Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis.

BACKGROUND: A new prolonged-release formulation of potassium citrate and potassium bicarbonate, ADV7103, has been shown to improve metabolic control, palatability, and gastrointestinal safety in patients with distal renal tubular acidosis (dRTA) when compared to standard of care (SoC) treatments. The present work evaluates safety and efficacy of ADV7103 during 24 months. METHODS: Thirty pediatric and adult patients were included in an open-label extension study after a phase II/III trial. Safety and tolerability were assessed. Plasma bicarbonate and potassium levels, as well as urine parameters, were evaluated over time. Acceptability, adherence, and quality of life were also assessed. The evolution of clinical consequences of dRTA in the cohort was explored. RESULTS: There were 104 adverse events (AEs) reported, but only 9 gastrointestinal events observed in five patients (17%) were considered to be related to ADV7103 treatment. There were no AEs leading to treatment discontinuation. Plasma bicarbonate and potassium levels were in the normal ranges at the different visits, respectively, in 69-86% and 83-93% of patients. Overall adherence rates were ≥ 75% throughout the whole study in 79% patients. An average improvement of quality of life of 89% was reported at 24 months of study. CONCLUSIONS: Common AEs concerned metabolism and gastrointestinal disorders; the former being related to the disease. Less than half of the gastrointestinal AEs were related to ADV7103 treatment and they were mostly mild in severity. Metabolic parameters were maintained in the normal ranges in most patients. Patient satisfaction was high and adherence to treatment was good and remained stable. TRIAL REGISTRATION NUMBER: Registered as EudraCT 2013-003828-36 on the 3rd of September 2013.

Correction to: Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

The published version of the article unfortunately contained a mistake.

Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments.

BACKGROUND: Distal renal tubular acidosis (dRTA), due to impaired acid secretion in the urine, can lead to severe long-term consequences. Standard of care (SoC) oral alkalizers, requiring several daily intakes, are currently used to restore normal plasma bicarbonate levels. A new prolonged-release formulation, ADV7103, has been developed to achieve a sustained effect with an improved dosing scheme. METHODS: In a multicenter, open-label, non-inferiority trial (n = 37), patients with dRTA were switched from SoC to ADV7103. Mean plasma bicarbonate values and proportion of responders during steady state therapy with both treatments were compared, as were other blood and urine parameters, as well as acceptability, tolerability, and safety. RESULTS: When switching from SoC to ADV7103, the number of daily intakes was reduced from a median of three to twice daily. Mean plasma bicarbonate was increased and non-inferiority of ADV7103 was demonstrated (p < 0.0001, per protocol), as was statistical superiority (p = 0.0008, intention to treat [ITT]), and the response rate increased from 43 to 90% with ADV7103 (p < 0.001, ITT). Urine calcium/citrate ratio was reduced below the threshold for risk of lithogenesis with ADV7103 in 56% of previously non-responders with SoC (p = 0.021, ITT). Palatability was improved (difference [95% CI] of 25 [10.7, 39.2] mm) and gastrointestinal discomfort was reduced (difference [95% CI] of - 14.2 [- 25.9, - 2.6] mm) with ADV7103. CONCLUSIONS: Plasma bicarbonate levels and response rate were significantly higher with ADV7103 than with SoC. Urine calcium/citrate ratio, palatability, and gastrointestinal safety were significantly improved, supporting the use of ADV7103 as first-line treatment for dRTA. TRIAL REGISTRATION: Registered as EudraCT 2013-002988-25 on the 1st July 2013 Graphical abstract.

Growth in children with chronic kidney disease: 13 years follow up study.

BACKGROUND: Growth retardation is one of the most visible comorbid conditions of chronic kidney disease (CKD) in children. To our knowledge, published data on longitudinal follow-up of growth in pediatric patients with CKD is lacking from the region of South-East Europe. Herein we report the results from the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: The data reported in the present prospective analysis were collected between 2000 and 2012. A total of 324 children with CKD were enrolled in the registry. RESULTS: Prevalence of growth failure at registry entry was 29.3 %. Mean height standard deviation scores (HtSDS) in children with stunting and those with normal stature were -3.00 [95 % confidence interval (CI) -3.21 to -2.79] and -0.08 (95 % CI -0.22 to 0.05) (p < 0.001), respectively. Children with hereditary nephropathy had worse growth at registration (-1.51; 95 % CI -1.97 to -1.04, p = 0.008). Those with CKD stages 4 and 5 before registration had more chance to have short stature at registration than those with CKD stages 2 and 3 [odds ratio (OR) = 0.458, CI 0.268-0.782, p = 0.004]. Dialysis was an independent negative predictor for maintaining optimal stature during the follow-up period (OR = 0.324, CI = 0.199-0.529, p < 0.001), while transplantation was an independent positive predictor for improvement of small stature during follow-up (OR = 3.706, CI = 1.785-7.696, p < 0.001). CONCLUSION: Growth failure remains a significant problem in children with CKD, being worst in patients with hereditary renal disease. Growth is not improved by standard dialysis, but transplantation has a positive impact on growth in children.

Hypertensive encephalopathy as a late complication of autonomic dysreflexia in a 12-year-old boy with a previous spinal cord injury.

UNLABELLED: The scope of paediatric autonomic disorders is not well recognised, and paediatricians seem to be generally unaware of the complexity and diversity of their clinical manifestations. We report a 12-year-old boy presenting with hypertensive encephalopathy caused by autonomic dysreflexia. CONCLUSION: This observation emphasises the importance of the recognition of this rare autonomic disorder, which can have potentially life-threatening neurological complications.

Molecular characterization of cystinuria in south-eastern European countries.

Cystinuria is an autosomal recessive disorder caused by defective transport of cystine and dibasic amino acids in the proximal renal tubules and small intestine. So far, more than 128 mutations in SLC3A1 gene, and 93 in SLC7A9 gene have been described as a cause of cystinuria. We present a molecular characterization of the cystinuria in 47 unrelated south-east European families. The molecular methodology included direct sequencing, single strand conformational polymorphism, and restriction fragment length polymorphism. A total of 93 (94.9 %) out of 98 unrelated cystinuric chromosomes have been characterized. Mutations in SLC3A1 gene account for 64.3 % and in SLC7A9 gene for 30.6 % of the cystinuric chromosomes. Ten different mutations in SLC3A1 gene were found, and two of them were novel (C242R and L573X), while in SLC7A9 gene seven mutations were found, of which three were novel (G73R, V375I and c.1048_1051delACTC). The most common mutations in this study were T216M (24.5 %), M467T (16.3 %) and R365L (11.2 %) in SLC3A1 and G105R (21.4 %) in SLC7A9 gene. A population specificity of cystinuria mutations was observed; T216M mutation was the only mutation present among Gypsies, G105R was the most common mutation among Albanians and Macedonians, and R365L among Serbs. The results of this study allowed introduction of rapid, simple and cost-effective genetic diagnosis of cystinuria that enables an early preventive care of affected patients and a prenatal diagnosis in affected families.

Epidemiology of chronic kidney disease in children in Serbia.

BACKGROUND: The epidemiological information from well-defined populations regarding childhood chronic kidney disease (CKD), particularly those concerning non-terminal stages, are scanty. The epidemiology of CKD in children is often based on renal replacement therapy (RRT) data, which means that a considerable number of children in earlier stages of CKD are missed as they will reach end-stage renal disease (ESRD) in adulthood. Here, we report the basic epidemiological data on childhood CKD in Serbia, gathered over the 10-year period of activity of the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: Since 2000-09, data on incidence, prevalence, aetiology, treatment modalities and outcome of children aged 0-18 years, with CKD Stages 2-4 and CKD Stage 5, were collected by reporting index cases from paediatric centres. RESULTS: Three hundred and thirty-six children were registered (211 boys, 125 girls, male/female ratio 1.7). The median age at registration was 9.0 years [interquartile range (IQR) 3-13]. Median follow-up was 4.0 years (IQR, 1-9). The median glomerular filtration rate (GFR) at the time of the registration was 39.6 mL/min/1.73m(2) (IQR, 13.8-65.4). Median annual incidence of CKD 2-5 stages was 14.3 per million age-related population (p.m.a.r.p.), while those of CKD 2-4 or CKD 5 were 9.1 and 5.7 p.m.a.r.p., respectively. The median prevalence of CKD 2-5 was 96.1 p.m.a.r.p., 52.8 p.m.a.r.p. in CKD 2-4 and 62.2 p.m.a.r.p. in CKD 5. The main causes of CKD were congenital anomalies of kidney and urinary tract and hereditary nephropathies. Kidney survival was the worst in children with glomerular diseases and in those with advanced CKD. Haemodialysis was the most common first modality of RRT. Mortality rate was 4.5%, mainly due to cardiovascular and infectious complications. CONCLUSIONS: Epidemiology of paediatric CKD in Serbia is similar to that reported from developed European countries. The knowledge of the epidemiology of earlier stages of CKD is essential for both institution of renoprotective therapy and planning of RRT, a fact of paramount importance in countries with limited resources.

Botulinum toxin type A in combination with standard urotherapy for children with dysfunctional voiding.

PURPOSE: We investigated the role of botulinum toxin type A and urotherapy in the treatment of children with dysfunctional voiding. MATERIALS AND METHODS: Nine female children with dysfunctional voiding refractory to standard urotherapy and alpha1-adrenergic blocking agents were included in the prospective clinical study. Botulinum toxin type A in a dose of 500 units was injected transperineally into the external urinary sphincter. Bladder rehabilitation was introduced 2 weeks after botulinum toxin type A treatment. Uroflow studies with ultrasound residual urine volumes were obtained before and 6 months after treatment. All children were tested before and 6 months after treatment using the empirically designed International Reflux Study in Children modified questionnaire. RESULTS: After treatment the mean +/- SD voided volume increased from 180 +/- 73 to 228 +/- 94 ml (p <0.05) while post-void residual urine volume decreased from 52 +/- 40 to 19 +/- 18 ml (p <0.05). Significant differences in other uroflowmetry parameters were not found. However, significant symptom score improvement was detected 6 months after treatment, being decreased by 7 vs 20 (p <0.01). No systemic side effects occurred following botulinum toxin type A injection. CONCLUSIONS: Our study demonstrates that the voiding mechanism in children with dysfunctional voiding refractory to standard therapy can be significantly improved and maintained at least 6 months after combined botulinum toxin type A injection and bladder rehabilitation.

[Functional voiding disorders: rehabilitation of children with urge syndrome].

Urge syndrome is a condition associated with functional voiding disorders. Urological symptoms (urgency, frequency and incontinence) are manifestations of uninhibited detrusor contractions. The goal of rehabilitation programs is to develop voluntary bladder control, to improve urologic symptoms and to increase bladder capacity. Bladder training, strategies to suppress urgency, electrical stimulations such are anogenital, transcutaneous and percutaneous electrical nerve stimulations have been used in the treatment.

Radionuclide voiding patterns in children with vesicoureteral reflux.

The purpose of this study was to evaluate bladder function in children with vesicoureteral reflux (VUR) by means of indirect radionuclide cystography (IRNC), and to investigate whether IRNC can identify those children with voiding dysfunction. The study enrolled 74 neurologically intact children, 14 boys and 60 girls aged 2-14 years, with VUR documented using contrast micturating cystourethrography as the initial method. In all patients, IRNC was performed using technetium-99m diethylene triamine penta-acetate (DTPA). Based on the urodynamic findings, three groups were distinguished: a group with VUR and normal urodynamic findings ( n=27), a group with VUR and detrusor hyper-reflexia ( n=43) and a group with VUR and detrusor-sphincter dyssynergia ( n=4). A control group comprised 64 healthy children, aged 2-13 years, without any symptoms of lower urinary tract dysfunction. The dynamics of bladder emptying were studied in the posterior view after intravenous injection of 37 MBq/10 kg b.w. DTPA, with acquisition of 90 2-s frames during voiding. The parameters evaluated were: voided urine volume (VV), bladder capacity, functional bladder capacity (FBC), residual urine, voiding time, average flow rate, peak flow rate (PFR) and ejection fraction (EF). With regard to the final urodynamic diagnosis, FBC, PFR and EF were found to be significant IRNC predictor variables using the logistic regression method. If abnormality on at least two of the three significant predictor variables was taken as the criterion of voiding dysfunction, the overall sensitivity, specificity and accuracy of IRNC in the detection of voiding dysfunction were 81%, 78% and 80%, respectively. Three radionuclide voiding patterns were detected in children with VUR: (1) a normal voiding pattern characterised by normal FBC with near-normal PFR and EF values, (2) a markedly reduced FBC with significantly reduced VV, PFR and EF values (in children with bladder instability), and (3) a higher bladder volume with a near-normal value for PFR and a slightly reduced or near-normal EF (in children with detrusor-sphincter dyssynergia). This study confirmed the association between lower urinary tract dysfunction and congenital VUR. IRNC was found to be a simple, non-invasive method which allows reliable differentiation of voiding patterns in patients with VUR. IRNC can be used as a first-line method for screening in children with VUR to identify those with abnormal voiding patterns.