Stegall, Mark D.

Abstract Introduction: Surveillance biopsies after kidney transplantation provide an opportunity to assess early renal disease processes, including diabetic nephropathy, before clinical manifestation. This study aimed to identify proteomic alterations in renal allografts at 5 years post-transplant (5yrPT) and their associations with histologic features in diabetic/obese (DM/OB) versus non-diabetic/non-obese (nDM/nOB) recipients. Methods: We studied protocol biopsies from 17 DM/OB and 14 nDM/nOB kidney transplant recipients at Mayo Clinic (2000–2012). Laser capture microdissection followed by mass spectrometry was used for proteomic profiling. Histologic assessment included Banff and Tervaert scoring and morphometric analysis. Statistical comparisons were performed using ANOVA with Tukey post-hoc testing. Results: DM/OB recipients demonstrated greater histologic and metabolic injury at 5yrPT. Proteomic analysis identified 101 glomerular and 86 non-glomerular proteins differentially expressed between groups. Significant alterations were observed in proteins associated with mitochondrial dysfunction, including VDAC1 (fold change [FC] 2.6, p = 0.03), NDUFB9 (FC 0.15, p = 0.009), and NDUFA9 (FC 1.72, p = 0.01). Extracellular matrix remodeling proteins COL6A1, COL6A2, and COL6A3 were upregulated (FC 1.6–1.8, p < 0.05). Immune and inflammatory markers C9 (FC 1.6, p < 0.03) and TGFBI (FC 1.7, p < 0.001), as well as oxidative stress–related CLU, were increased. GGACT showed the greatest decrease (FC 0.30, p < 0.001), implicating altered energy metabolism. Conclusion: Distinct proteomic signatures at 5yrPT in DM/OB recipients highlight early mitochondrial, metabolic, immune, and extracellular matrix pathways involved in diabetic kidney disease. These changes precede clinical disease and identify candidate biomarkers and therapeutic targets to improve graft longevity.

ABSTRACT Aim The supply of donor kidneys (living and deceased) has fallen far behind the need, while the number of patients with end stage kidney disease continues to rise, increasing their risk of cardiovascular mortality. Kidney transplant candidates frequently exhibit large artery calcification, a major contributor to cardiovascular death. This study aimed to evaluate the relationship between abdominal arterial calcification (AAC) and survival in patients awaiting kidney transplant. Methods We modified the coronary calcium scoring method (Modified Agatston Method) and applied it to quantify AAC. This retrospective study included all adult patients ( N = 4184) listed for kidney transplant from 2005 to 2023 who had undergone abdominal computed tomography (CT) scans. Patients were categorised into two groups: those who died while on the waiting list (DWL) and those who survived (SWL). Results Among 4184 candidates, 446 (10.7%) died while on the waiting list, and 3738 (89.3%) survived to transplant or study end. Patients in the DWL group had significantly higher AAC scores across all vascular sites. The median total AAC score was 3605.8 (IQR 780.1–9017.3) in the DWL group versus 940.1 (IQR 49.2–4915.0) in the SWL group. Each 1000‐point increase in total AAC was associated with a 5.1% increase in mortality risk (HR 1.051; p < 0.001). An AAC cutoff of > 1769 correlated with reduced 5‐year survival (45.4% vs. 77.4%, p < 0.001). Conclusion AAC scoring on non‐contrast abdominal CT represents a noninvasive biomarker of mortality in kidney transplant waitlist patients and may enhance risk stratification and personalised care.

ABSTRACT Predicting delayed graft function (DGF) relies on donor, recipient, and perioperative factors. Despite the growing recognition that DGF duration strongly influences patient outcomes, no models currently address or predict its impact—highlighting an important gap in current research and clinical practice. This study aimed to develop an ensemble‐based machine learning model using perioperative data to predict DGF occurrence and duration. The gradient‐boosted decision trees model was trained and validated on 2725 patients, with k‐fold cross‐validation in an external cohort of 284 patients. Model performance was evaluated based on accuracy, ROC‐AUC, and other metrics using R and Python libraries. The binary DGF prediction model achieved a ROC‐AUC of 0.77, while the DGF duration classification model had an accuracy of 79.2%. DGF duration AUC values by time interval were 0.76 for 0–1 weeks, 0.81 for >1–2 weeks, 0.80 for >2–3 weeks, and 0.87 for >3 weeks; the overall macro‐averaged AUC was 0.81. The mean Brier score for multi‐class predictions was 0.14. External validation showed a 78% accuracy for DGF duration prediction. Acute kidney injury (AKI) and donor donation after circulatory death (DCD) status were key DGF predictors. The use of gradient‐boosted decision trees (GBDT) improves the prediction of both the likelihood and duration of DGF, addressing a current gap in kidney transplant patient care. By facilitating personalized transplant care, this model supports more effective perioperative planning and timely interventions, which may contribute to better patient outcomes.

Background. Acute cellular rejection (ACR) remains a major cause of morbidity after heart transplantation despite advances in immunosuppression. Whole genome transcriptomic profiling offers a systems-based, unbiased approach to elucidate the molecular mechanisms underlying ACR. However, noninvasive, longitudinal biomarker assessments capable of capturing the temporal dynamics of rejection biology remain scarce. Methods. RNA sequencing of peripheral blood from heart transplant recipients before, during, and after ACR was compared with nonrejection controls. Pathway analysis was conducted using differentially expressed genes (DEGs), and a machine learning approach was applied to assess gene-based prediction of ACR. Results. A total of 235 rejection-specific significant DEGs and 863 postrejection DEGs (false discovery rate < 0.05) were identified. During ACR, DEGs were enriched for T-cell activation/differentiation, apoptosis, and B-cell receptor signaling pathways. By combining the 2 sets of DEGs, a panel of 71 common genes was identified that reflected the significant, longitudinal transcriptomic dynamics of ACR. In an elastic net machine learning–based classifier, DYNLL1 and SERF2 were identified as ACR predictive genes, and achieved a cross-validated area under the receiver operating characteristic curve of 0.63. Conclusions. Peripheral blood transcriptomics identify dynamic temporal responses in ACR including T- and B-cell pathways with potential ACR predictive genes that warrant further investigation.

ABSTRACT Background Abdominal arterial calcification (AAC) is a common comorbidity in patients with end‐stage kidney disease (ESKD) and a predictor of cardiovascular events post‐kidney transplant. However, prior studies lacked a standardized approach to evaluate AAC and its impact on post‐transplant outcomes. This study aimed to correlate AAC score values with post‐kidney transplant outcomes using a modified scoring system traditionally applied to coronary artery calcification. Methods This retrospective study included 14 339 adult patients listed for kidney transplant between 2002 and 2023 at three transplant centers. Among them, 3683 patients met the criteria of undergoing a kidney transplant and an abdominal computed tomography (CT) scan pre‐transplant. We modified the coronary calcium score software by adjusting intake data points to quantify calcification in the abdominal aorta, common iliac, external iliac, and internal iliac arteries. Outcomes focused on post‐transplant mortality. Results In 3683 kidney transplant recipients, higher AAC scores were significantly associated with increased mortality. Each 1000‐unit increase in AAC score elevated hazard ratios (HRs) across arterial regions, including 1.116 for the aorta and 1.389 for the internal iliac (all p < 0.001). Adjusted analyses confirmed AAC as an independent risk factor for mortality. Kaplan–Meier curves demonstrated lower survival with increasing AAC quartiles. Conclusions AAC, measured by a standardized score, is a significant mortality risk factor in kidney transplant recipients. Integrating AAC scores into pre‐transplant evaluations could enhance risk stratification and improve outcomes. Prospective studies are needed to validate these findings and explore interventions to reduce AAC and improve survival.

ABSTRACT Background Ureteral stents are commonly placed during kidney transplantation (KT) to mitigate urologic complications. The objective of this study was to compare clinical outcomes in KT recipients with either early stent removal when attached to the Foley catheter or late removal via cystoscopy when unattached. Methods We conducted a multi‐center retrospective analysis of consecutive living donor KT patients (8/18/21‐4/21/23) stratified into Foley‐attached and unattached stent groups. Outcomes assessed were ureteral stricture, urine leaks, UTIs at 90 days and allograft failure and BKV DNAemia (BK virus DNAemia) at 1 year. Data are reported as mean and standard deviation. Results Among 247 patients with attached and 260 with unattached stents, baseline demographics (age, sex, diabetes) were similar between groups. There was a difference in race (87.9% vs. 77.8% Caucasian; p = 0.004). Foley catheters remained longer in the attached group (3.7 ± 1.8 vs. 3.0 ± 2.0 days; p < 0.001), but stents were removed earlier (3.7 ± 1.8 vs. 21.9 ± 4.7 days; p < 0.001). Comparing attached versus unattached, there were no differences in ureteral stricture (0.4% vs. 1.5%; p = 0.197), urine leak (0.8% vs. 0.4%; p = 0.533), BKV DNAemia (17.7% vs. 16.9%; p = 0.616), or allograft failure (0% vs. 0.8%; p = 0.167). However, UTI incidence by 90 days was lower in the attached group (5.7% vs. 11.9% p = 0.013). Induction therapy differed significantly between groups, with Alemtuzumab more common in the unattached group (58.1% vs. 19.4%, p < 0.001), Basiliximab more common in the attached group (43.3% vs. 35.0%, p < 0.001), and Thymoglobulin more common in the attached group (36.0% vs. 6.9%, p < 0.001). Baseline steroid use was higher in the unattached group (81.9% vs. 57.9%, p < 0.001). Conclusion Early stent removal via connection to the Foley catheter had similarly low rates of ureteral complications while reducing urinary tract infections and avoiding cystoscopic removal.

ABSTRACTIntroductionThe incidence of mortality late in the pandemic, particularly after widespread vaccine availability, is not well understood. Herein, we elucidate the effect of this impact of the COVID pandemic as well as risk factors for mortality during it.MethodsThe primary end point was death with a functioning graft with secondary endpoints of mortality rates in subgroups and at different time intervals during the pandemic.ResultsDespite widespread vaccination, mortality rates for kidney transplant (KTx) recipients almost doubled during the COVID‐19 era (6.40 deaths per 100 person years vs. 3.54 pre‐COVID). Mortality increased in all racial/ethnic groups but increased more in Native Americans, Hispanics, and African Americans compared to non‐Hispanic Caucasians. The highest mortality rate occurred during the Delta and Omicron time frames. In contrast to the general population, mortality was more evenly spread across age groups in KTx recipients.ConclusionsMortality rates during the COVID‐19 era were extremely high, more than doubling in some racial/ethnic groups. We conclude that the KTx population was a particularly vulnerable group during the COVID‐19 era and suggests the need for further research into the management of variants in the future.

Background. The impact of induction type or high-risk viral discordance on older kidney transplant recipients is unclear. Herein, we analyzed the association between induction type, viral discordance, and outcomes for older recipients. Methods. We analyzed the Scientific Registry of Transplant Recipients standard analysis file for all primary kidney transplant recipients older than 55 y who were transplanted between 2005 and 2022. All transplants were crossmatch negative and ABO-compatible. Recipients were discharged on tacrolimus and mycophenolate ± steroids. Recipients were categorized into 3 groups by induction received: rabbit antithymocyte globulin (r-ATG; N = 51 079), interleukin-2 receptor antagonist (IL-2RA; N = 22 752), and alemtuzumab (N = 13 465). Kaplan-Meier curves were generated for recipient and graft survival, and follow-up was censored at 10 y. Mixed-effect Cox proportional hazard models examined the association between induction type, high-risk viral discordance, and outcomes of interest. Models were adjusted for pertinent recipient and donor characteristics. Results. Induction type did not predict recipient survival in the multivariable model, whereas Epstein-Barr virus high-risk discordance predicted 14% higher mortality (1.14 [1.07-1.21], P < 0.01). In the multivariable model for death-censored graft survival, alemtuzumab, but not IL-2RA, was associated with an increased risk of graft loss (1.18 [1.06-1.29], P < 0.01) compared with r-ATG. High-risk cytomegalovirus discordance predicted 10% lower death-censored graft survival (1.10 [1.01-1.19], P < 0.02). Live donor and preemptive transplantation were favorable predictors of survival. Conclusions. In this large cohort of older transplant recipients, alemtuzumab, but not IL-2RA, induction was associated with an increased risk of graft loss compared with r-ATG. Cytomegalovirus and Epstein-Barr virus high-risk viral discordance portended poor graft and recipient survival, respectively.