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Kidney Week

Abstract: FR-PO673

The Genetic Background of Persistent Hypogammaglobulinemia After Rituximab Treatment in Refractory Nephrotic Syndrome

Session Information

  • Pediatric Nephrology - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pediatric Nephrology

  • 1900 Pediatric Nephrology

Authors

  • Sai, Miyu, Tohoku Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Sendai, Miyagi, Japan
  • Uchida, Nao, Tohoku Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Sendai, Miyagi, Japan
Background

Rituximab (RTX) has been proven to be effective for refractory nephrotic syndrome(rNS); however, persistent severe hypogammaglobulinemia (HGG) is occasionally observed and causes health problems in some patients. We suspected the coexistence of common variable immunodeficiency (CVID) in these patients, and we proved that they had either genetic mutations associated with CVID or FCGR3A F176V polymorphism, that is, a missense variant, c.526T>G (p.Phe176Val) in FCGR3A gene (NM_000569.8).

Methods

We performed whole genome sequence analysis on patients who developed persistent HGG (<400 mg/dL, more than two years) after the last RTX therapy.

Results

Five patients were recruited (table). All of them developed rNS and were treated with repeated RTX <18 years old. Their HGG was persistent for more than five years after the last RTX therapy. Among the five patients, three (No.1-3) showed severe (<200 mg/dL) HGG, pan hypoimmunoglobulinemia, and susceptibility to infection. The other two (No.4 and 5) showed relatively mild HGG, normal to high levels of other types of immunoglobulin, and no clinical symptoms. Genetic analysis revealed that No.1 had a novel heterozygous mutation in NFKB1,
and No.3 had a heterozygous mutation in TNFSF12. Both genes were associated with CVID. FCGR3A F176V polymorphisms were found in No.2 and 3. Thus, patients who developed severe and symptomatic pan hypoimmunoglobulinemia had either a genetic mutation associated with CVID or FCGR3A F176V polymorphism.

Conclusion

Severe and symptomatic pan hypoimmunoglobulinemia after RTX treatment was accompanied by genetic alterations in CVID-associated genes or in FCGR3A genes. Advanced analysis of these genes before RTX administration could prevent, or at least delay, the development of symptomatic pan hypoimmunoglobulinemia.

No.genderIgG level (mg/dL)other Iggenetic mutationFCGR3A F176Vclinical symptoms
1female<100IgA↓, IgM↓NFKB1N.A.otitis media, respiratory infection
2female<100IgA↓, IgM↓otitis media, sinusitis
3male100-200IgA↓, IgM↓TNFSF12rota virus-associated encephalitis
4female200-300IgA↑, IgM→no symptoms
5female200-300IgA↑, IgM↑no symptoms