Post-transplant outcomes in recipients of living donor kidneys and intended recipients of living donor kidneys.

BACKGROUND: Long-term kidney transplant survival at the population level is consistently favorable, but this survival varies widely at an individual level due to both recipient and donor factors. The distinct contribution of recipient and donor factors to individual post kidney transplant outcome remains unclear. Comparing outcomes in deceased donor (DD) recipients with potential but non-actualized living donors (DD1) to those recipients with actualized living donors (LD), and to DD recipients without potential living donors (DD0) may provide transplant candidates with more information about their own post-transplant prognosis. METHODS: We conducted an observational retrospective cohort study of kidney transplant candidates presenting to our centre for evaluation between 01/01/06 and 31/12/18, and who also received a transplant during that time. Patients were followed to 31/08/2019. Candidates were classified as DD0, DD1, or LD based on whether they had an identified living donor at the time of initial pre-transplant assessment, and if the donor actualized or not. Primary outcome was 5-year death-censored graft survival, adjusted for common pre- and post-transplant donor and recipient risk factors. Secondary outcomes analyzed included patient survival and graft function. RESULTS: There were 453 kidney transplant recipients (LD = 136, DD1 = 83, DD0 = 234) who received a transplant during the study period. DD0 and DD1 did not differ in key donor organ characteristics. The 5-year death censored graft survival of DD1 was similar to LD (p = 0.19). DD0 graft survival was inferior to LD (p = 0.005), but also trended inferior to DD1 (p = 0.052). By multivariate Cox regression analysis, LD demonstrated similar 5-year graft survival to DD1 (HR for graft loss 0.8 [95% CI 0.25-2.6], p = 0.72) but LD graft survival was superior to DD0 (HR 0.34 [0.16-0.72], p = 0.005). The 5-year patient survival in DD1 was similar to LD (p = 0.26) but was superior to DD0 (p = 0.01). CONCLUSIONS: DD recipients with potential but non-actualized living donors exhibit similar mid-term graft and patient survival compared to LD recipients. Having an identified living donor at the time of pre-transplant assessment portends a favorable prognosis for the recipient.

Pattern separation beyond the hippocampus: A high-resolution whole-brain investigation of mnemonic discrimination in healthy adults.

Episodic memory depends on the computational process of pattern separation in order to establish distinct memory representations of similar episodes. Studies of pattern separation in humans rely on mnemonic discrimination tasks, which have been shown to tax hippocampal-dependent pattern separation. Although previous neuroimaging research has focused on hippocampal processing, little is known about how other brain regions, known to be involved in recognition memory performance, are involved in mnemonic discrimination tasks. Conversely, neuroimaging studies of pattern separation with whole-brain coverage lack spatial resolution to localize activation to hippocampal subfields. In this study, 48 healthy young adult participants underwent whole-brain high-resolution functional MRI (fMRI) scanning while completing a mnemonic discrimination task. A priori region-of-interest analyses revealed activation patterns consistent with pattern separation in distinct hippocampal subregions, particularly in the subiculum. Connectivity analyses revealed a network of cortical regions consistent with the memory retrieval network where fMRI activation was correlated with hippocampal activation. An exploratory whole-brain analysis revealed widespread activation differentially associated with performance of the mnemonic discrimination task. Taken together, these results suggest that a network of brain regions contribute to mnemonic discrimination performance, with the hippocampus and parahippocampal cortex as a hub in the network displaying clear signals consistent with pattern separation and regions such as the dorsal medial prefrontal cortex particularly important for successful lure discrimination.

Adverse Childhood Experiences (ACEs) and Headaches Among Children: A Cross-Sectional Analysis.

OBJECTIVES: This cross-sectional study examined the association between adverse childhood experiences (ACEs) and history of frequent headaches (including migraine) among children 3-17 years old using data from the 2016 and 2017 U.S. National Survey of Children's Health (NSCH). BACKGROUND: ACEs include abuse (physical, emotional, or sexual), parental divorce, death, mental illness, or addiction, and are linked to higher morbidity and mortality in adulthood. A relationship between ACEs and headaches exists among adults, but studies examining the relationship among children are lacking. To our knowledge, no studies have examined the link among children using NSCH data. METHODS: The NSCH is a nationally representative survey of U.S. children's physical and emotional well-being aimed at understanding their health needs. Parental-reported information was collected on child history of headaches and 9 ACEs for the selected child. The survey collected information on 71,881 children in 2016 and 2017 out of which 61,565 were eligible for the study (age ≥3 years and not missing data on history headaches). Children with missing values for headache, ACEs, or covariates (n = 58,958) were excluded from the final analysis. We used multivariable logistic regression with survey weighting and adjusted for demographics and comorbidities (anxiety, depression, epilepsy, and brain injury) to examine the association between ACEs and headaches overall and stratified by gender. We further assessed the independent relationship between each ACE and headaches. RESULTS: In the current study, out of 61,656 children, 26,884 (48.6%) experienced at least 1 ACE and 3426 (6.5%) experienced 4+ ACEs. Overall, compared with children with no ACEs, the adjusted odds of headache were 1.34 times higher among children with 1 reported ACE (95% CI: 1.07, 1.68), 2.15 times higher among children with 2 ACEs (95% CI: 1.66, 2.80), 1.89 times higher among children with 3 ACEs (95% CI: 1.40, 2.53), and 3.40 times higher among children with 4+ ACEs (95% CI: 2.61, 4.43). Females with 3 and 4+ ACEs were somewhat more likely to report headaches compared to males with the same number of ACEs. Individually, no ACE was independently associated with history of headaches except for difficulty due to family's income (aOR = 2.46, 95% CI: 1.98, 3.06). CONCLUSION: Experiencing one or more ACEs vs none was associated with higher risk of headaches in children, and difficulty due to family's income was the only ACE independently associated with headaches. Our findings support results of other studies on ACEs and headache in young adults and suggest that adverse ACE-related health outcomes begin earlier than previously recognized. Additionally, struggling due to low income may represent a constellation of chronic stressors that independently contribute to poor health outcomes in childhood as compared to other individual ACEs. Future research should examine the importance of specific ACE clusters and stressors during childhood.

Post-traumatic stress disorder and hypertensive disorders of pregnancy among military women.

BACKGROUND: Women are more likely to develop post-traumatic stress disorder (PTSD) than men. Limited research exists evaluating the risk of hypertensive disorders of pregnancy (HDP) among military women with PTSD. METHODS: We conducted a retrospective cohort study using US Department of Defense (DoD) data comprised of all active-duty women giving birth to their first, liveborn singleton infant using DoD-sponsored health insurance from 1 January 2004 to 31 December 2008 (n = 34 176). Birth hospitalisation records, maternal mental health visits, and Post-Deployment Health Assessment (PDHA) and Reassessment (PDHRA) screenings were included. The HDP outcome (yes vs no) was defined using ICD-9-CM codes in the maternal birth hospitalisation record. Women fit into one of four PTSD exposure categories (confirmed, probable, possible, none). Confirmed cases had a PTSD ICD-9-CM diagnosis code. Probable/possible cases were classified using PDHA screening items. We used multiple log-linear regression to assess PTSD (confirmed, any vs none) and the risk of HDP overall, and then explored effect modification by military service and demographic variables. We assessed the risk of HDP among deployed mothers with PTSD (confirmed, probable/possible vs none) who completed a PDHA, and explored effect modification by race/ethnicity. We also assessed risk of HDP with differing PTSD lead times. RESULTS: Overall, PTSD was not associated with HDP except among mothers whose PTSD was diagnosed ≥1 year prior to conception (RR 1.42, 95% CI 1.06, 1.90). CONCLUSIONS: Post-traumatic stress disorder preceding conception by at least a year appeared to confer an increased risk of HDP, but further research is needed using more thorough PTSD assessment.

Safety and efficacy of prophylaxis for Pneumocystis jirovecii pneumonia involving trimethoprim-sulfamethoxazole dose reduction in kidney transplantation.

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti-Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear. METHODS: We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed. RESULTS: Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26-0.83, p < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39-7.90, p = 0.006). CONCLUSIONS: TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.

Cardiovascular magnetic resonance left ventricular strain in end-stage renal disease patients after kidney transplantation.

BACKGROUND: Cardiovascular disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and kidney transplant (KT) patients. Compared with left ventricular (LV) ejection fraction (LVEF), LV strain has emerged as an important marker of LV function as it is less load dependent. We sought to evaluate changes in LV strain using cardiovascular magnetic resonance imaging (CMR) in ESRD patients who received KT, to determine whether KT may improve LV function. METHODS: We conducted a prospective multi-centre longitudinal study of 79 ESRD patients (40 on dialysis, 39 underwent KT). CMR was performed at baseline and at 12 months after KT. RESULTS: Among 79 participants (mean age 55 years; 30% women), KT patients had significant improvement in global circumferential strain (GCS) (p = 0.007) and global radial strain (GRS) (p = 0.003), but a decline in global longitudinal strain (GLS) over 12 months (p = 0.026), while no significant change in any LV strain was observed in the ongoing dialysis group. For KT patients, the improvement in LV strain paralleled improvement in LVEF (57.4 ± 6.4% at baseline, 60.6% ± 6.9% at 12 months; p = 0.001). For entire cohort, over 12 months, change in LVEF was significantly correlated with change in GCS (Spearman's r = - 0.42, p < 0.001), GRS (Spearman's r = 0.64, p < 0.001), and GLS (Spearman's r = - 0.34, p = 0.002). Improvements in GCS and GRS over 12 months were significantly correlated with reductions in LV end-diastolic volume index and LV end-systolic volume index (all p < 0.05), but not with change in blood pressure (all p > 0.10). CONCLUSIONS: Compared with continuation of dialysis, KT was associated with significant improvements in LV strain metrics of GCS and GRS after 12 months, which did not correlate with blood pressure change. This supports the notion that KT has favorable effects on LV function beyond volume and blood pessure control. Larger studies with longer follow-up are needed to confirm these findings.

Commercial kidney transplantation is an important risk factor in long-term kidney allograft survival.

Transplant tourism, a form of transplant commercialization, has resulted in serious short-term adverse outcomes that explain reduced short-term kidney allograft survival. However, the nature of longer-term outcomes in commercial kidney transplant recipients is less clear. To study this further, we identified 69 Canadian commercial transplant recipients of 72 kidney allografts transplanted during 1998 to 2013 who reported to our transplant center for follow-up care. Their outcomes to 8 years post-transplant were compared with 702 domestic living donor and 827 deceased donor transplant recipients during this period using Kaplan-Meier survival plots and multivariate Cox regression analysis. Among many complications, notable specific events included hepatitis B or C seroconversion (7 patients), active hepatitis and/or fulminant hepatic failure (4 patients), pulmonary tuberculosis (2 patients), and a type A dissecting aortic aneurysm. Commercial transplantation was independently associated with significantly reduced death-censored kidney allograft survival (hazard ratio 3.69, 95% confidence interval 1.88-7.25) along with significantly delayed graft function and eGFR 30 ml/min/1.73 m(2) or less at 3 months post-transplant. Thus, commercial transplantation represents an important risk factor for long-term kidney allograft loss. Concerted arguments and efforts using adverse recipient outcomes among the main premises are still required in order to eradicate transplant commercialization.

Metabolic syndrome definitions and components in predicting major adverse cardiovascular events after kidney transplantation.

Metabolic syndrome (MetS) associates with cardiovascular risk post-kidney transplantation, but its ambiguity impairs understanding of its diagnostic utility relative to components. We compared five MetS definitions and the predictive value of constituent components of significant definitions for major adverse cardiovascular events (MACE) in a cohort of 1182 kidney transplant recipients. MetS definitions were adjusted for noncomponent traditional Framingham risk factors and relevant transplant-related variables. Kaplan-Meier, logistic regression, and Cox proportional hazards analysis were utilized. There were 143 MACE over 7447 patient-years of follow-up. Only the World Health Organization (WHO) 1998 definition predicted MACE (25.3 vs 15.5 events/1000 patient-years, P = 0.019). Time-to-MACE was 5.5 ± 3.5 years with MetS and 6.8 ± 3.9 years without MetS (P < 0.0001). MetS was independent of pertinent MACE risk factors except age and previous cardiac disease. Among MetS components, dysglycemia provided greatest hazard ratio (HR) for MACE (1.814 [95% confidence interval 1.26-2.60]), increased successively by microalbuminuria (HR 1.946 [1.37-2.75]), dyslipidemia (3.284 [1.72-6.26]), hypertension (4.127 [2.16-7.86]), and central obesity (4.282 [2.09-8.76]). MetS did not affect graft survival. In summary, although the WHO 1998 definition provides greatest predictive value for post-transplant MACE, most of this is conferred by dysglycemia and is overshadowed by age and previous cardiac disease.

Assessing the economic impact of paternal involvement: a comparison of the generalized linear model versus decision analysis trees.

Lack of paternal involvement has been shown to be associated with adverse pregnancy outcomes, including infant morbidity and mortality, but the impact on health care costs is unknown. Various methodological approaches have been used in cost minimization and cost effectiveness analyses and it remains unclear how cost estimates vary according to the analytic strategy adopted. We illustrate a methodological comparison of decision analysis modeling and generalized linear modeling (GLM) techniques using a case study that assesses the cost-effectiveness of potential father involvement interventions. We conducted a 12-year retrospective cohort study using a statewide enhanced maternal-infant database that contains both clinical and nonclinical information. A missing name for the father on the infant's birth certificate was used as a proxy for lack of paternal involvement, the main exposure of this study. Using decision analysis modeling and GLM, we compared all infant inpatient hospitalization costs over the first year of life. Costs were calculated from hospital charges using department-level cost-to-charge ratios and were adjusted for inflation. In our cohort of 2,243,891 infants, 9.2% had a father uninvolved during pregnancy. Lack of paternal involvement was associated with higher rates of preterm birth, small-for-gestational age, and infant morbidity and mortality. Both analytic approaches estimate significantly higher per-infant costs for father uninvolved pregnancies (decision analysis model: $1,827, GLM: $1,139). This paper provides sufficient evidence that healthcare costs could be significantly reduced through enhanced father involvement during pregnancy, and buttresses the call for a national program to involve fathers in antenatal care.

Validation and clinical application of transactivation assays for RUNX1 variant classification.

Familial platelet disorder with associated myeloid malignancies (RUNX1-familial platelet disorder [RUNX1-FPD]) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies Variant Curation Expert Panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of 2 other variants. We demonstrated functionality of 4 VUS, but reclassification to (likely) benign was challenging and suggested the need for reevaluating current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of 7 families. Our data confirmed RUNX1-FPD suspicion in 3 families with RUNX1-FPD-specific family history, whereas for 3 variants identified in RUNX1-FPD-nonspecific families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.

Prevalence of major infections and adverse outcomes among hospitalized. ST-elevation myocardial infarction patients in Florida, 2006.

BACKGROUND: ST-elevation myocardial infarction (STEMI) patients have risk factors and co-morbidities and require procedures predisposing to healthcare acquired infections (HAIs). As few data exist on the extent and consequences of infections among these patients, the prevalence, predictors, and potential complications of major infections among hospitalized STEMI patients at all Florida acute care hospitals during 2006 were analyzed. METHODS: Sociodemographic characteristics, risk factors, co-morbidities, procedures, complications, and mortality were analyzed from hospital discharge data for 11, 879 STEMI patients age ≥ 18 years. We used multivariable logistic regression modeling to examine and adjust for multiple potential predictors of any infection, bloodstream infection (BSI), pneumonia, surgical site infection (SSI), and urinary tract infection (UTI). RESULTS: There were 2,562 infections among 16.6% of STEMI patients; 6.2% of patients had ≥2 infections. The most prevalent HAIs were UTIs (6.0%), pneumonia (4.6%), SSIs (4.1%), and BSIs (2.6%). Women were at 29% greater risk, Blacks had 23% greater risk, and HAI risk increased 11% with each 5 year increase in age. PCI was the only protective major procedure (OR 0.81, 95% CI, 0.69-0.95, p < .05). HAI lengthened hospital stays. STEMI patients with a BSI were almost 5 times more likely (31.3% vs. 6.5%, p < .0001), and those with pneumonia were 3 times more likely (19.6% vs. 6.5%, p < .0001) to die before discharge. CONCLUSIONS: The protective effect of PCI on risk of infection is likely mediated by its many benefits, including reduced length of hospitalizations.

The Increase in Paraoxonase 1 Is Associated With Decrease in Left Ventricular Volume in Kidney Transplant Recipients.

Background: Patients on dialysis have impaired cardiac function, in part due to increased fluid volume and ventricular stress. Restored kidney function through transplantation reduces left ventricular volume in both systole and diastole. We previously reported that the decrease in NT-proB-type natriuretic peptide (NT-proBNP) was associated with a decrease in adiponectin. Paraoxonase 1 (PON1) has been inversely associated with cardiovascular outcomes. We now report the association of changes in PON1 with changes in left ventricular volume and left ventricular mass after kidney transplantation. Design: Patients on dialysis were assessed at baseline and 12 months after kidney transplantation (n = 38). A comparison group of patients on dialysis who were not expected to receive a transplant in the next 24 months were studied (n = 43) to determine if the change of PON1 with kidney transplantation achieved a significance greater than that due to biologic variation. Left ventricular volume and mass were determined by cardiac magnetic resonance imaging. PON1 was measured by arylesterase activity and by mass. Results: PON1 mass and activity were not different between the groups at baseline. Both PON1 mass and activity were increased post-kidney transplantation (p < 0.0001 for change). The change in PON1 mass (p = 0.0062) and PON1 arylesterase activity (p = 0.0254) were inversely correlated with the change in NT-proBNP for patients receiving a kidney transplant. However, only the change in the PON1 mass, and not the change in PON1 arylesterase, was inversely correlated with the change in left ventricular volume (ml/m2.7) (p = 0.0146 and 0.0114 for diastolic and systolic, respectively) and with the change in hemoglobin (p = 0.0042). Conclusion: Both PON1 mass and arylesterase activity are increased by kidney transplantation. The increase in PON1 mass is consistent with a novel relationship to the increase in hemoglobin and decrease in left ventricular volume and NT-proBNP seen when kidney function is restored.

Retrospective Analysis of Tacrolimus Intrapatient Variability as a Measure of Medication Adherence.

BACKGROUND: Increased intrapatient variability (IPV) in tacrolimus levels is associated with graft rejection, de novo donor-specific antibodies, and graft loss. Medication nonadherence may be a significant contributor to high IPV. OBJECTIVE: The objective of this study is to determine the utility of tacrolimus IPV in detecting nonadherence by examining the relationship between self-reported adherence and tacrolimus coefficient of variability (COV), a measure of IPV. DESIGN: Retrospective cohort study. SETTING: St. Michael's Hospital, Toronto, Ontario. PATIENTS: All patients who were at least 1-year post-kidney transplant as of March 31, 2019, prescribed tacrolimus as an immunosuppressant and had a self-reported adherence status. Patients were excluded from the primary analysis of examining the correlation between COV and self-reported adherence if they lacked a calculatable COV. MEASUREMENTS: Self-reported adherence, COV, demographic data, transplant, and medication history. METHODS: A modified Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) administered by healthcare professionals to assess self-reported adherence was used. The COV of tacrolimus trough levels was calculated and its correlation to BAASIS response was noted. The median COV was used as a cutoff to examine the characteristics of patients deemed "high COV" and "low COV." RESULTS: A total of 591 patients fit the initial criteria; however, only 525 had a recent calculatable COV. Overall, 92.38% of the population were adherent by self-report. Primary analysis identified a COV of 25.2% and 29.6% in self-reported adherent and nonadherent patients, respectively, though the result was not significant (P = .2). Secondary analyses showed a significant correlation between younger age at transplant and at the time of adherence self-reporting with nonadherence (P = .01). In addition, there was a strong correlation between those nonadherent with routine post-transplant blood work and younger age (P < .01). LIMITATIONS: The limitations included modified nonvalidated BAASIS questionnaire, social desirability bias, BAASIS only administered in English, and patients with graft failure not active in clinic not being captured. CONCLUSIONS: The COV should not be used as the sole method for determining medication adherence. However, COV may have some utility in capturing individuals who are not adherent to their blood work or patients who are having a poor response to tacrolimus and should be switched to another medication.

CONTEXTE: Une plus grande variabilité intra-individuelle des taux de tacrolimus est associée au rejet de la greffe, aux anticorps spécifiques au donneur de novo et à la perte du greffon. La non-observance du traitement médicamenteux pourrait être un facteur important de cette variabilité élevée. OBJECTIF: L'objectif de cette étude était d'évaluer la pertinence de la variabilité intra-individuelle des taux de tacrolimus pour la détection de la non-observance en examinant la relation entre l'observance autodéclarée et le coefficient de variabilité (CoV) du tacrolimus, une mesure de la variabilité intra-individuelle. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: L'hôpital St Michael's de Toronto (Ontario). SUJETS: Tous les patients qui, au 31 mars 2019, avaient subi une transplantation depuis au moins un an, à qui on avait prescrit du tacrolimus comme immunosuppresseur et qui déclaraient adhérer à leur traitement. Les patients qui ne disposaient pas d'un CoV calculable ont été exclus de l'analyse principale examinant la corrélation entre le CoV et l'observance autodéclarée. MESURES: L'observance autodéclarée, le CoV, les données démographiques, ainsi que les antécédents de transplantation et pharmaceutiques des patients. MÉTHODOLOGIE: Une version modifiée du questionnaire BAASIS (Basel Assessment of Adherence to Immunosuppressive Medications Scale) administrée par les professionnels de la santé a été employée pour évaluer l'observance autodéclarée. Le CoV des concentrations minimales de tacrolimus a été calculé et sa corrélation avec les réponses au questionnaire BAASIS a été notée. Le CoV médian a été employé comme mesure limite pour examiner les caractéristiques des patients réputés avoir un « CoV élevé ¼ ou un « CoV faible ¼. RÉSULTATS: Au total, 591 patients satisfaisaient aux critères initiaux, mais seulement 525 disposaient d'une mesure récente et calculable du CoV. Dans l'ensemble, 92,38 % de la population étudiée déclarait adhérer au traitement. L'analyse primaire a permis d'établir le CoV à 25,2 % chez les patients adhérents et à 29,6 % chez les patients non-adhérents; bien que les résultats n'aient pas été jugés significatifs (p = 0,2). Les analyses secondaires ont montré une corrélation significative entre la non-observance autodéclarée au traitement et le fait d'être plus jeune au moment de la transplantation (p = 0,01). On a en outre observé une forte corrélation entre la non-observance des bilans sanguins habituels post-transplantation et un plus jeune âge (p < 0,01). LIMITES: La version modifiée du questionnaire BAASIS n'a pas été validée, l'étude comporte de possibles biais de désirabilité sociale, le questionnaire BAASIS n'a été passé qu'en anglais et les patients avec échec de la greffe qui étaient inactifs en clinique n'ont pu être saisis. CONCLUSION: Le coefficient de variabilité ne devrait pas être le seul élément à considérer pour déterminer l'adhérence au traitement. Ce coefficient peut cependant avoir une certaine utilité pour repérer les patients qui ne font pas leurs bilans sanguins ou les patients qui répondent peu au tacrolimus et qui devraient passer à un autre médicament.

Vitamin D Levels and the Risk of Posttransplant Diabetes Mellitus After Kidney Transplantation.

INTRODUCTION: Given the burden of posttransplant diabetes mellitus and the high prevalence of low vitamin D levels in kidney transplant recipients, it is reasonable to consider vitamin D as a novel and potentially modifiable risk factor in this patient population. RESEARCH QUESTION: To determine the association between 25- hydroxyvitamin D (25(OH)D) level and posttransplant diabetes among kidney transplant recipients. Design: In a multi-center cohort study of 442 patients who received a kidney transplant between January 1, 2005 and December 31, 2010, serum samples within one-year before transplant were analyzed for 25(OH)D levels. The association between 25(OH)D and posttransplant diabetes were examined in Cox proportional hazard models. RESULTS: The median 25(OH)D level was 66 nmol/L. The cumulative probability of diabetes at 12-months by quartiles of 25(OH)D (< 42, 42 to 64.9, 65 to 94.9, and > 95 nmol/L) were 23.4%, 26.9%, 21.4%, and 15.6%, respectively. Compared to the highest 25(OH)D quartile, hazard ratios (95% CI) for the risk were 1.85 (1.03, 3.32), 2.01 (1.12, 3.60), 1.77 (0.96, 3.25) across the first to third quartiles, respectively. The associations were accentuated in a model restricted to patients on tacrolimus. When modeled as a continuous variable, 25(OH)D levels were significantly associated with a higher risk of diabetes (hazard ratio 1.06, 95% CI: 1.01, 1.13 per 10 nmol/L decrease). DISCUSSION: Serum 25(OH)D was an independent predictor of posttransplant diabetes in kidney transplant recipients. These results may inform the design of trials using vitamin D to reduce the risk in kidney transplant recipients.

Evaluation of left atrial remodeling in kidney transplant patients using cardiac magnetic resonance imaging.

BACKGROUND: Increased left atrial (LA) size predicts cardiovascular events in patients with end-stage kidney disease. There is a paucity of data on LA changes after kidney transplantation (KT). Accordingly, we used cardiac magnetic resonance imaging (CMR) to evaluate LA remodeling after KT, and examined its relationship with left ventricular (LV) measurements, blood pressure and cardiac biomarkers. METHODS: In this prospective multi-center cohort study, 39 pre-transplant dialysis patients underwent KT and 42 eligible transplant recipients remained on dialysis. CMR, blood pressure and serum measurements for N-terminal pro b-type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), and growth differentiation factor-15 (GDF-15) were performed at baseline and 12 months. RESULTS: After 12 months, there were no significant changes in LA end-systolic volume index, LA end-diastolic volume index, or LA ejection fraction (LAEF) within the KT or dialysis group; changes over time did not differ between the 2 groups (all p > 0.25). At baseline and over 12 months, LA volumes and LAEF positively correlated with LV volumes and mass while LAEF positively correlated with LV function. Changes in LA volumes also positively correlated with NT-proBNP and systolic blood pressure (sBP) while LAEF negatively correlated with NT-proBNP. GDF-15 correlated with LA measurements at baseline but not in 12-month changes. hsCRP did not correlate with any LA measurements. CONCLUSIONS: LA volumes and function as measured by CMR did not change significantly over 12 months post-KT. There were significant associations between LA and LV remodeling, NT-proBNP and sBP, suggesting common underlying pathophysiological mechanisms.

Cardiac MRI assessment of the right ventricle pre-and post-kidney transplant.

Worsening renal function in chronic kidney disease correlates with worsening right ventricular (RV) systolic function. We evaluated the association between kidney transplantation (KT) and RV structure and systolic function, and the relationships between RV and left ventricular (LV) changes, blood pressure, and specific cardiac biomarkers, in patients with end-stage kidney disease using cardiac magnetic resonance imaging (CMR). In this prospective, multi-centre, cohort study, 39 adult patients on dialysis receiving KT and 42 patients eligible for, but not yet receiving KT, were recruited. CMR was performed at baseline, and repeated at 12 months. Among 81 patients (mean age 51 years, 30% female), RV end-diastolic volume index (RVEDVi), end-systolic volume index (RVESVi), mass index (RVMi), and ejection fraction (RVEF) did not change significantly within either the dialysis or KT group over 12 months (all p ≥ 0.10). There were no significant differences in the 12-month changes of these parameters between the dialysis and KT groups (all p ≥ 0.10). RVMI demonstrated positive correlations with NT-proBNP and systolic blood pressure, but not GDF-15, at baseline and at 12 months. Changes in RVEDVi, RVESVi, and RVEF were positively correlated with changes in LVEDVi, LVESVi, and LVEF, respectively over 12 months (Spearman r = 0.72, 0.52, and 0.41; all p < 0.001), but not mass index (Spearman r = 0.20, p = 0.078). In conclusion, there were no significant changes in RV mass, volumes, or systolic function 12 months after KT, as compared with continuation of dialysis. The associations between RV and LV remodeling may suggest similar underlying pathophysiologic mechanisms.

Twenty four-hour ambulatory blood pressure profiles 12 months post living kidney donation.

Summary Small blood pressure (BP) elevations may occur post kidney donation. This prospective study determined 24-h ambulatory BP (ABP) and other cardiovascular risk factor changes in 51 living donors over 12 months postdonation. Donors also provided 24-h urine collections for monitoring protein and creatinine clearance, 75 g oral glucose tolerance tests (OGTT), and fasting lipids. Nondipping was defined as night-day systolic (SBP) ratio >or=0.9. Baseline and 12-month pre to postdonation comparisons were made both for dippers and nondippers. Of 51 donors, 35 were dippers and 16 nondippers. In these two groups, predonation 24-h SBP were 115.2 +/- 8 and 115.6 +/- 10 mmHg; serum creatinine (SCr) 69.3 +/- 12 and 71.1 +/- 13 micromol/l; and 24-h urine protein 0.12 +/- 0.05 and 0.09 +/- 0.03 g (all P = NS) while at 12 months, 24-h SBP were 111.4 +/- 11 and 114.3 +/- 8 mmHg (P = 0.384), SCr 97.9 +/- 16 and 97.7 +/- 21 micromol/l (P = 0.810); and 24-h urine protein 0.139 +/- 0.09 and 0.111 +/- 0.07 g/d (P = 0.360) respectively. The 24-h SBP was significantly lower in the dippers at 12 months as compared with predonation (P = 0.036). OGTT and lipid profiles remained normal in both groups. Predonation nocturnal nondipping does not carry adverse postdonation consequences over 12 months.

A quality of life comparison in cyclosporine- and tacrolimus-treated renal transplant recipients across Canada.

BACKGROUND: Many Canadian renal transplant recipients receive either cyclosporine or tacrolimus as a long-term immunosuppressive agent. We investigated the effect of these drugs on quality of life (QoL) in Canadian transplant recipients. METHODS: We included adult single-organ recipients undergoing a transplant between July 1997 and March 2005, whose graft function was =18 months, recruited across 13 Canadian sites including 5 transplant centers (TCs) and 8 satellite centers (SCs). Patients were stratified 3:1 by cyclosporine vs. tacrolimus based on calcineurin inhibitor(s) (CNIs) received at 6 months posttransplant and matched 1:1 by TC vs. SC. Physical (PCS) and mental component summary (MCS) scores measured by the SF-12 scale for cyclosporine- and tacrolimus-treated recipients were compared. Patient opinions about their perceived CNI-related side effects captured by categorical questions or a numerical Likert scale (1-10) were compared by chi-square test or ANOVA, respectively. RESULTS: There were 231 participants (124 cyclosporine, 43 tacrolimus and 64 with dual experience) who responded to both questionnaires. Their SF-12-measured PCS and MCS scores were similar (PCS 42.0, 43.0 and 41.4, p=0.705; MCS 50.3, 47.8 and 47.1, p=0.115; respectively). However, patients receiving tacrolimus more strongly preferred to continue on this CNI than those receiving cyclosporine (67.4% vs. 44.4%, p=0.009), while more patients on cyclosporine wished to stop taking it (23.4 vs. 2.3%, p=0.004). Patient preference for CNI did not differ by center type. CONCLUSION: QoL among Canadian renal transplant recipients receiving cyclosporine or tacrolimus is similar. Although Canadian recipients prefer tacrolimus, CNI type does not significantly affect their QoL.

Validation of the Kidney Failure Risk Equation in Kidney Transplant Recipients.

BACKGROUND: Predicting allograft failure in kidney transplant recipients can help plan renal replacement therapy and guide patient-provider communication. The kidney failure risk equation (KFRE) accurately predicts the need for dialysis in patients with chronic kidney disease (CKD), but has not been validated in kidney transplant recipients. OBJECTIVE: We sought to validate the 4-variable KFRE (age, sex, estimated glomerular filtration rate [eGFR], and urine albumin-to-creatinine ratio [ACR]) for prediction of 2- and 5-year death-censored allograft failure. DESIGN: Retrospective cohort study. SETTING: Four independent North American Cohorts from Ontario, Canada; Alberta, Canada; Manitoba, Canada; and Wisconsin, United States, between January 1999 and December 2017. PATIENTS: Adult kidney transplant patients at 1-year posttransplantation. MEASUREMENTS: Kidney failure risk as measured by the KFRE (eGFR, urine ACR, age, and sex). METHODS: We included all adult patients who had at least 1 serum creatinine and at least 1 urine ACR measurement approximately 1 year following kidney transplantation. The performance of the KFRE was evaluated using the area under the receiver operating characteristic curve (C-statistic). C-statistics from the 4 cohorts were meta-analyzed using random-effects models. RESULTS: A total of 3659 patients were included. Pooled C-statistics were good in the entire population, at 0.81 (95% confidence interval: 0.72-0.91) for the 2-year KFRE and 0.73 (0.67-0.80) for the 5-year KFRE. Discrimination improved among patients with poorer kidney function (eGFR < 45 mL/min/1.73 m2), with a C-statistic of 0.88 (0.78-0.98) for the 2-year KFRE and 0.83 (0.74-0.91) for the 5-year KFRE. LIMITATIONS: The KFRE does not predict episodes of acute rejection and there was heterogeneity between cohorts. CONCLUSIONS: The KFRE accurately predicts kidney failure in kidney transplant recipients at 1-year posttransplantation. Further validation in larger cohorts with longer follow-up times can strengthen the case for clinical implementation.

CONTEXTE: En transplantation rénale, la capacité de prévoir la défaillance du greffon permet de planifier une thérapie de remplacement rénal et de guider la communication entre le patient et son soignant. L'équation KFRE (Kidney Failure Risk Equation) permet de prédire avec exactitude si les patients atteints d'insuffisance rénale chronique (IRC) auront éventuellement besoin de dialyse. Cette équation n'a toutefois pas encore été validée dans une population de receveurs d'une greffe rénale. OBJECTIF: Nous souhaitions valider le pouvoir prédictif de l'équation KFRE à 4 variables (âge, sexe, débit de filtration glomérulaire estimé [DFGe] et rapport albumine-créatine urinaire [RAC]) quant à la défaillance du greffon après deux ans et cinq ans. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Quatre cohortes indépendantes d'Amérique du Nord : trois provinces canadiennes (Ontario, Alberta et Manitoba) et un état américain (Wisconsin) entre janvier 1999 et décembre 2017. SUJETS: Des adultes receveurs d'une greffe rénale, un an après l'intervention. MESURES: Le risque d'évolution vers l'insuffisance rénale, tel que mesuré par l'équation KFRE (DFGe, RAC urinaire, âge et sexe). MÉTHODOLOGIE: Ont été inclus tous les patients adultes ayant eu au moins une mesure de la créatinine sérique et du RAC urinaire environ un an après la greffe. La performance de la KFRE a été évaluée par la surface sous la courbe ROC (statistique C). Des modèles à effets aléatoires ont été employés pour la méta-analyse des statistiques C pour les quatre cohortes. RÉSULTATS: Un total de 3 659 patients a été inclus. Les statistiques C regroupées ont été bonnes dans l'ensemble de la population étudiée, avec des valeurs de 0,81 (intervalle de confiance à 95 % : 0,72-0,91) pour la prédiction sur deux ans et de 0,73 (0,67-0,80) pour la prédiction sur cinq ans. La discrimination s'est avérée encore meilleure pour les patients qui présentaient une plus faible fonction rénale (DFGe < 45 ml/min/1,73 m2), avec une statistique C s'établissant à 0,88 (0,78-0,98) pour la prédiction sur deux ans et à 0,83 (0,74-0,91) pour la prédiction sur cinq ans. LIMITES: La KFRE ne peut prédire les épisodes de rejet aigu et les cohortes étudiées comportaient une grande hétérogénéité. CONCLUSION: L'équation KFRE prédit avec exactitude le risque de défaillance du greffon dans notre population de receveurs d'une greffe rénale, un an après l'intervention. Poursuivre la validation dans de plus vastes cohortes et pour des temps de suivi prolongés viendrait appuyer le cas en vue de son application clinique.

Serum Apolipoprotein B and A1 Concentrations Predict Late-Onset Posttransplant Diabetes Mellitus in Prevalent Adult Kidney Transplant Recipients.

BACKGROUND: Glucose metabolism links closely to cholesterol metabolism. Posttransplant diabetes mellitus (PTDM) adversely affects posttransplant outcomes, but its risk factors in relation to cholesterol metabolism have not been fully delineated. The apolipoprotein B/A1 (Apo B/A1) ratio, which is associated with insulin resistance, has not been evaluated in kidney transplant recipients as a risk factor for PTDM. OBJECTIVE: The objective of this study was to determine whether serum apolipoprotein profiles predict late PTDM, defined as a new onset diabetes occurring greater than 3 months posttransplant. DESIGN: Retrospective chart review of a prevalent population of kidney transplant recipients. SETTING: Large transplant center in Ontario, Canada. PATIENTS: We identified 1104 previously nondiabetic adults who received a kidney transplant between January 1, 1998, and December 1, 2015, and were followed at 1 transplant center. MEASUREMENTS: Recipients provided testing for serum apolipoprotein B (Apo B) and apolipoprotein A1 (Apo A1) concentrations from 2010, either at 3 months posttransplant for new transplant recipients or the next clinic visit for prevalent recipients. Late PTDM defined using Canadian Diabetes Association criteria as occurring ≥3 months posttransplant was recorded until May 1, 2016. METHODS: All analyses were conducted with R, version 3.4.0 (The R Foundation for Statistical Computing). Comparisons were made using Student t test, Fisher exact test or chi-square test, Kaplan-Meier methodology with the logrank test, or Cox proportional hazards analysis as appropriate. Covariates for the multivariate Cox proportional hazards models of PTDM as the outcome variable were selected based on significance of the univariate associations and biological plausibility. RESULTS: There were 53 incident late PTDM cases, or 1.71 cases per 100 patient-years. Incident late PTDM differed between the highest and lowest quartiles for Apo B/A1 ratio, 2.47 per 100 patient-years vs 0.88 per 100 patient-years (P = .005 for difference). In multiple Cox regression analysis, first measured serum Apo B/A1 concentration better predicted subsequent PTDM than low-density lipoprotein cholesterol (LDL-C; hazard ratio [HR] = 7.80 per unit increase, P = .039 vs HR = 1.05 per unit increase, P = .774). Non-high-density lipoprotein cholesterol (HDL-C) concentrations also did not predict PTDM (P = .136). By contrast to Apo B, Apo A1 was protective against PTDM in statin users (HR = 0.17 per unit increase, P = .016). LIMITATIONS: Posttransplant diabetes mellitus cases occurring before apolipoprotein testing was implemented were not included in the analysis. CONCLUSIONS: Apolipoproteins B and A1 better predict late PTDM than conventional markers of cholesterol metabolism.

CONTEXTE: Le métabolisme du glucose est étroitement lié à celui du cholestérol. Le diabète sucré post-transplantation (PTDM­Post-Transplant Diabetes Mellitus) compromet l'état de santé après la greffe, mais le risque qu'il représente sur le métabolisme du cholestérol n'est toujours pas clairement défini. Le taux d'apolipoprotéine B/A1 (Apo B/A1), associé à l'insulinorésistance, n'a toujours pas été évalué en tant que facteur de risque pour le PTDM chez les receveurs d'une greffe rénale. OBJECTIF: Cette étude visait à déterminer si les profils sériques de l'apolipoprotéine sont prédicteurs d'un PTDM d'apparition tardive, soit d'un diabète se déclenchant plus de trois mois post-transplantation. TYPE D'ÉTUDE: Une étude rétrospective des dossiers médicaux d'une population prévalente de receveurs d'une greffe rénale. CADRE: Un important centre de transplantation de l'Ontario (Canada). SUJETS: L'étude porte sur 1 104 adultes non-diabétiques ayant subi une greffe rénale entre le 1er janvier 1998 et le 1er décembre 2015 et ayant été suivis dans un centre de transplantation. MESURES: À partir de 2010, les sujets se sont soumis à une épreuve mesurant les concentrations sériques d'Apo B et Apo A1 trois mois post-greffe pour les nouveaux receveurs ou lors de la prochaine consultation en clinique pour les receveurs prévalents. La survenue d'un PTDM d'apparition tardive, soit au minimum trois mois post-greffe selon le critère de l'Association canadienne du diabète, a été enregistrée jusqu'au 1er mai 2016. MÉTHODOLOGIE: Toutes les analyses ont été menées avec le logiciel R (R Foundation for Statistical Computing version 3.4.0). Selon le cas, les comparaisons ont été effectuées par le test t de Student, le test de Fisher exact, le test de chi-deux, la méthode de Kaplan-Meier avec le test de Mantel-Haenzel ou l'analyse de régression aléatoire proportionnelle de Cox. Les covariables du modèle multivarié de régression aléatoire proportionnelle de Cox avec le PTDM comme variable résultat ont été choisies en fonction de l'importance des associations univariées et de la plausibilité biologique. RÉSULTATS: On a répertorié 53 nouveaux cas de PTDM d'apparition tardive, soit 1,71 cas par 100 années-patient. Le nombre de nouveaux cas de PTDM d'apparition tardive différait entre le quartile le plus élevé et le quartile le plus bas pour le taux d'Apo B/A1, avec 2,47 par 100 années-patient et 0,88 par 100 années-patient respectivement (P = 0,005 pour la différence). Selon l'analyse par régression multivariée de Cox, la première mesure de la concentration d'Apo B/A1 s'est avérée un meilleur prédicteur d'un PTDM subséquent que la mesure de LDL-C (RR à 7,80 par augmentation d'une unité pour Apo B/A1, P = 0,039 contre 1,05 par augmentation d'une unité pour LDL-C, P = 0,774). Les taux de cholestérol non HDL n'ont pas non plus prédit un PTDM (P = 0,136). Contrairement à Apo B, Apo A1 protégeait contre le déclenchement d'un PTDM chez les utilisateurs de statines (RR: 0,17 par augmentation d'une unité, P = 0,016). LIMITE: Les cas de PTDM survenus avant que l'épreuve d'apolipoprotéine ne soit mise en œuvre n'ont pas été inclus dans cette analyse. CONCLUSION: Les apolipoprotéines B et A1 ont mieux prédit la survenue du PTDM d'apparition tardive que les marqueurs traditionnels du métabolisme du cholestérol.