Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience.

BACKGROUND: Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. METHODS: We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists. RESULTS: We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established. CONCLUSIONS: PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.

Optimizing Nutrition in Neonates with Kidney Dysfunction.

The nutritional management of neonates with kidney disease is complex. There may be significant differences in nutritional needs based on the duration and cause of kidney dysfunction, including acute kidney injury (AKI) and chronic kidney disease (CKD). Furthermore, the treatment modality, including acute (continuous renal replacement therapy and peritoneal dialysis [PD]) and chronic (intermittent hemodialysis and PD) approaches may differentially affect nutritional losses and dietary needs. In this review, we discuss the pathophysiology of compromised nutrition in neonates with AKI and CKD. We also summarize the existing data and consensus recommendations on the provision of nutrition to neonates with AKI and CKD. We highlight the paucity of data on micronutrient losses and the need for future prospective studies to enhance nutritional supplementation to hopefully improve outcomes in these patients.

Pediatric peritoneal dialysis training program and its relationship to peritonitis: a study of the International Pediatric Peritoneal Dialysis Network.

BACKGROUND: The guidelines for training of patients and caregivers to perform home peritoneal dialysis (PD) uniformly include recommendations pertaining to the prevention of peritonitis. The objective of this study conducted by the International Pediatric Peritoneal Dialysis Network (IPPN) was to investigate the training practices for pediatric PD and to evaluate the impact of these practices on the peritonitis and exit-site infection (ESI) rate. METHODS: A questionnaire regarding details of the PD program and training practices was distributed to IPPN member centers, while peritonitis and ESI rates were either derived from the IPPN registry or obtained directly from the centers. Poisson univariate and multivariate regression was used to determine the training-related peritonitis and ESI risk factors. RESULTS: Sixty-two of 137 centers responded. Information on peritonitis and ESI rates were available from fifty centers. Training was conducted by a PD nurse in 93.5% of centers, most commonly (50%) as an in-hospital program. The median total training time was 24 hours, with a formal assessment conducted in 88.7% and skills demonstration in 71% of centers. Home visits were performed by 58% of centers. Shorter (< 20 hours) training duration and lower number of training tools (both p < 0.02) were associated with higher peritonitis rate, after adjustment for proportion of treated infants and income of country of residence. CONCLUSIONS: An association between training duration and the number of training tools represent potentially modifiable risk factors to reduce peritonitis rates within the pediatric PD population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Changes in bone biomarkers in response to different dosing regimens of cholecalciferol supplementation in children with chronic kidney disease.

BACKGROUND: The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD). METHODS: This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2-4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30 ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3 months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores. RESULTS: 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r = - 0.4, p < 0.001). CONCLUSIONS: Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

Infection-Related Glomerulonephritis in Children and Adults.

Infection-related glomerulonephritis is an immunologically mediated glomerular injury after an infection. Glomerulonephritis may occur with the infection or after a variable latent period. Poststreptococcal glomerulonephritis (PSGN) is the prototype of infection-related glomerulonephritis. The streptococcal antigens, nephritis-associated plasmin-like receptor and streptococcal exotoxin B, have emerged as major players in the pathogenesis of PSGN. Although PSGN is the most common infection-related glomerulonephritis in children, in adults, glomerulonephritis is secondary to bacteria such as staphylococci, viruses such as hepatitis C, and human immunodeficiency virus, and, rarely, parasitic infections. Supportive therapy is the mainstay of treatment in most infection-related glomerulonephritis. Treatment of the underlying infection with specific antibiotics and antiviral medications is indicated in some infections. Parasitic infections, although rare, may be associated with significant morbidity. Poststreptococcal glomerulonephritis is a self-limiting condition with a good prognosis. However, bacterial, viral, and parasitic infections may be associated with significant morbidity and long-term consequences. Epidemiologic studies are required to assess the global burden of infection-related glomerulonephritis. A better understanding of the pathogenesis of infection-related glomerulonephritis may unravel more treatment options and preventive strategies.

Clinical profile and outcome of arteriovenous fistulae in children on maintenance hemodialysis from a low-resource setting.

INTRODUCTION: Arteriovenous fistula (AVF) is the recommended access of choice in children on maintenance hemodialysis. The challenges of creating and maintaining a fistula in children are many. The objective of our study was to describe the clinical profile and outcomes of AVFs in children from a resource-limited setting. METHODS: A retrospective analysis of children who have had an AVF for maintenance hemodialysis from 2010 to 2020 was performed. The center protocol for creation and management of complications was followed. Failure of fistula to mature was defined as primary failure. Primary patency was defined as the time from creation of access to the first complication requiring intervention. The primary failure rate, duration of primary patency and associated risk factors, and 1- and 3-year primary fistula patency rates were studied. RESULTS: Thirty-six children (38 AVFs) with the median (interquartile range) age of 11 (8, 13) years were included. Brachiocephalic anastomosis was the most common site (75%) of AVF. The primary failure rate was 5.5% (2 of 36). The mean (95% confidence interval) duration of primary patency was 42.3 (29.9, 54.7) months. There were no particular factors associated with the duration of primary patency. The 1- and 3-year primary patency rate was 91% and 73%, respectively. CONCLUSIONS: In resource-limited settings, AVF had good primary patency and is a feasible and durable access for maintenance hemodialysis in children.

Population pharmacokinetics and dose optimisation of colecalciferol in paediatric patients with chronic kidney disease.

AIMS: The prevalence of vitamin D deficiency is high in children with chronic kidney disease (CKD). However, current dosing recommendations are based on limited pharmacokinetic (PK) data. This study aimed to develop a population PK model of colecalciferol that can be used to optimise colecalciferol dosing in this population. METHODS: Data from 83 children with CKD were used to develop a population PK model using a nonlinear mixed effects modelling approach. Serum creatinine and type of kidney disease (glomerular vs. nonglomerular disease) were investigated as covariates, and optimal dosing was determined based on achieving and maintaining 25-hydroxyvitamin D (25(OH)D) concentration of 30-48 ng/mL. RESULTS: The time course of 25(OH)D concentrations was best described by a 1-compartment model with the addition of a basal concentration parameter to reflect endogenous 25(OH)D production from diet and sun exposure. Colecalciferol showed wide between-subject variability in its PK, with total body weight scaled allometrically the only covariate included in the model. Model-based simulations showed that current dosing recommendations for colecalciferol can be optimised using a weight-based dosing strategy. CONCLUSION: This is the first study to describe the population PK of colecalciferol in children with CKD. PK model informed dosing is expected to improve the attainment of target 25(OH)D concentrations, while minimising the risk of overdosing.

Clinical Profile and Outcome of Emergencies in Pediatric Chronic Kidney Disease.

OBJECTIVE: To describe the clinical profile and outcome of emergencies in children with chronic kidney disease (CKD). METHODS: This retrospective analysis studied children with CKD presenting with acute emergencies. The clinical profile, renal and patient outcomes were compared between incidentally diagnosed - iCKD, previously diagnosed not on dialysis - pCKD and those on maintenance dialysis - dCKD groups. RESULTS: 82 children (67 boys, median age - 8 years) with 99 visits were included. Uremic encephalopathy was the most common emergency in iCKD (64.7%) and pCKD (38.4 %), and access-related infections (32.1%) in dCKD group. Children with iCKD had higher Pediatric Risk of Mortality score (P<0.001), emergent initiation of dialysis (P=0.03) and discontinuation of treatment (P<0.001) when compared to the pCKD group. CONCLUSION: Uremic encephalopathy and access-related infections were the most common emergencies in children with CKD. Incidentally diagnosed CKD had a worse clinical profile and outcome.

Paediatric nephrology in under-resourced areas.

BACKGROUND: Nearly 50% of the world population and 60% of children aged 0 to 14 years live in low- or lower-middle-income countries. Paediatric nephrology (PN) in these countries is not a priority for allocation of limited health resources. This article explores advancements made and persisting limitations in providing optimal PN services to children in such under-resourced areas (URA). METHODS: Medline, PubMed and Google Scholar online databases were searched for articles pertaining to PN disease epidemiology, outcome, availability of services and infrastructure in URA. The ISN and IPNA offices were contacted for data, and two online questionnaire surveys of IPNA membership performed. Regional IPNA members were contacted for further detailed information. RESULTS: There is a scarcity of published data from URA; where available, prevalence of PN diseases, managements and outcomes are often reported to be different from high income regions. Deficiencies in human resources, fluoroscopy, nuclear imaging, immunofluorescence, electron microscopy and genetic studies were identified. Several drugs and maintenance kidney replacement therapy are inaccessible to the majority of patients. Despite these issues, regional efforts with support from international bodies have led to significant advances in PN services and infrastructure in many URA. CONCLUSIONS: Equitable distribution and affordability of PN services remain major challenges in URA. The drive towards acquisition of regional data, advocacy to local government and non-government agencies and partnership with international support bodies needs to be continued. The aim is to optimise and achieve global parity in PN training, investigations and treatments, initially focusing on preventable and reversible conditions.

Determining the optimal cholecalciferol dosing regimen in children with CKD: a randomized controlled trial.

BACKGROUND: The optimal treatment regimen for correcting 25-hydroxyvitamin D (25OHD) deficiency in children with chronic kidney disease (CKD) is not known. We compared cholecalciferol dosing regimens for achieving and maintaining 25OHD concentrations ≥30 ng/mL in children with CKD stages 2-4. METHODS: An open-label, multicentre randomized controlled trial randomized children with 25OHD concentrations <30 ng/mL in 1:1:1 to oral cholecalciferol 3000 IU daily, 25 000 IU weekly or 100 000 IU monthly for 3 months (maximum three intensive courses). In those with 25OHD ≥30 ng/mL, 1000 IU cholecalciferol daily (maintenance course) was given for up to 9 months. Primary outcome was achieving 25OHD ≥30 ng/mL at the end of intensive phase treatment. RESULTS: Ninety children were randomized to daily (n = 30), weekly (n = 29) or monthly (n = 31) treatment groups. At the end of intensive phase, 70/90 (77.8%) achieved 25OHD ≥30 ng/mL; 25OHD concentrations were comparable between groups (median 44.3, 39.4 and 39.3 ng/mL for daily, weekly and monthly groups, respectively; P = 0.24) with no difference between groups for time to achieve 25OHD ≥30 ng/mL (P = 0.28). There was no change in calcium, phosphorus and parathyroid hormone, but fibroblast growth factor 23 (P = 0.002) and klotho (P = 0.001) concentrations significantly increased and were comparable in all treatment groups. Irrespective of dosing regimen, children with glomerular disease had 25OHD concentrations lower than non-glomerular disease (25.8 versus 41.8 ng/mL; P = 0.007). One child had a 25OHD concentration of 134 ng/mL, and 5.5% had hypercalcemia without symptoms of toxicity. CONCLUSION: Intensive treatment with oral cholecalciferol as daily, weekly or monthly regimens achieved similar 25OHD concentrations between treatment groups, without toxicity. Children with glomerular disease required higher doses of cholecalciferol compared with those with non-glomerular disease.

Clinical and dialysis outcomes of manual chronic peritoneal dialysis in low-body-weight children from a low-to-middle-income country.

BACKGROUND: Peritoneal dialysis (PD) is the preferred modality of renal replacement therapy in children with end-stage renal disease (ESRD). In developing countries, the challenges of initiating and sustaining chronic peritoneal dialysis (CPD) are many and are not well-described in the literature. METHODS: This was a retrospective study of children aged 0-18 years on manual PD. The objective was to compare the clinical (growth) and dialysis outcomes (dialysis adequacy and peritonitis rates) in young children with low body weight (LBW; ≤15 kg) on CPD with children weighing >15 kg. RESULTS: We found that at baseline, the dialysis prescription, sociodemographic parameters, and the prevalence of complications of ESRD were similar in both groups. On follow-up, however, growth was significantly more affected in LBW children than the rest of the cohort. The adequacy of dialysis and peritonitis rates were comparable between groups. CONCLUSIONS: Despite all the challenges, manual CPD is a feasible modality of dialysis in young children with LBW, and their outcomes are comparable to older children even in low-to-middle-income countries. Appropriate early management of associated complications and improving dialysis adequacy are necessary to improve the outcomes in these children.

Seroconversion following hepatitis B vaccination in children with chronic kidney disease.

Seroconversion following hepatitis B vaccination is low in children with chronic kidney disease (CKD). This study aimed to assess the seroconversion and persistence of protective immunity following hepatitis B vaccination in children with CKD. This prospective observational study was conducted in a tertiary pediatric nephrology centre to assess the seroconversion and maintenance of antibody titers (>10 mIU/mL) at one year following hepatitis B vaccination (10 µg at 0, 1, and 2 months) in children with CKD Stages II to V. Those who did not seroconvert after the schedule were re-vaccinated, and antibody titers were checked. Categorical data were expressed as proportions and analyzed using the Chi-square test. Pearson's correlation test was used to determine the correlation of antibody titers with other continuous variables. Seroconversion was observed in 72% (n = 26/36) after vaccination. Only 60% (n = 6/10) had seroconversion after the second course of vaccination. Only 60% of children (n = 12/20) who seroconverted had protective antibody titers at one year. Seroconversion following three doses of hepatitis B vaccine is low in children with CKD. Antibody titers should be monitored periodically as the protective immunity wanes rapidly.

Infections and the kidney: a tale from the tropics.

Tropical infections are caused by a variety of bacteria, viruses and parasitic organisms across varying geographical regions and are more often reported in adults than in children. Most of the infections are acute, presenting as a febrile illness with involvement of multiple organ systems, including the kidney. The gamut of renal manifestations extends from asymptomatic urinary abnormalities to acute kidney injury and-albeit rarely-chronic kidney disease. Tropical infections can involve the glomerular, tubulointerstitial and vascular compartments of the kidney. Leptospirosis, malaria, dengue, rickettsial fever and schistosomiasis are the most prevalent tropical infections which affect the kidneys of children living in the tropics. In this review we discuss renal involvement in these most prevalent tropical infections.

Chronic Kidney Disease (CKD): An Observational Study of Etiology, Severity and Burden of Comorbidities.

OBJECTIVES: To study the etiology and burden of comorbidities across stages of chronic kidney disease (CKD). METHODS: Children, 2-16 y of age with CKD Stages II- IV were recruited over 12 mo. The etiology, clinical presentation and severity of complications were studied. RESULTS: Among 78 children [Stage II (n = 21), Stage III (n = 26), Stage IV (n = 31)], congenital anomalies of the kidney and urinary tract (CAKUT) was the commonest etiology and 28 were newly diagnosed in Stage III /IV. High prevalence of comorbidities was observed with growth retardation (65%), hypertension (59%), hyperphosphatemia (32%), vitamin D deficiency (92%), dyslipidemia (64%), left ventricular hypertrophy (45%) and hyperparathyroidism (56%). While most comorbidities correlated with the estimated glomerular filtration rate and severity of CKD, hypertension, vitamin D deficiency and cardiovascular morbidity were prevalent even in early stages. CONCLUSIONS: CAKUT was the commonest cause of CKD. Late detection and high prevalence of comorbidities even in early stages of CKD were observed.

Use of oscillometric devices for the measurement of blood pressure-comparison with the gold standard.

The study was done to validate the use of automated devices (Datascope Duo) as a screening tool for measuring blood pressure. A cross sectional study was conducted in school children from urban slums of Bangalore. Blood pressure was recorded according to standard guidelines using a mercury sphygmomanometer and an automated device (Datascope Duo). The readings obtained using the two instruments were compared. One thousand four hundred eighty nine school children, both males and females, aged 5-16 y were included in the study. Readings with the Datascope Duo varied significantly when compared to the gold standard. The blood pressure measurements using Datascope Duo cannot be recommended as an accurate substitute for manual readings.