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.

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.

Dent disease in Poland: what we have learned so far?

PURPOSE: Dent disease (DD) is a rare tubulopathy characterized by proximal tubular dysfunction leading to chronic kidney disease (CKD). The aim of the study was to characterize patients with DD in Poland. METHODS: A retrospective analysis of a national cohort with genetically confirmed diagnosis. RESULTS: Of 24 males, all patients except one carried mutations in the CLCN5 gene; in one patient a mutation in the OCRL gene was disclosed. Molecular diagnosis was delayed 1 year on average (range 0-21 years). The most common features were tubular proteinuria (100%), hypercalciuria (87%), and nephrocalcinosis (56%). CKD (≤stage II) and growth deficiency were found in 45 and 22% of patients, respectively. Over time, a progression of CKD and persistence of growth impairment was noted. Subnephrotic and nephrotic proteinuria (20%) was found in most patients, but tubular proteinuria was assessed in only 67% of patients. In one family steroid-resistant nephrotic syndrome prompted a genetic testing, and reverse phenotyping. Five children (20%) underwent kidney biopsy, and two of them were treated with immunosuppressants. Hydrochlorothiazide and angiotensin-converting enzyme inhibitors were prescribed for a significant proportion of patients (42 and 37.5%, respectively), while supplemental therapy with phosphate, potassium, vitamin D (12.5% each), and alkali (4.2%) was insufficient, when compared to the percentages of patients requiring repletion. CONCLUSIONS: We found CLCN5 mutations in the vast majority of Polish patients with DD. Proteinuria was the most constant finding; however, tubular proteins were not assessed commonly, likely leading to delayed molecular diagnosis and misdiagnosis in some patients. More consideration should be given to optimize the therapy.

Dent disease in children: diagnostic and therapeutic considerations.

BACKGROUND: Dent disease (DD) is a rare X-linked tubulopathy characterized by a proximal tubular dysfunction leading to nephrocalcinosis/nephrolithiasis and progressive renal failure. The disease is associated with a mutation either in CLCN5 or OCRL genes. We aim to define clinical and genetic disease characteristics and summarize treatments of Polish patients with DD. METHODS: The study cohort consists of 10 boys (aged 5 - 16.5 years) whose data were collected through POLtube Registry. RESULTS: All of the patients had tubular proteinuria, hypercalciuria, and nephrocalcinosis/nephrolithiasis. Renal impairment and growth deficiency were found in 3 patients and rickets in 2 patients. In total, 9 of 10 patients carried a mutation in the CLCN5 gene. Five of 9 detected mutations were novel. In 1 patient with a clinical phenotype of DD, no mutations in either CLCN5 or OCRL were discovered. Therapy consisted of thiazides in 7 patients, and phosphate supplements and enalapril in 3 cases. Growth hormone therapy was initiated in 3 patients and resulted in improved growth rate. CONCLUSIONS: We report clinical and molecular characterization of Polish children with DD. Our study suggests that this tubulopathy may be generally under-diagnosed in Poland. The study revealed variable treatments, demonstrating a need for therapeutic guidelines.

Successes and pitfalls of chronic peritoneal dialysis in infants - a Polish nationwide outcome study.

INTRODUCTION: Peritoneal dialysis (PD) is a preferred method of renal replacement therapy for end-stage renal disease in children. Recent advances have allowed chronic PD to be provided to children of all ages and sizes. MATERIAL AND METHODS: The study was designed as a national (10 dialysis centres), multicentre retrospective analysis of the medical history of 33 children who started chronic peritoneal dialysis in their infancy between 1993 and 2005, with a follow-up period of at least 24 months. RESULTS: The nutritional status of the infants was unsatisfactory. The mean SDS of body weight at the start was -2.0, at 1 year of age -1.7. Only 40% of infants were adequately nourished at 1 year of age. Long-term follow-up analysis showed that 12 children received a kidney transplant, 13 were still on dialysis (4 changed method) and 6 died (mortality rate in the first year of life of 9%). In 2 children we observed an improvement of renal function. We observed a relatively high (1/8.8 patient-months) peritonitis rate in the analysed children when compared to 1 : 22 patient-months in all children undergoing PD in Poland. CONCLUSIONS: The results of our survey have shown that the management of dialysed infants is still a challenge for the medical team and families, but long-term results of the therapy are encouraging.

[Pre-emptive renal transplantation in a boy with obstructive uropathy following reconstruction procedures]. / Przeszczep nerki u pacjenta z zastawka cewki tylnej (ZCT) po zabiegach plastyki pecherza moczowego.

Patients with bladder dysfunction comprise over 30% of pediatric patients on renal replacement therapy. We report on a successful cadaveric pre-emptive renal transplantation performed in a boy born with posterior urethral valve. Following bilateral ureterocutaneostomies, left nephrectomy and valve resection, at 6 years of age a continent ileocolonocystoplasty was performed. The boy started intermittent daytime catheterization, passing urine both via urethra and fistula. At the age of 18 he received a renal transplant. Continuing the previous regime, at 1.5 years follow up his graft is well functioning (GFR >75 ml/min/1.73 m2) with sporadic episodes of urinary tract infection.

[Kidney transplantation into a neurogenic bladder in myelomeningocele patient (MMC)]. / Przeszczepienie nerki do pecherza neurogennego u pacjenta z przepuklina oponowo-rdzeniowa.

UNLABELLED: We report a 24-year-old patient with neurogenic bladder due to myelomeningocele (MMC) who received a kidney transplant without prior bladder reconstruction. Following transplantation recurrent episodes of febrile pyelonephritis were observed with elevations of creatinine. A year after Tx a bladder augmentation was performed with appendicostomy to enable intermittent catheterization. Following surgery only sporadic episodes of UTI have been observed and his renal function is stable. CONCLUSION: bladder reconstruction surgery in patients with neurogenic bladder is feasible post transplantation though the optimal timing is prior to a kidney Tx.

[LAMB2 gene mutation as a cause of congenital nephrotic syndrome with distinct eye abnormalities and hypotonia]. / Mutacja genu LAMB2 jako przyczyna wrodzonego zespolu nerczycowego zwiazanego z anomaliami galek ocznych i hipotonia miesni.

UNLABELLED: Mutations in the LAMB2 gene encoding laminin beta2, a component of the glomerular basement membrane and the neuro-muscular junction are responsible for the characteristic renal and eye abnormalities of Pierson syndrome. We report a girl with confirmed LAMB2 mutation who presented with early onset Congenital Nephrotic Syndrome (CNS) with renal failure and ocular findings of bilateral microcoria, persistent hyperplastic primary vitreous, right microphtalmia and left eye cataract. Automated peritoneal dialysis was started from the 3rd month of life. Severe muscle hypotonia with motor and mental delay were observed during the first year of life. She experienced numerous serious infections from birth and died at the age of 15 months due to a fulminant infection. Genetic studies revealed two novel mutations in LAMB2 gene (compound heterozygosity). CONCLUSIONS: 1. Mutations in LAMB2 gene should be included in the work-up of patients with CNS in the presence of eye anomalies. 2. Severe phenotypes of Pierson syndrome are associated with marked handicaps and a poor outcome.

[Chronic peritoneal dialysis in infants--preliminary results of the multicenter survey]. / Przewlekla dializa otrzewnowa u niemowlat--wstepna analiza ankiety wieloosrodkowej.

We retrospectively analysed peritoneal dialysis treatment in 29 infants dialysed in 9 paediatric centres in Poland in the years 1993-2004. The mean age at the start of dialysis was 4.9 +/- 3.5 months (range 2 days to 11 months), mean body mass 5.6 +/- 2.5 kg (range 2.5 to 11 kg). The mean duration of PD was 6.8 +/- 3.9 in the first year of life and total duration of the therapy 34 +/- 27 months. Of the 29 infants 4 died (2 in infancy), 11 underwent renal transplantation, in 2 children PD was stopped (they received a conventional treatment) and 12 were still dialysed at the date of data collection. The peritonitis rate was 1/9.5 patient-month and exit site infection rate 1/16 patient-month up to 1 year of life. 9 children (31%) required hernia repairs and in 9 catheters were replaced. Chronic peritoneal dialysis in infants is associated with high risk of infections and surgical complications and remains a challenge for paediatric nephrologists.

[Percutaneus endoscopic gastrostomy (PEG) in an infant with chronic renal failure]. / Przezskórna endoskopowa gastrostomia (PEG) u niemowlecia z przewlekla niewydolnoscia nerek.

Malnutrition is a major problem in patients with chronic renal failure, especially in children in the first three years of life. Meeting high energy needs in these patients may be difficult because of anorexia and vomiting, which are common in predialysis renal failure. Nutritional support for children with chronic renal failure often involves the use of nasogastric tubes or gastrostomy feeding. We describe an infant with pre-dialysis renal failure and severe malnutrition in whom only insertion of percutaneus endoscopic gastrostomy provided adequate caloric intake and satisfactory weight gain.

[Successful prophylactic plasma infusions in recurrent atypical hemolytic-uremic syndrome]. / Skuteczna profilaktyka nawrotów atypowego zespolu hemolityczno-mocznicowego przy pomocy cyklicznych wlewów osocza.

UNLABELLED: Atypical, recurrent hemolytic uraemic syndrome (HUS) often leads to end-stage renal disease and can relapse after a renal transplantation. Plasmapheresis and fresh frozen plasma (FFP) therapies are used to treat acute relapses. We report on the prophylactic use of FFP in a child with atypical recurrent HUS with low serum C3. The girl experienced four episodes of atypical HUS over a year from the age of 18 months. During the first relapse a decreased level of C3--0,62 g/l (normal: 0.88-2.01 g/l) was revealed. Initially daily plasma infusions were given (8-14 ml/kg for 5-15 days) during acute episodes. Following the 4th episode prophylactic FFP therapy was started. Three-times weekly plasma transfusions were continued for three months and then doses were tapered off over the next months to once-weekly FFP. During the one year follow-up no relapse has been observed. At the age of 3 1/2 years she is thriving (10th percentile for height and weight). She has severe but well controlled hypertension without end-organ involvement. The child demonstrates signs of stage 2 chronic kidney disease (CKD): serum creatinine--0.65 mg/dl, Schwartz estimated GFR--79.9 ml/min/ 1.73 m2, persistent slight proteinuria and haematuria, increased renal cortical echogenicity on ultrasound. Genetic studies for the known atypical HUS mutations and assessment of complement activation proteins (factors H and I) are under investigation. CONCLUSION: Prophylactic FFP infusions can be successful in preventing relapses and further progressive renal damage in individual patients with atypical HUS associated with low C3.

[Problems of nephroblastoma therapy in children with chronic renal failure--report of two cases]. / Problemy leczenia nerczaka zarodkowego u dzieci z przewlela niewydolnoscia nerek--opis dwóch przypadków.

UNLABELLED: Chronic renal failure (CRF) in children with nephroblastoma occurs in less than 4% of cases. THE AIM of the study was to present the diagnostic and therapeutic difficulties in two children with nephroblastoma in whom chemotherapy was conducted in the phase of CRF. MATERIAL AND METHODS: 52 children with nephroblastoma were treated in the Department of Paediatrics, Haematology, Oncology and Endocrinology, Medical University of Gdansk, between 1992 and 2004. Chronic renal failure occurred in two of them. In one patient (case 1) CRF was associated with a congenital complex urinary tract defect (cystic dysplasia of the left kidney, megaureter and bilateral hydronephrosis), in the second one (case 2), CRF resulted from bilateral nephrectomy in the course of relapsing bilateral nephroblastoma. CONCLUSIONS: Chemotherapy in children with CRF is a serious therapeutical dilemma. The effective dose of the cytotoxic drug, the time of its administration and the periods between the chemotherapy cycles are very difficult to assess for this group of patients. Problems also occur with the achievement of proper energy intake and good physical development of the child.