Intravenous methylprednisolone (MP) pulse therapy remains the standard first-line treatment for acute T-cell-mediated rejection following kidney transplantation. However, the dose and duration of this therapy were established empirically more than three decades ago rather than by contemporary rigorous dose-finding trials. The most common treatment regimens consist of 250–500 mg MP daily for three to five days, but substantial between-center variability persists. This narrative review explores the historical development of steroid pulse dosing, the available comparative clinical data, and the biological rationale underlying current practice. The commonly used dose range of 250–500 mg daily for three to five days rests largely on historical convention rather than on contemporary dose-finding evidence. A series of small prospective and randomized studies failed to demonstrate superior efficacy of more intensive regimens when compared with doses broadly resembling current practice. Mechanistically, glucocorticoids act through genomic and rapid non-genomic pathways, supporting a hypothesis-generating dose-window concept rather than a simple linear dose-response model. Contemporary data further indicate that clinical response does not reliably predict histologic resolution and that MP pulse rejection treatment carries significant toxicity. Overall, steroid pulse therapy remains biologically plausible and clinically entrenched; however, the optimal dose and duration have yet to be established under current tacrolimus- and mycophenolate-based immunosuppression. More precise response monitoring will also be required to develop more effective and less toxic treatment regimens.

Progressive allograft fibrosis remains a major obstacle in kidney transplantation. Early identification of patients at high risk could be instrumental to improve outcomes. Here, we investigated Lysyl oxidase like 2 (LOXL2) as a biomarker for graft fibrosis and dysfunction. Using single-cell sequencing and imaging of transplant biopsies, we found that LOXL2 labeled an intertubular myofibroblast-like cell type with a smooth muscle actin (SMA)-negative, CD68-positive phenotype and high extracellular matrix activity. These cells were present in non-fibrotic and fibrotic regions using collagen 3 as a scaffold. Native kidneys also harbored LOXL2+ myofibroblasts, albeit at much lower levels. Following transplant surgery, LOXL2+ cells could rapidly emerge within days, particularly during episodes of rejection, where they associated with leukocyte aggregates. Elevated cell numbers were not irreversible as shown in follow-up biopsies. A retrospective analysis of 118 biopsies revealed a significant association with fibrosis, inflammation, and kidney function but not with other Banff parameters. Non-rejecting allografts displayed high variability in LOXL2+ cells, with high abundance serving as a long-term predictor of reduced allograft function. Our findings point to a new subset of inflammation-associated myofibroblasts that may be useful as a biomarker for early fibrogenesis.

Kidney transplantation is the preferred treatment for suitable patients with end-stage renal disease; however, access to transplantation declines dramatically with increasing HLA sensitization. While the acceptable mismatch (AM) program by Eurotransplant improves transplantability for highly sensitized candidates, a clinically relevant subgroup with extremely low donor frequency or ineligible for AM remains disadvantaged. In carefully selected cases, the controlled delisting of unacceptable HLA antigens and the use of peri-transplant desensitization (e.g., imlifidase) may enable transplantation. In order to provide better guidance, this German expert consensus report was compiled by the Kidney and Immunology Commissions of the German Transplantation Society and the Organ Transplantation Commission of the German Society for Immunogenetics. Within the German legal framework of urgency and chances for success, the report proposes a practical guide for candidate selection, multidisciplinary governance, risk-adapted HLA delisting, assessment of organ offers, use of imlifidase, perioperative immunosuppression, prophylaxis for infection, post-transplant monitoring, and management of antibody-mediated rejection. These recommendations are intended for experienced transplant centers and aim to balance transplant opportunity against immunological risk in highly sensitized kidney transplant candidates. The primary scope of this article is highly sensitized adult wait-listed candidates considered for deceased-donor kidney transplantation after compatibility-preserving pathways have been exhausted or are unlikely to succeed; HLA-incompatible living-donor transplantation with imlifidase is addressed separately as a potential off-label scenario for selected highly sensitized patients.

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) are established therapies in chronic kidney disease (CKD), but comparative data in kidney transplant recipients (KTR) remain limited.MethodsWe retrospectively matched 100 KTR receiving SGLT2i to 100 controls not receiving SGLT2i and assessed body mass index (BMI), HbA1c, urine albumin-to-creatinine ratio (uACR), estimated glomerular filtration rate (eGFR), serum potassium, RAAS inhibitor use, blood pressure, and safety outcomes at 6 and 12 months. Furthermore, we compared the Jaffé and enzymatic methods to examine the effect of SGLT2i-associated glucosuria on urinary creatinine measurements and the resulting uACR.ResultsBMI decreased in the intervention group and increased in controls; the overall adjusted between-group difference across follow-up remained statistically significant. Descriptive between-group differences in HbA1c were observed at 6 and 12 months, but were not confirmed after multivariable adjustment. Neither uACR nor eGFR differed significantly at 12 months, despite an initial decline in eGFR at 6 months. Serum potassium remained stable over time. Hyperkalemia was associated with lower eGFR, but not with SGLT2i treatment, and RAAS inhibitor persistence did not differ between groups. No statistically detectable differences or clear new safety signals were observed for blood pressure, urinary tract infections, cardiovascular events, or hospitalizations during follow-up. Jaffé-based creatinine measurements were lower than enzymatic measurements, increasing calculated uACR by approximately 8.5% (p < 0.001), with rare albuminuria stage reclassification.ConclusionsSGLT2i use was associated with favorable metabolic changes, particularly a reduction in BMI, without evidence of increased potassium-related risk. No improvement in graft function or albuminuria was observed over 1 year. SGLT2i-associated glucosuria systematically increased Jaffé-based uACR estimates, although clinically relevant albuminuria reclassification was uncommon.

Background: Clinical tools to structure kidney transplant waitlist management at the time of listing are limited. We evaluated a simple, donor-independent clinical grading applied at waitlist registration to stratify patients according to post-transplant risk. Methods: We retrospectively analyzed 465 adult kidney transplant recipients from two German centers (2018-2023). Patients were assigned to three clinical grading groups based on age and comorbidities, and to three immunologic groups based on pre-immunization. One-year outcomes included mortality, graft loss, eGFR, albuminuria, and rejection. Results: Higher clinical grades were associated with worse one-year outcomes, including lower eGFR and higher rates of death or graft loss, whereas immunologic grading was associated with waiting time but not short-term post-transplant outcomes. These associations appeared robust to donor characteristics in sensitivity analyses. Conclusions: A simple, listing-time clinical grading may support structured waitlist management before donor information is available. External validation is required.

Tacrolimus trough concentrations are essential after kidney transplantation but do not describe the dose required to achieve them. The concentration-to-dose (C/D) ratio adds this denominator and provides a low-cost, time-dependent dose-requirement phenotype from routine data. A low C/D ratio identifies recipients with high dose requirements and is associated with impaired kidney function, rejection, BK virus complications, graft failure, and mortality. Large registry data show graded risk as the C/D ratio decreases and more favorable outcomes when the low C/D ratio normalizes than when it remains low. The C/D ratio can therefore support risk stratification and selective area under the concentration-time curve value-based exposure assessment, but it is not a stand-alone treatment algorithm: interpretation requires valid sampling, assay, timing, formulation, and clinical context, and the outcome benefit from a C/D ratio-guided intervention remains unproven.

Abstract Background First-year kidney allograft loss comprises death with a functioning graft (DWFG) and death-censored graft loss (DCGF), each arising from diverse clinical causes. Few studies have examined how endpoint-specific causes are distributed over the first post-transplant year within the same cohort. Methods We retrospectively reviewed adult kidney transplant events performed at a German transplant center between 2007 and 2023. For each first-year all-cause graft-loss event, endpoint type and one primary cause were assigned from the documented clinical sequence; additional complications were retained as contributing events. Granular source causes were mapped into higher-order groups defined before examination of their distribution across 0–30, 31–90, and 91–365 day windows. Results Among 1400 adult kidney transplant events, 92 first-year all-cause graft-loss events occurred (6.6%, 95% CI 5.4-8.0): 57 DCGF and 35 DWFG. The leading DCGF cause group was vascular/thrombotic or microangiopathic loss (18/57), followed by infection/sepsis (8/57), rejection (7/57), and cardiorenal decompensation/cardiac failure (6/57). Among DWFG events, cardiovascular causes (15/35) and sepsis (9/35) predominated. The proportion of events classified as DWFG increased from 5/32 in the first 30 days to 7/15 at days 31–90 and 23/45 at days 91–365. Six DCGF events were followed by recipient death within the same first year. Conclusions First-year all-cause graft loss contained distinct cause and timing patterns. Early losses were predominantly vascular or perioperative DCGF, whereas later events increasingly reflected cardiovascular, infectious, and other medical causes, including DWFG. These findings support phase-specific surveillance and prospective multicenter validation using prespecified assessment of primary and contributing causes.

Highly sensitized kidney transplant candidates are difficult to transplant because anti-human leukocyte antigen (HLA) sensitization restricts access to immunologically compatible organs, as transplantation across donor-specific antibodies (DSA) increases the risk of antibody-mediated rejection (AMR) and premature graft loss. Management should therefore move beyond antibody characteristics alone and assess whether a compatible offer remains realistic for the individual patient within the relevant allocation system. This review proposes a sequential, compatibility-first access framework. Compatible transplantation should remain the preferred goal and may be achieved through kidney paired exchange, compatible living-donor pathways, sensitization-aware prioritization, and dedicated allocation programs. International experience shows that allocation design can mitigate access restrictions for moderately sensitized candidates, while highly sensitized candidates require more targeted prioritization. The Eurotransplant acceptable mismatch program exemplifies this principle by combining expert-defined acceptable antigens with allocation priority, thereby promoting compatible transplantation with excellent outcomes in a restricted highly sensitized cohort without therapeutic crossing of the immunological barrier. Compatible pathways should be tried and optimized before intervention-based strategies are considered. In candidates without a realistic compatible option within a reasonable timeframe, conventional desensitization, risk-adapted delisting of selected unacceptable antigens, or imlifidase-enabled transplantation may become justified, particularly when severe dialysis-related problems exist. Imlifidase can rapidly enable selected positive-crossmatch deceased-donor transplantation, but AMR remains frequent and strict governance, candidate selection, and posttransplant surveillance are mandatory. Novel AMR treatments, including CD38-directed therapies, may improve the long-term feasibility of barrier-crossing strategies. Emerging B-cell and plasma-cell targeting approaches, including interleukin-6-, CAR-T-cell-, and BCMA-directed strategies, remain investigational. Optimal care requires integrating immunologic precision, allocation design, intervention thresholds, and structured monitoring into an individualized compatibility-first strategy.

BACKGROUND:Tacrolimus is a key component of immunosuppressive therapy after renal transplantation but is characterized by a narrow therapeutic index and considerable pharmacokinetic variability. Although the month 3 concentration-to-dose (C/D) ratio identifies fast metabolizers at an increased risk of inferior outcomes after transplantation, very early C/D ratios lack prognostic value. Therefore, identifying early exposure metrics that capture cumulative tacrolimus exposure rather than single time-point concentrations represents an important challenge for therapeutic drug monitoring. This study evaluated whether early tacrolimus underexposure (trough concentration <8 ng/mL during postoperative days 1-10) predicts 12-month acute rejection (AR) and examined its association with the month 3 metabolizer phenotype. METHODS:This retrospective single-center study analyzed 374 kidney transplant recipients with complete pharmacokinetic data for the month 3 C/D classification and an extended cohort of 609 recipients transplanted between 2007 and 2018 for rejection analyses. RESULTS:The primary end point was biopsy-proven AR within 12 months. A threshold of 0.29 for the proportion of postoperative days 1-10 with trough levels <8 ng/mL provided the highest sensitivity-specificity balance. Values above this cutoff independently predicted 12-month AR. Early tacrolimus exposure patterns showed only a modest ability to discriminate the month 3 metabolizer phenotype. CONCLUSIONS:Early tacrolimus underexposure is a simple and clinically relevant predictor of 12-month AR, complementing C/D-ratio-based risk stratification at 3 months. These findings align with the evidence that high early tacrolimus clearance and low tacrolimus exposure increase AR risk and support the recommendations for optimizing early tacrolimus dosing.

Introduction Microvascular inflammation (MVI) on kidney biopsy is associated with reduced graft survival following kidney transplantation (KT). CD38-targeting regimens, including the monoclonal antibody daratumumab, have recently emerged as a promising therapeutic strategy to counteract MVI and stabilize graft function. Methods Here, we retrospectively collected data on eGFR, albuminuria, kidney allograft pathology, donor specific antibodies (DSA) and donor-derived cell-free DNA (dd-cfDNA) levels from 70 KT patients both prior to and after initiation of daratumumab treatment. Safety signals were also documented. Results The study cohort consisted of 59 patients diagnosed with antibody mediated rejection (AMR) and 11 patients showing DSA- and C4d-negative MVI. Median time between transplantation and diagnosis of MVI was 36 months. Daratumumab treatment was initiated at a median of 1.6 months following diagnosis of MVI. A mixed linear model showed stabilization of eGFR from -1.6 ml/min/1.73m2/month in the year prior to the diagnosis of MVI to +0.3 ml/min/1.73m2/month after starting daratumumab. Six patients lost their graft during follow-up. Median albuminuria and dd-cfDNA levels decreased early during treatment, whereas the effect on DSA was heterogeneous. Both the number of doses and treatment duration had no measurable impact on outcome. Conclusions Our preliminary data suggest efficacy of daratumumab in stabilizing kidney function in KT recipients with MVI.

BackgroundABO-incompatible living kidney transplantation (ABOi-LKT) has become an established procedure with long-term patient and graft survival comparable to ABO-compatible transplantation. However, intensified immunosuppression increases the risk of severe infectious complications, particularly in the early post-transplant period. This study investigated whether ABOi-LKT in patients with low baseline anti-ABO isoagglutinin titers can be performed safely without rituximab and thereby reduce infectious complications.MethodsIn this multicenter retrospective cohort study, recipients of ABOi-LKT with low pretransplant anti-ABO titers (≤1:16) were compared according to rituximab use. Clinical outcomes, graft function, rejection episodes, surgical complications, and infectious events were analyzed.ResultsEleven German transplant centers identified 46 patients who underwent ABOi-LKT without rituximab between 2016 and 2024 and 85 low-titer recipients who received rituximab (single dose 375 mg/m²). Baseline characteristics and median pretransplant anti-ABO titers (1:2) were comparable between groups. Patients underwent a median of two extracorporeal antibody eliminations and received comparable immunosuppression. Graft function at discharge and after 3 and 12 months, as well as proteinuria, did not differ between cohorts. One graft loss due to acute antibody-mediated rejection occurred in the rituximab-free group, whereas two graft losses (one rejection, one BK polyomavirus nephropathy) and one patient death occurred in the rituximab group. Rates of surgical complications (34.8% vs. 36.5%), blood transfusions (21.7% vs. 17.6%), and rejection episodes (15% vs. 20%; p=0.499) were similar. In contrast, infectious complications were significantly more frequent among rituximab-treated patients, with a 2.4-fold increased infection risk (p=0.018). Infection-related hospitalizations occurred significantly more often in the rituximab group (64.6% vs. 31.3%; p=0.003).ConclusionsABOi-LKT without rituximab appears safe in recipients with low pretransplant anti-ABO titers. Short-term graft function, graft survival, patient survival, and immunological outcomes were comparable to rituximab-based desensitization. Importantly, omission of rituximab was associated with significantly fewer infectious complications and infection-related hospitalizations, supporting a tailored, lower-intensity immunosuppressive approach in selected low-risk patients.

IntroductionABO-incompatible kidney transplantation (ABOi-KT) expands the donor pool, yet baseline anti-ABO isoagglutinin titres ≥ 1:512 remain challenging and practice is highly variable. We surveyed the German transplant centres to capture current management of very high-titre ABOi candidates and centre responses to insufficient titre decline.MethodsThirty-six centres were invited to complete an anonymised 19-item web-based questionnaire (January–March 2025) on (i) centre activity, (ii) isoagglutinin testing and isoagglutinin titre limits (iii) desensitisation protocol, (iv) ABO abort criteria and (v) escalation & re-attempt strategies. Data are reported descriptively.ResultsOf 36 eligible programmes, 27 (75%) responded. Thirteen (48%) accept any isoagglutinin titre; the rest cap at 1:512 (15%), 1:1024 (26%) or 1:2048 (11%). Centres without a cap reported greater 5-year ABOi experience (median 20 vs 9 cases). IgG isoagglutinin titres are monitored in 26/27 centres, IgM in 18/27. All centres use rituximab, usually 4 weeks pre-transplant. Antigen-specific immunoadsorption (IA) is the principal antibody-removal method in 88%, while 54% also employ plasma exchange (PLEX). In cases of insufficient titre decline, different strategies are employed. Desensitisation is halted mainly for refractory isoagglutinin titres or serious complications; 67% of programmes would re-attempt after 3–6 months, typically with intensified apheresis and/or additional B-cell depletion.DiscussionGerman centres display marked protocol heterogeneity, but all accept very high titres, relying on rituximab plus IA. Greater experience correlates with abandonment of fixed cut-offs. Harmonised isoagglutinin titre assays, evidence-based futility criteria and multicentre registries are needed to optimise high-titre ABOi-KT.

Background/Objectives: The tacrolimus (Tac) concentration-to-dose ratio (C/D ratio) has been described as a predictive marker for several outcome parameters after renal transplantation (RTx). Different C/D ratio values are used to define fast (low C/D ratio) and slow Tac metabolizers (high C/D ratio). In this study, the R package was used to determine the optimal C/D ratio cut-off value to define the Tac metabolism type with a high predictive value for the development of renal function. Methods: The data of 389 RTx patients who received an initial immunosuppression with immediate-release tacrolimus (IR-Tac), mycophenolate, prednisolone, and an induction with basiliximab were analyzed. The Tac C/D ratio (ng/mL × 1/mg) of all patients was calculated 3 months after RTx and the maximally selected Wilcoxon statistic was applied to determine the optimal C/D ratio cut-off value for renal function development over a 5-year follow-up. Results: A C/D ratio of 0.94 provided the optimal differentiation between fast and slow Tac metabolism in relation to renal function development at 1, 2, 3, and 4 years of follow-up, and at 0.95 five years after RTx. Conclusions: As fast Tac metabolism is associated with the development of an impaired renal function, it is essential to identify patients at risk early after RTx. In order to keep the application simple for clinical routine, we suggest calculating the C/D ratio 3 months after RTx and using 1.0 (≤1.0 = fast metabolizer) as the cut-off, which is very close to the optimal value.