Cardiac biomarkers in pediatric CKD-a prospective follow-up study.

BACKGROUND: The N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive cardiac-specific troponin T (hs-cTnT) are associated with abnormal cardiac structure and function and an increased risk of cardiovascular death in chronic kidney disease (CKD) patients. There is limited knowledge about these cardiac markers in pediatric CKD patients. METHODS: Longitudinal levels of NT-proBNP and hs-cTnT were analyzed in 48 pediatric patients, 22 with CKD (GFR range 8.8-68 mL/min/1.73 m2) and 26 transplanted patients (CKD-T; GFR range 30-99 mL/min/1.73 m2). Follow-up was scheduled after 1 and 3 years. Longitudinal patterns and associations to kidney function, cardiovascular risk markers, and echocardiographic parameters were assessed. RESULTS: High NT-proBNP was present in 27% of CKD and 11% of CKD-T patients. Similarly 32% of CKD and 8% of CKD-T patients had elevated hs-cTnT levels. In longitudinal multivariate analyses, high log NT-proBNP was associated with low GFR (ß = - 0.01, p = 0.01) and elevated left ventricular mass index (LVMI; ß = 0.02, p = 0.05). The strong association to LVMI remained when using GFR-adjusted NT-proBNP in similar analysis. Patients with left ventricular hypertrophy (LVH) also had higher NT-proBNP (235 [146-301] ng/L) than patients without LVH (86 [11-477] ng/L), p = 0.02. High hs-cTnT over-time was also associated with low GFR (ß = - 0.007, p = 0.01) and a low cc-TDI e´/a´, indicating a worse LV diastolic function (ß = - 0.09, p = 0.05). This association did not persist for GFR-adjusted hs-cTnT. CONCLUSIONS: NT-proBNP and hs-cTnT are elevated in pediatric CKD and CKD-T patients. GFR-adjusted NT-proBNP was associated with longitudinal levels of elevated LVMI suggesting this might be a marker for early subclinical myocardial damage. A higher resolution version of the Graphical abstract is available as Supplementary information.

Atrio-ventricular block and takotsubo syndrome: A review illustrated with two case reports.

Takotsubo syndrome (TS) can be complicated by life-threatening arrhythmias. Data on the association of AV-block, pacemaker implantation, and TS are scarce. We describe two cases of AV-block associated with TS. AV-block persisted despite the recovery of left ventricular dysfunction during follow-up. A review of AV-block and TS association is provided.

Epidemiology of Aortic Stenosis/Aortic Valve Replacement (from the Nationwide Swedish Renal Registry).

Contemporary data on the prevalence and incidence of aortic stenosis (AS) and aortic valve replacement (AVR) in patients initiating dialysis are scarce. This observational cohort study aimed to estimate (1) the point prevalence of AS and AVR at dialysis start and (2) the AS incidence and associated factors prospective to dialysis initiation. The study included 14,550 patients initiating dialysis registered in the Swedish Renal Registry between 2005 and 2018. AS was defined by the International Statistical Classification of Diseases, Tenth Revision codes, and AVR by the surgical procedure codes. Associations between covariates and outcomes were assessed in Cox regression models. The median age was 68 (57 to 77), 66% were males, and the point prevalence of AS and AVR was 3.4% and 1.1%, respectively. In those without known AS/AVR at dialysis initiation (n = 14,050), AS was diagnosed in 595 patients (incidence 16.3/1000 person-years, 95% confidence interval [CI] 15.1 to 17.7/1,000 person-years) during a median follow-up of 2.7 years (interquartile range 1.1 to 5.7). In adjusted Cox regression models, higher age (hazard ratio [HR] 1.03, 95% CI 1.02 to 1.04), male gender (HR 1.51, 95% CI 1.25 to 1.83), atrial fibrillation (HR 1.32, 95% CI 1.06 to 1.64), and hypertension (HR 1.65, 95% CI 1.03 to 2.65) were associated with incident AS. Peritoneal dialysis patients had a nonsignificant trend toward higher AS risk compared with hemodialysis (HR 1.18, 95% CI 0.99 to 1.40). About 20% of patients (n = 113) diagnosed with incident AS underwent AVR (incidence 3.1/1000 person-years, 95% CI 2.6 to 3.7/1,000). Only the male gender was associated with AVR (HR 2.07, 95% CI 1.30 to 3.30). In conclusion, the prevalence and incidence of AS and AVR in patients initiating dialysis are high. A fifth of newly diagnosed AS underwent AVR after dialysis onset.

Kidney Dysfunction and the Risk of Developing Aortic Stenosis.

BACKGROUND: Chronic kidney disease (CKD) and aortic stenosis (AS) share many risk factors. OBJECTIVES: This study sought to evaluate whether kidney dysfunction is associated with the development of AS in the community. METHODS: The study included 1,121,875 Stockholm citizens without a prior diagnosis of AS from the SCREAM (Stockholm CREAtinine Measurements) project. Estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) was calculated from serum creatinine. AS incidence during follow-up was ascertained by clinical diagnostic codes. The association between eGFR and AS incidence was estimated with multivariable Cox proportional hazards models. Sensitivity analyses included analysis of possible reverse causation bias by excluding the first 6 months to 2 years after enrollment and excluding individuals with comorbid heart failure. RESULTS: The median age was 50 years (interquartile range [IQR]: 36 to 64 years), and 54% of participants were women. Median eGFR was 96 ml/min/1.73 m2 (IQR: 82 to 109 ml/min/1.73 m2), and 66,949 (6.0%) participants had CKD (eGFR <60 ml/min/1.73 m2). During a median follow-up of 5.1 years (IQR: 3.3 to 6.1 years), 5,858 (0.5%) individuals developed AS (incidence rate [IR] 1.13/1,000 person-years). Compared with eGFR >90 (IR 0.34/1,000 person-years), lower eGFR strata were associated with higher hazards of AS: eGFR 60 to 90 ml/min/1.73 m2; IR: 1.88; hazard ratio (HR): 1.14; 95% confidence interval (CI): 1.05 to 1.25; eGFR 45 to 59 ml/min/1.73 m2; IR: 4.61; HR: 1.17; 95% CI: 1.05 to 1.30; eGFR 30 to 44 ml/min/1.73 m2; IR: 6.62; HR: 1.22; 95% CI: 1.07 to 1.39; and eGFR 30 ml/min/1.73 m2; IR: 8.27; HR: 1.56; 95% CI: 1.29 to 1.87. Sensitivity analysis attenuated only slightly the magnitude of the association; individuals with eGFR ≤44 ml/min/1.73 m2 remained at an approximate 20% risk of AS both when excluding events within the 2 years after baseline (HR: 1.22; 95% CI: 1.06 to 1.42) and when excluding participants with heart failure (HR: 1.20; 95% CI: 1.03 to 1.39). CONCLUSIONS: CKD, even in moderate to severe stages, is associated with an increased risk of AS.

The FGF23-Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study.

BACKGROUND: Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS: This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m2) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m2) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS: The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (ß = -0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (ß = 1.8, p = 0.06). In addition, high log FGF23 (ß = -0.43, p = 0.01) and low log Klotho (ß = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e'/a') in CKD-T patients. CONCLUSIONS: In pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.

Risk factors for worsening renal function and their association with long-term mortality following transcatheter aortic valve implantation: data from the SWEDEHEART registry.

BACKGROUND: The occurrence of persistent acute kidney injury (pAKI) following transcatheter aortic valve implantation (TAVI) has serious implications. METHODS: There were 1540 patients undergoing and surviving TAVI included in the nationwide SWEDEHEART registry between 2008 and 2015. Creatinine was measured at baseline and discharge, and those with baseline estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 or dialysis were excluded. pAKI was defined by and encompassing theValve Academic Research Consortium-2 (VARC-2) criteria: increase in serum creatinine concentration ≥26.5 µmol/L or increase by ≥50% (1.5×), or start of in-hospital dialysis until hospital discharge. Logistic regression analysis was used to find baseline factors associated with pAKI. Adjusted Cox regression analysis was used to assess the association of pAKI with mortality. Median follow-up was 1.8 years (IQR 0.7-3.0). RESULTS: pAKI occurred in 6.1% (n=94) of the patients (71.3% male). These patients had higher creatinine level (117±50 vs 100±35 mmol/L, p<0.001), but similar baseline eGFR (59±21 vs 56±23 mL/min/1.73 m2, p=0.18) and received higher contrast volume (129 mL ±89 vs 110 mL ±78, p=0.027). On multivariable logistic regression analysis, pAKI was predicted by eGFR (OR 0.88, 95% CI (0.79 to 0.98), p=0.019), male gender (OR 2.68, 95% CI (1.63 to 4.38), p<0.001) and apical access (OR 2.23, 95% CI (1.35 to 3.69), p=0.002), whereas contrast volume/10 mL (OR 1.02, 95% CI (1.00 to 1.05), p=0.052) did not reach statistical significance. Mortality at 1 year/end of follow-up was 10.4%/26.9%. pAKI was associated with a doubled risk of death (HR 2.04, 95% CI (1.49 to 2.81), p<0.001). CONCLUSION: Persistent AKI after TAVI occurs in 6.1% and is associated with a doubled long-term mortality. Special efforts to avoid AKI should be taken, especially among vulnerable patients.

Assessing longitudinal trends in cardiac function among pediatric patients with chronic kidney disease.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) is an early marker of cardiac disease in pediatric chronic kidney disease (CKD), but few studies have analyzed longitudinal trends. We conducted a prospective 3-year follow-up study in pediatric CKD and kidney transplant (CKD-T) patients. METHODS: The patient cohort comprised 30 CKD and 42 CKD-T patients. The results of annual clinical and echocardiographic analyses using tissue Doppler imaging (TDI) and pulse wave Doppler (PWD) were assessed, and associations to predictive risk factors were studied using multivariate modeling. RESULTS: The mean age of CKD and CKD-T patients at inclusion was 9.8 ± 4.4 and 11.8 ± 4.3 years, respectively; the glomerular filtration rate was 35.3 ± 18.3 and 60.3 ± 18.8 mL/min/1.73 m(2), respectively. The prevalence of left ventricular diastolic dysfunction (LVDD), as assessed using TDI (lateral z-score e') was 7.1 and 12.5 % in CKD and CKD-T patients, respectively; the corresponding values with PWD E were 3.3 and 2.4 %, respectively. In unadjusted analyses, both TDI and PWD markers of diastolic function worsened over the follow-up period; following adjustments, an elevated systolic ambulatory blood pressure was the most important predictor of cardiac disease. CONCLUSIONS: Children with CKD show early signs of LVDD, with TDI being more sensitive than PWD in terms of diagnostic potential. An increased ambulatory systolic blood pressure predicted progression in diastolic function, suggesting opportunities for future interventions.

An observational cohort study of the effect of hypertension on the loss of renal function in pediatric kidney recipients.

BACKGROUND: Post-transplant hypertension impacts negatively on renal graft survival. Our primary objective was to analyze the effect of hypertension on the glomerular filtration rate (GFR) slope. METHODS: All clinical charts of children who underwent renal transplantation since the introduction of the routine use of ambulatory blood pressure monitoring (ABPM) were reviewed. Eligibility criteria for inclusion were measurement of GFR at 3 months, at 1 year post-transplant, and thereafter at yearly intervals; ABPM performed annually after transplantation; and functioning graft for a minimum of 2 years. RESULTS: Sixty-eight (39 males) of 79 patients, aged 9.1±5.3 years, met the inclusion criteria. The mean follow-up was 6.2±2.8 years. Twenty-four patients had normotension or controlled hypertension throughout their follow-up (normotensive group). Forty-four patients had hypertension or noncontrolled hypertension at some point(s) during the follow-up period (hypertensive group). GFR slope was -1.6ml/min/1.73 m(2) per year (95% confidence interval (CI = -3.7 to 0.4) in the normotensive group and -2ml/min/1.73 m(2) per year (95% CI = -3 to -1.1) in the hypertensive group (P = 0.42). There was no difference between groups with regard to the change in GFR values from 3 months to 1 year and to last control (P = 0.87). At most recent control, the overall prevalence of controlled hypertension was 78.2% (95% CI = 63.6-89.1). CONCLUSIONS: Although the results of our study are encouraging, they need to be confirmed in a larger prospective study using the same post-transplant follow-up protocol.

Left ventricular diastolic dysfunction by tissue Doppler echocardiography in pediatric chronic kidney disease.

BACKGROUND: Myocardial dysfunction is common in chronic kidney disease (CKD) and related to poor outcomes. New non-invasive methods to assess cardiac function have been introduced, but comparative studies evaluating their clinical usefulness in pediatric CKD are lacking. We studied left ventricular (LV) function in pediatric CKD and renal transplant patients, comparing conventional pulse-wave Doppler echocardiography (cPWD) with newer tissue Doppler imaging (TDI) and relating the results to known cardiovascular risk factors. METHODS: The study included 34 children/adolescents with CKD stages 2-5, 44 renal transplant patients and 19 patients with a normal renal function. The mean age was 11.4 (range 0.8-18.8) years. RESULTS: Both patient groups had significantly lower LV diastolic function than those with a normal renal function. The most sensitive determinants were TDI E'/A' and cPWD E/TDI E' ratios. In a stepwise linear regression analysis, high blood pressure, young age and the presence of albuminuria all independently predicted LV diastolic function. CONCLUSIONS: Our study confirms the high prevalence of LV diastolic dysfunction in pediatric CKD patients and following renal transplantation, where TDI appears to be more sensitive than cPWD in assessing early myocardial dysfunction. Our results also underline the importance of preventive measures, such as rigorous blood pressure control, in pediatric CKD.

Use of annual ABPM, and repeated carotid scan and echocardiography to monitor cardiovascular health over nine yr in pediatric and young adult renal transplant recipients.

In adult hypertensive patients, increased cIMT and LVH are independent risk factors for cardiovascular events. We have previously observed that in pediatric RTRs with tight control of BP, cIMT did not progress over time. This investigation is an extension of the aforementioned study aimed at re-examining cIMT and also reporting serial echocardiography results. Twenty-two RTRs aged 9.4 ± 3.3 yr at their baseline carotid scan underwent two additional vascular ultrasounds during a follow-up of 9.1 ± 0.9 yr. Carotid scan and echocardiography examinations were carried out simultaneously with ABPM. Antihypertensive therapy was determined according to the recipient's ABPM results, which were performed at yearly intervals. Baseline cIMT was significantly greater in RTRs than in healthy controls. There was no statistical evidence of systematic changes in cIMT over time. At the last examination, 14 of 17 RTRs with treated hypertension had controlled hypertension (prevalence 82%; 95% CI, 56.5-96.2), and the overall prevalence of LVH was 4.5% (95% CI, -0.01 to 23.5). The lack of progression of cIMT over time and the low prevalence of LVH might reflect the effect of long-standing BP control.