b) Management of monogenic glomerular disease
Monogenic variants in over 60 genes have been identified as the cause of steroid-resistant nephrotic syndrome (SRNS; defined as lack of complete remission at 4 weeks of therapy with daily prednisolone at standard dose) in approximately 30% of pediatric patients. As such, genetic testing should be considered in children, adolescents and young adults who develop SRNS, prioritizing those with a strong family history of proteinuria, hematuria or CKD of unknown origin. It may then help clinicians decide whether to continue immunosuppression in patients with steroid-resistant or partially responsive nephrotic syndrome. Such testing can provide a convenient and cost-effective method of diagnosis while minimizing the risks involved in kidney biopsy, and avoiding the pitfalls of misdiagnoses, potentially harmful diagnostic procedures and incorrect treatments.
A confirmed genetic diagnosis also leads to the delivery of a more targeted therapy, such as enzyme and CoQ10 replacement for Fabry’s disease and CoQ10 deficient SRNS, respectively. In Alport syndrome (AS), it enables early initiation of renin-angiotensin-aldosterone system blockade which is beneficial in slowing down disease progression in the kidneys. In patients with complement-mediated TMA (CM-TMA), a negative genotyping result is associated with a low risk of relapse, potentially allowing the discontinuation of C5 inhibitor therapy such as eculizumab.
c) Prognostication of glomerular disease
Genetic diagnosis of AS helps prognosticate disease course and progression. X-linked (COL4A5) and autosomal recessive forms of AS (COL4A3/4) typically present with progressive kidney dysfunction and bilateral sensorineural hearing loss, while autosomal dominant forms of AS (COL4A3/4) present with a milder form of progression without hearing loss.
Complement gene testing provides information regarding the risk of disease recurrence in kidney allografts post-transplantation. In the pre-eculizumab era, a confirmed pathogenic variant in CFH, CFB, TBHD or CFH:CFHR1 rearrangements conferred a high recurrence risk of almost 80-90% while a moderate recurrence risk between 40-75% was observed in those with a negative complement genotyping study or confirmed isolated CFI or C3 mutation. An isolated MCP or DGKE mutation conferred a low recurrence risk of less than 20%. According to a systematic review and meta-analysis on the outcomes of patients with CM-TMA who were treated with prophylactic eculizumab post-kidney transplantation, less than 6% of patients experienced disease recurrence when eculizumab therapy was stopped.
d) Screening for an at-risk individual who is a potential kidney donor
In the setting of living-related kidney transplantation, genetic testing offers a non-invasive way of screening potential donors at risk of developing a hereditary glomerular disease. Individuals with a confirmed pathogenic variant are usually excluded from kidney donation. Genetic testing of at-risk family members enables early disease detection and allows future family planning by clarifying inheritance patterns.