"Long-term effects of center volume on transplant outcomes in adult kidney transplant recipients".

BACKGROUND: The influence of center volume on kidney transplant outcomes is a topic of ongoing debate. In this study, we employed competing risk analyses to accurately estimate the marginal probability of graft failure in the presence of competing events, such as mortality from other causes with long-term outcomes. The incorporation of immunosuppression protocols and extended follow-up offers additional insights. Our emphasis on long-term follow-up aligns with biological considerations where competing risks play a significant role. METHODS: We examined data from 219,878 adult kidney-only transplantations across 256 U.S. transplant centers (January 2001-December 2015) sourced from the Organ Procurement and Transplantation Network registry. Centers were classified into quartiles by annual volume: low (Q1 = 28), medium (Q2 = 75), medium-high (Q3 = 121), and high (Q4 = 195). Our study investigated the relationship between center volume and 5-year outcomes, focusing on graft failure and mortality. Sub-population analyses included deceased donors, living donors, diabetic recipients, those with kidney donor profile index >85%, and re-transplants from deceased donors. RESULTS: Adjusted cause-specific hazard ratios (aCHR) for Five-Year Graft Failure and Patient Death were examined by center volume, with low-volume centers as the reference standard (aCHR: 1.0). In deceased donors, medium-high and high-volume centers showed significantly lower cause-specific hazard ratios for graft failure (medium-high aCHR = 0.892, p<0.001; high aCHR = 0.953, p = 0.149) and patient death (medium-high aCHR = 0.828, p<0.001; high aCHR = 0.898, p = 0.003). Among living donors, no significant differences were found for graft failure, while a trend towards lower cause-specific hazard ratios for patient death was observed in medium-high (aCHR = 0.895, p = 0.107) and high-volume centers (aCHR = 0.88, p = 0.061). CONCLUSION: Higher center volume is associated with significantly lower cause-specific hazard ratios for graft failure and patient death in deceased donors, while a trend towards reduced cause-specific hazard ratios for patient death is observed in living donors.

Cytomegalovirus Matching in Deceased Donor Kidney Allocation: Results From a U.S. National Simulation Model.

Background: Cytomegalovirus (CMV) infects >60% of adults and can pose an independent risk factor for allograft loss and mortality in solid organ transplant recipients. The purpose of this study is to evaluate the impact of a nationwide implementation of CMV seromatching (donor/recipient: D-/R- and D+/R+) in the U.S. deceased donor kidney allocation system (KAS). Methods: Adult candidates on the U.S. kidney-only transplant waiting list and deceased donor kidneys offered to the U.S. transplant centers were considered. A discrete-event simulation model, simulating the pre-COVID-19 period from January 1, 2015, to January 1, 2018, was used to compare the performances of currently employed KAS-250 policy (without CMV matching) to various simulated CMV matching policies parameterized by calculated panel reactive antibody exception threshold. Outcomes included CMV serodistribution, waiting time, access to transplantation among various groups, transplant rate, graft survival, kidney discard rate, and antigen-mismatch distribution, stratified by CMV serostatus. Results: CMV matching policy with a calculated panel reactive antibody exception threshold of 50% (namely, the CMV">50%" policy) strikes a better balance between benefits and drawbacks of CMV matching. Compared with KAS-250, CMV">50%" reduced CMV high-risk (D+/R-) transplants (6.1% versus 18.1%) and increased CMV low-risk (D-/R-) transplants (27.2% versus 13.1%); increased transplant rate for CMV R- patients (11.54 versus 12.57) but decreased for R+ patients (10.68 versus 10.48), yielding an increase in aggregate (11.09 versus 10.94); and reduced mean time to transplantation (by 6 wk); and reduced kidney discard rate (25.7% versus 26.2%). Conclusions: Our findings underscore the feasibility and potential advantages of a nationwide CMV seromatching policy in kidney transplantation.

Should Transplant Nephrology Pursue Recognition from the Accreditation Council for Graduate Medical Education (ACGME)?

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis.

Comparison of Short-Term Outcomes in Kidney Transplant Recipients from SARS-CoV-2-Infected versus Noninfected Deceased Donors.

BACKGROUND: Acceptable post-transplant outcomes were reported in kidney transplant recipients from donors with coronavirus disease 2019 (COVID-19); however, there are no comparative studies with well-matched controls. METHODS: This multicenter, prospective observational study, which included three transplant centers in the United States, enrolled 61 kidney recipients from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected deceased donors. Using optimal matching methods, we matched every recipient to three comparators receiving kidneys from SARS-CoV-2-negative deceased donors with otherwise highly similar characteristics in the same transplant centers to compare 6-month eGFR. RESULTS: Among recipients of SARS-CoV-2-infected donor kidneys, one recipient died with a functional graft within 6 months. Mean 6-month eGFR was not significantly different between SARS-CoV-2-infected and noninfected donor groups (55±21 and 57±25 ml/min per 1.73 m 2 , respectively; P = 0.61). Six-month eGFR in recipients from SARS-CoV-2-infected donors who died of reasons other than COVID-19 was not significantly different from those from SARS-CoV-2-negative donors (58±22 and 56±25 ml/min per 1.73 m 2 , respectively; P = 0.51). However, recipients from donors who died of COVID-19 had significantly lower 6-month eGFR than those from SARS-CoV-2-negative donors (46±17 and 58±27 ml/min per 1.73 m 2 , respectively; P = 0.03). No donor-to-recipient SARS-CoV-2 transmission was observed. CONCLUSIONS: Six-month eGFR was not significantly different between recipients of kidneys from SARS-CoV-2-infected and noninfected donors. However, those receiving kidneys from donors who died of COVID-19 had significantly lower 6-month eGFR. Donor-to-recipient SARS-CoV-2 transmission was not observed.

Contemporary Monoclonal Antibody Utilization in Glomerular Diseases.

Therapeutic monoclonal antibodies (MAbs) have been one of the fastest growing drug classes in the past 2 decades and are indicated in the treatment of cancer, autoimmune disorders, solid organ transplantation, and glomerular diseases. The Food and Drug Administration has approved 100 MAbs between 1986 and 2021, and MAbs account for 20% of Food and Drug Administration's new drug approval every year. MAbs are preferred over traditional immunosuppressive agents because of their high specificity, reduced number of drug-drug interactions, and low toxicity, which make them a prime example of personalized medicine. In this review article, we provide an overview of the taxonomy, pharmacology, and therapeutic applications of MAbs in glomerular diseases. We searched the literature through PubMed using the following search terms: monoclonal antibodies, glomerular diseases, pharmacokinetics, pharmacodynamics, immunoglobulin, murine, chimeric,humanized, and fully human, and limited our search to years 2018-2023. We selected peer-reviewed journal articles with an evidence-based approach, prioritizing randomized control trials in specific glomerular diseases, if available. Advances in the MAb field have resulted in a significant paradigm shift in targeted treatment of immune-mediated glomerular diseases, and multiple randomized control trials are currently being conducted. Increased recognition is critical to expand their use in experimental research and personalized medicine.

The Independent Effects of Kidney Length and Vascular Plaque on Ten-Year Outcomes of Extended Criteria Donor Kidney Transplants.

The independent effects of deceased donor kidney length and vascular plaque on long-term graft survival are not established. Utilizing DonorNet attachments from 4,480 expanded criteria donors (ECD) recovered between 2008 and 2012 in the United States with at least one kidney biopsied and transplanted, we analyzed the relationship between kidney length and vascular plaques and 10-year hazard of all-cause graft failure (ACGF) using causal inference methods in a Cox regression framework. The composite plaque score (range 0-4) and the presence of any plaque (yes, no) was also analyzed. Kidney length was modeled both categorically (<10, 10-12, >12 cm) as well as numerically, using a restricted cubic spline to capture nonlinearity. Effects of a novel composite plaque score 4 vs. 0 (HR 1.08; 95% CI: 0.96, 1.23) and the presence of any vascular plaque (HR 1.08; 95% CI: 0.98, 1.20) were attenuated after adjustment. Likewise, we identified a potential nonlinear relationship between kidney length and the 10-year hazard of ACGF, however the strength of the relationship was attenuated after adjusting for other donor factors. The independent effects of vascular plaque and kidney length on long-term ECD graft survival were found to be minimal and should not play a significant role in utilization.

Lack of effectiveness of Bebtelovimab monoclonal antibody among high-risk patients with SARS-Cov-2 Omicron during BA.2, BA.2.12.1 and BA.5 subvariants dominated era.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N = 1,091) compared to propensity score (PS) matched control (N = 1,091). The primary composite outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary composite outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p = 0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or ≥65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026-0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.

The Impact of Nirmatrelvir-Ritonavir in Reducing Hospitalizations Among High-Risk Patients With SARS-CoV-2 During the Omicron Predominant Era.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality in high-risk populations. Several therapeutics have been developed to reduce the risk of complications related to COVID-19, hospitalizations, and death. In several studies, nirmatrelvir-ritonavir (NR) was reported to reduce the risk of hospitalizations and death. We aimed to evaluate the efficacy of NR in preventing hospitalizations and death during the Omicron predominant period. METHODS: We retrospectively evaluated patients from June 1, 2022, through September 24, 2022. There were a total of 25,939 documented COVID-19 cases. Using propensity matching, we matched 5754 patients treated with NR with untreated patients. RESULTS: Postmatching, the median age of the NR-treated group was 58 years (interquartile range, 43-70 years) and 42% were vaccinated. Postmatching composite outcome of the 30-day hospitalization and mortality in the NR-treated group were 0.9% (95% confidence interval [CI]: 0.7%-1.2%) versus 2.1% (95% CI: 1.8%-2.5%) in the matched control group, with a difference of -1.2 (-1.7, -0.8), P value <.01. The difference rates (NR vs. control) in 30-day all-cause hospitalizations and mortality were -1.2% (95% CI: -1.6% to -0.7%, P value <.01) and -0.1% (95% CI: -0.2% to 0.0%, P value = 0.29), respectively. We found similar finding across different age groups (≥65 vs. <65) and the vaccinated group. CONCLUSION: We report a significant benefit with the use of NR in reducing hospitalizations among various high-risk COVID-19 groups during the Omicron BA.5 predominant period.

Utilization of hepatitis C virus-positive donors in kidney transplantation.

PURPOSE OF REVIEW: Direct-acting antivirals (DAA) have transformed kidney transplantation by increasing the donor pool from hepatitis C virus (HCV)-infected donors and allowing HCV nucleic acid amplification testing (NAT) donor-positive/recipient-negative (D+/R-) transplantation over the last 7 years. Willingness to accept kidneys from HCV-infected donors and timing/duration of DAA therapy have been evolving. RECENT FINDINGS: By 2021, most of the HCV NAT+ kidneys (92.6%) were transplanted to HCV-naive recipients. Despite the availability of effective DAA therapy, the discard rate of HCV NAT kidneys has been stagnant around 25%. The proportion of wait-listed patients willing to accept a deceased donor kidney from HCV Ab+ and HCV NAT+ donors increased 20-fold between 2015 and 2022. Wait-listed time to receive HCV NAT+ kidneys has been rising and most of the kidneys are transplanted to HCV-naive recipients. The proportion of deceased donor kidney transplants performed in recipients with HCV seropositivity decreased from 5.1 to 2.8% during the same period. Relatively short courses of DAA therapy (7-8 days) appear to be effective to decrease HCV transmission (<5%) and achieve sustained virological response at 12 weeks if administered prior to revascularization. SUMMARY: Further studies are needed to evaluate long-term outcomes of HCV NAT D+/R- transplantation and the best course of DAA treatment.

The Prevention of COVID-19 in High-Risk Patients Using Tixagevimab-Cilgavimab (Evusheld): Real-World Experience at a Large Academic Center.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with increased morbidity and mortality among immunocompromised patients. Tixagevimab-cilgavimab (Tix-Cil) is a combination of 2 monoclonal antibodies approved for the prevention of COVID-19 complications in this high-risk group. METHODS: We retrospectively reviewed the charts of patients who received Tix-Cil during the Omicron variant period (January 17 to April 23, 2022), with a follow-up period until May 24, 2022. We collected data about patient underlying comorbidities and post Tix-Cil COVID-19 infections, deaths, and hospitalizations. RESULTS: There were 463 patients with a median age of 68 years, of which 51% were male, 79% White, 13.2% Hispanic, 1.7% Black/African American, and 5.8% identified as Other. A total of 18% had undergone a solid organ transplantation or hematopoietic stem cell transplantation. Only 6/98 (6.1%) had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detected by polymerase chain reaction (PCR) at a median 48 days (interquartile range [IQR] 27.5, 69) follow-up. Forty-two patients (9.1%) were hospitalized, and 4 (0.9%) died, but none were attributed to COVID-19 or Tix-Cil. One hospitalized patient had an incidental, asymptomatic, positive SARS-CoV 2 by PCR. The median days from Tix-Cil administration to non-COVID-19-related hospitalization and death were 30 (IQR 17, 55) and 53 (IQR 18, 91), respectively. CONCLUSION: Tix-Cil provides protection against COVID-19 complications in immunocompromised patients with suboptimal immune responses to vaccines.

Effect of age and rural residency on perceptions about SARS-CoV-2 pandemic and vaccination in kidney transplant recipients.

BACKGROUND: Transplant patients have poor outcomes in coronavirus-disease 2019 (COVID-19). The pandemic's effects on rural patients' overall care experience, attitudes to telemedicine, and vaccination are poorly understood. METHODS: We administered a cross-sectional survey to adult kidney transplant recipients in central Pennsylvania across four clinical sites between March 29, 2021 and June 2, 2021. We assessed the pandemic's impact on care access, telemedicine experience, attitudes toward preventive measures, vaccination, and variation by sociodemographic variables. RESULTS: Survey completion rate was 51% (303/594). Of these, 52.8% were rural residents. The most common impact was use of telemedicine (79.2%). Predominant barriers to telemedicine were lack of video devices (10.9%), perceived complexity (5.6%), and technical issues (5.3%). On a 0-10 Likert scale, the mean positive impression for telemedicine was 7.7; lower for patients with telephone-only versus video visits (7.0 vs. 8.2; p < .001), and age ≥60 years (7.4 vs. 8.1; p = .01) on univariate analyses. Time/travel savings were commonly identified (115/241, 47.7%) best parts of telemedicine and lack of personal connection (70/166, 42.2%) the worst. Only 68.9% had received any dose of COVID vaccination. The vaccinated group members were older (58.4 vs. 53.5 years; p = .007), and less likely rural (47.8% vs. 65.2%; p = .005). Common themes associated with vaccine hesitancy included concerns about safety (27/59, 46%), perceived lack of data (19/59, 32%), and distrust (17/59, 29%). At least one misconception about the vaccines or COVID-19 was quoted by 29% of vaccine-hesitant patients. CONCLUSIONS: Among respondents, the pandemic significantly impacted healthcare experience, especially in older patients in underserved communities. COVID-19 vaccination rate was relatively low, driven by misconceptions and lack of trust.

Effectiveness of Casirivimab-Imdevimab Monoclonal Antibody Treatment Among High-Risk Patients With Severe Acute Respiratory Syndrome Coronavirus 2 B.1.617.2 (Delta Variant) Infection.

Background: Real-world data on the effectiveness of neutralizing casirivimab-imdevimab monoclonal antibody (Cas-Imd mAb) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients may inform the response to future SARS-CoV-2 variants. Methods: This study covers an observational retrospective data analysis in Banner Health Care System sites, mainly in Arizona. During the study period, the prevalence of SARS-CoV-2 Delta variant was between 95% and 100%. Of 29 635 patients who tested positive for coronavirus disease 2019 (COVID-19) between 1 August 2021 and 30 October 2021, in the Banner Health Care System, the study cohort was split into 4213 adult patients who received Cas-Imd mAb (1200 mg) treatment compared to a PS-matched 4213 untreated patients. The primary outcomes were the incidence of all-cause hospitalization, intensive care unit (ICU) admission, and mortality within 30 days of Cas-Imd mAb administration or Delta variant infection. Results: Compared to the PS-matched untreated cohort, the Cas-Imd mAb cohort had significantly lower all-cause hospitalization (4.2% vs 17.6%; difference in percentages, -13.4 [95% confidence interval {CI}, -14.7 to -12.0]; P < .001), ICU admission (0.3% vs 2.8%; difference, -2.4 [95% CI, -3.0 to -1.9]; P < .001), and mortality (0.2% vs 2.0%; difference, -1.8 [95% CI, -2.3 to -1.3]; P < .001) within 30 days. The Cas-Imd mAb treatment was associated with lower rate of hospitalization (hazard ratio [HR], 0.22 [95% CI, .19-.26]; P < .001) and mortality (HR, 0.11 [95% CI, .06-.21]; P < .001). Conclusions: Cas-Imd mAb treatment was associated with a lower hospitalization rate, ICU admission, and mortality within 30 days among patients infected with the SARS-CoV-2 Delta variant.

Navigating the initial diagnosis and management of adult IgA vasculitis: A review.

Background: IgA vasculitis in adults has not been thoroughly studied. This has left a practice gap related to the management and follow-up of a population that is at an increased risk of comorbidities and potentially poor outcomes. For this reason, it is important to synthesize evidence from the current literature because this can help direct the movement for more robust studies to clarify best practice recommendations. Objective: We sought to create a narrative review for the practicing dermatologist when diagnosing and leading the care of IgA vasculitis in adult patients. Methods: A broad literature search was performed with a focus on articles that were published after the introduction of the most updated European Alliance of Associations for Rheumatology/Pediatric Rheumatology International Trials Organization/Pediatric Rheumatology European Society criteria. Results: The characteristics and management guidelines for IgA vasculitis in adults have been refined, although more rigorous studies are needed to develop best practice recommendations. Limitations: Because of the lack of sufficient randomized controlled trials on IgA vasculitis in adults, this narrative review is composed of mostly observational, descriptive studies. Conclusion: Adults with IgA vasculitis are at an increased risk of complicated disease course, necessitating formal diagnostic assessment and clear-cut follow-up recommendations to manage and prevent poor health outcomes related to various comorbidities.

Vignette-Based Reflections to Inform Genetic Testing Policies in Living Kidney Donors.

Family history of kidney disease increases risk of end-stage kidney disease (ESKD) in donors. Pre-donation genetic testing is recommended in evaluation guidelines and regulatory policy. Collaborating across several institutions, we describe cases to illustrate the utility as well as practical issues in incorporating genetic testing in transplant protocols. Case 1 is from 2009, before pervasive genetic testing. A healthy 27-year-old Caucasian male had an uneventful donor evaluation for his mother, who had early onset ESKD of unclear cause. He participated in paired-exchange kidney donation, but developed progressive kidney disease and gout over the next 10 years. A uromodulin gene mutation (NM_003361.3(UMOD):c.377 G>A p.C126Y) was detected and kidney biopsy showed tubulointerstitial kidney disease. The patient subsequently required kidney transplantation himself. Case 2 was a 36-year-old African American female who had an uneventful kidney donor evaluation. She underwent gene panel-based testing to rule out ApolipoproteinL1 risk variants, for which was negative. Incidentally, a sickle-cell trait (NM_000518.5(HBB):c.20A>T p.Glu7Val) was noted, and she was declined for kidney donation. This led to significant patient anguish. Case 3 was a 26-year-old Caucasian female who underwent panel-based testing because the potential recipient, her cousin, carried a variant of uncertain significance in the hepatocyte nuclear factor-1-ß (HNF1B) gene. While the potential donor did not harbor this variant, she was found to have a likely pathogenic variant in complement factor I (NM_000204.4(CFI):c.1311dup:p.Asp438Argfs*8), precluding kidney donation. Our cases emphasize that while genetic testing can be invaluable in donor evaluation, transplant centers should utilize detailed informed consent, develop care pathways for secondary genetic findings, and share experience to develop best practices around genetic testing in donors.