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Abstract: PO1994

Mendelian Causes Are Identified at a Relatively Low Rate and Show a Unique Pattern in Brazilian Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis

Session Information

Category: Pediatric Nephrology

  • 1700 Pediatric Nephrology

Authors

  • Watanabe, Andreia, University of Sao Paulo, Sao Paulo, SP, Brazil
  • Neves, Precil D., University of Sao Paulo, Sao Paulo, SP, Brazil
  • Watanabe, Elieser H., University of Sao Paulo, Sao Paulo, SP, Brazil
  • Lerario, Antonio M., University of Michigan, Ann Arbor, Michigan, United States
  • Malheiros, Denise M., University of Sao Paulo, Sao Paulo, SP, Brazil
  • Vaisbich, Maria H, University of Sao Paulo, Sao Paulo, SP, Brazil
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
  • Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
  • Onuchic, Luiz F., University of Sao Paulo, Sao Paulo, SP, Brazil
Background

Genetic and non-genetic factors have been associated with faster progression to chronic kidney failure (CKF) in children with steroid-resistant nephrotic syndrome (SRNS). The contribution profile of such factors in admixed populations, however, is still not well characterized.

Methods

101 patients/98 families with idiopathic SRNS, age of onset <18yr, were sequenced for 62 NS genes or submitted to whole exome sequencing. Causative variants and APOL1 risk alleles were confirmed by Sanger sequencing. Clinical data were retrospectively reviewed.

Results

Age of NS onset was 2.9yr (1.5-6.8), 61 (60.4%) were male, 61 (60.4%) self-declared white, 6 (5.9%) had parental consanguinity, and 14 (13.9%) familial disease. Focal segmental glomerulosclerosis (FSGS) was diagnosed in 54/95 (56.8%) , minimal change disease (MCD) in 20/95 (21.1%) and collapsing glomerulopathy in 12/95 (12.6%). 43/101 (42.6%) progressed to CKF in 29 months (12.0-61.9) and 9/29 (31%) had recurrence after kidney transplant (KT). APOL1 high risk genotypes (HRG) were identified in 8/98 (8.2%) and were associated with later NS onset [11.0 (10.0-14.5) vs 2.7 (1.4-4.9) yr, p<0.001]. Mendelian causes were found in other 14/98 (14.3%) families: NPHS1=4, NPHS2=3, PLCE1=2, WT1=2, COQ2=1, and phenocopies in CUBN=1 and COL4A5=1, all APOL1 G0/G0. Poorer renal survival was observed in APOL1 HRG vs non-Mendelian/non-APOL1 HRG (p<0.001), and a trend in Mendelian vs non-Mendelian/non-APOL1 HRG (p=0.06). The APOL1 or Mendelian cases had no post-KT recurrence. Using Cox regression, age of onset <1yr (OR=6.5, CI:2.3-16.9, p=0.0007) or ≥ 9yr (OR=3.3, CI:1.3-7.9, p=0.015) were associated with reduced renal survival, independently of genetic findings, as well as self-declared non-white (OR=2.6, CI:1.3-5.64, p=0.01) and non-MCD histology (OR=14.2, CI:2.1-948, p=0.002).

Conclusion

Mendelian causes of SRNS/FSGS were identified in 14.3% - a lower rate than in PodoNET, SRNS Study Group and RaDar - and APOL1 HRG in 8.2% of patients in this admixed population with a low frequency of parental consanguinity. Genetics factors, age of NS onset, ethnicity and biopsy pattern were independently associated with progression to CKF.