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%).

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).

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.

Furosemide stress test to predict acute kidney injury progression in critically ill children.

BACKGROUND: Furosemide stress test (FST) is a novel functional biomarker for predicting severe acute kidney injury (AKI); however, pediatric studies are limited. METHODS: Children 3 months to 18 years of age admitted to the intensive care unit (ICU) of a tertiary care hospital from Nov 2019 to July 2021 were screened and those who developed AKI stage 1 or 2 within 7 days of admission underwent FST (intravenous furosemide 1 mg/kg). Urine output was measured hourly for the next 6 h; a value > 2 ml/kg within the first 2 h was deemed furosemide responsive. Other biomarkers like plasma neutrophil gelatinase-associated lipocalin (NGAL) and proenkephalin (PENK) were also evaluated. RESULTS: Of the 480 admitted patients, 51 developed AKI stage 1 or 2 within 7 days of admission and underwent FST. Nine of these patients were furosemide non-responsive. Thirteen (25.5%) patients (eight of nine from FST non-responsive group) developed stage 3 AKI within 7 days of FST, nine (17.6%) of whom (seven from non-responsive group) required kidney support therapy (KST). FST emerged as a good biomarker for predicting stage 3 AKI and need for KST with area-under-the-curve (AUC) being 0.93 ± 0.05 (95% CI 0.84-1.0) and 0.96 ± 0.03 (95% CI 0.9-1.0), respectively. FST outperformed NGAL and PENK in predicting AKI stage 3 and KST; however, the combination did not improve the diagnostic accuracy. CONCLUSIONS: Furosemide stress test is a simple, inexpensive, and robust biomarker for predicting stage 3 AKI and KST need in critically ill children. Further research is required to identify the best FST cut-off in children.

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.

Clinical characteristics and genetic profile of children with WDR72-associated distal renal tubular acidosis: a nationwide experience.

BACKGROUND: Limited data, primarily from small case series, exist regarding the clinical profile, genetic variants, and outcomes of WDR72-associated distal renal tubular acidosis (WDR72-dRTA). METHODS: Our study enrolled children diagnosed with WDR72-dRTA below 18 years of age from 9 Indian centers and analyzed their clinical characteristics, genetic profiles, and outcomes. Potential genotype-phenotype correlations were explored. RESULTS: We report 22 patients (59% female) with WDR72-dRTA who were diagnosed at a median age of 5.3 (3, 8) years with polyuria (n = 17; 77.3%), poor growth (16; 72.7%), and rickets (9; 40.9%). Amelogenesis imperfecta was present in 21 (95.5%) cases. At presentation, all patients had normal anion gap metabolic acidosis; hypokalemia and nephrocalcinosis were seen in 17 (77.3%) patients each. Seven (31.8%) patients had concomitant proximal tubular dysfunction. Genetic analysis identified biallelic nonsense variants in 18 (81.8%) patients, including novel variants in 6 cases. A previously reported variant, c.88C > T, and a novel variant, c.655C > T, were the most frequent variants, accounting for 10 (45.5%) cases. Over a median follow-up of 1.3 (1, 8) years, the height velocity improved by 0.74 (0.2, 1.2) standard deviation scores, while 3 children (13.6%) progressed to chronic kidney disease (CKD) stage 2, with eGFR ranging from 67 to 76 mL/min/1.73 m2, respectively, after 11.3-16 years of follow-up. No specific genotype-phenotype correlation could be established. CONCLUSIONS: WDR72-dRTA should be considered in children with typical features of amelogenesis imperfecta and dRTA. Biallelic nonsense variants are common in Asians. While most patients respond well to treatment with improved growth and preserved eGFR, on long-term follow-up, a decline in eGFR may occur.

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.

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection.

BACKGROUND: The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger. METHODS: We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi. RESULTS: We report 5 patients, 4-13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25-85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m2; one patient was dialysis-dependent. CONCLUSION: Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. A higher resolution version of the Graphical abstract is available as Supplementary information.

SARS-CoV-2 infection in children with chronic kidney disease.

BACKGROUND: Information on the course of SARS-CoV-2 infection in children with chronic kidney disease (CKD) is limited. METHODS: We retrospectively reviewed the presentation and outcomes of SARS-CoV-2 infection in patients with CKD followed at any of the four pediatric nephrology centers in New Delhi from April 2020 to June 2021. Outcomes, including cardiopulmonary and renal complications, were reported in relation to underlying disease category and illness severity at presentation. RESULTS: Underlying illness in 88 patients included nephrotic syndrome (50%), other CKD stages 1-4 (18.2%), CKD 5D (17%), and CKD 5T (14.8%). Thirty-two of 61 patients with symptomatic COVID-19 and 9/27 asymptomatic patients were admitted for median 10 (interquartile range 7-15) days. Seventeen (19.3%) patients developed moderate or severe COVID-19. Systemic complications, observed in 30 (34.1%), included acute kidney injury (AKI, 34.2%), COVID-19 pneumonia (15.9%), unrelated pulmonary disease (2.3%), and shock (4.5%). Nineteen (21.6%) had severe complications (AKI stage 2-3, encephalopathy, respiratory failure, shock). Eight (11%) of twelve (16.4%) patients with severe AKI required dialysis. Three (3.4%) patients, two with steroid-resistant nephrotic syndrome in relapse and one with CKD 1-4, died due to respiratory failure. Univariate logistic regression indicated that patients presenting with nephrotic syndrome in relapse or moderate to severe COVID-19 were at risk of AKI (respective odds ratio, 95%CI: 3.62, 1.01-12.99; 4.58, 1.06-19.86) and/or severe complications (respective odds ratio, 95%CI: 5.92, 1.99-17.66; 61.2, 6.99-536.01). CONCLUSIONS: Children with CKD presenting with moderate-to-severe COVID-19 or in nephrotic syndrome relapse are at risk of severe complications, including severe AKI and mortality. A higher resolution version of the Graphical abstract is available as Supplementary information.

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.

Management of Acute Kidney Injury in Critically Ill Children.

Acute kidney injury (AKI) is common in critically ill patients, affecting almost one in four critically ill children and one in three neonates. Higher stages of AKI portend worse outcomes. Identifying AKI timely and instituting appropriate measures to prevent and manage severe AKI is important, since it is independently associated with mortality. Methods to predict severe AKI should be applied to all critically ill patients. Assessment of volume status to prevent the development of fluid overload is useful to prevent adverse outcomes. Patients with metabolic or clinical complications of AKI need prompt kidney replacement therapy (KRT). Various modes of KRT are available, and the choice of modality depends most on the technical competence of the center, patient size, and hemodynamic stability. Given the significant risk of chronic kidney disease, patients with AKI require long-term follow-up. It is important to focus on improving awareness about AKI, incorporate AKI prevention as a quality initiative, and improve detection, prevention, and management of AKI with the aim of reducing acute and long-term morbidity and mortality.

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 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.