NephMadness 2015: Genetic Nephrology Region

Conall O'Seaghdha, MB MRCPI; Paul Phelan, MD

Disclosures

March 02, 2015

Editorial Collaboration

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In This Article

Familial FSGS vs APOL1

These 2 powerhouses know each other well. There is no love lost between the two, with APOL1 being a franchise breakaway in recent years that has gone on to make a name for itself in the Genetics conference. APOL1 continues to captivate audiences, although there is still a lot we don't know about this exciting team.

Familial FSGS is a conference stalwart dating back to the old "Podocyte Conference" with its breakthrough player Nephrin, but has continued to attract new talent as discussed below.

Familial FSGS

FSGS is the third leading cause of ESRD in the United States with an increasing incidence in recent years. It describes a pattern of injury with many etiologies and proteinuria as the predominant clinical feature. It is caused by podocyte injury manifested by foot process effacement histologically.

Several single-gene mutations have been identified that cause FSGS, which has helped us understand the pathogenesis of glomerular disease. The genes have mostly been in podocyte-protein genes, a notable exception being LAMB2, which localizes to the glomerular basement membrane and causes Pierson syndrome (diffuse mesangial sclerosis, microcoria, and neurological anomalies).

Inheritance may be AD or AR, with AD conditions having a less severe and later onset phenotype and often exhibiting incomplete penetrance. FSGS due to single-gene mutations does not recur post-kidney transplantation.

The first described gene was NPHS1 which codes for nephrin, an integral slit diaphragm protein, a mutation in which causes congenital nephrotic syndrome (so called "Finnish type"). This landmark study demonstrated the importance of the podocyte in congenital nephrotic syndrome/FSGS with multiple subsequent genes being described causing congenital nephrotic syndrome/FSGS (see Table below).

The proteins of interest are often integral slit diaphragm proteins (nephrin, podocin, CD2AP), foot process cytoskeleton components (ACTN4, INF2), or involved in regulation/expression of these proteins (WT1, perhaps PLCE1). Transient receptor potential cation channel type 6 ( TRPC6 ) is a calcium channel located in the body of the foot process as well as the slit diaphragm. Mutations in TRPC6 are gain-of-function causing increased intracellular calcium influx. TRPC6 knockout mice are protected from albuminuria following angiotensin II infusion but how the gene causes podocyte injury remains unknown.

The advent of next-generation sequencing (see below section) has enabled the recent identification of additional single-gene causes of FSGS including ANLN, which codes for the F-actin binding protein Anillin. Potentially of more interest, next-generation sequencing has also expanded the phenotypic spectrum of known genes to include familial FSGS. These include PAX2 , mutations which were previously described to cause congenital abnormalities of the kidney and urinary tract and mutations in COL4A3 & COL4A4, which have recently been reported to be disease segregating in 10% of a large cohort of familial FSGS families, without an Alport phenotype.

The Wilms tumor 1 gene (WT1) encodes a zinc finger binding protein critical for kidney and genitourinary development. It is also involved in expression of essential slit diaphragm proteins such as nephrin, podocin, and podocalyxin. Renal phenotypes associated with WT1 mutations include Wilms tumor and several syndromic forms of FSGS associated with genitourinary anomalies and mental retardation. These include WAGR syndrome (with aniridia, genitourinary malformations, and mental retardation), Denys-Drash syndrome (with diffuse mesangial sclerosis, male pseudohermaphroditism), and Frasier syndrome (male pseudohermaphroditism, FSGS and gonadoblastoma).

A recent study employed next-generation sequencing to identify WT1 mutations causing non-syndromic FSGS. Functional studies implicated WT1 in the transcriptional regulation of nephrin as well as synaptopodin expression, another crucial podocyte protein.

Genetic testing for familial FSGS has moved a step closer with the advent of next-generation sequencing, although precisely when and how it may be useful remains a challenge. In transplantation, it may be helpful to assess risk of recurrence or to screen potential living related donors. In adolescents or young adults presenting with FSGS, having a molecular diagnosis may help tailor treatment as the presumption is that immunosuppression will not work in familial FSGS. However, it is not as simple as this, and certain agents, particularly cyclosporine (blocking calcineurin-mediated dephosphorylation of synaptopodin) and rituximab, may have beneficial podocyte-specific effects, possibly regardless of etiology of the podocytopathy.

This team has strong comparisons and connections to Duke in the NCAA. FSGS is a perennial competitor with a rich tradition and will expect to go far in the tourney. APOL1 represents a huge early potential banana skin.

Table 2. List of Major Genes Implicated in Familial FSGS

Gene Phenotype
Autosomal Recessive
NPHS1 (Nephrin) FSGS; Congenital Nephrotic Syndrome
NPHS2 (Podocin) FSGS; Congenital Nephrotic Syndrome
NPHS3 (PLCE1) FSGS
LAMB2 FSGS; Pierson Syndrome
MYH9 FSGS; Sensorineural Deafness; Macrothrombocytopenia; Epstein, Fechtner and Sebastian Syndromes
MYOE1 FSGS
PAX2 FSGS; Papillorenal Syndrome
Autosomal Dominant
ACTN4 FSGS
ANLN FSGS
ARHGAP24 FSGS
CD2AP FSGS
TRPC6 FSGS
INF2 FSGS; Charcot-Marie-Tooth Disease
LMX1B FSGS; Nail-Patella Syndrome
WT-1 FSGS; Denys-Drash, WAGR and Frasier Syndrome

APOL1

Apolipoprotein 1 (APOL1) related nephropathy is surely one of the biggest nephrology genetics stories in recent times. The APOL1 risk alleles, G1 and G2, are mutually exclusive (never occur on the same chromosome copy) and 2 copies are necessary to confer kidney disease risk (genotype may be G1/G1, G2/G2, or the compound heterozygous state of G1/G2).

The alleles are common in individuals of West African ancestry and almost unheard of in those of European ancestry. Variation in these alleles is now known to be responsible for the vast majority excess risk of non-diabetic kidney disease including FSGS, HIV-associated nephropathy, severe lupus nephritis, and unspecified CKD (often previously labelled as hypertensive nephropathy in African Americans). The alleles are common, with about half of African Americans having either one or two risk alleles, and 10%–15% possessing both. The effect size is large, with a 7-10 fold increased risk of FSGS or unspecified ESRD, and an even higher risk for HIVAN. Despite this, they should be considered risk alleles rather than a single-gene disorder. The presence of the alleles is not enough to have the phenotype, and additional "hits" are necessary, which may be genetic, environmental, or both.

The origin of the APOL1 variants is a fascinating story, with initial genome-wide approaches suggesting MYH9 as the gene of interest in African American patients with FSGS. This was a reasonable theory given the fact that MYH9 is expressed in the podocyte and mutations in the gene cause syndromic FSGS (see Team Familial FSGS). However, the excess risk was found to be due to variants in the nearby APOL1 gene. These alleles have risen to high frequency in individuals of African descent via a beneficial effect in resistance to Trypanosoma brucei rhodesiense. A succinct review of APOL1 (and other genetic nephropathies) is worth exploring.

A recent study reported in NEJM examined APOL1 variants in 2 large CKD cohorts, AASK and CRIC. AASK enrolled all African American patients with CKD attributed to hypertension that did not have diabetes. The CRIC study included black and white patients with CKD, approximately half of whom had diabetes. Interestingly this finding was also evident in the patients with diabetic kidney disease. Diabetic nephropathy has not been previously identified as phenotype influenced by APOL1 variation.

Little is known about the kidney-specific biology of APOL1. Only the genomes of humans and a few primate species carry the APOL1 gene, making study in animal models difficult. Recent work has explored the role of innate viral immunity in over-expression of APOL1, particularly of the variant APOL1 which is more injurious to cells than the wild type. In the study, several patients (10/11 African American) were noted to develop a collapsing FSGS pattern of injury after treatment with interferon. Interferons and Toll-like receptor agonists hugely increased APOL1 expression. Note that HIV is a potent inducer of interferons, with HIV nephropathy being a particular risk with possession of the APOL1 risk alleles. Lupus nephritis, another high interferon state, has been recently recognized as lying within the sphere of APOL1 nephropathies.

Keeping with the viral pathway theme, another study demonstrated that in African Americans with both APOL1 risk variants, JC viruria was associated with a lower prevalence of kidney disease. How would JC virus protect from development of APOL1-associated nephropathy? Is it a clue to an environmental "second hit" whereby the JC virus may inhibit infection with other more nephrotoxic viruses? These questions and more will need to be answered in the coming years.

The effect of transplanting kidneys from APOL1 nephropathy risk donors demonstrated that deceased donor allografts possessing both APOL1 risk variants failed more rapidly than those with one or no risk alleles. This concept was well, but tragically, illustrated in a recent case report of a young Afro-Caribbean monozygotic twin transplant pair. The recipient had unspecified FSGS, the donor was normal at screening. There was clinical and histological evidence of FSGS at 30 months post-transplant and allograft failure occurred early. The donor subsequently developed proteinuria and renal dysfunction, undoubtedly aggravated by his reduced nephron mass. The twins were later genotyped confirming the presence of both APOL1 risk variants.

This leads to the utility of testing for APOL1 variants. Certainly a case could be made in transplantation, illustrated by the case report described above. Also, if the risk of allograft failure with possession of the APOL1 risk alleles in the donor could be validated, it would suggest that genotyping donors of African origin could be beneficial.

In the general CKD population, it is less clear. Certainly the alleles confer significant risk, but that risk is not absolute, so not all G1 & G2 carriers will develop kidney disease. Also, as there is no specific treatment for APOL1-related nephropathies, the utility for general testing in the African American CKD population is not evident.

Team APOL1 will be a tourney regular for years to come and may grow in coming seasons to be a big dance favorite. It's a team full of potential but remains somewhat of an unknown quantity.

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