Comparison of eGFR Equations to Guide Dosing of Medications for Kidney Transplant Recipients.

BACKGROUND: Clinicians caring for kidney transplant recipients (KTRs) most commonly use estimated glomerular filtration rate (eGFR) to guide medication dosing as it is the most readily available measure of kidney function. Which eGFR equations provide the most accurate medication dosing guidance for KTRs remains uncertain. METHODS: We studied 415 stable KTRs in Canada and New Zealand. Participants completed same-day measurements of creatinine and cystatin C and measured GFR (diethylenetriaminepentaacetic acid). Chronic Kidney Disease Epidemiology Collaboration, European Kidney Function Consortium, and transplant-specific eGFR equations were compared with both Cockcroft-Gault creatinine clearance (CrCl) and measured GFR. eGFR equations were assessed both indexed to a standardized body surface area (BSA) of 1.73 m2 (milliliter per minute per 1.73 m2, as is conventional reporting from most clinical laboratories) and nonindexed (milliliter per minute) accounting for actual BSA. The primary outcome was the proportion of medication dosing discordance relative to Cockcroft-Gault CrCl or measured GFR for 8 commonly prescribed medications. Stratified analyses were performed on the basis of obesity status. RESULTS: Nonindexed eGFR equations (milliliter per minute) resulted in substantially lower medication dosing discordance compared with indexed eGFR equations (milliliter per minute per 1.73 m2). These findings were most pronounced among KTRs with obesity, in whom underdosing was frequent. When compared with Cockcroft-Gault CrCl, the lowest proportion of discordance was found with the nonindexed 2023 transplant-specific equation. When compared with measured GFR, the lowest proportion of discordance was found with the nonindexed 2021 Chronic Kidney Disease Epidemiology CollaborationCr/CysC equation. CONCLUSIONS: Nonindexed eGFR values accounting for actual BSA should be used by clinicians for medication dosing in KTRs. These findings may inform KT providers about which eGFR equations provide the safest, most accurate medication dosing guidance for KTRs.

Epidemiology of Cancer in Kidney Transplant Recipients.

Kidney transplantation is the ideal treatment modality for patients with end-stage kidney disease, with excellent outcomes post-transplant compared with dialysis. However, kidney transplant recipients are at increased risk of infections and cancer because of the need for immunosuppression. Kidney transplant recipients have approximately two to three times greater risk of developing cancer than the general population, and cancer is a major contributor to morbidity and mortality. Most of the increased risk is driven by viral-mediated cancers such as post-transplant lymphoproliferative disorder, anogenital cancers, and Kaposi sarcoma. Nonmelanoma skin cancer is the most frequent type of cancer in kidney transplant recipients, likely due to an interaction between ultraviolet radiation exposure and decreased immune surveillance. Occurrence of the more common types of solid organ cancers seen in the general population, such as breast, prostate, lung, and colorectal cancers, is not, or is only mildly, increased post-transplant. Clinical care and future research should focus on prevention and on improving outcomes for important immunosuppression-related malignancies, and treatment options for other cancers occurring in the transplant setting.

Psychometric Evaluation of the Multidimensional Scale-Uremic Pruritus in Dialysis Patients (UP-Dial): Comparison in Hemodialysis and Peritoneal Dialysis Patients with Chronic Pruritus.

BACKGROUND: High-quality patient-reported outcome (PRO) measures for dialysis patients with chronic pruritus are urgently needed. However, no known, well-validated multidimensional tools have been investigated to measure pruritus symptoms in dialysis patients. OBJECTIVES: To examine the psychometric properties of a multidimensional tool of chronic pruritus, the Uremic Pruritus in Dialysis (UP-Dial) 14-item, by comparing hemodialysis and peritoneal dialysis modality. METHODS: This validation study used data from the Thai Renal Outcomes Research-Uremic Pruritus, a prospective, multicenter, longitudinal study. Data for this study were collected from February 1, 2019, to May 31, 2022. The adult sample of 226 hemodialysis and 327 peritoneal dialysis patients fulfilled the criteria of chronic pruritus based on the International Forum for the Study of Itch. Psychometric properties of the UP-Dial included validity and reliability, as measured across hemodialysis and peritoneal dialysis patients. Patients completed a set of anchor-based measurement tools, including global itching, Dermatology Life Quality Index (DLQI), EuroQoL-5 dimension-5 level (EQ-5D-5L), Kidney Disease Quality of Life-36 (KDQOL-36), Pittsburgh Sleep Quality Index (PSQI), global fatigue, Somatic Symptom Scale-8 (SSS-8), and Patient Health Questionnaire-9 (PHQ-9). RESULTS: From the patient's perspective, face validity was satisfactory for both dialysis samples. Psychometric analyses of the UP-Dial for each dialysis sample had good convergent validity. Spearman rho correlations indicate a positively strong correlation (0.73 to 0.74) with global itching, a positively moderate correlation (0.33 to 0.58) with DLQI, PSQI, global fatigue, SSS-8, and PHQ-9, and a negatively moderate correlation (-0.39 to -0.58) with EQ-5D-5L and KDQOL-36. The discriminant validity was satisfactory with a group of moderate and severe burden of pruritus for both dialysis samples. For scale reliability, the UP-Dial revealed excellent internal consistency (Cronbach's α = 0.89 and McDonald's ω = 0.90) and reproducibility (intraclass correlation: 0.84 to 0.85) for both dialysis samples. Regarding psychometric properties, no statistically significant differences between dialysis samples were observed (all P > 0.05). CONCLUSIONS: The findings reaffirm good measurement properties of the UP-Dial 14-items in hemodialysis and peritoneal dialysis patients with chronic pruritus. These suggest a transferability of the UP-Dial as a PRO measure in clinical trial and practice settings.

Impaired Renal Function and Major Cardiovascular Events in Young Adults.

BACKGROUND: Cardiovascular (CV) disease in young adults (aged 18-39 years) is on the rise. Whether subclinical reductions in kidney function (ie, estimated glomerular filtration rate [eGFR] above the current threshold for chronic kidney disease but below age-expected values) are associated with elevated CV risk is unknown. OBJECTIVES: The goal of this study was to examine age-specific associations of subclinical eGFR reductions in young adults with major adverse cardiovascular events (MACEs) and MACE plus heart failure (MACE+). METHODS: A retrospective cohort study of 8.7 million individuals (3.6 million aged 18-39 years) was constructed using linked provincial health care data sets from Ontario, Canada (January 2008-March 2021). Cox models were used to examine the association of categorized eGFR (50-120 mL/min/1.73 m2) with MACE (first of CV mortality, acute coronary syndrome, and ischemic stroke) and MACE+, stratified according to age (18-39, 40-49, and 50-65 years). RESULTS: In the study cohort (mean age 41.3 years; mean eGFR 104.2 mL/min/1.73 m2; median follow-up 9.2 years), a stepwise increase in the relative risk of MACE and MACE+ was observed as early as eGFR <80 mL/min/1.73 m2 in young adults (eg, for MACE, at eGFR 70-79 mL/min/1.73 m2, ages 18-30 years: 2.37 events per 1,000 person years [HR: 1.31; 95% CI: 1.27-1.40]; ages 40-49 years: 6.26 events per 1,000 person years [HR: 1.09; 95% CI: 1.06-1.12]; ages 50-65 years: 14.9 events per 1,000 person years [HR: 1.07; 95% CI: 1.05-1.08]). Results persisted for each MACE component and in additional analyses (stratifying according to past CV disease, accounting for albuminuria at index, and using repeated eGFR measures). CONCLUSIONS: In young adults, eGFR below age-expected values were associated with an elevated risk for MACE and MACE+, warranting age-appropriate risk stratification, proactive monitoring, and timely intervention.

Physical Frailty and Functional Status in Patients With Advanced Chronic Kidney Disease: A Systematic Review.

Background: With an aging population and growing number of patients with chronic kidney disease (CKD), integrating the latest risk factors when deciding on a treatment plan can result in better patient care. Frailty remains a prevalent syndrome in CKD resulting in adverse health outcomes. However, measures of frailty and functional status remain excluded from clinical decision making. Objective: To examine the degree to which different measures of frailty and functional status are associated with mortality, hospitalization, and other clinical outcomes in patients with advanced CKD. Design: Systematic review. Setting: Observation studies including cohort study, case-control study, or cross-sectional study examining frailty and functional status on clinical outcomes. There were no restrictions on type of setting or country of origin. Patients: Adults with advanced CKD, including both types of dialysis patients. Measurements: Data including demographic information (e.g., sample size, follow-up time, age, country), assessments of frailty or functional status and their domains, and outcomes including mortality, hospitalization, cardiovascular events, kidney function, and composite outcomes were extracted. Methods: A search was conducted using databases Medline, Embase, and Cochrane Central Register for Controlled Trials. Studies were included from inception to March 17, 2021. The eligibility of studies was screened by 2 independent reviewers. Data were presented by instrument and clinical outcome. Point estimates and 95% confidence intervals from the fully adjusted statistical model were reported or calculated from the raw data. Results: A total of 117 unique instruments were found among 140 studies. The median sample size of studies was 319 (interquartile range, 161-893). Most studies focused on incident and chronic dialysis patient populations, with only 15% of studies examining non-dialysis CKD patients. Frailty and lower functional status were associated with an increased risk for adverse clinical outcomes such as mortality and hospitalization. The 5 individual domains of frailty were also found to be associated with poor health outcomes. Limitations: Meta-analysis could not be performed due to significant heterogeneity between studies and methods used to measure frailty and functional status. Many studies had issues with methodological rigor. Selection bias and the validity of data collection could not be ascertained for some studies. Conclusion: Frailty and functional status measures should be integrated to help guide clinical care decision making for a comprehensive assessment of risk for adverse outcomes among patients with advanced CKD. Registration PROSPERO: CRD42016045251.

Contexte: Compte tenu du vieillissement de la population et du nombre croissant de patients atteints d'insuffisance rénale chronique (IRC), l'intégration des plus récents facteurs de risque dans le processus de prise de décision d'un plan de traitement pourrait améliorer les soins aux patients. La fragilité demeure un syndrome prévalant en contexte d'IRC, qui entraîne des effets néfastes sur la santé. Pourtant, les mesures de la fragilité et de l'état fonctionnel demeurent exclues de la prise de décisions cliniques. Objectif: Déterminer à quel point les différentes mesures de la fragilité et de l'état fonctionnel sont associées à la mortalité, à l'hospitalisation et à d'autres résultats cliniques chez les patients atteints d'IRC avancée. Type d'étude: Examen systématique. Sources: Des études d'observation, y compris des études de cohorte, des études cas-témoins ou des études transversales examinant le rôle de la fragilité et de l'état fonctionnel sur les résultats cliniques. Il n'y avait pas de restrictions quant au cadre ou au pays d'origine de l'étude. Sujets: Des adultes atteints d'IRC avancée, y compris les deux types de patients sous dialyse. Mesures: Les données suivantes ont été extraites : les données démographiques (taille de l'échantillon, temps de suivi, âge des patients, pays), les évaluations de la fragilité ou de l'état fonctionnel et de leurs domaines, et les résultats cliniques (mortalité, hospitalisation, événements cardiovasculaires, fonction rénale et résultats composites). Méthodologie: Une recherche a été effectuée dans les bases de données Medline, embase et Cochrane Central Register for Controlled Trials pour répertorier les études de la création jusqu'au 17 mars 2021. L'admissibilité des études a été déterminée par deux examinateurs indépendants. Les données ont été présentées par instrument et par résultat clinique. Des estimations ponctuelles et des intervalles de confiance à 95 % du modèle statistique ajusté ont été rapportés ou calculés à partir des données brutes. Résultats: Parmi les 140 études répertoriées, 117 instruments uniques ont été trouvés. La taille médiane des échantillons était de 319 patients (ÉIQ : 161 à 893). La plupart des études portaient sur des populations de patients incidents et sous dialyse chronique, seulement 15 % des études portaient sur des patients atteints d'IRC non dialysés. La fragilité et un faible état fonctionnel ont été associés à un risque accru de résultats cliniques défavorables comme une hospitalisation ou le décès. Les cinq domaines individuels de la fragilité ont également été associés à de mauvais résultats de santé. Limites: L'hétérogénéité significative entre les études et les méthodes utilisées pour mesurer la fragilité et l'état fonctionnel ne permettait pas de procéder à une méta-analyse. De nombreuses études n'étaient pas rigoureuses sur le plan méthodologique. Les biais de sélection et la validité de la collecte des données n'ont pas pu être vérifiés pour certaines études. Conclusion: Les mesures de la fragilité et de l'état fonctionnel devraient être intégrées au processus de prise de décision afin d'orienter les soins cliniques et de permettre une évaluation complète du risque d'effets indésirables chez les patients atteints d'IRC avancée. Enregistrement PROSPERO: CRD42016045251.

Associations between modest reductions in kidney function and adverse outcomes in young adults: retrospective, population based cohort study.

OBJECTIVE: To study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes. DESIGN: Retrospective, population based cohort study. SETTING: Linked healthcare administrative datasets in Ontario, Canada. PARTICIPANTS: Adult residents (18-65 years) with at least one outpatient eGFR value (categorized in 10 unit increments from 50 mL/min/1.73m2 to >120 mL/min/1.73m2), with no history of kidney disease. MAIN OUTCOME MEASURES: eGFRs and hazard ratios of composite adverse outcome (all cause mortality, any cardiovascular event, and kidney failure) stratified by age (18-39 years, 40-49 years, and 50-65 years), and relative to age specific eGFR referents (100-110 mL/min/1.73m2) for ages 18-39 years, 90-100 for 40-49 years, 80-90 for 50-65 years). RESULTS: From 1 January 2008 to 31 March 2021, among 8 703 871 adults (mean age 41.3 (standard deviation 13.6) years; mean index eGFR 104.2 mL/min/1.73m2 (standard deviation 16.1); median follow-up 9.2 years (interquartile range 5.7-11.4)), modestly reduced eGFR measurements specific to age were recorded in 18.0% of those aged 18-39, 18.8% in those aged 40-49, and 17.0% in those aged 50-65. In comparison with age specific referents, adverse outcomes were consistently higher by hazard ratio and incidence for ages 18-39 compared with older groups across all eGFR categories. For modest reductions (eGFR 70-80 mL/min/1.73m2), the hazard ratio for ages 18-39 years was 1.42 (95% confidence interval 1.35 to 1.49), 4.39 per 1000 person years; for ages 40-49 years was 1.13 (1.10 to 1.16), 9.61 per 1000 person years; and for ages 50-65 years was 1.08 (1.07 to 1.09), 23.4 per 1000 person years. Results persisted for each individual outcome and in many sensitivity analyses. CONCLUSIONS: Modest eGFR reductions were consistently associated with higher rates of adverse outcomes. Higher relative hazards were most prominent and occurred as early as eGFR <80 mL/min/1.73m2 in younger adults, compared with older groups. These findings suggest a role for more frequent monitoring of kidney function in younger adults to identify individuals at risk to prevent chronic kidney disease and its complications.

Progression of Kidney Disease in Kidney Transplant Recipients With a Failing Graft: A Matched Cohort Study.

Background: Few studies have assessed outcomes in transplant recipients with failing grafts as most studies have focused on outcomes after graft loss. Objective: To determine whether renal function declines faster in kidney transplant recipients with a failing graft than in people with chronic kidney disease of their native kidneys. Design: Retrospective cohort study. Setting: Alberta, Canada (2002-2019). Patients: We identified kidney transplant recipients with a failing graft (2 estimated glomerular filtration rate [eGFR] measurements 15-30 mL/min/1.73 m2 ≥90 days apart). Measurements: We compared the change in eGFR over time (eGFR with 95% confidence limits, LCLeGFRUCL) and the competing risks of kidney failure and death (cause-specific hazard ratios [HRs], LCLHRUCL). Methods: Recipients (n = 575) were compared with propensity-score-matched, nontransplant controls (n = 575) with a similar degree of kidney dysfunction. Results: The median potential follow-up time was 7.8 years (interquartile range, 3.6-12.1). The hazards for kidney failure (HR1.101.331.60) and death (HR1.211.592.07) were significantly higher for recipients, while the eGFR decline over time was similar (recipients vs controls: -2.60-2.27-1.94 vs -2.52-2.21-1.90 mL/min/1.73 m2 per year). The rate of eGFR decline was associated with kidney failure but not death. Limitations: This was a retrospective, observational study, and there is a risk of bias due to residual confounding. Conclusions: Although eGFR declines at a similar rate in transplant recipients as in nontransplant controls, recipients have a higher risk of kidney failure and death. Studies are needed to identify preventive measures to improve outcomes in transplant recipients with a failing graft.

Contexte: Peu d'études ont évalué les résultats chez les patients transplantés dont le greffon est défaillant; la majorité des études s'étant plutôt concentrées sur les résultats après la perte du greffon. Objectif: Vérifier si la fonction rénale décline plus rapidement chez les patients transplantés dont le greffon est défaillant que chez les personnes souffrant d'une insuffisance chronique sur reins natifs. Conception: Étude de cohorte rétrospective. Cadre: Alberta, Canada (2002 à 2019). Sujets: Nous avons identifié des patients transplantés dont le greffon est défaillant (défini par deux mesures du débit de filtration glomérulaire estimé [DFGe] de 15-30 ml/min/1,73 m2 à au moins 90 jours d'intervalle). Mesures: Nous avons comparé l'évolution du DFGe dans le temps (DFGe avec intervalles de confiance [IC] à 95 % inférieur et supérieur: ICIDFGeICS) et les rapports de risque d'insuffisance rénale et de décès (intervalles de rapport de risque (RR) lié à la cause: ICIRRICS). Méthodologie: Les transplantés dont le greffon est défaillant (n=575) ont été comparés à des témoins non transplantés (n=575) appariés selon le score de propension et présentant un niveau similaire de dysfonctionnement rénal. Résultats: Le temps médian de suivi potentiel était de 7,8 ans (ÉIQ: 3,6 à 12,1). Les risques d'insuffisance rénale (RR: 1,101,331,60) et de décès (RR: 1,211,592,07) étaient significativement plus élevés chez les transplantés dont le greffon est défaillant, mais le déclin du DFGe au fil du temps était similaire dans les deux groupes (receveurs: -2,60-2,27-1,94 ml/min/1,73 m2 par an; témoins: -2,52-2,21-1,90 ml/min/1,73 m2 par an). Le taux de déclin du DFGe a été associé à une insuffisance rénale terminale, mais pas au décès. Limites: Il s'agit d'une étude observationnelle rétrospective et il existe un risque de biais dû à des facteurs de confusion résiduels. Conclusion: Bien que le DFGe décline à un rythme similaire chez les transplantés dont le greffon est défaillant et les témoins non transplantés, le risque d'insuffisance rénale terminale et de décès est plus élevé pour les transplantés. D'autres études sont nécessaires pour identifier les mesures préventives qui pourraient améliorer les résultats des patients transplantés dont le greffon est défaillant.

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.

The association of venous thromboembolism with blood transfusion in kidney transplant patients.

BACKGROUND: Red blood cell transfusion (RBCT) is common after kidney transplantation and could have pro-thrombotic effects predisposing to venous thromboembolism (VTE). The risks for developing of VTE after RBCT in kidney transplant patients are unknown. STUDY DESIGN AND METHODS: This was a retrospective cohort study of adult kidney transplant recipients from 2002 to 2018. The exposure of interest was receipt of RBCT after transplant. Cox proportional hazards models were used to calculate hazard ratios (HR) for the outcomes of venous thromboembolism [VTE] (deep venous thrombosis [DVT] or pulmonary embolism [PE]) using RBCT as a time-varying, cumulative exposure. RESULTS: Out of 1258 kidney transplants recipients, 468 (37%) were transfused during the study period. Seventy-nine study participants (6.3%) developed VTE, 72 DVT (5.7%), and 22 PE (1.8%). For the receipt of 1, 2, 3-5, and >5 RBCT, compared to individuals never transfused, the number of events and adjusted HR (95%CI) for VTE were 6 (6.2%) HR 1.57 (0.69-3.58), 9 (7.6%) HR 2.54 (1.30-4.96), 15 (11.9%) HR 2.73 (1.38-5.41), and 23 (18.1%) HR 5.77 (2.99-11.14) respectively; for DVT, it was 6 (6.2%) HR 1.94 (0.84-4.48), 9 (7.6%) HR 2.92 (1.44-5.94), 14 (11.1%) HR 3.29 (1.63-6.65), and 21 (16.5%) HR 6.97 (3.53-13.76), respectively. For PE, among transfused individuals, there were 14 events (3.0%) and the HR was 2.40 (1.02-5.61). CONCLUSION: The risks for developing VTE, DVT, and PE were significantly increased in kidney transplant patients receiving RBCT after transplant. Receipt of RBCT should prompt considerations for judicious monitoring and assessment for thrombosis.

Association Between Pretransplant Dialysis Modality and Kidney Transplant Outcomes: A Systematic Review and Meta-analysis.

Importance: The benefits and disadvantages of different pretransplant dialysis modalities and their posttransplant outcomes remain unclear in contemporary kidney transplant care. Objective: To summarize the available evidence of the association of different pretransplant dialysis modalities, including hemodialysis and peritoneal dialysis (PD), with posttransplant outcomes. Data Sources: MEDLINE, Embase, PubMed, Cochrane Library, Scopus, CINAHL, and gray literature were searched from inception to March 18, 2022 (updated to April 1, 2022), for relevant studies and with no language restrictions. Study Selection: Randomized clinical trials and nonrandomized observational (case-control and cohort) studies that investigated the association between pretransplant dialysis modality and posttransplant outcomes regardless of age or donor sources (living or deceased) were abstracted independently by 2 reviewers. Data Extraction and Synthesis: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines, 2 reviewers independently extracted relevant information using a standardized approach. Random-effects meta-analysis was used to estimate pooled adjusted hazard ratio (HR) or odds ratio and 95% CI. Main Outcomes and Measures: Primary outcomes included all-cause mortality, overall graft failure, death-censored graft failure, and delayed graft function. Secondary outcomes included acute rejection, graft vessel thrombosis, oliguria, de novo heart failure, and new-onset diabetes after transplant. Results: The study analyzed 26 nonrandomized studies (1 case-control and 25 cohort), including 269 715 patients (mean recipient age range, 14.5-67.0 years; reported proportions of female individuals, 29.4%-66.9%) whose outcomes associated with pretransplant hemodialysis vs pretransplant PD were compared. No significant difference, with very low certainty of evidence, was observed between pretransplant PD and all-cause mortality (13 studies; n = 221 815; HR, 0.92 [95% CI, 0.84-1.01]; P = .08) as well as death-censored graft failure (5 studies; n = 96 439; HR, 0.98 [95% CI, 0.85-1.14]; P = .81). However, pretransplant PD was associated with a lower risk for overall graft failure (10 studies; n = 209 287; HR, 0.96 [95% CI, 0.92-0.99]; P = .02; very low certainty of evidence) and delayed graft function (6 studies; n = 47 118; odds ratio, 0.73 [95% CI, 0.70-0.76]; P < .001; low certainty of evidence). Secondary outcomes were inconclusive due to few studies with available data. Conclusions and Relevance: Results of the study suggest that pretransplant PD is a preferred dialysis modality option during the transition to kidney transplant. Future studies are warranted to address shared decision-making between health care professionals, patients, and caregivers as well as patient preferences.

Use of Thiazide Diuretics and Risk of All Types of Skin Cancers: An Updated Systematic Review and Meta-Analysis.

Background: The use of thiazide diuretics is associated with skin cancer risk; however, whether this applies to all skin cancer types is unclear. Methods: In this meta-analysis, we searched multiple electronic databases and gray literature up to 10 April 2022, with no language restrictions, to identify relevant randomized controlled trials (RCTs) and non-randomized studies (cohort, case-control) that investigated the association between thiazide diuretics and skin cancer. The primary outcomes of interest were malignant melanoma and non-melanoma skin cancer (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]). Secondary outcomes included other skin cancers (lip cancer, Merkel cell carcinoma, malignant adnexal skin tumors, oral cavity cancer, and precursors of skin cancer). We used a random-effects meta-analysis to estimate pooled adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Thirty non-randomized studies (17 case-control, 13 cohort, no RCTs) were included. Thiazide diuretic users had a higher risk of malignant melanoma (17 studies; n = 10,129,196; pooled adjusted OR, 1.10; 95% CI, 1.04−1.15; p < 0.001; strength of evidence, very low; very small harmful effect), BCC (14 studies; n = 19,780,476; pooled adjusted OR, 1.05; 95% CI, 1.02−1.09; p = 0.003; strength of evidence, very low; very small harmful effect), and SCC (16 studies; n = 16,387,862; pooled adjusted OR, 1.35; 95% CI, 1.22−1.48; p < 0.001; strength of evidence, very low; very small harmful effect) than non-users. Thiazide diuretic use was also associated with a higher risk of lip cancer (5 studies; n = 161,491; pooled adjusted OR, 1.92; 95% CI, 1.52−2.42; p < 0.001; strength of evidence, very low; small harmful effect), whereas other secondary outcomes were inconclusive. Conclusions: Thiazide diuretics are associated with the risk of all skin cancer types, including malignant melanoma; thus, they should be used with caution in clinical practice.

Performance of the 2021 Race-Free CKD-EPI Creatinine- and Cystatin C-Based Estimated GFR Equations Among Kidney Transplant Recipients.

RATIONALE & OBJECTIVE: Race-free estimated glomerular filtration rate (eGFR) equations incorporating creatinine with and without cystatin C were recently developed and recommended for routine use. However, the performance of these equations among kidney transplant recipients (KTRs) remains unknown. STUDY DESIGN: Cross-sectional study to validate the 2021 race-free Chronic Kidney Disease (CKD) Epidemiology Collaboration (CKD-EPI) eGFR equation based on creatinine alone (eGFRcr) or based on creatinine and cystatin C (eGFRcr-cys) among KTRs. SETTING & PARTICIPANTS: KTRs in stable condition (N = 415) from Canada and New Zealand with same-day measurements of creatinine, cystatin C, and glomerular filtration rate (GFR) using radiolabeled diethylenetriaminepentaacetic acid. TESTS COMPARED: The 2009 CKD-EPI eGFRcr, 2021 CKD-EPI eGFRcr, 2012 CKD-EPI eGFRcr-cys, 2021 CKD-EPI eGFRcr-cys, 2012 CKD-EPI eGFRcys, and Modification of Diet in Renal Disease (MDRD) Study eGFR equations were compared with measured GFR. OUTCOMES: Bias, precision, accuracy, and correct classification by CKD stage. Bias was defined as the difference between estimated and measured GFR. Precision was represented by the interquartile range. Accuracy was defined as the percentages of participants with eGFRs within 10%/20%/30% (P10/P20/P30) of measured GFR, root mean square error, and mean absolute error. RESULTS: 87% of patients studied were White, 3% Black, and 10% other races. Mean measured GFR was 53 ± 19 (SD) mL/min/1.73 m2. The 2009 and 2021 CKD-EPI eGFRcr equations demonstrated similar median bias (-2.3 vs -0.2 mL/min/1.73 m2, respectively), precision (14.5 vs 14.9 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/65%/84% vs 33%/63%/84%). The 2012 and 2021 CKD-EPI eGFRcr-cys equations also demonstrated similar median bias (-3.6 vs 0.3 mL/min/1.73 m2, respectively), precision (13.3 vs 14.3 mL/min/1.73 m2), and accuracy (P10/P20/P30, 32%/63%/80% vs 32%/67%/83%). No clear difference in performance was detected between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations among KTRs. The proportion of correct classification by CKD stage was similar across all eGFR equations. LIMITATIONS: Moderate sample size, few patients had a GFR <30 mL/min/1.73 m2, and the large majority of patients were White. CONCLUSIONS: Among KTRs, the 2021 race-free CKD-EPI eGFR equations perform similarly to the previous CKD-EPI equations that included race correction terms. No significant difference in performance was observed between the 2021 CKD-EPI eGFRcr and eGFRcr-cys equations in the kidney transplant population.

Blood transfusion and the risk for infections in kidney transplant patients.

BACKGROUND: Receipt of a red blood cell transfusion (RBCT) post-kidney transplantation may alter immunity which could predispose to subsequent infection. METHODS: We carried out a single-center, retrospective cohort study of 1,258 adult kidney transplant recipients from 2002 to 2018 (mean age 52, 64% male). The receipt of RBCT post-transplant (468 participants transfused, total 2,373 RBCT) was analyzed as a time-varying, cumulative exposure. Adjusted cox proportional hazards models were used to calculate hazard ratios (HR) for outcomes of bacterial or viral (BK or CMV) infection. RESULTS: Over a median follow-up of 3.8 years, bacterial infection occurred in 34% of participants at a median of 409 days post-transplant and viral infection occurred in 25% at a median of 154 days post-transplant. Transfusion was associated with a step-wise higher risk of bacterial infection (HR 1.35, 95%CI 0.95-1.91; HR 1.29, 95%CI 0.92-1.82; HR 2.63, 95%CI 1.94-3.56; HR 3.38, 95%CI 2.30-4.95, for 1, 2, 3-5 and >5 RBCT respectively), but not viral infection. These findings were consistent in multiple additional analyses, including accounting for reverse causality. CONCLUSION: Blood transfusion after kidney transplant is associated with a higher risk for bacterial infection, emphasizing the need to use transfusions judiciously in this population already at risk for infections.

Blood Transfusion and Adverse Graft-related Events in Kidney Transplant Patients.

BACKGROUND: The impact of posttransplant red blood cell transfusion (RBCT) and their potential immunomodulatory effects on kidney transplant recipients are unclear. We examined the risks for adverse graft outcomes associated with post-kidney transplant RBCT. METHODS: We conducted a retrospective cohort study of all adult kidney transplant recipients at The Ottawa Hospital from 2002 to 2018. The exposure of interest was receipt of an RBCT after transplant categorized as 1, 2, 3 to 5, and >5 RBC. Outcomes of interest were rejection and death-censored graft loss (DCGL). Cox proportional hazards models were used to calculate hazard ratios (HR) with RBCT as a time-varying, cumulative exposure. RESULTS: Among 1258 kidney transplant recipients, 468 (37.2%) received 2373 total RBCTs, 197 (15.7%) had rejection and 114 (9.1%) DCGL. For the receipt of 1, 2, 3 to 5, and >5 RBCT, compared with individuals never transfused, the adjusted HRs (95% confidence interval [CI]) for rejection were 2.47 (1.62-3.77), 1.27 (0.77-2.11), 1.74 (1.00-3.05), and 2.23 (1.13-4.40), respectively; DCGL 2.32 (1.02-5.27), 3.03 (1.62-5.64), 7.50 (4.19-13.43), and 14.63 (8.32-25.72), respectively. Considering a time-lag for an RBCT to be considered an exposure before an outcome to limit reverse causation, RBCT was not associated with rejection; the HRs for DCGL attenuated but remained similar. RBCT was also associated with a negative control outcome, demonstrating possible unmeasured confounding. CONCLUSION: RBCT after kidney transplant is not associated with rejection, but may carry an increased risk for DCGL.

Thinking Outside the Box: Novel Kidney Protective Strategies in Kidney Transplantation.

Despite the reduction in the incidence of acute rejection, a major risk factor for graft loss, there has been only modest improvement in long-term graft survival. Most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or calcineurin inhibitor nephrotoxicity. Distinct immunologic and nonimmunologic factors conspire to lead to a common pathway of allograft fibrosis. It remains plausible that mitigating nonimmunologic damage using strategies proven effective in native kidney disease may yield benefit in kidney transplantation. In this review, we will focus on nonimmunologic aspects of kidney transplant care that may prove to be valuable adjuncts to a well-managed immunosuppression regimen. Topics to be addressed include the roles of hypertension and agents used to treat it, lipid lowering, sodium and water intake, elevated uric acid, metabolic acidosis, and the use of sodium-glucose cotransporter 2 inhibitors on long-term kidney transplant health.

Ambulatory Treatments for RAAS Inhibitor-Related Hyperkalemia and the 1-Year Risk of Recurrence.

BACKGROUND AND OBJECTIVE: The optimal ambulatory management of renin-angiotensin-aldosterone system inhibitor (RAASi)-related hyperkalemia to reduce the risk of recurrence is unknown. We examined the risk of hyperkalemia recurrence on the basis of outpatient pharmacologic changes following an episode of RAASi-related hyperkalemia. DESIGN: We performed a population-based, retrospective cohort study of older adults (n=49,571; mean age 79 years) who developed hyperkalemia (potassium ≥5.3 mEq/L) while on a RAASi and were grouped as follows: no intervention, RAASi discontinuation, RAASi dose decrease, new diuretic, diuretic dose increase, or sodium polystyrene sulfonate within 30 days. The primary outcome was hyperkalemia recurrence, with secondary outcomes of cardiovascular events and all-cause mortality within 1 year. RESULTS: Among patients who received a pharmacologic intervention (23% of the cohort), RAASi discontinuation was the most commonly prescribed strategy (74%), followed by RAASi decrease (15%), diuretic increase (7%), new diuretic (3%), and sodium polystyrene sulfonate (1%). A total of 16,977 (34%) recurrent hyperkalemia events occurred within 1 year. Compared with no intervention (35%, referent), the cumulative incidence of recurrent hyperkalemia was lower with RAASi discontinuation (29%; hazard ratio, 0.82; 95% confidence interval, 0.78 to 0.85), whereas there was no difference with RAASi dose decrease (36%; hazard ratio, 0.94; 95% confidence interval, 0.86 to 1.02), new diuretic (32%; hazard ratio, 0.95; 95% confidence interval, 0.78 to 1.17), or diuretic increase (38%; hazard ratio, 0.99; 95% confidence interval, 0.87 to 1.12) and a higher incidence with sodium polystyrene sulfonate (55%; hazard ratio, 1.30; 95% confidence interval, 1.04 to 1.63). RAASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio, 0.96; 95% confidence interval, 0.91 to 1.02) or all-cause mortality (hazard ratio, 1.05; 95% confidence interval, 0.96 to 1.15) compared with no intervention. CONCLUSIONS: Among older adults with RAASi-related hyperkalemia, RAASi discontinuation is associated with the lowest risk of recurrent hyperkalemia, with no apparent increase in short-term risks for cardiovascular events or all-cause mortality.

Kidney, Cardiac, and Safety Outcomes Associated With α-Blockers in Patients With CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVES: Alpha-blockers (ABs) are commonly prescribed for control of resistant or refractory hypertension in patients with and without chronic kidney disease (CKD). The association between AB use and kidney, cardiac, mortality, and safety-related outcomes in CKD remains unknown. STUDY DESIGN: Population-based retrospective cohort study. SETTINGS & PARTICIPANTS: Ontario (Canada) residents 66 years and older treated for hypertension in 2007 to 2015 without a prior prescription for an AB. EXPOSURES: New use of an AB versus new use of a non-AB blood pressure (BP)-lowering medication. OUTCOMES: 30% or greater estimated glomerular filtration rate (eGFR) decline; dialysis initiation or kidney transplantation (kidney replacement therapy); composite of acute myocardial infarction, coronary revascularization, congestive heart failure, or atrial fibrillation; safety (hypotension, syncope, falls, and fractures) events; and mortality. ANALYTICAL APPROACH: New users of ABs (doxazosin, terazosin, and prazosin) were matched to new users of non-ABs by a high dimensional propensity score. Cox proportional hazards and Fine and Gray models were used to examine the association of AB use with kidney, cardiac, mortality, and safety outcomes. Interactions by eGFR categories (≥90, 60-89, 30-59, and<30mL/min/1.73m2) were explored. RESULTS: Among 381,120 eligible individuals, 16,088 were dispensed ABs and matched 1:1 to non-AB users. AB use was associated with higher risk for≥30% eGFR decline (HR, 1.14; 95% CI, 1.08-1.21) and need for kidney replacement therapy (HR, 1.28; 95% CI, 1.13-1.44). eGFR level did not modify these associations, P interaction=0.3and 0.3, respectively. Conversely, AB use was associated with lower risk for cardiac events, which was also consistent across eGFR categories (HR, 0.92; 95% CI, 0.89-0.95; P interaction=0.1). AB use was also associated with lower mortality risk, but only among those with eGFR<60mL/min/1.73m2 (P interaction<0.001): HRs were 0.85 (95% CI, 0.78-0.93) and 0.71 (95% CI, 0.64-0.80) for eGFR of 30 to 59 and<30mL/min/1.73m2, respectively. LIMITATIONS: Observational design, BP measurement data unavailable. CONCLUSIONS: AB use in CKD is associated with higher risk for kidney disease progression but lower risk for cardiac events and mortality compared with alternative BP-lowering medications.

Simultaneous glomerular filtration rate determination using inulin, iohexol, and 99mTc-DTPA demonstrates the need for customized measurement protocols.

Urinary inulin clearance is considered the gold standard of glomerular filtration rate (GFR) measurement but plasma clearance of less expensive and more accessible tracers is more commonly performed. Many plasma sampling protocols exist but little is known about their accuracy. Here, the study objectives were to compare plasma iohexol and 99mTc-DTPA GFR with varying sampling strategies to the GFR measured by urinary inulin and to identify protocols with the greatest accuracy according to clinical characteristics. GFR was measured simultaneously using urinary inulin, plasma iohexol, and plasma 99mTc DTPA clearance. Blood was sampled from 2 to 10 hours after injection. For each method, bias, precision, and accuracy (P30 and mean absolute error) were calculated for the entire cohort and for eGFR-EPI creatinine subgroups (<30, 30-59, and ≥60 ml/min/1.73m2) and the edema stage using urinary inulin clearance as the gold standard. The mean inulin GFR of the 77 participants was 33 ml/min/1.73m2. Delay of both the initial and the final samples in plasma iohexol protocols yielded the highest accuracy in the setting of low GFR (<30 ml/min/1.73m2). Early initial and final samples yielded the highest accuracy in the setting of high GFRs (≥60 ml/min/1.73m2). No sampling strategy was accurate in edematous patients. Thus, our study demonstrates that customization of GFR protocols according to the anticipated level of GFR are required to optimize protocol accuracy.