Design, cohort profile and comparison of the KTD-Innov study: a prospective multidimensional biomarker validation study in kidney allograft rejection.

There is an unmet need for robust and clinically validated biomarkers of kidney allograft rejection. Here we present the KTD-Innov study (ClinicalTrials.gov, NCT03582436), an unselected deeply phenotyped cohort of kidney transplant recipients with a holistic approach to validate the clinical utility of precision diagnostic biomarkers. In 2018-2019, we prospectively enrolled consecutive adult patients who received a kidney allograft at seven French centers and followed them for a year. We performed multimodal phenotyping at follow-up visits, by collecting clinical, biological, immunological, and histological parameters, and analyzing a panel of 147 blood, urinary and kidney tissue biomarkers. The primary outcome was allograft rejection, assessed at each visit according to the international Banff 2019 classification. We evaluated the representativeness of participants by comparing them with patients from French, European, and American transplant programs transplanted during the same period. A total of 733 kidney transplant recipients (64.1% male and 35.9% female) were included during the study. The median follow-up after transplantation was 12.3 months (interquartile range, 11.9-13.1 months). The cumulative incidence of rejection was 9.7% at one year post-transplant. We developed a distributed and secured data repository in compliance with the general data protection regulation. We established a multimodal biomarker biobank of 16,736 samples, including 9331 blood, 4425 urinary and 2980 kidney tissue samples, managed and secured in a collaborative network involving 7 clinical centers, 4 analytical platforms and 2 industrial partners. Patients' characteristics, immune profiles and treatments closely resembled those of 41,238 French, European and American kidney transplant recipients. The KTD-Innov study is a unique holistic and multidimensional biomarker validation cohort of kidney transplant recipients representative of the real-world transplant population. Future findings from this cohort are likely to be robust and generalizable.

Characterizing proximity and transfers of deceased organ donors to donor care units in the United States.

Some United States organ procurement organizations transfer deceased organ donors to donor care units (DCUs) for recovery procedures. We used Organ Procurement and Transplantation Network data, from April 2017 to June 2021, to describe the proximity of adult deceased donors after brain death to DCUs and understand the impact of donor service area (DSA) boundaries on transfer efficiency. Among 19 109 donors (56.1% of the cohort) in 25 DSAs with DCUs, a majority (14 593 [76.4%]) were in hospitals within a 2-hour drive. In areas with DCUs detectable in the study data set, a minority of donors (3582 of 11 532 [31.1%]) were transferred to a DCU; transfer rates varied between DSAs (median, 27.7%, range, 4.0%-96.5%). Median hospital-to-DCU driving times were not meaningfully shorter among transferred donors (50 vs 51 minutes for not transferred, P < .001). When DSA boundaries were ignored, 3241 cohort donors (9.5%) without current DCU access were managed in hospitals within 2 hours of a DCU and thus potentially eligible for transfer. In summary, approximately half of United States deceased donors after brain death are managed in hospitals in DSAs with a DCU. Transfer of donors between DSAs may increase DCU utilization and improve system efficiency.

Deceased Organ Donor Management and Organ Distribution From Organ Procurement Organization-Based Recovery Facilities Versus Acute-Care Hospitals.

Introduction: Organ recovery facilities address the logistical challenges of hospital-based deceased organ donor management. While more organs are transplanted from donors in facilities, differences in donor management and donation processes are not fully characterized. Research Question: Does deceased donor management and organ transport distance differ between organ procurement organization (OPO)-based recovery facilities versus hospitals? Design: Retrospective analysis of Organ Procurement and Transplant Network data, including adults after brain death in 10 procurement regions (April 2017-June 2021). The primary outcomes were ischemic times of transplanted hearts, kidneys, livers, and lungs. Secondary outcomes included transport distances (between the facility or hospital and the transplant program) for each transplanted organ. Results: Among 5010 deceased donors, 51.7% underwent recovery in an OPO-based recovery facility. After adjustment for recipient and system factors, mean differences in ischemic times of any transplanted organ were not significantly different between donors in facilities and hospitals. Transplanted hearts recovered from donors in facilities were transported further than hearts from hospital donors (median 255 mi [IQR 27, 475] versus 174 [IQR 42, 365], P = .002); transport distances for livers and kidneys were significantly shorter (P < .001 for both). Conclusion: Organ recovery procedures performed in OPO-based recovery facilities were not associated with differences in ischemic times in transplanted organs from organs recovered in hospitals, but differences in organ transport distances exist. Further work is needed to determine whether other observed differences in donor management and organ distribution meaningfully impact donation and transplantation outcomes.

Therapeutic Donor Kidney Transplant Outcomes: Comparing Early US Experiences Using Optimal Matching.

Background: Therapeutic donors (TDs) are individuals who undergo organ removal for medical treatment with no replacement organ, and the organ is then transplanted into another person. Transplant centers in the United States have started using TDs for kidney transplantation (KT). TD-KT recipient outcomes may be inferior to those of non-TD-living-donor (non-TD-LD)-KT or deceased-donor (DD)-KT because of the conditions that led to nephrectomy; however, these outcomes have not been sufficiently evaluated. Methods: This was a retrospective cohort study using Organ Procurement and Transplantation Network data. Via optimal matching methods, we created 1:4 fivesomes with highly similar characteristics for TD-KT and non-TD-LD-KT recipients and then separately for TD-KT and DD-KT recipients. We compared a 6-mo estimated glomerular filtration rate (eGFR) between groups (primary endpoint) and a composite of death, graft loss, or eGFR <30 mL/min/1.73 m2 at 6 mo (secondary). Results: We identified 36 TD-KT recipients with 6-mo eGFR. There was also 1 death and 2 graft losses within 6 mo. Mean ± SD 6-mo eGFR was not significantly different between TD-KT, non-TD-LD-KT, and DD-KT recipients (59.9 ± 20.7, 63.3 ± 17.9, and 59.9 ± 23.0 mL/min/1.73 m2, respectively; P > 0.05). However, the 6-mo composite outcome occurred more frequently with TD-KT than with non-TD-LD-KT and DD-KT (18%, 2% [P < 0.001], and 8% [P = 0.053], respectively). Conclusions: Early graft function was no different between well-matched groups, but TD-KT demonstrated a higher risk of otherwise poor 6-mo outcomes compared with non-TD-LD-KT and DD-KT. Our results support selective utilization of TD kidneys; however, additional studies are needed with more detailed TD kidney information to understand how to best utilize these kidneys.

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.

The SHELTER Trial of Transplanting Hepatitis C Virus-Infected Lungs Into Uninfected Recipients.

SHELTER is a trial of transplanting lungs from deceased donors with hepatitis C virus (HCV) infection into HCV-negative candidates (sponsor: Merck; NCT03724149). Few trials have reported outcomes using thoracic organs from HCV-RNA+ donors and none have reported quality of life (QOL). Methods: This study is a single-arm trial of 10 lung transplants at a single center. Patients were included who were between 18 and 67 y of age and waitlisted for lung-only transplant. Patients were excluded who had evidence of liver disease. Primary outcome was HCV cure (sustained virologic response 12 wk after completing antiviral therapy). Recipients longitudinally reported QOL using the validated RAND-36 instrument. We also applied advanced methods to match HCV-RNA+ lung recipients to HCV-negative lung recipients in a 1:3 ratio at the same center. Results: Between November 2018 and November 2020, 18 patients were consented and opted-in for HCV-RNA+ lung offers in the allocation system. After a median of 37 d (interquartile range [IQR], 6-373) from opt-in, 10 participants received double lung transplants. The median recipient age was 57 y (IQR, 44-67), and 7 recipients (70%) had chronic obstructive pulmonary disease. The median lung allocation score at transplant was 34.3 (IQR, 32.7-86.9). Posttransplant, 5 recipients developed primary graft dysfunction grade 3 on day 2 or 3, although none required extracorporeal membrane oxygenation. Nine patients received elbasvir/grazoprevir, whereas 1 patient received sofosbuvir/velpatasvir. All 10 patients were cured of HCV and survived to 1 y (versus 83% 1-y survival among matched comparators). No serious adverse events were found to be related to HCV or treatment. RAND-36 scores showed substantial improvement in physical QOL and some improvement in mental QOL. We also examined forced expiratory volume in 1 s-the most important lung function parameter after transplantation. We detected no clinically important differences in forced expiratory volume in 1 s between the HCV-RNA+ lung recipients versus matched comparators. Conclusions: SHELTER adds important evidence regarding the safety of transplanting HCV-RNA+ lungs into uninfected recipients and suggests QOL benefits.

Decision-making Among Hepatitis C Virus-negative Transplant Candidates Offered Organs from Donors with HCV Infection.

Background: Historically, many organs from deceased donors with hepatitis C virus (HCV) were discarded. The advent of highly curative direct-acting antiviral (DAA) therapies motivated transplant centers to conduct trials of transplanting HCV-viremic organs (nucleic acid amplification test positive) into HCV-negative recipients, followed by DAA treatment. However, the factors that influence candidates' decisions regarding acceptance of transplant with HCV-viremic organs are not well understood. Methods: To explore patient-level perceptions, influences, and experiences that inform candidate decision-making regarding transplant with organs from HCV-viremic donors, we conducted a qualitative semistructured interview study embedded within 3 clinical trials investigating the safety and efficacy of transplanting lungs and kidneys from HCV-viremic donors into HCV-negative recipients. The study was conducted from June 2019 to March 2021. Results: Among 44 HCV-negative patients listed for organ transplant who were approached for enrollment in the applicable clinical trial, 3 approaches to decision-making emerged: positivist, risk analyses, and instinctual response. Perceptions of risk contributed to conceptualizations of factors influencing decisions. Moreover, most participants relied on multiple decision-making approaches, either simultaneously or sequentially. Conclusions: Understanding how different decisional models influence patients' choices regarding transplant with organs from HCV-viremic donors may promote shared decision-making among transplant patients and providers.

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Acute Kidney Injury in Deceased Organ Donors and Kidney Transplant Outcomes: A National Cohort Study Using a Novel Data Source.

OBJECTIVE: The aim of this study was to determine graft function and survival for kidney transplants from deceased donors with acute kidney injury (AKI) that persists at the time of organ procurement. BACKGROUND: Kidneys from donors with AKI are often discarded and may provide an opportunity to selectively expand the donor pool. METHODS: Using Organ Procurement and Transplantation Network and DonorNet data, we studied adult kidney-only recipients between May 1, 2007 and December 31, 2016. DonorNet was used to characterize longitudinal creatinine trends and urine output. Donor AKI was defined using KDIGO guidelines and terminal creatinine ≥1.5 mg/dL. We compared outcomes between AKI kidneys versus "ideal comparator" kidneys from donors with no or resolved AKI stage 1 plus terminal creatinine <1.5mg/dL. We fit proportional hazards models and hierarchical linear regression models for the primary outcomes of all-cause graft failure (ACGF) and 12-month estimated glomerular filtration rate (eGFR), respectively. RESULTS: We identified 7660 donors with persistent AKI (33.2% with AKI stage 3) from whom ≥1 kidney was transplanted. Observed rates of ACGF within 3 years were similar between recipient groups (15.5% in AKI vs 15.1% ideal comparator allografts, P = 0.2). After risk adjustment, ACGF was slightly higher among recipients of AKI kidneys (adjusted hazard ratio 1.05, 95% confidence interval: 1.01-1.09). The mean 12-month eGFR for AKI kidney recipients was lower, but differences were not clinically important (56.6 vs 57.5 mL/min/1.73m 2 for ideal comparator kidneys; P < 0.001). There were 2888 kidneys discarded from donors with AKI, age ≤65 years, without hypertension or diabetes, and terminal creatinine ≤4 mg/dL. CONCLUSION: Kidney allografts from donors with persistent AKI are often discarded, yet those that were transplanted did not have clinically meaningful differences in graft survival and function.

Assessment of the Utility of Kidney Histology as a Basis for Discarding Organs in the United States: A Comparison of International Transplant Practices and Outcomes.

BACKGROUND: Many kidneys donated for transplant in the United States are discarded because of abnormal histology. Whether histology adds incremental value beyond usual donor attributes in assessing allograft quality is unknown. METHODS: This population-based study included patients who received a deceased donor kidney that had been biopsied before implantation according to a prespecified protocol in France and Belgium, where preimplantation biopsy findings are generally not used for decision making in the allocation process. We also studied kidneys that had been acquired from deceased United States donors for transplantation that were biopsied during allocation and discarded because of low organ quality. Using donor and recipient characteristics, we fit multivariable Cox models for death-censored graft failure and examined whether predictive accuracy (C index) improved after adding donor histology. We matched the discarded United States kidneys to similar kidneys transplanted in Europe and calculated predicted allograft survival. RESULTS: In the development cohort of 1629 kidney recipients at two French centers, adding donor histology to the model did not significantly improve prediction of long-term allograft failure. Analyses using an external validation cohort from two Belgian centers confirmed the lack of improved accuracy from adding histology. About 45% of 1103 United States kidneys discarded because of histologic findings could be accurately matched to very similar kidneys that had been transplanted in France; these discarded kidneys would be expected to have allograft survival of 93.1% at 1 year, 80.7% at 5 years, and 68.9% at 10 years. CONCLUSIONS: In this multicenter study, donor kidney histology assessment during allocation did not provide substantial incremental value in ascertaining organ quality. Many kidneys discarded on the basis of biopsy findings would likely benefit United States patients who are wait listed.

Racial disparities in preemptive waitlisting and deceased donor kidney transplantation: Ethics and solutions.

Kidney transplantation prior to dialysis, known as "preemptive transplant," enables patients to live longer and avoid the substantial quality of life burdens due to chronic dialysis. Deceased donor kidneys are a public resource that ought to provide health benefits equitably. Unfortunately, White, better educated, and privately insured patients enjoy disproportionate access to preemptive transplantation using deceased donor kidneys. This problem has persisted for decades and is exacerbated by the first-come, first-served approach to kidney allocation for predialysis patients. In this Personal Viewpoint, we describe the diverse barriers to preemptive waitlisting and kidney transplant. The analysis focuses on healthcare system features that particularly disadvantage Black patients, such as the waitlisting eligibility criterion of a single glomerular filtration rate or creatinine clearance ≤20 ml/min, and neglect of wide variation in the rate of progression to end-stage kidney disease (ESKD) in allocating preemptive transplants. We propose initiatives to improve equity including: (1) standardization of waitlisting eligibility criteria related to kidney function; (2) aggressive education for clinicians about early transplant referral; (3) innovations in electronic medical record capabilities; and (4) rapid status 7 listing by centers. If those initiatives fail, the transplant field should consider eliminating preemptive waitlisting and transplantation with deceased donor kidneys.

Effect of Neighborhood Food Environment and Socioeconomic Status on Serum Phosphorus Level for Patients on Chronic Dialysis.

BACKGROUND: Elevated blood phosphorus levels are common and associated with a greater risk of death for patients receiving chronic dialysis. Phosphorus-rich foods are prevalent in the American diet, and low-phosphorus foods, including fruits and vegetables, are often less available in areas with more poverty. The relative contributions of neighborhood food availability and socioeconomic status to phosphorus control in patients receiving dialysis are unknown. METHODS: Using longitudinal data from a national dialysis provider, we constructed hierarchical, linear mixed-effects models to evaluate the relationships between neighborhood food environment or socioeconomic status and serum phosphorus level among patients receiving incident dialysis. RESULTS: Our cohort included 258,510 patients receiving chronic hemodialysis in 2005-2013. Median age at dialysis initiation was 64 years, 45% were female, 32% were Black, and 15% were Hispanic. Within their residential zip code, patients had a median of 25 "less-healthy" food outlets (interquartile range, 11-40) available to them compared with a median of four "healthy" food outlets (interquartile range, 2-6). Living in a neighborhood with better availability of healthy food was not associated with a lower phosphorus level. Neighborhood income also was not associated with differences in phosphorus. Patient age, race, cause of ESKD, and mean monthly dialysis duration were most closely associated with phosphorus level. CONCLUSIONS: Neither neighborhood availability of healthy food options nor neighborhood income was associated with phosphorus levels in patients receiving chronic dialysis. Modifying factors, such as nutrition literacy, individual-level financial resources, and adherence to diet restrictions and medications, may be more powerful contributors than food environment to elevated phosphorus.

National Trends in Utilization and 1-Year Outcomes with Transplantation of HCV-Viremic Kidneys.

BACKGROUND: Recent pilot trials have demonstrated the safety of transplanting HCV-viremic kidneys into HCV-seronegative recipients. However, it remains unclear if allograft function is impacted by donor HCV-viremia or recipient HCV-serostatus. METHODS: We used national United States registry data to examine trends in HCV-viremic kidney use between 4/1/2015 and 3/31/2019. We applied advanced matching methods to compare eGFR for similar kidneys transplanted into highly similar recipients of kidney transplants. RESULTS: Over time, HCV-seronegative recipients received a rising proportion of HCV-viremic kidneys. During the first quarter of 2019, 200 HCV-viremic kidneys were transplanted into HCV-seronegative recipients, versus 69 into HCV-seropositive recipients, while 105 HCV-viremic kidneys were discarded. The probability of HCV-viremic kidney discard has declined over time. Kidney transplant candidates willing to accept a HCV-seropositive kidney increased from 2936 to 16,809 from during this time period. When transplanted into HCV-seronegative recipients, HCV-viremic kidneys matched to HCV-non-viremic kidneys on predictors of organ quality, except HCV, had similar 1-year eGFR (66.3 versus 67.1 ml/min per 1.73 m2, P=0.86). This was despite the much worse kidney donor profile index scores assigned to the HCV-viremic kidneys. Recipient HCV-serostatus was not associated with a clinically meaningful difference in 1-year eGFR (66.5 versus 71.1 ml/min per 1.73 m2, P=0.056) after transplantation of HCV-viremic kidneys. CONCLUSIONS: By 2019, HCV-seronegative patients received the majority of kidneys transplanted from HCV-viremic donors. Widely used organ quality scores underestimated the quality of HCV-viremic kidneys based on 1-year allograft function. Recipient HCV-serostatus was also not associated with worse short-term allograft function using HCV-viremic kidneys.