By Dr Benjamin Tan, MB BCh BaO (NUI), MRCP (UK)
Nephrologist
Queen Elizabeth Hospital, Kota Kinabalu, Sabah

Table 1. Genetic testing modalities, indications, advantages and disadvantages

Abbreviations: CNV, copy nucleotide variant; DNA, deoxyribonucleic acid; GC, glucocorticoid; INDEL, insertion-deletion; SNV, single nucleotide variant.

The genetic diagnoses of glomerular diseases can be classified based on the anatomical and pathological involvement within the glomerulus (Figure 2). Podocyte-associated genetic defects affect the slit diaphragm function and disrupt the actin-cytoskeleton framework within the podocyte foot processes that anchor to the glomerular basement membrane (GBM). Genetic defects may also be seen in several GBM components, such as the cross-linkage network of type 4 collagen chains embedded within triple-helical protomers as well as laminin. In endocapillary-related genetic defects, a prothrombotic state ensues, leading to thrombotic microangiopathy (TMA), a histopathological feature commonly observed in both thrombotic thrombocytopenic purpura and atypical HUS (complement-mediated TMA). Mutations in mitochondrial genes may also result in glomerular disorders. Using a Drosophila model to investigate the relationship between COQ2 mutation and structural changes within the podocyte, Zhu et al. suggested the role of oxidative stress injury in podocytes as a postulated mechanism of glomerular injury in patients with coenzyme Q10 (CoQ10) deficient-related glomerular disorders, otherwise known as primary CoQ10 nephropathy. To date, these mutations (PDSS1, PDSS2, COQ2, COQ6 and COQ8B/ADCK4) within the CoQ10 biosynthesis pathway have been associated with glomerular involvement. Lastly, the effects of systemic genetic diseases on the glomerular filtration barrier are thought to be indirect, ranging from disruption of normal cellular metabolism within the glomerular cells to excessive deposition of substances such as lipoproteins and immune complexes within the glomerulus.

Figure 2. Classification of monogenic glomerular dIsease based on the anatomical and pathological involvement within the glomerulus.

a) Diagnosis of patients exhibiting features of syndromic glomerulopathies

The diagnostic performance of genetic testing in monogenic glomerular disease correlates inversely with age of onset, ranging from almost 100% at birth to about 50-70% in children and young adults. These disorders present with a variety of extra-renal clinical features and are resistant to standard glucocorticoid therapy (Table 2).

Table 2. Syndromic glomerulopathies based on the age of onset and predominant extra-renal features

Abbreviations: MYH-9, myosin heavy chain 9; SRNS, steroid-resistant nephrotic syndrome.

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.

Genetic testing faces multiple barriers to access and use. Whereas genetic testing is inaccessible in most developing countries, such services have high costs and long turnaround times, often with more accessible coverage for children than adults in countries offering reimbursements. There is limited data on the cost-effectiveness of genetic testing in managing glomerular diseases, with a few prospective studies demonstrating cost-effectiveness amongst children with suspected monogenic kidney disorders. 

Limited genetics literacy amongst nephrologists is another major barrier. Genetics is seldom incorporated into the curriculum of nephrology fellowship training programs in many countries, making the analysis and interpretation of test results challenging for the nephrologist. A recent survey conducted to explore the attitude of nephrologists toward genomics showed that even though the majority believed in the usefulness of genetic testing, only less than a quarter felt confident to use the results. Interpreting the sequence data requires gene- and variant-level analyses, phenotypic-level comparison and determination of actionability. Commonly encountered terminologies such as variants of undetermined significance and incidental findings can be challenging to interpret and may hence require the expertise of a clinical geneticist or a trained genetics counselor.

Another challenging aspect is the psychosocial implications associated with genetic testing. Stress and anxiety may arise among patients, followed by stigmatization from their families or community members who may not comprehend their genetic diagnosis. Patient insurability and confidentiality may also be affected despite laws being legislated to protect patients from being discriminated against by employers and insurance companies.

The future of nephrogenetics in glomerular disease is bright. Recent advances in genomics technology, data collection and experimental research models have paved the way for a greater understanding of the pathogenetic and molecular mechanisms of monogenic glomerular disease. Such understanding may allow the development of specific therapeutic targets that are safe and effective. With precision medicine on the horizon, we must be cognizant of the potential challenges in bridging translational research to clinical medicine.