Comparison of COVID-19 Hospitalization and Death Between Solid Organ Transplant Recipients and the General Population in Canada, 2020-2022.

Background: Solid organ transplant recipients have a high risk of severe outcomes from SARS-CoV-2 infection. A comprehensive understanding of the impact of the COVID-19 pandemic across multiple waves in the solid organ transplant population and how this compares to the general population is limited. We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada to answer this question. Methods: We included 15 306 solid organ transplant recipients and 12 160 904 individuals from the general population. Our primary outcome was the rate (per 100 person-years) of severe COVID-19 (ie, hospitalization or death with a positive SARS-CoV-2 test) occurring between January 25, 2020, and November 30, 2022. Results: Compared with the general population, solid organ transplant recipients had almost a 6 times higher rate of severe COVID-19 (20.39 versus 3.44 per 100 person-years), with almost 5.5 times as high a rate of death alone (4.19 versus 0.77 per 100 person-years). Transplant recipients with severe COVID-19 were substantially younger (60.1 versus 66.5 y) and had more comorbidities. The rate of severe COVID-19 declined over time in the solid organ transplant population, with an incidence rate of 41.25 per 100 person-years in the first wave (January 25, 2020, to August 31, 2020) and 18.41 in the seventh wave (June 19, 2022, to November 30, 2022, Omicron era). Conclusions: Solid organ transplant recipients remain at high risk of severe outcomes when they are infected with SARS-CoV-2. Resources and strategies to mitigate the impact of SARS-CoV-2 exposure are needed in this vulnerable patient population.

Impact of early surgical complications on kidney transplant outcomes.

BACKGROUND: Kidney transplantation (KT) improves clinical outcomes of patients with end stage renal disease. Little has been reported on the impact of early post-operative surgical complications (SC) on long-term clinical outcomes following KT. We sought to determine the impact of vascular complications, urological complications, surgical site complications, and peri-graft collections within 30 days of transplantation on patient survival, graft function, and hospital readmissions. METHODS: We conducted a single-centre, observational cohort study examining adult patients (≥ 18 years) who received a kidney transplant from living and deceased donors between January 1st, 2005 and December 31st, 2015 with follow-up until December 31st, 2016 (n = 1,334). Univariable and multivariable analyses were performed with Cox proportional hazards models to analyze the outcomes of SC in the early post-operative period after KT. RESULTS: The cumulative probability of SC within 30 days of transplant was 25%, the most common SC being peri-graft collections (66.8%). Multivariable analyses showed significant relationships between Clavien Grade 1 SC and death with graft function (HR 1.78 [95% CI: 1.11, 2.86]), and between Clavien Grades 3 to 4 and hospital readmissions (HR 1.95 [95% CI: 1.37, 2.77]). CONCLUSIONS: Early SC following KT are common and have a significant influence on long-term patient outcomes.

Hemophagocytic Lymphohistiocytosis in a Remote Kidney Transplant Recipient Triggered by HSV Infection With Complete Recovery: An Educational Case Report.

Rationale: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by excessive immune activation. It is more commonly seen in children but increasingly recognized in adults. Primary HLH relies on a genetic predisposition, whereas secondary HLH develops in the context of infections, malignancies, or autoimmune diseases. Hemophagocytic lymphohistiocytosis has been rarely described in patients on immunosuppressive therapy after kidney transplant. Here, we describe a case of HLH in a patient with a remote history of kidney transplant, triggered by a viral infection. Presenting Concerns: A 45-year-old female, with a kidney transplant in 2009 for IgA nephropathy, presented with fever, vomiting, and back pain of 1-week duration. She was on triple immunosuppression consisting of daily doses of prednisone 5 mg, azathioprine 100 mg, and tacrolimus extended release 1 mg, and a baseline creatinine of 130 µmol/L. Diagnosis: Initial investigations showed anemia, leukopenia, elevated serum creatinine, transaminitis, and markedly increased ferritin of 67 600 µg/L which prompted a bone marrow biopsy to rule out HLH. The bone marrow showed an increased proportion of CD68+ cells (macrophages) with more than 5 in 1000 hemophagocytic macrophages. Her soluble IL-2 receptor (CD25) level was 3406 pg/mL (606-2299 pg/mL) which was mildly elevated. She fulfilled 4 of the 8 criteria for HLH and with an H score was 223 which suggested a diagnosis of HLH with 96.9% probability. An extensive secondary workup for possible triggers for HLH led to a swab from genital ulcers that was positive for herpes simplex virus (HSV) type 2. The polymerase chain reaction (PCR) in the blood for HSV type 2 was also positive. Interventions: Given the diagnosis of HSV type 2 as the putative trigger for HLH, she was started on parenteral acyclovir for 2 weeks followed by oral valacyclovir for 2 more weeks. In the context of infection, the azathioprine was stopped while low-dose steroid and tacrolimus were continued. Outcomes: With the initiation of treatment for HSV infection, leukopenia, creatinine, and transaminases improved along with ferritin levels. At her 6-month follow-up, her blood counts and liver enzymes had normalized, and ferritin was 566 µg/L. Teaching points: Hemophagocytic lymphohistiocytosis is a rare disease in kidney transplant recipients with a high mortality rate. It can occur even in remote kidney transplant recipients so a high degree of suspicion is necessary to lead to a prompt diagnosis. Infections are common triggers for secondary HLH. Early identification and treatment of the triggering infection may improve outcomes.

Justification: La lymphohistiocytose hémophagocytaire (HLH) est une maladie potentiellement mortelle caractérisée par une activation excessive du système immunitaire. Elle est plus fréquente chez les enfants, mais de plus en plus observée chez les adultes. La HLH primaire se manifeste en raison d'une prédisposition génétique, tandis que la HLH secondaire se développe dans le contexte d'une infection, d'un cancer ou d'une maladie auto-immune. La HLH a rarement été décrite chez les patients sous traitement immunosuppresseur à la suite d'une transplantation rénale. Nous présentons un cas de HLH déclenché par une infection virale chez une patiente avec des antécédents lointains de transplantation rénale. Présentation du cas: Une femme de 45 ans, greffée du rein en 2009 en raison d'une néphropathie à IgA, a consulté pour de la fièvre, des vomissements et des douleurs dorsales depuis une semaine. Son triple traitement immunosuppresseur consistait en des doses quotidiennes de prednisone (5 mg), d'azathioprine (100 mg) et de tacrolimus à libération prolongée (1 mg). Son taux de créatinine usuel était de 130 umol/L. Diagnostic: Les premières investigations ont révélé une anémie, de la leucopénie, un taux de créatinine sérique élevé, une transaminite et un taux de ferritine nettement élevé de 67 600 ug/L, ce qui a justifié une biopsie de la moelle osseuse pour exclure une HLH. Les résultats ont montré une plus grande proportion de cellules CD68+ (macrophages), avec plus de 5 macrophages hémophagocytaires sur 1000. Le taux de récepteurs solubles de l'IL-2 (CD25) s'établissait à 3 406 pg/ml (606 à 2 299 pg/ml), ce qui est légèrement élevé. La patiente répondait à quatre des huit critères de la HLH et présentait un score H de 223, ce qui suggérait une probabilité de 96,9 % pour un diagnostic de HLH. L'examen secondaire approfondi des possibles déclencheurs de la HLH a inclus un prélèvement sur des ulcères génitaux qui s'est avéré positif pour le virus de l'herpès simplex (HSV) de type 2. La PCR d'échantillons sanguins était également positive pour HSV de type 2. Interventions: L'infection par HSV de type 2 ayant été identifiée comme le déclencheur présumé de la HLH, la patiente a reçu un traitement parentéral d'acyclovir pendant deux semaines, suivi d'un traitement oral de valacyclovir pour deux semaines supplémentaires. Dans le contexte de l'infection, l'azathioprine a été cessée, mais le tacrolinus et les stéroïdes à faible dose ont été maintenus. Résultats: L'amorce du traitement antiviral a entraîné une amélioration de la leucopénie, du taux de créatinine et des transaminases, ainsi que des taux de ferritine. Lors du dernier suivi à 6 mois, la numérisation sanguine et les enzymes hépatiques de la patiente s'étaient normalisées et son taux de ferritine était de 566 ug/L. Enseignements tirés: La lymphohistiocytose hémophagocytaire est une maladie rare chez les greffés rénaux et elle entraîne un taux élevé de mortalité. La maladie peut survenir même chez des greffés rénaux de longue date, de sorte qu'il est nécessaire d'exercer un degré élevé de vigilance afin de poser rapidement un diagnostic. Les infections sont de fréquents déclencheurs de la HLH secondaire. Les résultats peuvent être améliorés par l'identification et le traitement précoces de l'infection ayant déclenché la maladie.

Impact of donor smoking history on kidney transplant recipient outcomes: A systematic review and meta-analysis.

BACKGROUND: Impact of donor smoking history on kidney transplant recipient outcomes is undefined. METHODS: We systematically searched, critically appraised, and summarized associations between donor smoking and primary outcomes of death-censored and all-cause graft failure (DCGF, ACGF), and secondary outcomes of allograft histology, delayed graft function, serum creatinine, estimated glomerular filtration rate, and mortality. We searched MEDLINE, Embase, and Cochrane Databases from 2000 to 2023. Risk of bias was assessed using Risk of Bias in Non-randomized Studies - of Exposure tool. Quality of evidence was assessed by Grading of Recommendations Assessment, Development and Evaluation Working Group recommendations. We pooled results using inverse variance, random-effects model and reported hazard ratios for time-to-event outcomes or binomial proportions. Statistical heterogeneity was assessed with I2 statistic. RESULTS: From 1785 citations, we included 17 studies. Donor smoking was associated with modestly increased DCGF (HR 1.05 (95% CI: 1.01, 1.09); I2 = 0%; low quality of evidence), predominantly in deceased donors, and ACGF in adjusted analyses (HR 1.12 (95% CI: 1.06, 1.19); I2 = 20%; very low quality of evidence). Other outcomes could not be pooled meaningfully. CONCLUSIONS: Kidney donor smoking history was associated with modestly increased risk of death-censored graft failure and all-cause graft failure. This review emphasizes the need for further research, standardized reporting, and thoughtful consideration of donor factors like smoking in clinical decision-making on kidney utilization and allocation.

Organ Donation and Transplantation Registries Across the Globe: A Review of the Current State.

BACKGROUND: The current landscape of organ donation and transplantation (ODT) registries is not well established. This narrative review sought to identify and characterize the coverage, structure, and data capture of ODT registries globally. METHODS: We conducted a literature search using Ovid Medline and web searches to identify ODT registries from 2000 to 2023. A list of ODT registries was compiled based on publications of registry design, studies, and reports. Extracted data elements included operational features of registries and the types of donor and recipient data captured. RESULTS: We identified 129 registries encompassing patients from all continents except Antarctica. Most registries were active, received funding from government or professional societies, were national in scope, included both adult and pediatric patients, and reported patient-level data. Registries included kidney (n = 99), pancreas (n = 32), liver (n = 44), heart (n = 35), lung (n = 30), intestine (n = 15), and islet cell (n = 5) transplants. Most registries captured donor data (including living versus deceased) and recipient features (including demographics, cause of organ failure, and posttransplant outcomes) but there was underreporting of other domains (eg, donor comorbidities, deceased donor referral rates, waitlist statistics). CONCLUSIONS: This review highlights existing ODT registries globally and serves as a call for increased visibility and transparency in data management and reporting practices. We propose that standards for ODT registries, a common data model, and technical platforms for collaboration, will enable a high-functioning global ODT system responsive to the needs of transplant candidates, recipients, and donors.

Long-term Kidney Transplant Survival Across the Globe.

BACKGROUND: The outcomes after kidney transplantation (KT), including access, wait time, and other issues around the globe, have been studied. However, issues do vary from one country to another. METHODS: We obtained data from several countries from North America, South America, Europe, Asia, and Australia, including the number of patients awaiting KT from 2015, transplant rate per million population (pmp), proportion of living donor and deceased donor (LD/DD) KT, and posttransplant survival. We also sought opinions on key difficulties faced by each of these countries with respect to KT and long-term survival. RESULTS: Variation in access to KT across the globe was noted. Countries with the highest rates of KT pmp included the United States (79%) and Spain (71%). A higher proportion of LD transplants was noted in Japan (93%), India (85%), Singapore (63%), and South Korea (63%). A higher proportion of DD KTs was noted in Spain (90%), Brazil (90%), France (85%), Italy (85%), Finland (85%), Australia-New Zealand (80%), and the United States (77%). The 5-y graft survival for LD was highest in South Korea (95%), Singapore (94%), Italy (93%), Finland (93%), and Japan (93%), whereas for DD, it was South Korea (93%), Italy (88%), Japan (86%), and Singapore (86%). The common issues surrounding KTs are access and a limited number of LDs and DDs. Key issues identified for long-term survival were increasing age of donors and recipients, higher recipient comorbidity, and posttransplant events, such as alloimmune injury to the kidney, infection, cancer, and suboptimal adherence to therapy. CONCLUSIONS: A unified approach is necessary to improve issues surrounding KT as the demand continues to increase.

Defining pre-emptive living kidney donor transplantation as a quality indicator.

Quality indicators in kidney transplants are needed to identify care gaps and improve access to transplants. We used linked administrative health care databases to examine multiple ways of defining pre-emptive living donor kidney transplants, including different patient cohorts and censoring definitions. We included adults from Ontario, Canada with advanced chronic kidney disease between January 1, 2013, to December 31, 2018. We created 4 unique incident patient cohorts, varying the eligibility by the risk of progression to kidney failure and whether individuals had a recorded contraindication to kidney transplant (eg, home oxygen use). We explored the effect of 4 censoring event definitions. Across the 4 cohorts, size varied substantially from 20 663 to 9598 patients, with the largest reduction (a 43% reduction) occurring when we excluded patients with ≥1 recorded contraindication to kidney transplantation. The incidence rate (per 100 person-years) of pre-emptive living donor kidney transplant varied across cohorts from 1.02 (95% CI: 0.91-1.14) for our most inclusive cohort to 2.21 (95% CI: 1.96-2.49) for the most restrictive cohort. Our methods can serve as a framework for developing other quality indicators in kidney transplantation and monitoring and improving access to pre-emptive living donor kidney transplants in health care systems.

Effectiveness of a Fourth COVID-19 mRNA Vaccine Dose Against the Omicron Variant in Solid Organ Transplant Recipients.

BACKGROUND: The effectiveness of booster doses of COVID-19 vaccines in solid organ transplant recipients is unclear. We conducted a population-based matched cohort study using linked administrative healthcare databases from Ontario, Canada to estimate the marginal vaccine effectiveness of a fourth versus third dose of the BNT162b2 and mRNA-1273 vaccines against clinically important outcomes (ie, hospitalization or death) and infection during the era of the Omicron variant. METHODS: We matched 3120 solid organ transplant recipients with a third COVID-19 vaccine dose (reference) to 3120 recipients with a fourth dose. Recipients were matched on the third dose date (±7 d). We used a multivariable Cox proportional hazards model to estimate the marginal vaccine effectiveness with outcomes occurring between December 21, 2021 and April 30, 2022. RESULTS: The cumulative incidence of COVID-19-related hospitalization or death was 2.8% (95% confidence interval [CI], 2.0-3.7) in the third dose group compared with 1.1% (95% CI, 0.59-1.8) in the fourth dose group after 84 d of follow-up (P < 0.001). The adjusted marginal vaccine effectiveness was 70% (95% CI, 47-83) against clinically important outcomes and 39% (95% CI, 21-52) against SARS-CoV-2 infection. CONCLUSIONS: Compared with a third dose, a fourth dose of the COVID-19 vaccine was associated with improved protection against hospitalization, death, and SARS-CoV-2 infection during the Omicron era. Results highlight the importance of a booster COVID-19 vaccine dose in solid organ transplant recipients.

Mental health and addiction service utilization among people living with chronic kidney disease.

BACKGROUND: Mental health problems, particularly anxiety and depression, are common in patients with chronic kidney disease (CKD), and negatively impact quality of life, treatment adherence, and mortality. However, the degree to which mental health and addictions services are utilized by those with CKD is unknown. We examined the history of mental health and addictions service use of individuals across levels of kidney function. METHODS: We performed a population-based cross-sectional study using linked healthcare databases from Ontario, Canada from 2009 to 2017. We abstracted the prevalence of individuals with mental health and addictions service use within the previous 3 years across levels of kidney function (eGFR$\ \ge $60, 45 to < 60, 30 to < 45, 15 to < 30, <15 mL/min per 1.73m2 and maintenance dialysis). We calculated prevalence ratios (PR) to compare prevalence across kidney function strata, while adjusting for age, sex, year of cohort entry, urban versus rural location, area-level marginalization, and Charlson comorbidity scores. RESULTS: Of 5 956 589 adults, 9% (n = 534 605) had an eGFR<60 mL/min per 1.73m2 or were receiving maintenance dialysis. Fewer individuals with eGFR < 60 had a history of any mental health and addictions service utilization (crude prevalence range 28% to 31%), compared to individuals with eGFR ≥ 60 (35%). Compared to eGFR ≥ 60, the lowest prevalence of individuals with any mental health and addictions service utilization was among those with eGFR 15 to < 30 (adjusted PR 0.86, 95% CI 0.85 to 0.88), eGFR < 15 (adjusted PR 0.81, 95% CI 0.76 to 0.86) and those receiving maintenance dialysis (adjusted PR 0.83, 95% CI 0.81 to 0.84). Less use of outpatient services accounted for differences in service utilization. CONCLUSIONS: Mental health and addictions service utilization is common but less so in individuals with advanced CKD in Ontario, Canada.

A Population-Based Analysis of the Impact of the COVID-19 Pandemic on Solid Organ Transplantation in Ontario, Canada: Policy Response and Changes in Volume and 90-Day Outcomes.

Objectives: To evaluate the impact of the COVID-19 pandemic on solid organ transplantation. Background: COVID-19 caused unprecedented disruption to solid organ transplantation (kidney, liver, heart, lung). Concerns about safety and decreases in deceased donors due to pandemic lockdowns have been described as potential causes. Methods: We report population-based rates of transplantation during the first 3 waves of COVID-19 in Ontario, Canada (March 1, 2020-July 3, 2021) versus a pre-COVID-19 baseline period (January 1, 2017-February 29, 2020). Poisson models were used to predict transplantation rates during COVID-19, based on pre-COVID-19 rates, and generate observed to expected rate ratios (RRs). Ninety-day transplant outcomes (mortality, retransplantation, transplant nephrectomy) were captured. Results: A 34.4% decrease (RR, 0.656; 95% confidence interval [CI], 0.586-0.734) in transplant rates was observed, coinciding with wave 1 and the deployment of a provincial transplant triaging system. Transplants decreased by 14.6% in wave 2 (RR, 0.854; 95% CI, 0.770-0.947) and 23.1% in wave 3 (RR, 0.769; 95% CI, 0.690-0.857) despite the triaging system not being activated. Overall, there was a 24.3% decrease (RR, 0.757; 95% CI, 0.679-0.844) in transplant rates, equivalent to 409 fewer transplants. No sustained changes were observed in heart or liver but sustained and large decreases were seen for lung (RR, 0.664; 95% CI, 0.482-0.915) and kidney (RR, 0.721; 95% CI, 0.602-0.863) transplantation. A low prevalence (1.7%) of COVID-19 infection within 90 days of transplantation was seen. No differences were observed in other 90-day outcomes. Conclusions: Early safety concerns limited transplantation to immediate life-saving procedures; however, the reductions in kidney and lung transplants continued for the rest of the pandemic, where no restrictions were in place.

Glomerular hyperfiltration is an independent predictor of postoperative outcomes: A NSQIP multi-specialty surgical cohort analysis.

AIM: While high estimated glomerular filtration rate (eGFR) has been associated with increased overall mortality, its effect on postoperative outcomes is relatively understudied. We sought to investigate the association between high eGFR and 30-day postoperative outcomes using a multi-specialty surgical cohort. METHODS: Using the National Surgical Quality Improvement Program database, we selected adult for whom eGFR could be calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration equation. Based on sex-specific distributions of eGFR stratified by age quintiles, we classified patients into low (<5th percentile), normal (5-95th percentile) and high eGFR (>95th percentile). The primary outcome was a composite of any 30-day major adverse outcomes, including: death, reoperation, cardiac arrest, myocardial infarction and stroke. Secondary outcomes included 30-day infectious complications, venous thromboembolism (VTE), bleeding requiring transfusion, prolonged length of stay and unplanned readmission. After matching for demographic differences, comorbidity burden and operative characteristics, logistic regression models were used to evaluate the association between extremes of eGFR and the outcomes of interest. RESULTS: Of 1 668 447 patients, 84 115 (5.07%) had a high eGFR. High eGFR was not associated with major adverse outcomes (odds ratio [OR] 1.00 [95% confidence interval (CI): 0.97, 1.03]); however, it was associated with reoperation (OR 1.04 [95% CI: 1.00,1.08]), infectious complications (OR 1.14 [95% CI: 1.11, 1.16]), VTE (OR 1.15 [95% CI: 1.09, 1.22]) and prolonged length of stay (OR 1.19 [95% CI: 1.16, 1.21]). CONCLUSION: Our findings support an association between high eGFR and adverse 30-day postoperative outcomes.

Renal Dysfunction After Heart Transplant.

BACKGROUND: Moderate or severe renal dysfunction (MSRD) is a frequent complication after heart transplantation. Strategies to delay progression and improve outcomes, such as renoprotective medications and timely referral to nephrology, remain important in providing care to heart transplant recipients with MSRD. RESEARCH QUESTION: What are chronic renal dysfunction's prevalence, risk factors, and optimal clinical management strategies in heart transplant recipients? DESIGN: This single-center, cross-sectional study examined patients who received a heart transplant from January 1, 2000, to June 30, 2011, and followed until December 31, 2011. Moderate or severe renal dysfunction was defined as a glomerular filtration rate of <60 mL/min/1.73 m2. RESULTS: The prevalence of MSRD among 195 heart transplant recipients was 60%. Variables associated with MSRD were female sex (odds ratio [OR]: 4.82; 95% CI, 1.72-13.54), greater age (OR: 1.10 per year; 95% CI, 1.06-1.14), time since transplant (OR: 1.0004 per year; 95% CI, 1.0001-1.0007), and mTOR inhibitor use (OR: 2.89; 95% CI, 1.24-6.71). Tacrolimus use (OR: 0.19; 95% CI, 0.05-0.71) and cyclosporine use (OR: 0.21; 95% CI, 0.05-0.80) were associated with patients without MSRD. Among patients with MSRD, 19.6% were referred to a nephrologist. Median eGFR remained stable at approximately 60 mL/min/1.73 m2 for 3 years after the study. CONCLUSIONS: Our results suggest that female sex, older age at transplant, and time since transplant are associated with MSRD in heart transplant recipients. Tacrolimus and cyclosporine use seemed renoprotective, but lower usage and increased mTOR inhibitor use may more likely indicate existing treatment patterns for patients with MSRD.

Renal cell carcinoma in kidney transplant recipients: incidence, trends, clinical management & outcomes.

OBJECTIVE: To describe the incidence, characteristics, clinical management, and outcomes of renal cell carcinoma (RCC) among a large, single-centre cohort of kidney transplant recipients (KTR). METHODS: We conducted an observational cohort study looking at KTR transplanted between January 2000-December 2017 (n = 2443) with ≥ 1 year of follow-up. Simultaneous kidney/pancreas transplants were excluded. The Kaplan-Meier product-limit method was used to determine the incidence of RCC. Characteristics and management of RCC were examined using descriptive statistics. Risk factors and clinical outcomes were analyzed using Cox regression models. RESULTS: The incidence of RCC among our cohort was 0.32 per 100 person-years, 2.1% of all KTRs. Almost half (47.1%) of cases occurred within 4 years post-transplant. The majority of cases were T1a (86.3%), clear-cell (45.1%), and in the native kidney (80.4%). KTR diagnosed with RCC had a twofold higher incidence of other malignancies versus KTR without RCC. Overall mortality, but not cancer-specific mortality, at 2- and 5-years post-transplant was threefold higher among KTR with RCC than those without. CONCLUSIONS: Incidence of RCC among our KTR was slightly higher than the general population; majority of cases occur in the native kidneys and are low stage, low grade. Indolent histologic variants were more common than the general population. KTR with RCC had a higher incidence of other malignancies. Overall, but not cancer-specific, mortality was higher among KTRs diagnosed with RCC.

Variation in Kidney Transplant Referral Across Chronic Kidney Disease Programs in Ontario, Canada.

Background: Eligible patients with kidney failure should have equal access to kidney transplantation. Transplant referral is the first crucial step toward receiving a kidney transplant; however, studies suggest substantial variation in the rate of kidney transplant referral across regions. The province of Ontario, Canada, has a public, single-payer health care system with 27 regional chronic kidney disease (CKD) programs. The probability of being referred for kidney transplant may not be equal across CKD programs. Objective: To determine whether there is variability in kidney transplant referral rates across Ontario's CKD programs. Design: Population-based cohort study using linked administrative health care databases from January 1, 2013, to November 1, 2016. Setting: Twenty-seven regional CKD programs in the province of Ontario, Canada. Patients: Patients approaching the need for dialysis (advanced CKD) and patients receiving maintenance dialysis (maximum follow-up: November 1, 2017). Measurements: Kidney transplant referral. Methods: We calculated the 1-year unadjusted cumulative probability of kidney transplant referral for Ontario's 27 CKD programs using the complement of Kaplan-Meier estimator. We calculated standardized referral ratios (SRRs) for each CKD program, using expected referrals from a 2-staged Cox proportional hazards model, adjusting for patient characteristics in the first stage. Standardized referral ratios with a value less than 1 were below the provincial average (maximum possible follow-up of 4 years 10 months). In an additional analysis, we grouped CKD programs according to 5 geographic regions. Results: Among 8641 patients with advanced CKD, the 1-year cumulative probability of kidney transplant referral ranged from 0.9% (95% confidence interval [CI]: 0.2%-3.7%) to 21.0% (95% CI: 17.5%-25.2%) across the 27 CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.4) to 4.2 (95% CI: 2.1-7.5). Among 6852 patients receiving maintenance dialysis, the 1-year cumulative probability of transplant referral ranged from 6.4% (95% CI: 4.0%-10.2%) to 34.5% (95% CI: 29.5%-40.1%) across CKD programs. The adjusted SRR ranged from 0.2 (95% CI: 0.1-0.3) to 1.8 (95% CI: 1.6-2.1). When we grouped CKD programs according to geographic region, we found that patients residing in Northern regions had a substantially lower 1-year cumulative probability of transplant referral. Limitations: Our cumulative probability estimates only captured referrals within the first year of advanced CKD or maintenance dialysis initiation. Conclusions: There is marked variability in the probability of kidney transplant referral across CKD programs operating in a publicly funded health care system.

Contexte: Les patients atteints d'insuffisance rénale qui y sont admissibles devraient bénéficier d'un accès égal à la transplantation rénale. L'aiguillage vers un programme de transplantation est la première étape essentielle pour recevoir une greffe de rein. Des études suggèrent cependant qu'il existe des variations substantielles dans les taux d'aiguillage vers une greffe de rein selon les régions. La province de l'Ontario, au Canada, dispose d'un système public de santé à payeur unique comptant 27 programmes régionaux d'insuffisance rénale chronique (IRC). La probabilité d'être aiguillé vers une transplantation rénale n'est pas forcément la même dans tous les programmes d'IRC. Objectif: Déterminer s'il existe une variabilité dans les programmes d'IRC de l'Ontario en ce qui concerne les taux d'aiguillage vers une greffe de rein. Conception: Étude de cohorte représentative d'une population réalisée en Ontario (Canada) entre le 1er janvier 2013 et le 1er novembre 2016 à partir des données administratives en santé. Cadre: Les 27 programmes régionaux d'IRC de la province de l'Ontario (Canada). Sujets: Des patients approchant le besoin de dialyse (IRC de stade avancé) et des patients recevant des traitements de dialyse d'entretien (suivi maximum jusqu'au 1er novembre 2017). Mesures: L'aiguillage vers une greffe de rein. Méthodologie: Nous avons calculé la probabilité cumulative non ajustée d'être aiguillé à l'intérieur d'un an vers une transplantation rénale dans chacun des 27 programmes d'IRC de l'Ontario en utilisant le complément de l'estimateur Kaplan-Meier. Nous avons calculé les ratios d'aiguillage normalisés (SRR­Standardized Reference Ratios) des programmes d'IRC en utilisant les taux d'aiguillge attendus à partir d'un modèle de risques proportionnels de Cox en deux étapes, avec correction en fonction des caractéristiques du patient dans la première étape. Les ratios d'aiguillage normalisés d'une valeur inférieure à 1 étaient inférieurs à la moyenne provinciale (suivi maximum possible de 4 ans et 10 mois). Dans une analyse supplémentaire, nous avons regroupé les programmes d'IRC selon cinq régions géographiques. Résultats: Parmi les 8 641 patients atteints d'IRC de stade avancé, la probabilité cumulative d'aiguillage en un an pour une transplantation rénale variait de 0,9 % (IC 95 %: 0,2-3,7 %) à 21,0 % (IC 95 %: 17,5-25,2 %) pour l'ensemble des 27 programmes d'IRC. Le SRR corrigé variait de 0,2 (IC à 95 %: 0,1-0,4) à 4,2 (IC 95 %: 2,1-7,5). Parmi les 6 852 patients qui recevaient une dialyse d'entretien, la probabilité cumulative d'aiguillage en un an vers la transplantation variait de 6,4 % (IC 95 %: 4,0-10,2 %) à 34,5 % (IC 95 %: 29,5-40,1 %) pour l'ensemble des programmes d'IRC. Le SRR corrigé variait de 0,2 (IC 95 %: 0,1-0,3) à 1,8 (IC 95 %: 1,6-2,1). En regroupant les programmes d'IRC en fonction de la région géographique, nous avons constaté que les patients résidant dans les régions du Nord avaient une probabilité cumulative nettement plus faible d'être aiguillés vers la transplantation en un an. Limites: Nos estimations de la probabilité cumulative n'ont permis de saisir que les aiguillages au cours de la première année d'IRC de stade avancé ou de l'amorce d'une dialyse d'entretien. Conclusion: Il existe une variabilité marquée dans la probabilité d'être aiguillé vers une transplantation rénale dans les programmes d'IRC opérant dans un système de santé financé par l'État.

The epidemiology of early deep vein thrombosis in kidney transplant recipients.

BACKGROUND: Because kidney transplant recipients may be at increased risk for deep vein thrombosis (DVT) following transplantation, we investigated the incidence, risk factors, treatments and outcomes of early DVT among kidney transplant recipients. METHODS: An observational, single-centre cohort study was conducted among adult kidney transplant recipients from Jan. 1, 2005, to Dec. 31, 2016 with 1-year followup. Time to DVT was assessed using the Kaplan-Meier method. Cox proportional hazards and linear regression models were used to analyze risk factors for and outcomes of DVT. RESULTS: The cumulative incidence of DVT was 4.25% at 3 months after transplant. In multivariable analysis, the use of depleting induction agents (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.05-4.35]), white recipient race (HR 1.84. 95% CI 1.08-3.12), the use of kidneys from expanded criteria donors (HR 2.13, 95% CI 1.05-4.32) and lower recipient body mass index (HR 0.95, 95% CI 0.91-1.00) increased the risk for early DVT. Peritransplant DVT prophylaxis was not associated with early DVT. Early DVT was not associated with reduced graft function, death, graft failure or first hospital readmission. CONCLUSION: Risk factors for early DVT in our cohort of kidney transplant recipients included white recipient race, use of depleting agents, lower recipient body mass index and use of expanded criteria donors. As practice patterns of donor and recipient selection in kidney transplantation evolve, the results of this study may aid in perioperative risk assessments and decision-making about the use of DVT prophylaxis.

Incidence of cardiovascular disease and mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation. METHODS: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used. RESULTS: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively. CONCLUSIONS: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information.

Risk Factors for First and Recurrent Fractures among Kidney Transplant Recipients.

Introduction: Kidney transplantation is associated with increased risk of bone fracture. Current literature reports widely variable fracture burden and contains limited data on risk factors for recurrent fractures. Methods: The incidence of all and major osteoporotic fractures (hip, forearm, thoracolumbar, and proximal humerus) were assessed. The risk factors for first and recurrent fractures among 1285 Canadian kidney transplant recipients transplanted between January 1, 2004, and December 31, 2013 were also identified. Results: The 10-year cumulative incidence of all fractures and major osteoporotic fractures in this population was 27.1% (95% CI: 22.5, 32.4) and 17.8% (95% CI: 13.4, 23.5), respectively. On multivariable analysis, female sex (HR = 1.64 [95% CI: 1.20, 2.26]), history of fracture (HR = 1.54 [95% CI: 1.12, 2.11]), and pretransplant diabetes (HR = 1.85 [95% CI: 1.29, 2.65]) were recipient factors found to increase the risk for any first fracture posttransplant. These risk factors persist in analysis with the time origin 3-months posttransplant, where transplant age (HR = 1.01 [95% CI: 1.00, 1.03]) and increased time on pretransplant dialysis (HR = 1.06 [95% CI: 1.00, 1.12]) also emerge as risk factors for first fracture. On multivariable shared frailty model analysis, increased risk of recurrent fractures was associated with recipient female sex (HR = 1.74 [95% CI: 1.21, 2.51]) and history of diabetes (HR = 1.76 [95% CI: 1.17, 2.66]). Discussion: The results suggested that some risk factors for first fracture may not inform risk of recurrent fractures. As such, fracture risk should be assessed accordingly to optimize long-term care and implement preventive measures.

Tacrolimus Formulation, Exposure Variability, and Outcomes in Kidney Transplant Recipients.

INTRODUCTION: Few studies have compared within-patient variability measures of tacrolimus trough levels by formulation and assessed within-patient variability on outcomes of kidney transplant recipients. RESEARCH QUESTIONS: (1) To compare within-patient variability of trough levels when converting from twice-daily to once-daily tacrolimus using standard deviation, coefficient of variation, and intrapatient variability percent. (2) To use the 3 measures of variability to examine the relationship between tacrolimus once-daily within-patient variability and total graft failure (i.e., return to chronic dialysis, pre-emptive retransplant, death with graft function). DESIGN: In this observational cohort study, within-patient variability of trough levels pre- and post-conversion from twice-daily to once-daily tacrolimus were compared using Wilcoxon matched-pairs signed-rank test. Graft outcomes were analyzed using Kaplan-Meier curves and multivariable Cox proportional hazards models. RESULTS: In 463 patients, within-patient variability differences pre- and post-conversion of median standard deviation, coefficient of variation, and intrapatient variability percent were -0.16 (P = 0.09), -0.01 (P = 0.52), and -1.41 (P = 0.32), respectively. Post-conversion, every 1 unit increase in within-patient variability standard deviation and intrapatient variability percent and every 0.1 unit increase in the coefficient of variation was associated with an increased hazard ratio [1.19 (P = 0.004), 1.02 (P = 0.030), 1.13 (P = 0.001), respectively] of total graft failure. Post-conversion, within-patient variability above cohort medians using standard deviation and coefficient of variation had a significantly higher risk of total graft failure. DISCUSSION: Under a program-wide conversion, no significant difference was observed in within-patient variability post-conversion from twice-daily to once-daily tacrolimus using the three measures of variability. High within-patient variability was associated with adverse transplant outcomes post-conversion.

Outcomes of keratolimbal allograft from ABO compatible donors for severe bilateral limbal stem cell deficiency.

PURPOSE: To report outcomes of keratolimbal allograft (KLAL) compatible for both human leukocyte (HLA) and/or blood type using oral prednisone, mycophenolate, and tacrolimus, with basiliximab if panel reactive antibodies (PRA) are present. Intravenous immunoglobulin (IVIG) was used post-operatively if donor-specific anti-HLA antibodies (DSA) were present. METHODS: Retrospective interventional series of consecutive patients with KLAL for limbal stem cell deficiency (LSCD) from HLA and/or blood type compatible deceased donors with a minimum follow-up time of 12 months. Main outcome measures were ocular surface stability, visual acuity and systemic immunosuppression (SI) adverse events. RESULTS: Eight eyes of eight patients with mean age of 48.6 ± 10.1 years (range 34-65 years) were included. Mean follow-up time was 37.3 ± 22.7 months (range 12-71 months) following KLAL; four (50%) had combined LR-CLAL surgery. The etiologies of LSCD were Stevens-Johnson Syndrome (n = 4/8), aniridia (n = 2/8), chemical injury (n = 1/8) and atopic eye disease (n = 1/8). All patients had PRA present and received basiliximab infusions. 5/8 patients received IVIG based on DSA identified pre-operatively. At last follow-up, 7 eyes (87.5%) had a stable ocular surface; 1 eye (12.5%) developed failure and had keratoprosthesis implantation. There was a significant improvement in visual acuity from 1.65 ± 0.48 to 0.68 ± 0.34 logMAR (p = 0.01). SI was tolerated well with minimal adverse events. CONCLUSIONS: Preliminary outcomes of KLAL with ABO compatible tissue using the Cincinnati protocol, preoperative basiliximab (when PRA present) and post-operative IVIG (when DSA present) are encouraging. This protocol may allow for utilization of deceased donor tissue with results approximating those of living donor tissue transplanted for severe bilateral LSCD.