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

Abstract

Background and objectivesIntensified 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, & measurementsPediatric 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.ResultsOf 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.ConclusionsPatients 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.

Podocytopathies

“…Approximately 60% of steroid-resistant patients may respond to ciclosporin or tacrolimus at moderate doses with reduced proteinuria and slower or halted CKD progression 196 . A genetic cause is usually not found in these patients 65,67,156 . As relapse is frequent after the withdrawal of these drugs 196 , prolonging treatment for 1-3 years after remission is achieved is advisable 157 .…”

“…Genetic variants in >50 nuclear and mitochondrial genes have been associated with FSGS and most cases are resistant to steroid therapy 65,67,156 . Inheritance patterns include autosomal recessive, autosomal dominant and sex-linked.…”

“…Progressive CKD is infrequent in children or adults with minimal change lesions 6,152 but it is common among those with a podocytopathy, persistent proteinuria and FSGS lesions 157 . Response to glucocorticoids is critical in defining patient subsets 158 and prognosis 156 , as those who achieve remission (75-92% with minimal change lesions 146,159 and 47-66% in those with FSGS lesions 160 ) do not usually develop ESKD 161 . Conversely, resistance to steroids is the strongest independent predictor of kidney function decline, with a kidney survival of 30% at 10 years from diagnosis.…”

Clinical Genetic Screening in Adult Patients with Kidney Disease

“…Importantly, a genetic diagnosis can have strong implications for patient management and should always be considered in earlyonset disease, particularly in the presence of a clear family history. For example, most genetic forms of steroidresistant nephrotic syndrome may not respond to immunosuppression therapy (69). Therefore, a positive finding may spare a patient from unwanted complications from this therapy (70).…”

Response to Steroid and Immunosuppressive Therapies May Predict Post-transplant Recurrence of Focal Segmental Glomerulosclerosis

“…Studies have shown that a higher proportion of genetictesting-negative patients achieve remission with immunosuppressive agents than those with genetic FSGS [26,27]. This nding suggests that those who respond to immunosuppressants are likely to have primary FSGS or CFs-mediated FSGS [26,27]. As shown in Fig.…”