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Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy, caused by dysregulation of the complement alternative pathway. Deletion of the complement factor H–related genes, CFHR1 and CFHR3, together with the presence of CFH autoantibodies are reported in aHUS patients, representing 10% of cases of patients with aHUS. Case presentation: We report here on a case of 4-year-old girl with anti-CFH antibody-associated aHUS. The measurement of complement factors and anti-factor H antibodies, was the main guideline for making an accurate diagnosis and providing the appropriate therapy, with the patient responding positively to plasma exchanges (PEs) and cyclophosphamide pulses. We then, one year after disease onset, continued with glucocorticoids and mycophenolate mofetil (MMF), as maintenance therapy. There were no complications during the therapy other than neutropenia. Now, one year after the cessation of the immune suppression therapy, she is in remission with normal kidney function, no signs of hemolysis, normal C3 levels, and normal range proteinuria. The anti-factor H autoantibody titer decreased but still remained positive, the factor H antigen values remained low all throughout. Close follow-up is applied with frequent urine testing and complete blood count with an intention for early detection of relapse of the disease. Conclusion: The purpose of this case report is to emphasize the value of complement factor measurements and also to separate anti-CFH antibody-associated aHUS as an entity, because immunosuppressive therapy provides an excellent response..

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in approximately 12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1 or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 62 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

Aim Aim of the study was to determine if carotid intima media thickness in children with idiopathic nephrotic syndrome is greater than in healthy subjects, and to assess whether carotid intima media thickness in children with nephrotic syndrome is associated with clinical (including disease duration, cumulative dose of steroids, number of relapses) and biochemical parameters. Methods A cross-sectional study included 40 patients with nephrotic syndrome (mean age 11.7 ± 4.7 years). Steroid dependent nephrotic syndrome was established in 32 patients (80%), while 8 (20%) had steroid resistant nephrotic syndrome. Control group consisted of 20 age and gender matched healthy children. Blood pressure based on 24-h ambulatory blood pressure monitoring (ABPM), carotid intima media thickness, fasting glucose, insulin, HbA1c, lipid concentrations were measured in all children. Results A significant difference was detected in carotid intima media thickness values (P = 0.036). Children with nephrotic syndrome had significantly greater carotid intima media thickness compared with healthy children (0.42 ± 0.06 and 0.38 ± 0.03 mm). Carotid intima-media thickness was positively associated with duration of nephrotic syndrome (r = 0.45; P = 0.004), body mass index (r = 0.48; P = 0.002), daytime systolic blood pressure (r = 0.46; P = 0.003) and night-time systolic blood pressure (r = 0.52; P = 0.001). Multiple linear regression showed that duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness in children with nephrotic syndrome (R2 = 0.244; β=0.327; P = 0.037). Conclusion The findings of the present study suggest subclinical vascular damage in patients with nephrotic syndrome. Duration of nephrotic syndrome was the only independent predictor of carotid intima media thickness.

Rationale & Objective Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders. Study Design Cross-sectional cohort study. Setting & Participants 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and “other.” Results A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing–solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n = 5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome. Strictly targeted gene panels ( Limitations The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease). Conclusions Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.

Summary Background Acute kidney injury occurs in one in four children admitted to an intensive care unit (ICU) and its severity is independently associated with increased patient morbidity and mortality. Early prediction of acute kidney injury has the potential to improve outcomes. In smaller, single-centre trial populations, we have previously derived and validated the performance of a renal angina index, a context-driven risk stratification system, to predict severe acute kidney injury in children and adolescents. Here, we tested the predictive accuracy of this index for severe acute kidney injury in a large heterogeneous population. Methods We did a prospective, observational study (AWARE) that recruited patients in the ICUs of 32 hospitals in nine countries across Asia, Australia, Europe, and North America. All patients aged between 3 months and 25 years who were admitted to an ICU at least 48 h previously were eligible. Exclusion criteria were a history of stage 5 chronic kidney disease (ie, estimated glomerular filtration rate 2 or on maintenance dialysis) or kidney transplantation in the preceding 90 days. Patients' medical records were reviewed to collect data up to 3 months before (serum creatinine only), daily during the first 7 days, and on day 28 after ICU admission. For the assessment of the renal angina index, we included patients from the AWARE study who had full data from the day of ICU admission, day 3, and day 28, including serum creatinine concentrations and urine output measurements. The primary outcome was the presence of severe acute kidney injury (stage 2–3 acute kidney injury, according to Kidney Disease Improving Global Outcomes [KDIGO] guidelines) on the third day after ICU admission. We compared the performance of the renal angina index with changes in serum creatinine relative to baseline for prediction of the primary outcome. A score of eight points or more on the renal angina index defined fulfilment of renal angina; serum creatinine concentration relative to baseline was calculated using maximum serum creatinine concentration in the first 12 h of ICU admission). This trial is registered with ClinicalTrials.gov, number NCT01987921. Findings Between Jan 1 and Dec 31, 2014, we obtained data for 1590 patients. 286 patients (18%) had fulfilment of renal angina. At day 3, severe acute kidney injury occurred in 121 (42%) patients positive for renal angina and 247 (19%) patients negative for renal angina (relative risk [RR] 2·23, 95% CI 1·87–2.66, p vs 18 [2%], p vs 53 [4%], p=0·01). Fulfilment of renal angina showed better prediction for severe acute kidney injury than serum creatinine greater than baseline (RR 1.61, 95% CI 1·33–1·93; p vs serum creatinine greater than baseline 0·68, 0·49–4·94). Interpretation Earlier and better prediction of severe acute kidney injury has the potential to improve patient outcomes associated with acute kidney injury. Compared with isolated, context-free changes in serum creatinine, renal angina risk assessment improved accuracy for prediction of severe acute kidney injury in critically ill children and young people. Funding US National Institutes of Health.

Introduction. The group of autosomal dominant disorders - Epstein syndrome, Sebastian syndrome, Fechthner syndrome and May-Hegglin anomaly - are characterised by thrombocytopenia with giant platelets, inclusion bodies in granulocytes and variable levels of deafness, disturbances of vision and renal function impairment. A common genetic background of these disorders are mutations in MYH9 gene, coding for the nonmuscle myosin heavy chain IIA. Differential diagnosis is important for the adequate treatment strategy. The aim of this case report was to present a patient with MYH9 disorder in Serbia. Case report. A 16-year-old boy was referred to our hospital with the diagnosis of resistant immune thrombocytopenia for splenectomy. Thrombocytopenia was incidentally discovered at the age of five. The treatment with corticosteroids on several occasions was unsuccessful. Although the platelet count was below 10 × 109/L, there were no bleeding symptoms. Besides thrombocytopenia with giant platelets, on admission the patient also suffered sensorineuronal hearing loss and proteinuria. The diagnosis was confirmed with immunofluorescence and genetic analyses. Conclusion. Early recognition of MYH9-related diseases is essential to avoid unnecessary and potentially harmful treatments for misdiagnosed immune thrombocytopenia, and also for timely and proper therapy in attempt to delay end-stage renal failure and improve quality of life. [Projekat Ministartsva nauke Republike Srbije, br. 175056 i br. 15079]

Renal tubular acidosis (RTA) is common in adults with primary Sjogren syndrome (pSS) but to date this condition has only been identified in 12 pediatric cases of pSS. Here we present the case of a 13-year-old, otherwise asymptomatic girl in whom the search for the etiology of incidentally found nephrocalcinosis led to diagnosis of distal RTA and nephrogenic diabetes insipidus secondary to SS-associated tubulointerstitial nephritis. Immunosupressive treatment and alkali/electrolyte supplementation resulted in stable renal function over the 6-year follow-up. A review of the literature focuses on two aspects of pSS: (1) the difficulties in diagnosing pSS in childhood and (2) clinical-pathological features, treatment and outcome of renal tubulointerstitial disease in childhood pSS. SS should be considered in older children, particularly females with otherwise unexplained RTA. A careful search for other renal dysfunctions is necessary, and renal biopsy may be of value in assessing the extent of renal damage and the need for immunomodulatory therapy.

Introduction. Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in paediatric population. Objective. The aim of the study was analysis of aetiology, staging and associated complications of CKD at the time of diagnosis. Methods. Data of 97 patients (56 boys) of average age 7.8±5.8 years, referred for the first time to the Institute for Mother and Child Healthcare „Dr Vukan Cupic”, Belgrade in the period 1998- 2009, due to CKD, stage 2-5, were analysed. In each patient illness history was obtained, and physical examination, laboratory, X-ray and other investigations were performed according to the indications. CKD was classified according to the glomerular filtration rate into four grades: 2 - mild (60-90 ml/min/1.73 m2); 3 - moderate (30-60 ml/min/1.73 m2); 4 - advanced (15-30 ml/ min/1.73 m2); and 5 - terminal (

Introduction. Infants with urinary tract malformations (UTM) presenting with urinary tract infection (UTI) are prone to develop transient type 1 pseudohypoaldosteronism (THPA1). Objective. Report on patient series with characteristics of THPA1, UTM and/or UTI and suggestions for the diagnosis and therapy. Methods. Patients underwent blood and urine electrolyte and acid-base analysis, serum aldosterosterone levels and plasma rennin activity measuring; urinalysis, urinoculture and renal ultrasound were done and medical and/or surgical therapy was instituted. Results. Hyponatraemia (120.9?5.8 mmol/L), hyperkalaemia (6.9?0.9 mmol/L), metabolic acidosis (plasma bicarbonate, 11?1.4 mmol/L), and a rise in serum creatinine levels (145?101 ?mol/L) were associated with inappropriately high urinary sodium (51.3?17.5 mmol/L) and low potassium (14.1?5.9 mmol/L) excretion. Elevated plasma aldosterone concentrations (170.4?100.5 ng/dL) and the very high levels of the plasma aldosterone to potassium ratio (25.2?15.6) together with diminished urinary K/Na values (0.31?0.19) indicated tubular resistance to aldosterone. After institution of appropriate medical and/or surgical therapy, serum electrolytes, creatinine, and acid-base balance were normalized. Imaging studies showed ureteropyelic or ureterovesical junction obstruction in 3 and 2 patients, respectively, posterior urethral valves in 3, and normal UT in 1 patient. According to our knowledge, this is the first report on THPA1 in the Serbian literature. Conclusion. Male infants with hyponatraemia, hyperkalaemia and metabolic acidosis have to have their urine examined and the renal ultrasound has to be done in order to avoid both, the underdiagnosis of THPA1 and the inappropriate medication.

INTRODUCTION. Congenital nephrotic syndrome is usually presented with heavy proteinuria, hypoproteinaemia, oedema and hyperlipidaemia in a child from its birth until the age of 3 months. Aetiology of the disease is mutation in the relevant gene or it develops secondary to various infections. The most common form of congenital nephrotic syndrome is caused by mutation in gene for nephrin, the most important protein of the slit diaphragm. CASE OUTLINE. We present the patient with the clinical and laboratory signs of nephrotic syndrome expressed in the first day of life. Despite the adequate and regular substitution, antiproteinuric and antithrombotic therapy, complications occurred and the patient deceased. Genetic analysis revealed homozygous mutation in gene for nephrin (614del8ins2TT). Three years later, in the patient’s mother who was in the 12th week of pregnancy at that time, biopsy of chorionic villi was performed and the foetal genetic material showed heterozygosity for the same recessive mutation which meant that the foetus had the status of a carrier. To the best of our knowledge, this is the first family in Serbia in which prenatal molecular - genetic testing for the congenital nephrotic syndrome was accomplished. CONCLUSION. We wish to stress the importance of molecular diagnosis in patients with congenital nephrotic syndrome in order to perform early prenatal diagnosis in future pregnancies.

Eight boys aged 2-12 weeks with urinary tract malformations (UTMs) exhibited features of transient type 1 pseudo-hypoaldosteronism (TPHA1) in the course of urinary tract infection (UTI). Hyponatremia (120.9+/-5.8 mmol/l), hyperkalemia (6.9+/-0.9 mmol/l), metabolic acidosis (plasma bicarbonate 11+/-1.4 mmol/l), and a rise in serum creatinine levels (145+/-101 micromol/l) were associated with high urinary sodium (Na) and low potassium (K) excretion. Tubular resistance to aldosterone was indicated by high plasma aldosterone concentrations (170.4+/-100.5 ng/dl), high levels of the plasma aldosterone to potassium ratio (25.2+/-15.6), and diminished urinary K/Na values (0.31+/-0.19). With appropriate therapy, serum electrolytes, creatinine, and acid-base balance normalized within 2 weeks. A Medline search revealed another 85 cases of TPHA1 reported to date. All of the 93 patients were less than 7 months of age and 90% were less than 3 months of age, 90.3% suffered from UTM, with associated UTI in 89% of them, 11% had UTMin the absence of UTI, and 9.7% showed isolated UTI. These findings indicate that early infancy is the main contributing factor for TPHA1 to occur and that UTI and UTMare additional factors, with at least one being required for its development.