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Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients.
Bostom, A, Pasch, A, Madsen, T, Roberts, MB, Franceschini, N, Steubl, D, Garimella, PS, Ix, JH, Tuttle, KR, Ivanova, A, et al
American journal of nephrology. 2018;(1):21-31
Abstract
BACKGROUND "T50," shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. METHODS The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. RESULTS During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20-2.89); fetuin-A, (HR 2.25; 95% CI 1.38-3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. CONCLUSIONS Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.
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Calciphylaxis in end-stage liver and renal disease patients before and after transplant.
Couri, T, Stier, M, Mikolajczyk, A, Aronsohn, A
Clinical transplantation. 2018;(6):e13272
Abstract
Calciphylaxis is a rare vascular disorder characterized by calcification of arterioles which causes tissue inflammation and necrosis. It is associated with the metabolic disturbances seen in end-stage renal disease (ESRD) and has also been described in patients with cirrhosis with preserved kidney function. Characteristic calciphylaxis lesions are black eschars surrounded by retiform purpura, and the gold standard for diagnosis is skin biopsy. Reported 1-year mortality rates range between 45% and 80%. No treatment modality has been evaluated in a prospective randomized trial, and reports of treatment efficacy vary. Kidney transplant has been reported as a successful therapy for calciphylaxis; however, cases exist of the initial onset of calciphylaxis following kidney transplant as well as simultaneous liver-kidney (SLK) transplant. The decision to maintain a patient with end-stage renal and liver disease on the waiting list for SLK transplant following the onset of calciphylaxis must consider the high 1-year mortality associated with this condition. More research is necessary to understand how to allocate donor allografts to manage patients with calciphylaxis and ESRD and/or cirrhosis effectively.
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Is there relationship between epicardial fat and cardiovascular parameters in incident kidney transplant patients? A post-hoc analysis.
Yazbek, DC, Carvalho, AB, Barros, CS, Medina Pestana, JO, Rochitte, CE, Dos Santos Filho, RD, Canziani, MEF
PloS one. 2018;(2):e0191009
Abstract
BACKGROUND Epicardial fat (EF) has been related to increased cardiovascular risk in chronic kidney disease patients. Kidney transplantation is associated with weight gain, especially within the first 12 months. Recently an association between EF and left ventricular mass (LVM) has been suggested in kidney transplant (KTX) recipients. OBJECTIVE Evaluate the EF in KTX recipients and its association with cardiovascular parameters in a 12-month follow-up study. METHODS EF volume was determined using thoracic computed tomography. The EF progressor group (EF gain) was defined by any increment in EF after 12 months. LVM and LVM index were calculated by echocardiography. RESULTS Ninety-eight incident KTX patients [57% men, 41.2 ± 10.1 years, mean dialysis time prior to transplant of 24 (11-60) months] were analyzed. At baseline and after 12 months, EF was 318.6 (275.2-392.6) ml and 329.5 (271.7-384.8) ml, respectively (p = 0.03). When compared to patients who EF decreased (n = 33), those with EF gain (n = 65) had a greater increase of body mass index, abdominal circumference and blood glucose. These patients also had a lower reduction of LVM index. However in the multivariate analysis, there was no difference in LVM index change between groups (interaction p = 0.565), even after adjustment for hypertension, glucose and coronary calcium score (interaction p = 0.538). CONCLUSION The impact of EF gain on ventricular mass after KTX could not be definitely confirmed. Further prospective studies in a large sample of KTX patients should be considered to address a possible causal relationship between EF gain and cardiac hypertrophy in this population.
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4.
Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients.
Erro, R, Bacchin, R, Magrinelli, F, Tomei, P, Geroin, C, Squintani, G, Lupo, A, Zaza, G, Tinazzi, M
Journal of neurology. 2018;(7):1676-1683
Abstract
INTRODUCTION Tremor is the most frequent and disabling neurological side effect under Calcineurin inhibitor-induced immunosuppression, but no studies have defined its phenomenology, severity, distribution, the impact on quality of life, as well as of other neurological symptoms associated. METHODS 126 consecutive kidney-transplanted patients, under treatment with Cyclosporin A, Tacrolimus and non-Calcineurin inhibitors, within therapeutic range, were enrolled. Participants underwent a deep neurological examination by two blinded to the treatment raters, and a blood sampling to assess plasmatic immunosuppressant level and nephrological function tests. Tremor and cerebellar signs were scored according to the Fahn-Tolosa-Marin and the SARA scale. Parkinsonism was excluded applying the UPDRS (part III). RESULTS Tremor was more common and severe in the Tacrolimus group, similar to impairment in ADL. Regardless of treatment, tremor involved both upper and lower limbs and was activated by action, but in about 50% of cases presented in action and rest condition. Plasmatic level of Tacrolimus was higher in patients with tremor than in those without, while cholesterol was significantly lower. Cerebellar and neuropathic signs were overall mild and were not significantly different across the three groups comparing patients with and without tremor. CONCLUSIONS Non-Calcineurin inhibitors such as Sirolimus have the lowest propensity to induce tremor and with a milder severity, while Calcineurin inhibitors, especially Tacrolimus, the highest, and regardless of the formulation. Plasmatic concentration of Tacrolimus was higher in tremulous patients; further research needs to validate the role of cholesterol plasmatic concentration in predicting the occurrence of tremor in patients on Tacrolimus.
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Efficacy and Safety of Different Bisphosphonates for Bone Loss Prevention in Kidney Transplant Recipients: A Network Meta-Analysis of Randomized Controlled Trials.
Yang, Y, Qiu, S, Tang, X, Li, XR, Deng, LH, Wei, Q, Fu, P
Chinese medical journal. 2018;(7):818-828
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Abstract
BACKGROUND Mineral and bone disorder is one of the severe complications in kidney transplant recipients (KTRs). Previous studies showed that bisphosphonates had favorable effects on bone mineral density (BMD). We sought to compare different bisphosphonate regimens and rank their strategies. METHODS We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 01, 2017, for randomized controlled trials (RCTs) comparing bisphosphonate treatments in adult KTRs. The primary outcome was BMD change. We executed the tool recommended by the Cochrane Collaboration to evaluate the risk of bias. We performed pairwise meta-analyses using random effects models and network meta-analysis (NMA) using Bayesian models and assessed the quality of evidence. RESULTS A total of 21 RCTs (1332 participants) comparing 6 bisphosphonate regimens were included. All bisphosphonates showed a significantly increased percentage change in BMD at the lumbar spine compared to calcium except clodronate. Pamidronate with calcium and Vitamin D analogs showed improved BMD in comparison to clodronate with calcium (mean difference [MD], 9.84; 95% credibility interval [CrI], 1.06-19.70). The combination of calcium and Vitamin D analogs had a significantly lower influence than adding either pamidronate or alendronate (MD, 6.34; 95% CrI, 2.59-11.01 and MD, 6.16; 95% CrI, 0.54-13.24, respectively). In terms of percentage BMD change at the femoral neck, both pamidronate and ibandronate combined with calcium demonstrated a remarkable gain compared with calcium (MD, 7.02; 95% CrI, 0.30-13.29 and MD, 7.30; 95% CrI, 0.32-14.22, respectively). The combination of ibandronate with calcium displayed a significant increase in absolute BMD compared to any other treatments and was ranked best. CONCLUSIONS Our NMA suggested that new-generation bisphosphonates such as ibandronate were more favorable in KTRs to improve BMD. However, the conclusion should be treated with caution due to indirect comparisons.
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Low 5-year cumulative incidence of post-transplant lymphoproliferative disorders after solid organ transplantation in Switzerland.
Steiner, R, Kridel, R, Giostra, E, McKee, T, Achermann, R, Mueller, N, Manuel, O, Dickenmann, M, Schuurmans, MM, de Leval, L, et al
Swiss medical weekly. 2018;:w14596
Abstract
BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of transplantation occurring in the setting of immunosuppression and oncogenic viral infections. However, little is known about the cumulative incidence, histological subtypes, risk determinants and outcome of PTLD in solid organ transplant (SOT) recipients in Switzerland. METHODS This retrospective observational study investigated adult SOT recipients from two sequential cohorts, the pre-SCTS (Swiss Transplant Cohort Study) series, with data collected from January 1986 to April 2008, and the STCS series, with data collected from May 2008 to December 2014 in Switzerland. SOT recipients were cross-referenced with the data of all the patients with a lymphoma diagnosis in each transplant centre and with the data of the Swiss Transplant Cohort Study (STCS) to determine the cumulative incidence of PTLD, pre-therapeutic clinical features, clinical course and outcome. Kaplan-Meier analysis was performed for overall survival after PTLD. RESULTS We identified 79 cases of PTLD during the study period in the two cohorts: pre-STCS from 1986 to 2008 (n = 62) and STCS from 2008 to 2014 (n = 17). Histological subgroups included: early lesions (pre-STCS n = 2, STCS n = 0); polymorphic PTLD (pre-STCS n = 8, STCS n = 7); monomorphic PTLD (pre-STCS n = 47, STCS n = 10), and Hodgkin's lymphoma (pre-STCS n = 5, STCS n = 0). Median time to PTLD diagnosis was 90 months (range 3-281 months) and 14 months (range 2-59 months) in the pre-STCS and STCS cohorts, respectively. Median follow-up after transplantation was 141 months for the pre-STCS patients and 33 months for the STCS patients. Cumulative incidences of PTLD during the STCS period at 0.5, 1 and 5 years were 0.17% (95% confidence interval 0.07-0.46%), 0.22% (0.09-0.53%) and 0.96% (0.52-1.80%), respectively. For the pre-STCS case series, it was not possible to estimate the incidence rate of PTLD. Survival after PTLD diagnosis was 80% (68-87%) at 1 year and 56% (42-68%) at 5 years for the pre-STCS and STCS cohorts combined. CONCLUSIONS At 5 years, the cumulative incidence of PTLD, regardless of the organ transplanted, was only 0.96% in the STCS cohort, which is lower than that reported in the literature.
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Arterial stiffness is associated with visceral fat mass in kidney transplanted patients-A nationwide cohort study.
von Düring, ME, Jenssen, T, Bollerslev, J, Godang, K, Hartmann, A, Åsberg, A
Clinical transplantation. 2018;(8):e13341
Abstract
Arterial stiffness, visceral fat, and hyperglycemia are acknowledged risk factors for adverse outcomes after transplantation, but whether arterial stiffness is associated with visceral adipose tissue and hyperglycemia is unknown. We studied 162 non-diabetic kidney transplant recipients 8-10 weeks after transplantation. Arterial stiffness was measured as pulse wave velocity (PWV) by SphygmoCor and visceral fat using a validated software applied on DXA scans. Also a standard oral glucose tolerance test was performed. Median PWV was 8.6 m/s (IQR 7.3-10.4 m/s). Patients in the upper quartile of PWV had 31%-106% higher visceral fat percentage (P < 0.001), they were older (P < 0.001) and had a fasting plasma glucose of 5.8 mmol/L that was higher than in the other quartiles (P = 0.006). In univariate analysis, visceral fat percentage and age were the parameters strongest associated with PWV (P < 0.001), but cholesterol and glucose were also significant (P < 0.05). In multivariate analysis, visceral fat was the only significant predictor of PWV along with age (P < 0.001). In conclusion, arterial stiffness is significantly associated with visceral fat but not hyperglycemia in non-diabetic kidney transplant patients. We identified age and VAT as risk variables for arterial stiffness. A potential reversibility of arterial wall stiffness with reduction in VAT needs further study.
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The Associations of Endotoxemia With Systemic Inflammation, Endothelial Activation, and Cardiovascular Outcome in Kidney Transplantation.
Chan, W, Bosch, JA, Phillips, AC, Chin, SH, Antonysunil, A, Inston, N, Moore, S, Kaur, O, McTernan, PG, Borrows, R
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2018;(1):13-27
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Abstract
OBJECTIVE Cardiovascular disease is the leading cause of death in kidney transplant recipients (KTRs), yet incompletely accountable by traditional risk factors. Inflammation is an unconventional cardiovascular risk factor, with gut-derived endotoxemia potentially driving inflammation and endothelial disease. Comparable data are lacking in kidney transplantation. This study investigated the associations of endotoxemia with inflammation, endothelial activation, and 5-year cardiovascular events in KTRs. Determinants of endotoxemia were also explored. DESIGN AND METHODS This is a single-center cross-sectional study with prospective follow-up from a prevalent cohort of 128 KTRs. MAIN OUTCOME MEASURES Demographic, nutritional and clinical predictors of inflammation (high-sensitivity C-reactive protein [hsCRP]), endothelial activation (sE-selectin), and endotoxemia (endotoxin) were assessed. Follow-up data on 5-year cardiovascular event rates were collected. RESULTS Endotoxemia (P = .03), reduced 25-hydroxyvitamin D (P = .04), high fructose intake (P < .001), decreased fiber intake (P < .001), and abdominal obesity (P = .002) were independently associated with elevated hsCRP. In turn, endotoxemia (P = .007) and increasing hsCRP (P = .02) were both independently associated with raised sE-selectin. Furthermore, endotoxemia predicted increased cardiovascular event rate (P = .02), independent of hsCRP and a global measure of cardiovascular risk estimated by a validated algorithm of 7-year risk for major adverse cardiac events in kidney transplantation. Determinants of endotoxemia included reduced 25-hydroxyvitamin D (P < .001), hypertriglyceridemia (P < .001), increased fructose intake (P = .01), and abdominal obesity (P = .01). CONCLUSIONS Endotoxemia in KTRs contributes to inflammation, endothelial activation, and increased cardiovascular events. This study highlights the clinical relevance of endotoxemia in KTRs, suggesting future interventional targets.
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Hypertension guidelines: How do they apply to kidney transplant recipients.
Aziz, F, Clark, D, Garg, N, Mandelbrot, D, Djamali, A
Transplantation reviews (Orlando, Fla.). 2018;(4):225-233
Abstract
Hypertension is common among kidney transplant recipients and may result from traditional risk factors or transplant specific variables, which commonly include donor associated causes, immunosuppression, or transplant renal artery stenosis. Uncontrolled blood pressure in this patient population is associated with increased cardiovascular mortality and morbidity, and decreased graft survival. Despite these negative associations, there are no randomized controlled trials looking at the optimal blood pressure targets and identifying the best antihypertensive regimen for this special patient population. Multiple hypertension guidelines have been published in the last 10 years, but the Kidney Disease: Improving Global Outcomes (KDIGO) and American Society of Transplantation (AST) guidelines are the only to recommended a target blood pressure in kidney transplant recipients. In this manuscript, we will review the available evidence based on randomized clinical trials and large observational studies in kidney transplant recipients. Pending new interventional trials, we believe that: a) a blood pressure target of ≤130/80 is a reasonable goal as suggested by KDIGO; b) the choice of antihypertensive agent should be based on the patients' other comorbidities; and c) achieving good blood pressure control is more important than the choice of the antihypertensive agent; however, the initial choice of antihypertensive medications should be calcium channel blockers, beta-blockers, diuretics, and angiotensin converting enzyme inhibitors/angiotensin receptor blockers as they have all been shown to reduce cardiovascular events in the general population.
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Risk of Colorectal Cancer in Chronic Kidney Disease: A Systematic Review and Meta-Analysis.
Komaki, Y, Komaki, F, Micic, D, Ido, A, Sakuraba, A
Journal of clinical gastroenterology. 2018;(9):796-804
Abstract
BACKGROUND Association between chronic kidney disease and colorectal cancer (CRC) remains unclear. GOALS To assess the risk of CRC in patients with various chronic kidney diseases before and after kidney transplantation. STUDY Electronic databases were searched for cohort studies assessing the risk of CRC in patients with chronic kidney diseases. The primary outcome was the risk of CRC among studies that reported the risk as standardized incidence rate (SIR). RESULTS Fifty-four studies, including 1,208,767 patients that reported the incidence of CRC in chronic kidney diseases were identified. SIR of CRC were obtained from 17 retrospective cohort studies. Among the 3 studies (4 reports) that included chronic kidney disease patients without kidney transplantation, there was a significant increased risk of CRC (pooled SIR 1.18) (95% confidence interval, 1.01-1.37; P=0.033). High heterogeneity was seen (I=85.6%), and metaregression showed that there were positive correlations between the risk of CRC and the proportions of males, age and follow-up period. Among the 15 studies (17 reports) that included postkidney transplant patients, the pooled SIR was significantly increased at 1.40 (95% confidence interval, 1.15-1.71; P=0.00080). High heterogeneity was seen (I=88.9%), and metaregression showed that the follow-up period correlated with the risk of CRC. CONCLUSIONS In the present systematic review and meta-analysis, we demonstrated that patients with chronic kidney disease, regardless of a history of transplant, have a significant increased risk of CRC. A more intensive surveillance for CRC is required in this population.