C1q Nephropathy in Children with Nephrotic Syndrome: Treatment Strategies and Outcomes.

Introduction: There is a paucity of clinical data on C1q nephropathy (C1qN) in children in India and Southeast Asia. This is the first detailed analysis conducted to elucidate the prevalence, clinicopathological profile, and response to different immunosuppressives in children with C1qN in India. Materials and Methods: Detailed demographic profile, clinical features, urine and blood chemistries, kidney biopsy, and response to different immunosuppressives of the study participants were analyzed between August 2015 and October 2020 for steroid-dependent/-resistant nephrotic syndrome (NS). Results: C1qN was diagnosed in 16 (14.13%) of 113 children who underwent biopsy for steroid-dependent/-resistant NS. The mean age was 44 months (range 18-99 months) and male and female number was 12 (75%) and four (25%), respectively, and mean follow-up was 3.5 years. Eight (50%) had coexistent minimal-change nephrotic syndrome (MCNS) pattern, seven (43.7%) had focal segmental glomerulosclerosis (FSGS), and one (6.2%) had diffuse mesangial hypercellularity. Thirteen children had complete follow-up, of which eight (61.5%) and four (30.7%) cases presented as steroid-dependent and primary steroid-resistant NS, respectively, whereas one (7.6%) had joint pain with rashes. At presentation, seven (53.8%) had hypertension, 12 (92.3%) had nephrotic range proteinuria, and six cases (46.1%) had hematuria. Nine (75%) of 12 cases achieved complete remission with calcineurin inhibitor (CNI) therapy, and two were non responders, one was a partial responder, and one responded to mycophenolate. Of six FSGS cases, four had complete remission, one had partial remission, and one was in non-remission. Of six cases with MCNS, five had complete remission and one was in non-remission. Renal functions remained normal in all except one case who had progression to chronic kidney disease Stage 3. Conclusion: One out of seven children with difficult NS can have underlying C1qN. CNIs are most beneficial to attain and maintain remission. Renal functions remain normal in the majority. Along with C1q deposits, MCNS and FSGS patterns are seen equally and respond almost similarly to CNIs.

Peritoneal dialysis for the management of pediatric patients with acute kidney injury.

Renal replacement therapy (RRT) is the most important supportive measure used in the management of acute kidney injury (AKI). Peritoneal dialysis (PD) is a safe, simple and inexpensive procedure and has been used in pediatric AKI patients, ranging from neonates to adolescents. It is the modality of choice for RRT in developing countries with cost constraints and limited resources. However, its use has declined with the availability of newer types of extracorporeal modalities for RRT in the developed world. Much controversy exists regarding the dosing and adequacy of PD in the management of AKI. Data in infants and children have shown that PD can provide adequate clearance, ultrafiltration and correction of metabolic abnormalities even in those who are critically ill. Although there are no prospective studies in children, data from retrospective studies reveal no differences in mortality rates between different modalities of RRT. In this review, we discuss the advantages and limitations of PD, indications for acute PD, strategies to improve the efficiency of acute PD and outcomes of PD in children with AKI.

Detecting reflux: does ureteric jet Doppler waveform have a role?

BACKGROUND: Vesicoureteral reflux (VUR) has a prevalence of 30-40 % post-febrile urinary tract infection (UTI). If not detected early and treated, renal scarring, hypertension, and renal failure may occur. Micturating cystourethrography (MCU) is an invasive procedure associated with radiation exposure. Hence, this study aimed at evaluating the utility of ureteric jet Doppler waveform (UJDW) as a screening tool in detecting VUR, and at assessing the feasibility of performing it in children aged 2-4 years. METHODS: Any child 2-18 years old who needed an MCU was included. Exclusion criteria were active UTI, indwelling catheter, and inability to drink the required amount of fluid. The UJDW was performed prior to the MCU. RESULTS: One hundred eighty-two ureteric units were analyzed. Sensitivity and specificity of UJDW in detecting VUR was 80.3 and 87.9 %. Twenty-three children (45 ureteric units), aged 2-4 years were compared with 73 children (137 ureteric units), aged 5-18 years. Sensitivity and specificity of UJDW in detecting VUR in 2-4 years was 77.3 and 91.3 %, respectively; while in children ≥5 years, it was 81.8 and 87.1 %, respectively. CONCLUSIONS: UJDW has a uniformly high specificity regardless of age or etiological groups, making it a good tool for follow-up. UJDW is a feasible technique, even in children aged 2-4 years.

NPHS2 mutations in Indian children with sporadic early steroid resistant nephrotic syndrome.

We examined the frequency and spectrum of podocin NPHS2 mutations in Indian children with sporadic steroid resistant nephrotic syndrome (SRNS). Of 25 children screened, only one (4%) had a pathogenic mutation resulting in a stop codon. The allele and genotype frequencies of the four known single nucleotide polymorphisms detected in the cohort were similar to that of controls. This finding emphasizes the need to screen for mutations in other genes involved in the pathogenesis of SRNS.

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.

Evaluation of High Resolution Melting analysis as an alternate tool to screen for risk alleles associated with small kidneys in Indian newborns.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are the most common forms of sequence variations in the human genome. They contribute to the human phenotypic spectrum and are associated with variations in response to pathogens, drugs and vaccines. Recently, SNPs in three human genes involved in kidney development (RET, PAX2 and ALDH1A2) have been reported to be associated with variation in renal size and function. These known SNPs could potentially be used in the clinic as markers for identifying babies who may have smaller kidneys and permit close follow up for early detection of hypertension and acquired renal dysfunction. The aim of this study was to evaluate the use of High Resolution Melting technique (HRM) as a tool for detecting the known SNPs in these three genes in comparison to sequencing which is the gold standard. METHODS: High resolution melting analysis was performed on 75 DNA samples that were previously sequenced for the known polymorphisms in RET (rs1800860), PAX2 (rs11190688) and ALDH1A2 (rs7169289) genes. The SNPs were G > A transitions in RET and PAX2 and A > G in ALDH1A2 gene. A blinded assessment was performed on these samples for evaluation of the HRM technique as compared to sequencing. RESULTS: Each variant had a unique melt curve profile that was reproducible. The shift in melting temperature (Tm) allowed visual discrimination between the homozygous alleles (major and minor) in all three genes. The shape of the melting curve as compared to the major allele homozygous curve allowed the identification of the heterozygotes in each of the three SNPs. For validation, HRM was performed on 25 samples for each of the three SNPs. The results were compared with the sequencing results and 100% correct identification of the samples was obtained for RET, PAX2, and ALDA1H2 gene. CONCLUSION: High Resolution Melting analysis is a simple, rapid and cost effective technique that could be used in a large population to identify babies with the risk alleles. These high risk children could be followed up for early detection of hypertension and acquired renal dysfunction.

Management of steroid sensitive nephrotic syndrome: revised guidelines.

JUSTIFICATION: In 2001, the Indian Pediatric Nephrology Group formulated guidelines for management of patients with steroid sensitive nephrotic syndrome. In view of emerging scientific evidence, it was felt necessary to review the existing recommendations. PROCESS: Following a preliminary meeting in March 2007, a draft statement was prepared and circulated among pediatric nephrologists in the country to arrive at a consensus on the evaluation and management of these patients. OBJECTIVES: To revise and formulate recommendations for management of steroid sensitive nephrotic syndrome. RECOMMENDATIONS: The need for adequate cortico-steroid therapy at the initial episode is emphasized. Guidelines regarding the initial evaluation, indications for renal biopsy and referral to a pediatric nephrologist are updated. It is proposed that patients with frequently relapsing nephrotic syndrome should, at the first instance, be treated with long-term, alternate-day prednisolone. The indications for use of alternative immunosuppressive agents, including levamisole, cyclophosphamide, mycophenolate mofetil and cyclosporin are outlined. The principles of dietary therapy, management of edema, and prevention and management of complications related to nephrotic syndrome are described. These guidelines, formulated on basis of current best practice, are aimed to familiarize physicians regarding management of children with steroid sensitive nephrotic syndrome.

Effects of maternal vitamin A status on kidney development: a pilot study.

Nephron endowment ranges widely in normal human populations. Recent autopsy studies have drawn attention to the possibility that subtle congenital nephron deficits may be associated with increased risk of developing hypertension later in life. Since modest maternal vitamin A deficiency reduces nephron number in rats, we designed a pilot study to determine the prevalence of maternal vitamin A deficiency in Montreal (Canada) and Bangalore (India) and the usefulness of newborn renal volume as a surrogate for nephron endowment. Among 48 pregnant Montreal women, two (4%) had one isolated mid-gestation retinol level slightly below the accepted limit of normal (0.9 mumol/L), whereas 25 (55%) of 46 pregnant women in Bangalore had at least one sample below this limit. Average estimated retinoid intake was correlated with mean serum retinol in pregnant women from Bangalore. In Montreal where maternal vitamin A deficiency was negligible, we found that newborn renal volume (estimated by renal ultrasonography at 2-6 weeks of age) was correlated with surface area at birth and was inversely correlated with serum creatinine at 1 month. Interestingly, renal volume adjusted for body surface area in Montreal (184+/-44 ml/m(2)) was significantly greater than in Bangalore (114+/-33 ml/m(2)) (p<0.01). Definitive studies are needed to establish whether maternal vitamin A deficiency accounts for subtle renal hypoplasia in Indian newborns. If so, there may be important public health implications for regions of the world where maternal vitamin A deficiency is prevalent.

Steroid sparing effect of a herbal preparation in steroid-dependent nephrotic syndrome.

Investigations on plants are revealing the potential therapeutic benefits of medicinal herbs in treating immunological disorders. Nephrotic syndrome has emerged as an immunological disorder. Steroid dependence poses a therapeutic challenge in the management of nephrotic syndrome. Our pilot study compares the efficacy of an ayurvedic polyherbal preparation 'Shathavaryadi Yoga (NS001)' with oral cyclophosphamide in maintaining remission in steroid-dependent nephrotic syndrome.

Cyclosporine in steroid dependent and resistant childhood nephrotic syndrome.

OBJECTIVE: To evaluate the efficacy of cyclosporine (CyA) monotherapy in steroid resistant (SRNS) and steroid dependent (SDNS) nephrotic syndrome in children. DESIGN: A retrospective study. SETTING: Tertiary kidney care center for children at Bangalore. METHODS: Forty-one children with SDNS and SRNS with normal renal functions were treated with CyA at a dose of 6 mg/kg/day initially and maintained at 3 to 4 mg/kg/day if remission was sustained. The dosage was adjusted according to the CyA blood levels in non-responders. RESULTS: The median age of patients was 93 months (range 48-936) months. Thirteen children had minimal change disease (MCNS), 10 had mesangial proliferative glomerulonephritis (GN). Ten had membrano-proliferative (GN) (MPGN) and 8 had focal segmental glomerulosclerosis (FSGS). Median age at onset of disease and median time for CyA usage from disease onset was 22 months and 16 months respectively. Median duration of CyA therapy was 24 months (range 6-72) months. The data was analyzed to determine significance of variables on the outcome. Median follow up was 71 months (range 20-205) months. Eleven children were CyA resistant. Of the remaining 30 who were CyA responders, 22 (73.33%) were CyA dependent. Seven children developed chronic renal failure (CRF). CONCLUSIONS: The predictors for CyA non-responsiveness were steroid resistance, non MCNS on biopsy and longer duration between onset of nephrotic syndrome and CyA usage, irrespective of the age of onset of the disease. There was a higher incidence of CyA dependence among young responders. Patients with CyA resistance are at high risk for significant infections and CRF.

Pediatric renal transplantation: the Bangalore experience.

A retrospective analysis was done on 47 pediatric renal transplants performed over last 16 years at Bangalore, Karnataka. The median age and weight of the recipients at transplantation were 120 months and 21 kg respectively; male to female ratio was 30 to 17. Twenty two children had underlying glomerular disease and 23 had tubulointerstitial disease. Preemptive transplantation was done in 33.3% of patients, 57.2% received hemodialysis and 9.5% received peritoneal dialysis prior to transplantation. The mean duration of dialysis was 2.6 months. The most common source of donor organ was the mother. Immunosuppression medications included cyclosporine, azathioprine, and corticosteroids. Graft survival at 1 year, 5 years, and 10 years was 80%, 45.8% and 37.5% respectively. Renal transplantation is the most optimal way to manage children with ESRD with satisfactory long term results.

Training in pediatric nephrology for developing countries.

During recent years, there has been an increasing demand for specialized care for children with kidney diseases, even in developing countries with limited resources. It is imperative to provide suitable facilities for appropriate and relevant training in pediatric nephrology to promote growth of pediatric nephrology in these areas. The training should give emphasis on preventive aspects, early diagnosis of common diseases and their optimum management with available resources. It should focus on locally prevalent renal diseases. The training programs should take into consideration the socioeconomic and cultural framework of the local community when designing curricula. To overcome the shortage of pediatric nephrology health professionals in the developing countries, the International Pediatric Nephrology Association has taken initiatives to support development of such training programs.

Catastrophic antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome (APS) is characterized by recurrent thrombosis with the presence of circulating antiphospholipid antibodies. A diagnosis of APS requires the presence of at least one clinical and one laboratory criteria (detection of aCL IgG or IgM antibodies or the presence of lupus anticoagulant on two or more consecutive occasions 6 weeks apart). A severe, rapidly progressive form characterized by clinical involvement of at least three different organ systems with histopathological evidence of small and large vessel occlusion is termed catastrophic antiphospholipid syndrome. Early recognition of APS is crucial since aggressive management can result in a favorable outcome. We present the case of a 12-year-old boy who presented with a devastating illness with multiple thrombotic episodes and rapidly progressive renal failure.

Congenital Nephrotic Syndrome with adrenal calcification and cardiac malformation.

Congenital Nephrotic Syndrome (CNS) with adrenal calcification and CNS with congenital heart disease (CHD) have rarely been reported. However, CNS with both these rare associations has never been previously reported. Here we report a case of CNS with both rare associations, perhaps the first report from India to the best of our knowledge.

Snakebite-induced acute renal failure. A case report and review of the literature.

Snakebite is not an uncommon cause of acute renal failure (ARF) in developing countries. We report a12-year-old boy who presented with oliguric ARF following snakebite. He had pallor, icterus, generalized edema, hypertension, and was oliguric. Investigations revealed severe azotemia, microangiopathic hemolytic anemia, thrombocytopenia, prolonged coagulation parameters, and raised fibrin degradation products, suggesting disseminated intravascular coagulation as the cause of ARF. The patient improved with antisnake venom, dialysis, and other supportive treatment.

Acute renal failure in children with idiopathic nephrotic syndrome.

Acute renal failure (ARF) is an uncommon but alarming complication of idiopathic nephrotic syndrome. The renal failure could be secondary to causes evident from the history and evaluation, such as severe intravascular volume depletion, acute tubular necrosis, allergic interstitial nephritis, bilateral renal vein thrombosis, acute pyelonephritis, or rapid progression of the original glomerular disease. It may be termed idiopathic if the underlying cause is undetermined. We present three children with idiopathic nephrotic syndrome who were admitted with acute renal failure. One case was due to drug-induced allergic interstitial nephritis. The other two were idiopathic in nature. Improvement in renal function occurred in the three patients over a variable period of 10 days to 4 weeks. After careful exclusion of well-known causes of acute renal failure, idiopathic acute renal failure (IARF) should be considered as a diagnostic possibility in these patients. The exact pathophysiology of IARF is not understood. Possible proposed explanations include interstitial edema, tubular obstruction, altered glomerular permeability, and unrecognized hypovolemia.

Acute renal failure due to acute tubulointerstitial nephritis.

Acute interstitial nephritis (AIN) should be ruled out in children with unexplained acute renal failure. We present a 4 1/2 year old girl who presented with oliguric acute renal failure preceded by a febrile illness. Renal histopathology revealed features of drug induced AIN. She recovered with dialysis, other supportive treatment and a course of steroids.