Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Hypertension and Kidney Function After Living Kidney Donation.

Importance: Recent guidelines call for better evidence on health outcomes after living kidney donation. Objective: To determine the risk of hypertension in normotensive adults who donated a kidney compared with nondonors of similar baseline health. Their rates of estimated glomerular filtration rate (eGFR) decline and risk of albuminuria were also compared. Design, Setting, and Participants: Prospective cohort study of 924 standard-criteria living kidney donors enrolled before surgery and a concurrent sample of 396 nondonors. Recruitment occurred from 2004 to 2014 from 17 transplant centers (12 in Canada and 5 in Australia); follow-up occurred until November 2021. Donors and nondonors had the same annual schedule of follow-up assessments. Inverse probability of treatment weighting on a propensity score was used to balance donors and nondonors on baseline characteristics. Exposure: Living kidney donation. Main Outcomes and Measures: Hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure [DBP] ≥90 mm Hg, or antihypertensive medication), annualized change in eGFR (starting 12 months after donation/simulated donation date in nondonors), and albuminuria (albumin to creatinine ratio ≥3 mg/mmol [≥30 mg/g]). Results: Among the 924 donors, 66% were female; they had a mean age of 47 years and a mean eGFR of 100 mL/min/1.73 m2. Donors were more likely than nondonors to have a family history of kidney failure (464/922 [50%] vs 89/394 [23%], respectively). After statistical weighting, the sample of nondonors increased to 928 and baseline characteristics were similar between the 2 groups. During a median follow-up of 7.3 years (IQR, 6.0-9.0), in weighted analysis, hypertension occurred in 161 of 924 donors (17%) and 158 of 928 nondonors (17%) (weighted hazard ratio, 1.11 [95% CI, 0.75-1.66]). The longitudinal change in mean blood pressure was similar in donors and nondonors. After the initial drop in donors' eGFR after nephrectomy (mean, 32 mL/min/1.73 m2), donors had a 1.4-mL/min/1.73 m2 (95% CI, 1.2-1.5) per year lesser decline in eGFR than nondonors. However, more donors than nondonors had an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up (438/924 [47%] vs 49/928 [5%]). Albuminuria occurred in 132 of 905 donors (15%) and 95 of 904 nondonors (11%) (weighted hazard ratio, 1.46 [95% CI, 0.97-2.21]); the weighted between-group difference in the albumin to creatinine ratio was 1.02 (95% CI, 0.88-1.19). Conclusions and Relevance: In this cohort study of living kidney donors and nondonors with the same follow-up schedule, the risks of hypertension and albuminuria were not significantly different. After the initial drop in eGFR from nephrectomy, donors had a slower mean rate of eGFR decline than nondonors but were more likely to have an eGFR between 30 and 60 mL/min/1.73 m2 at least once in follow-up. Trial Registration: ClinicalTrials.gov Identifier: NCT00936078.

Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.

BACKGROUND: There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency. METHODS: This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described. RESULTS: There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease. CONCLUSION: Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.

A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression.

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.

The Living Kidney Donor Safety Study: Protocol of a Prospective Cohort Study.

Background: Living kidney donation is considered generally safe in healthy individuals; however, there is a need to better understand the long-term effects of donation on blood pressure and kidney function. Objectives: To determine the risk of hypertension in healthy, normotensive adults who donate a kidney compared with healthy, normotensive non-donors with similar indicators of baseline health. We will also compare the 2 groups on the rate of decline in kidney function, the risk of albuminuria, and changes in health-related quality of life. Design Participants and Setting: Prospective cohort study of 1042 living kidney donors recruited before surgery from 17 transplant centers (12 in Canada and 5 in Australia) between 2004 and 2014. Non-donor participants (n = 396) included relatives or friends of the donor, or donor candidates who were ineligible to donate due to blood group or cross-match incompatibility. Follow-up will continue until 2021, and the main analysis will be performed in 2022. The anticipated median (25th, 75th percentile, maximum) follow-up time after donation is 7 years (6, 8, 15). Measurements: Donors and non-donors completed the same schedule of measurements at baseline and follow-up (non-donors were assigned a simulated nephrectomy date). Annual measurements were obtained for blood pressure, estimated glomerular filtration rate (eGFR), albuminuria, patient-reported health-related quality of life, and general health. Outcomes: Incident hypertension (a systolic/diastolic blood pressure ≥ 140/90 mm Hg or receipt of anti-hypertensive medication) will be adjudicated by a physician blinded to the participant's donation status. We will assess the rate of change in eGFR starting from 12 months after the nephrectomy date and the proportion who develop an albumin-to-creatinine ratio ≥3 mg/mmol (≥30 mg/g) in follow-up. Health-related quality of life will be assessed using the 36-item RAND health survey and the Beck Anxiety and Depression inventories. Limitations: Donation-attributable hypertension may not manifest until decades after donation. Conclusion: This prospective cohort study will estimate the attributable risk of hypertension and other health outcomes after living kidney donation.

Contexte: Chez les personnes en bonne santé, faire don d'un rein est généralement considéré comme sûr. Il convient toutefois de mieux comprendre les effets à long terme de ce don sur la pression artérielle et la fonction rénale. Objectifs: Déterminer le risque d'hypertension chez les adultes sains et normotendus qui donnent un rein par rapport à des non-donneurs sains et normotendus ayant des indicateurs de santé de base similaires. Nous comparerons également le taux de réduction de la fonction rénale, le risque d'albuminurie et les changements dans la qualité de vie liée à la santé entre les deux groupes. Cadre type d'étude et participants: Étude de cohorte rétrospective menée sur 1 042 donneurs de rein vivants, recrutés avant la chirurgie dans 17 centres de transplantation (12 au Canada et 5 en Australie) entre 2004 et 2014. Le groupe des non-donneurs (n=396) était constitué de parents ou amis du donneur, ou de candidats donneurs non admissibles à faire un don en raison d'une incompatibilité de groupe sanguin ou lors du test de compatibilité croisée. Le suivi s'est poursuivi jusqu'en 2021 et l'analyse principale sera effectuée en 2022. Le temps de suivi médian prévu (25e percentile, 75e percentile, maximum) après le don est de 7 ans (6, 8, 15 ans). Mesures: Les donneurs et les non-donneurs ont complété le même calendrier de mesures à l'inclusion et pendant le suivi (une date simulée de néphrectomie a été attribuée aux non-donneurs). Des mesures annuelles de pression artérielle, de débit de filtration glomérulaire estimé (DFGe), d'albuminurie, de qualité de vie liée à la santé autodéclarée et de santé générale ont été obtenues. Issues principales: L'hypertension incidente (pression artérielle systolique/diastolique ≥ 140/90 mm Hg ou prise d'un médicament antihypertenseur) sera jugée par un médecin aveugle au statut de don du participant. Nous évaluerons le taux de variation du DFGe à partir de 12 mois après la date de la néphrectomie et la proportion de participants qui développeront un rapport albumine/créatinine ≥ 3 mg/mmol (≥ 30 mg/g) pendant le suivi. La qualité de vie liée à la santé sera évaluée à l'aide du questionnaire de santé RAND de 36 questions et de l'Inventaire d'anxiété et de dépression de Beck. Limites: L'hypertension attribuable au don pourrait ne pas se manifester avant des décennies après le don. Conclusion: Cette étude de cohorte prospective permettra d'estimer le risque d'hypertension attribuable au don et d'autres effets sur la santé du donneur après un don de rein.

Immunosuppressant Medication Use in Patients with Kidney Allograft Failure: A Prospective Multicenter Canadian Cohort Study.

BACKGROUND: Patients with kidney transplant failure have a high risk of hospitalization and death due to infection. The optimal use of immunosuppressants after transplant failure remains uncertain and clinical practice varies widely. METHODS: This prospective cohort study enrolled patients within 21 days of starting dialysis after transplant failure in 16 Canadian centers. Immunosuppressant medication use, death, hospitalized infection, rejection of the failed allograft, and anti-HLA panel reactive antibodies were determined at 1, 3, 6, and 12 months and and then twice yearly until death, repeat transplantation, or loss to follow-up. RESULTS: The 269 study patients were followed for a median of 558 days. There were 33 deaths, 143 patients hospitalized for infection, and 21 rejections. Most patients (65%) continued immunosuppressants, 20% continued prednisone only, and 15% discontinued all immunosuppressants. In multivariable models, patients who continued immunosuppressants had a lower risk of death (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.17 to 0.93) and were not at increased risk of hospitalized infection (HR, 1.81; 95% CI, 0.82 to 4.0) compared with patients who discontinued all immunosuppressants or continued prednisone only. The mean class I and class II panel reactive antibodies increased from 11% to 27% and from 25% to 47%, respectively, but did not differ by immunosuppressant use. Continuation of immunosuppressants was not protective of rejection of the failed allograft (HR, 0.81; 95% CI, 0.22 to 2.94). CONCLUSIONS: Prolonged use of immunosuppressants >1 year after transplant failure was not associated with a higher risk of death or hospitalized infection but was insufficient to prevent higher anti-HLA antibodies or rejection of the failed allograft.

The negative impact of T cell-mediated rejection on renal allograft survival in the modern era.

The prevalence and long-term impact of T cell-mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate-based maintenance therapy. This observational study evaluated 775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for-cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow-up biopsies. Alloimmune risk categories based on the HLA-DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death-censored and all-cause graft loss when adjusted for baseline covariates and other significant time-dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA-DR/DQ molecular mismatch scores, remain under-immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.

Impact of Perioperative Complications on Living Kidney Donor Health-Related Quality of Life and Mental Health: Results From a Prospective Cohort Study.

BACKGROUND: Although living kidney donation is safe, some donors experience perioperative complications. OBJECTIVE: This study explored how perioperative complications affected donor-reported health-related quality of life, depression, and anxiety. DESIGN: This research was a conducted as a prospective cohort study. SETTING: Twelve transplant centers across Canada. PATIENTS: A total of 912 living kidney donors were included in this study. MEASUREMENTS: Short Form 36 health survey, Beck Depression Inventory and Beck Anxiety Inventory. METHODS: Living kidney donors were prospectively enrolled predonation between 2009 to 2014. Donor perioperative complications were graded using the Clavien-Dindo classification system. Mental and physical health-related quality of life was assessed with the 3 measurements; measurements were taken predonation and at 3- and 12-months postdonation. RESULTS: Seventy-four donors (8%) experienced a perioperative complication; most were minor (n = 67 [91%]), and all minor complications resolved before hospital discharge. The presence (versus absence) of a perioperative complication was associated with lower mental health-related quality of life and higher depression symptoms 3-month postdonation; neither of these differences persisted at 12-month. Perioperative complications were not associated with any changes in physical health-related quality of life or anxiety 3-month postdonation. LIMITATIONS: Minor complications may have been missed and information on complications postdischarge were not collected. No minimal clinically significant change has been defined for kidney donors across the 3 measurements. CONCLUSIONS: These findings highlight a potential opportunity to better support the psychosocial needs of donors who experience perioperative complications in the months following donation. TRIAL REGISTRATION: NCT00319579 and NCT00936078.

CONTEXTE: Bien que le don vivant d'un rein soit une procédure sécuritaire, certains donneurs souffrent tout de même de complications périopératoires. OBJECTIFS: Cette étude a examiné l'incidence des complications périopératoires sur la qualité de vie liée à la santé et les symptômes de dépression et d'anxiété rapportés par les donneurs. TYPE D'ÉTUDE: Étude de cohorte prospective. CADRE: Douze centers de transplantation à travers le Canada. SUJETS: 912 donneurs vivants d'un rein. MESURES: Un questionnaire abrégé de 36 questions sur l'état de santé, l'inventaire de dépression Beck et l'inventaire d'anxiété Beck. MÉTHODOLOGIE: Les donneurs ont été inscrits avant le don de façon prospective entre 2009 et 2014. Les complications périopératoires des donneurs ont été classées à l'aide du système de classification Clavien-Dindo. La qualité de vie liée à la santé physique et mentale a été évaluée à l'aide des trois outils de mesure; ces mesures ont été faites avant le don, puis 3 et 12 mois après le don. RÉSULTATS: Au total, 74 donneurs (8 %) ont souffert d'une complication périopératoire; la plupart étaient mineures (n = 67 [91 %]) et ont été résolues avant le congé de l'hôpital. La présence (par rapport à l'absence) d'une complication périopératoire a été associée à une plus faible qualité de vie liée à la santé mentale et à des symptômes de dépression plus graves 3 mois après le don; aucune de ces différences n'a persisté après 12 mois. Les complications périopératoires n'ont pas été associées à des changements dans la qualité de vie liée à la santé physique ou à l'anxiété 3 mois après le don. LIMITES: Certaines complications mineures ont pu être manquées. L'information sur les complications survenues après le congé n'a pas été recueillie. Dans les trois outils de mesure, aucune variation minimale cliniquement significative n'a été définie pour les donneurs d'un rein. CONCLUSION: Ces résultats soulignent une occasion de mieux répondre aux besoins psychosociaux des donneurs d'un rein qui présentent des complications périopératoires dans les mois suivant le don.

Living Kidney Donors' Financial Expenses and Mental Health.

BACKGROUND: Living kidney donors incur donation-related expenses, but how these expenses impact postdonation mental health is unknown. METHODS: In this prospective cohort study, the association between mental health and donor-incurred expenses (both out-of-pocket costs and lost wages) was examined in 821 people who donated a kidney at one of the 12 transplant centers in Canada between 2009 and 2014. Mental health was measured by the RAND Short Form-36 Health Survey along with Beck Anxiety Inventory and Beck Depression Inventory. RESULTS: A total of 209 donors (25%) reported expenses of >5500 Canadian dollars. Compared with donors who incurred lower expenses, those who incurred higher expenses demonstrated significantly worse mental health-related quality of life 3 months after donation, with a trend towards worse anxiety and depression, after controlling for predonation mental health-related quality of life and other risk factors for psychological distress. Between-group differences for donors with lower and higher expenses on these measures were no longer significant 12 months after donation. CONCLUSIONS: Living kidney donor transplant programs should ensure that adequate psychosocial support is available to all donors who need it, based on known and unknown risk factors. Efforts to minimize donor-incurred expenses and to better support the mental well-being of donors need to continue. Further research is needed to investigate the effect of donor reimbursement programs, which mitigate donor expenses, on postdonation mental health.

Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection.

Prognostic biomarkers of T cell-mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA-DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor-specific antibodies (P = .002). HLA-DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA-DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA-DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA-DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA-DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Toluene Toxicity: A Case Report of Transdermal Exposure Causing Hypokalemic Paralysis.

RATIONALE: Hypokalemia is a common finding. Typically asymptomatic presentations of neuromuscular weakness emerge at levels below 2.5 mmol/L. Causes include gastrointestinal losses, renal losses, or intracellular shift, with gastrointestinal losses and diuretics accounting for the majority. Although the cause is often apparent on clinical assessment, a systematic approach incorporating urine biochemistry can aid in narrowing the differential in obscure cases. PRESENTATION: We describe a case of a previously healthy 27-year-old man who presented with acute ascending paralysis, with an associated severe hypokalemia and metabolic acidosis. There were no apparent causes on clinical assessment. DIAGNOSIS: Based on analysis of urine biochemistry, we concluded that a pathologic kaluresis was present, and given his acidemia and transient pathology, we diagnosed the patient with hypokalemic paralysis secondary to toluene toxicity. INTERVENTIONS: We provided supportive care and electrolyte repletion for our patient; no specific therapies for toluene were required. Our patient was counseled regarding appropriate protective measures when handling toluene. OUTCOMES: Complete neurologic recovery and biochemical normalization occurred within 48 hours of presentation with supportive care. He continued to use proper precautions when handling toluene, and experienced no symptom relapse, or further abnormalities on both blood and urine chemistry. LESSONS LEARNED: Using this case, we review an algorithmic approach incorporating urine biochemistries to aid in the workup of hypokalemia. We review toluene as a toxicologic entity and highlight its role as a cause of hypokalemia.

JUSTIFICATION: L'hypokaliémie est fréquente et généralement asymptomatique. Les symptômes de faiblesse neuromusculaire se manifestent à des concentrations inférieures à 2,5 mmol/L. Les pertes de potassium au niveau gastro-intestinal ou rénal et les déplacements intracellulaires sont parmi les causes; les pertes gastro-intestinales et les diurétiques constituant les principales causes. Bien que l'étiologie soit souvent apparente à l'évaluation clinique, une approche systématique intégrant la biochimie de l'urine pourrait aider à réduire le diagnostic différentiel dans les cas plus incertains. PRÉSENTATION DU CAS: Nous discutons du cas d'un homme de 27 ans précédemment en bonne santé qui présentait une paralysie ascendante aigüe associée à une grave hypokaliémie et à une acidose métabolique. Aucune étiologie n'était apparente lors de l'évaluation clinique. DIAGNOSTIC: L'analyse biochimique de l'urine a permis de confirmer la présence d'une kaliurèse pathologique et, compte tenu de l'acidémie et de la pathologie transitoire, de diagnostiquer une paralysie hypokaliémique consécutive à une intoxication au toluène. INTERVENTIONS: Le patient a reçu le traitement médical et la supplémentation en électrolytes appropriés. Aucun traitement spécifique pour le toluène n'était nécessaire. Le patient a été informé des mesures de protection adéquates à prendre pour la manipulation du toluène. RÉSULTATS: Une récupération neurologique complète et une normalisation biochimique ont été constatées dans les 48 heures suivant le début du traitement. Le patient a pris les mesures de protection appropriées lors de la manipulation du toluène et n'a éprouvé aucun symptôme de rechute ou anomalie biochimique du sang ou de l'urine depuis. ENSEIGNEMENTS TIRÉS: Avec ce cas, nous avons analysé une approche algorithmique intégrant la biochimie urinaire pour faciliter le diagnostic de l'hypokaliémie. Nous avons également examiné le toluène en tant qu'agent toxique et souligné son rôle comme étiologie de l'hypokaliémie.

Perioperative Complications During Living Donor Nephrectomy: Results From a Multicenter Cohort Study.

BACKGROUND: While living kidney donation is considered safe in healthy individuals, perioperative complications can occur due to several factors. OBJECTIVE: We explored associations between the incidence of perioperative complications and donor characteristics, surgical technique, and surgeon's experience in a large contemporary cohort of living kidney donors. DESIGN: Living kidney donors enrolled prospectively in a multicenter cohort study with some data collected retrospectively after enrollment was complete (eg, surgeon characteristics). SETTING: Living kidney donor centers in Canada (n = 12) and Australia (n = 5). PATIENTS: Living kidney donors who donated between 2004 and 2014 and the surgeons who performed the living kidney donor nephrectomies. MEASUREMENTS: Operative and hospital discharge medical notes were collected prospectively, with data on perioperative (intraoperative and postoperative) information abstracted from notes after enrollment was complete. Complications were graded using the Clavien-Dindo system and further classified into minor and major. In 2016, surgeons who performed the nephrectomies were invited to fill an online survey on their training and experience. METHODS: Multivariable logistic regression models with generalized estimating equations were used to compare perioperative complication rates between different groups of donors. The effect of surgeon characteristics on the complication rate was explored using a similar approach. Poisson regression was used to test rates of overall perioperative complications between high- and low-volume centers. RESULTS: Of the 1421 living kidney donor candidates, 1042 individuals proceeded with donation, where 134 (13% [95% confidence interval (CI): 11%-15%]) experienced 142 perioperative complications (55 intraoperative; 87 postoperative). The most common intraoperative complication was organ injury and the most common postoperative complication was ileus. No donors died in the perioperative period. Most complications were minor (90% of 142 complications [95% CI: 86%-96%]); however, 12 donors (1% of 1042 [95% CI: 1%-2%]) experienced a major complication. No statistically significant differences were observed between donor groups and the rate of complications. A total of 43 of 48 eligible surgeons (90%) completed the online survey. Perioperative complication rates did not vary significantly by surgeon characteristics or by high- versus low-volume centers. LIMITATIONS: Operative and discharge reporting is not standardized and varies among surgeons. It is possible that some complications were missed. The online survey for surgeons was completed retrospectively, was based on self-report, and has not been validated. We had adequate statistical power only to detect large effects for factors associated with a higher risk of perioperative complications. CONCLUSIONS: This study confirms the safety of living kidney donation as evidenced by the low rate of major perioperative complications. We did not identify any donor or surgeon characteristics associated with a higher risk of perioperative complications. TRIAL REGISTRATIONS: NCT00319579: A Prospective Study of Living Kidney Donation (https://clinicaltrials.gov/ct2/show/NCT00319579)NCT00936078: Living Kidney Donor Study (https://clinicaltrials.gov/ct2/show/NCT00936078).

CONTEXTE: Bien que le don vivant d'un rein soit sécuritaire chez un individu en santé, plusieurs facteurs sont susceptibles d'engendrer des complications périopératoires. OBJECTIF: Nous avons exploré l'association entre l'incidence des complications périopératoires et les caractéristiques du donneur, la technique chirurgicale employée et l'expérience du chirurgien au sein d'une vaste cohorte contemporaine de donneurs vivants d'un rein. TYPE D'ÉTUDE: Une étude de cohorte multicentrique où certaines données (notamment les renseignements concernant le chirurgien) ont été recueillies rétrospectivement, après l'inclusion complète des sujets (donneurs vivants d'un rein). CADRE: Des centres de transplantation au Canada (n=12) et en Australie (n=5). SUJETS: Des individus ayant fait don d'un rein entre 2004 et 2014, et les chirurgiens qui ont procédé à la néphrectomie. MESURES: Les notes médicales au dossier, opératoires et à la sortie de l'hôpital, ont été recueillies de façon prospective; les données concernant les renseignements périopératoires (peropératoires et postopératoires) ayant été extraites des notes une fois l'inclusion du sujet complétée. Les complications ont été catégorisées selon la classification de Clavien-Dindo, puis caractérisées comme étant mineures ou majeures. En 2016, les chirurgiens ayant pratiqué les néphrectomies ont été invités à répondre à un sondage en ligne au sujet de leur formation et de leur expérience. MÉTHODOLOGIE: Des modèles de régression logistique multivariée utilisant des équations d'estimation généralisées ont été employés pour comparer les taux de complications périopératoires entre les différents groupes de donneurs. L'effet exercé sur le taux de complications par les caractéristiques du chirurgien a été exploré selon une approche similaire. Une régression de Poisson a été utilisée pour évaluer et comparer les taux globaux de complications entre les centres à volume élevé et les centres à faible volume. RÉSULTATS: Des 1 421 candidats répertoriés, 1 042 individus ont subi une néphrectomie, desquels 134 (13 % [IC 95 %: 11­15 %]) ont vécu un total de 142 complications périopératoires (55 peropératoires; 87 postopératoires). La complication peropératoire la plus fréquente était une lésion à l'organe, alors qu'un iléus s'est avéré la principale complication postopératoire. Aucun donneur n'est décédé en période périopératoire. La plupart des complications rencontrées étaient mineures (90 % des 142 complications répertoriées [IC 95 %: 86­96 %]). Toutefois, 12 donneurs (1 % des 1 042 donneurs [IC 95 %: 1­2 %]) ont souffert de complications majeures. Aucune différence significative du point de vue statistique n'a été observée entre les groupes de donneurs et le taux de complications. Des 48 chirurgiens admissibles, 43 (90 %) ont répondu au sondage en ligne. Les taux de complications périoperatoires n'ont pas varié de façon significative en fonction des caractéristiques des chirurgiens, ou selon le volume de patients de l'hôpital. LIMITES: La façon d'inscrire les renseignements médicaux (opératoires ou à la sortie de l'hôpital) dans les dossiers des patients n'est pas normalisée et varie d'un chirurgien à l'autre. Certaines complications pourraient ne pas avoir été notées. Le sondage en ligne destiné aux chirurgiens a été rempli rétrospectivement, il reposait sur des déclarations volontaires et n'avait pas fait l'objet d'une validation. Nous ne disposions d'une puissance statistique que pour détecter les effets importants des facteurs associés à un risque accru de complications périopératoires. CONCLUSION: Cette étude confirme le caractère sécuritaire d'un don vivant de rein, comme en témoigne le très faible taux de complications périopératoires majeures. Nous n'avons pu établir de caractéristiques, du donneur ou du chirurgien, qui soit associées à un risque accru de complications périopératoires.

HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity.

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA-DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA-DR/DQ whole antigen mismatch, HLA-DR/DQ single molecule eplet mismatch improved the correlation with de novo donor-specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell-mediated rejection (P = .0006), HLA-DR/DQ de novo donor-specific antibody development (P < .0001), antibody-mediated rejection (P < .0001), as well as all-cause graft loss (P = .0012) and each of these correlations persisted in multivariate models. Thus, HLA-DR/DQ single molecule eplet mismatch may represent a precise, reproducible, and widely available prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Financial Costs Incurred by Living Kidney Donors: A Prospective Cohort Study.

BACKGROUND: Approximately 40% of the kidneys for transplant worldwide come from living donors. Despite advantages of living donor transplants, rates have stagnated in recent years. One possible barrier may be costs related to the transplant process that potential willing donors may incur for travel, parking, accommodation, and lost productivity. METHODS: To better understand and quantify the financial costs incurred by living kidney donors, we conducted a prospective cohort study, recruiting 912 living kidney donors from 12 transplant centers across Canada between 2009 and 2014; 821 of them completed all or a portion of the costing survey. We report microcosted total, out-of-pocket, and lost productivity costs (in 2016 Canadian dollars) for living kidney donors from donor evaluation start to 3 months after donation. We examined costs according to (1) the donor's relationship with their recipient, including spousal (donation to a partner), emotionally related nonspousal (friend, step-parent, in law), or genetically related; and (2) donation type (directed, paired kidney, or nondirected). RESULTS: Living kidney donors incurred a median (75th percentile) of $1254 ($2589) in out-of-pocket costs and $0 ($1908) in lost productivity costs. On average, total costs were $2226 higher in spousal compared with emotionally related nonspousal donors (P=0.02) and $1664 higher in directed donors compared with nondirected donors (P<0.001). Total costs (out-of-pocket and lost productivity) exceeded $5500 for 205 (25%) donors. CONCLUSIONS: Our results can be used to inform strategies to minimize the financial burden of living donation, which may help improve the donation experience and increase the number of living donor kidney transplants.

Duration of Living Kidney Transplant Donor Evaluations: Findings From 2 Multicenter Cohort Studies.

BACKGROUND: A prolonged living kidney donor evaluation may result in worse outcomes for transplant recipients. Better knowledge of the duration of this process may help inform future donors and identify opportunities for improvement. STUDY DESIGN: 1 prospective and 1 retrospective cohort study. SETTING & PARTICIPANTS: At 16 Canadian and Australian transplantation centers (prospective cohort) and 5 Ontario transplantation centers (retrospective cohort), we assessed the duration of living kidney donor evaluation and explored donor, recipient, and transplantation factors associated with longer evaluation times. Data were obtained from 2 sources: donor medical records using chart abstraction and health care administrative databases. PREDICTORS: Donor and recipient demographics, direct versus paired donation, center-level variables. OUTCOMES: Duration of living donor evaluation. RESULTS: The median total duration of transplantation evaluation (time from when the candidate started the evaluation until donation) was 10.3 (IQR, 6.5-16.7) months. The median duration from evaluation start until approval to donate was 7.9 (IQR, 4.6-14.1) months, and from approval until donation was 0.7 (IQR, 0.3-2.4) months, respectively. The median time between the first and last consultation among donors who completed a nephrology, surgery, and psychosocial assessment in the prospective cohort was 3.0 (IQR, 1.0-6.3) months, and between computed tomography angiography and donation was 4.8 (IQR, 2.6-9.2) months. After adjustment, the total duration of transplantation evaluation was longer if the donor participated in paired donation (6.6 [95% CI, 1.6-9.7] months) and if the recipient was referred later relative to the donor's evaluation start date (0.9 [95% CI, 0.8-1.0] months [per month of delayed referral]). Results depended on whether the recipient was receiving dialysis. LIMITATIONS: Living donor candidates who did not donate were not included and proxy measures were used for some dates in the donor evaluation process. CONCLUSIONS: The duration of kidney transplant donor evaluation is variable and can be lengthy. Better understanding of the reasons for a prolonged evaluation may inform quality improvement initiatives to reduce unnecessary delays.

Class II Eplet Mismatch Modulates Tacrolimus Trough Levels Required to Prevent Donor-Specific Antibody Development.

Despite more than two decades of use, the optimal maintenance dose of tacrolimus for kidney transplant recipients is unknown. We hypothesized that HLA class II de novo donor-specific antibody (dnDSA) development correlates with tacrolimus trough levels and the recipient's individualized alloimmune risk determined by HLA-DR/DQ epitope mismatch. A cohort of 596 renal transplant recipients with 50,011 serial tacrolimus trough levels had HLA-DR/DQ eplet mismatch determined using HLAMatchmaker software. We analyzed the frequency of tacrolimus trough levels below a series of thresholds <6 ng/ml and the mean tacrolimus levels before dnDSA development in the context of HLA-DR/DQ eplet mismatch. HLA-DR/DQ eplet mismatch was a significant multivariate predictor of dnDSA development. Recipients treated with a cyclosporin regimen had a 2.7-fold higher incidence of dnDSA development than recipients on a tacrolimus regimen. Recipients treated with tacrolimus who developed HLA-DR/DQ dnDSA had a higher proportion of tacrolimus trough levels <5 ng/ml, which continued to be significant after adjustment for HLA-DR/DQ eplet mismatch. Mean tacrolimus trough levels in the 6 months before dnDSA development were significantly lower than the levels >6 months before dnDSA development in the same patients. Recipients with a high-risk HLA eplet mismatch score were less likely to tolerate low tacrolimus levels without developing dnDSA. We conclude that HLA-DR/DQ eplet mismatch and tacrolimus trough levels are independent predictors of dnDSA development. Recipients with high HLA alloimmune risk should not target tacrolimus levels <5 ng/ml unless essential, and monitoring for dnDSA may be advisable in this setting.

ANCA Associated Vasculitis Secondary to Levamisole-Adultered Cocaine with Associated Membranous Nephropathy: A Case Series.

BACKGROUND: Cocaine is a risk factor for acute kidney injury and chronic kidney disease with progression to end-stage renal disease. Levamisole is an adulterant that is added to cocaine to enhance its euphoric effects. Levamisole-adulterated cocaine (LAC) is associated with the distinct clinical syndromes of agranulocytosis, leukocytoclastic vasculitis, cocaine-induced midline destructive lesions (CIMDL), and ANCA-associated vasculitis (AAV) with pauci-immune necrotizing glomerulonephritis. METHODS: We reviewed all cases of AAV secondary to LAC at our institution. RESULTS: We report 3 cases of AAV secondary to LAC and associated membranous nephropathy (MN). The first and second cases are concurrent AAV secondary to LAC and associated MN while the third case involves the development of MN after AAV secondary to LAC. CONCLUSIONS: Clinicians should be aware of this novel association of LAC with MN.

Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10.

BACKGROUND: The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination. METHODS: Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed. RESULTS: PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen κ, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose. CONCLUSIONS: Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal transplant patients.

Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial.

IMPORTANCE: BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE: To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS: Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES: The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS: The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE: Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01353339.

Elevated urinary CCL2: Cr at 6 months is associated with renal allograft interstitial fibrosis and inflammation at 24 months.

BACKGROUND: We have demonstrated that 6-month urinary CCL2: Cr is a predictor of interstitial fibrosis and tubular atrophy (IFTA) on 24-month biopsy and death-censored graft loss. However, IFTA is no longer considered prognostically significant, whereas patients with graft loss frequently have interstitial fibrosis and inflammation (IF+i=ci>0+i>0). As early CCL2: Cr predicts late graft loss, the goal of this study was to determine if 6-month urinary CCL2: Cr was a predictor of IF+i at 24 months. METHODS: Urinary CCL2 at 6 months was measured with ELISA and correlated with IF+i on 24-month surveillance biopsies from a prospective, multicenter adult renal transplant cohort (n=111). RESULTS: Six-month urinary CCL2: Cr was significantly higher in IF+i and transplant glomerulopathy patients compared with normal histology at 24 months. By multivariate analysis, 6-month urinary CCL2: Cr was independently correlated with IF+i at 24 months (OR 2.78, 95% CI 1.38-6.12, AUC 0.695, P=0.003). Six-month urinary CCL2: Cr was also an independent correlate of 6-month IF+i (OR 1.99, 95% CI 1.03-4.18, AUC 0.63, P=0.04). Six-month urinary CCL2: Cr distinguished noninflamed renal tissue (normal, fibrosis) from IF+i with a sensitivity/specificity of 0.71/0.62 at a cutoff of 15 ng CCL2/mmol Cr (AUC 0.695, P=0.003, n=91). CONCLUSIONS: Urinary CCL2: Cr may be useful for the noninvasive identification of patients with or at risk for IF+i. These patients may benefit from avoidance of drug minimization/withdrawal protocols and more intensive post-transplant surveillance. Furthermore, urinary CCL2: Cr may also identify individuals who may benefit from novel interventional trials targeting IF+i.