Publications by authors named "Ipek Kaplan Bulut"

27 Publications

  • Page 1 of 1

Hemodiafiltration maintains a sustained improvement in blood pressure compared to conventional hemodialysis in children-the HDF, heart and height (3H) study.

Pediatr Nephrol 2021 Feb 24. Epub 2021 Feb 24.

University College London Great Ormond Street Hospital for Children and Institute of Child Health, London, UK.

Background: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF).

Methods: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile.

Results: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (β = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (β = 0.13 [95%CI 0.06-0.19]; p = 0.0003).

Conclusions: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups.
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http://dx.doi.org/10.1007/s00467-021-04930-2DOI Listing
February 2021

Active vitamin D is cardioprotective in experimental uraemia but not in children with CKD Stages 3-5.

Nephrol Dial Transplant 2021 Feb;36(3):442-451

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: Uraemic cardiac remodelling is associated with vitamin D and Klotho deficiency, elevated fibroblast growth factor 23 (FGF23) and activation of the renin-angiotensin system (RAS). The cardioprotective properties of active vitamin D analogues in this setting are unclear.

Methods: In rats with 5/6 nephrectomy (5/6Nx) treated with calcitriol, the cardiac phenotype and local RAS activation were investigated compared with controls. A nested case-control study was performed within the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study, including children with chronic kidney disease (CKD) Stages 3-5 [estimated glomerular filtration rate (eGFR) 25 mL/min/1.73 m2] treated with and without active vitamin D. Echocardiograms, plasma FGF23 and soluble Klotho (sKlotho) were assessed at baseline and after 9 months.

Results: In rats with 5/6Nx, left ventricular (LV) hypertrophy, LV fibrosis and upregulated cardiac RAS were dose-dependently attenuated by calcitriol. Calcitriol further stimulated FGF23 synthesis in bone but not in the heart, and normalized suppressed renal Klotho expression. In the 4C study cohort, treatment over a mean period of 9 months with active vitamin D was associated with increased FGF23 and phosphate and decreased sKlotho and eGFR compared with vitamin D naïve controls, whereas LV mass index did not differ between groups.

Conclusions: Active vitamin D ameliorates cardiac remodelling and normalizes renal Klotho expression in 5/6Nx rats but does not improve the cardiac phenotype in children with CKD Stages 3-5. This discrepancy may be due to further enhancement of circulating FGF23 and faster progression of CKD associated with reduced sKlotho and higher serum phosphate in vitamin D-treated patients.
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http://dx.doi.org/10.1093/ndt/gfaa227DOI Listing
February 2021

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children.

PLoS One 2020 27;15(10):e0240446. Epub 2020 Oct 27.

Division of Pediatric Nephrology, Center of Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591021PMC
December 2020

Cytomegalovirus Experience in Pediatric Kidney Transplantation in 26 Years' Time.

Transplant Proc 2020 Dec 6;52(10):3186-3191. Epub 2020 Jul 6.

Department of Pediatric Nephrology, Ege University Faculty of Medicine Children's Hospital, Bornova-İzmir, Turkey.

Introduction: In this study,we investigated the presence of cytomegalovirus (CMV) infection in kidney transplanted children and its effect on kidney dysfunction.

Material And Methods: One hundred thirty-five pediatric renal transplant patients were included in this study. The presence of CMV infection, CMV risk status, and other clinical features of the patients were evaluated retrospectively.

Results: Fifty-three percent of all patients and 68.8% of patients with CMV were male. The mean age was 12 years in all patients and CMV groups. According to the CMV risk classification, 40.9% of the patients with CMV infection/disease were in the high-risk group (CMV D+R-). In CMV risk groups, the presence of CMV infection/disease was similar. Cold ischemia time, male sex (patients and donors), deceased donor, higher HLA-mismatches, and cumulative antithymocyte globulin dose were found as risk factors for CMV infection/disease. Acute rejection/graft failure was observed in 27% of all patients. CMV infection has no effect on rejection/graft failure and survival.

Discussion: The frequency and risk factors of CMV in renal transplant children in our study were consistent with the literature.

Conclusions: CMV infection was found in one-fifth of our patients and the majority (71.9%) of them developed infection in the first 6 months. In one-third of our patients acute rejection/graft failure was observed. There was no effect of CMV infection on rejection/graft failure and survival in pediatric patients with proper and effective treatment.
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http://dx.doi.org/10.1016/j.transproceed.2020.03.023DOI Listing
December 2020

Discontinuation of RAAS Inhibition in Children with Advanced CKD.

Clin J Am Soc Nephrol 2020 05 6;15(5):625-632. Epub 2020 Apr 6.

Division of Pediatric Nephrology, University Hospital Heidelberg, Heidelberg, Germany.

Background And Objectives: Although renin-angiotensin-aldosterone system inhibition (RAASi) is a cornerstone in the treatment of children with CKD, it is sometimes discontinued when kidney function declines. We studied the reasons of RAASi discontinuation and associations between RAASi discontinuation and important risk markers of CKD progression and on eGFR decline in the Cardiovascular Comorbidity in Children with CKD study.

Design, Setting, Participants, & Measurements: In this study, 69 children with CKD (67% male, mean age 13.7 years, mean eGFR 27 ml/min per 1.73 m) who discontinued RAASi during prospective follow-up were included. Initial change in BP, albuminuria, and potassium after discontinuation were assessed (median time 6 months). Rate of eGFR decline (eGFR slope) during a median of 1.9 years before and 1.2 years after discontinuation were estimated using linear mixed effects modeling.

Results: Physician-reported reasons for RAASi discontinuation were increase in serum creatinine, hyperkalemia, and symptomatic hypotension. After discontinuation of RAASi, BP and albuminuria increased, whereas potassium decreased. eGFR declined more rapidly after discontinuation of RAASi (-3.9 ml/min per 1.73 m per year; 95% confidence interval, -5.1 to -2.6) compared with the slope during RAASi treatment (-1.5 ml/min per 1.73 m per year; 95% confidence interval, -2.4 to -0.6; =0.005). In contrast, no change in eGFR slope was observed in a matched control cohort of patients in whom RAASi was continued.

Conclusions: Discontinuation of RAASi in children with CKD is associated with an acceleration of kidney function decline, even in advanced CKD.
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http://dx.doi.org/10.2215/CJN.09750819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269205PMC
May 2020

Membranous nephropathy in a child with crescentic glomerulonephritis: Coincidence or comorbidity?

Saudi J Kidney Dis Transpl 2019 Sep-Oct;30(5):1156-1160

Department of Pediatrics, Pediatric Nephrology Units, Faculty of Medicine, Ege University, Izmir, Turkey.

Rapidly progressive glomerulonephritis (RPGN) is rare syndrome in children, characterized by clinical features of glomerulonephritis and rapid loss of renal function, and is associated with crescentic glomerulonephritis. Primary membranous nephropathy (MN) is an immune-complex-mediated cause of the adult nephrotic syndrome but occurs less frequently in children. RPGN is rarely observed in adults with primary MN. In this article, we report a case of MN, which developed during long-term follow-up of previously treated RPGN. Our case may be the first to demonstrate primary MN and crescentic glomerulonephritis in a child. We would like to underline the importance of not dropping the long-term follow-up of cases with primary RPGN (not accompanied by other glomerulonephritis and vasculitis symptoms) who had improved with treatment.
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http://dx.doi.org/10.4103/1319-2442.270273DOI Listing
April 2020

Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease.

Pediatr Nephrol 2019 12 19;34(12):2571-2582. Epub 2019 Aug 19.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany.

Background: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients.

Methods: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m.

Results: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 μmol/l (8.7) and 17.0 μmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors.

Conclusions: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.
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http://dx.doi.org/10.1007/s00467-019-04331-6DOI Listing
December 2019

Pediatric Kidney Transplantation in Patients With Urologic Anomalies.

Transplant Proc 2019 Sep 7;51(7):2257-2261. Epub 2019 Aug 7.

Pediatric Nephrology, Ege University Faculty of Medicine, İzmir, Turkey.

Introduction: and Aim. End-stage renal disease owing to structural urologic anomalies is frequent in the pediatric population. Impaired bladder function is thought to have a negative effect on graft function and survival. The aim of this study was to present our single-center experience and long-term follow-up results in pediatric patients who underwent renal transplantation for urologic reasons and to compare graft survival among patients who underwent transplantation for nonurologic reasons.

Method: The paper records of renal transplanted children (<18 years of age) held by Ege University Medical Faculty between 1998 and 2018 were evaluated retrospectively. Patients with normal bladder function who underwent transplantation for urologic reasons were defined as group A, whereas patients who had impaired bladder function and underwent transplantation for urologic reasons were defined as group B; a control group was defined as group C.

Results: Eighty-three patients were included in the study. The creatinine values of the patients at their last visit were no different between groups (P = .930). One-, 5-, and 10-year graft survival rates were 97%, 89%, and 74%, respectively, in group A; 100% for all years in group B; and 97%, 94%, and 80%, respectively, in group C. There was no statistically significant difference in terms of graft survival between groups (P = .351).

Conclusion: Children with end-stage renal disease owing to urologic abnormalities may be good candidates for kidney transplantation with a favorable prognosis for graft function and survival.
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http://dx.doi.org/10.1016/j.transproceed.2019.01.155DOI Listing
September 2019

Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study.

J Hypertens 2019 11;37(11):2247-2255

Center for Pediatrics and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.

Introduction: Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD.

Methods: Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension.

Results: Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT.

Conclusion: INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function.
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http://dx.doi.org/10.1097/HJH.0000000000002160DOI Listing
November 2019

Low levels of urinary epidermal growth factor predict chronic kidney disease progression in children.

Kidney Int 2019 07 20;96(1):214-221. Epub 2019 Mar 20.

Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Urinary epidermal growth factor (uEGF) has recently been identified as a promising biomarker of chronic kidney disease (CKD) progression in adults with glomerular disease. Low levels of uEGF predict CKD progression and appear to reflect the extent of tubulointerstitial damage. We investigated the relevance of uEGF in pediatric CKD. We performed a post hoc analysis of the Cardiovascular Comorbidity in Children with CKD (4C) study, which prospectively follows children aged 6-17 years with baseline estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73 m. uEGF levels were measured in archived urine collected within 6 months of enrollment. Congenital abnormalities of the kidney and urinary tract were the most common cause of CKD, with glomerular diseases accounting for <10% of cases. Median eGFR at baseline was 28 ml/min/1.73 m, and 288 of 623 participants (46.3%) reached the composite endpoint of CKD progression (50% eGFR loss, eGFR < 10 ml/min/1.73 m, or initiation of renal replacement therapy). In a Cox proportional hazards model, higher uEGF/Cr was associated with a decreased risk of CKD progression (HR 0.76; 95% CI 0.69-0.84) independent of age, sex, baseline eGFR, primary kidney disease, proteinuria, and systolic blood pressure. The addition of uEGF/Cr to a model containing these variables resulted in a significant improvement in C-statistics, indicating better prediction of the 1-, 2- and 3-year risk of CKD progression. External validation in a prospective cohort of 222 children with CKD demonstrated comparable results. Thus, uEGF may be a useful biomarker to predict CKD progression in children with CKD.
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http://dx.doi.org/10.1016/j.kint.2019.01.035DOI Listing
July 2019

Acute dialysis in children: results of a European survey.

J Nephrol 2019 Jun 4;32(3):445-451. Epub 2019 Apr 4.

Nephrology and Dialysis Unit, Pediatric Subspecialties Department, Institute for Scientific Research, Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy.

The number of children with acute kidney injury (AKI) requiring dialysis is increasing. To date, systematic analysis has been largely limited to critically ill children treated with continuous renal replacement therapy (CRRT). We conducted a survey among 35 European Pediatric Nephrology Centers to investigate dialysis practices in European children with AKI. Altogether, the centers perform dialysis in more than 900 pediatric patients with AKI per year. PD and CRRT are the most frequently used dialysis modalities, accounting for 39.4% and 38.2% of treatments, followed by intermittent HD (22.4%). In units treating more than 25 cases per year and in those with cardiothoracic surgery programs, PD is the most commonly chosen dialysis modality. Also, nearly one quarter of centers, in countries with a gross domestic product below $35,000/year, do not utilize CRRT at all. Dialysis nurses are exclusively in charge of CRRT management in 45% of the cases and pediatric intensive care nurses in 25%, while shared management is practiced in 30%. In conclusion, this survey indicates that the choice of treatment modalities for dialysis in children with AKI in Europe is affected by the underlying ethiology of the disease, organization/set-up of centers and socioeconomic conditions. PD is utilized as often as CRRT, and also intermittent HD is a commonly applied treatment option. A prospective European AKI registry is planned to provide further insights on the epidemiology, management and outcomes of dialysis in pediatric AKI.
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http://dx.doi.org/10.1007/s40620-019-00606-1DOI Listing
June 2019

Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD: The HDF, Heart and Height Study.

J Am Soc Nephrol 2019 04 7;30(4):678-691. Epub 2019 Mar 7.

Nephrology Unit, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Hypertension and cardiovascular disease are common in children undergoing dialysis. Studies suggest that hemodiafiltration (HDF) may reduce cardiovascular mortality in adults, but data for children are scarce.

Methods: The HDF, Heart and Height study is a nonrandomized observational study comparing outcomes on conventional hemodialysis (HD) versus postdilution online HDF in children. Primary outcome measures were annualized changes in carotid intima-media thickness (cIMT) SD score and height SD score.

Results: We enrolled 190 children from 28 centers; 78 on HD and 55 on HDF completed 1-year follow-up. The groups were comparable for age, dialysis vintage, access type, dialysis frequency, blood flow, and residual renal function. At 1 year, cIMT SD score increased significantly in children on HD but remained static in the HDF cohort. On propensity score analysis, HD was associated with a +0.47 higher annualized cIMT SD score compared with HDF. Height SD score increased in HDF but remained static in HD. Mean arterial pressure SD score increased with HD only. Factors associated with higher cIMT and mean arterial pressure SD-scores were HD group, higher ultrafiltration rate, and higher 2-microglobulin. The HDF cohort had lower 2-microglobulin, parathyroid hormone, and high-sensitivity C-reactive protein at 1 year; fewer headaches, dizziness, or cramps; and shorter postdialysis recovery time.

Conclusions: HDF is associated with a lack of progression in vascular measures versus progression with HD, as well as an increase in height not seen in the HD cohort. Patient-related outcomes improved among children on HDF correlating with improved BP control and clearances. Confirmation through randomized trials is required.
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http://dx.doi.org/10.1681/ASN.2018100990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442347PMC
April 2019

Effect of haemodiafiltration vs conventional haemodialysis on growth and cardiovascular outcomes in children - the HDF, heart and height (3H) study.

BMC Nephrol 2018 08 10;19(1):199. Epub 2018 Aug 10.

Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany.

Background: Cardiovascular disease is prevalent in children on dialysis and accounts for almost 30% of all deaths. Randomised trials in adults suggest that haemodiafiltration (HDF) with high convection volumes is associated with reduced cardiovascular mortality compared to high-flux haemodialysis (HD); however paediatric data are scarce. We designed the haemodiafiltration, heart and height (3H) study to test the hypothesis that children on HDF have an improved cardiovascular risk profile, growth and nutritional status and quality of life, compared to those on conventional HD. We performed a non-randomised parallel-arm intervention study within the International Paediatric Haemodialysis Network Registry comparing children on HDF and conventional HD to determine annualised change in cardiovascular end-points and growth. Here we present the 3H study design and baseline characteristics of the study population.

Methods: 190 children were screened and 177 (106 on HD and 71 on HDF) recruited from 28 centres in 10 countries. There was no difference in age, underlying diagnosis, comorbidities, previous dialysis therapy, dialysis vintage, residual renal function, type of vascular access or blood flow between HD and HDF groups. High flux dialysers were used in 63% of HD patients and ultra-pure water was available in 52%. HDF patients achieved a median convection volume of 13.3 L/m; this was associated with the blood flow rate only ((p = 0.0004, r = 0.42) and independent of access type (p = 0.38).

Discussion: This is the largest study on dialysis outcomes in children that involves deep phenotyping across a wide range of cardiovascular, anthropometric, nutritional and health-related quality of life measures, to test the hypothesis that HDF leads to improved cardiovascular and growth outcomes compared to conventional HD.

Trial Registration: ClinicalTrials.gov: NCT02063776 . The trial was prospectively registered on the 14 Feb 2014.
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http://dx.doi.org/10.1186/s12882-018-0998-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086045PMC
August 2018

Effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism in children with chronic kidney disease.

Nephrol Dial Transplant 2018 12;33(12):2208-2217

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.

Background: We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD).

Methods: In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated.

Results: Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2.

Conclusions: Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.
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http://dx.doi.org/10.1093/ndt/gfy012DOI Listing
December 2018

Familial Mediterranean fever in children from the Aegean region of Turkey: gene mutation frequencies and phenotype-genotype correlation.

Turk J Med Sci 2015 ;45(6):1198-206

Background/aim: Familial Mediterranean fever (FMF) is diagnosed by fever episodes with sterile peritonitis, arthritis, pleurisy, and erysipelas-like erythema. The relationship between phenotype and genotype in FMF has not been adequately explained. The aim of this study was to characterize the phenotype and genotype correlation in FMF.

Materials And Methods: Clinical diagnosis of FMF was conducted according to the Tel Hashomer criteria. Pras scoring was used to determine clinical severity. FMF strip assay analysis was used, and the hotspot regions were observed with PCR amplification and automatic DNA sequence analysis method.

Results: We showed commonly seen mutations (most frequently M694V) in a study group of 191 patients. The disease severity score of patients with M694V mutation was high on the Pras scoring system. Patients with M694V mutation needed high colchicine dosages to control disease activity. R202Q was the most commonly seen polymorphism in 70 patients. The coexpression of R314R single nucleotide polymorphism on third exon was shown in our study. Moreover, D102D, G138G, and A165A subhaplotypes and E474E, Q476Q, and D510D subhaplotypes were also shown.

Conclusion: DNA sequence analysis should be a commonly used method for progress in the field of molecular genetics and for the better understanding of the FMF phenotype and genotype relationships in all populations.
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February 2016

The long-term outlook to final outcome and steroid treatment results in children with idiopathic nephrotic syndrome.

Ren Fail 2015 27;37(8):1267-72. Epub 2015 Aug 27.

c Department of Pediatric Nephrology, Medical Faculty , Ege University , Izmir , Turkey.

Idiopathic Nephrotic Syndrome (INS) was defined as combination of a nephrotic syndrome and non-specific histological abnormalities of the kidney. Among these abnormalities, minimal change nephrotic syndrome (MCNS) is the most common. We report our experience with MCNS; its clinical course, treatments and outcomes. One-hundred twenty children (66 male, 54 female) with MCNS, admitted to Nephrology Department between 1987-2009 was assessed. Their clinical presentations, treatment and disease courses were reviewed. The mean duration of follow-up was 11.5 ± 1.9 years. Initially, all patients given prednisone 2 mg/kg/ day single dose per four weeks a followed by eight weeks of the same daily dose given every other day. After week 12, prednisone was progressively tapered off at the rate of 0.5 mg/kg per 15 daily intervals until complete discontinuation had been achieved by week 16. Steroid resistance was accepted as no achievement of remission following four weeks of prednisone 2 mg/kg/day followed by three intravenous pulses of corticosteroids. At the end of the initial steroid treatment, 106 (88.3%) patients were determinate steroid responsive while 14 (11.7%) patients were steroid resistance. Thirty-eight patients underwent biopsy. At the end of study recovery rate was increased from 88.3% to 94.1%. In conclusion, most of patients entered remission by our therapy end of follow up time. With the support of our satisfactory results among the whole study group, long-term prednisolone treatment still remains valid.
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http://dx.doi.org/10.3109/0886022X.2015.1073051DOI Listing
June 2016

The long-term outlook to final outcome and steroid treatment results in children with idiopathic nephrotic syndrome.

Ren Fail 2015 Aug 14:1-6. Epub 2015 Aug 14.

Department of Pediatric Nephrology, Ankara Children Health and Research Hematology Oncology Education Research Hospital , Ankara , Turkey .

Idiopathic Nephrotic Syndrome (INS) was defined as combination of a nephrotic syndrome and non-specific histological abnormalities of the kidney. Among these abnormalities, minimal change nephrotic syndrome (MCNS) is the most common. We report our experience with MCNS; its clinical course, treatments and outcomes. One-hundred twenty children (66 male, 54 female) with MCNS, admitted to Nephrology Department between 1987-2009 was assessed. Their clinical presentations, treatment and disease courses were reviewed. The mean duration of follow-up was 11.5 ± 1.9 years. Initially, all patients given prednisone 2 mg/kg/ day single dose per four weeks a followed by eight weeks of the same daily dose given every other day. After week 12, prednisone was progressively tapered off at the rate of 0.5 mg/kg per 15 daily intervals until complete discontinuation had been achieved by week 16. Steroid resistance was accepted as no achievement of remission following four weeks of prednisone 2 mg/kg/day followed by three intravenous pulses of corticosteroids. At the end of the initial steroid treatment, 106 (88.3%) patients were determinate steroid responsive while 14 (11.7%) patients were steroid resistance. Thirty-eight patients underwent biopsy. At the end of study recovery rate was increased from 88.3% to 94.1%. In conclusion, most of patients entered remission by our therapy end of follow up time. With the support of our satisfactory results among the whole study group, long-term prednisolone treatment still remains valid.
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August 2015

Bioimpedance for assessing volume status in children with nephrotic syndrome.

Turk J Med Sci 2015 ;45(2):339-44

Background/aim: The effectiveness of assessing volume load via bioimpedance in pediatric patients with nephrotic syndrome (NS) was investigated.

Materials And Methods: Patients with NS (n = 34) were compared with healthy controls (n = 20). The inferior vena cava index and inferior vena cava collapsibility index (IVCCI) scores were determined for all subjects. Bioimpedance measurements were used to directly determine volume load. Clinical findings, relative fluid load, and echocardiographic measurements were determined and compared with bioimpedance in calculating volume load.

Results: The sensitivity and specificity of bioimpedance in determining volume load were found to be 65% and 90%, respectively. IVCCI was lower in NS patients than in controls. There were also significant differences in IVCCI values between patients with localized and generalized edema. Relative fluid load was higher in NS patients with generalized edema as opposed to patients with localized edema. For calculating volume load, the sensitivity of bioimpedance, clinical findings, and echocardiographic measurements was 87%, 95%, and 83%, respectively, whereas the specificity of determining volume load by bioimpedance, clinical findings, and echocardiographic measurements was 50%, 10%, and 80%, respectively.

Conclusion: Our data suggest that bioimpedance may be superior to echocardiography in determining volume load in children with NS, because it is cost-effective, reliable, and relatively simple to perform.
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July 2015

Are we late for the diagnosis of acute kidney injury in the intensive care units in pediatric patients? A preliminary, retrospective observational study among 66 patients.

Minerva Pediatr 2016 Aug 20;68(4):256-61. Epub 2014 Nov 20.

Department of Pediatric Nephrology, Ege University Faculty of Medicine Izmir, Izmir, Turkey -

Background: The purposes of this study were to emphasize the importance of Risk, Injury, Failure, Loss, and End-Stage (RIFLE) classification in early diagnose and prognosis of acute kidney injury (AKI), and to evaluate the practicability of the RIFLE criteria in intensive care units.

Methods: Sixty-six patients applied acute peritoneal dialysis were included into the study. Patients having acute peritoneal dialysis within the first 24 hours of intensive care unit admission were named group 1, between 24-48 hours group 2, and those who had acute peritoneal dialysis 48 hours or more after admission to the intensive care unit were named group 3. Retrospectively, we evaluated patients by RIFLE criteria at the consultation time, and patients who had been just in AKI were called late referral patients. The mean interval time between the onset of AKI and the consultation time was defined as delay time in late referral patients.

Results: There were 20 patients in group 1, 15 were in group 2 and 31 in group 3. In total there were 18/66 patients in risk, 13/66 in injury while 35/66 in failure. There was statistically difference between delay times of in risk and failure class in group 3 (P<0.05). Also delayed patient numbers of both risk and failure class were found statistically highly significant (P<0.001).

Conclusions: Most of the patients were in failure class at the time of consultation. We guess that if they would have been diagnosed earlier, prognosis might have been better. Therefore early diagnosis of AKI with RIFLE criteria and early initiation of acute peritoneal dialysis would probably improve prognosis.
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August 2016

Cardiovascular functional and structural changes in children with primary hypertension.

Minerva Pediatr 2016 Feb 20;68(1):27-35. Epub 2014 Nov 20.

Department of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Turkey -

Background: Primary hypertension in children is not a benign condition because of end-organ damage. Early investigations of cardiovascular effects rely on vascular structural and functional changes. We aimed to determine presence of early cardiovascular involvement in children with primary hypertension. For this purposes, we investigated functional and morphological changes in vascular system.

Methods: Seventy-five consecutive patients with primary hypertension and 35 healthy children comparable for age and gender were studied. Patients were classified according to the stages of blood pressure. Intima-media thickness of the carotid arteries (cIMT), carotid-femoral pulse wave velocity (PWVcf) and Pulse Wave Augmentation Index (AIx) and Left Ventricular Mass Index (LVMi) were investigated.

Results: PWVcf and AIx were higher in patients (5.87±0.87 m/s vs. 5.29±0.67 m/s, P=0.02; 9.41±8.54% vs. 8.36±3.59%, P=0.04, respectively) than in controls. cIMT was evaluated significantly higher in study group than controls (0.46±0.06 mm vs. 0.35±0.12 mm, respectively, P=0.01). The mean LVMi was higher in patients (32.9±11.5 vs. 28.8±1.55, P=0.01).

Conclusion: Our results demonstrated that vascular findings were more sensitive for target organ changes than the more frequently utilized LVMi in patients with pre-hypertension.
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February 2016

Success of continuous veno-venous hemodiafiltration treatment in children monitored in the intensive care units.

Ren Fail 2014 Oct;36(9):1411-5

Denizli State Hospital , Denizli , Turkey .

Introduction: As intensive care units (ICU) have improved, presence of multiple-organ dysfunctions in majority of patients with acute renal failure (ARF) has become clearer. To facilitate multi-organ support, continuous renal replacement therapy (CRRT) techniques have been developed. This study is the one that reports the experience on children including newborns receiving CRRT monitored in ICU.

Materials And Methods: The study was performed retrospectively in children who had Continuous Veno- Venous Hemodiafiltration (CVVHDF) as a CRRT modality in ICU. Clinical data, primary cause, consultation time, duration and initiation time of CVVHDF were recorded. Patients were classified as cardiac and non-cardiac in respect to primary dysfunction. Stage of renal failure was evaluated according to pRIFLE criteria. Outcome was identified as primary and secondary. Primary outcome was accepted as the composite correction of uremia and metabolic parameters, and regression of fluid overload, while secondary outcomes were assessed as improvement of hemodynamic instability and survival.

Results: A total of 36 patients' files were scanned. There were 10 cases in cardiac group and 26 cases in non-cardiac group. There were statistically better differences between primary and secondary outcome rates of cardiac cases. Although there was no difference between cardiac and non-cardiac cases in terms of primary outcome, secondary outcome was statistically significant. Timing of consultation and CVVHDF was not found to have an effect on the outcome.

Conclusion: Our results indicated that CVVHDF treatment was successful even in cardiac patients with high mortality and in patients at their later stage of ARF.
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http://dx.doi.org/10.3109/0886022X.2014.950932DOI Listing
October 2014

Reference values for serum dehydroepiandrosterone-sulphate in healthy children and adolescents with emphasis on the age of adrenarche and pubarche.

Clin Endocrinol (Oxf) 2015 May 21;82(5):712-8. Epub 2014 Oct 21.

Zeynep Kamil Maternity and Children's Diseases Research and Training State Hospital, Altunizade, Istanbul, Turkey; Faculty of Medicine, Department of Pediatric Endocrinology, Marmara University, Pendik, Istanbul, Turkey.

Objective: Adrenarche is a component of normal pubertal development. Recent decades have witnessed changes in the timing and tempo of puberty in different populations. We aimed to obtain normative data on dehydroepiandrosterone-sulphate (DHEA-S) secretion in healthy children and to evaluate the age of adrenarche, pubarche and the DHEA-S levels at which pubarche starts in both sexes.

Methods: Serum DHEA-S concentrations were measured in 531 healthy (291 female) Turkish children aged 1 month-18 years by an automated chemiluminescence method. Pubic hair development was evaluated. DHEA-S concentrations >108·4 nmol/l (40 μg/dl) were regarded as adrenarche. Age-related normative data were constructed. Age at adrenarche and pubarche and the DHEA-S levels at pubarche were estimated using ROC analyses.

Results: Serum DHEA-S levels were high in the first 6 months of life then declined below 108·4 nmol/l (40 μg/dl) with a cut-off age of 0·46 years for girls and 0·61 years for boys with 98% and 96% statistical sensitivity. Stable minimum levels were observed for the following 5 years. The cut-off age for DHEA-S levels rising above 108·4 nmol/l (40 μg/dl) was 8·0 and 7·0 years for girls for boys, respectively. DHEA-S levels at transition from Tanner stage P1 to P2 was 90·5 nmol/l (33·4 μg/dl) in girls and 118 nmol/l (43·6 μg/dl) in boys. Median (CI) DHEA-S levels were 170·7(94·8-336) and 244(119·2-357·7) nmo/l [63(35-124) and 90(44-132) μg/dl] in girls and boys, respectively, with Tanner stage P2 pubic hair.

Conclusions: We established reference data of serum DHEA-S levels in a large group of children. Currently, adrenarche (DHEA-S>108·4 nmol/l) starts 1 year earlier in boys but higher DHEA-S levels are needed for transition from P1 to P2 in boys.
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http://dx.doi.org/10.1111/cen.12612DOI Listing
May 2015

Single center experience in patients with unilateral multicystic dysplastic kidney.

J Pediatr Urol 2014 Aug 30;10(4):763-8. Epub 2014 Apr 30.

Zeynep Kamil Maternity and Children's Training and Research Hospital, Pediatric Nephrology, Istanbul, Turkey. Electronic address:

Objective: To determine the clinical features, long-term outcomes, and additional urological anomalies of patients treated for multicystic dysplastic kidney (MDK).

Materials And Methods: Patients with MDK who were followed between January 2004 and October 2012 were reviewed retrospectively. Demographic, clinical, laboratory, and radiological data were evaluated.

Results: A total of 68 patients with MDK were followed for a mean period of 46.8 ± 32.4 months. MDK was detected by antenatal ultrasound in 64 (94.1%) of the patients. Ten patients had (14.7%) additional urological anomalies in contralateral kidney. Vesicoureteral reflux was found in five patients (7.3%). Other urological anomalies were megaureter (two), cortical renal cyst (two), ureteropelvic junction obstruction (one), and renal ectopy (one). Urinary tract infection was detected in 14 (20.5%) patients. Four (5.9%) patients had hypertension. Compensatory hypertrophy was detected in 29 (42.6%) patients. Eight (11.8%) of these 29 patients had glomerular hyperfiltration and three (4.4%) of these eight patients also had proteinuria. Follow-up ultrasound revealed complete involution in 19 (35.8%) patients. Nephrectomy was performed in 15 (22.0%) patients. Indications of nephrectomy were, recurrent urinary infection (four), hypertension (three), ureterocele (two), renal calculi (one), flank pain (one), hematuria (one), persistent large cystic kidney (three), and atypical US findings (two).

Conclusion: In patients with MDK, depending on the clinical, laboratory, and radiological findings, appropriate timing of operation by multidisciplinary approach is important for early detection and treatment of any possible complications.
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http://dx.doi.org/10.1016/j.jpurol.2014.03.008DOI Listing
August 2014

The predictive value of urinary UPIb mRNA levels in VUR and recurrent urinary tract infections.

Clin Nephrol 2014 Mar;81(3):152-8

Department of Pediatric Nephrology, and Department of Pediatrics, Molecular Medicine Laboratory, Ege University Faculty of Medicine, Izmir, Turkey.

Background: Vesicoureteral reflux (VUR) is a risk factor for progressive kidney damage especially when it is accompanied by urinary tract infections (UTIs). Uroplakins (UPs) are integral proteins found in the structure of urothelium. In the present study, we evaluated the usefulness of urinary UPIb messenger ribonucleic acid (mRNA) levels as an early and noninvasive diagnostic tool for VUR and as an indicator for predisposition to UTI.

Methods: Urinary UPIb mRNA levels were determined in patients experiencing their first UTI episode (n = 28) or recurrent UTI (n = 31) as well as patients having UTI with VUR (n = 30). These results were compared to a control group (n = 26).

Results: The UPIb mRNA values among patients diagnosed with their first UTI were lower, but not statistically different, than those in the control group. The UPIb mRNA levels of patients with recurrent UTI and UTI with VUR were significantly lower than those observed in control individuals.

Conclusion: Urine UPIb levels may be useful for predicting the risk of recurrent UTI in patients diagnosed with their first UTI and may also be considered as a noninvasive screening test for VUR.
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http://dx.doi.org/10.5414/cn107778DOI Listing
March 2014

Does NPHS1 polymorphism modulate P118l mutation in NPHS2?

Saudi J Kidney Dis Transpl 2013 Nov;24(6):1210-3

Department of Pediatric Nephrology, Ege University Faculty of Medicine, Bornova, Izmir, Turkey.

Nephrotic syndrome (NS) in the first year of life is uncommon and makes up a heterogeneous group of disorders. Subsequent studies have further defined the phenotype associated with mutations in the NPHS2 gene, revealing that patients usually develop NS from birth to 6 years of age. We report a child aged 4 months with steroid-resistant NS who had polymorphism of NPHS1 (E117K) and mutation of NPHS2 (P118L). Our patient was carrying a polymorphic NPHS1 mutation, while phenotypically she had a poor prognostic NPHS2 mutation. However, it must be questioned whether this polymorphic change (E117K) alters the signaling pathways of the podocytes and leads to P118L mutation, thus making it behave differently. Perhaps, this would be called a genetic modifier in future.
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http://dx.doi.org/10.4103/1319-2442.121300DOI Listing
November 2013

An infant with Imersland-Gräsbeck syndrome.

Saudi J Kidney Dis Transpl 2012 May;23(3):569-71

Department of Pediatric Nephrology, Ege University, Faculty of Medicine, Bornova Izmir, Turkey.

The Imersland-Gräsbeck Syndrome (IGS) is a rare inherited disorder characterized by megaloblastic anemia due to a selective Vitamin B₁₂ malabsorption in association with mild proteinuria. This syndrome can be diagnosed and treated easily. Herein, we describe an infant with IGS as a rare etiology of growth retardation with diarrhea, vomiting and therapy-resistant proteinuria.
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May 2012

Outcome results in children with IgA nephropathy: a single center experience.

Int J Nephrol Renovasc Dis 2012 20;5:23-8. Epub 2012 Jan 20.

Ege University Faculty of Medicine Department of Pediatric Nephrology, Izmir.

Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis. Patients manifest variable clinical symptoms (eg, microhematuria) with preserved or progressive deterioration of renal function resulting in end-stage renal disease. The aim of this study was to evaluate patients from a single center to describe the clinical features, treatments, and follow-up results of those with the disease.

Methods: This is a retrospective data study of all children with IgAN. Patients who had a histopathologically proven diagnosis of IgAN and were followed up for at least 5 years were included in the study. Renal biopsy, graded as Hass classification, was performed on all patients. A total of 39 patients were included in the study.

Results: The mean follow-up time (± standard deviation) was 10.4 ± 3.51 (range 5-16) years. Twenty-nine patients (74.4%) were male and ten (25.6%) were female. Nineteen (48.7%) patients presented with recurrent macroscopic hematuria, ten (25.6%) with microscopic hematuria ± proteinuria, six (15.4%) with nephritic syndrome, and four (10.3%) with nephrotic syndrome. All patients underwent a renal biopsy, which was graded according to the Hass classification. At the end of follow-up time, 18 (46.1%) patients were normal, 15 (38.5%) had minor urinary abnormalities, three (7.7%) had active renal disease, and three (7.7%) developed renal failure.

Conclusion: The results of the present study are better than those from most other series. The majority of children with IgAN in this study were admitted with recurrent macroscopic hematuria and found to have a good prognosis. We suggest that children with IgAN have a good prognosis in the first 5-year follow-up period.
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http://dx.doi.org/10.2147/IJNRD.S24684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278251PMC
October 2012