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.
This study of kidney transplant failures following biopsies for indication finds that most failures are due to antibody‐mediated rejection, with nonadherence playing an important role.
Single‐antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts ...have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor‐specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single‐antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third‐party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death‐censored graft survival (DCGS) and risk factors for rejection. Antibody‐mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell‐mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization.
When stratifying kidney transplant recipients by sensitization history and day of transplant serum analysis, univariate and multivariate analysis reveals donor‐specific sensitization to be the most important risk factor for rejection.
Predicting long‐term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence ...and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long‐term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA‐DR, ≥17 HLA‐DQ) or low epitope‐mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA‐DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA‐DQ locus nonadherent recipients with HLA‐DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring.
Using electronic monitors in medication vial caps and HLA class II epitope mismatch analysis, the authors find that medication nonadherence and HLA class II epitope mismatch act synergistically to predict renal allograft rejection and graft loss. See editorial from Glotz and Tambur on page 2021.
Advances in multimodal immunotherapy have significantly reduced acute rejection rates and substantially improved 1‐year graft survival following renal transplantation. However, long‐term (10‐year) ...survival rates have stagnated over the past decade. Recent studies indicate that antibody‐mediated rejection (ABMR) is among the most important barriers to improving long‐term outcomes. Improved understanding of the roles of acute and chronic ABMR has evolved in recent years following major progress in the technical ability to detect and quantify recipient anti‐HLA antibody production. Additionally, new knowledge of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. Still, questions regarding the classification of ABMR, the precision of diagnostic approaches, and the efficacy of various strategies for managing affected patients abound. This review article provides an overview of current thinking and research surrounding the pathophysiology and diagnosis of ABMR, ABMR‐related outcomes, ABMR prevention and treatment, as well as possible future directions in treatment.
This review addresses the spectrum of antibody‐mediated rejection after kidney transplantation, including its pathogenesis, risk factors, phenotypes, the revised Banff 2013 classification, treatment options, and outcomes. Also see meeting report by Haas et al on page 272.
OPTN/SRTR 2013 Annual Data Report: Kidney Matas, A. J.; Smith, J. M.; Skeans, M. A. ...
American journal of transplantation,
January 2015, 2015-Jan, 2015-01-00, 20150101, Volume:
15, Issue:
S2
Journal Article
Peer reviewed
ABSTRACT
A new kidney allocation system, expected to be implemented in late 2014, will characterize donors on a percent scale (0%‐100%) using the kidney donor profile index (KDPI). The 20% of ...deceased donor kidneys with the greatest expected posttransplant longevity will be allocated first to the 20% of candidates with the best expected posttransplant survival; kidneys that are not accepted will then be offered to remaining 80% of candidates. Waiting time will start at the time of maintenance dialysis initiation (even if before listing) or at the time of listing with an estimated glomerular filtration rate of 20 mL/min/1.73 m2 or less. Under the current system, the number of candidates on the waiting list continues to increase, as each year more candidates are added than are removed. Median waiting times for adults increased from 3 years in 2003 to more than 4.5 years in 2009. Donation rates have not increased. Short‐term outcomes continue to improve; death‐censored graft survival at 90 days posttransplant was 97% or higher for deceased donor transplants and over 99% for living donor transplants. In 2013, 883 pediatric candidates were added to the waiting list; 65.8% of pediatric candidates on the list in 2013 underwent deceased donor transplant. Five‐year graft survival was highest for living donor recipients aged younger than 11 years (89%) and lowest for deceased donor recipients aged 11 to 17 years (68%).
OPTN/SRTR 2011 Annual Data Report: Kidney Matas, A. J.; Smith, J. M.; Skeans, M. A. ...
American journal of transplantation,
January 2013, 2013-Jan, 2013-01-00, 20130101, Volume:
13
Journal Article
Peer reviewed
Open access
ABSTRACT A shortage of kidneys for transplant remains a major problem for patients with end‐stage renal disease. The number of candidates on the waiting list continues to increase each year, while ...organ donation numbers remain flat. Thus, transplant rates for adult wait‐listed candidates continue to decrease. However, pretransplant mortality rates also show a decreasing trend. Many kidneys recovered for transplant are discarded, and discard rates are increasing. Living donation rates have been essentially unchanged for the past decade, despite introduction of desensitization, non‐directed donations, and kidney paired donation programs. For both living and deceased donor recipients, early posttransplant results have shown ongoing improvement, driven by decreases in rates of graft failure and return to dialysis. Immunosuppressive drug use has changed little, except for the Food and Drug Administration approval of belatacept in 2011, the first approval of a maintenance immunosuppressive drug in more than a decade. Pediatric kidney transplant candidates receive priority under the Share 35 policy. The number of pediatric transplants peaked in 2005, and decreased to a low of 760 in 2011. Graft survival and short‐term renal function continue to improve for pediatric recipients. Posttransplant lymphoproliferative disorder is an important concern, occurring in about one‐third of pediatric recipients.
In the Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors (BENEFIT‐EXT), extended criteria donor kidney recipients were randomized ...to receive belatacept‐based (more intense MI or less intense LI) or cyclosporine‐based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent‐to‐treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI–treated, 138 of 175 belatacept LI–treated and 108 of 184 cyclosporine‐treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval CI 0.625–1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634–1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m2 were 0.754 (95% CI 0.536–1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499–0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept‐ and cyclosporine‐based treatment were similar. De novo donor‐specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.
In patients transplanted with an extended donation criteria kidney, belatacept‐based immunosuppression is associated with a similar death/graft loss and improved renal function at 7 years posttransplant as a cyclosporine‐based immunosuppression, with a safety profile consistent with previous reports.
The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute ...rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new‐onset late graft dysfunction (N = 337). We found inflammation (‘iatr’) and tubulitis (‘tatr’) in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death‐censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, 1.10–4.83; p = 0.0262) or TA (hazard ratio = 2.42, 1.16–5.08; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.
A more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide critical insight into the prognosis of late graft injury.
The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to ...determine if there were age‐related differences in metabolism and dose requirements. We studied 348 young (18–34 years), 1831 middle (35–64 years) and 374 older (65–84 years) adult kidney transplant recipients enrolled in a seven‐center prospective study. Troughs were obtained from each patient 2×/week in weeks 1–8 and 2×/month in months 3–6. A multivariable linear‐mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1–2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age‐related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly.
This study demonstrates that elderly kidney transplant recipients receive significantly lower doses of calcineurin inhibitors than younger recipients but yet maintain higher trough concentrations, suggesting age‐related changes in metabolism.
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