Clinical features, diagnostic, aetiology and outcome of hospitalised solid organ recipients with community-acquired pneumonia: a retrospective cohort analysis.

BACKGROUND: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Limited evidence is available on the most effective diagnostic approaches, management strategies, and long-term outcomes for CAP in patients who have undergone solid organ transplantation. RESEARCH QUESTION: What is the acute and long-term morbidity and mortality after CAP in organ transplant recipients? STUDY DESIGN AND METHODS: We retrospectively analysed hospitalisations for CAP in solid organ recipients at the largest German transplant centre. The study included patients admitted between 1 January 2010 and 31 May 2021. The reported outcomes are in-hospital and 1-year mortality, risk of cardiovascular events during hospitalisation and at one year, admission to the intensive care unit, and risk of pneumonia with P. aeruginosa. Multivariable binary logistic regression using stepwise forward selection was performed to determine predictive factors for pneumonia with P. aeruginosa. RESULTS: We analysed data from 403 hospitalisations of 333 solid organ recipients. In over 60% of cases, patients had multiple comorbidities, with cardiovascular and chronic kidney disease being the most prevalent. More than half of the patients required oxygen supplementation after admission. In-hospital mortality (13.2%) and the death rate at one year post-event (24.6%) were higher than data reported from immunocompetent patients. We also observed high rates of acute cardiovascular events and events occurring one year after admission. Early blood cultures and bronchoscopy in the first 24 hours significantly increased the odds of establishing an aetiology. In our low-resistance setting, the burden of antimicrobial resistance was driven by bacteria from chronically colonised patients, mostly lung transplant recipients. INTERPRETATION: This comprehensive analysis highlights the high morbidity associated with CAP after transplantation. It also emphasises the need for prospective multicenter studies to guide evidence-based practices and improve outcomes for these vulnerable patients.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.

Cognitive-behavioral and dietary weight loss intervention in adult kidney transplant recipients with overweight and obesity: Results of a pilot RCT study (Adi-KTx).

The obesity epidemic and its health consequences have not spared the population of kidney transplant (KTx) candidates and recipients. In addition, KTx recipients are susceptible to weight gain after transplantation. Overweight and obesity after KTx are strongly associated with adverse outcomes. Therefore, we designed a randomized controlled, mono-center study to specifically test the effectiveness of a primarily cognitive-behavioral approach supplemented by nutritional counseling for weight reduction following KTx as the intervention group (IG) in comparison to a brief self-guided intervention as control group (CG). The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00017226). Fifty-six KTx patients with a BMI from 27 to 40 kg/m2 were included in this study and randomized to the IG or CG. Main outcome was the number of participants achieving a 5% weight loss during the treatment phase. Additionally, participants were assessed 6 and 12 months after the end of the 6-month treatment phase. Participants significantly lost weight without group differences. 32.0% (n = 8) of the patients in the IG and 16.7% (n = 4) of the patients in the CG achieved a weight loss of 5% or more. Weight loss was largely maintained during follow-up. Retention and acceptance rate in the IG was high, with 25 (out of 28) patients completing all 12 sessions and one patient completing 11 sessions. Short-term, cognitive-behaviorally oriented weight loss treatment seems to be feasible and acceptable for patients after KTx who suffer from overweight or obesity. This clinical trial was ongoing at the onset of the COVID-19 pandemic which might have influenced study conduct and results. Clinical Trial Registration: https://clinicaltrials.gov/ DRKS-ID: DRKS00017226.

Live Donor Assessment Tool (LDAT): Reliability and Validity of the German Version in Living Kidney Donor Candidates.

BACKGROUND: The Live Donor Assessment Tool (LDAT) is a semi-structured psychosocial assessment tool for evaluating potential organ donors. It enables standardization of the psychosocial evaluation across institutions and allows the quantification of the evaluation result. OBJECTIVE: To evaluate the validity and reliability of the German version of the LDAT in living kidney donors. METHODS: We assessed the internal consistency and convergent validity (using known groups) of the German version of the LDAT in donor candidates who were evaluated at Hannover Medical School from May 2017 to December 2021. RESULTS: One hundred fifty-two donor candidates were evaluated. The mean age was 50.9 (standard deviation, 12.0), 99 were female (65.1%) and 53 (34.9%) were male candidates. LDAT scores ranged from 39 to 78 (possible maximum score = 82). The mean and median LDAT scores in the entire sample were 69 (standard deviation, 6.4) and 71 (95% confidence interval, 68; 70), respectively. The LDAT items demonstrated good internal consistency (α = 0.737). LDAT scores were significantly lower in high and moderate risk donors compared to a low/no risk group as determined by clinical evaluation. We found a significant positive association of the LDAT total score with age and a negative correlation with levels of depression and anxiety. The best cutoff score in our sample was 66.5 with an area under the curve of 93%. CONCLUSIONS: The German version of the LDAT was found to be a reliable and valid tool, which seems suitable to support psychosocial donor evaluation.

Relating Molecular T Cell-mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis.

BACKGROUND: We studied the variation in molecular T cell-mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant. METHODS: We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study ( ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier. RESULTS: Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection ("mixed") activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity. CONCLUSIONS: TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.

Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes.

We studied the clinical, histologic, and molecular features distinguishing DSA-negative from DSA-positive molecularly defined antibody-mediated rejection (mABMR). We analyzed mABMR biopsies with available DSA assessments from the INTERCOMEX study: 148 DSA-negative versus 248 DSA-positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA-positivity varied with mABMR stage: early-stage (EABMR) 56%; fully developed (FABMR) 70%; and late-stage (LABMR) 58%. DSA-negative patients with mABMR were usually sensitized, 60% being HLA antibody-positive. Compared with DSA-positive mABMR, DSA-negative mABMR was more often C4d-negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR-associated transcripts were identical in DSA-negative versus DSA-positive mABMR, for example, NK-associated (e.g., KLRD1 and GZMB) and IFNG-inducible (e.g., PLA1A). Genome-wide class comparison between DSA-negative and DSA-positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA-negative ABMR. Three-year graft loss in DSA-negative mABMR was the same as DSA-positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA-positive mABMR, DSA-negative mABMR is on average earlier, less active, and more often C4d-negative but has similar graft loss, and genome-wide analysis suggests that it involves the same mechanisms. SUMMARY SENTENCE: In 398 kidney transplant biopsies with molecular antibody-mediated rejection, the 150 DSA-negative cases are earlier, less intense, and mostly C4d-negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA-positive cases.

Archetypal Analysis of Injury in Kidney Transplant Biopsies Identifies Two Classes of Early AKI.

All transplanted kidneys are subjected to some degree of injury as a result of the donation-implantation process and various post-transplant stresses such as rejection. Because transplants are frequently biopsied, they present an opportunity to explore the full spectrum of kidney response-to-wounding from all causes. Defining parenchymal damage in transplanted organs is important for clinical management because it determines function and survival. In this study, we classified the scenarios associated with parenchymal injury in genome-wide microarray results from 1,526 kidney transplant indication biopsies collected during the INTERCOMEX study. We defined injury groups by using archetypal analysis (AA) of scores for gene sets and classifiers previously identified in various injury states. Six groups and their characteristics were defined in this population: No injury, minor injury, two classes of acute kidney injury ("AKI," AKI1, and AKI2), chronic kidney disease (CKD), and CKD combined with AKI. We compared the two classes of AKI, namely, AKI1 and AKI2. AKI1 had a poor function and increased parenchymal dedifferentiation but minimal response-to-injury and inflammation, instead having increased expression of PARD3, a gene previously characterized as being related to epithelial polarity and adherens junctions. In contrast, AKI2 had a poor function and increased response-to-injury, significant inflammation, and increased macrophage activity. In random forest analysis, the most important predictors of function (estimated glomerular filtration rate) and graft loss were injury-based molecular scores, not rejection scores. AKI1 and AKI2 differed in 3-year graft survival, with better survival in the AKI2 group. Thus, injury archetype analysis of injury-induced gene expression shows new heterogeneity in kidney response-to-wounding, revealing AKI1, a class of early transplants with a poor function but minimal inflammation or response to injury, a deviant response characterized as PC3, and an increased risk of failure. Given the relationship between parenchymal injury and kidney survival, further characterization of the injury phenotypes in kidney transplants will be important for an improved understanding that could have implications for understanding native kidney diseases (ClinicalTrials.gov #NCT01299168).

Graft function and pregnancy outcomes after kidney transplantation.

BACKGROUND: After kidney transplantation, pregnancy and graft function may have a reciprocal interaction. We evaluated the influence of graft function on the course of pregnancy and vice versa. METHODS: We performed a retrospective observational study of 92 pregnancies beyond the first trimester in 67 women after renal transplantation from 1972 to 2019. Pre-pregnancy eGFR was correlated with outcome parameters; graft function was evaluated by Kaplan Meier analysis. The course of graft function in 28 women who became pregnant after kidney transplantation with an eGFR of < 50 mL/min/1.73m2 was compared to a control group of 79 non-pregnant women after kidney transplantation during a comparable time period and with a matched basal graft function. RESULTS: Live births were 90.5% (fetal death n = 9). Maternal complications of pregnancy were preeclampsia 24% (graft loss 1, fetal death 3), graft rejection 5.4% (graft loss 1), hemolytic uremic syndrome 2% (graft loss 1, fetal death 1), maternal hemorrhage 2% (fetal death 1), urinary obstruction 10%, and cesarian section. (76%). Fetal complications were low gestational age (34.44 ± 5.02 weeks) and low birth weight (2322.26 ± 781.98 g). Mean pre-pregnancy eGFR was 59.39 ± 17.62 mL/min/1.73m2 (15% of cases < 40 mL/min/1.73m2). Pre-pregnancy eGFR correlated with gestation week at delivery (R = 0.393, p = 0.01) and with percent eGFR decline during pregnancy (R = 0.243, p = 0.04). Pregnancy-related eGFR decline was inversely correlated with the time from end of pregnancy to chronic graft failure or maternal death (R = -0.47, p = 0.001). Kaplan Meier curves comparing women with pre-pregnancy eGFR of ≥ 50 to < 50 mL/min showed a significantly longer post-pregnancy graft survival in the higher eGFR group (p = 0.04). Women after kidney transplantation who became pregnant with a low eGFR of > 25 to < 50 mL/min/1.73m2 had a marked decline of renal function compared to a matched non-pregnant control group (eGFR decline in percent of basal eGFR 19.34 ± 22.10%, n = 28, versus 2.61 ± 10.95%, n = 79, p < 0.0001). CONCLUSIONS: After renal transplantation, pre-pregnancy graft function has a key role for pregnancy outcomes and graft function. In women with a low pre-pregnancy eGFR, pregnancy per se has a deleterious influence on graft function. TRIAL REGISTRATION: Since this was a retrospective observational case series and written consent of the patients was obtained for publication, according to our ethics' board the analysis was exempt from IRB approval. Clinical Trial Registration was not done. The study protocol was approved by the Ethics Committee of Hannover Medical School, Chairman Prof. Dr. H. D. Troeger, Hannover, December 12, 2015 (IRB No. 2995-2015).

Antiviral T-Cell Frequencies in a Healthy Population: Reference Values for Evaluating Antiviral Immune Cell Profiles in Immunocompromised Patients.

Viral infections and reactivations are major causes of morbidity and mortality after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) as well as in patients with immunodeficiencies. Latent herpesviruses (e.g., cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6), lytic viruses (e.g., adenovirus), and polyomaviruses (e.g., BK virus, JC virus) can cause severe complications. Antiviral drugs form the mainstay of treatment for viral infections and reactivations after transplantation, but they have side effects and cannot achieve complete viral clearance without prior reconstitution of functional antiviral T-cell immunity. The aim of this study was to establish normal ranges for virus-specific T-cell (VST) frequencies in healthy donors. Such data are needed for better interpretation of VST frequencies observed in immunocompromised patients. Therefore, we measured the frequencies of VSTs against 23 viral protein-derived peptide pools from 11 clinically relevant human viruses in blood from healthy donors (n = 151). Specifically, we determined the VST frequencies by interferon-gamma enzyme-linked immunospot assay and classified their distribution according to age and gender to allow for a more specific evaluation and prediction of antiviral immune responses. The reference values established here provide an invaluable tool for immune response evaluation, intensity of therapeutic drugs and treatment decision-making in immunosuppressed patients. This data should make an important contribution to improving the assessment of immune responses in immunocompromised patients.

The Biology and Molecular Basis of Organ Transplant Rejection.

Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.

Determination of unacceptable HLA antigen mismatches in kidney transplant recipients.

With the introduction of the virtual allocation crossmatch in the Eurotransplant (ET) region in 2023, the determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients is of utmost importance for histocompatibility laboratories and transplant centers. Therefore, a joined working group of members from the German Society for Immunogenetics (Deutsche Gesellschaft für Immungenetik, DGI) and the German Transplantation Society (Deutsche Transplantationsgesellschaft, DTG) revised and updated the previous recommendations from 2015 in light of recently published evidence. Like in the previous version, a wide range of topics is covered from technical issues to clinical risk factors. This review summarizes the evidence about the prognostic value of contemporary methods for HLA antibody detection and identification, as well as the impact of UAM on waiting time, on which these recommendations are based. As no clear criteria could be determined to differentiate potentially harmful from harmless HLA antibodies, the general recommendation is to assign all HLA against which plausible antibodies are found as UAM. There is, however, a need for individualized solutions for highly immunized patients. These revised recommendations provide a list of aspects that need to be considered when assigning UAM to enable a fair and comprehensible procedure and to harmonize risk stratification prior to kidney transplantation between transplant centers.

Donor-Specific Antibody Is Associated with Increased Expression of Rejection Transcripts in Renal Transplant Biopsies Classified as No Rejection.

BACKGROUND: Donor -specific HLA antibody (DSA) is present in many kidney transplant patients whose biopsies are classified as no rejection (NR). We explored whether in some NR kidneys DSA has subtle effects not currently being recognized. METHODS: We used microarrays to examine the relationship between standard-of-care DSA and rejection-related transcript increases in 1679 kidney transplant indication biopsies in the INTERCOMEX study (ClinicalTrials.gov NCT01299168), focusing on biopsies classified as NR by automatically assigned archetypal clustering. DSA testing results were available for 835 NR biopsies and were positive in 271 (32%). RESULTS: DSA positivity in NR biopsies was associated with mildly increased expression of antibody-mediated rejection (ABMR)-related transcripts, particularly IFNG-inducible and NK cell transcripts. We developed a machine learning DSA probability (DSAProb) classifier based on transcript expression in biopsies from DSA-positive versus DSA-negative patients, assigning scores using 10-fold cross-validation. This DSAProb classifier was very similar to a previously described "ABMR probability" classifier trained on histologic ABMR in transcript associations and prediction of molecular or histologic ABMR. Plotting the biopsies using Uniform Manifold Approximation and Projection revealed a gradient of increasing molecular ABMR-like transcript expression in NR biopsies, associated with increased DSA (P<2 × 10-16). In biopsies with no molecular or histologic rejection, increased DSAProb or ABMR probability scores were associated with increased risk of kidney failure over 3 years. CONCLUSIONS: Many biopsies currently considered to have no molecular or histologic rejection have mild increases in expression of ABMR-related transcripts, associated with increasing frequency of DSA. Thus, mild molecular ABMR-related pathology is more common than previously realized.

Factors associated with kidney graft survival in pure antibody-mediated rejection at the time of indication biopsy: Importance of parenchymal injury but not disease activity.

We studied the relative association of clinical, histologic, and molecular variables with risk of kidney transplant failure after an indication biopsy, both in all kidneys and in kidneys with pure antibody-mediated rejection (ABMR). From a prospective study of 1679 biopsies with histologic and molecular testing, we selected one random biopsy per patient (N = 1120), including 321 with pure molecular ABMR. Diagnoses were associated with actuarial survival differences but not good predictions. Therefore we concentrated on clinical (estimated GFR [eGFR], proteinuria, time posttransplant, donor-specific antibody [DSA]) and molecular and histologic features reflecting injury (acute kidney injury [AKI] and atrophy-fibrosis [chronic kidney disease (CKD)] and rejection. For all biopsies, univariate analysis found that failure was strongly associated with low eGFR, AKI, CKD, and glomerular deterioration, but not with rejection activity. In molecular ABMR, the findings were similar: Molecular and histologic activity and DSA were not important compared with injury. Survival in DSA-negative and DSA-positive molecular ABMR was similar. Multivariate survival analysis confirmed the dominance of molecular AKI, CKD, and eGFR. Thus, at indication biopsy, the dominant predictors of failure, both in all kidneys and in ABMR, were related to molecular AKI and CKD and to eGFR, not rejection activity, presumably because rejection confers risk via injury.

Discovering novel injury features in kidney transplant biopsies associated with TCMR and donor aging.

We previously characterized the molecular changes in acute kidney injury (AKI) and chronic kidney disease (CKD) in kidney transplant biopsies, but parenchymal changes selective for specific types of injury could be missed by such analyses. The present study searched for injury changes beyond AKI and CKD related to specific scenarios, including correlations with donor age. We defined injury using previously defined gene sets and classifiers and used principal component analysis to discover new injury dimensions. As expected, Dimension 1 distinguished normal vs. injury, and Dimension 2 separated early AKI from late CKD, correlating with time posttransplant. However, Dimension 3 was novel, distinguishing a set of genes related to epithelial polarity (e.g., PARD3) that were increased in early AKI and decreased in T cell-mediated rejection (TCMR) but not in antibody-mediated rejection. Dimension 3 was increased in kidneys from older donors and was particularly important in survival of early kidneys. Thus high Dimension 3 scores emerge as a previously unknown element in the kidney response-to-injury that affects epithelial polarity genes and is increased in AKI but depressed in TCMR, indicating that in addition to general injury elements, certain injury elements are selective for specific pathologic mechanisms. (ClinicalTrials.gov NCT01299168).

Sex Differences in Subclinical Cardiovascular Organ Damage After Renal Transplantation: A Single-Center Cohort Study.

Background: Cardiovascular disease (CVD) is the leading cause of death after renal transplantation (RT). Sex-specific differences in CVD in the general population are well known. The aim of this study was to evaluate sex-specific differences in prevalence and course of subclinical cardiovascular (CV) organ damage in RT recipients during the first year after RT. Methods: In a prospective longitudinal study, we enrolled 121 patients (male 64%, age 51 ± 15 years). CV risk factors, left ventricular mass index (LVMI), and pulse wave velocity (PWV) were assessed at time of RT and 1 year later. Results: Women showed less prediagnosed CVD and better blood pressure (BP) control, and were less likely to be treated with calcium channel blockers (CCBs). Despite similar transplant function, LVMI increased in women and decreased in men (p = 0.027). In multivariable analysis, changes in LVMI were independently associated with female sex and systolic BP. Importantly, women receiving CCBs showed a decrease in LVMI and PWV. Conclusions: Our findings indicate a sex-specific association between RT and changes in LVMI. CCBs seem to have a positive impact on CV risk after RT, especially in women. Further studies on the effect of sex and CCB use in RT recipients are warranted.

Pretransplant dialysis modality and long-term patient and kidney allograft outcome: a 15-year retrospective single-centre cohort study.

Among factors determining long-term kidney allograft outcome, pretransplant renal replacement therapy (RRT) is the most easily modifiable. Previous studies analysing RRT modality impact on patient and graft survival are conflicting. Studies on allograft function are scarce, lack sufficient size and follow-up. We retrospectively studied patient and allograft survival together with allograft function and its decline in 2277 allograft recipients during 2000-2014. Pretransplant RRT modality ≥60 days as grouped into "no RRT" (n = 136), "haemodialysis (HD)" (n = 1847), "peritoneal dialysis (PD)" (n = 159), and "HD + PD" (n = 135) was evaluated. Kaplan-Meier analysis demonstrated superior 5-/10-/15-year patient (93.0/81.8/73.1% vs. 86.2/71.6/49.8%), death-censored graft (90.8/85.4/71.5% vs. 84.4/75.2/63.2%), and 1-year rejection-free graft survival (73.8% vs. 63.8%) in PD versus HD patients. Adjusted Cox regression revealed 34.5% [1.5-56.5%] lower hazards of death, whereas death-censored graft loss was similar [HR = 0.707 (0.469-1.064)], and rejection was less frequent [HR = 0.700 (0.508-0.965)]. Allografts showed higher 1-/3-/5-year estimated glomerular filtration rate (eGFR) in "PD" versus "HD" groups. Living donation benefit for allograft function was most pronounced in groups "no RRT" and "PD". Functional allograft decline (eGFR slope) was lowest for "PD". Allograft recipients on pretransplant PD versus HD demonstrated superior all-cause patient and rejection-free graft survival along with better allograft function (eGFR).

Discrepancy analysis comparing molecular and histology diagnoses in kidney transplant biopsies.

Discrepancy analysis comparing two diagnostic platforms offers potential insights into both without assuming either is always correct. Having optimized the Molecular Microscope Diagnostic System (MMDx) in renal transplant biopsies, we studied discrepancies within MMDx (reports and sign-out comments) and between MMDx and histology. Interpathologist discrepancies have been documented previously and were not assessed. Discrepancy cases were classified as "clear" (eg, antibody-mediated rejection [ABMR] vs T cell-mediated rejection [TCMR]), "boundary" (eg, ABMR vs possible ABMR), or "mixed" (eg, Mixed vs ABMR). MMDx report scores showed 99% correlations; sign-out interpretations showed 7% variation between observers, all located around boundaries. Histology disagreed with MMDx in 37% of biopsies, including 315 clear discrepancies, all with implications for therapy. Discrepancies were distributed widely in all histology diagnoses but increased in some scenarios; for example, histology TCMR contained 14% MMDx ABMR and 20% MMDx no rejection. MMDx usually gave unambiguous diagnoses in cases with ambiguous histology, for example, borderline and transplant glomerulopathy. Histology lesions or features associated with more frequent discrepancies (eg, tubulitis, arteritis, and polyomavirus nephropathy) were not associated with increased MMDx uncertainty, indicating that MMDx can clarify biopsies with histologic ambiguity. The patterns of histology-MMDx discrepancies highlight specific histology diagnoses in which MMDx assessment should be considered for guiding therapy.

Preformed Donor-Specific HLA Antibodies in Living and Deceased Donor Transplantation: A Multicenter Study.

BACKGROUND AND OBJECTIVES: The prognostic value of preformed donor-specific HLA antibodies (DSA), which are only detectable by sensitive methods, remains controversial for kidney transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The outcome of 4233 consecutive kidney transplants performed between 2012 and 2015 in 18 German transplant centers was evaluated. Most centers used a stepwise pretransplant antibody screening with bead array tests and differentiation of positive samples by single antigen assays. Using these screening results, DSA against HLA-A, -B, -C, -DRB1 and -DQB1 were determined. Data on clinical outcome and possible covariates were collected retrospectively. RESULTS: Pretransplant DSA were associated with lower overall graft survival, with a hazard ratio of 2.53 for living donation (95% confidence interval [95% CI], 1.49 to 4.29; P<0.001) and 1.59 for deceased donation (95% CI, 1.21 to 2.11; P=0.001). ABO-incompatible transplantation was associated with worse graft survival (hazard ratio, 2.09; 95% CI, 1.33 to 3.27; P=0.001) independent from DSA. There was no difference between DSA against class 1, class 2, or both. Stratification into DSA <3000 medium fluorescence intensity (MFI) and DSA ≥3000 MFI resulted in overlapping survival curves. Therefore, separate analyses were performed for 3-month and long-term graft survival. Although DSA <3000 MFI tended to be associated with both lower 3-month and long-term transplant survival in deceased donation, DSA ≥3000 MFI were only associated with worse long-term transplant survival in deceased donation. In living donation, only strong DSA were associated with reduced graft survival in the first 3 months, but both weak and strong DSA were associated with reduced long-term graft survival. A higher incidence of antibody-mediated rejection within 6 months was only associated with DSA ≥3000 MFI. CONCLUSIONS: Preformed DSA were associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI were associated with worse graft survival. This association was stronger in living than deceased donation.