Clinical profile of a Polish cohort of children and young adults with cystinuria.

BACKGROUND: Cystinuria is an inherited disorder that results in increased excretion of cystine in the urine. It accounts for about 1-2% of pediatric kidney stones. In this study, we sought to identify the clinical characteristics of patients with cystinuria in a national cohort. METHODS: This was a retrospective study involving 30 patients from the Polish Registry of Inherited Tubulopathies. Initial data and that from a 6-month follow-up were analyzed. Mutational analysis was performed by targeted Sanger sequencing and, if applicable, MLPA analysis was used to detect large rearrangements. RESULTS: SLC7A9 mutations were detected in 15 children (50%; 10 males, 5 females), SLC3A1 mutations in 14 children (47%; 5 males, 9 females), and bigenic mutations in one male patient. The first clinical symptoms of the disease were detected at a median of 48 months of age (range 3-233 months). When individuals with different mutations were compared, there were no differences identified in gender, age of diagnosis, presence of UTI or urolithiasis, eGFR, calcium, or cystine excretion. The most common initial symptoms were urolithiasis in 26 patients (88%) and urinary tract infections in 4 patients (13%). Urological procedures were performed in 18 out of 30 (60%). CONCLUSIONS: The clinical course of cystinuria is similar among patients, regardless of the type of genetic mutation. Most patients require surgery before diagnosis or soon after it. Patients require combined urological and pharmacological treatment for prevention of stone recurrence and renal function preservation.

Multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab in children with steroid-resistant nephrotic syndrome.

The aim of the study was a multicenter analysis of the efficacy and safety of a non-standard immunosuppressive therapy with rituximab (Rtx) in children with steroid-resistant nephrotic syndrome (SRNS) with particular emphasis on the possibility of permanent discontinuation or dose reduction of other immunosuppressive drugs such as glucocorticoids and cyclosporine A after 6 months of observation. The study group consisted of 30 children with idiopathic nephrotic syndrome, who were unresponsive to standard immunosuppressive treatment, and hospitalized in the years 2010-2017 in eight paediatric nephrology centres in Poland. The children were administered a single initial infusion of rituximab at the dose of 375 mg/m2 of the body surface area. Proteinuria, the daily supply of glucocorticoids, and cyclosporine were assessed at the moment of the start of the treatment and after 6 months since its commencement. Before Rtx therapy, complete remission was found in 13 patients (43%) and partial remission was found in 8 patients (26%). These numbers increased to 16 (53%) and 12 (40%), respectively. At the start of the treatment 23 patients (76.6%) were treated with cyclosporine A. After 6 months, this number decreased to 15 patients (35%). At the start of the treatment, 18 patients (60%) were treated with prednisone. After 6 months, this number decreased to 8 patients (44%). Children with SRNS may potentially benefit from Rtx treatment despite relative risk of side effects. The benefits may include reduction of proteinuria or reduction of other immunosuppressants.

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

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.

Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations.

BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder exhibiting a high risk for progressive chronic kidney disease (CKD). METHODS: This is a retrospective multicentre study of 25 paediatric cases with FHHNC in Poland. Median age at diagnosis was 4 years and median follow-up time was 4.8 years. RESULTS: All cases of FHHNC carried recessive mutations in CLDN16. The founder mutation in CLDN16, Leu151Phe, was the most frequent cause of FHHNC in Polish patients, with 13 (52%) cases being homozygous and 5 (20%) carrying Leu151Phe allele in compound heterozygosity. All cases showed nephrocalcinosis, increased urinary fractional excretion of magnesium and hypercalciuria. Other disease features included hypomagnesaemia (76%), hyperparathyroidism (76%), hyperuricaemia (56%) and hypocitraturia (60%). Treatment with thiazides effectively reduced hypercalciuria in most cases. During follow-up, renal function declined in 60% of patients; 12% of patients reached CKD stage 3 or 4 and one patient developed end-stage renal failure. CONCLUSIONS: We report one of the largest cohorts of FHHNC cases caused by CLDN16 mutations. A missense variant of CLDN16, Leu151Phe, is the most common mutation responsible for FHHNC in Poland. Additionally, we found that normomagnesaemia does not exclude FHHNC and the calculation of fractional excretion of Mg can be diagnostic in the setting of normomagnesaemia. We also demonstrate the efficacy of a treatment with thiazides in terms of hypercalciuria in the majority of patients.

Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome.

BACKGROUND: The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked multi-systemic disorder, almost always characterized by the triad of congenital cataract, cognitive and behavioral impairment and a proximal tubulopathy. METHODS: Twenty-eight novel patients with suspected Lowe syndrome were studied. RESULTS: All patients carried OCRL gene defects with mutational hot spots at CpG dinucleotides. Mutations previously unknown in Lowe syndrome were observed in ten of the 28 patients, and carriership was identified in 30.4 % of the mothers investigated. Mapping the exact breakpoints of a complete OCRL gene deletion revealed involvement of several flanking repeat elements. We noted a similar pattern of documented clinically relevant symptoms, and even though the patient cohort comprised relatively young patients, 32 % of these patients already showed advanced chronic kidney disease. Thrombocytopenia was seen in several patients, and hyperosmia and/or hyperacusis were reported recurrently. A p.Asp523Asn mutation in a Polish patient, associated with the typical cerebrorenal spectrum but with late cataract (10 year), was also evident in two milder affected Italian brothers with ocular involvement of similar progression. CONCLUSIONS: We have identified clinical features in 28 patients with suspected Lowe syndrome that had not been recognized in Lowe syndrome prior to our study. We also provide further evidence that OCRL mutations cause a phenotypic continuum with selective and/or time-dependent organ involvement. At least some of these mutants might exhibit a genotype-phenotype correlation.

[Diabetes mellitus as a rare complication of hemolytic uremic syndrome--case report]. / Cukrzyca jako rzadkie powiklanie zespolu hemolityczno-mocznicowego--opis przypadku.

A 4-year-old girl was hospitalized in a local hospital with bloody diarrhoea, vomitus and abdominal pain. Because of acute abdominal symptoms she underwent appendectomy after which convulsions and acute respiratory distress were noticed. The child was transferred to the intensive care unit. During the examination she was unconscious, pale, oedematous with scattered ecchymoses, severe hypertension and urine output diminished to several ml per day. Routine blood tests showed microangiopathic anaemia, thrombocytopenia (52000/ul.) and uremia. Proteinuria and hematuria were revealed on urine examination. Among coagulation parameters kaolin-kefalin time (69 s) and D-dimers (2000-4000/ul.) were abnormal. On the strength of history, clinical and laboratory investigation the diagnosis of D-positive hemolytic uremic syndrome was established. Controlled artificial respiration (for 10 weeks), total parenteral alimentation (TPN), antihypertensive treatment and diuretics (furosemide, dopamine) were introduced. Daily temporary access hemodialyses were performed for 4 weeks. Subsequently peritoneal dialysis was started for 2 weeks. Despite the appropriate TPN glucose blood levels were unexpectedly high from first days from admission (200-330 mg%). Intensive intravenous insulin therapy was performed for 50 days. The child was discharged after 72 days with moderate renal function impairment (blood urea-53 mg%, creatinine-1,2 mg%), mild hypertension and proteinuria. Additional factor prone to thrombotic events was the 4G/4G genotype responsible for increased PAI-1 blood concentration, which may result in intensified fibrinolysis inhibition. Diabetes mellitus as a rare immunological complication of haemolytic uremic syndrome was suspected on the following evidence: positive anti-GAD antibodies (ELISA), elevated levels of glycosylated haemoglobin A1c, three-fold reduction of blood C-peptide concentration, negative family history for diabetes. After 12 y of follow up glucose and C-peptide concentrations were normal. Glucose loading test gave adequate response. Kidney function was decreased with serum creatinine 1.7-1.9 mg/dl and urea 60-75 mg/dl.

[Acute renal failure in the course of IgA nephropathy in a 16-year-old boy]. / Ostra niewydolnosc nerek w przebiegu nefropatii IgA u 16-letniego chlopca.

Acute renal failure (ARF) is a rare presentation of IgA nephropathy (IgAN). It can be associated with the episodes of macroscopic haematuria, being then usually reversible, or it develops in the course of progressive glomerulopathy with extracapillary proliferation. In the first case ARF is attributed to tubular obstruction by red blood cell casts. We present the case of a 16-year-old boy with non-oliguric ARF in the course of IgAN. He was admitted to the urology unit with 4-day history of gross haematuria, severe loin pain, fever and vomiting. A year before admission he had a short episode of macrohaematuria without any other accompanying symptoms. His family history was not relevant. As the patient was suspected to have acute renal colic in the course of nephrolithiasis, intravenous urography was performed. Since no urinary tract visualisation was obtained, laboratory investigation was carried out revealing marked renal dysfunction with serum creatinine level of 743.3 mumol/l and serum urea of 49.3 mmol/l. The patient was transferred to our department, where conservative treatment was administered (dialysis was not instituted). A rapid improvement in renal function was observed; it returned to normal within 2 weeks. The biopsy findings were consistent with IgAN.

[Beneficial effect of angiotensin converting enzyme inhibitor treatment in severe cystine urolithiasis]. / Korzystny efekt leczenia inhibitorem enzymu konwertujacego angiotensyne w ciezkiej cystynowej kamicy nerkowej.

Cystinuria is an autosomal recessive defect in transepithelial transport of dibasic amino acids (e.g. cystine) which involves the proximal canaliculi, small intestine and central nervous system. It is the least common cause of nephrolithiasis, accounting for 1 to 3% of renal calculi. The natural course of the disease, characterised by recurrent stone formation, can frequently lead to renal failure, if left untreated. Until recently, treatment of cystinuria has been limited to symptomatic management including intensive hydration and urine alkalinisation. Different drugs that react with cystine to form soluble complexes have been used but their efficacy remains questionable. We present the case of a 6-year-old boy with severe, recurrent cystine urolithiasis treated with captopril. The diagnosis of cystine urolithiasis was established after a 3-year course of clinically apparent nephrolithiasis, characterised by stone passage. At the age of 5 years he underwent lithotripsy and nephrolithotomy for removal of staghorn calculi. Since then treatment with citrate and magnesium supplementation combined with captopril was introduced. After a follow-up of 12 months the patient remained stone-free. Urinary cystine decreased from 230 to 136 mg per gram creatinine. We conclude that captopril can be useful in the treatment of cystine urolithiasis in children.

[Shunt nephritis]. / Shunt nephritis.

The term "shunt nephritis" stands for an immune-complex-mediated glomerulonephritis which develops as a complication of chronically infected ventriculoatrial or rarely ventriculoperitoneal shunt inserted for the treatment of hydrocephalus. The renal outcome of shunt nephritis is good if early diagnosis and treatment is provided. Due to a wide clinical spectrum of this disorder, as well as indolent courses of shunt infections, the diagnosis is often delayed. We present the case of 13-year-old girl with a severe course of shunt nephritis in whom the diagnosis was both overlooked and delayed. Misinterpretation of her symptoms led to erroneous diagnosis of lupus nephritis and introduction of immunosuppressive therapy.

[The results of conservative treatment of oxalate urolithiasis in children]. / Wyniki leczenia zachowawczego kamicy szczawianowej u dzieci.

UNLABELLED: Hyperoxaluria is defined as urinary oxalate excretion exceeding 0.45 mmol/1.73 m2/day and accounts for 15% of recurrent urolithiasis. There have been only a few reports on the prevalence and treatment of oxalate urolithiasis in children. THE AIM: Of the study was to assess the efficacy and safety of the protocol of intensive and combined treatment of hyperoxaluria in children. MATERIAL AND METHODS: Seventeen children at the mean age of 11.5 +/- 4.5 years with positive history of urolithiasis and diagnosis of hyperoxaluria were studied. In this group hyperoxaluria was an isolated defect in 9 of 17 children, but in 3/17 it was accompanied by hyperuricosuria, in 5/17 by hypomagnesuria and in 1 case by hypercalciuria. During the 12-month period the children were intensively hydrated and received a low-oxalate diet and supplemental therapy with vitamin B6, magnesium, citrates and lactic acid bacteria preparations. RESULTS: In all but one child oxaluria decreased below 0.45 mmol/1.73 m2/day (decrease by 45%). No new stone formation was seen during the observation period. In all patients abdominal pain and haematuria subsided. CONCLUSIONS: We conclude that the intensive, complex, conservative treatment of hyperoxaluria in children is effective and safe. It allows to decrease hyperoxaluria and prevent the recurrence of urolithiasis.

[Congenital nephrotic syndrome]. / Wrodzony zespóll nerczyowy.

In strict sense, the term "congenital nephrotic syndrome" (CNS) refers to those cases of the nephrotic syndrome in which clinical symptoms, e.g. massive proteinuria, hypoalbuminemia and oedema are present at birth. However, the term is often extended to babies presenting with nephrotic syndrome before 3 months of age in whom proteinuria is likely to be present earlier, before the signs of the nephrotic syndrome become clinically manifest. The most common and probably the most severe type of CNS is the congenital nephrotic syndrome of the Finnish type (CNF), which is considered as the prototype of CNS. On the basis of this syndrome the clinical course, diagnosis and complex treatment strategy are described. A well-documented case of Denys-Drash syndrome - a rare type of congenital nephrotic syndrome is also presented.