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Abstract: PO1544

Treatment-Resistant Membranous Nephropathy in a Patient with NPHS2 Mutation

Session Information

Category: Glomerular Diseases

  • 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

  • Ailincai, Ioana, Fundeni Clinical Institute, Bucharest, Romania
  • Lupusoru, Gabriela, Fundeni Clinical Institute, Bucharest, Romania
  • Costea, George C., Fundeni Clinical Institute, Bucharest, Romania
  • Fratila, Georgiana, Fundeni Clinical Institute, Bucharest, Romania
  • Ion, Oana, Fundeni Clinical Institute, Bucharest, Romania
  • Ismail, Gener, Fundeni Clinical Institute, Bucharest, Romania
Introduction

Membranous nephropathy (MN) is one of the most frequent causes of nephrotic syndrome (NS) in adults. NPHS2 gene encodes podocin, a protein of the slit diaphragm that is essential for recruitment of nephrin into the lipid rafts and for maintaining the glomerular filtration barrier. Recessively transmitted mutations in NPHS2 cause familial forms of steroid-resistant NS that progress to end-stage renal disease (ESRD).

Case Description

A 37-year-old male was referred to our clinic with NS and hypertension. Admission labs showed creatinine of 3 mg/dl, serum albumin of 3 g/dl, proteinuria of 20 g/d and microscopic hematuria (30 cells/µl). Immunological testing – ANA, ANCA, anti-C1q, anti-GBM – was negative, C3 and C4 were normal. Kidneys appeared normal on ultrasound examination. A renal biopsy was performed. Light microscopy revealed 19/23 glomeruli with global sclerosis and 4/23 glomeruli with thickening of GBM, podocyte hypertrophy and segmental sclerosis; there was also diffuse tubular atrophy, interstitial fibrosis and arteriolar hyalinosis. Electron microscopy showed subepithelial electron dense deposits with spike formation, with granular capillary loop staining for IgG4 in immunofluorescence. The histopathological diagnosis was stage II MN associated with diffuse glomerulosclerosis secondary to hypertension. In the meantime, the anti-PLA2R antibodies returned positive (titer 1/320). Therapy was started with Rituximab 1000 mg; a second dose was administered after 14 days. Despite treatment, NS persisted and kidney function worsened; hemodialysis was initiated 6 months after the diagnosis. One year later, the patient’s 16-year-old son was diagnosed with NS, resistant to steroids. Genetic testing identified NPHS2 c.947C>T p.(Pro316Leu) heterozygous mutation in the family; the son was also heterozygous for c.3447dup, p.(Val1150Cysfs*39) in KANK1, inherited from the mother.

Discussion

Recent data suggest an important role of genes in the pathogenesis of MN; NPHS1 polymorphisms are associated with low remission rate after treatment and high disease progression. Our patient has a heterozygous mutation in NHPS2, resulting in abnormal signaling through the nephrin-podocin complex and podocyte disfunction. Therefore, it is very probable that in this case of primary MN genetics played a major role in treatment resistance and progression to ESRD.