Browsing by Author "Kostić, Mirjana (56247970900)"

Background: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR∗28). The aim of this study was to assess the impact of age, CYP3A5∗3, CYP3A4∗22, and POR∗28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. Methods: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5∗3, CYP3A4∗22, and POR∗28. Results: CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 6 12.75 versus 22.44 6 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR∗28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR∗1/∗1 genotype (165.54 6 70.40 versus 210.55 6 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 6 4.72 versus 34.19 6 11.89, P = 0.001) and C2/dose (106.75 6 26.99 versus 209.20 6 71.57, P < 0.001) compared with older children. Carriers of CYP3A5∗3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR∗28 allele aged #6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P, 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016). Conclusions: Younger age, POR∗28 allele, and CYP3A5∗3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background: The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene (POR∗28). The aim of this study was to assess the impact of age, CYP3A5∗3, CYP3A4∗22, and POR∗28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. Methods: Renal transplant patients receiving CsA (n = 47) were genotyped for CYP3A5∗3, CYP3A4∗22, and POR∗28. Results: CYP3A5 nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 6 12.75 versus 22.44 6 7.12, P = 0.01). CYP3A5 nonexpressers carrying POR∗28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with POR∗1/∗1 genotype (165.54 6 70.40 versus 210.55 6 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 6 4.72 versus 34.19 6 11.89, P = 0.001) and C2/dose (106.75 6 26.99 versus 209.20 6 71.57, P < 0.001) compared with older children. Carriers of CYP3A5∗3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of POR∗28 allele aged #6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and CYP3A5 variation (P, 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and POR variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both CYP3A5 and POR variations (P < 0.016). Conclusions: Younger age, POR∗28 allele, and CYP3A5∗3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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 E 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. © 2016, Serbia Medical Society. All rights reserved.

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. © 2012 IPNA.

Background: This study was conducted to retrospectively investigate the indications for renal biopsy in native kidneys and to analyze pathological findings in the last 10 years in a single tertiary pediatric hospital in Serbia. Methods: All patients who underwent renal biopsy at our hospital between 2001 and 2010 were included in the present study. Renal biopsy was performed under fluoroscopy with a biopsy gun. All renal biopsies were studied under light and immunofluorescent microscopy, while electron microscopy was rarely performed. Results: The study group included 150 patients (56% female) who underwent 158 percutaneous native kidney biopsies. Median age was 11.5 years (range 0.2-20 years). The most frequent indications for renal biopsy were nephrotic syndrome (32.9%), asymptomatic hematuria (23.4%), urinary abnormalities in systemic diseases (15.8%) and proteinuria (11.4%). Primary glomerulonephritis (GN) was the most common finding (57.4%), followed by secondary GN (15.5%) and tubulointerstitial diseases (4.5%). According to histopathological diagnosis, the most common causes of primary GN were focal segmental glomerulosclerosis (20.9%), mesangioproliferative GN (14.6%), IgA nephropathy (8.9%) and minimal change disease (13%). Lupus nephritis (6%) and Henoch-Schönlein nephritis (4%) were the most common secondary glomerular diseases. Conclusions: The epidemiology of glomerular disease in our single-center report is similar to that in data from adjacent Croatia and Greece. Focal segmental glomerulosclerosis was the dominant histopathological finding, followed by mesangioproliferative GN and IgA nephropathy. © 2012 Società Italiana di Nefrologia.

Introduction/Objective Jeune syndrome (JS) is a rare hereditary ciliopathy characterized by asphyxiating thoracic dystrophy, shortened limbs and brachydactyly. Extraskeletal anomalies such as chronic renal failure (CRF), hepatic fibrosis, and retinitis pigmentosa may be a part of the JATD phenotype. The aim of this study is to present long-term follow-up of JS patients with early progressive kidney disease. Methods This is a retrospective study of pediatric patients with JS and CRF who were treated at the University Children’s Hospital between January 1980 and December 2014. The patients’ data were retrospectively reviewed from the medical records. Results There were thirteen patients from 11 families, five girls and eight boys mean aged 4.3 years at the time of diagnosis. All of the patients had characteristic skeletal findings, retinal degeneration and an early onset of CRF at age range from 1.5 to 7 years. Five patients had neonatal respiratory distress and congenital liver fibrosis was diagnosed in five patients. One patient died due to complications of CRF, while others survived during follow-up of mean 11 years. IFT140 mutations were found in four genetically tested patients. Conclusion The average incidence rate of JS with renal phenotype in Serbia was about 0.2 per one million of child population. Long-term survival of JS patients depends on renal replacement therapy, while skeletal dysplasia, growth failure, respiratory and eyes problems have impact on the patients’ quality of life. © 2017, Serbia Medical Society. All rights reserved.

We report the clinical and morphological features of a distinctive hepatorenal disorder in four patients and review the five similar patients in the literature. The main clinical characteristics were early onset of cholestatic liver disease and progressive tubulointerstitial nephritis leading to renal death in early childhood. Liver histology showed disturbed architecture with nodular and acinar formations and portal fibrosis and bile duct proliferation. Histological abnormalities in the kidney were severe interstitial fibrosis and tubular atrophy and dilatation, while the typical features of nephronophthisis were lacking. These clinical and morphological characteristics distinguish our patients from the majority described, as having nephronophthisis and congenital hepatic fibrosis or any other known syndrome with concomitant hepatorenel involvement. We suggest that the association of cholestatic liver disease and progressive tubulointerstitial nephritis represents a new syndrome. © 1993 IPNA.

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 bio-markers) of gadolinium-based contrast media (Gd-DTPA, gadopentetate dimeglumine) and iodinated-based contrast media (iopromide) in pediatric patients with normal kidney function. Material/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 admin-istration. 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 (base-line), 24 hours, and 48 hours after contrast exposure. Results: After 24 hours, serum NGAL increase of ³25% 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 in-crease in urinary KIM-1 24 hours after the procedure. Normalized urinary KIM-1, 24 hours after contrast expo-sure, was a better predictive factor for CI-AKI than other biomarkers (AUC 0.757, cut off 214 pg/mg, sensitivi-ty 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. © Med Sci Monit.