The significance of central blood pressure for cardiovascular target organ damage in children and adolescents after kidney transplantation.

BACKGROUND: Cardiovascular (CV) complications are important causes of morbidity and mortality in children after kidney transplantation (KTx). In adults, central blood pressure (cBP) is an accepted predictor of CV sequelae. We aimed to assess the prognostic value of cBP over peripheral blood pressure (pBP) for existing CV damage. METHODS: We measured cBP and pBP in 48 pediatric KTx recipients (mean age: 13.5 ± 4.2 years). Assessment of left ventricular mass index (LVMI) and aortic pulse wave velocity (PWV) allowed detection of CV target organ damage. LVMI and PWV were used as endpoints in multivariable linear regression models, in which cBP and pBP were compared for their predictive value. RESULTS: Using cBP z-scores, we identified a larger number of patients with uncontrolled or untreated hypertension compared to pBP (36% vs. 7%). Central systolic blood pressure (cSBP) was a significant independent predictor of LVMI, while peripheral systolic blood pressure (pSBP) was not. Comparing central (cDBP) and peripheral (pDBP) diastolic blood pressure for their predictive value on PWV revealed a greater estimate for cDBP (0.035 vs. 0.026 for pDBP) along with a slightly better model fit for cDBP. CONCLUSIONS: Our data in a small group of patients provide first evidence that cBP measurements in pediatric KTx recipients might be helpful in identifying patients at risk for the development of CV sequelae. Investigating a larger patient number, ideally repeatedly, is needed to create further evidence supporting our findings. In light of available devices measuring cBP noninvasively, the implementation of such clinical studies post-KTx care should be feasible. A higher resolution version of the Graphical abstract is available as Supplementary information.

Effect of Sex on Mortality and Left Ventricular Remodeling After Transcatheter Aortic Valve Implantation.

BACKGROUND: The effect of sex on mortality is controversial; furthermore, sex differences in left ventricular (LV) remodeling after transcatheter aortic valve implantation (TAVI) remain unknown.Methods and Results:This study included 2,588 patients (1,793 [69.3%] female) enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI Japanese multicenter registry between October 2013 and May 2017. We retrospectively analyzed the effect of sex on mortality, and evaluated changes in the LV mass index (LVMI) after TAVI. Female sex was significantly associated with lower all-cause and cardiovascular mortality (log-rank P<0.001 for both). Multivariate analysis showed that female sex was independently associated with lower cumulative long-term mortality (hazard ratio 0.615; 95% confidence interval 0.512-0.738; P<0.001). Regression in the LVMI was observed in both sexes, and there was no significant difference in the percentage LVMI regression from baseline to 1 year after TAVI between women and men. Women had a survival advantage compared with men among patients with LVMI regression at 1 year, but not among patients with no LVMI regression. CONCLUSIONS: We found that female sex is associated with better survival outcomes after TAVI in a large Japanese registry. Although LVMI regression was observed in women and men after TAVI, post-procedural LV mass regression may be related to the sex differences in mortality.

Isolated nocturnal hypertension is associated with increased left ventricular mass index in children.

BACKGROUND: Isolated nocturnal hypertension (INH) is associated with increased prevalence of left ventricular hypertrophy (LVH) and cardiovascular morbidity and mortality in adult patients. Unlike in adults, data illustrating the possible association between INH and cardiac target organ damage is lacking in children. This study aimed to investigate whether INH is associated with increased left ventricular mass index (LVMI) and LVH in children. METHODS: Retrospective data from all untreated children with confirmed ambulatory hypertension (HT) in our center was reviewed. Ambulatory blood pressure monitoring (ABPM) and echocardiography were performed concurrently. Ambulatory normotensive children served as controls. LVH was defined as LVMI ≥ 95th percentile. RESULTS: There were 102 ABPM studies; of these, 79 children had renal HT, and 23 had primary HT. Median age of children was 13.2 years (3.8-18.9). Nineteen children had INH, 9 children had isolated daytime HT, 54 had daytime and nighttime HT, and 20 were normotensive. The LVMI adjusted for age (patient's LVMI/95th percentile of the LVMI) was significantly higher in children with INH than in normotensive children (0.83 ± 0.03 vs. 0.74 ± 0.03, p = 0.03). Left ventricular hypertrophy was present in 11% of children with INH; this was not significantly higher than in normotensive children (0%, p = 0.23). CONCLUSIONS: This study investigated the association between INH and cardiac structure in children with primary and renal HT and showed children with INH had higher LVMI adjusted for age than normotensive children and children with INH had similar LVMI adjusted for age to children with isolated daytime HT.

Early-onset subclinical cardiovascular damage assessed by non-invasive methods in children with Juvenile Idiopathic Arthritis: analytical cross-sectional study.

Chronic inflammation starting early in life and continuing into adulthood may predispose children with Juvenile Idiopathic Arthritis (JIA) to cardiovascular (CV) complications. To compare non-invasive CV risk markers- left ventricular mass index (LVMi), brachial artery flow mediated dilatation (FMD) and carotid artery intima-media thickness (CIMT) between patients with JIA and healthy controls. Measurements of LVMi, CIMT and FMD and lipid profile were compared between 4 and 18 year old 81 patients with JIA and 78 age and sex matched healthy controls. Among 81, 20 had systemic onset, 19 enthesitis related arthritis, 9 polyarticular rheumatoid factor (RF) + ve, 19 polyarticular RF -ve, 11 oligo-articular, and 3 un-differentiated JIA. FMD was significantly lower (p < 0.001), CIMT and LVMi significantly higher in patients (p ≤ 0.001). CIMT showed positive correlation with blood pressure (p = 0.001), disease duration (p ≤ 0.001) and negative correlation with high density lipoprotein (HDL) (p ≤ 0.001). FMD correlated positively with HDL (p = 0.006) and negatively with disease duration (p ≤ 0.001). CIMT (p = 0.017) and FMD (p = 0.04) were significantly worse in active than inactive disease. Children with JIA have worse lipid profile, increased LVMi, CIMT, and reduced brachial artery FMD, suggestive of early cardiovascular dysfunction.

A randomised controlled trial to examine the effects of cinacalcet on bone and cardiovascular parameters in haemodialysis patients with advanced secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism may lead to increased cardiovascular risk. The use of cinacalcet may improve bone and cardiovascular health with improved parathormone (PTH) and phosphate control. METHODS: This is an open-label prospective randomised controlled trial to compare progression of cardiovascular and chronic kidney disease mineral and bone disorder (CKD-MBD) parameters. Patients were randomised to receive cinacalcet alongside standard therapy or standard therapy alone. Thirty-six haemodialysis patients who had > 90 days on dialysis, iPTH > 300 pg/mL, calcium > 2.1 mmol/L and age 18-75 years were included. Following randomization, all 36 patients underwent an intensive 12-week period of bone disease management aiming for iPTH 150-300 pg/mL. The primary outcome was change in vascular calcification using CT agatston score. Secondary outcomes included pulse wave velocity (PWV), left ventricular mass index (LVMI), carotid intima-media thickness (CIMT), augmentation index (Aix) and bone measurements. The above measurements were obtained at baseline and 12 months. RESULTS: There was no evidence of a group difference in the progression of calcification (median change (IQR) cinacalcet: 488 (0 to1539); standard therapy: 563 (50 to 1214)). In a post hoc analysis combining groups there was a mean (SD) phosphate reduction of 0.3 mmol/L (0.7) and median (IQR) iPTH reduction of 380 pg/mL (- 754, 120). Regression of LVMI and CIMT was seen (P = 0.03 and P = 0.001) and was significantly associated with change of phosphate on multi-factorial analyses. CONCLUSIONS: With a policy of intense CKD-MBD parameter control, no significant benefit in bone and cardiovascular markers was seen with the addition of cinacalcet to standard therapy over one year. Tight control of hyperphosphataemia and secondary hyperparathyroidism may lead to a reduction in LVMI and CIMT but this needs further investigation. Although the sample size was small, meticulous trial supervision resulted in very few protocol deviations with therapy.

Prevalence of and risk factors for abnormal left ventricular geometrical patterns in hypertensive subjects administered irbesartan.

BACKGROUND: Distinct populations differ in LVH prevalence and impaired LV geometry. Currently, the prevalence of and risk factors for LV geometric patterns in Chinese hypertensives administered irbesartan have not been specifically addressed in large studies. METHODS: Totally 10,883 patients (6623 men and 4260 women) completed the survey, including 1181 hypertensives administered irbesartan (488 males and 693 females) that were finally enrolled. Based on LVMI and RWT derived from comprehensive echocardiography, the LV geometric patterns of irbesartan-treated hypertensive individuals were classified into four types, including the normal, concentric remodeling, and concentric and eccentric hypertrophy groups. Logistic regression analysis was applied in males and females, respectively, for determining odds ratios (ORs) and 95% confidence intervals (CIs) for various potential risk factors for abnormal LV geometrical patterns in irbesartan-treated hypertensives. RESULTS: The clinical and echocardiographic data differed significantly between males and females. The prevalence rates of concentric remodeling, concentric hypertrophy, and eccentric hypertrophy were 36.3%, 15.4%, and 6.1% in males, respectively, and 23.5%, 20.3%, and 23.8% in females, accordingly. Gender, daily dose of irbesartan, BMI, SBP, WtHR, and neck-circumference were significantly associated with LV geometric patterns. After adjustment for confounding factors, risk factors for LVH and impaired LV geometry included SBP, WtHR in males, and MAU-Cr and WtHR in females. CONCLUSIONS: LVH and impaired LV geometric patterns are more prevalent in females (67.7%) compared with that in males (57.8%) among hypertensives upon irbesartan administration. For such population, risk factors beyond elevated blood pressure may be involved in the progression of LVH and impaired LV geometric patterns in both genders.

The impact of body mass index on left ventricular mass index, right ventricular function, and cardiac dimension of children with sickle cell anemia in Enugu City.

BACKGROUND: Body mass index is a major determinant of cardiac annular valvar dimension and left ventricular mass index in children with sickle cell anemia. OBJECTIVES: The study is aimed at ascertaining the impact of Body Mass Index on Left ventricular mass index, right ventricular function and cardiac dimension of children with sickle cell anemia. METHODS: A case control study in which echocardiographic measurement of cardiac function and structures were ascertained among children with sickle cell anemia compared with hemoglobin AA genotype. RESULTS: There were 51 subjects and 50 controls. The subjects comprised 54.9% males and controls, 52.0% male. There was a strong positive correlation between BMI and most cardiac structure diameters among children with normal hemoglobin genotype (Pearson's correlation coefficient value, P < 0.001) There was also statistically significant positive correlation between BMI and LV mass among the subjects (n = 50, r = 0.5, P < 0.001). There was significant positive correlation between BMI and TAPSE in both subjects and controls as well as between BMI and RVSP among the subjects, but not the controls (p < 0.001). There was no significant difference in the number with left ventricular hypertrophy (LVH) based on their nutritional status (n = 51, χ^2 = 7.03, P = 0.32). The BMI correlated negatively with left ventricular mass index (LVMI) among the subjects, but the correlation was not statistically significant (r = -0.1, P = 0.53). CONCLUSION: There was significant positive correlation between BMI and TAPSE in both subjects and controls as well as between BMI and RVSP among the subjects, but not the controls. Body mass index correlated negatively with left ventricular mass index (LVMI) among the subjects.

Adiposity, Sex, and Cardiovascular Disease Risk in Children With CKD: A Longitudinal Study of Youth Enrolled in the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Traditional and nontraditional cardiovascular disease risk factors are highly prevalent in children with chronic kidney disease (CKD). We examined the longitudinal association of adiposity with cardiac damage among children with CKD and explored whether this association was modified by sex. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study at 49 pediatric nephrology centers across North America. EXPOSURE: Age- and sex-specific body mass index (BMI) z score. OUTCOME: Age- and sex-specific left ventricular mass index (LVMI) z score and left ventricular hypertrophy (LVH). ANALYTICAL APPROACH: Longitudinal analyses using mixed-effects models to estimate sex-specific associations of BMI z scores with LVMI z score and with LVH, accounting for repeated measurements over time. RESULTS: Among 725 children with 2,829 person-years of follow-up, median age was 11.0 years and median estimated glomerular filtration rate was 52.6mL/min/1.73m2. Nearly one-third of both boys and girls were overweight or obese, median LVMI z score was 0.18 (IQR: -0.67, 1.08), and 11% had LVH. Greater BMI z scores were independently associated with greater LVMI z scores and greater odds of LVH. For each 1-unit higher BMI z score, LVMI z score was 0.24 (95% CI, 0.17-0.31) higher in boys and 0.38 (95% CI, 0.29-0.47) higher in girls (Pinteraction = 0.01). For each 1-unit higher BMI z score, the odds of LVH was 1.5-fold (95% CI, 1.1-2.1) higher in boys and 3.1-fold (95% CI, 1.8-4.4) higher in girls (Pinteraction = 0.005). LIMITATIONS: Not all children had repeated measurements. LVH is a surrogate and not a hard cardiac outcome. The observational design limits causal inference. CONCLUSIONS: In children, adiposity is independently associated with the markers of cardiac damage, LVMI z score and LVH. This association is stronger among girls than boys. Pediatric overweight and obesity may therefore have a substantial impact on cardiovascular risk among children with CKD.

Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients.

BACKGROUND: Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. METHODS: This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2⁻3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. RESULTS: Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization (p = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy (p = 0.050); concentric hypertrophy (p = 0.041), and serum phosphate ≥ 3.6 mg/dL (p = 0.025), FGF-23 ≥ 168 (p = 0.0149), α-klotho < 313 (p = 0.044). CONCLUSIONS: In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD.

Correlation of Arterial Stiffness With Left Atrial Volume Index and Left Ventricular Mass Index in Young Adults: Evaluation by Coronary Computed Tomography Angiography.

BACKGROUND: Increased arterial stiffness is reportedly associated with cardiac remodelling, including the left atrium and left ventricle, in middle-aged and older adults. However, little is known about this association in young adults. METHODS: In total, 73 patients (44 (60%) men) aged 25 to 45 years with suspected coronary artery disease were included in the analysis. The left atrial volume index (LAVI), left ventricular volume index (LVVI), and left ventricular mass index (LVMI) were measured using coronary computed tomography angiography (CCTA). Arterial stiffness was assessed with the cardio-ankle vascular index (CAVI). An abnormally high CAVI was defined as that above the age- and sex-specific cut-off points of the CAVI. RESULTS: Compared with patients with a normal CAVI, those with an abnormally high CAVI were older and had a greater prevalence of diabetes mellitus, higher diastolic blood pressure, greater coronary artery calcification score, and a greater LAVI (33.5±10.3 vs. 43.0±10.3mL/m2, p <0.01). In contrast, there were no significant differences in the LVVI or LVMI between the subgroups with a normal CAVI and an abnormally high CAVI. Multivariate linear regression analysis showed that the LAVI was significantly associated with an abnormally high CAVI (standardised regression coefficient=0.283, p=0.03). CONCLUSIONS: The present study demonstrated that increased arterial stiffness is associated with the LAVI, which reflects the early stages of cardiac remodelling, independent of various comorbidity factors in young adults with suspected coronary artery disease.

Evolution of Echocardiographic Measures of Cardiac Disease From CKD to ESRD and Risk of All-Cause Mortality: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: Abnormal cardiac structure and function are common in chronic kidney disease (CKD) and end-stage renal disease (ESRD) and linked with mortality and heart failure. We examined changes in echocardiographic measures during the transition from CKD to ESRD and their associations with post-ESRD mortality. STUDY DESIGN: Prospective study. SETTING & PARTICIPANTS: We studied 417 participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) who had research echocardiograms during CKD and ESRD. PREDICTOR: We measured change in left ventricular mass index, left ventricular ejection fraction (LVEF), diastolic relaxation (normal, mildly abnormal, and moderately/severely abnormal), left ventricular end-systolic (LVESV), end-diastolic (LVEDV) volume, and left atrial volume from CKD to ESRD. OUTCOMES: All-cause mortality after dialysis therapy initiation. ANALYTICAL APPROACH: Cox proportional hazard models were used to test the association of change in each echocardiographic measure with postdialysis mortality. RESULTS: Over a mean of 2.9 years between pre- and postdialysis echocardiograms, there was worsening of mean LVEF (52.5% to 48.6%; P<0.001) and LVESV (18.6 to 20.2mL/m2.7; P<0.001). During this time, there was improvement in left ventricular mass index (60.4 to 58.4g/m2.7; P=0.005) and diastolic relaxation (11.11% to 4.94% with moderately/severely abnormal; P=0.02). Changes in left atrial volume (4.09 to 4.15mL/m2; P=0.08) or LVEDV (38.6 to 38.4mL/m2.7; P=0.8) were not significant. Worsening from CKD to ESRD of LVEF (adjusted HR for every 1% decline in LVEF, 1.03; 95% CI, 1.00-1.06) and LVESV (adjusted HR for every 1mL/m2.7 increase, 1.04; 95% CI, 1.02-1.07) were independently associated with greater risk for postdialysis mortality. LIMITATIONS: Some missing or technically inadequate echocardiograms. CONCLUSIONS: In a longitudinal study of patients with CKD who subsequently initiated dialysis therapy, LVEF and LVESV worsened and were significantly associated with greater risk for postdialysis mortality. There may be opportunities for intervention during this transition period to improve outcomes.

Dietary intervention with a specific micronutrient combination for the treatment of patients with cardiac arrhythmias: the impact on insulin resistance and left ventricular function.

BACKGROUND: Cardiac arrhythmias (CA) are very common and may occur with or without heart disease. Causes of these disturbances can be components of the metabolic syndrome (MetS) or deficits of micronutrients especially magnesium, potassium, B vitamins and coenzyme Q10. Both causes may also influence each other. Insulin resistance (IR) is a risk factor for diastolic dysfunction. One exploratory outcome of the present pilot study was to assess the impact of a dietary intervention with specific micronutrients on the lowering of IR levels in patients with CA with the goal to improve the left ventricular (LV) function. METHODS: This was a post hoc analysis of the randomized double blind, placebo-controlled pilot study in patients with CA (VPBs, SVPBs, SV tachycardia), which were recruited using data from patients who were 18-75 years of age in an Outpatient Practice of Cardiology. These arrhythmias were assessed by Holter ECG and LV function by standard echocardiography. Glucose metabolism was measured by fasting glucose, fasting insulin level and the Homeostasis Model Assessment of IR (HOMA-IR) at baseline and after 6 weeks of dietary supplementation. RESULTS: A total of 54 randomized patients with CA received either a specific micronutrient combination or placebo. Dietary intervention led to a significant decrease in fasting insulin ≥58 pmol/l (p = 0.020), and HOMA-IR (p = 0.053) in the verum group after 6 weeks. At the same time, parameters of LV diastolic function were improved after intervention in the verum group: significant reduction of LV mass index (p = 0.003), and in tendency both a decrease of interventricular septal thickness (p = 0.053) as well as an increase of E/A ratio (p = 0.051). On the other hand, the premature beats (PBs) were unchanged under verum. CONCLUSIONS: In this pilot study, dietary intervention with specific micronutrient combination as add-on to concomitant cardiovascular drug treatment seems to improve cardio metabolic health in patients with CA. Further studies are required. STUDY REGISTRATION: The study was approved by the Freiburg Ethics Commission International and was retrospectively registered with the U.S. National Institutes of Health Clinical Trials gov ID NCT 02652338 on 16 December 2015.

Estimated GFR and Subsequent Higher Left Ventricular Mass in Young and Middle-Aged Adults With Normal Kidney Function: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

BACKGROUND: Left ventricular hypertrophy is common and is associated with cardiovascular events and death among patients with known chronic kidney disease. However, the link between reduced glomerular filtration rate (GFR) and left ventricular mass index (LVMI) remains poorly explored among young and middle-aged adults with preserved kidney function. In this study, we examined the association of cystatin C-based estimated GFR (eGFRcys) and rapid decline in eGFR with subsequent LVMI. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We included 2,410 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort with eGFRcys > 60mL/min/1.73m(2) at year 15 and who had an echocardiogram obtained at year 25. PREDICTOR: eGFRcys at year 15 and rapid decline in eGFRcys (defined as >3% per year over 5 years from years 15 to 20). OUTCOME: LVMI measured at year 25. MEASUREMENTS: We adjusted for age, sex, race, diabetes, body mass index, low- and high-density lipoprotein cholesterol levels, cumulative systolic blood pressure, and albuminuria. RESULTS: Mean age was 40±4 (SD) years, 58% were women, and 43% were black. After 10 years of follow-up, mean LVMI was 39.6±13.4g/m(2.7). Compared with eGFRcys > 90mL/min/1.73m(2) (n = 2,228), eGFRcys of 60 to 75mL/min/1.73m(2) (n = 29) was associated with 5.63 (95% CI, 0.90-10.36) g/m(2.7) greater LVMI (P = 0.02), but there was no association of eGFRcys of 76 to 90mL/min/1.73m(2) (n = 153) with LVMI after adjustment for confounders. Rapid decline in eGFRcys was associated with higher LVMI compared with participants without a rapid eGFRcys decline (ß coefficient, 1.48; 95% CI, 0.11-2.83; P = 0.03) after adjustment for confounders. LIMITATIONS: There were a limited number of participants with eGFRcys of 60 to 90mL/min/1.73m(2). CONCLUSIONS: Among young and middle-aged adults with preserved kidney function, eGFRcys of 60 to 75mL/min/1.73m(2) and rapid decline in eGFRcys were significantly associated with subsequently higher LVMI. Further studies are needed to understand the mechanisms that contribute to elevated LVMI in this range of eGFRcys.

Levocarnitine Improves Cardiac Function in Hemodialysis Patients With Left Ventricular Hypertrophy: A Randomized Controlled Trial.

BACKGROUND: Levocarnitine deficiency in hemodialysis patients is common. Although the effect of levocarnitine therapy on uremic anemia has been studied in small trials, its effects on cardiac function remain unclear. STUDY DESIGN: Multicenter, prospective, open-label, parallel, randomized, controlled trial. SETTING & PARTICIPANTS: Patients undergoing maintenance hemodialysis with carnitine deficiency (free carnitine plasma concentration < 40µmol/L) enrolled in 3 hemodialysis centers. INTERVENTION: Random assignment to treatment for 12 months with oral levocarnitine therapy at a dose of 20mg/kg/d or control group (no levocarnitine therapy). OUTCOMES & MEASUREMENTS: Cardiac function was assessed by echocardiography. The primary end point was change in ejection fraction from baseline at the end of the study. Secondary end points included changes in left ventricular mass index and clinical parameters from baseline at the end of the study. RESULTS: 222 patients were randomly assigned, of whom 148 patients (levocarnitine group, n=75; control group, n=73) were analyzed. Ejection fraction increased from baseline to the end of the study in the levocarnitine group by 5.43% (95% CI, 4.53%-6.32%), but not in the control group (change, -0.14%; between-group difference, 5.57% [95% CI, 4.48%-6.66%]; P<0.001). Left ventricular mass index decreased from baseline to the end of the study in the levocarnitine group (change of -8.89 [95% CI, -11.7 to -6.09] g/m(2)), but not in the control group (change of 1.62g/m(2); between-group difference, 10.50 [95% CI, 7.51 to 13.60] g/m(2); P<0.001). Levocarnitine therapy reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and improved the erythropoietin responsiveness index, whereas no such effects were observed in the control group. LIMITATIONS: Not a double-blinded study. CONCLUSIONS: Levocarnitine therapy is useful for hemodialysis patients with carnitine deficiency; these patients may benefit from such therapy, with amelioration of cardiac function and reduction of left ventricular mass index.

Predictive factors associated with increased progression to dialysis in early chronic kidney disease (stage 1-3) patients.

BACKGROUND: It has been reported that echocardiographic parameters are independently associated with the progression to dialysis in patients with chronic kidney disease (CKD) (stages 3-5). The objective of the present study was to evaluate whether physical, biochemical, and echocardiographic parameters are associated with the progression to dialysis in early CKD (stage 1-3) patients. METHODS: This retrospective study enrolled 272 CKD patients who underwent echocardiography at the time of diet education, renal biopsy, and the examination of kidney injuries at Juntendo University Hospital, Tokyo, Japan, from 2001 to 2010. All of these CKD patients were classified into stages 1-3. The study patients received regular follow-up at our outpatient clinic in our division. The renal end point was defined as commencement of dialysis. RESULTS: Patients with progression to dialysis were significantly associated with higher levels of left ventricular mass index (LVMI), urinary protein, systolic blood pressure, many kinds of anti-hypertensive drugs, and lower levels of albumin and hemoglobin. In a Cox proportional hazard regression analysis, LVMI [hazard ration (HR) 1.018; 95 % confidence interval (CI) 1.007-1.029; p = 0.002], urinary protein and hemoglobin were independently associated with factors for progression to dialysis in early CKD patients. CONCLUSION: This study of patients in early CKD demonstrated that higher LVMI and urinary protein and that lower levels of hemoglobin in blood were associated with progression to dialysis. LVMI evaluated by echocardiography may identify a high risk of progression to dialysis in early CKD patients.

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study.

BACKGROUND: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (VO(2peak)). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. STUDY DESIGN: Prospective matched-cohort study. SETTING & PARTICIPANTS: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. PREDICTOR: CKF versus essential hypertension without cardiovascular disease. MEASUREMENTS & OUTCOMES: VO(2peak) was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in VO(2peak) between study groups, statistically significant predictors of VO(2peak) in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. RESULTS: VO(2peak) was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P<0.001). Independent predictors of VO(2peak) for CKF included left ventricular (LV) filling pressure (E/mean e'; unstandardized regression coefficient: change in VO(2peak) [in mL/min·kg] per 1-unit change of variable = -5.1) and pulse wave velocity (-4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (-8.8). The interaction effect of VO(2peak) between patient groups with LV mass index (P<0.001), LV end-diastolic volume index (P<0.001), and peak heart rate (P<0.01) were significantly stronger in the hypertension group, whereby higher values led to greater VO(2peak). LIMITATIONS: Skeletal muscle strength was not assessed. CONCLUSION: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension.

Changes in the cardiovascular risk profile in children approaching kidney replacement therapy.

Background: Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods: The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings: 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation: This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable. Funding: Supported by EU4Health Programme (101085068) and Kidney Research UK (RP39/2013).

Enzyme replacement therapy in two Japanese siblings with Fabry disease, and its effectiveness on angiokeratoma and neuropathic pain.

Enzyme replacement therapy (ERT) for Fabry disease does not show a clear benefit in angiokeratoma. We describe two Japanese siblings with Fabry disease, who were diagnosed when angiokeratomas were found on the older sibling at the age of 13 years. Neither of the boys complained of pain, while both suffered from hypohidrosis. We evaluated the safety and efficacy of ERT with recombinant human agalsidase alfa (Replagal®, Dainippon-Sumitomo Pharma. Co., Osaka, Japan) in these siblings over a 5-year period. In both siblings, sweating was observed 3 months after the initiation of ERT, which motivated them to adhere to ERT. Pain sensation was regained after 12 to 36 months of ERT, followed by a decrease after 48 to 60 months. Angiokeratomas on the lateral side of the knee of the older sibling partially disappeared after 48 months of ERT. Although the height of both siblings at baseline was lower than the corresponding average age-related heights in the normal Japanese population, during ERT they were within, or close to, the average +1 standard deviation in the non-Fabry population. Their growth rate seemed to indicate catch-up growth. Other clinical symptoms were maintained at baseline levels. Immunoglobulin G anti-agalsidase alfa antibodies were not detected in both sibling during ERT, and no infusion-associated reaction was observed. The treatment was generally well tolerated. ERT was a safe and effective treatment for angiokeratoma and neuropathic pain for these two siblings with Fabry disease.

B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease.

OBJECTIVE: To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. STUDY DESIGN: Six subjects with Pompe disease (including 4 cross-reacting immunologic material-negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. RESULTS: Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. CONCLUSION: B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.

Targeted literature review exploring the predictive value of estimated glomerular filtration rate and left ventricular mass index as indicators of clinical events in Fabry disease.

BACKGROUND: Fabry disease is a rare, progressive X-linked lysosomal storage disorder. It is caused by mutations in the GLA gene resulting in deficiency of α-galactosidase A (α-Gal A), leading to peripheral neuropathy, cardiovascular disease, stroke, end-stage renal disease, gastrointestinal disorders and premature death. Given the long-term nature of disease progression, trials in Fabry disease are often not powered to capture these clinical events. Clinical measures such as estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) are often captured instead. eGFR and LVMI are believed to be associated with long-term Fabry disease clinical events of interest, but the precise relationships are unclear. OBJECTIVE: We aimed to identify published literature exploring the link between eGFR/LVMI and long-term clinical events in Fabry disease. METHODS: A comprehensive literature search was conducted in Embase® and MEDLINE® (using Embase.com), and a targeted literature review was conducted. Studies reporting a quantitative relationship between eGFR and/or LVMI and clinical events in Fabry disease were extracted, and narrative synthesis was conducted to understand these predictive relationships. RESULTS: Eight studies, consisting of seven patient-level retrospective analyses plus one prospective cohort study, met the inclusion criteria. Seven of these studies reported eGFR and six reported LVMI, with five reporting both. All studies presented results for either a composite measure including a range of key Fabry disease clinical events, or a composite outcome that included at least one key Fabry disease clinical event. All studies employed Cox proportional hazards survival modelling. The studies consistently reported that eGFR and LVMI are predictors of key clinical events in Fabry disease, with the findings remaining consistent regardless of the therapy received by patients in the studies. CONCLUSIONS: The evidence identified suggests that eGFR and LVMI outcomes may be appropriate indicators for long-term clinical events in Fabry disease, and all identified papers implied the same directional relationship. However, additional research is needed to further understand the specific details of these relationships and to quantify them.