Miklos Zsolt Molnar

Introduction: Eplet mismatch load is a molecular measure of donor–recipient histocompatibility that has been associated with alloimmune outcomes after kidney transplantation. However, its relationship with comprehensive markers of early allograft injury remains incompletely defined. Methods: In this single-center retrospective cohort study, we evaluated 657 adult kidney transplant recipients who underwent transplantation between January 2021 and December 2024. Eplet mismatch load was calculated at the HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci using the HLA Eplet Registry. The primary outcome was a composite of early allograft injury, defined as the independent occurrence of de novo donor-specific antibodies, histologic rejection, molecular rejection assessed by the Molecular Microscope Diagnostic System, or elevation of donor-derived cell-free DNA within the first year after transplantation. Results: During the first post-transplant year, 248 patients (37.7%) experienced the primary outcome. Median eplet mismatch load was significantly higher among patients with the primary outcome across most HLA loci. In adjusted Cox regression models, higher eplet mismatch load (per one-eplet increase) was independently associated with increased risk of the primary outcome for HLA-DRB1 (hazard ratio 1.025; 95% confidence interval 1.011–1.038), HLA-DQA1 (hazard ratio 1.075; 95% confidence interval 1.025–1.127), and HLA-DQB1 (hazard ratio 1.038; 95% confidence interval 1.020–1.057). Compared with zero eplet mismatch, high-risk class II eplet mismatch categories were associated with approximately two- to three-fold higher risk of early allograft injury. Associations for class I loci were weaker and pattern-dependent after adjustment. Conclusion: In conclusion, a higher class II HLA-eplet mismatch load was independently associated with early kidney allograft injury during the first post-transplant year.

Key Points: The integrative box showed accurate discrimination, overall fit, and clinical utility in 3866 kidney transplant recipients from North America. Predictive performance was maintained in African American and non-African American kidney transplant recipients. These results support the robustness of the integrative box as a risk prediction tool. Background: The integrative box (iBox) is a validated prognostication system that predicts long-term death-censored graft loss in kidney transplant recipients, but its performance in the specific population of African American recipients has not been fully studied. Methods: We conducted a multicenter study including 3866 kidney transplant recipients from North America, of whom 1040 (27%) were African American, to assess the impact of race on the iBox's performance in predicting graft loss. Discrimination, calibration, overall fit, and clinical utility were evaluated in the whole cohort and in African American and non-African American recipients. Results: Performance metrics for the prediction of graft loss were similar in both subgroups in discrimination (C-index 0.80 [95% confidence interval (CI), 0.77 to 0.83] in African American recipients and 0.83 [95% CI, 0.81 to 0.85] in non-African American recipients, P = 0.07) and observed/expected ratios (1.08 [95% CI, 0.95 to 1.23] and 0.99 [95% CI, 0.88 to 1.10], respectively, P = 0.28). No significant interaction between iBox score values and race was found in multivariable analysis stratified by transplant center ( P = 0.24 for the interaction term). The results were consistent between the subgroups regardless of the equation used to estimate eGFR (Kidney Recipient Specific, CKD-Epidemiology Collaboration, or Modification of Diet in Renal Disease), but with variations in calibration across equations. Conclusions: The iBox prognostication system showed accurate discrimination, overall fit, and clinical utility up to 7 years after risk evaluation in African American and non-African American kidney transplant recipients, supporting its robustness in this population. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT03474003.

Objective: To perform comprehensive validations of the integrative Box (iBox) system, a prediction model for long term risk of kidney allograft failure, for extension of its context of use in clinical trials as well as for its wider implementation in clinical practice. Design: Extended validation study. Setting: Paris Transplant Group database (comprising kidney recipients with transplantations between 1 January 2005 and 1 January 2014) and European, North American, and South American hospitals (comprising recipients of kidneys transplanted beween 1 January 2000 and 1 January 2022). Patients were followed until 1 November 2024. Participants: 12 683 kidney tranplant recipients from 21 academic centres in Europe, North America, and South America; 4000 patients in the derivation cohort and 8683 in the validation cohorts. Main outcome measures: Performance of the iBox, including flexible iBox versions in specific clinical contexts (race-free estimated glomerular filtration rate (eGFR) equations (ie, without including race as a factor in the calculation), in specific clinical contexts (initial nephropathy recurrence, BK virus associated nephropathy, and different immunosuppressive strategies), and over-extended follow-up periods. Predictive performance was assessed by discrimination, calibration, overall fit, and clinical utility. Results: 12 683 kidney transplant recipients were included in the study (n=4000 in the derivation cohort and n=8683 in the validation cohorts). Median follow-up time after risk evaluation was 5.78 years (interquartile range (IQR) 3.51-7.00) in the derivation cohort and 4.68 years (2.48-7.00) in the validation cohorts. 549 (13.7%) and 991 (11.4%) patients had graft loss in the derivation and validation cohorts, respectively. All versions of the iBox algorithm maintained good discrimination and overall fit performance in the derivation and validation cohorts (C index range 0.79-0.87, Brier scores 0.08-0.11). Calibration was adequate in some but not all external validation cohorts, with trends toward overestimation or underestimation of predicted risks. Decision curve analysis showed positive and comparable net benefit for all iBox algorithms across decision thresholds up to 40% in the derivation cohort (net benefit 0.07-0.08 at 20% threshold) and validation cohorts (net benefit 0.03-0.11 at 20% threshold). Accounting for the competing risk of death with a functioning graft resulted in similar performance, except for calibration which varied across cohorts, without any model consistently outperforming any other model. The model performed well with different race-free eGFR equations (C index 0.81), in various clinical scenarios, including disease recurrence and BK virus nephropathy, with different immunosuppressive strategies, such as calcineurin inhibitors and mTOR (mechanistic target of rapamycin) inhibitors (C index range 0.74-0.87), and when extending the prediction period to 10 years after risk evaluation (C index 0.79). The iBox predictive performance was not modified when various histological indices were used. The iBox was also superior to eGFR slope (C index 0.81 v 0.62) and circulating anti-HLA donor specific antibodies (C index 0.81 v 0.57) in its predictive ability. Conclusions: In this study, the robust predictive performance of the iBox system across diverse real world settings and clinical scenarios was shown. These results highlight the versatility and reliability of the iBox system, and support its use for risk stratification in routine clinical practice and as a surrogate endpoint for clinical trials.

The presence of pretransplant anti-human leukocyte antigen (HLA) donor-specific antibodies (DSAs) is still a significant barrier to successful kidney transplantation, as it increases the risk of rejection and graft failure. Rituximab (anti-CD20 antibody) has been administered in hopes of suppressing DSA production and rejection in those with preformed DSAs. However, existing studies report conflicting outcomes, underscoring the need for more data to guide clinical practice. Thus, we evaluated the efficacy of early posttransplant rituximab administration in a cohort of kidney transplant recipients with pretransplant anti-HLA DSAs. In this retrospective study of 77 patients, we compared 1-year transplant outcomes between patients treated with and without rituximab for pretransplant anti-HLA DSAs. Infectious complications tended to occur more often in the rituximab group (BK polyomavirus DNAemia >10,000 copies/mL, 3 [19%] vs. 8 [13%]; quantifiable cytomegalovirus DNAemia, 8 [50%] vs. 19 [31%]; infection requiring hospitalization, 5 [31%] vs. 11 [18%]), but none of these differences reached statistical significance. The incidence of biopsy-proven rejection (2 [13%] vs. 12 [20%]) and high plasma donor-derived cell-free DNA (2 [18%] vs. 12 [27%]) tended to be more frequent in the no-rituximab group, but none of these reached statistical significance. Preexisting DSA persisted or recurred in 44% of the patients that received rituximab, and in 46% of patients who did not receive rituximab. Similarly, de novo DSA occurred in 31% of those who received rituximab versus in 25% of those who did not. Rituximab administration did not result difference in graft and patient survival or rejection rates or recurrence of preexisting DSA.

With the development of potential prevention therapies for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN), risk prediction models are needed to identify kidney transplant recipients at high risk for BKPyVAN. This single-center retrospective study aimed to develop a risk prediction model and an integer-based risk score for BKPyVAN development, defined as plasma BKPyV-DNA >10,000 copies/mL and/or biopsy-proven BKPyVAN, within 1-year post-transplant, using donor and recipient characteristics at the time of transplantation. We randomly split patients into development and validation cohorts and applied logistic regression with backward selection to identify significant variables. Model performance was evaluated using the area under the receiver-operating characteristic curve (AUC) and calibration plots. This study included 560 patients, of whom 75 (13%) patients had BKPyVAN. Age >50 years, male sex, and prior kidney transplant were selected for the final model. The total integer score ranged from 0 to 4 points, with 1 point assigned for age >50 years and male sex, and 2 points for prior kidney transplant. The AUC was 0.65 in both development and validation cohorts. Calibration plots showed an incremental increase in risk with higher total scores. The integer score indicated that patients with a total score of 2 or higher (i.e. males aged >50 years or those with prior kidney transplants) have a predicted risk of 20% or greater. Although the AUC was suboptimal, the results suggest that our model may still be valuable for identifying high-risk patients.

Sleep disorders such as insomnia, restless legs syndrome (RLS), and sleep apnea (SA) are common in patients with CKD. These conditions tend to become more prevalent and more severe as kidney function deteriorates and when a patient reaches ESKD. The prevalence of insomnia in the general population ranges from 4% to 29% compared with ( 1 ) 30%–67%, ( 2 ) 39%–54%, ( 3 ) 41%–79%, and ( 4 ) 9%–49% in patients with CKD, on hemodialysis, on peritoneal dialysis (PD), or in kidney transplant recipients (KTRs), respectively. RLS occurs in approximately 1%–15% of the general population compared with ( 1 ) 5%–18%, ( 2 ) 24%–33%, ( 3 ) 23%–64%, and ( 4 ) 6%–8% in patients with CKD, on hemodialysis, on PD, or in KTRs, respectively. Obstructive SA has been reported in ( 1 ) 40%–69%, ( 2 ) 25%–47%, ( 3 ) 9%–52%, and ( 4 ) 25%–30% in patients with CKD, on hemodialysis, on PD, or in KTRs, respectively. Fatigue is a complex symptom that has been reported in patients with CKD, ESKD, and in KTRs and can be associated with sleep disorders. Fatigue and sleep disorders have been associated with negative outcomes such as progression of CKD, increased risk of morbidity, mortality, and lower health-related quality of life. In this review, we highlight nonpharmacologic and pharmacologic options for treatment of these sleep disorders. Specifically, the diagnosis and evaluation, epidemiology, risk factors and associations, outcomes (such as CKD progression, morbidity, and mortality), treatment, and post-transplant outcomes for sleep disorders (insomnia, RLS, and SA) and fatigue will be discussed.

Simple and validated physical function measures are needed for kidney transplant candidates because pretransplant low physical function is a common and potentially modifiable risk factor. This single-center retrospective study investigated the associations between pretransplant physical function assessed by the Patient-Reported Outcomes Measurement Information System^® Physical Function (PROMIS-PF) computer adaptive testing and early posttransplant outcomes. We analyzed 154 adult kidney-alone transplant recipients. The median pretransplant PROMIS-PF score was 43 (interquartile range, 39–47). Patient characteristics were not significantly different across the score category (normal, score ≥45; mild, score of 40–45; and moderate/severe, score <40). The PROMIS-PF score was not associated with length of transplant hospital stay, delayed graft function, 6-month and 12-month graft function, or 12-month patient and graft survival. However, a lower PROMIS-PF score was significantly associated with a higher risk of emergency room visits [adjusted odds ratios compared to normal: mild, 1.68 (95% confidence interval, 0.76–3.83); moderate/severe, 3.23 (1.34–7.79)] and rehospitalization [adjusted odds ratios: mild, 2.61 (1.16–5.90); moderate/severe, 2.53 (1.07–6.00)] within 1 month posttransplant. Results suggest that PROMIS-PF is a practical tool for assessing physical function in kidney transplant candidates. Larger studies are needed to confirm the utility of PROMIS-PF to identify transplant candidates who would benefit from pretransplant prehabilitation.

Background.: In the United States, universal screening for human T-lymphotropic virus (HTLV) in deceased organ donors was discontinued in 2009. Since then, the transplant guideline suggests considering targeted screening. However, the outcomes of this change in HTLV screening have not been evaluated. Methods.: Using the Organ Procurement and Transplantation Network database between 2010 and 2022, we analyzed the HTLV antibody screening frequency and seroprevalence in potential deceased organ donors and their correlations with HTLV infection risks, including race and high-risk behaviors for blood-borne pathogen infection. Although targeted screening has not been established for HTLV, we hypothesized that screening rates should correlate with the proportions of donors with infection risk if screening is targeted. We also evaluated the organ utilization of HTLV-seropositive donors. Results.: Of 130 284 potential organ donors, 22 032 (16.9%) were tested for HTLV antibody. The proportion of donors tested for HTLV varied between Organ Procurement Organizations (median [interquartile range], 3.8% [1.0%–23.2%]; range, 0.2%–99.4%) and was not correlated to HTLV infection risks. There were 48 seropositive donors (0.22%), and at least 1 organ from 42 of these donors (87.5%) was transplanted. The number of organs recovered and transplanted per donor was significantly lower in HTLV-seropositive than in HTLV-negative donors (recovered, 2 [2–3] versus 3 [3–5], P < 0.001; transplanted, 2 [1–3] versus 3 [2–4], P < 0.001). However, HTLV-1 infection was not attributed as the cause of nonrecovery except for only 1 HTLV-seropositive donor. Conclusions.: HTLV screening practices varied across the United States. Our findings suggest that targeted screening was not performed after the elimination of universal screening.

Background.: It is unclear whether kidney grafts from deceased donors with acute kidney injury (AKI) are more vulnerable to calcineurin inhibitor nephrotoxicity, and whether de novo use of belatacept is more beneficial than tacrolimus for recipients of these types of kidney transplants. Methods.: In this retrospective cohort study using the US Organ Procurement and Transplantation Network database, we created 1:4 matches with highly similar characteristics for recipients of AKI-donor kidneys receiving belatacept versus tacrolimus for initial maintenance immunosuppression and compared outcomes for graft function, patient and graft survival, and rejection. Results.: The matched cohort consisted of 567 and 2268 recipients administered belatacept and tacrolimus, respectively. Posttransplant estimated glomerular filtration rate was significantly higher in the belatacept group at 6 mo (58.2 ± 24.2 versus 54.6 ± 21.6 mL/min/1.73 m², P < 0.001); however, the between-group difference did not reach statistical significance at 12 mo (57.2 ± 24.3 versus 55.7 ± 22.2 mL/min/1.73 m², P = 0.057). Median follow-up periods were 3.2 and 3.1 y for patient and graft survival, respectively. There were no significant differences between belatacept versus tacrolimus for mortality (hazard ratio 1.18 [95% confidence interval, 0.95-1.47], P = 0.14) or death-censored graft failure (hazard ratio 1.17 [0.85-1.61], P = 0.33). Rejection rate within 12 mo was significantly higher in the belatacept group (13% versus 7%, P < 0.001). Conclusions.: In this matched cohort study, initial use of belatacept for AKI-donor kidney recipients was associated with small benefits in early graft function when compared with tacrolimus. Although rejection risk was significantly higher in recipients administered belatacept, patient and graft survival were not significantly different between groups.