Anti-nephrin antibodies in idiopathic nephrotic syndrome in Japanese children

Abstract


Introduction:
Deoxyribonucleases are in charge of extracellular DNA degradation, limiting inflammatory response.Deoxyribonuclease 1 like 3 (DNASE1L3) of DNase I family is known to be essential for the prevention of autoimmune disorders by sustaining plasma extracellular DNA homeostasis.Therefore, DNase1L3 gene mutation might cause autoimmune disorders, although only the cases of systemic lupus erythematous (SLE) had been reported previously.Here we report two siblings, sharing same compound heterozygote pathogenic variants of DNASE1L3, who were diagnosed with two different chronic glomerulonephritis.
Case Description: An eight-year-old boy presented hematuria with proteinuria and diagnosed as C1q nephropathy after kidney biopsy.Past medical history and family history were unremarkable.Despite treatment with immunosuppressive agents including steroid and tacrolimus, his kidney function deteriorated and lost at his age of 12.After living-donor kidney transplantation (KT), his allograft function has been well maintained until the last follow-up after 2 years of KT without proteinuria or any other extra-renal symptoms.His brother also presented hematuria and proteinuria at his age of 6 and diagnosed as membranous nephropathy at his first kidney biopsy.Steroid and weekly rituximab treatment led to partial remission, but became resistant to immunosuppressant treatment.Follow-up biopsy revealed membranoproliferative glomerulonephritis type 2 and now he has been managed with medications including tacrolimus and mycophenolate.At his last follow-up on age of 13, his eGFR was 110mL/min/1.73m 2 but nephrotic range proteinuria still persisted.On multiple parallel sequencing, both siblings were found to have same compound heterozygote likely pathogenic variants of DNASE1L3, c.401_402dup and c.556A>G, which were inherited from their father and mother, respectively.
Discussion: Here we report sibling cases of DNASE1L3 associated nephropathy, suggesting that dysfunction of deoxyribonucleases and predisposition to autoimmune diseases can be one of the pathogenic mechanisms of chronic glomerulonephritis.Interestingly, two siblings with same genetic predisposition showed different spectrum of nephropathies with distinct clinical courses, implying that there might be other modifying factors than the genetic predisposition.

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Pediatric Nephrology -II

Persistent Proteinuria Associated with CUBN Variants in Korean Children
Yun Young Choi, 1 Naye Choi, 1,5 Jeesu Min, 3,5 Eujin Park, 2 Yo Han Ahn, 1,5 Hee Gyung Kang, 1,5 Hyun Kyung Lee.Introduction: Persistent proteinuria is a risk factor of progression for chronic kidney disease (CKD).However, the recent discovery suggests that not all proteinuria is damaging.CUBN, encoding the membrane glycoprotein cubilin, forms cubilinamnionless-megalin complex that is responsible for the receptor-mediated endocytosis of albumin in the proximal tubules.A defect of cubilin decreases albumin reuptake, consequently resulting in proteinuria.Interestingly, variants located at the N-terminal of CUBN result in severe proteinuria and megaloblastic anemia, whereas variants at the C-terminal are associated with benign, isolated proteinuria.
Case Description: Here, we report 6 Korean patients (M:F=3:3) presented with persistent proteinuria with homozygous or compound heterozyous C-terminal CUBN variants.All patients presented with incidentally found isolated asymptomatic proteinuria, at their median age of 5 years (range 18 months ~ 9years).Their mean urine protein creatinine ratios was 1.13 (range 0.94 ~ 1.5) mg/mg at presentation and laboratory findings were unremarkable at presentation for eGFR, serum albumin, lipid, hemoglobin, urine 2-microglobulin and N-acetyl-beta-D-glucosaminidase.None had hypertension, and kidney ultrasound was normal.Two patients underwent kidney biopsy, which revealed non-specific findings.Their median follow-up duration was 4 years (range 6 months ~ 12 years), median age at the last follow-up was 8.5 years (range 2 years ~21 years) and the amount of proteinuria and the kidney function did not change significantly over time regardless of renin-angiotensin-aldosterone system (RAS) inhibition with mean urine protein creatinine ratio at the last follow up of 0.965 (range 0.75 ~ 1.175).
Discussion: These cases are similar to previously reported cases, indicating that asymptomatic subnephrotic range proteinuria patients should be suspected of C-terminal variants of CUBN gene.There are still debates on whether CUBN C-terminal mutation is truly benign proteinuria, and whether clinicians should treat these patients with RASi.
Background: Many patients with childhood idiopathic nephrotic syndrome are steroid-sensitive, suggesting the involvement of the immune system in the pathogenesis.Several genome-wide association studies have suggested a polygenic contribution, particularly in the HLA DR/DQ region and a locus including NPHS1, but the etiology remains unclear.Anti-nephrin antibodies have recently been reported in both adults and children with biopsy proven minimal change disease (MCD), but the presence of antinephrin antibodies in Japanese childhood idiopathic nephrotic syndrome (INS) has not been investigated.
Methods: Anti-nephrin antibodies were measured by ELISA in paired plasma samples obtained from 14 Japanese pediatric patients with INS (male/female: 8/6), at initial disease onset (active disease) and following steroid monotherapy.Clinical characteristics were compared between the anti-nephrin antibodies positive and negative groups.
Results: The median age at the onset was 75.5 months (interquartile range (IQR): 45-113).Steroid sensitivity resulted in complete remission in 13 patients and almost complete remission in one patient after 4 weeks of glucocorticoid monotherapy.Circulating anti-nephrin antibodies were detected in seven of 14 patients during active disease.In all cases, anti-nephrin antibodies were significantly reduced following treatment concordant with clinical response.There were no differences between the positive and negative groups in pre-treatment parameters.Of the 13 patients who achieved complete remission, nine had at least one relapse during a median follow-up of 851 days (IQR: 808-973).There was also no significant difference in the relapse-free period after the onset between the two groups (P=0.658).
Conclusions: We have identified circulating anti-nephrin antibodies at initial presentation in half of Japanese pediatric INS, which is a higher proportion than previously reported for a North American cohort of adults and children with biopsy proven MCD.Further studies are needed to establish the prognostic implications of antinephrin antibodies in childhood INS and the relationship with the NPHS1 risk variants in this population.
4 1 Seoul National University Hospital, Jongno-gu, Seoul, Republic of Korea; 2 Korea University Guro Hospital, Seoul, Republic of Korea; 3 Chungnam National University Sejong Hospital, Sejong, Republic of Korea; 4 Kangwon National University Hospital, Chuncheon, Kangwon, Republic of Korea; 5 Seoul National University College of Medicine, Seoul, Republic of Korea.