2004; 4: 1289-1295Crossref PubMed Scopus (535) Google Scholar,2Lamb KE Lodhi S Meier-Kriesche HU Long-term renal allograft survival in the United States: A critical reappraisal.Am J Transplant. 2010; PubMed Google Scholar). In the United States, 5469 kidney transplants developed end-stage kidney failure in 2008 (data provided by Jon Snyder from USRDS), making kidney transplant failure the fourth leading cause of end-stage renal disease. The reasons for failure are not well understood. Some have postulated that late deterioration reflects dysregulated fibrosis, drug toxicity (3Nankivell BJ Borrows RJ Fung CL O’Connell PJ Allen RD Chapman JR The natural history of chronic allograft nephropathy.N Engl J Med. 2003; 349: 2326-2333Crossref PubMed Scopus (1687) Google Scholar) or progressive “chronic allograft nephropathy” (3Nankivell BJ Borrows RJ Fung CL O’Connell PJ Allen RD Chapman JR The natural history of chronic allograft nephropathy.N Engl J Med. 2003; 349: 2326-2333Crossref PubMed Scopus (1687) Google Scholar, 4Solez K Axelsen RA Benediktsson H et al.International standardization of criteria for the histologic diagnosis of renal allograft rejection: The Banff working classification of kidney transplant pathology.Kidney Int. 1993; 44: 411-422Abstract Full Text PDF PubMed Scopus (1301) Google Scholar, 5Nankivell BJ Chapman JR Chronic allograft nephropathy: Current concepts and future directions.Transplant. 2006; 81: 643-654Crossref PubMed Scopus (305) Google Scholar), although this term has been dismissed by the Banff pathology consensus because it does not represent a specific disease entity (6Solez K Colvin RB Racusen LC et al.Banff ‘05 Meeting report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’).Am J Transplant. 2007; 7: 518-526Crossref PubMed Scopus (934) Google Scholar). The more likely explanation is that kidney transplants are essentially stable after recovering from the stress of implantation until specific diseases or conditions develop (7Halloran PF Call for revolution: A new approach to describing allograft deterioration.Am J Transplant. 2002; 2: 195-200Crossref PubMed Scopus (94) Google Scholar), including antibody-mediated rejection (ABMR) and recurrent renal diseases (8Haas M Kraus ES Samaniego-Picota M Racusen LC Ni W Eustace JA Acute renal allograft rejection with intimal arteritis: Histologic predictors of response to therapy and graft survival.Kidney Int. 2002; 61: 1516-1526Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 9Macdonald FI Ashraf S Picton M et al.Banff criteria as predictors of outcome following acute renal allograft rejection.Nephrol Dial Transplant. 1999; 14: 1692-1697Crossref PubMed Scopus (43) Google Scholar, 10Briganti EM Russ GR McNeil JJ Atkins RC Chadban SJ Risk of renal allograft loss from recurrent glomerulonephritis.N Engl J Med. 2002; 347: 103-109Crossref PubMed Scopus (443) Google Scholar, 11El Zoghby ZM Stegall MD Lager DJ et al.Identifying specific causes of kidney allograft loss.Am J Transplant. 2009; 9: 527-535Crossref PubMed Scopus (626) Google Scholar, 12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). Recognition of C4d-negative ABMR (12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar,13Sis B Jhangri G Bunnag S Allanach K Kaplan B Halloran PF Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining.Am J Transplant. 2009; 9: 2312-2323Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar) created a new scenario: 50% of ABMR is currently missed, with the biopsy findings and clinical phenotypes wrongfully attributed to other processes such as “chronic allograft nephropathy” or calcineurin inhibitor toxicity (14Halloran PF de Freitas DG Einecke G et al.An integrated view of molecular changes, histopathology, and outcomes in kidney transplants.Am J Transplant. 2010; 10: 2223-2230Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar,15Gaston RS Cecka JM Kasiske BL et al.Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure 1.Transplantation. 2010; 90: 68-74Crossref PubMed Scopus (395) Google Scholar). Thus many patients presenting late with a biopsy for clinical indications have ABMR due to de novo donor-specific HLA antibodies, usually anti class II (16Hidalgo LG Campbell PM Sis B et al.De novo donor specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar), either C4d-positive or C4d-negative. This raises the question of why immunosuppression fails to prevent the development of de novo donor-specific antibodies (DSA) and ABMR. One possibility is nonadherence, which is difficult to detect until it presents as rejection, often resistant to therapy (17Butler JA Roderick P Mullee M Mason JC Peveler RC Frequency and impact of nonadherence to immunosuppressants after renal transplantation: A systematic review.Transplantation. 2004; 77: 769-776Crossref PubMed Scopus (427) Google Scholar, 18Denhaerynck K Dobbels F Cleemput I et al.Prevalence, consequences, and determinants of nonadherence in adult renal transplant patients: A literature review.Transpl Int. 2005; 18: 1121-1133Crossref PubMed Scopus (316) Google Scholar, 19Pinsky BW Takemoto SK Lentine KL Burroughs TE Schnitzler MA Salvalaggio PR Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression.Am J Transplant. 2009; 9: 2597-2606Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 20Prendergast MB Gaston RS Optimizing medication adherence: An ongoing opportunity to improve outcomes after kidney transplantation.Clin J Am Soc Nephrol. 2010; 5: 1305-1311Crossref PubMed Scopus (126) Google Scholar, 21Gaston RS Hudson SL Ward M Jones P Macon R Late renal allograft loss: Noncompliance masquerading as chronic rejection.Transplant Proc. 1999; 31: 21S-23SCrossref PubMed Scopus (106) Google Scholar). Another possibility is under-immunosuppression to avoid calcineurin inhibitor-induced failure, assuming that the nonspecific hyalinosis and fibrosis in late biopsies reflect progressive calcineurin inhibitor toxicity (3Nankivell BJ Borrows RJ Fung CL O’Connell PJ Allen RD Chapman JR The natural history of chronic allograft nephropathy.N Engl J Med. 2003; 349: 2326-2333Crossref PubMed Scopus (1687) Google Scholar). Thus some clinicians “minimize” immunosuppression, exactly the wrong action if a major risk is de novo HLA antibody formation and ABMR (16Hidalgo LG Campbell PM Sis B et al.De novo donor specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). Understanding the phenotype of every individual failure is an essential step in transplant progress (7Halloran PF Call for revolution: A new approach to describing allograft deterioration.Am J Transplant. 2002; 2: 195-200Crossref PubMed Scopus (94) Google Scholar). We previously postulated that progression to failure of a kidney transplant can be assigned to specific disease entities on the basis of such data as biopsy diagnosis and HLA antibody (7Halloran PF Call for revolution: A new approach to describing allograft deterioration.Am J Transplant. 2002; 2: 195-200Crossref PubMed Scopus (94) Google Scholar). Attribution of causality is not the same as biopsy diagnosis, which predicts future risk to some extent, but actually leaves many failures unexplained. Attribution involves assembling all evidence—biopsy, antibody and clinical—and deciding the best explanation for the clinical course. El-Zoghby et al. (11El Zoghby ZM Stegall MD Lager DJ et al.Identifying specific causes of kidney allograft loss.Am J Transplant. 2009; 9: 527-535Crossref PubMed Scopus (626) Google Scholar), in a retrospective review of failures at their center, although with incomplete HLA antibody data, found that glomerular pathologies cause the largest proportion of graft loss, with alloimmune mechanisms playing a major role. In a prospective study of patients followed after indication biopsies, we showed that kidneys diagnosed with ABMR or glomerulonephritis have a high probability of progression to failure (12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar), but that many cases of ABMR are currently misclassified as calcineurin inhibitor toxicity because they are C4d-negative. The high risk associated with ABMR was confirmed in a second prospective study (15Gaston RS Cecka JM Kasiske BL et al.Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure 1.Transplantation. 2010; 90: 68-74Crossref PubMed Scopus (395) Google Scholar). However, many individual cases are not explained in these studies because failure is related to conditions that begin the future (e.g. nonadherence) but not operating at the time of biopsy. Moreover, the biopsy diagnosis may have a complex relationship to the subsequent failure, which is not obvious. For example, treated T-cell–mediated rejection (TCMR) without DSA per se does not predict poorer graft survival (12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar), but if a late biopsy shows TCMR with no DSA and the graft subsequently fails with DSA, the TCMR may have been an indicator of nonadherence that eventually triggered DSA and ABMR. Thus, attributing causality to failure requires not only the biopsy findings, but also other features. The present prospective consented study in all patients enrolled at the time of an indication biopsy aimed to attribute a cause to each failure. This required the development of rules for attributing failures, based on biopsy diagnoses, anti-HLA, clinical information, and clinicians’ concerns about nonadherence. Written informed consent was obtained from all study patients. Patients were recruited from three centers: the University of Alberta (n = 180), the University of Minnesota (n = 99) and the University of Illinois (n = 35). The study was approved by the University of Alberta Health Research Ethics Board (Issue #5299), by the University of Illinois, Chicago (protocol #2006–0544) and by the University of Minnesota (protocol #0606M87646). Consenting patients undergoing a renal transplant biopsy for clinical indication (deterioration in function, proteinuria or stable but impaired function) as standard of care between September, 2004, and October, 2008, were included. Patients who received multiorgan transplants were excluded. Paraffin sections were prepared and graded according to the Banff criteria (22Sis B Mengel M Haas M et al.Banff ’09 meeting report: Antibody mediated graft deterioration and implementation of banff working groups.Am J Transplant. 2010; 10: 464-471Crossref PubMed Scopus (639) Google Scholar). C4d staining was performed on frozen sections using a monoclonal anti-C4d antibody (Quidel, San Diego, CA, USA) by indirect immunofluorescence. Diffuse linear C4d staining (i.e. in >50% of peritubular capillaries) was interpreted as positive. Biopsies were classified using a modified Banff classification (22Sis B Mengel M Haas M et al.Banff ’09 meeting report: Antibody mediated graft deterioration and implementation of banff working groups.Am J Transplant. 2010; 10: 464-471Crossref PubMed Scopus (639) Google Scholar) including C4d-negative ABMR and probable ABMR. C4d positive ABMR was defined according to the Banff criteria (22Sis B Mengel M Haas M et al.Banff ’09 meeting report: Antibody mediated graft deterioration and implementation of banff working groups.Am J Transplant. 2010; 10: 464-471Crossref PubMed Scopus (639) Google Scholar). C4d-negative ABMR was based on our previous description (12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar): DSA positive, nondiffuse C4d staining (negative or minimal focal or focal) and any of the following microcirculation lesions: peritubular capillaritis (ptc > 0), glomerulitis (g > 0), thromboses and transplant glomerulopathy (cg > 0). Probable ABMR was defined identically with the exception of being panel reactive antibody (PRA) positive but DSA negative (NDSA). Biopsies diagnosed as “no major abnormalities” were defined as having a ci-score (interstitial fibrosis) of <2 and no features of a disease process. Biopsies diagnosed as “atrophy–fibrosis” were defined as having a ci-score of >1 and no features of a disease process. Of 412 renal allograft biopsies, 372 had available serum at the time of biopsy for HLA antibody testing. HLA antibody testing method varied depending on the transplant center. Antibody specificities were either determined by Luminex single antigen beads for a small subset of samples (n = 15, 4%) or by FlowPRA single antigen I and II beads (One Lambda, Canoga Park, CA, USA) after a positive HLA antibody screening test using FlowPRA beads (n = 357, 86%) (16Hidalgo LG Campbell PM Sis B et al.De novo donor specific antibody at the time of kidney transplant biopsy associates with microvascular pathology and late graft failure.Am J Transplant. 2009; 9: 2532-2541Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). Blood samples for HLA antibody testing collected after the biopsy and used for these analyses were acquired before the date of kidney failure. No antibodies to non-HLA antigens were tested. Graft failure was either due to patient death or kidney function loss requiring renal replacement therapy and/or retransplantation. Nonadherence was recorded retrospectively by medical chart review, based on records of patient admission or strong clinical suspicion by the attending clinicians, independent of the study. Based on that definition, nonadherence was recorded at the time of biopsy in 22 patients and sometime after the last biopsy in four patients. For 35 patients whose charts were not available for review, we assumed adherence. Data analyses were performed using the statistical programming and graphics language “R”. Chi-square or Fisher’s exact tests were used for comparisons between groups for categorical data. We calculated conditional density plots using the “R” package “cdplot”. Probabilities are derived by applying a smoothing filter to the “R”“density” function. For the diagnostic categories, densities were derived from our dataset of indication biopsies, using the time of biopsy posttransplant. The nonadherence curve was plotted using only one data point per patient (i.e. the time posttransplant when nonadherence was recorded), as otherwise patients with more than one biopsy would create duplicate nonadherence times in the analysis. We prospectively studied 315 unselected consenting kidney transplant recipients undergoing 412 biopsies for clinical indications, 6 days to 32 years (median 17 months) posttransplant, with a median follow-up postbiopsy of 31.4 months. Detailed demographics are published elsewhere (23Sellares J de Freitas DG Mengel M et al.Inflammation lesions in kidney transplant biopsies: Association with survival is due to the underlying diseases.Am J Transplant. 2011; 11: 489-499Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Biopsies were classified by the Banff criteria incorporating C4d-negative ABMR (12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). The main diagnostic groups were ABMR (n = 73) (n = 17 C4d-positive and n = 56 C4d-negative, all but one of which had chronic active ABMR features), probable ABMR (n = 14), mixed rejection (n = 25), TCMR (n = 36), borderline (n = 39), polyoma virus nephropathy (PVN) (n = 12), glomerular diseases (n = 43), no major abnormalities (n = 119), atrophy–fibrosis (n = 31) and uncommon entities (“other”) (n = 20) (Figure 1A). During follow-up, 74 of 315 (24%) of allografts were lost: 60 due to kidney failure and 14 due to death with functioning kidney. The most frequent diagnoses in 182 early biopsies (<1 year) were acute kidney injury or TCMR/borderline (Figure 1A). In the first 6 weeks posttransplant (n = 79), 62% showed no major abnormalities, indicating that the dysfunction that triggered these biopsies mainly reflected acute kidney injury. (Because the centers participating in this study seldom perform transplants with positive crossmatches, early ABMR was rare.) In the 6 weeks to 6 months interval (n = 62), most biopsies showed no major abnormalities (39%), TCMR (24%) or borderline (14%). The diagnoses between 6 and 12 months (n = 41) were similar, except for more PVN (17%). The mix was different in the 230 late biopsies, including ABMR (29%), glomerular diseases (16%) or unexplained atrophy–fibrosis (11%). The probability of TCMR declined with time, being rare after a year. Clinical concerns about nonadherence were almost always recorded in relationship to late biopsies (25/26). Conditional probability plots (Figure 1B) show how the probability of each diagnosis (e.g. TCMR, ABMR) changes with time posttransplant. Thus the timing of the biopsy strongly influenced the probability of the biopsy diagnosis and the incidence of concerns about nonadherence by the attending clinicians. Fourteen patients died with a functioning graft (19% of failures): six from malignancies, two from sepsis, two from cardiovascular disease and four in which no cause could be assigned. Two deaths occurred in the first year, seven between years 1 and 5 and five after 5 years. Failure with return to dialysis or retransplantation occurred in 60 patients. In the last biopsies of kidneys that failed, the most frequent histologic diagnoses were ABMR/mixed (34 [56%]) and glomerulonephritis (12 [20%]). The ABMR/mixed group included 21 C4d-negative ABMR, seven C4d-positive ABMR, and six mixed rejection. Although the patients presenting for early and late biopsies have been followed for similar times postbiopsy, almost all failures occurred in patients presenting for late biopsies. Histologic diagnoses were different in the 60 kidneys that subsequently failed, compared to the 255 that had not failed: more ABMR or mixed rejection and fewer borderline or no major abnormalities (Table 1). Glomerular diseases were found both in kidneys that failed and those that did not, but the type differed: kidneys that progressed to failure had more aggressive diseases such as membrano-proliferative glomerulonephritis (MPGN) or focal segmental glomerulosclerosis, whereas grafts that did not fail often displayed IgA nephropathy. Four grafts displayed diabetic nephropathy, but none has failed.Table 1:Histological diagnosis and HLA antibody status of the transplants that failed during follow-up period versus those that did not fail, in the last biopsy available per patientCurrent status of the graftGrafts that did not failin the study periodFailed graftsTime of biopsy posttransplant15.4aMedian and brange shown in months. (0.2–427)b50aMedian and brange shown in months. (0.8–381.7)bDuration of follow-up after biopsy31.4aMedian and brange shown in months. (0–60.7)b24.6aMedian and brange shown in months. (0.3–36.9)bHistological diagnosisn%n%p-ValuesAntibody-mediated rejection3714%2847%4.66E-07Probable ABMR94%23%0.26Mixed rejection73%610%0.002T-cell–mediated rejection177%12%0.13Borderline2710%12%0.03Polyoma virus nephropathy52%12%0.88Glomerular diseases26cIg A nephropathy n = 8; Diabetic nephropathy n = 4; Membrano-proliferative glomerulonephritis (GN) n = 4; Focal and segmental glomerulosclerosis n = 2; Membranous nephropathy n = 1; Immuno-complex GN n = 3; Focal proliferative GN n = 2; Mesangial GN of unknown etiology n = 1; Chronic advanced GN with double contours n = 1.10%12dMembrano-proliferative GN n = 3; Focal and segmental glomerulosclerosis n = 4; Fibrillary GN n = 1; Immune complex GN n = 1; Crescentic GN n = 1; Focal proliferative GN n = 1; Severe parenchymal atrophy and fibrosis with one crescent in one glomerulus n = 1. ABMR = antibody-mediated rejection.20%0.15No major abnormalities9236%35%2.04E-06Atrophy-fibrosis239%35%0.25Other125%35%0.92Total255100%60100%Patients with donor-specific antibody at time or after the biopsy6626%3863%2.85E-08Patients with recorded non-adherence73%1932%0.0001a Median and brange shown in months.c Ig A nephropathy n = 8; Diabetic nephropathy n = 4; Membrano-proliferative glomerulonephritis (GN) n = 4; Focal and segmental glomerulosclerosis n = 2; Membranous nephropathy n = 1; Immuno-complex GN n = 3; Focal proliferative GN n = 2; Mesangial GN of unknown etiology n = 1; Chronic advanced GN with double contours n = 1.d Membrano-proliferative GN n = 3; Focal and segmental glomerulosclerosis n = 4; Fibrillary GN n = 1; Immune complex GN n = 1; Crescentic GN n = 1; Focal proliferative GN n = 1; Severe parenchymal atrophy and fibrosis with one crescent in one glomerulus n = 1. ABMR = antibody-mediated rejection. Open table in a new tab Concerns about nonadherence were recorded 10 times more frequently in patients whose graft subsequently failed (32%) than in those whose grafts have not failed (3%, p = 0.0001). Progression to failure after an indication biopsy does not necessarily mean that the failure was related to the biopsy diagnosis: A patient biopsied for acute kidney injury may later develop unrelated complications, e.g. recurrent disease. We sought to develop rules for attributing causality to each failure, to achieve rigor, transparency and accuracy. While development of rules requires arbitrary choices, these rules are largely based on published associations of failures with time and biopsy diagnosis (Figure 2, Table S1). Table 2 shows the precedence rules for resolving ambiguous situations. A full account of the logic and literature basis of the choices here will be published separately (Sellares et al., in preparation).Table 2:Precedence rules for resolving ambiguities in the attribution systemPrecedence rules1. Major medical/surgical events that lead to graft loss take precedence over the remaining attributed causes of failure2. Ambiguous failures are defined as those with moderate or severe atrophy-fibrosis and sclerotic glomeruli, and which have evidence for two attributions e.g. a nonrejection disease (e.g. recurrent GN, diabetic nephropathy, PVN) and ABMR (e.g. nonadherence, de novo DSA or NDSA). In ambiguous failures, only one cause will be attributed, based on the clinical judgment of the attributing physicians (JS and PFH).ABMR = antibody-mediated rejection; DSA = donor specific antibodies; NDSA = PRA positive with no identified DSA; GN = glomerulonephritis; PVN = polyoma virus nephropathy. Open table in a new tab ABMR = antibody-mediated rejection; DSA = donor specific antibodies; NDSA = PRA positive with no identified DSA; GN = glomerulonephritis; PVN = polyoma virus nephropathy. For example, Banff recognizes only two TCMR phenotypes: TCMR and chronic active TCMR. TCMR seldom progresses to failure in recent clinical trials and biopsy studies (23Sellares J de Freitas DG Mengel M et al.Inflammation lesions in kidney transplant biopsies: Association with survival is due to the underlying diseases.Am J Transplant. 2011; 11: 489-499Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 24Rasko JEJ Bailey CG Kowalczuk S et al.Genetics of human aminoacidurias.FEBS J. 2008; 275: 98Google Scholar, 25Famulski KS Einecke G Sis B et al.Defining the canonical form of T-cell-mediated rejection in human kidney transplants.Am J Transplant. 2010; 10: 810-820Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), but if it did, it should do so within a few months (11El Zoghby ZM Stegall MD Lager DJ et al.Identifying specific causes of kidney allograft loss.Am J Transplant. 2009; 9: 527-535Crossref PubMed Scopus (626) Google Scholar). If it fails many months or years later, there will often be a new condition operating. Chronic active TCMR may progress slowly but is uncommon, and in fact, was never diagnosed in this series. The predetermined rules incorporated all available biopsy information for the patient, as well as the clinical parameters such as eGFR, hematuria, proteinuria, HLA antibody status and major medical or surgical events after transplantation. Attribution was possible in 56 of 60 kidneys that progressed to failure (93%), assigning 36 to rejection (64%), 10 to glomerulonephritis (18%); four to suspected or proven PVN (7%) and six to intercurrent medical/surgical events (11%) (Figure 3B). Each failure was given a number (KF1–KF60) according to the date of failure (Table S2). Missing clinical information precluded attribution of four failures. No losses were attributed to unexplained fibrosis or calcineurin inhibitor toxicity, in keeping with previous studies (11El Zoghby ZM Stegall MD Lager DJ et al.Identifying specific causes of kidney allograft loss.Am J Transplant. 2009; 9: 527-535Crossref PubMed Scopus (626) Google Scholar,12Einecke G Sis B Reeve J et al.Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure.Am J Transplant. 2009; 9: 2520-2531Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar,15Gaston RS Cecka JM Kasiske BL et al.Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure 1.Transplantation. 2010; 90: 68-74Crossref PubMed Scopus (395) Google Scholar). All 36 rejection-related losses involved ABMR: 28 ABMR (all with features of chronic active ABMR, of which seven were C4d-positive), five probable ABMR and three mixed rejection. None was attributable to TCMR alone or chronic a" @default.
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• W2127001878 title "Understanding the Causes of Kidney Transplant Failure: The Dominant Role of Antibody-Mediated Rejection and Nonadherence" @default.
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• W2127001878 doi "https://doi.org/10.1111/j.1600-6143.2011.03840.x" @default.
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