Stefan Reuter

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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.

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.

The process of living kidney donation transforms a one-time acceptance or refusal decision into a lifelong relationship with an otherwise healthy volunteer. Genetic testing is often treated as similarly definitive, yet many results are variants of uncertain significance (VUS): findings for which evidence is insufficient to classify a variant as benign or pathogenic. Their meaning may change as population, segregation, functional, and genotype-phenotype data accumulate. In healthy donors facing a once-in-a-lifetime decision, variants initially considered insignificant may later become clinically relevant whereas likely pathogenic variants may remain clinically silent. Yet current care structures do not define who should monitor, reinterpret, and communicate updated genetic findings after nephrectomy. Targeted donor genetics must therefore be linked to registrysupported lifelong donor care.In current practice, genetic testing in living donor evaluation is targeted: it is considered when family history, young donor age, genetically unexplained kidney disease in the intended recipient or family, or features such as persistent hematuria, albuminuria, cystic disease, recurrent nephrolithiasis, congenital urogenital anomalies, or extrarenal phenotypes suggest inherited risk, preferably after index-case testing. Universal testing would mean broad sequencing of all donor candidates irrespective of such suspicion. Schott et al. tested 46 approved donors prospectively and 122 donors who developed adverse renal outcomes retrospectively; pathogenic or likely pathogenic variants were identified in 4% and 19% of these cohorts, respectively, and VUS in 59% of all 168 donors (1). These findings support targeted testing in high-risk constellations. However, the baseline prevalence of pathogenic variants in donors without adverse outcomes remains unknown, causality between identified variants and subsequent morbidity is uncertain, and many genetic results retain interpretive uncertainty. These data raise important questions about donor selection, counseling, and post-donation responsibilities.In a dedicated renal genetics cohort, variant reclassification occurred in 5% of cases; when it did, it led to a new or revised diagnosis in 60% and significant management changes in 67%, with a median time to reclassification of 8.4 months (2). Genetic results issued before donation cannot therefore be considered definitive. Baseline variant uncertainty combined with clinically meaningful post-issuance reclassification creates a longitudinal care obligation that current evaluation frameworks do not address.Current practice resources guide testing indications, recommend index-case testing and counseling, and caution against inappropriate donor exclusion for VUS (3,4). KDIGO frames living donor evaluation and care as risk estimation, informed consent, and postdonation follow-up (5). These documents define the predonation pathway, including use of genetics to inform donor selection, but do not assign responsibility for genetic findings afterward. Even in hereditary oncology, where variant reclassification is well recognized, it remains contested whether there is a duty to actively seek reclassification and, if a clinically relevant reclassification becomes known, who should recontact the patient (6). Transplant medicine has no equivalent debate, let alone resolution, despite the additional ethical complexity of healthy-volunteer donors.We propose integrating genetic findings obtained during donor evaluation into lifelong donor care across three dimensions. Clinical stewardship requires systematic documentation of genetic results and index-case diagnoses, a mechanism to receive clinically relevant updates from genetics or laboratory services, and cascade testing when index-case findings change. Longitudinal communication requires defined recontact pathways when relevant reclassifications are flagged or when a new genetic diagnosis is established in the family. Psychosocial support addresses anxiety or decisional burden from uncertain findings or late reclassifications. This approach does not treat every genetic uncertainty as a contraindication; it accepts that uncertainty must be managed after donation. Currently, no guideline designates whether anyone should actively seek reclassification, who should flag updates, or who-the transplant centre, referring nephrologist, renal genetics service, laboratory, or donor-should recontact donors after nephrectomy. This is the governance gap that structured lifelong donor care must address.A positive or reclassified genetic finding rarely creates a genotype-specific therapy, but it should lower the monitoring threshold and narrow the time window for clinical detection.A donor carrying a heterozygous COL4A3 or COL4A4 variant, or a COL4A5 variant may warrant earlier assessment for hematuria, albuminuria, and hypertension than one without known genetic risk-not because treatment differs, but because earlier detection enables earlier intervention. Health behavior; and timely renoprotection may modify risk. As the DESCARTES working group emphasized, donor information, health-promoting behavior, and individualized long-term risk assessment are central after living donation (7).Genetically informed postdonation surveillance should therefore address blood pressure, albuminuria, kidney function, lifestyle modification, and avoidance of nephrotoxins; reninangiotensin-aldosterone system blockade and sodium-glucose cotransporter 2 inhibitor therapy should be initiated when guideline-supported indications arise (8).The implementation question is where this longitudinal responsibility should reside.Routine clinical care is episodic and visit-dependent, not designed to track variant reinterpretation, family diagnoses, or psychosocial outcomes. The Safety of the Living Kidney Donor-German National Registry (SOLKID-GNR) offers a structural model, with sustained donor contact (9) and...

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.

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.

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.