Publications by authors named "Dusan Paripovic"

41 Publications

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

Determinants of Statural Growth in European Children With Chronic Kidney Disease: Findings From the Cardiovascular Comorbidity in Children With Chronic Kidney Disease (4C) Study.

Front Pediatr 2019 5;7:278. Epub 2019 Jul 5.

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

Failure of statural growth is one of the major long-term sequelae of chronic kidney disease (CKD) in children. In recent years effective therapeutic strategies have become available that lead to evidence based practice recommendations. To assess the current growth performance of European children and adolescents with CKD, we analyzed a cohort of 594 patients from 12 European countries who were followed prospectively for up to 6 years in the 4C Study. While all patients were on conservative treatment with a mean estimated glomerular filtration rate of 28 ml/min/1.73 m at study entry, 130 children commenced dialysis during the observation period. At time of enrolment the mean height standard deviation score (SDS) was -1.57; 36% of patients had a height below the third percentile. The prevalence of growth failure varied between countries from 7 to 44% Whereas patients on conservative treatment showed stable growth, height SDS gradually declined on those on dialysis. Parental height, pubertal status and treatment with recombinant growth hormone (GH) were positively, and the diagnosis of syndromic disease and CKD stage were negatively associated with height SDS during the observation period. Unexpectedly, higher body mass index (BMI) SDS was associated with lower height SDS both at enrolment and during follow up. Renal anemia, metabolic acidosis, and hyperparathyroidism were mostly mild and not predictive of growth rates by multivariable analysis. GH therapy was applied in only 15% of growth retarded patients with large variation between countries. When adjusting for all significant covariates listed above, the country of residence remained a highly significant predictor of overall growth performance. In conclusion, growth failure remains common in European children with CKD, despite improved general management of CKD complications. The widespread underutilization of GH, an approved efficacious therapy for CKD-associated growth failure, deserves further exploration.
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http://dx.doi.org/10.3389/fped.2019.00278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625460PMC
July 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

The influence of oxidative stress on cardiac remodeling in obese adolescents.

Scand J Clin Lab Invest 2018 Nov - Dec;78(7-8):595-600

a Nephrology Department , University Children's Hospital , Belgrade , Serbia.

Oxidative stress seems to be an important link between obesity and cardiovascular disease. The aim of our study was to assess oxidative stress in obese patients stratified according to ambulatory blood pressure status and to determine independent predictors of abnormal left ventricular geometry.A cross-sectional study was conducted. A total of 113 obese participants referred for 24-h ambulatory blood pressure monitoring (ABPM) aged 9-19 years, and 29 healthy controls were enrolled. In addition to anthropometric and biochemical measurements, such as fasting serum levels of glucose, insulin, lipid profile, and oxidative biomarkers, ABPM and echocardiography were performed.According to ABPM results, obese subjects were split in two groups: 57 hypertensive and 56 normotensive. Both hypertensive and normotensive obese participants had higher levels of oxidative stress parameters (pro-oxidative/antioxidative balance and total oxidant status) compared with control group. Levels of superoxide anion (O) and sulfhydryl groups were higher in obese hypertensive participants as compared to obese normotensive and control groups. Abnormal left ventricular geometry among obese participants was independently associated with O (p = .006) and body mass index z score (p = .020), with no significant impact of gender, while age and systolic blood pressure exhibited interaction term for the outcome.The independent effect of oxidative mechanisms on left ventricular geometry appears to start in childhood. Oxidative stress occurs in obese adolescents prior to the development of sustained hypertension.
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http://dx.doi.org/10.1080/00365513.2018.1528504DOI Listing
April 2019

Prevalence of Hypertension in Children with Early-Stage ADPKD.

Clin J Am Soc Nephrol 2018 06 19;13(6):874-883. Epub 2018 Apr 19.

Division of Nephrology, Department of Pediatric Subspecialties, and

Background And Objectives: Autosomal dominant polycystic kidney disease is the most common inheritable kidney disease, frequently thought to become symptomatic in adulthood. However, patients with autosomal dominant polycystic kidney disease may develop signs or symptoms during childhood, in particular hypertension. Although ambulatory BP monitoring is the preferred method to diagnose hypertension in pediatrics, data in children with autosomal dominant polycystic kidney disease are limited.

Design, Setting, Participants, & Measurements: Our retrospective multicenter study was conducted to collect ambulatory BP monitoring recordings from patients with autosomal dominant polycystic kidney disease age <18 years old. Basic anthropometric parameters as well as data on kidney function, BP treatment, and kidney ultrasound were also collected.

Results: Data from 310 children with autosomal dominant polycystic kidney disease with a mean age of 11.5±4.1 years old were collected at 22 European centers. At the time when ambulatory BP monitoring was performed, 95% of children had normal kidney function. Reference data for ambulatory BP monitoring were available for 292 patients. The prevalence rates of children with hypertension and/or those who were treated with antihypertensive drugs were 31%, 42%, and 35% during daytime, nighttime, or the entire 24-hour cycle, respectively. In addition, 52% of participants lacked a physiologic nocturnal BP dipping, and 18% had isolated nocturnal hypertension. Logistic regression analysis showed a significant association between a categorical cyst score that was calculated on the basis of the number of cysts >1 cm per kidney and daytime hypertension (odds ratio, 1.70; 95% confidence interval, 1.21 to 2.4; =0.002), nighttime hypertension (odds ratio, 1.31; 95% confidence interval, 1.05 to 1.63; =0.02), or 24-hour hypertension (odds ratio, 1.39; 95% confidence interval, 1.08 to 1.81; =0.01). Kidney length, expressed as SD score, was also significantly associated with nighttime hypertension (odds ratio, 1.23; 95% confidence interval, 1.06 to 1.42; =0.10).

Conclusions: These data indicate high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages.
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http://dx.doi.org/10.2215/CJN.11401017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989684PMC
June 2018

Associations of Apgar score and size at birth with lipoprotein subclasses in juvenile obesity

Turk J Med Sci 2017 Dec 19;47(6):1804-1812. Epub 2017 Dec 19.

Background/aim: Juvenile obesity is associated with several metabolic abnormalities, one of them being atherogenic dyslipidemia. Suboptimal fetal growth is associated with obesity risk in childhood, but also with increased rate of metabolic diseases in later life. This study investigated associations of neonatal data (Apgar score, birth weight and birth length) with low-density lipoprotein and high-density lipoprotein (LDL and HDL) subclasses in a group of obese children, as well as a possible impact of breastfeeding duration on obesity-associated lipoprotein subclasses distributions.Materials and methods: We included 42 obese children, aged 14.2 ± 2.1 years. LDL and HDL subfractions were separated by gradient gel electrophoresis and biochemical parameters were assessed by routine methods.Results: Compared with obese children with Apgar ≥ 9, the group with Apgar < 9 had significantly higher percentages of small, dense LDL particles (P < 0.05), due to reduced LDL I (P < 0.01) and increased LDL III subclasses (P < 0.05). Birth weight was positively associated with the proportions of LDL I particles (P < 0.001), whereas birth height positively correlated with the amount of HDL 2b subclasses (P < 0.05). The group of never or less than 3 months breastfed children had significantly smaller LDL size (P < 0.01) and lower proportion of HDL 2a particles (P < 0.05) than their ≥3 months breastfed peers.Conclusion: The results showed significant associations of neonatal characteristics with LDL and HDL particle distributions in obese children. In addition, our results point toward positive aspects of longer breastfeeding duration on lipoprotein particle distributions in obese children.
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http://dx.doi.org/10.3906/sag-1702-164DOI Listing
December 2017

Alterations of HDL Particles in Children with End-stage Renal Disease.

J Med Biochem 2017 Oct 28;36(4):358-365. Epub 2017 Oct 28.

Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Background: Unfavorable lipid profile presents one of most important risk factor for cardiovascular disease in renal pathology. Myeloperoxidase (MPO) as enzyme which oxidizes lipoproteins and paraoxonase1 (PON1) as anti-oxidative enzyme have been involved in pathogenesis of cardiovascular disease. In the present study we sought to assess oxidative stress status, lipoprotein subclasses distribution as well as functionality of high density lipoprotein (HDL) trough MPO/PON1 ratio in children with chronic kidney disease (CKD) and children after renal transplantation.

Methods: PON1 activity and oxidative stress parameters were measured spectrophotometrically, while MPO concentration was determined using immunoassay. Separation of lipoprotein subclasses was performed by vertical gradient gel electrophoresis in 19 children with different stage of CKD and 19 post-transplantation patients (PT).

Results: CKD patients had increased MPO/PON1 ratio and higher prevalence of smaller HDL subclasses when compared to PT subjects. Also, there was a significant positive correlation between MPO level and MPO/PON1 ratio with relative proportion of smaller HDL subclasses.

Conclusion: Children with CKD have impaired HDL distribution that is improved after kidney transplantation. Since that measurement of HDL distribution and functionality are not routinely available, MPO/PON1 ratio may be useful marker that could provide necessary information.
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http://dx.doi.org/10.1515/jomb-2017-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294087PMC
October 2017

Serum Neutrophil Gelatinase-Associated Lipocalin and Urinary Kidney Injury Molecule-1 as Potential Biomarkers of Subclinical Nephrotoxicity After Gadolinium-Based and Iodinated-Based Contrast Media Exposure in Pediatric Patients with Normal Kidney Function.

Med Sci Monit 2017 Sep 6;23:4299-4305. Epub 2017 Sep 6.

School of Medicine, University of Belgrade, Belgrade, Serbia.

BACKGROUND New renal biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) show promise in early diagnosis of contrast media induced acute kidney injury (CI-AKI). The purpose of our study was to compare the subclinical nephrotoxicity (a condition without changes in standard renal biomarkers) of gadolinium-based contrast media (Gd-DTPA, gadopentetate dimeglumine) and iodinated-based contrast media (iopromide) in pediatric patients with normal kidney function. MATERIAL AND METHODS The first group (n=58) of patients included in the study were undergoing angiography with iopromide, and the second group (n=65) were undergoing magnetic resonance (MR) angiography/urography with Gd-DTPA administration. The concentrations of NGAL and KIM-1 were measured four times in the urine (pre-contrast, then at four hours, 24 hours, and 48 hours after contrast administration), and serum NGAL was measured at 0 (baseline), 24 hours, and 48 hours after contrast exposure. RESULTS After 24 hours, serum NGAL increase of ≥25% was noticed in 32.6% of the patients in the iopromide group and in 25.45% of the patients in the gadolinium group, with significantly higher average percent of this increase in first group (62.23% vs. 36.44%, p=0.002). In the Gd-DTPA group, we observed a statistically significant increase in urinary KIM-1 24 hours after the procedure. Normalized urinary KIM-1, 24 hours after contrast exposure, was a better predictive factor for CI-AKI than other biomarkers (AUC 0.757, cut off 214 pg/mg, sensitivity 83.3%, specificity 54.2%, p=0.035). CONCLUSIONS In children with normal renal function, exposure to iodinated-based and gadolinium-based media might lead to subclinical nephrotoxicity, which could be detected using serum NGAL and urinary KIM-1.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598745PMC
http://dx.doi.org/10.12659/msm.903255DOI Listing
September 2017

Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children.

JAMA Pediatr 2017 11 6;171(11):e172914. Epub 2017 Nov 6.

Department of Medicine, Rush University Medical Center, Chicago, Illinois.

Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults.

Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD.

Design, Setting, And Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016.

Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy.

Main Outcomes And Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2.

Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007).

Conclusions And Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.
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http://dx.doi.org/10.1001/jamapediatrics.2017.2914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121753PMC
November 2017

Association of Myeloperoxidase and the Atherogenic Index of Plasma in Children with End-Stage Renal Disease.

J Med Biochem 2017 Jan 25;36(1):23-31. Epub 2017 Jan 25.

Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Background: The aim of this study was to explore oxidative stress status, especially the enzyme myeloperoxidase in children with end-stage renal disease. Also, we investigated possible associations between the atherogenic index of plasma and these parameters.

Methods: Lipid status parameters, oxidative stress status parameters, and myeloperoxidase concentration were measured in the sera of 20 children in the last stage of chronic renal disease (ESRD) and 35 healthy children of matching age and sex. The Atherogenic Index of Plasma (AIP) was calculated according to the appropriate equation.

Results: We did not find any significant differences in myeloperoxidase concentrations between the investigated groups (p=0.394). Oxidative stress parameters were, however, significantly higher in the patient group (p<0.001), as well as the atherogenic index of plasma (p<0.001). Myeloperoxidase concentration and advanced oxidation protein product (AOPP) concentration were independently associated with increased AIP in the patient group (p<0.05).

Conclusions: Changes in AIP in children with ERSD are associated with the oxidative stress status and myeloper-oxidase concentration.
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http://dx.doi.org/10.1515/jomb-2016-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471656PMC
January 2017

Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children.

J Am Soc Nephrol 2017 Oct 31;28(10):3055-3065. Epub 2017 May 31.

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

We investigated the value of genetic, histopathologic, and early treatment response information in prognosing long-term renal outcome in children with primary steroid-resistant nephrotic syndrome. From the PodoNet Registry, we obtained longitudinal clinical information for 1354 patients (disease onset at >3 months and <20 years of age): 612 had documented responsiveness to intensified immunosuppression (IIS), 1155 had kidney biopsy results, and 212 had an established genetic diagnosis. We assessed risk factors for ESRD using multivariate Cox regression models. Complete and partial remission of proteinuria within 12 months of disease onset occurred in 24.5% and 16.5% of children, respectively, with the highest remission rates achieved with calcineurin inhibitor-based protocols. Ten-year ESRD-free survival rates were 43%, 94%, and 72% in children with IIS resistance, complete remission, and partial remission, respectively; 27% in children with a genetic diagnosis; and 79% and 52% in children with histopathologic findings of minimal change glomerulopathy and FSGS, respectively. Five-year ESRD-free survival rate was 21% for diffuse mesangial sclerosis. IIS responsiveness, presence of a genetic diagnosis, and FSGS or diffuse mesangial sclerosis on initial biopsy as well as age, serum albumin concentration, and CKD stage at onset affected ESRD risk. Our findings suggest that responsiveness to initial IIS and detection of a hereditary podocytopathy are prognostic indicators of favorable and poor long-term outcome, respectively, in children with steroid-resistant nephrotic syndrome. Children with multidrug-resistant sporadic disease show better renal survival than those with genetic disease. Furthermore, histopathologic findings may retain prognostic relevance when a genetic diagnosis is established.
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http://dx.doi.org/10.1681/ASN.2016101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619960PMC
October 2017

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Nephrol Dial Transplant 2018 01;33(1):85-94

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

Background: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies.

Methods: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point.

Results: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD.

Conclusions: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.
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http://dx.doi.org/10.1093/ndt/gfw350DOI Listing
January 2018

Granulomatous interstitial nephritis associated with influenza A: H1N1 infection--A case report.

Srp Arh Celok Lek 2016 Mar-Apr;144(3-4):215-8

Introduction: The causes of acute tubulointerstitial nephritis can be grouped into four broad categories: medications, infections, immunologic diseases, or idiopathic processes. Here we report a 17-year-old female who developed acute kidney injury (AKI) due to granulomatous interstitial nephritis (GIN) associated with influenza A: H1N1 infection.

Case Outline: The illness presented after two weeks of respiratory tract infection, skin rash and hypermenorrhea. On admission the patient was febrile, with bilateral pedal edema, macular skin rash, and auscultatory finding that suggested pneumonia. Laboratory investigations showed normocytic anemia, azotemia, hematuria and proteinuria. Renal ultrasound was normal. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant, antiphospholipid antibodies were negative with normal complement. Urine cultures including analysis for Mycobacterium tuberculosis were negative. The diagnosis of influenza A: H1N1 infection was made by positive serology. A kidney biopsy showed interstitial nephritis with peritubular granulomas. Glomeruli were normal. Staining for immunoglobulins A, M, G, and F was negative. The girl was treated with oseltamivir phosphate (Tamiflu; Genentech, Inc., South San Francisco, CA, USA) for five days, as well as with tapered prednisone after a starting dose of 2 mg/kg. The treatment resulted in a complete remission during two years of follow-up.

Conclusion: We present a severe but reversible case of GIN and AKI associated with influenza A: H1N1 infection. Although a causal effect cannot be confirmed, this case suggests that influenza A: H1N1 should be considered in the differential diagnosis of GIN manifested with AKI in children.
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August 2016

Hypertension, lipoprotein subclasses and lipid transfer proteins in obese children and adolescents.

Scand J Clin Lab Invest 2016 Oct 5;76(6):472-8. Epub 2016 Jul 5.

a Department of Medical Biochemistry, Faculty of Pharmacy , University of Belgrade , Belgrade , Serbia ;

Background: Obesity-related childhood hypertension is associated with disturbances of serum lipids, but less is known about distribution of lipoprotein subclasses and activities of proteins involved in reverse cholesterol transport in hypertensive obese children. Our objective was to determine low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses distribution and activities of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) in hypertensive and non-hypertensive obese children.

Methods: A total of 40 hypertensive and 25 non-hypertensive obese children were enrolled. Lipoprotein subclasses were assessed by polyacrylamide gradient gel electrophoresis. LCAT and CETP activities were determined as a rate of formation and a rate of transfer of cholesteryl esters.

Results: Despite of comparable values of serum lipid parameters, a shift toward smaller LDL and HDL subclasses was observed in hypertensive compared to normotensive obese children. Activities of LCAT were similar, but proatherogenic CETP activities were significantly higher in the hypertensive group (p = 0.036). LCAT/net CETP ratio inversely correlated with relative proportion of small, dense LDL particles (ρ = -0.423; p = 0.025) in the group with hypertension.

Conclusions: The results of our study demonstrated a tendency toward altered distribution of lipoprotein subclasses in favor of more proatherogenic particles in childhood hypertension. Also, hypertensive obese children had increased proatherogenic CETP activity.
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http://dx.doi.org/10.1080/00365513.2016.1201849DOI Listing
October 2016

Mortality risk in European children with end-stage renal disease on dialysis.

Kidney Int 2016 06 13;89(6):1355-62. Epub 2016 Apr 13.

ESPN/ERA-EDTA Registry and ERA-EDTA Registry, Amsterdam, the Netherlands.

We aimed to describe survival in European pediatric dialysis patients and compare the differential mortality risk between patients starting on hemodialysis (HD) and peritoneal dialysis (PD). Data for 6473 patients under 19 years of age or younger were extracted from the European Society of Pediatric Nephrology, the European Renal Association, and European Dialysis and Transplant Association Registry for 36 countries for the years 2000 through 2013. Hazard ratios (HRs) were adjusted for age at start of dialysis, sex, primary renal disease, and country. A secondary analysis was performed on a propensity score-matched (PSM) cohort. The overall 5-year survival rate in European children starting on dialysis was 89.5% (95% confidence interval [CI] 87.7%-91.0%). The mortality rate was 28.0 deaths per 1000 patient years overall. This was highest (36.0/1000) during the first year of dialysis and in the 0- to 5-year age group (49.4/1000). Cardiovascular events (18.3%) and infections (17.0%) were the main causes of death. Children selected to start on HD had an increased mortality risk compared with those on PD (adjusted HR 1.39, 95% CI 1.06-1.82, PSM HR 1.46, 95% CI 1.06-2.00), especially during the first year of dialysis (HD/PD adjusted HR 1.70, 95% CI 1.22-2.38, PSM HR 1.79, 95% CI 1.20-2.66), when starting at older than 5 years of age (HD/PD: adjusted HR 1.58, 95% CI 1.03-2.43, PSM HR 1.87, 95% CI 1.17-2.98) and when children have been seen by a nephrologist for only a short time before starting dialysis (HD/PD adjusted HR 6.55, 95% CI 2.35-18.28, PSM HR 2.93, 95% CI 1.04-8.23). Because unmeasured case-mix differences and selection bias may explain the higher mortality risk in the HD population, these results should be interpreted with caution.
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http://dx.doi.org/10.1016/j.kint.2016.02.016DOI Listing
June 2016

Associated extrarenal vascular diseases may complicate the treatment and outcome of renovascular hypertension.

Acta Paediatr 2016 Jan 4;105(1):e35-41. Epub 2015 Nov 4.

Nephrology Department, University Children's Hospital, Belgrade, Serbia.

Aim: This studied reviewed renovascular hypertension (RVH) due to renal artery stenosis (RAS) in two Serbian paediatric centres from 2001 to 2013.

Methods: The patients' demographic data, underlying syndromes, blood pressure (BP), antihypertensive treatments and outcomes were reviewed.

Results: The incidence of RVH was 1.9 per million children per year during the study period, and there were 25 patients with RAS, aged 10.4 ± 5.2 years. At presentation, their mean blood pressure (BP) standard deviation scores were 6.9 ± 3.4 systolic and 5.2 ± 2.6 diastolic. BP loads on 24-hour ambulatory BP were 88 ± 14% systolic and 80 ± 29% diastolic. We found that 72% had fibromuscular dysplasia and 28% had underlying syndromes. RAS was unilateral in 64% and bilateral in 28%, and 8% had RAS of a single kidney. Antihypertensive treatment included antihypertensive drugs (100%), percutaneous transluminal angioplasty (92%), renal auto-transplantation (16%), surgical revascularisation (12%) and nephrectomy (12%). After 4.4 ± 3.6 years of follow-up, high BP was cured in 40% of the patients and 39.4% of the kidneys and improved in 48% (75.7%), with BP decreases of 20.3 ± 3.7% systolic and 16.3 ± 6.2% diastolic.

Conclusion: Fibromuscular dysplasia was the most common cause of RVH in this study, and hypertension was cured or improved in 88% of the patients.
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http://dx.doi.org/10.1111/apa.13229DOI Listing
January 2016

Left ventricular mass and diastolic function in obese children and adolescents.

Pediatr Nephrol 2015 Apr 30;30(4):645-52. Epub 2014 Oct 30.

Nephrology Department, University Children's Hospital, Tiršova 10, 11 000, Belgrade, Serbia,

Background: Our aims were to assess left ventricular structure and diastolic function in obese subjects stratified according to ambulatory blood pressure status, and to investigate independent predictors of the left ventricular mass (LVM) index.

Methods: Obese subjects aged 9-19 years referred for ambulatory blood pressure monitoring (ABPM) were evaluated in the cross-sectional study. In addition to biochemical and anthropometric measurements, subjects underwent ABPM, Doppler echocardiography, and treadmill exercise test.

Results: According to ABPM results, 103 subjects with obesity (mean age 14.1 ± 2 years) were split in two groups: 49 hypertensive, and 54 without hypertension. Left ventricular hypertrophy was found in 16.3 % of hypertensive, and 5.6 % of normotensive. Variables included in stepwise regression analysis as potential determinants of LVM index were age, body mass index z score, waist circumference, peak systolic blood pressure on exercise test, 24-h heart rate, and night heart rate. Peak systolic blood pressure (adjusted R(2) = 0.051, β = 0.245, p = 0.013) remained as the independent predictor of LVM index. Diastolic function evaluated by mitral E/A ratio was decreased in both obese groups.

Conclusions: Early markers of cardiac disease including hypertrophy and diastolic dysfunction of the left ventricle are present in youths with obesity prior to the development of sustained hypertension.
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http://dx.doi.org/10.1007/s00467-014-2992-3DOI Listing
April 2015

Glomerular nestin expression: possible predictor of outcome of focal segmental glomerulosclerosis in children.

Pediatr Nephrol 2015 Jan 18;30(1):79-90. Epub 2014 Aug 18.

Medical Faculty, University of Belgrade, Belgrade, Serbia.

Background: A high prevalence of chronic kidney disease among children with focal segmental glomerulosclerosis (FSGS) leads to a permanent quest for good predictors of kidney dysfunction. Thus, we carried out a retrospective cohort study in order to examine known clinical and morphological predictors of adverse outcome, as well as to investigate glomerular nestin expression as a potential new early predictor of kidney dysfunction in children with FSGS. Relationships between nestin expression and clinical and morphological findings were also investigated.

Methods: Among 649 renal biopsy samples, obtained from two children's hospitals, FSGS was diagnosed in 60 children. Thirty-eight patients, who met the criteria for this study, were followed up for 9.0 ± 5.2 years. Using Kaplan-Meier and Cox's regression analysis, potential clinical and morphological predictors were applied in two models of prediction: after disease onset and after the biopsy.

Results: The present study revealed the following significant predictors of kidney dysfunction: patients' ages at disease onset, as well as age at biopsy, resistance to corticosteroid treatment, serum creatinine level, urine protein/creatinine ratio, vascular involvement, tubular atrophy, interstitial fibrosis, and decreased glomerular nestin expression.

Conclusions: The most important finding of our study is that nestin can be used as a potential new early morphological predictor of kidney dysfunction in childhood onset of FSGS, since nestin has been obviously decreased in both sclerotic and normal glomeruli seen by light microscopy.
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http://dx.doi.org/10.1007/s00467-014-2893-5DOI Listing
January 2015

[Acute kidney injury in children].

Srp Arh Celok Lek 2014 May-Jun;142(5-6):371-7

Acute kidney injury (AKI) is a clinical condition considered to be the consequence of a sudden decrease (> 25%) or discontinuation of renal function. The term AKI is used instead of the previous term acute renal failure, because it has been demonstrated that even minor renal lesions may cause far-reaching consequences on human health. Contemporary classifications of AKI (RIFLE and AKIN) are based on the change of serum creatinine and urinary output. In the developed countries, AKI is most often caused by renal ischemia, nephrotoxins and sepsis, rather than a (primary) diffuse renal disease, such as glomerulonephritis, interstitial nephritis, renovascular disorder and thrombotic microangiopathy. The main risk factors for hospital AKI are mechanical ventilation, use of vasoactive drugs, stem cell transplantation and diuretic-resistant hypervolemia. Prerenal and parenchymal AKI (previously known as acute tubular necrosis) jointly account for 2/3 of all AKI causes. Diuresis and serum creatinine concentration are not early diagnostic markers of AKI. Potential early biomarkers of AKI are neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM-1), interleukins 6, 8 and 18, and liver-type fatty acid-binding protein (L-FABP). Early detection of kidney impairment, before the increase of serum creatinine, is important for timely initiated therapy and recovery. The goal of AKI treatment is to normalize the fluid and electrolyte status, as well as the correction of acidosis and blood pressure. Since a severe fluid overload resistant to diuretics and inotropic agents is associated with a poor outcome, the initiation of dialysis should not be delayed. The mortality rate of AKI is highest in critically ill children with multiple organ failure and hemodynamically unstable patients.
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http://dx.doi.org/10.2298/sarh1406371pDOI Listing
October 2015

Oxidative status parameters in children with urinary tract infection.

Biochem Med (Zagreb) 2014 15;24(2):266-72. Epub 2014 Jun 15.

Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Introduction: Urinary tract infection (UTI) is one of the most common bacterial infectious diseases in children. The aim of this study was to determine the total prooxidant and antioxidant capacity of children with UTI, as well as changes of oxidative status parameters according to acute inflammation persistence and acute kidney injury (AKI) development.

Materials And Methods: The patients enrolled in the study comprised 50 Caucasian children (median age was 6 months) with UTI. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), inflammation marker C-reactive protein (CRP) and renal function parameters urea and creatinine were analyzed in patient's serums.

Results: According to duration of inflammation during UTI, TAS values were significantly higher (0.99 vs. 0.58 mmol/L, P = 0.017) and OSI values were significantly lower (0.032 vs. 0.041 AU, P = 0.037) in the subjects with longer duration of inflammation than in the subjects with shorter duration of inflammation. We did not find significant difference in basal values of oxidative status parameters according to AKI development.

Conclusion: OSI values could detect the simultaneous change of TAS and TOS due to change in the oxidative-antioxidant balance during the recovery of children with UTI. TAS and OSI as markers of oxidative stress during UTI are sensitive to accompanying inflammatory condition. Further investigations are needed to evaluate whether TAS, TOS and OSI could be used to monitor disease severity in children with UTI.
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http://dx.doi.org/10.11613/BM.2014.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083578PMC
July 2014

Growth in children with chronic kidney disease: 13 years follow up study.

J Nephrol 2014 Oct 23;27(5):537-44. Epub 2014 Apr 23.

Medical Faculty, University of Belgrade, Belgrade, Serbia,

Background: Growth retardation is one of the most visible comorbid conditions of chronic kidney disease (CKD) in children. To our knowledge, published data on longitudinal follow-up of growth in pediatric patients with CKD is lacking from the region of South-East Europe. Herein we report the results from the Serbian Pediatric Registry of Chronic Kidney Disease.

Methods: The data reported in the present prospective analysis were collected between 2000 and 2012. A total of 324 children with CKD were enrolled in the registry.

Results: Prevalence of growth failure at registry entry was 29.3 %. Mean height standard deviation scores (HtSDS) in children with stunting and those with normal stature were -3.00 [95 % confidence interval (CI) -3.21 to -2.79] and -0.08 (95 % CI -0.22 to 0.05) (p < 0.001), respectively. Children with hereditary nephropathy had worse growth at registration (-1.51; 95 % CI -1.97 to -1.04, p = 0.008). Those with CKD stages 4 and 5 before registration had more chance to have short stature at registration than those with CKD stages 2 and 3 [odds ratio (OR) = 0.458, CI 0.268-0.782, p = 0.004]. Dialysis was an independent negative predictor for maintaining optimal stature during the follow-up period (OR = 0.324, CI = 0.199-0.529, p < 0.001), while transplantation was an independent positive predictor for improvement of small stature during follow-up (OR = 3.706, CI = 1.785-7.696, p < 0.001).

Conclusion: Growth failure remains a significant problem in children with CKD, being worst in patients with hereditary renal disease. Growth is not improved by standard dialysis, but transplantation has a positive impact on growth in children.
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http://dx.doi.org/10.1007/s40620-014-0094-8DOI Listing
October 2014

Renal hypertension and cardiovascular disorder in children with chronic kidney disease.

Srp Arh Celok Lek 2014 Jan-Feb;142(1-2):113-7

Renal hypertension is one of the earliest and the most prevalent complications of pediatric chronic kidney disease (CKD). Among renal patients, hypertension is frequently underdiagnosed and undertreated. For casual blood pressure measurement, the best method is auscultatory, while for ambulatory blood pressure measurement, oscillometric method is the most commonly used. Both casual and ambulatory blood pressure measurement provide more powerful means of diagnosing hypertension. Masked hypertension is a condition in which casual blood pressure is normal but ambulatory blood pressure is elevated. The risk of cardiovascular morbidity and mortality is higher with masked hypertension as compared to the controls. Children and adolescents with CKD are at high risk of cardiovascular disease that has been established as the leading cause of death in patients with end stage renal disease. Left ventricular hypertrophy remains the most thoroughly documented form of end-organ damage caused by hypertension in children and adolescents with CKD. Based on clear evidence on the correlation between blood pressure and cardiovascular morbidity, mortality, and renal function, renal hypertension must be aggressively treated. Target blood pressure for patients with renal hypertension should be at low normal values: < 75 percentile for patients without proteinuria and <50 percentile for patients with proteinuria. Renin-angiotensin system antagonists are considered the first choice pharmacological option in hypertensive CKD 2-4 patients while the management of volume overload is the most important in dialysis patients. Successful transplantation can eliminate or significantly improve uremia-related cardiovascular risk factors and increase predicted life expectancy.
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http://dx.doi.org/10.2298/sarh1402113pDOI Listing
October 2015

Post-transplant lymphoproliferative disorder--case reports of three children with kidney transplant.

Srp Arh Celok Lek 2014 Jan-Feb;142(1-2):83-8

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy.

Outline Of Cases: We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease.

Conclusion: Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.
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http://dx.doi.org/10.2298/sarh1402083sDOI Listing
October 2015

Underweight, overweight and obesity in paediatric dialysis and renal transplant patients.

Nephrol Dial Transplant 2013 Nov 23;28 Suppl 4:iv195-iv204. Epub 2013 Aug 23.

ESPN/ERA-EDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: The prevalence of childhood overweight is rising worldwide, but in children on renal replacement therapy (RRT) a poor nutritional status is still the primary concern. We aimed to study the prevalence of, and factors associated with, underweight and overweight/obesity in the European paediatric RRT population. Moreover, we assessed the evolution of body mass index (BMI) after the start of RRT.

Methods: We included 4474 patients younger than 16 years from 25 countries of whom BMI data, obtained between 1995 and 2010, were available within the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry. Prevalence estimates for under- and overweight/obesity were calculated using age and sex-specific criteria of the World Health Organization (WHO, 0-1 year olds) and the International Obesity Task Force cut-offs (2-15 year olds).

Results: The prevalence of underweight was 3.5%, whereas 20.8% of the patients were overweight and 12.5% obese. Factors associated with being underweight were receiving dialysis treatment and infant age. Among transplanted recipients, a very short stature (OR: 1.64, 95% CI: 1.40-1.92) and glucocorticoid treatment (OR: 1.23, 95% CI: 1.03-1.47) were associated with a higher risk of being overweight/obese. BMI increased post-transplant, and a lower BMI and a higher age at the start of RRT were associated with greater BMI changes during RRT treatment.

Conclusions: Overweight and obesity, rather than underweight, are highly prevalent in European children on RRT. Short stature among graft recipients had a strong association with overweight, while underweight appears to be only a problem in infants. Our findings suggest that nutritional management in children receiving RRT should focus as much on the prevention and treatment of overweight as on preventing malnutrition.
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http://dx.doi.org/10.1093/ndt/gft259DOI Listing
November 2013

Clinical application neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 as indicators of inflammation persistence and acute kidney injury in children with urinary tract infection.

Biomed Res Int 2013 9;2013:947157. Epub 2013 Jul 9.

Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.

Background: The aim of this study was to examine the novel renal biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) to assist pediatricians in the assessment of longer duration of inflammation and acute kidney injury (AKI) development during urinary tract infection (UTI).

Methods: The patients enrolled in the study comprised 50 children (mean age was 6 months) with UTI. NGAL in serum and urine (sNGAL and uNGAL, resp.) and KIM-1 in urine were measured by enzyme-linked immunosorbent assays.

Results: uNGAL levels in subjects with longer duration of inflammation were higher (115.37 ng/mL) than uNGAL levels in subjects with shorter duration of inflammation (67.87 ng/mL, P = 0.022). Difference in sNGAL and KIM-1 levels was not significant (P = 0.155 and P = 0.198, resp.). Significant difference was seen in KIM-1 excretion among groups with and without AKI (P = 0.038). KIM-1 was not able to discriminate between subjects with and without AKI (area under the curves (AUC) = 0.620, P = 0.175).

Conclusions: uNGAL cannot be used for screening of the duration of inflammation during UTI. Accuracy of KIM-1 in screening of AKI development in children with UTI is low. We suggest larger studies to check the negative predictive value of KIM-1 for the development of AKI.
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http://dx.doi.org/10.1155/2013/947157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723056PMC
March 2014

Bladder control training in girls with lower urinary tract dysfunction.

Int Braz J Urol 2013 Jan-Feb;39(1):118-26; discussion 127

Medical School of University of Belgrade, Belgrade, Serbia.

Purpose: To evaluate the efficacy of standard and biofeedback bladder control training (BCT) on the resolution of dysfunctional elimination syndrome (primary outcome), and on the reduction of urinary tract infections (UTI) and the use of medications such as antibacterial prophylaxis and/or anticholinergic/alpha-blockers (secondary outcome) in girls older than aged least 5 years.

Materials And Methods: 72 girls, median age of 8 years (interquartile range, IQR 7-10) were subjected to standard BCT (cognitive, behavioural and constipation treatment) and 12 one-hour sessions of animated biofeedback using interactive computer games within 8 weeks. Fifty patients were reevaluated after median 11 (IQR, 6-17) months. Effectiveness of BCT was determined by reduction of dysfunctional voiding score (DVS), daytime urinary incontinence (DUI), constipation, UTI, nocturnal enuresis (NE), post void residual (PVR), and improvements in bladder capacity and uroflow/EMG patterns.

Results: BCT resulted in significant normalization of DUI, NE, constipation, bladder capacity, uroflow/EMG, while decrease of PVR didn't reach statistical significance. In addition, the incidence of UTI, antibacterial prophylaxis and medical urotherapy significantly decreased. There were no significant differences in DVS, DVI, NE, bladder capacity and voiding pattern at the end of the BCT and at the time of reevaluation. The success on BCT was supported by parenteral perception of the treatment response in 63.9% and full response in additional 15.3% of the patients.

Conclusion: Combination of standard and biofeedback BCT improved dysfunctional elimination syndrome and decreased UTI with discontinuation of antibacterial prophylaxis and/or anticholinergic/alpha-blockers in the majority of the patients. Better training results are expected in patients with higher bladder wall thickness as well as in those with vesicoureteral reflux, while presence of nocturnal enuresis may be a negative predictor of the training effect.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2013.01.15DOI Listing
December 2013

Hyperlipidemia, oxidative stress, and intima media thickness in children with chronic kidney disease.

Pediatr Nephrol 2013 Feb 2;28(2):295-303. Epub 2012 Nov 2.

Department for Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, P. Box 146, 11000 Belgrade, Serbia.

Background: The roles of dyslipidemia and oxidative stress in the early phases of atherosclerosis were tested in children with chronic kidney disease (CKD). Intima media thickness of common carotid arteries (cIMT) is used as a measure of early atherosclerosis.

Methods: Fifty-two pediatric CKD patients were enrolled in the study (10 with chronic renal failure [CRF], 22 with a renal transplant [RT], 20 with chronic hemodialysis (cHD) patients, and 36 healthy children (control group, CG). Lipid status, oxidative stress, and paraoxonase 1 (PON1) status were assessed. cIMT was measured by ultrasound, adjusted for age and sex, and presented as standard deviation scores (SDS).

Results: Children with CKD had disturbed lipid content, which was most pronounced in cHD children, with higher free cholesterol and triglycerides compared with healthy children. Oxidative stress was markedly increased (malodialdehyde [MDA, μmol/L]: CRF 1.50 ± 0.26, RT 1.55 ± 0.40, cHD 1.77 ± 0.34, CG 0.97 ± 0.33, p < 0.001) and antioxidative defense was compromised (superoxide dismutase [SOD, U/L]: CG 120 ± 21, CRF 84 ± 25, RT 93 ± 12, cHD 119 ± 37, p < 0.001). Multiple linear regression analysis showed that a model that included disease duration, blood pressure, urea, lipid, and oxidative status parameters accounted for more than 90% of the variability of cIMT-SDS.

Conclusions: Early atherosclerosis in CKD children is caused, at least in part, by dyslipidemia and oxidative stress. Monitoring of vessel wall changes, along with assessment of oxidative stress status and high density lipoprotein (HDL) functionality is necessary to ensure better therapeutic strategies for delaying atherosclerotic changes in their asymptomatic phase.
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http://dx.doi.org/10.1007/s00467-012-2323-5DOI Listing
February 2013

In vivo susceptibility of ESBL producing Escherichia coli to ceftriaxone in children with acute pyelonephritis.

Srp Arh Celok Lek 2012 May-Jun;140(5-6):321-5

School of Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: The choice of empiric therapy of acute pyelonephritis (APN) in children should be based on the knowledge of Escherichia coli (E. coli) as the most common uropathogen and its antibiotic sensitivities considering that nowadays ESBL-producing [ESBL (+)] E. coli is on the rise worldwide.

Objective: To examine in vivo susceptibility of ESBL (+) E. coli to ceftriaxone (CTX), and to evaluate the options for empiric therapy for APN in children.

Methods: Retrospective study of CTX empiric therapy of APN in children treated at the University Children's Hospital in Belgrade from January 2005 to December 2009. ESBL phenotypic confirmatory test with ceftazidime, CTX and cefotaxime was performed for all urine isolates by disc diffusion method on Mueller-Hinton agar plates. In vivo sensitivity of CTX documented by clinical response to empiric CTX therapy was compared between two groups of children: group I with ESBL (+) E. coli and group II with ESBL (-) E. coli APN.

Results: Group I with ESBL (+) APN consisted of 94 patients and group II of 120 patients with ESBL (-) APN, respectively. All patients received CTX as empiric therapy at a mean dose of 66.9 mg during 7.2 +/- 2.6 days of therapy. Clinical effect of CTX was similar in patients with ESBL (+) compared to those with ESBL (-) APN.

Conclusions: In vitro resistance of ESBL E. coli to CTX determined by standard methods is not sufficiently predictive for its in vivo sensitivity. Therefore CTX may be used as empiric therapy for acute pyelonephritis in children.
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August 2012

Renal functional reserve in children with apparently normal congenital solitary functioning kidney.

Clin Biochem 2012 Oct 23;45(15):1173-7. Epub 2012 Jun 23.

Medical Faculty, University of Belgrade, Belgrade, Serbia.

Objective: The aim of the study was to investigate renal functional reserve (RFR) and to assess its relationship with serum cystatin C and blood pressure in children with apparently normal congenital solitary functioning kidney (SFK).

Material And Methods: RFR was obtained from the difference of endogenous creatinine clearance (CrCs) before and after a meat-free oral protein load (OPL) in the patients who were pre-treated with cimetidine. Serum cystatin C and urinary protein excretion were determined before and after OPL.

Results: Among 22 patients (13 boys), aged 9.5 ± 4.3 years, 72.7% had increased serum cystatin C, and 54.5% had decreased RFR. Following OPL, CrCs and urine creatinine increased, while serum creatinine and cystatin C remained unchanged. The multiple regression analysis demonstrated that cystatin C could predict more than 90% of RFR variability.

Conclusion: Half of the patients with apparently normal SFK had decreased RFR. Serum cystatin C is one of the best predictors of RFR.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.06.018DOI Listing
October 2012

Antibiotic resistance of uropathogens in newborns and young children with acute pyelonephritis.

Srp Arh Celok Lek 2012 Mar-Apr;140(3-4):179-83

School of Medicine, University of Belgrade, Belgrade, Serbia.

Introduction: Urinary tract infection is common in childhood. Depending on the localization of the infection, severity of its clinical presentation and possible acute and long-term complications, it may be described as either acute cystitis or acute pyelonephritis.

Objective: The aim of this study was to assess the resistance patterns of uropathogens during the last 5 years in newborns and young children with acute pyelonephritis.

Methods: Uropathogens resistance to commonly usable anti-microbial agents (ampicillin, a combination of sulphamethoxasole and trimethoprim, cephalexin, ceftriaxone, cefotaxime, ceftazidime, gentamycin, amikacin, ciprofloxacin, imipenem and nalidixic acid) was retrospectively studied in newborns and young children treated during early (2005-2007) and late (2008-2009) study periods. Anti-bacterial susceptibility testing of the urine isolates was performed by the standard disc diffusion method.

Results: 117 newborns and 294 children aged 9.3 +/- 0.7 months were treated during early (n=136) or late (n=275) study period due to the first episode of acute pyelonephritis. Escherichia coli was the most common bacterial pathogen (85.5%). Compared to children older than one month, newborns had higher degree of antibacterial resistance to 2nd and 3rd generation cephalosporins, aminoglycosides, and nalidixic acid during early, and to ceftazidime, aminoglycosides and nalidixic acid during late study period. Also, multidrug resistance was more common in newborns during the early study period.

Conclusion: Newborns had higher rate of antibacterial resistance than young children.The progressive increase of anti-microbial resistance in children with acute pyelonephritis is of great concern.
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June 2012