BACKGROUND:Donor-derived cell-free DNA (dd-cfDNA) shows good diagnostic performance for the detection of antibody-mediated rejection (AMR) in kidney transplant recipients (KTR). However, the clinical benefits of dd-cfDNA monitoring need to be established. Early diagnosis of AMR at potentially reversible stages may be increasingly important due to emerging treatment options for AMR. We hypothesized that monitoring dd-cfDNA in KTR with de novo donor-specific anti-HLA antibodies (dnDSA) and performing kidney biopsy in case of increased dd-cfDNA may reduce time to AMR diagnosis in comparison with clinical indication biopsy. METHODS:In this diagnostic, single-center, open-label, randomized clinical trial, we assigned 40 KTR with prevalent dnDSA and estimated glomerular filtration rate ≥20 mL/min/1.73 m2, but without previous biopsy-proven AMR, to either dd-cfDNA-guided biopsy (intervention group) or clinician-guided biopsy (control group) over a 12-month period. In both groups, dd-cfDNA was assessed at inclusion and 1, 3, 6, 9 and 12 months. In the intervention group, dd-cfDNA >50 copies/mL indicated a biopsy. Biopsies for clinical indication could be performed at any point during the study period in both groups. A protocol biopsy was scheduled after 12 months for patients without dd-cfDNA-guided biopsy or clinical indication biopsy until study completion. The primary endpoint was time from study inclusion to diagnosis of active or chronic active AMR. RESULTS:Thirty-nine of 40 patients had functioning grafts at study completion. From these, 26 patients underwent biopsy, 13 in each group. AMR was diagnosed earlier in the intervention group than in the control group [median 2.8 months, interquartile range (IQR) 1.7-5.3 vs median 14.5 months, IQR 13.3-16.7, P = .003]. Longitudinal dd-cfDNA monitoring had 77% positive predictive value and 85% negative predictive value for AMR. CONCLUSIONS:Dd-cfDNA-guided biopsy in KTR with prevalent dnDSA can reduce the time to AMR diagnosis and hereby expedite therapy initiation. TRIAL REGISTRATION:ClinicalTrials.gov, NCT04897438.

Background: The object of this study was to investigate the utility of Neutrophil gelatinase-associated lipocalin (NGAL) and Calprotectin (CPT) to predict long-term graft survival in stable kidney transplant recipients (KTR).Methods: 709 stable outpatient KTR were enrolled >2 months post-transplant. The utility of plasma and urinary NGAL (pNGAL, uNGAL) and plasma and urinary CPT at enrollment to predict death-censored graft loss (GL) was evaluated during a 58-month follow-up.Results: Among biomarkers, pNGAL showed best predictive ability for graft loss and was the only biomarker with an AUC > 0.7 for GL within 5 years. Patients with GL within 5 years (n=49) had a median pNGAL of 304[IQR 235-358] versus 182[IQR 128 -246]ng/ml with surviving grafts (p<0.001). Time-dependent Receiver operating characteristic analyses at 58 months indicated an Area-Under-the-Curve (AUC) for pNGAL of 0.795, serum creatinine (sCr) based estimated glomerular filtration rate (eGFR) CKD EPI had an AUC of 0.866. pNGAL added to a model based on conventional risk factors for GL with death as competing risk (age, transplant age, presence of donor specific antibodies, presence of proteinuria, history of delayed graft function) had a strong independent association with GL (subdistribution Hazard ratio (sHR) for binary log transfomed pNGAL (log2 (pNGAL)) (3.4 95% CI 2.24-5.15), p<0.0001). This association was substantially attenuated when eGFR was added to the model (sHR for log2 (pNGAL) 1.63 95% CI 0.92-2.88, p=0.095). Category-free net reclassification improvement of a risk model including log2(pNGAL) additionally to conventional risk factors and eGFR was 54.3% (95% CI 9.2 to 99.3%) but C-statistic did not improve significantly.Conclusions: pNGAL was an independent predictor of renal allograft loss in stable KTR from one transplant center but did not show consistent added value when compared to baseline predictors including the conventional marker eGFR. Future studies in larger cohorts are warranted.

Background:Patients with autosomal dominant polycystic kidney disease (ADPKD) represent >10% of patients awaiting kidney transplantation. These patients are prone to potentially severe urinary tract (UTI) and liver cyst infections after transplantation. Whether such infections compromise outcome is unclear. Methods:Between 2000 and 2017 we performed 193 kidney transplantations in patients with ADPKD. In 189 patients, we assessed the occurrence, frequency, and severity of infection episodes requiring inpatient treatment and their impact on graft and patient outcomes compared with 189 matched controls. Risk factors were analyzed by uni- and multivariable analyses. Results:During a mean observation period of 77 months UTIs occurred more frequently in ADPKD patients (39.1% vs. 26.7%, P = .022; 0.8 ± 1.4 vs. 0.5 ± 1.1 episodes, P < .001). Eight ADPKD patients suffered from 19 episodes of liver cyst infection. Steroid medication (RR 3.04; P < .001) and recipient age (RR 1.05; P = .003) increased the risk for UTI/urosepsis, while nephrectomy reduced it (unilateral, RR 0.60; P = .088; bilateral, RR 0.45; P = .020). Patient survival was similar in both groups. The risk of graft failure was lower in ADPKD patients [hazard ratio (HR) 0.67; P = .047] due to a lower risk of death-censored graft loss (HR 0.47; P = .014). Donor age (HR 1.34; P = .002) and rejection (HR 8.47; P < .001) were risk factors for death-censored graft loss. Conclusions:ADPKD patients are at increased risk of UTI and liver cyst infection after transplantation. Steroid medication and recipient age seem to increase the risk of UTI/urosepsis, while nephrectomy seems to reduce it. Nevertheless, patient survival was similar compared to non-ADPKD patients and death-censored graft survival even better.

Background Recent advances in hardware and software enabled the use of artificial intelligence (AI) algorithms for analysis of complex data in a wide range of daily-life use cases. We aim to explore the benefits of applying AI to a specific use case in transplant nephrology: risk prediction for severe posttransplant events. For the first time, we combine multinational real-world transplant data, which require specific legal and technical protection measures. Objective The German-Canadian NephroCAGE consortium aims to develop and evaluate specific processes, software tools, and methods to (1) combine transplant data of more than 8000 cases over the past decades from leading transplant centers in Germany and Canada, (2) implement specific measures to protect sensitive transplant data, and (3) use multinational data as a foundation for developing high-quality prognostic AI models. Methods To protect sensitive transplant data addressing the first and second objectives, we aim to implement a decentralized NephroCAGE federated learning infrastructure upon a private blockchain. Our NephroCAGE federated learning infrastructure enables a switch of paradigms: instead of pooling sensitive data into a central database for analysis, it enables the transfer of clinical prediction models (CPMs) to clinical sites for local data analyses. Thus, sensitive transplant data reside protected in their original sites while the comparable small algorithms are exchanged instead. For our third objective, we will compare the performance of selected AI algorithms, for example, random forest and extreme gradient boosting, as foundation for CPMs to predict severe short- and long-term posttransplant risks, for example, graft failure or mortality. The CPMs will be trained on donor and recipient data from retrospective cohorts of kidney transplant patients. Results We have received initial funding for NephroCAGE in February 2021. All clinical partners have applied for and received ethics approval as of 2022. The process of exploration of clinical transplant database for variable extraction has started at all the centers in 2022. In total, 8120 patient records have been retrieved as of August 2023. The development and validation of CPMs is ongoing as of 2023. Conclusions For the first time, we will (1) combine kidney transplant data from nephrology centers in Germany and Canada, (2) implement federated learning as a foundation to use such real-world transplant data as a basis for the training of CPMs in a privacy-preserving way, and (3) develop a learning software system to investigate population specifics, for example, to understand population heterogeneity, treatment specificities, and individual impact on selected posttransplant outcomes. International Registered Report Identifier (IRRID) DERR1-10.2196/48892

ABSTRACT Background High numbers of unknown classifications and inconsistent methodologies in previous studies make the interpretation of causes leading to graft loss difficult. In addition, data on a holistic view looking at both death with a functioning graft (DWFG) and death-censored graft failure (DCGF) are sparse. Methods In this single-centre study we included 1477 adult kidney transplants performed between 1997 and 2017, of which all 286 DWFGs until the end of observation were analysed and causes for death assigned. Additionally, the results were compared with the causes of 303 DCGFs of the same cohort to evaluate the impact of causes for overall graft loss. Results The most frequent causes for DWFG were cardiovascular disease (CVD) in 30.8%, malignancy in 28.3% and infections in 21%. Only 9.4% of reasons for DWFG were unknown. Sudden death occurred in 40% (35/88) of patients classified as DWFG due to CVD. Overall graft loss was related to the effect of immunosuppression in 36.2% [infection 20.9% (123/589), malignancy 15.3% (90/589)] and CVD in 22.4% (132/589). In 27.4% (161/589), graft failure was associated with underimmunosuppression (rejection). For infections (60 DWFG, 63 DCGF) and CVD (88 DWFG, 44 DCGF), a considerable overlap was observed between DWFG and DCGF. For patients >70 years of age at transplantation, medical events accounted for 78% of overall graft losses and only 6.5% were associated with rejection. Conclusions DWFG and DCGF share more causes for graft loss than previously reported and sudden death plays an underestimated role in death with a functioning graft.

Women of childbearing age show increased fertility after kidney transplantation. Of concern, preeclampsia, preterm delivery, and allograft dysfunction contribute to maternal and perinatal morbidity and mortality. We performed a retrospective single-center study, including 40 women with post-transplant pregnancies after single or combined pancreas–kidney transplantation between 2003 and 2019. Outcomes of kidney function up to 24 months after the end of pregnancy were compared with a matched-pair cohort of 40 transplanted patients without pregnancies. With a maternal survival rate of 100%, 39 out of 46 pregnancies ended up with a live-born baby. The eGFR slopes to the end of 24 months follow-up showed mean eGFR declines in both groups (−5.4 ± 14.3 mL/min in pregnant versus −7.6 ± 14.1 mL/min in controls). We identified 18 women with adverse pregnancy events, defined as preeclampsia with severe end-organ dysfunction. An impaired hyperfiltration during pregnancy was a significant risk contributor for both adverse pregnancy events (p < 0.05) and deterioration of kidney function (p < 0.01). In addition, a declining renal allograft function in the year before pregnancy was a negative predictor of worsening allograft function after 24 months of follow-up. No increased frequency of de novo donor-specific antibodies after delivery could be detected. Overall, pregnancies in women after kidney transplantation showed good allograft and maternal outcomes.

Abstract Background and Aims Cardiovascular (CV) morbidity and mortality are highly prevalent in renal transplant recipients (RTRs). As such, assessments of CV status using troponin concentrations could help to identify patients at risk for death or CV events and as a predictor for deterioration of graft function. The aim of the study was to investigate the biomarker troponin for the prediction of adverse renal and cardiovascular outcomes in stable RTRs. Method 305 stable RTRs with a median age of 53 years, (60.6% male) transplanted between 1994 and 2018 were enrolled in the study. General characteristics are shown in Table 1. At baseline, troponin, NT-pro BNP, carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP) were measured. Troponin was measured during a routine baseline visit in stable RTR without cardiac symptoms. The median troponin concentration (11 ng/l) was used as cut-off. Patients were divided into two groups high (≥11 ng/l) and low (<11 ng/l) troponin and followed for 54 months. During this time CV events (stroke, myocardial infarction, peripheral artery thrombosis) death, graft loss and deterioration of renal graft function (increasing creatinine ≥30%) or proteinuria (urine protein creatinine ratio UPCR ≥500 mg/g) were monitored. Results At baseline, significant differences were observed between groups in terms of creatinine, eGFR, troponin, UPCR, PP, and PWV. In the group with baseline troponin ≥11ng/l, more patients had coronary artery disease/peripheral obliterans artery disease (CAD/POAD), heart failure (HF), and diabetes. Baseline troponin correlated only weakly with age (R = 0.47), cfPWV (R = 0.41), eGFR (R = −0.52). During follow-up, patients with high troponin experienced more frequently an increase in creatinine ≥30% (32.9% vs 13%), doubling creatinine (11.2% vs 3.1%), an increase in UPCR (22.4% vs 9.2%), graft loss (16.1% vs 1,8%), death (13.3% vs 0%), and CV events (6.3% vs 4.9%). Conclusion 1. Age, arterial stiffness, and eGFR only have a weakly impact on troponin in stable RTR. 2. Higher troponin is associated with poor outcomes and might be useful not only for the identification of patients with high-risk CV events but also for the deterioration of allograft function.

(1) Background: CMV infections remain a problem after kidney transplantation, particularly if patients are refractory or resistant (r/r) to treatment with valganciclovir (VGCV) or ganciclovir (GCV). (2) Methods: In a single-center retrospective study, kidney transplant recipients (KTR) receiving letermovir (LTV) as rescue therapy for VGCV-/GCV-r/r CMV disease were analyzed regarding CMV history, immunosuppression, and outcomes. (3) Results: Of 201 KTR treated for CMV between 2017 and 2022, 8 patients received LTV following treatment failure with VGCV/GCV. All patients received CMV prophylaxis with VGCV according to the center’s protocol, and 7/8 patients had a high-risk (D+/R−) CMV constellation. In seven of eight cases, rising CMV levels occurred during prophylaxis. In seven of eight patients, a mutation in UL97 associated with a decreased response to VGCV/GCV was detected. In four of eight patients, LTV resulted in CMV clearance after 24 ± 10 weeks (16–39 weeks), two of eight patients stabilized at viral loads <2000 cop/mL (6–20 weeks), and two of eight patients developed LTV resistance (range 8–10 weeks). (4) Conclusion: LTV, which is currently evaluated for CMV prophylaxis in kidney transplantation, also shows promising results for the treatment of patients with VGCV/GCV resistance despite the risk of developing LTV resistance. Additional studies are needed to further define its role in the treatment of patients with CMV resistance.

BackgroundDe novo donor-specific HLA antibodies (dnDSA) are key factors in the diagnosis of antibody-mediated rejection (ABMR) and related to graft loss.MethodsThis retrospective study was designed to evaluate the natural course of dnDSA in graft function and kidney allograft survival and to assess the impact of mean fluorescence intensity (MFI) evolution as detected by annual Luminex® screening. All 400 kidney transplant recipients with 731 dnDSA against the last graft (01/03/2000-31/05/2021) were included.ResultsDuring 8.3 years of follow-up, ABMR occurred in 24.8% and graft loss in 33.3% of the cases, especially in patients with class I and II dnDSA, and those with multiple dnDSA. We observed frequent changes in MFI with 5-year allograft survivals post-dnDSA of 74.0% in patients with MFI reduction ≥ 50%, 62.4% with fluctuating MFI (MFI reduction ≥ 50% and doubling), and 52.7% with doubling MFI (log-rank p < 0.001). Interestingly, dnDSA in 168 (24.3%) cases became negative at some point during follow-up, and 38/400 (9.5%) patients became stable negative, which was associated with better graft survival. Multivariable analysis revealed the importance of MFI evolution and rejection, while class and number of dnDSA were not contributors in this model.ConclusionIn summary, we provide an in-depth analysis of the natural course of dnDSA after kidney transplantation, first evidence for the impact of MFI evolution on graft outcomes, and describe a relevant number of patients with a stable disappearance of dnDSA, related to better allograft survival.

Background: In the information extraction and natural language processing domain, accessible datasets are crucial to reproduce and compare results. Publicly available implementations and tools can serve as benchmark and facilitate the development of more complex applications. However, in the context of clinical text processing the number of accessible datasets is scarce -- and so is the number of existing tools. One of the main reasons is the sensitivity of the data. This problem is even more evident for non-English languages. Approach: In order to address this situation, we introduce a workbench: a collection of German clinical text processing models. The models are trained on a de-identified corpus of German nephrology reports. Result: The presented models provide promising results on in-domain data. Moreover, we show that our models can be also successfully applied to other biomedical text in German. Our workbench is made publicly available so it can be used out of the box, as a benchmark or transferred to related problems.

Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m(2)), and responders were younger (53.0 vs. 57.4 years). Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose (AUC 0.84 vs. 0.62, p < 0.001). Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.

BackgroundTransplant glomerulopathy (TG) may indicate different disease entities including chronic AMR (antibody-mediated rejection). However, AMR criteria have been frequently changed, and long-term outcomes of allografts with AMR and TG according to Banff 2017 have rarely been investigated.Methods282 kidney allograft recipients with biopsy-proven TG were retrospectively investigated and diagnosed according to Banff'17 criteria: chronic AMR (cAMR, n = 72), chronic active AMR (cAAMR, n = 76) and isolated TG (iTG, n = 134). Of which 25/72 (34.7%) patients of cAMR group and 46/76 (60.5%) of cAAMR group were treated with antihumoral therapy (AHT).ResultsUp to 5 years after indication biopsy, no statistically significant differences were detected among iTG, cAMR and cAAMR groups in annual eGFR decline (−3.0 vs. −2.0 vs. −2.8 ml/min/1.73 m2 per year), 5-year median eGFR (21.5 vs. 16.0 vs. 20.0 ml/min/1.73 m2), 5-year graft survival rates (34.1 vs. 40.6 vs. 31.8%) as well as urinary protein excretion during follow-up. In addition, cAMR and cAAMR patients treated with AHT had similar graft and patient survival rates in comparison with those free of AHT, and similar comparing with iTG group. The TG scores were not associated with 5-year postbiopsy graft failure; whereas the patients with higher scores of chronic allograft scarring (by mm-, ci- and ct-lesions) had significantly lower graft survival rates than those with mild scores. The logistic-regression analysis demonstrated that Banff mm-, ah-, t-, ci-, ct-lesions and the eGFR level at biopsy were associated with 5-year graft failure.ConclusionsThe occurrence of TG is closely associated with graft failure independent of disease categories and TG score, and the long-term clinical outcomes were not influenced by AHT. The Banff lesions indicating progressive scarring might be better suited to predict an unfavorable outcome.

Patient care after kidney transplantation requires integration of complex information to make informed decisions on risk constellations. Many machine learning models have been developed for detecting patient outcomes in the past years. However, performance metrics alone do not determine practical utility. We present a newly developed clinical decision support system (CDSS) for detection of patients at risk for rejection and death-censored graft failure. The CDSS is based on clinical routine data including 1,516 kidney transplant recipients and more than 100,000 data points. In a reader study we compare the performance of physicians at a nephrology department with and without the CDSS. Internal validation shows AUC-ROC scores of 0.83 for rejection, and 0.95 for graft failure. The reader study shows that predictions by physicians converge toward the CDSS. However, performance does not improve (AUC-ROC; 0.6413 vs. 0.6314 for rejection; 0.8072 vs. 0.7778 for graft failure). Finally, the study shows that the CDSS detects partially different patients at risk compared to physicians. This indicates that the combination of both, medical professionals and a CDSS might help detect more patients at risk for graft failure. However, the question of how to integrate such a system efficiently into clinical practice remains open.

The Banff 2017 report permits the diagnosis of pure chronic antibody-mediated rejection (cAMR) in absence of microcirculation inflammation. We retrospectively investigated renal allograft function and long-term outcomes of 67 patients with cAMR, and compared patients who received antihumoral therapy (cAMR-AHT, n = 21) with patients without treatment (cAMRwo, n = 46). At baseline, the cAMR-AHT group had more concomitant T-cell-mediated rejection (9/46 (19.2%) vs. 10/21 (47.6%); p = 0.04), a higher g-lesion score (0.4 ± 0.5 versus 0.1 ± 0.3; p = 0.01) and a higher median eGFR decline in the six months prior to biopsy (6.6 vs. 3.0 mL/min; p = 0.04). The median eGFR decline six months after biopsy was comparable (2.6 vs. 4.9 mL/min, p = 0.61) between both groups, and three-year graft survival after biopsy was statistically lower in the cAMR-AHT group (35.0% vs. 61.0%, p = 0.03). Patients who received AHT had more infections (0.38 vs. 0.20 infections/patient; p = 0.04). Currently, antihumoral therapy is more often administered to patients with cAMR and rapidly deteriorating renal function or concomitant TCMR. However, long-term graft outcomes remain poor, despite treatment.