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. 2020 Jul 1;15(7):983-994.
doi: 10.2215/CJN.13371019. Epub 2020 Apr 21.

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Anna E Mason  1 , Ethan S Sen  1 , Agnieszka Bierzynska  1 , Elizabeth Colby  1 , Maryam Afzal  1 , Guillaume Dorval  2 , Ania B Koziell  3 , Maggie Williams  4 , Olivia Boyer  2 , Gavin I Welsh  1 , Moin A Saleem  1 ; UK RaDaR/NephroS Study
Affiliations

Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome

Anna E Mason et al. Clin J Am Soc Nephrol. .

Abstract

Background and objectives: Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence.

Design, setting, participants, & measurements: Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings.

Results: Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome.

Conclusions: Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.

Keywords: Base Sequence; Biopsy; Cohort Studies; Disease Progression; Exome; Genetic Testing; Radar; Registries; Renal Insufficiency; Rituximab; immunosuppression; nephrotic syndrome; pediatric nephrology; progression of renal failure; transplant outcomes.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Summary of patient selection. Steroid-resistant nephrotic syndrome includes patients with primary, presumed, and secondary steroid resistance. A total of 184 patients were part of the original whole-exome sequencing cohort, which has been previously described by Bierzynska et al. (7). RaDaR, National Registry of Rare Kidney Diseases.
Figure 2.
Figure 2.
Response to intensified immunosuppression, and associated outcomes. immunosuppression medications and kidney survival in genetic-testing-negative patients. Response to (A) all or (B) first-administered intensified immunosuppression medications. The number of treatments with response data available is given in parentheses. No data were available for 29 of 335 treatment episodes (first intensified immunosuppression in three patients). (C) Kidney survival analyzed by response to first intensified immunosuppression treatment. Numbers in the table represent the number of patients at risk for each time point.
Figure 3.
Figure 3.
Patient stratification by genetic testing and response to intensified immunosuppression. The three stratified patient groups are indicated in the gray highlighted boxes.
Figure 4.
Figure 4.
Outcome of patients according to Rituximab response.
See this image and copyright information in PMC

Comment in

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