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.

New insights from the genetic work-up in early onset nephrotic syndrome: report from a registry in western India.

BACKGROUND: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India. METHODS: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life. RESULTS: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%. CONCLUSIONS: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis.

Physical functional capacity assessment in children with chronic kidney disease: A cross sectional observational study.

BACKGROUND: Chronic kidney disease (CKD) leads to reduced muscle mass and strength in children resulting in a decrease in functional capacity. The objectives of this cross-sectional observational study were to evaluate and compare the functional capacity and muscle strength in children with CKD stage I - V (group A), on dialysis (stage VD) (group B), and kidney transplant recipients (KTR) (group C) in Indian children. MATERIALS AND METHODS: 60 children, 20 each in groups A, B, and C were enrolled. Children who could not do the tests and transplant recipients within 6 months of transplantation were excluded. Functional capacity and muscle strength were assessed by 6-minute walk distance (SMWD), timed floor-to-stand test (TFTS), and hand grip strength (HGS). RESULTS: The mean age of the group was 12.54 ± 2.96 years. Among groups A, B, and C, the SMWD in meters (465.90 ± 68.85, 381.45 ± 50.88, 509.05 ± 43.37), TFTS in seconds (9.93 ± 1.77, 10.36 ± 1.30, and 7.68 ± 0.76), and HGS in kg were (12.7 ± 3.85, 10.4 ± 3.02, 19.75 ± 4.45), respectively (p < 0.001). Group C had the best physical functional capacity. The SMWD and HGS had a moderate positive correlation (r = 0.658, 0.658, respectively), and TFTS had a negative correlation (r = -0.605) with estimated glomerular filtration rate (eGFR). The mean HGS and TFTS were different between groups A, C, and B, C (p < 0.05) and not between A and B. The SMWT was however different between A, B, and C (p < 0.001). CONCLUSION: Muscle strength and functional capacity were most impaired in Indian children on hemodialysis and best preserved in KTR.

Clinical utility of genetic testing in Indian children with kidney diseases.

BACKGROUND: Kidney diseases with genetic etiology in children present with an overlapping spectrum of manifestations. We aimed to analyze the clinical utility of genetic testing in the diagnosis and management of suspected genetic kidney diseases in children. METHODS: In this retrospective study, children ≤ 18 years in whom a genetic test was ordered were included. Clinical indications for genetic testing were categorized as Glomerular diseases, nephrolithiasis and/or nephrocalcinoses, tubulopathies, cystic kidney diseases, congenital abnormality of kidney and urinary tract, chronic kidney disease of unknown aetiology and others. Clinical exome sequencing was the test of choice. Other genetic tests ordered were sanger sequencing, gene panel, multiplex ligation-dependent probe amplification and karyotyping. The pathogenicity of the genetic variant was interpreted as per the American College of Medical Genetics classification. RESULTS: A total of 86 samples were sent for genetic testing from 76 index children, 8 parents and 2 fetuses. A total of 74 variants were reported in 47 genes. Out of 74 variants, 42 were missense, 9 nonsense, 12 frameshifts, 1 indel, 5 affected the splicing regions and 5 were copy number variants. Thirty-two were homozygous, 36 heterozygous and 6 were hemizygous variants. Twenty-four children (31.6%) had pathogenic and 11 (14.5%) had likely pathogenic variants. Twenty-four children (31.6%) had variants of uncertain significance. No variants were reported in 17 children (22.3%). A genetic diagnosis was made in 35 children with an overall yield of 46%. The diagnostic yield was 29.4% for glomerular diseases, 53.8% for tubular disorders, 81% for nephrolithiasis and/or nephrocalcinoses, 60% for cystic kidney diseases and 50% for chronic kidney disease of unknown etiology. Genetic testing made a new diagnosis or changed the diagnosis in 15 children (19.7%). CONCLUSION: Nearly half (46%) of the children tested for a genetic disease had a genetic diagnosis. Genetic testing confirmed the clinical diagnoses, changed the clinical diagnoses or made a new diagnosis which helped in personalized management.

Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child.

Lipoprotein glomerulopathy (LPG) is a rare condition of renal lipidosis characterized by lipoprotein thrombi in glomeruli, an abnormal plasma lipoprotein profile, and a marked increase in serum apolipoprotein E (apo E) levels. It is a monogenic disorder with autosomal dominant inheritance and the average age of presentation is 32 years (4-69 years). It is rare in children. The presentation can be nephrotic syndrome, hematuria, or progressive renal failure. Here we report the first described case of LPG in an Indian 7.5-year-old boy who presented with steroid-resistant nephrotic syndrome with normal renal function. A renal biopsy was suggestive of lipoprotein glomerulopathy. The detection of a pathogenic variant in apo E, Kyoto type, by exome sequencing, confirmed the diagnosis of lipoprotein glomerulopathy. Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates.

De novo Donor-specific Anti-human Leukocyte Antigen Antibody and Its Outcome in Pediatric Renal Transplant Recipients: A Single-center Experience in India.

Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR.

Clinical exome sequencing uncovers an unsuspected diagnosis of Bartter syndrome type 2 in a child with incidentally detected nephrocalcinosis.

Nephrocalcinosis is a characteristic feature of both type 1 and type 2 Bartter syndrome. Bartter syndrome type 2 presents antenatally and very early in life. Late-onset presentation with isolated nephrocalcinosis is extremely rare. We describe an 11-year-old girl with incidentally detected medullary nephrocalcinosis on renal ultrasonography. She was clinically suspected to have primary hyperoxaluria based on high urine oxalate. However, clinical exome sequencing revealed a pathogenic missense variant in the KCNJ1 gene leading to the molecular diagnosis of Bartter syndrome type 2. Both parents were heterozygous carriers of the same variant. Subsequent investigations did reveal a mild Bartter syndrome phenotype with mild metabolic alkalosis, high urine chloride and high renin and aldosterone. Our case illustrates phenotypic heterogeneity of Bartter syndrome type 2 and the usefulness of genetic testing in establishing the correct diagnosis and guiding further management in such cases.

Coronavirus Disease-2019 in Children with Primary Kidney Disease: A Case series.

Underlying comorbid illness is a known risk factor for severe coronavirus disease-2019 (COVID-19). Clinical course of COVID-19 in children with primary kidney disease is not well understood. We present the clinical profile and management of COVID-19 in three children at a COVID hospital in India. These children had nephrotic syndrome, hemolytic uremic syndrome, and chronic kidney disease, respectively. The first two were immunosuppressed, mandating to stop their immunosuppressive medications temporarily. Both had mild course of illness. Third child presented with respiratory distress requiring oxygen support, falling into moderate disease. Renal functions were normal in all of them. They all responded well to oral azithromycin and supportive management. None of them received chloroquine, corticosteroids, or monoclonal antibodies. All three recovered without complications.

COVID-19 in children treated with immunosuppressive medication for kidney diseases.

BACKGROUND: Children are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity. METHODS: Cross-sectional study hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. Anonymised data were submitted online for any child (age <20 years) with COVID-19 taking immunosuppressive medication for a kidney condition. Study recruited for 16 weeks from 15 March 2020 to 05 July 2020. The primary outcome was severity of COVID-19. RESULTS: 113 children were reported in this study from 30 different countries. Median age: 13 years (49% male). Main underlying reasons for immunosuppressive therapy: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Immunosuppressive medications used include: glucocorticoids (76%), mycophenolate mofetil (MMF) (54%), tacrolimus/ciclosporine A (58%), rituximab/ofatumumab (11%). 78% required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications. CONCLUSIONS: This global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection. We therefore suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.

Proteinuria in children with juvenile idiopathic arthritis: Making the case for early urinary screening.

Systemic onset juvenile idiopathic arthritis (SOJIA) can be associated with proteinuria due to various renal pathologies. We report two pediatric cases with SOJIA and nephrotic syndrome secondary to renal amyloidosis, a very rare complication in children. Once present, amyloidosis heralds a poor prognosis for the patient, though early detection may allow some improvement if the inflammatory arthritis is controlled.