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.

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.

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.

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.

Growth differentiation factor 15 is decreased by kidney transplantation.

BACKGROUND: Growth differentiation factor 15 (GDF15) is markedly increased in end-stage kidney disease and has been related to increased mortality in patients on dialysis. We hypothesized that kidney transplantation would decrease both GDF15 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and that GDF-15 decrease relates to post-kidney transplantation allograft function. METHODS: End-stage kidney disease patients on dialysis awaiting a living donor kidney transplantation (n = 39), and those expected to be on the deceased donor waitlist for at least 12 months (n = 43) were enrolled at three transplant centers. Serum GDF15 and NT-proBNP were measured at 0, 3, and 12 months post-kidney transplantation or post-enrollment. Change in serum GDF15 and NT-proBNP concentrations, and their relation to estimated glomerular filtration rate (eGFR) were assessed by non-parametric tests and regression analyses. RESULTS: Median baseline GDF15 was 4744 pg/ml and 5451 pg/ml for the kidney transplantation and dialysis groups, respectively (p = 0.09). Kidney transplantation resulted in a significant decrease in GDF15 (month 12 median 1631 pg/ml, p < 0.0001 vs. baseline), whereas there was no change for the dialysis group (month 12 median 5658 pg/ml, p = 0.31). Post-kidney transplantation NT-proBNP highly correlated with GDF15 (ρ = 0.64, p < 0.0001). GDF15 inversely correlated with post-transplant eGFR for the kidney transplantation group (ρ = -0.42, p = 0.0081). Month 12 NT-proBNP explained 15.8% and 40.1% of the variance in month 12 GDF15 in the dialysis and kidney transplantation groups, respectively. The relationship of GDF15 with eGFR was no longer significant when NT-proBNP was included in the models. CONCLUSIONS: Kidney transplantation significantly decreases serum GDF15 concentrations. The post-kidney transplantation association of GDF15 with NT-proBNP is consistent with a gradient of post- kidney transplantation cardiovascular risk.

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.

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.

Monitoring Kidney Dysfunction in Kugelberg-Welander Syndrome.

BACKGROUND Kugelberg-Welander (K-W) syndrome is a type of spinal muscular atrophy that causes weakness of the hip-girdle muscles. If severe enough, this weakness can confine patients to a wheelchair in adult life. Proteinuria, a manifestation of kidney dysfunction, is associated with disorders of many organ systems. The evaluation of kidney function in the context of K-W syndrome is challenging. CASE REPORT A 45-year-old man with K-W syndrome first diagnosed at 5 years of age developed peripheral edema and was found to have proteinuria under 1 g/24 h. His past history was significant for hypertension for 7 years. He was managed conservatively initially, but over the next year the serum creatinine concentration increased from 18 to 32 µmol/L (0.2 to 0.36 mg/dL). A percutaneous kidney biopsy was performed in the fetal position due to an inability of the patient to lay prone or supine. Minimal change disease (MCD) was diagnosed. Treatment consisted of dietary salt restriction, ramipril, amiloride, and hydrochlorothiazide, while avoiding corticosteroids. The serum creatinine concentration initially returned to the 18-20 µmol/L (0.2-0.22 mg/dL) range with increased fluid intake, but then slowly declined to 6 µmol/L (0.07 mg/dL) over the next 14 years. Muscle strength remained poor. CONCLUSIONS K-W syndrome, when associated with proteinuria, presents novel diagnostic and therapeutic challenges to the latter. The serum creatinine concentration may be unhelpful in assessing kidney function in K-W syndrome. A conservative management approach to MCD is reasonable to minimize comorbidity.

Pre-Transplant Left Ventricular Geometry and Major Adverse Cardiovascular Events After Kidney Transplantation.

BACKGROUND Preventing major adverse cardiovascular events (MACE) after kidney transplantation motivates pre-transplant cardiac evaluation that includes two-dimensional transthoracic echocardiography (TTE). The relationship of relative wall thickness (RWT) to left ventricular mass index (LVMI) in predicting post-transplant MACE is unclear. MATERIAL AND METHODS In this multi-ethnic Canadian single-center cohort study, we identified 1063 adults undergoing pre-transplant TTE within 1 year pre-transplant and with minimum 6 months of post-kidney transplant follow-up for MACE, defined as a composite of coronary revascularization, myocardial infarction, stroke, and cardiac death. Left ventricular hypertrophy (LVH, >131 g/m² in men and >100 g/m² in women) and increased RWT (>0.45) were a priori used to define normal (no LVH, normal RWT), concentric remodeling (no LVH, increased RWT), eccentric hypertrophy (LVH, normal RWT), and concentric hypertrophy (LVH, increased RWT). RESULTS There were 134 MACE over 3577 patient-years of post-transplant follow-up. Both LVH (HR 1.58, p=0.022) and high RWT (HR 1.44, p=0.041) predicted MACE in multivariate survival regression analysis independently of common pre-transplant MACE risk factors. Concentric remodeling, concentric hypertrophy, and eccentric hypertrophy all increased the risk for MACE (4.44, 5.05, and 5.55 events per 100 patient-years, respectively) versus normal echocardiography (2.71 events per 100 patient-years, all p<0.05 for difference). In Cox interactive regression analysis, LVMI and RWT were independently associated with MACE (p=0.015, p=0.025) and significantly interacted (p=0.008). CONCLUSIONS LV geometric parameters beyond LVH alone can assist post-transplant prognostication in kidney transplant candidates.

Determinants of Left Ventricular Characteristics Assessed by Cardiac Magnetic Resonance Imaging and Cardiovascular Biomarkers Related to Kidney Transplantation.

BACKGROUND: Cardiac magnetic resonance (CMR) imaging accurately and precisely measures left ventricular (LV) mass and function. Identifying mechanisms by which LV mass change and functional improvement occur in some end-stage kidney disease (ESKD) patients may help to appropriately target kidney transplant (KT) recipients for further investigation and intervention. The concentration of serum adiponectin, a cardiovascular biomarker, increases in cardiac failure, its production being enhanced by B-type natriuretic peptide (BNP), and both serum adiponectin and BNP concentrations decline posttransplantation. OBJECTIVE: We tested the hypothesis that kidney transplantation alters LV characteristics that relate to serum adiponectin concentrations. DESIGN: Prospective and observational cohort study. SETTING: The study was performed at 3 adult kidney transplant and dialysis centers in Ontario, Canada. PATIENTS: A total of 82 KT candidate subjects were recruited (39 to the KT group and 43 to the dialysis group). Predialysis patients were excluded. MEASUREMENTS: Subjects underwent CMR with a 1.5-tesla whole-body magnetic resonance scanner using a phased-array cardiac coil and retrospective vectorographic gating. LV mass, LV ejection fraction (LVEF), LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV) were measured by CMR pre-KT and again 12 months post-KT (N = 39), or 12 months later if still receiving dialysis (N = 43). LV mass, LVESV, and LVEDV were indexed for height (m2.7) to calculate left ventricular mass index (LVMI), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI), respectively. Serum total adiponectin and N-terminal proBNP (NT-proBNP) concentrations were measured at baseline, 3 months, and 12 months. METHODS: We performed a prospective 1:1 observational study comparing KT candidates with ESKD either receiving a living donor organ (KT group) or waiting for a deceased donor organ (dialysis group). RESULTS: Left ventricular mass index change was -1.98 ± 5.5 and -0.36 ± 5.7 g/m2.7 for KT versus dialysis subjects (P = .44). Left ventricular mass change was associated with systolic blood pressure (SBP) (P = .0008) and average LV mass (P = .0001). Left ventricular ejection fraction did not improve (2.9 ± 6.6 vs 0.7 ± 4.9 %, P = .09), while LVESVI and LVEDVI decreased more post-KT than with continued dialysis (-3.36 ± 5.6 vs -0.22 ± 4.4 mL/m2.7, P < .01 and -4.9 ± 8.5 vs -0.3 ± 9.2 mL/m2.7, P = .02). Both adiponectin (-7.1 ± 11.3 vs -0.11 ± 7.9 µg/mL, P < .0001) and NT-proBNP (-3811 ± 8130 vs 1665 ± 20013 pg/mL, P < .0001) declined post-KT. Post-KT adiponectin correlated with NT-proBNP (P = .001), but not estimated glomerular filtration rate (eGFR) (P = .13). Change in adiponectin did not correlate with change in LVEF in the KT group (Spearman ρ = 0.16, P = .31) or dialysis group (Spearman ρ = 0.19, P = .21). LIMITATIONS: Few biomarkers of cardiac function were measured to fully contextualize their role during changing kidney function. Limited intrapatient biomarker sampling and CMR measurements precluded constructing dose-response curves of biomarkers to LV mass and function. The CMR timing in relation to dialysis was not standardized. CONCLUSIONS: The LVESVI and LVEDVI but not LVMI or LVEF improve post-KT. LVMI and LVEF change is independent of renal function and adiponectin. As adiponectin correlates with NT-proBNP post-KT, improved renal function through KT restores the normal heart-endocrine axis.

CONTEXTE: L'imagerie par résonnance magnétique (IRM) cardiaque mesure avec précision et exactitude la masse et la fonction du ventricule gauche (VG). L'identification des mécanismes par lesquels la variation de la masse et l'amélioration de la fonction du VG se produisent chez certains patients atteints d'insuffisance rénale terminale (IRT) pourrait contribuer à cibler adéquatement les receveurs d'une greffe rénale, en vue d'investiguer et d'intervenir de façon plus poussée. La concentration d'adiponectine sérique, un biomarqueur cardiovasculaire, augmente lors d'une défaillance cardiaque, sa production étant rehaussée par le peptide natriurétique de type B (BNP), et les concentrations d'adiponectine et de BNP diminuent après la transplantation. OBJECTIF: Nous avons testé l'hypothèse selon laquelle la greffe rénale modifierait les caractéristiques du VG et que ceci serait en lien avec la concentration d'adiponectine sérique. TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte observationnelle et prospective. CADRE: L'étude a eu lieu dans trois centres de dialyse et de transplantation rénale pour adultes en Ontario (Canada). SUJETS: Un total de 82 candidats à la greffe ont été recrutés (39 patients dans le groupe transplantation rénale [TR] et 43 sujets dans le groupe de patients dialysés [dialyse]). Les patients en pré-dialyse ont été exclus. MESURES: Les sujets ont été soumis à une IRM à l'aide d'un scanner pour le corps entier de 1,5 Tesla utilisant une bobine cardiaque en réseau phasé et une synchronisation d'images vectographiques rétrospective. La masse du VG, la fraction d'éjection du VG (FEVG), le volume télésystolique du VG (VTSVG) et le volume télédiastolique du VG (VTDVG) ont été mesurés par IRM avant la greffe et 12 mois post-greffe (n=39) ou 12 mois plus tard si le patient était toujours dialysé (n=43). La masse du VG, le VTSVG et le VTDGV ont été indexés pour la taille du patient (m2,7) pour les calculs respectifs de l'indice de masse du VG (IMVG), de l'indice de volume télésystolique du VG (IVTSVG) et de l'indice de volume télédiastolique du VG (IVTDVG). Les concentrations sériques totales d'adiponectine et de NT-proBNP ont été mesurées au début de l'étude, après 3 mois et après 12 mois. MÉTHODOLOGIE: Nous avons procédé à une étude observationnelle prospective comparant, dans un rapport d'un pour un (1:1), des candidats à la greffe rénale atteints d'IRT qui devaient soit recevoir un rein d'un donneur vivant (groupe de TR), soit attendre un organe d'un donneur décédé (groupe de dialyse). RÉSULTATS: Les variations de l'IMVG se situaient à -1,98 ± 5,5 g/m2.7 pour le groupe TR et à -0,36 ± 5,7 g/m2.7 pour le groupe dialysé (p=0,44). Les variations dans la masse du VG ont été associées à la pression artérielle systolique (p=0,0008) et à la masse moyenne du VG (p=0,0001). La FEVG ne s'est pas améliorée (2,9 ± 6,6 % [TR] contre 0,7 ± 4,9 % [dialyse], p=0.09), alors que l'IVTSVG (-3,36 ± 5,6 ml/m2,7 [TR] contre -0,22 ± 4,4 ml/m2,7 [dialyse], p<0,01) et l'IVTDVG (-4,9 ± 8,5 ml/m2,7 [TR] contre -0,3 ± 9,2 ml/m2,7 [dialyse], p=0.02) ont diminué davantage chez les greffés que chez les patients qui poursuivaient la dialyse. L'adiponectine (-7,1 ± 11,3 µg/ml [TR] contre -0,11 ± 7,9 µg/ml [dialyse], p<0,0001) et le NT-proBNP (-3 811 ± 8 130 pg/ml [TR] contre 1 665 ± 20 013 pg/ml [dialyse], p<0,0001) ont diminué après la greffe. Les concentrations d'adiponectine post-greffe ont corrélé avec les taux de NT-proBNP (p=0,001), mais pas avec le débit de filtration glomérulaire estimé (DFGe) (p=0,13). Les variations dans les taux d'adiponectine n'ont pas corrélé avec les changements observés pour la FEVG (coefficient de corrélation des rangs de Spearman = 0,16; p=0,31 [TR] et 0,19; p=0,21 [dialyse]). LIMITES DE L'ÉTUDE: Trop peu de biomarqueurs de la fonction cardiaque ont été mesurés pour permettre de contextualiser pleinement leur rôle lors d'un changement dans la fonction rénale. L'échantillonnage limité de biomarqueurs intra-patients de même que le faible nombre de mesures d'IRM ont empêché l'établissement de courbes dose-réponse des biomarqueurs pour la masse et la fonction du VG. Enfin, la synchronisation de l'IRM par rapport à la dialyse n'était pas standardisée. CONCLUSION: Contrairement à l'IMVG et à la FEVG, l'IVTSVG et l'IVTDVG se sont améliorés après la greffe rénale. Les variations observées pour l'IMVG et la FEVG sont indépendantes de la fonction rénale et de la concentration sérique d'adiponectine. Étant donné que l'adiponectine corrèle avec le NT-proBNP post-greffe, l'amélioration de la fonction rénale par la greffe rétablit l'axe normal cœur-système endocrinien.

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.

The Impact of Total Gastrectomy on Pharmacokinetics in Kidney Transplant Immunosuppressive Drug Regimes: A Case Study.

BACKGROUND: Ensuring reliable gastrointestinal drug absorption of orally administered immunosuppressive medications posttransplant is critical to ensuring graft survival. METHODS: A 66-year-old man of East Asian origin with a previous total gastrectomy was evaluated for living donor kidney transplantation. Pretransplant pharmacokinetic testing was performed to determine the most appropriate posttransplant medication strategy. The Gastrointestinal Quality of Life Index and Gastrointestinal Rating Scale questionnaires were administered to gauge immunosuppressive medication-related side effects in the absence of a stomach. RESULTS: The patient's ability to absorb cyclosporin, tacrolimus (Tac), enteric-coated mycophenolate sodium (EC-MPS) and sirolimus (SRL) in oral dosage forms was well-preserved. Compared to nongastrectomy reference populations, the rate and extent of absorption of SRL and mycophenolic acid from EC-MPS were similar. The absorption of Tac and cyclosporin was greater than expected. Mycophenolate mofetil did not provide mycophenolic acid absorption as well as EC-MPS. The patient had worsened gastrointestinal symptoms with mycophenolate mofetil or EC-MPS in combination with Tac and cyclosporin, but this was not seen with isolated SRL. CONCLUSIONS: This case demonstrates that commonly used postkidney transplantation immunosuppressive regimes may be prescribed after total gastrectomy as long as their limitations are noted.

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.

A comparison of the extended-release and standard-release formulations of tacrolimus in de novo kidney transplant recipients: a 12-month outcome study.

BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.

Paraoxonase 1 Phenotype and Mass in South Asian versus Caucasian Renal Transplant Recipients.

South Asian renal transplant recipients have a higher incidence of cardiovascular disease compared with Caucasian renal transplant recipients. We carried out a study to determine whether paraoxonase 1, a novel biomarker for cardiovascular risk, was decreased in South Asian compared with Caucasian renal transplant recipients. Subjects were matched two to one on the basis of age and sex for a total of 129 subjects. Paraoxonase 1 was measured by mass, arylesterase activity, and two-substrate phenotype assay. Comparisons were made by using a matched design. The frequency of PON1 QQ, QR and RR phenotype was 56%, 37%, and 7% for Caucasian subjects versus 35%, 44%, and 21% for South Asian subjects (χ(2) = 7.72, P = 0.02). PON1 mass and arylesterase activity were not significantly different between South Asian and Caucasian subjects. PON1 mass was significantly associated with PON1 phenotype (P = 0.0001), HDL cholesterol (P = 0.009), LDL cholesterol (P = 0.02), and diabetes status (P < 0.05). Arylesterase activity was only associated with HDL cholesterol (P = 0.003). Thus the frequency of the PON1 RR phenotype was higher and that of the QQ phenotype was lower in South Asian versus Caucasian renal transplant recipients. However, ethnicity was not a significant factor as a determinant of PON1 mass or arylesterase activity, with or without analysis including PON1 phenotype. The two-substrate method for determining PON1 phenotype may be of value for future studies of cardiovascular complications in renal transplant recipients.

Lower total and percent of high-molecular-weight adiponectin concentration in South Asian kidney transplant recipients.

BACKGROUND: Ethnicity is an important determinant of post-renal transplant outcomes. Limited data are available on cardiovascular risk differences in kidney transplant recipients (KTR) based on ethnicity. METHODS: A group of 129 clinically stable age-matched KTR [43 South Asian (SA), 86 Caucasian]) were assessed for plasma total and high-molecular-weight (HMW) adiponectin, cystatin C, apolipoproteins A1 and B, C-reactive protein, uric acid, urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR) and transplant-specific plus traditional Framingham risk factors. SA and Caucasians were compared by t-tests, Wilcoxon rank-sum or chi-square testing. Accounting for the matched design, multivariable linear regression was performed to determine predictors of adiponectin concentrations. RESULTS: SA did not differ from Caucasians in background cardiac disease or cardioprotective medication use or risk factors other than smoking (26 versus 56%, P = 0.001). Total adiponectin (9.5 ± 3.5 versus 12.9 ± 6.7 µmg/mL, P < 0.001) and HMW adiponectin (22 ± 9 versus 29 ± 11%, P < 0.001) were significantly lower in SA. Determinants of total adiponectin included SA ethnicity (P = 0.02), cystatin C-eGFR (P < 0.001), high-density lipoprotein (HDL) cholesterol (P < 0.0001) and waist-to-hip ratio (P < 0.001), while those of HMW adiponectin included SA ethnicity (P < 0.001), cystatin C-eGFR (P = 0.03) and HDL cholesterol (P = 0.001). There were no important differences in the other measured biomarkers. CONCLUSION: Total and HMW adiponectin concentrations are lower in SA KTR and may be promising exploratory biomarkers of post-transplant cardiovascular risk.

Framingham risk score and novel cardiovascular risk factors underpredict major adverse cardiac events in kidney transplant recipients.

BACKGROUND: Framingham Risk Score (FRS) is an insufficient cardiovascular event predictor in unselected kidney transplant recipients. Its role in different risk subgroups and the value of adding novel risk factor candidates to FRS is unknown. METHODS: We reviewed patients who underwent transplantation from 1998 to 2008 with minimum 3 months graft function, determining FRS-ascertained 10-year risk at 3 months along with relevant clinical and laboratory information. Major adverse cardiac events (MACE) (myocardial infarction, coronary artery revascularization, or cardiac death) 3 months posttransplant were captured. Time-to-MACE multivariate Cox modeling with FRS and novel risk factors (C-reactive protein, uric acid, urine albumin-to-creatinine ratio) as independent variables was performed. RESULTS: Of 956 patients, 89 experienced MACE (2.17 events/100 patient-years). FRS-predicted 10-year risk was 14.7% ± 10.0% in males with and 9.2% ± 8.2% in those without subsequent MACE (P < 0.0001), although FRS substantially underestimated MACE (actual-to-predicted event ratio 1.2-8.4 in different subgroups, all P < 0.0001). Although patients with MACE had a higher C-reactive protein (5.4 ± 6.0 vs. 3.8 ± 2.5 mg/L, P = 0.026) and uric acid (417 ± 109 vs. 386 ± 101 µmol/L, P = 0.012) level as well as lower 3-month estimated glomerular filtration rate (50.1 ± 20.1 vs. 54.8 ± 18.3 mL/min/1.73 m(2), P = 0.022), only FRS more than or equal to 10% (hazard ratio 2.313, 95% confidence interval 1.49-3.58, P = 0.0002) and estimated glomerular filtration rate less than 50 mL/min/1.73 m(2) (hazard ratio 2.291, 95% confidence interval 1.06-4.94, P = 0.034) predicted MACE in multivariate analysis. Adding novel risk factors to FRS did not improve FRS prediction. CONCLUSION: FRS substantially underpredicts MACE in kidney transplant recipients among all risk subgroups. Commonly available novel risk factors do not improve FRS predictive value.

South Asian ethnicity as a risk factor for major adverse cardiovascular events after renal transplantation.

BACKGROUND AND OBJECTIVES: South Asians (SAs) comprise 25% of all Canadian visible minorities. SAs constitute a group at high risk for cardiovascular disease in the general population, but the risk in SA kidney transplant recipients has never been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cohort study of 864 kidney recipients transplanted from 1998 to 2007 and followed to June 2009, we identified risk factors including ethnicity associated with major cardiac events (MACEs, a composite of nonfatal myocardial infarction, coronary intervention, and cardiac death) within and beyond 3 months after transplant. Kaplan-Meier methodology and multivariate Cox regression analysis were used to determine risk factors for MACEs. RESULTS: There was no difference among SAs (n = 139), whites (n = 550), blacks (n = 65), or East Asians (n = 110) in baseline risk, including pre-existing cardiac disease. Post-transplant MACE rate in SAs was 4.4/100 patient-years compared with 1.31, 1.16, and 1.61/100 patient-years in whites, blacks, and East Asians, respectively (P < 0.0001 versus each). SA ethnicity independently predicted MACEs along with age, male gender, diabetes, systolic BP, and prior cardiac disease. SAs also experienced more MACEs within 3 months after transplant compared with whites (P < 0.0001), blacks (P = 0.04), and East Asians (P = 0.006). However, graft and patient survival was similar to other groups. CONCLUSIONS: SA ethnicity is an independent risk factor for post-transplant cardiac events. Further study of this high-risk group is warranted.

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.