Noninvasive biomarkers are needed to assess immune risk and ultimately guide therapeutic decision‐making following kidney transplantation. A requisite step toward these goals is validation of markers ...that diagnose and/or predict relevant transplant endpoints. The Clinical Trials in Organ Transplantation‐01 protocol is a multicenter observational study of biomarkers in 280 adult and pediatric first kidney transplant recipients. We compared and validated urinary mRNAs and proteins as biomarkers to diagnose biopsy‐proven acute rejection (AR) and stratify patients into groups based on risk for developing AR or progressive renal dysfunction. Among markers tested for diagnosing AR, urinary CXCL9 mRNA (odds ratio OR 2.77, positive predictive value PPV 61.5%, negative predictive value NPV 83%) and CXCL9 protein (OR 3.40, PPV 67.6%, NPV 92%) were the most robust. Low urinary CXCL9 protein in 6‐month posttransplant urines obtained from stable allograft recipients classified individuals least likely to develop future AR or a decrement in estimated glomerular filtration rate between 6 and 24 months (92.5–99.3% NPV). Our results support using urinary CXCL9 for clinical decision‐making following kidney transplantation. In the context of acute dysfunction, low values can rule out infectious/immunological causes of injury. Absent urinary CXCL9 at 6 months posttransplant defines a subgroup at low risk for incipient immune injury.
In this multicenter observational study of 280 kidney transplant recipients, the investigators determine that, among multiple urinary mRNA and protein biomarkers studied, results of urinary CXCL9 protein ELISAs best identify patients at the lowest risk for ongoing and/or incipient immune‐mediated allograft injury. See editorial by Srinivas and Kaplan on page 2519.
The natural history for patients with de novo donor‐specific antibodies (dnDSA) and the risk factors for its development have not been well defined. Furthermore, clinical and histologic correlation ...with serologic data is limited. We studied 315 consecutive renal transplants without pretransplant DSA, with a mean follow‐up of 6.2 ± 2.9 years. Protocol (n = 215) and for cause (n = 163) biopsies were analyzed. Solid phase assays were used to screen for dnDSA posttransplant. A total of 47 out of 315 (15%) patients developed dnDSA at a mean of 4.6 ± 3.0 years posttransplant. Independent predictors of dnDSA were HLA‐DRβ1 MM > 0 (OR 5.66, p < 0.006); and nonadherence (OR 8.75, p < 0.001); with a strong trend toward clinical rejection episodes preceding dnDSA (OR 1.57 per rejection episode, p = 0.061). The median 10‐year graft survival for those with dnDSA was lower than the No dnDSA group (57% vs. 96%, p < 0.0001). Pathology consistent with antibody‐mediated injury can occur and progress in patients with dnDSA in the absence of graft dysfunction and furthermore, nonadherence and cellular rejection contribute to dnDSA development and progression to graft loss.
Prospective monitoring for de novo donor‐specific antibody in renal transplantation using clinical, serological and histopathological methods uncovers distinct clinical phenotypes and the pathology associated with them, as well as the independent risk factors for their development. See editorial by Kokko and Colvin on page 1077.
De novo donor‐specific antibody (dnDSA) develops in 15–25% of renal transplant recipients within 5 years of transplantation and is associated with 40% lower graft survival at 10 years. HLA epitope ...matching is a novel strategy that may minimize dnDSA development. HLAMatchmaker software was used to characterize epitope mismatches at 395 potential HLA‐DR/DQ/DP conformational epitopes for 286 donor–recipient pairs. Epitope specificities were assigned using single antigen HLA bead analysis and correlated with known monoclonal alloantibody epitope targets. Locus‐specific epitope mismatches were more numerous in patients who developed HLA‐DR dnDSA alone (21.4 vs. 13.2, p < 0.02) or HLA‐DQ dnDSA alone (27.5 vs. 17.3, p < 0.001). An optimal threshold for epitope mismatches (10 for HLA‐DR, 17 for HLA‐DQ) was defined that was associated with minimal development of Class II dnDSA. Applying these thresholds, zero and 2.7% of patients developed dnDSA against HLA‐DR and HLA‐DQ, respectively, after a median of 6.9 years. Epitope specificity analysis revealed that 3 HLA‐DR and 3 HLA‐DQ epitopes were independent multivariate predictors of Class II dnDSA. HLA‐DR and DQ epitope matching outperforms traditional low‐resolution antigen‐based matching and has the potential to minimize the risk of de novo Class II DSA development, thereby improving long‐term graft outcome.
This article provides a comprehensive evaluation of HLA Class II epitope mismatch load and epitope immunogenicity as predictors for de novo Class II donor‐specific antibody development in renal transplant recipients. See editorial by Tambur and Claas on page 3059.
Understanding rates and determinants of clinical pathologic progression for recipients with de novo donor‐specific antibody (dnDSA), especially subclinical dnDSA, may identify surrogate endpoints and ...inform clinical trial design. A consecutive cohort of 508 renal transplant recipients (n = 64 with dnDSA) was studied. Recipients (n = 388) without dnDSA or dysfunction had an eGFR decline of −0.65 mL/min/1.73 m2/year. In recipients with dnDSA, the rate eGFR decline was significantly increased prior to dnDSA onset (−2.89 vs. −0.65 mL/min/1.73 m2/year, p < 0.0001) and accelerated post‐dnDSA (−3.63 vs. −2.89 mL/min/1.73 m2/year, p < 0.0001), suggesting that dnDSA is both a marker and contributor to ongoing alloimmunity. Time to 50% post‐dnDSA graft loss was longer in recipients with subclinical versus a clinical dnDSA phenotype (8.3 vs. 3.3 years, p < 0.0001). Analysis of 1091 allograft biopsies found that dnDSA and time independently predicted chronic glomerulopathy (cg), but not interstitial fibrosis and tubular atrophy (IFTA). Early T cell–mediated rejection, nonadherence, and time were multivariate predictors of IFTA. Independent risk factors for post‐dnDSA graft survival available prior to, or at the time of, dnDSA detection were delayed graft function, nonadherence, dnDSA mean fluorescence intensity sum score, tubulitis, and cg. Ultimately, dnDSA is part of a continuum of mixed alloimmune‐mediated injury, which requires solutions targeting T and B cells.
In this study, the authors analyze clinical and histologic risk factors available at the time of de novo donor‐specific antibody detection to determine clinical and histologic predictors of subsequent allograft failure, and their importance for clinical trial design.
•We provide an overview of EEG-based techniques in the prognostic and diagnostic assessment of DoC.•We highlight bridging principles between conventional and investigational approaches.•We share ...expert opinions and considerations on the technical and conceptual caveats.
The analysis of spontaneous EEG activity and evoked potentialsis a cornerstone of the instrumental evaluation of patients with disorders of consciousness (DoC). Thepast few years have witnessed an unprecedented surge in EEG-related research applied to the prediction and detection of recovery of consciousness after severe brain injury,opening up the prospect that new concepts and tools may be available at the bedside. This paper provides a comprehensive, critical overview of bothconsolidated and investigational electrophysiological techniquesfor the prognostic and diagnostic assessment of DoC.We describe conventional clinical EEG approaches, then focus on evoked and event-related potentials, and finally we analyze the potential of novel research findings. In doing so, we (i) draw a distinction between acute, prolonged and chronic phases of DoC, (ii) attempt to relate both clinical and research findings to the underlying neuronal processes and (iii) discuss technical and conceptual caveats.The primary aim of this narrative review is to bridge the gap between standard and emerging electrophysiological measures for the detection and prediction of recovery of consciousness. The ultimate scope is to provide a reference and common ground for academic researchers active in the field of neurophysiology and clinicians engaged in intensive care unit and rehabilitation.
Previous studies suggest that quantifying donor‐reactive memory T cells prior to kidney transplantation by interferon gamma enzyme‐linked immunosorbent spot assay (IFNγELISPOT) can assist in ...assessing risk of posttransplant allograft injury. Herein, we report an analysis of IFNγELISPOT results from the multicenter, Clinical Trials in Organ Transplantation‐01 observational study of primary kidney transplant recipients treated with heterogeneous immunosuppression. Within the subset of 176 subjects with available IFNγELISPOT results, pretransplant IFNγELISPOT positivity surprisingly did not correlate with either the incidence of acute rejection (AR) or estimated glomerular filtration rate (eGFR) at 6‐ or 12‐month. These unanticipated results prompted us to examine potential effect modifiers, including the use of T cell‐depleting, rabbit anti‐thymocyte globulin (ATG). Within the no‐ATG subset, IFNγELISPOTneg subjects had higher 6‐ and 12‐month eGFRs than IFNγELISPOTpos subjects, independent of biopsy‐proven AR, peak PRA, human leukocyte antigen mismatches, African‐American race, donor source, and recipient age or gender. In contrast, IFNγELISPOT status did not correlate with posttransplant eGFR in subjects given ATG. Our data confirm an association between pretransplant IFNγELISPOT positivity and lower posttransplant eGFR, but only in patients who do not receive ATG induction. Controlled studies are needed to test the hypothesis that ATG induction is preferentially beneficial to transplant candidates with high frequencies of donor‐reactive memory T cells.
Analysis of data from the Clinical Trials in Organ Transplantation‐01 study associates a positive pretransplant donor‐reactive ELISPOT assay for interferon gamma with low posttransplant glomerular filtration rate, but only in patients who do not receive T cell‐depleting induction therapy with rabbit anti‐thymocyte globulin.
The first direct experimental observation of an electric quadrupole (E2) absorption transition between bound states of an atomic negative ion has been made. The transition was observed in the ...negative ion of bismuth by resonant (1+1) photon detachment from Bi^{-} via ^{3}P_{2}→^{3}P_{0} excitation. The E2 transition properties were completely independently calculated using a hybrid theoretical approach to account for the strong multilevel electron interactions and relativistic effects. The experimental and ab initio theoretical results are in excellent agreement, providing valuable new insight into this complex system and forbidden transitions in negative ions more generally.
Body linear measurements, and specifically heart girth (HG), have been shown to be useful predictors of cattle liveweight. To test the accuracy of body linear measurements for predicting liveweight, ...crossbred dairy cattle of different genotypes were measured and weighed. A total of 352 mature cows and 100 heifers were weighed using an electronic weighing scale and measurements of HG, body length, height at withers were taken using an ordinary measuring tape and body condition scored (BCS) using a five-point scale. The animals were grouped according to genotype and age. Genotype classification was undertaken from farmer recall and by visual appraisal as 40–60, 61–80 or 81–100 % exotic (non-indigenous). Age classification was simply as mature cows or heifers. Liveweight of the animals ranged from 102 to 433 kg. Liveweight was strongly correlated with HG (r = 0.84) and body condition scores (r = 0.70) and moderately correlated with body length (r = 0.64) and height at withers (0.61). Regressing LW on HG measurements gave statistically significant (P < 0.01) equations with R
2
ranging from of 0.53 to 0.78 and residual standard deviation ranging from 18.11 to 40.50 kg. The overall model developed (adjusted R
2
= 0.71) had a prediction error of 26 kg (or 11 % of the mean) and predicted LW of over 95 % of crossbred dairy cattle in the range of 100–450 kg, regardless of age and breed group. Including BCS in the model slightly improved the model fit but not the prediction error. It was concluded that the model can be useful in making general management decisions in smallholder farms.
De novo donor‐specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of ...first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell–mediated rejection (TCMR) or antibody‐mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post‐dnDSA graft loss was observed more frequently in recipients with C1q‐positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.
De novo donor‐specific antibody titer and C1q are not independent predictors of allograft survival following de novo donor‐specific antibody development after adjustment for nonadherence and clinical phenotype.
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