Publications by authors named "Aysun Bayazit"

75 Publications

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

Evaluation of non-infectious complications of peritoneal dialysis in children: a multicenter study.

Pediatr Nephrol 2021 Feb 29;36(2):417-423. Epub 2020 Jul 29.

Faculty of Medicine, Department of Pediatric Nephrology, Erciyes University, Kayseri, Turkey.

Background: Peritoneal dialysis (PD) is the most common kidney replacement therapy in children. Complications associated with PD affect treatment success and sustainability. The aim of this study was to investigate the frequency of PD-related non-infectious complications and the predisposing factors.

Methods: Retrospective data from 11 centers in Turkey between 1998 and 2018 was collected. Non-infectious complications of peritoneal dialysis (NICPD), except metabolic ones, in pediatric patients with regular follow-up of at least 3 months were evaluated.

Results: A total of 275 patients were included. The median age at onset of PD and median duration of PD were 9.1 (IQR, 2.5-13.2) and 7.6 (IQR, 2.8-11.9) years, respectively. A total of 159 (57.8%) patients encountered 302 NICPD within the observation period of 862 patient-years. The most common NIPCD was catheter dysfunction (n = 71, 23.5%). At least one catheter revision was performed in 77 patients (28.0%). Longer PD duration and presence of swan neck tunnel were associated with the development of NICPD (OR 1.191; 95% CI 1.079-1.315, p = 0.001 and OR 1.580; 95% CI 0.660-0.883, p = 0.048, respectively). Peritoneal dialysis was discontinued in 145 patients; 46 of whom (16.7%) switched to hemodialysis. The frequency of patients who were transferred to hemodialysis due to NICPD was 15.2%.

Conclusions: Peritoneal dialysis-related non-infectious complications may lead to discontinuation of therapy. Presence of swan neck tunnel and long duration of PD increased the rate of NICPD. Careful monitoring of patients is necessary to ensure that PD treatment can be maintained safely.
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http://dx.doi.org/10.1007/s00467-020-04719-9DOI Listing
February 2021

From infancy to adulthood: challenges in congenital nephrogenic diabetes insipidus.

J Pediatr Endocrinol Metab 2020 Jul 4. Epub 2020 Jul 4.

Department of Pediatric Nephrology, Cukurova Univsersity Faculty of Medicine, Adana, Turkey.

Objectives Congenital nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder which is characterized by unresponsiveness to arginine vasopressin (AVP) in collecting ducts and leads to polyuria and polydipsia. The wide clinical spectrum of congenital NDI can cause difficulties in early diagnosis. We aimed to evaluate clinical prognosis of children with congenital NDI in long-term period. Methods Nineteen children with congenital NDI followed up in Pediatric Nephrology Department were enrolled to the study. This study is a single-center retrospective study, which reports clinical follow-up and genetic results of children with congenital NDI. Results Presenting symptoms of patients were mostly dehydration and fever due to polyuria and polydipsia. Four male patients had bilateral nonobstructive hydroureteronephrosis (HUN) and neurogenic bladder which requires clean intermittent catheterization (CIC). One patient had intracranial calcification which is a rarely seen complication in congenital NDI due to recurrent hypernatremic dehydration and severe brain dehydration. The causative mutations were identified in all patients. The identified mutations in six of them (31.6%) were hemizygous mutations in AVPR2 gene and homozygous mutations of AQP2 gene in the rest 13 cases (68.4%). More than that, four of these mutations (two in AVPR2 and two in AQP2) were novel mutations. Noncompliance with the treatments is associated with high risk of morbidity due to neurogenic bladder and chronic kidney disease (CKD). Conclusions The prognosis of congenital NDI is good when diagnosis can be made early and treatment is started immediately. Genetic counseling and prenatal testing for hereditary diseases are recommended especially in regions with relatively higher rates of consanguineous marriages.
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http://dx.doi.org/10.1515/jpem-2019-0529DOI Listing
July 2020

Evaluation of phenotypic and genotypic features of children with distal kidney tubular acidosis.

Pediatr Nephrol 2020 12 1;35(12):2297-2306. Epub 2020 Jul 1.

Department of Pediatric Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey.

Background: The present study aimed to assess genotype-phenotype correlations with long-term prognosis in children with distal kidney tubular acidosis (dKTA). The kidney function of children with dKTA could be impaired in the long-term.

Methods: Thirty-one children with dKTA from 23 families were included in the present study. Demographic features, growth parameters, clinical manifestations, follow-up results, and genetic analysis results of the patients were recorded.

Results: Eighteen children (58.1%) were male. The median age at diagnosis was 3 months. The median follow-up period was 77 months and the longest was 23.5 years. Eight (28.8%) patients had chronic kidney disease (CKD) stage 2 or 3. Three patients aged 24, 23, and 19 years had CKD stage 3 with an estimated glomerular filtration rate of 54, 57, and 48 mL/min/1.73 m, respectively. Thirteen patients had mutations in the ATP6V0A4 gene, eight had mutations in the ATP6V1B1 gene, and three had mutations in the SLC4A1 gene. There was no significant correlation between molecular diagnosis and CKD. Growth retardation with a height below a standard deviation (SD) score of - 2 was found in 14 patients (45.1%) at the time of diagnosis. The mean height SD score at the last visit was significantly higher in patients who had adequate metabolic control at > 75% of all visits as compared with that in patients who did not.

Conclusion: Patients with dKTA usually have a good clinical prognosis in childhood with appropriate treatment; however, dRTA is characterized by deterioration of kidney function in adulthood, particularly after puberty.
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http://dx.doi.org/10.1007/s00467-020-04685-2DOI 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

Long-term follow-up results of patients with ADCK4 mutations who have been diagnosed in the asymptomatic period: effects of early initiation of CoQ10 supplementation.

Turk J Pediatr 2019 ;61(5):657-663

Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara.

Atmaca M, Gülhan B, Atayar E, Karabay Bayazıt A, Candan C, Arıcı M, Topaloğlu R, Özaltın F. Long-term follow-up results of patients with ADCK4 mutations who have been diagnosed in the asymptomatic period: effects of early initiation of CoQ10 supplementation. Turk J Pediatr 2019; 61: 657-663. ADCK4-related glomerulopathy is a recently recognized clinical entity associated with insidious onset in young children and a high potential to progress to chronic kidney disease in adolescents. Early initiation of exogenous coenzyme Q10 (CoQ10) supplementation in the asymptomatic period could be protective on renal functions. In the present study, we aimed to investigate long-term follow-up of patients that we have diagnosed during the asymptomatic period and in whom we started CoQ10 treatment. We analyzed long-term effects of CoQ10 on proteinuria and estimated glomerular filtration rate (eGFR) in this patient population. A total of 8 patients (4 female, 4 male) from 6 different families were included. The mean age at diagnosis and at last visit were 16.8±11.2 years and 20.7±11.7 years, respectively. None of the patients had extrarenal system involvement. At the time of initiation of treatment; median eGFR was 107.8 ml/min/1.73 m2, median proteinuria was 1008 mg/m2/day. After a median follow-up period of 25.3±5.8 months, median proteinuria decreased to 318.5 mg/m2/day (p=0.03) and median eGFR remained stable at 99.6 ml/min/1.73 m2 (p=0.21). Coenzyme Q10 treatment is effective for reducing proteinuria and seems to be renoprotective.
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http://dx.doi.org/10.24953/turkjped.2019.05.003DOI Listing
July 2020

Proptosis in a child with chronic kidney disease: Questions.

Pediatr Nephrol 2020 05 11;35(5):787-788. Epub 2019 Dec 11.

Department of Pediatric Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04422-4DOI Listing
May 2020

Proptosis in a child with chronic kidney disease: Answers.

Pediatr Nephrol 2020 05 10;35(5):789-791. Epub 2019 Dec 10.

Department of Pediatric Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04423-3DOI Listing
May 2020

Trientine-induced Rhabdomyolysis in an Adolescent with Wilson's Disease.

Indian J Crit Care Med 2019 Oct;23(10):489-490

Department of Pediatrics, Division of Pediatric Nephrology, Cukurova University, Faculty of Medicine, Adana, Turkey.

Background: Drugs are very important in the etiology of nontraumatic rhabdomyolysis.

Case Descriptions: A 16-year-old male patient with Wilson's disease was admitted for myoclonic contractions. Oral trientine was started for neurological problems and tremor on the hands due to D-penicillamine 1 month ago. Patient was oligoanuric, and his creatine kinase level was 15197 U/L. Rhabdomyolysis was associated with trientine, and trientine treatment was stopped. Hemodiafiltration was performed. The patient began to urinate on the 24th day.

Conclusion: This is the first pediatric patient with rhabdomyolysis induced by trientine. Drugs used should be questioned carefully in patients with rhabdomyolysis.

How To Cite This Article: Aslan N, Yavuz S, Yildizdas D, Horoz OO, Coban Y, Tumgor G, et al. Trientine-induced Rhabdomyolysis in an Adolescent with Wilson's Disease. Indian J Crit Care Med 2019;23(10):489-490.
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http://dx.doi.org/10.5005/jp-journals-10071-23271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842836PMC
October 2019

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

Haemodiafiltration does not lower protein-bound uraemic toxin levels compared with haemodialysis in a paediatric population.

Nephrol Dial Transplant 2020 04;35(4):648-656

Department of Internal Medicine & Pediatrics, Ghent University, Ghent, Belgium.

Background: Haemodiafiltration (HDF) is accepted to effectively lower plasma levels of middle molecules in the long term, while data are conflicting with respect to the additive effect of convection on lowering protein-bound uraemic toxins (PBUTs). Here we compared pre-dialysis β2-microglobulin (β2M) and PBUT levels and the percentage of protein binding (%PB) in children on post-dilution HDF versus conventional high- (hf) or low-flux (lf) haemodialysis (HD) over 12 months of treatment.

Methods: In a prospective multicentre, non-randomized parallel-arm intervention study, pre-dialysis levels of six PBUTs and β2M were measured in children (5-20 years) on post-HDF (n = 37), hf-HD (n = 42) and lf-HD (n = 18) at baseline and after 12 months. Analysis of variance was used to compare levels and %PB in post-HDF versus conventional hf-HD and lf-HD cross-sectionally at 12 months and longitudinal from baseline to 12 months.

Results: For none of the PBUTs, no difference was found in either total and free plasma levels or %PB between post-HDF versus the hf-HD and lf-HD groups. Children treated with post-HDF had lower pre-dialysis β2M levels [median 23.2 (21.5; 26.6) mg/dL] after 12 months versus children on hf-HD [P<0.01; 35.2 (29.3; 41.2) mg/dL] and children on lf-HD [P<0.001; 47.2 (34.3; 53.0) mg/dL]. While β2M levels remained steady in the hf-HD and lf-HD group, a decrease in β2M was demonstrated for children on post-HDF (P<0.01).

Conclusions: While post-HDF successfully decreased β2M, no additive effect on PBUT over 12 months of treatment was found. PBUT removal is complex and hampered by several factors. In children, these factors might be different from adults and should be explored in future research.
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http://dx.doi.org/10.1093/ndt/gfz132DOI Listing
April 2020

Arterial tissue transcriptional profiles associate with tissue remodeling and cardiovascular phenotype in children with end-stage kidney disease.

Sci Rep 2019 07 16;9(1):10316. Epub 2019 Jul 16.

Department of Pediatric Nephrology and Center for Cardiovascular Research, Charité - University Medicine, Berlin, Germany.

Chronic kidney disease (CKD) greatly increases the risk for cardiovascular disease (CVD). However, molecular mechanisms underlying CKD-induced arterial remodeling are largely unknown. We performed a systematic analysis of arterial biopsies from children with stage 5 predialysis CKD participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4 C) study. For comparison, we studied biopsies from children without CKD, coronary bypass vessels from adults with atherosclerotic coronary heart disease without CKD and aortic sections of subtotally nephrectomized rats. In pediatric CKD patients, gene expression was correlated to the cardiovascular phenotype assessed by surrogate end-points. The arterial calcium content correlated with the intima-media thickness (IMT) of biopsied vessels from pediatric CKD patients, was markedly increased compared to biopsies from children without CKD and comparable to adult coronary bypass patients. Significant transcriptional changes included ECM components, pro-calcifying factors, and physiological calcification inhibitors; most were highly accordant with changes observed in adults with atherosclerosis and in uremic rats. Individual gene expression levels were significantly associated with the left ventricular mass index and carotid intima media thickness. Thus, inflammatory processes (TNF, IL-10), calcification inhibitors (CA2), the Wnt-pathway (FGF-2) and foremost, ECM components (HMGA1, VNN1, VCAN), impact pathobiological responses in arteries from children with CKD.
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http://dx.doi.org/10.1038/s41598-019-46805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635360PMC
July 2019

An infant with hyponatremia, hyperkalemia, and metabolic acidosis associated with urinary tract infection: Answers.

Pediatr Nephrol 2019 10 3;34(10):1739-1741. Epub 2019 May 3.

Faculty of Medicine, Department of Pediatric Nephrology, Cukurova University, Adana, Turkey.

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http://dx.doi.org/10.1007/s00467-019-04254-2DOI Listing
October 2019

Association between timing of dialysis initiation and clinical outcomes in the paediatric population: an ESPN/ERA-EDTA registry study.

Nephrol Dial Transplant 2019 11;34(11):1932-1940

Department of Pediatric Nephrology, Gazi University, Ankara, Turkey.

Background: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment.

Methods: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias.

Results: The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7-14.5 versus 9.4, IQR: 2.6-14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings.

Conclusions: We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival.
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http://dx.doi.org/10.1093/ndt/gfz069DOI Listing
November 2019

Uremic Toxin Concentrations are Related to Residual Kidney Function in the Pediatric Hemodialysis Population.

Toxins (Basel) 2019 04 24;11(4). Epub 2019 Apr 24.

Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.

Protein-bound uremic toxins (PBUTs) play a role in the multisystem disease that children on hemodialysis (HD) are facing, but little is known about their levels and protein binding (%PB). In this study, we evaluated the levels and %PB of six PBUTs cross-sectionally in a large pediatric HD cohort ( = 170) by comparing these with healthy and non-dialysis chronic kidney disease (CKD) stage 4-5 ( = 24) children. In parallel β2-microglobulin (β2M) and uric acid (UA) were evaluated. We then explored the impact of age and residual kidney function on uremic toxin levels and %PB using analysis of covariance and Spearman correlation coefficients (). We found higher levels of β2M, p-cresyl glucuronide (pCG), hippuric acid (HA), indole acetic acid (IAA), and indoxyl sulfate (IxS) in the HD compared to the CKD4-5 group. In the HD group, a positive correlation between age and pCG, HA, IxS, and pCS levels was shown. Residual urine volume was negatively correlated with levels of β2M, pCG, HA, IAA, IxS, and CMPF ( -0.2 to -0.5). In addition, we found overall lower %PB of PBUTs in HD versus the CKD4-5 group, and showed an age-dependent increase in %PB of IAA, IxS, and pCS. Furhtermore, residual kidney function was overall positively correlated with %PB of PBUTs. In conclusion, residual kidney function and age contribute to PBUT levels and %PB in the pediatric HD population.
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http://dx.doi.org/10.3390/toxins11040235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521157PMC
April 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

Juvenile systemic lupus erythematosus: a single-center experience from southern Turkey.

Clin Rheumatol 2019 May 16;38(5):1459-1468. Epub 2019 Jan 16.

Department of Pediatric Rheumatology, Faculty of Medicine, Cukurova University, Adana, Turkey.

Objectives: This study was conducted to analyze clinical characteristics, laboratory data, disease activity, and outcome of juvenile systemic lupus erythematosus (jSLE) patients from southern Turkey.

Methods: Fifty-three patients with jSLE diagnosed according to the revised American College of Rheumatology 1997 criteria between January 2005 and June 2018 were included in the present study.

Results: The median age at the diagnosis was 12.8 (range, 5.1-17.7) years. The female to male ratio was 9.6:1. The most prevalent clinical features were mucocutaneous involvement (96.2%) and constitutional manifestations (94.3%). Renal manifestations, hematological manifestations, and neuropsychiatric involvement were detected in 40 (75%), in 38 (71.7%), and in 13 (24.5%) patients, respectively. Renal biopsy was performed to 49 patients (92.5%). Class IV lupus nephritis (LN) (34%) and class II LN (20.4%) were the most common findings. Mycophenolate mofetil, cyclophosphamide with corticosteroid were the main treatment options. Eighteen patients received rituximab and one tocilizumab. The mean SLE Disease Activity Index (SLEDAI) score at the time of diagnosis was 22.47 ± 8.8 (range = 3-49), and 1.34 ± 1.85 (range = 0-7) at last visit. Twenty-one patients (39.6%) had damage in agreement with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (PedSDI; mean = 0.60 ± 0.94; range = 0-5) criteria. Growth failure was the most prevalent cause of damage (n = 13, 26%). One patient deceased due to severe pulmonary hemorrhage and multiple cerebral thromboses.

Conclusion: jSLE patients in this cohort have severe disease in view of the higher frequency of renal and neurologic involvement. Nevertheless, multicenter studies are needed to make a conclusion for all Turkish children with jSLE.
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http://dx.doi.org/10.1007/s10067-019-04433-4DOI Listing
May 2019

Infants with congenital nephrotic syndrome have comparable outcomes to infants with other renal diseases.

Pediatr Nephrol 2019 04 29;34(4):649-655. Epub 2018 Oct 29.

Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.

Background: Children with congenital nephrotic syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children.

Methods: We conducted a retrospective case note review across members of the European Society for Pediatric Nephrology Dialysis Working Group to evaluate dialysis management, complications of dialysis, and outcomes in children with CNS.

Results: Eighty children (50% male) with CNS were identified form 17 centers over a 6-year period. Chronic dialysis was started in 44 (55%) children at a median age of 8 (interquartile range 4-14) months. Of these, 17 (39%) were on dialysis by the age of 6 months, 30 (68%) by 1 year, and 40 (91%) by 2 years. Peritoneal dialysis (PD) was the modality of choice in 93%, but 34% switched to hemodialysis (HD), largely due to catheter malfunction (n = 5) or peritonitis (n = 4). The peritonitis rate was 0.77 per patient-year. Weight and height SDS remained static after 6 months on dialysis. In the overall cohort, at final follow-up, 29 children were transplanted, 18 were still on dialysis (15 PD, 3 HD), 19 were in pre-dialysis chronic kidney disease (CKD), and there were 14 deaths (8 on dialysis). Median time on chronic dialysis until transplantation was 9 (6-18) months, and the median age at transplantation was 22 (14-28) months.

Conclusions: Infants with CNS on dialysis have a comparable mortality, peritonitis rate, growth, and time to transplantation as infants with other primary renal diseases reported in international registry data.
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http://dx.doi.org/10.1007/s00467-018-4122-0DOI Listing
April 2019

Management of children with congenital nephrotic syndrome: challenging treatment paradigms.

Nephrol Dial Transplant 2019 08;34(8):1369-1377

Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Background: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective.

Methods: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS.

Results: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3-8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1-8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2-9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7-16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died.

Conclusion: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy.
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http://dx.doi.org/10.1093/ndt/gfy165DOI Listing
August 2019

Genetic associations of hemoglobin in children with chronic kidney disease in the PediGFR Consortium.

Pediatr Res 2019 02 15;85(3):324-328. Epub 2018 Aug 15.

Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Genome-wide association studies (GWAS) in healthy populations have identified variants associated with erythrocyte traits, but genetic causes of hemoglobin variation in children with CKD are incompletely understood.

Methods: The Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE), and Cardiovascular Comorbidity in Children with CKD (4C). We performed cross-sectional and longitudinal association studies of single-nucleotide polymorphisms (SNPs) in 1125 patients.

Results: Children of European (n = 725) or Turkish (n = 400) ancestry (EA or TA) were included. In cross-sectional analysis, two SNPs (rs10758658 and rs12718597) previously associated with RBC traits were significantly associated with hemoglobin levels in children of EA and TA. In longitudinal analysis, SNP rs2540917 was nominally associated with hemoglobin in EA and TA children.

Conclusions: SNPs associated with erythrocyte traits in healthy populations were marginally significant for an association with hemoglobin. Further analyses/replication studies are needed in larger CKD cohorts to investigate SNPs of unknown significance associated with hemoglobin. Functional studies will be required to confirm that the observed associations between SNPs and clinical phenotype are causal.
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http://dx.doi.org/10.1038/s41390-018-0148-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377354PMC
February 2019

Time-averaged hemoglobin values, not hemoglobin cycling, have an impact on outcomes in pediatric dialysis patients.

Pediatr Nephrol 2018 11 13;33(11):2143-2150. Epub 2018 Aug 13.

Department of Pediatric Nephrology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey.

Background: During erythropoietin-stimulating agent (ESA) treatment, hemoglobin (Hb) levels usually fluctuate; this phenomenon is known as "Hb cycling (HC)." In this study, we aimed to evaluate the predictors of HC and its impact on left ventricular hypertrophy (LVH) as a patient-important outcome parameter in pediatric dialysis patients.

Methods: Records of patients followed up in nine pediatric nephrology centers between 2008 and 2013 were reviewed. More than 1 g/dL decrease or increase in Hb level was considered as HC. Patients were divided into two groups according to 12-month Hb trajectory as rare cycling (RC) (≤ 3) and frequent cycling (FC) (> 3 fluctuation) as well as three groups based on T-A-Hb levels: < 10, 10-11, and > 11 g/dL.

Results: Two hundred forty-five dialysis (160 peritoneal dialysis (PD) and 85 hemodialysis (HD)) patients aged 12.3 ± 5.1 (range 0.5-21) years were enrolled in this study. Fifty-two percent of the patients had RC, 45% had FC, and only 3% had no cycling. There were no differences between HC groups with respect to age, dialysis modality, having anemia, hospitalization rate, residual urine volume, and mortality. Although left ventricular mass index (LVMI) tended to be higher in RC than FC group (65 ± 37 vs 52 ± 23 g/m, p = 0.056), prevalence of LVH was not different between the groups (p = 0.920). In regression analysis, FC was not a risk factor for LVH, but low T-A Hb level (< 10 g/dL) was a significant risk for LVH (OR = 0.414, 95% CI 0.177-0.966, p = 0.04). The target Hb levels were more often achieved in PD patients, and the number of deaths was significantly lower in non-anemic patients (Hb level > 11 g/dL).

Conclusion: Hb cycling is common among dialysis patients. Severity of anemia rather than its cycling has more significant impact on the prevalence of LVH and on inflammatory state.
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http://dx.doi.org/10.1007/s00467-018-4013-4DOI Listing
November 2018

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

Neutral pH and low-glucose degradation product dialysis fluids induce major early alterations of the peritoneal membrane in children on peritoneal dialysis.

Kidney Int 2018 08;94(2):419-429

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

The effect of peritoneal dialysates with low-glucose degradation products on peritoneal membrane morphology is largely unknown, with functional relevancy predominantly derived from experimental studies. To investigate this, we performed automated quantitative histomorphometry and molecular analyses on 256 standardized peritoneal and 172 omental specimens from 56 children with normal renal function, 90 children with end-stage kidney disease at time of catheter insertion, and 82 children undergoing peritoneal dialysis using dialysates with low-glucose degradation products. Follow-up biopsies were obtained from 24 children after a median peritoneal dialysis of 13 months. Prior to dialysis, mild parietal peritoneal inflammation, epithelial-mesenchymal transition and vasculopathy were present. After up to six and 12 months of peritoneal dialysis, blood microvessel density was 110 and 93% higher, endothelial surface area per peritoneal volume 137 and 95% greater, and submesothelial thickness 23 and 58% greater, respectively. Subsequent peritoneal changes were less pronounced. Mesothelial cell coverage was lower and vasculopathy advanced, whereas lymphatic vessel density was unchanged. Morphological changes were accompanied by early fibroblast activation, leukocyte and macrophage infiltration, diffuse podoplanin presence, epithelial mesenchymal transdifferentiation, and by increased proangiogenic and profibrotic cytokine abundance. These transformative changes were confirmed by intraindividual comparisons. Peritoneal microvascular density correlated with peritoneal small-molecular transport function by uni- and multivariate analysis. Thus, in children on peritoneal dialysis neutral pH dialysates containing low-glucose degradation products induce early peritoneal inflammation, fibroblast activation, epithelial-mesenchymal transition and marked angiogenesis, which determines the PD membrane transport function.
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http://dx.doi.org/10.1016/j.kint.2018.02.022DOI Listing
August 2018

Early Effects of Renal Replacement Therapy on Cardiovascular Comorbidity in Children With End-Stage Kidney Disease: Findings From the 4C-T Study.

Transplantation 2018 03;102(3):484-492

Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany.

Background: The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis.

Methods: We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis).

Results: RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ß = -0.67; P < 0.001) and intima media thickness (ß = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ß = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ß = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ß = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ß = 1.47; P = 0.01).

Conclusions: In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001948DOI Listing
March 2018

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

PLoS One 2017 10;12(8):e0180926. Epub 2017 Aug 10.

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

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552097PMC
October 2017

Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease.

Kidney Int 2017 12 18;92(6):1507-1514. Epub 2017 Jul 18.

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

Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression.
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http://dx.doi.org/10.1016/j.kint.2017.05.006DOI Listing
December 2017