The Assisted Reproductive Technology Act 2021- Provisions and Implications.

The desire for parenthood among infertile individuals is often fulfilled by resorting to the ever-evolving Assisted Reproductive Techniques (ART). Since the birth of Durga, India's first baby born using ART in 1981, the lucrative fertility industry has grown exponentially in our country. The Government of India passed the Assisted Reproductive Technology (Regulatory) Act in 2021 to provide regulatory support to these services. The legislation offers clarity on various aspects of ART, including measures to safeguard children born through these procedures. The effective implementation of the ART Act is crucial to ensure that ART services become affordable, ethical, and socially acceptable in India. This article aims to discuss the controversies with ART services and issues that could compromise the wellbeing of children, while highlighting the provisions provided under the Act to address these.

Kidney outcomes in children with primary focal segmental glomerulosclerosis from a low- and middle- income country.

BACKGROUND: Limited data exists regarding the clinical course and outcomes of children with primary focal segmental glomerulosclerosis (FSGS) from low- and middle- income countries. METHODS: Children aged 1-18 years with biopsy-proven primary FSGS followed from January 2010-June 2023 in a tertiary-care center were enrolled and their clinical profile, histological characteristics, kidney outcomes, and predictors of adverse outcomes were determined. RESULTS: Over 13 years, 73 (54.8% boys) children with median (IQR) age at FSGS diagnosis 6.7 (3,10) years were recruited and followed up for median 4 (2.5,8) years. FSGS-not otherwise specified (NOS) was the most common histological subtype, in 64 (87.6%) children, followed by collapsing variant in 5 (6.8%) children. At last follow-up, 43 (58.9%), 2 (2.7%) and 28 (38.3%) children were in complete remission (CR), partial remission (PR), and no remission (NR) respectively. Calcineurin inhibitors led to CR or PR in 39 (62%) children. Overall, 21 (28.7%) children progressed to chronic kidney disease (CKD) stage 2-5 (19 from NR vs. 2 from PR group; p = 0.03); with 41% of those NR at 12 months progressing to CKD 4-5 by last follow-up. On multivariable analysis, collapsing variant [adjusted HR 2.5 (95%CI 1.5, 4.17), p = 0.001] and segmental sclerosis > 25% [aHR 9.9 (95%CI 2.2, 45.2), p = 0.003] predicted kidney disease progression. CONCLUSIONS: In children with FSGS, response to immunosuppression predicts kidney survival as evidenced by nil to lower progression to CKD 2-5 by median follow-up of 4 (2.5,8) years in children with CR and PR, compared to those with no remission at 12 months from diagnosis. Segmental sclerosis > 25% and collapsing variant predicted progression to advanced CKD.

Clinical Profile and Outcomes of Children with Acute Liver Failure in a Tertiary Care Center in South India: A Retrospective Study.

Purpose: In this study, we investigated the clinical profile, survival at discharge, and proportion of children with acute liver failure (ALF) meeting the criteria for, yet surviving without, liver transplantation (LT). Methods: Medical case records of children aged >28 days to ≤15 years over a period of 7 years, identified from pediatric admission and discharge registers, were screened. Children satisfying the criteria for ALF were included in this study. Results: A total of 71 records meeting the pediatric ALF (PALF) criteria were included. The survival rate at discharge was 61% (n=44). A considerable proportion of children satisfied the King's College Criteria (KCC) (56.3%) and the European Association for the Study of the Liver (EASL) criteria (7%) for LT at admission. Nonetheless, the survival rate in the absence of LT was 42.5% in children who satisfied the KCC and 20% in those who met the EASL criteria. Infection (29.5%) and paracetamol overdose (19.7%) were the major identifiable causes of PALF. Hepatitis A was the most common infection identified. No significant predictors of poor outcomes were identified in multivariable analysis. Conclusion: Our study highlights the changing survival rates and the clinical and etiological profiles of patients with PALF. In areas with poor access to LT services, survival in these children could be improved through early referral to centers with adequate intensive care facilities. Preventing ALF and referring patients to LT services are paramount to reducing mortality.

Distal renal tubular acidosis as presenting manifestation of Wilson disease in a 11-year-old girl.

A 11-year-old girl was referred to the pediatric nephrology services of our hospital for evaluation of vitamin-D-refractory rickets. She was born to second-degree consanguineous parents. On examination, she had wrist widening and bilateral genu varum. She had normal anion gap metabolic acidosis, hypokalemia, and hyperchloremia. The fractional excretion of bicarbonate was 3% and the urine anion gap was positive. She also had hypercalciuria, but no phosphaturia, glucosuria or aminoaciduria. In view of a family history of an elder sister having rigidity with cognitive and speech impairment, an ophthalmic evaluation by slit lamp examination was performed in the index case that revealed bilateral Kayser-Fleischer rings. Serum ceruloplasmin was low and 24-h urine copper was elevated in the index case. Whole exome sequencing unveiled a novel pathogenic variant in exon 2 of the ATP7B gene (chr13: c.470del; Depth: 142x) (homozygous) that resulted in a frameshift and premature truncation of the protein, 15 amino acids downstream to codon 157 (p. Cys157LeufsTer15; NM_000053.4) confirming Wilson disease. There were no mutations in the ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, WDR72 genes or other genes that are known to cause distal RTA. Therapy with D-penicillamine and zinc supplements was initiated. A low dose of 2.5 mEq/kg/day of potassium citrate supplementation normalized the serum bicarbonate levels. This case was notable for the absence of hepatic or neurological involvement at admission. Wilson disease is well known to cause proximal renal tubular acidosis and Fanconi syndrome, with relatively lesser involvement of the distal renal tubules in the literature. However, isolated distal renal tubular involvement as presenting manifestation of Wilson disease (without hepatic or neurological involvement) is rare and can lead to diagnostic confusion.

Intravenous cyclophosphamide therapy in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome in a resource-limited setting.

BACKGROUND: In pediatric steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as first-line therapy, with efficacy ranging between 60 and 80%, implying a substantial proportion will exhibit CNI resistance. Which alternate immunosuppressive therapy should be used in non-genetic pediatric SRNS exhibiting CNI resistance is especially relevant in low- to middle-income countries (LMIC), where the prohibitive costs of certain drugs such as monoclonal antibodies often determine therapy choice. METHODS: The primary objective was to assess the efficacy of intravenous cyclophosphamide in a proportion of children aged 1-18 years with CNI-resistant SRNS with a complete response (CR) or partial response (PR) at 6 months from commencement of pulse therapy. The secondary objectives were to assess the proportion and profile of infections and adverse effects. RESULTS: Of 90 children with idiopathic SRNS presenting between January 2013 and December 2022, 29 (32.2%) had CNI resistance and were enrolled. They were administered monthly intravenous cyclophosphamide pulses (6 pulses). Median (IQR) duration of follow-up was 48 (29.5, 63.5) months. At the end of 6 months of cyclophosphamide therapy, 13 (44.8%) attained CR and 4 (13.8%) attained PR, with an overall cyclophosphamide success rate of 58.6%. The efficacy of intravenous cyclophosphamide was higher in secondary (9/10; 90%) versus primary CNI resistance (8/19; 42.1%) (p = 0.029). Three children (3/29; 10.3%) developed systemic infections within 12 months of initiation of cyclophosphamide therapy, similar to the rate of systemic infections among children receiving CNI for SRNS management (6/41; 14.6%) (p = 0.85). CONCLUSIONS: It is prudent to try intravenous cyclophosphamide in CNI-resistant SRNS in LMIC, given the reasonable cost and good efficacy rates (58.6%).

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.

Congenital nephrotic syndrome with diffuse mesangial sclerosis caused by compound heterozygous mutation in LAMA5 gene.

A two-and-a-half-month-old female infant presented with generalized edema for 10 days. At presentation, she had periorbital puffiness, moderate ascites, and pedal edema. Laboratory investigations revealed serum albumin 1.3 g/dL, spot urine protein to creatinine ratio (Up:Uc) 20.87 mg/mg, total cholesterol 380 mg/dL, and serum creatinine 0.31 mg/dL. Exome sequencing revealed compound heterozygous variants in LAMA5 gene (NM_005560.6). There was a heterozygous likely pathogenic missense variant in exon 2: LAMA5: c.385C > A (depth 195 ×) and another heterozygous pathogenic variant in exon 31: LAMA5: c.3932_3936dup; parental segregation by Sanger sequencing proved that the variants were in trans. Kidney biopsy showed diffuse mesangial sclerosis (DMS). Our case adds LAMA5 gene to the constellation of genes causing DMS, in addition to the classically described WT1, LAMB2, and PLCE1 genes and to the list of genes causing congenital nephrotic syndrome (CNS).

Urinary Apolipoprotein A1 and Neutrophil Gelatinase-associated Lipocalin in Children with Idiopathic Nephrotic Syndrome.

Urinary biomarkers are a promising diagnostic modality whose role was explored in nephrotic syndrome (NS). We estimated urinary apolipoprotein A1 (Apo A1) and neutrophil gelatinase-associated lipocalin (NGAL) in children with first-episode NS (FENS) and controls with a longitudinal follow-up to see the serial changes during remission. The study groups comprised 35 children with FENS and an equal number of age- and sex-matched controls. Patients were followed up at regular intervals, and 32 patients were classified as having steroid-sensitive NS (SSNS) and 3 as having steroid-resistant NS (SRNS). The mean follow-up period was 8.7 ± 4.2 months. Three patients in the SSNS group were labeled as having frequent relapses or steroid-dependent disease during follow-up. Of the three children with SRNS, two had minimal changes in the disease and one had idiopathic membranous nephropathy. The levels of Apo A1:creatinine, NGAL:creatinine, and spot urinary protein:urinary creatinine ratios were significantly higher in children with FENS compared with controls. The levels of the urine biomarkers decreased significantly at subsequent follow-up with remission. The Apo A1 and NGAL levels in SSNS patients were significantly high compared with both the controls and FENS patients. Urinary Apo A1 levels in SRNS patients were lower at initial presentation. This longitudinal study revealed changes in the urinary Apo A1 and NGAL in NS over the course of the disease.

Genetic Studies in Infants with Congenital Nephrotic Syndrome: A Case Series.

Information on the genetic profile of congenital nephrotic syndrome (CNS) from India is scarce. The management of CNS is largely supportive of the setting of developing countries, mainly via the administration of intravenous albumin infusions, angiotensin-converting enzyme inhibitors, and levothyroxine. Inadequate infrastructure and management facilities, including genetic analyses, further hamper the outcome. These infants may progress to end-stage renal disease, and mortality is high in infancy. Here, we report a case series of four infants (aged 14-60 days) with CNS from our center with genetic mutations (including mutations in the NPHS1 and LAMB2 genes) that were not described in previous reports from India. Although responsiveness to enalapril has been documented in anecdotal reports of NPHS1 mutations, our case series of four infants did not exhibit any response to enalapril. Our case series adds to the existing literature regarding the genetic profile of CNS in India.

Etiology and Outcomes of Rapidly Progressive Glomerulonephritis in Children: A Retrospective Cohort Study.

OBJECTIVE: To study the clinico-etiological spectrum and outcomes of children with rapidly progressive glomerulonephritis (RPGN). METHODS: This retrospective cohort study evaluated patients <18 years with RPGN, over an 8-year period (2014-2022), for etiology and kidney outcomes. RESULTS: Among 68 RPGN cases [median age 10 (7,12) years], 23 (33.8%) had lupus nephritis, 21 (30.9%) C3 glomerulopathy, and 15 (22.1%) infection-related glomerulonephritis (IRGN). At presentation, 18 (26.4%) patients had pulmonary edema, 20 (29.4%) had hypertensive emergency and 22 (32.4%) required dialysis. Median (IQR) follow-up duration was 24.5 (12,48) months. The median (IQR) admission eGFR was 19 (10.93, 38.60) mL/min/1.73 m2, which increased to 126 (102.7,142) mL/min/1.73m2 at the last follow-up. At the last follow-up, 39 (57.3%) and 13 (19.1%) patients attained complete and partial renal recovery, respectively; while 16 (23.5%) progressed to CKD stage 2 and beyond. The prevalence of end stage kidney disease (ESKD) was 7.3% at 1-year and 7.7% at the last follow-up. Factors predicting kidney survival were duration of symptoms prior to presentation ≥7 days, crescents ≥37.5%, and presence of fibrous crescents/segmental sclerosis. CONCLUSION: Lupus nephritis, was the commonest etiology of RPGN in children. Renal outcomes were determined by pre-admission symptoms, and percentage and stage of crescents.

Growth Parameters in Adolescents With Idiopathic Nephrotic Syndrome Diagnosed at the Age of 1-6 Years.

OBJECTIVE: To determine the prevalence of impaired growth parameters (height and BMI z scores) among adolescents aged 10-19 years, with onset of idiopathic nephrotic syndrome between the age of 1 and 6 years. METHODS: A cross-sectional study was conducted among adolescents aged 10-19 years with onset of idiopathic nephrotic syndrome between the age of 1-6 years, and under regular follow-up at our center. The data were retrieved for a 10-year period (2012-2022). The current weight, height and body mass index (BMI) were recorded and interpreted as per world Health Organization (WHO) growth standards. RESULTS: 116 adolescents [60 Frequently relapsing nephrotic syndrome (FRNS)/Steroid dependent nephrotic syndrome (SDNS), and 56 Steroid resistant nephrotic syndrome (SRNS)] patients were enrolled with median (IQR) age of 133 (120,168) months and age at disease onset of 48 (26,68) months. The proportion of children with overweight (BMI for age >1z and cushingoid features), obesity (BMI for age >2z), stunting (height for age (HFA) <2z), and severe stunting (HFA <3z) were 29 (25%), 3 (2.6%), 31 (26.7%), and 7 (6%), respectively. The median (IQR) cumulative steroid dose for FRNS/SDNS and SRNS group was 19986.96 (14597.1, 26181.96) mg/m2 and 14385 (10758.82, 21355.95) mg/m2, respectively (P=0.003). CONCLUSION: The proportion of short stature and overweight was high among adolescents with nephrotic syndrome, emphasizing the need for measures to reduce steroid use and other measures to support growth.

Etiology and outcomes of acute kidney disease in children: a cohort study.

BACKGROUND: There is paucity of information regarding the etiology and outcomes of Acute Kidney Disease (AKD) in children. METHODS: The objectives of this cohort study were to evaluate the etiology and outcomes of AKD; and analyze predictors of kidney survival (defined as free of CKD 2, 3a, 3b, 4 or 5). Patients aged 1 month to 18 years who developed AKD over a 4-year-period (January 2018-December 2021) were enrolled. Survivors were followed-up at the pediatric nephrology clinic, and screened for residual kidney injury. RESULTS: Among 5710 children who developed AKI, 200 who developed AKD were enrolled. The median (IQR) eGFR was 17.03 (10.98, 28) mL/min/1.73 m2. Acute glomerulonephritis, acute tubular necrosis (ATN), hemolytic uremic syndrome (HUS), sepsis-associated AKD, and snake envenomation comprised of 69 (34.5%), 39 (19.5%), 24 (12%), 23 (11.5%) and 15 (7.5%) of the patients respectively. Overall, 88 (44%) children required kidney replacement therapy (KRT). There were 37 (18.5%) deaths within the AKD period. At a follow-up of 90 days, 32 (16%) progressed to chronic kidney disease stage-G2 or greater. At a median (IQR) follow-up of 24 (6, 36.5) months (n = 154), 27 (17.5%) had subnormal eGFR, and 20 (12.9%) had persistent proteinuria and/or hypertension. Requirement of KRT predicted kidney survival (free of CKD 2, 3a, 3b, 4 or 5) in AKD (HR 6.7, 95% CI 1.2, 46.4) (p 0.04). CONCLUSIONS: Acute glomerulonephritis, ATN, HUS, sepsis-associated AKD and snake envenomation were common causes of AKD. Mortality in AKD was 18.5%, and 16% progressed to CKD-G2 or greater at 90-day follow-up.

Etiology, Comorbidities, and Rate of Progression of Pediatric Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: To evaluate the etiology of pediatric chronic kidney disease (CKD), assess comorbidities, and identify rate of progression of CKD and its risk factors. METHODS: Children aged 2-18 y with the Kidney Disease Improving Global Outcome (KDIGO) CKD stages 2-4 were enrolled. The etiology of CKD and its comorbidities were recorded. Kaplan-Meier survival curves were used to analyze the time to progression of CKD. RESULTS: Of the 131 patients enrolled, CKD stages 2, 3a, 3b, and 4 constituted 62 (47.3%), 17 (13%), 26 (19.8%), and 26 (19.8%), respectively. At the last follow-up [at median (IQR) 24 (12, 30) mo], the number of children in CKD stages 2, 3a, 3b, 4 and 5 were 48 (36.6%), 16 (12.2%), 23 (17.6%), 28 (21.4%), and 16 (12.2%), respectively. Etiologies of CKD included obstructive uropathy [48 (36.6%)], chronic glomerular disease [19 (14.5%)], reflux nephropathy [14 (10.7%)] and cystic renal disease [11 (8.3%)]. Comorbidities during follow-up included CKD-MBD [87 (66.4%)], metabolic acidosis [95 (72.5%)], hypertension [88 (67.1%)], growth retardation [69 (52.6%)], and anemia [63 (48.1%)]. The number of patients with metabolic acidosis, hypertension, MBD and anemia in CKD stage 2 were 27 (56%), 26 (54.2%), 24 (50%), 15 (30%), respectively. The median (IQR) rate of decline in eGFR was 3.3 (2, 4.6) mL/min/1.73 m2/y. On multivariable analysis, proteinuria [hazard ratio 3.5 (95% CI 1.4, 8.8) p = 0.01] and hyperphosphatemia [hazard ratio 2.2 (95% CI 1.1, 4.3) p = 0.03] were significant predictors for progression of CKD. CONCLUSIONS: Even the earlier stages of CKD had significant comorbidities. The median decline in eGFR was 3.3 mL/min/1.73 m2/y. Proteinuria and hyperphosphatemia were the risk factors for progression of CKD.