Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.

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

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 (O2-) 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 O2- (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.

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.

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.

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

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.

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

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.

Best Practice of Peritoneal Dialysis-Associated Gram-Negative Peritonitis in Children: Insights From the International Pediatric Peritoneal Dialysis Network Registry.

Introduction: Gram-negative peritonitis (GNP) is associated with significant morbidity in children receiving long-term peritoneal dialysis (PD) and current treatment recommendations are based on limited data. Methods: Analysis of 379 GNP episodes in 308 children (median age 6.9 years, interquartile range [IQR]: 3.0-13.6) from 45 centers in 28 countries reported to the International Pediatric Peritoneal Dialysis Network registry between 2011 and 2023. Results: Overall, 74% of episodes responded well to empiric therapy and full functional recovery (FFR) was achieved in 82% of cases. In vitro bacterial susceptibility to empiric antibiotics and lack of severe abdominal pain at onset were associated with a good initial response. Risk factors for failure to achieve FFR included severe abdominal pain at onset and at 60 to 72 hours from treatment initiation (odds ratio [OR]: 3.81, 95% confidence interval [CI]: 2.01-7.2 and OR: 3.94, 95% CI: 1.06-14.67, respectively), Pseudomonas spp. etiology (OR: 1.73, 95% CI: 1.71-4.21]) and in vitro bacterial resistance to empiric antibiotics (OR: 2.40, 95% CI: 1.21-4.79); the risk was lower with the use of monotherapy as definitive treatment (OR: 0.40, 95% CI: 0.21-0.77). Multivariate analysis showed no benefit of dual antibiotic therapy for treatment of Pseudomonas peritonitis after adjustment for age, presenting symptomatology, 60 to 72-hour treatment response, and treatment duration. Monotherapy with cefazolin in susceptible Enterobacterales peritonitis resulted in a similar FFR rate (91% vs. 93%) as treatment with ceftazidime or cefepime monotherapy. Conclusion: Detailed microbiological assessment, consisting of patient-specific and center-specific antimicrobial susceptibility data, should guide empiric treatment. Treatment "deescalation" with the use of monotherapy and narrow spectrum antibiotics according to susceptibility data is not associated with inferior outcomes and should be advocated in the context of emerging bacterial resistance.

Lipoproteins and cholesterol homeostasis in paediatric nephrotic syndrome patients.

Introduction: The aim of this study was to investigate lipoprotein particle distributions and the likelihood of achieving cholesterol homeostasis in the remission phase of nephrotic syndrome (NS) in paediatric patients. We hypothesized that lipoprotein particle distributions moved toward less atherogenic profile and that cholesterol homeostasis was achieved. Materials and methods: Thirty-three children, 2 to 9 years old with NS were recruited. Blood sampling took place both in the acute phase and during remission. Serum low-density lipoprotein particles (LDL) and high-density lipoprotein particles (HDL) were separated using non-denaturing polyacrylamide gradient gel (3-31%) electrophoresis. Serum non-cholesterols sterols (NCSs), desmosterol, lathosterol, 7-dehydrocholesterol (7-DHC), campesterol and ß-sitosterol were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Results: All patients had desirable serum HDL cholesterol concentrations during remission. The dominant lipoprotein diameters and LDL subclass distribution did not change significantly during follow-up. In contrast, HDL lipoprotein particle distribution shifted towards larger particles. The absolute concentration of desmosterol was significantly lower during remission (P = 0.023). ß-sitosterol concentration markedly increased during remission (P = 0.005). Desmosterol/ß-sitosterol (P < 0.001) and 7-DHC/ß-sitosterol (P = 0.005) ratios significantly declined during disease remission. Conclusions: Favourable changes in the serum lipid profiles, HDL particle subclass distribution and cholesterol metabolism in paediatric patients with NS during remission took place. For the first time, we found that cholesterol homeostasis changed in favour of increased cholesterol absorption during disease remission. Nevertheless, complete cholesterol homeostasis was not achieved during disease remission.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

Peritoneal Dialysis Vintage and Glucose Exposure but Not Peritonitis Episodes Drive Peritoneal Membrane Transformation During the First Years of PD.

The impact of peritoneal dialysis (PD) associated peritonitis on peritoneal membrane integrity is incompletely understood. Children are particularly suited to address this question, since they are largely devoid of preexisting tissue damage and life-style related alterations. Within the International Peritoneal Biobank, 85 standardized parietal peritoneal tissue samples were obtained from 82 children on neutral pH PD fluids with low glucose degradation product (GDP) content. 37 patients had a history of peritonitis and 16 of the 37 had two or more episodes. Time interval between tissue sampling and the last peritonitis episode was 9 (4, 36) weeks. Tissue specimen underwent digital imaging and molecular analyses. Patients with and without peritonitis were on PD for 21.0 (12.0, 36.0) and 12.8 (7.3, 27.0) months (p = 0.053), respectively. They did not differ in anthropometric or histomorphometric parameters [mesothelial coverage, submesothelial fibrosis, blood, and lymphatic vascularization, leukocyte, macrophage and activated fibroblast counts, epithelial-mesenchymal transition (EMT), podoplanin positivity and vasculopathy]. VEGF and TGF-ß induced pSMAD abundance were similar. Similar findings were also obtained after matching for age and PD vintage and a subgroup analysis according to time since last peritonitis (<3, <6, >6 months). In patients with more than 24 months of PD vintage, submesothelial thickness, vessel number per mmm section length and ASMA fibroblast positivity were higher in patients with peritonitis history; only the difference in ASMA positivity persisted in multivariable analyses. While PD duration and EMT were independently associated with submesothelial thickness, and glucose exposure and EMT with peritoneal vessel density in the combined groups, submesothelial thickness was independently associated with EMT in the peritonitis free patients, and with duration of PD in patients with previous peritonitis. This detailed analysis of the peritoneal membrane in pediatric patients on PD with neutral pH, low GDP fluids, does not support the notion of a consistent long-term impact of peritonitis episodes on peritoneal membrane ultrastructure, on inflammatory and fibrotic cell activity and EMT. Peritoneal alterations are mainly driven by PD duration, dialytic glucose exposure, and associated EMT.

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.

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

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.

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

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.

[Develooment of the lower urinary tract and its functional disorders].

A normal development of lower urinary tract function control evolves from involuntary bladder empting (incontinence) during infancy to daytime urinary continence, and finally a successful day and night continence that is generally achieved by the 5th to 7th year of age.This gradual process primarily depends on the progressive maturation of the neural control of the lower urinary tract, but it is also influenced by behavioral training that evolves through social support. Functional voiding disorders (bladder dysfunction) are common problems during childhood. They are present in 5-15 % of general pediatric population, and in one-fifth of school-age children or in over one-third of patients of the pediatric urologist or nephrologist. More than half of children with bladder dysfunction have vesicoureteral reflux, and more than two-thirds have recurrent urinary tract infections. There is also a frequent association of bladder dysfunction with constipation and encopresis (dysfunctional elimination syndrome). Bladder dysfunction may cause a permanent damage to the upper urinary tract and kidneys. In addition, urinary incontinence, as the most common manifestation of bladder dysfunction can be the cause of major stress in school- age children and have a negative effect on the child's feeling of self-esteem. Thus, a timely detection and treatment of this group of disorders in children is highly significant.

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

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.

Proteinuria in Frasier syndrome.

INTRODUCTION: Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms'tumour suppressor gene (WT1). Proteinuria in FS has been traditionally considered unresponsive to any medication and FS inevitably progresses to end stage renal failure. CASE OUTLINE: We present a patient with FS who had atypical clinical manifestation and unusual beneficial antiproteinuric response to renin-angiotensin system (RAS) inhibitors given in combination with indomethacin. After 13 years of follow-up, the patient is now 17-year old with normal renal functions and no proteinuria. CONCLUSION: RAS inhibitors combined with indomethacin showed beneficial effect in our patient. Thus, this combination might be the initial treatment of patients with FS. If this treatment strategy was not satisfied for at least 3 months, then CsA would be considered to be administered taking account of the nephrotoxicity and the increased risk of malignancy. Further prospective study is required to clarify this issue.

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

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.

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

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.

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

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.

Henoch-Schönlein purpura outcome in children: a ten-year clinical study.

INTRODUCTION: Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood. It is characterized by symptoms including nonthrombocytopenic purpura, abdominal pain, haematuria/proteinuria, and arthralgia/arthritis. The pleiomorphism of clinical signs in HSP could be confused with other conditions or other vasculitis forms. OBJECTIVE: Evaluation of HSP clinical presentation, the onset and severity of renal manifestation in affected children and their outcome. METHODS: A retrospective study of 49 patients diagnosed with HSP was conducted from September 1999 to September 2009. Children with severe renal manifestations (nephrotic range proteinuria, with or without nephrotic or nephritic syndrome) have undergone kidney biopsy. RESULTS: Twenty-five patients developed renal manifestations after onset of the disease. In our study child's older age was a risk factor for association with HSP nephritis. Six of the patients required kidney biopsy. They were successfully treated with various immunosuppressive protocols, as well as three of nine patients with nephrotic range proteinuria. Two patients developed most severe form of HSP nephritis, nephrotic-nephritic syndrome with histology grade IIIb/IVb. During the study period (average followup 6 years), all patients had a normal global renal function with mild proteinuria in only two cases. The prognosis of renal involvement was better than reports from other patient series. CONCLUSION: Long-term morbidity of HSP is predominantly attributed to renal involvement. During the study period, no patient had renal insufficiency or end stage renal disease after various combinations of immunosuppressive treatment. It is recommended that patients with HSP nephritis are followed for longer periods of time with a regular measurement of renal function and proteinuria.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis: the first four patients in Serbia.

INTRODUCTION: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disease characterized by excessive renal magnesium and calcium wasting, bilateral nehrocalcinosis and progressive renal failure. This is the first report of FHHNC of four patients in Serbia. OUTLINE OF CASES: The first three patients were siblings from the same family. The index case, a 9-year-old girl, presented with severe growth retardation, polyuria and polydipsia, while her brothers, 11 and 7 years old, were disclosed during family member screening. The father had a urolithiasis when aged 18 years, while intermittent microhaematuria and bilateral microlithiasis persisted later on. The fourth patient, a 16-year-old boy with sporadic FHHNC was discovered to have increased proteinuria at routine examination of urine before registration for secondary school. He was well grown up, normotensive, but had moderate renal failure (CKD 3 stage), mild hypomagnesaemia and severe hypercalciuria and nephrocalcinosis. Beside typical clinical and biochemical data, the diagnosis of FHHNC was confirmed by mutation analysis of the CLDN16 gene; in all four affected individuals a homozygous CLDN16 mutation (Leu151Phe) was found. Treatment with magnesium supplementation resulted in the normalization of serum magnesium levels only in one patient (patient 4), but hypercalciuria persisted and renal failure progressed in all patients. CONCLUSION: FHHNC is a rare cause of chronic renal failure. The first four patients with FHHNC in Serbia have been here described. The diagnosis of FHNNC based on the findings of nephrocalcinosis with hypomagnesiaemia and hypercalciuria, was confirmed by homozygous paracellin1-mutation exhibiting a Leu151Phe.