Genetic Basis of Health Disparity in Childhood Nephrotic Syndrome

Abstract

Nephrotic syndrome is the most common glomerular disease in children. There is wide variation in the incidence of nephrotic syndrome in different populations, with a higher incidence in children of South Asian descent. However, nephrotic syndrome with a more indolent course and poor prognosis is more common in African American children. The disparity in the prevalence and severity of nephrotic syndrome is likely due to complex interactions between environmental and biological factors. Recent advances in genome science are providing insight into some of the biological factors that may explain these disparities. For example, risk alleles in the gene encoding apolipoprotein L1 (APOL1) have been established as the most important factor in the high incidence of chronic glomerular diseases in African Americans. Conversely, the locus for childhood steroid-sensitive nephrotic syndrome in the gene encoding major histocompatibility complex-class II-DQ-alpha 1 (HLA-DQA1) is unlikely to be the explanation for the high incidence of steroid-sensitive nephrotic syndrome in Asian children because the same variants are equally common in whites and African Americans. There is a need for collaborative large-scale studies to identify additional risk loci to explain disparities in disease incidence and response to therapy. Findings from such studies have the potential to lead to the identification of new therapeutic targets for nephrotic syndrome.

Introduction

Nephrotic syndrome is a clinical condition characterized by massive proteinuria, hypoalbuminemia, and edema, with or without hyperlipidemia.¹ Though the etiology remains unclear, nephrotic syndrome is caused by defects in the glomerular filtration barrier, a charge- and size-specific barrier that is made up of specialized fenestrated endothelium, glomerular basement membrane, and specialized glomerular epithelial cells called podocytes.¹

Idiopathic nephrotic syndrome has a prevalence of 16 in 100,000 children, and its annual incidence is estimated to be 2 to 7 per 100,000 children.² However, there is wide variation in the epidemiology based on race and environment.^3–6 The incidence of nephrotic syndrome is higher in children of Asian descent compared with those of European descent, whereas African American and Hispanic children are more likely to be resistant to treatment and have worse outcomes.^1,3–5 A European survey conducted in the 1970s demonstrated that 3.3% of patients with idiopathic nephrotic syndrome had an affected family member.⁷ Although there is a male to female ratio of 2:1 in young children, both sexes are similarly affected in adolescence.⁶ Although nephrotic syndrome is rare in the general population, it is the most common glomerular disease seen in pediatric practice and the second most common condition seen in pediatric nephrology clinics, second only to congenital anomalies of the kidney and urinary tract.

Prevalence and Severity of Nephrotic Syndrome in Different Populations

Differences in the prevalence and severity of nephrotic syndrome have been described in small epidemiologic studies, raising the question as to whether there is health disparity between different populations with nephrotic syndrome, and if so, what the basis of this disparity may be. Health disparity is defined by Wheeler and Bryant⁸ as “an increased burden of an adverse health outcome or health determinant within a specific subset of the population.”^8(p1) More than $245 billion annually go toward ethnic disparity–related outcomes, including $35 billion in excess health expenditure, $200 billion in premature deaths, and $10 billion in lost productivity due to illness.⁹ The causes and risk factors for health disparity are multifactorial and are due to the interaction of different factors such as social status (wealth, education, and employment status), patient factors (race, ethnicity, and genetic variations), provider factors (implicit bias), and health care factors (access to care or mistrust of the health care system by patients).

The role of ethnicity and/or ancestry in susceptibility to nephrotic syndrome has been demonstrated in single-center and a few population-based epidemiologic studies.^3,5,10 In a survey in Leicester, United Kingdom, Feehally et al⁵ showed that nephrotic syndrome is 7 times more common among South Asian children compared with non-Asian children (9.4 vs 1.3/100,000). A similar pattern was reported from northwest England almost 15 years later.¹⁰ More recently, a larger study from Ontario, Canada, confirmed the same pattern.³ In all these studies, the authors ascribed the disparity in the prevalence of nephrotic syndrome among different ethnicities to a combination of genetic and environmental factors.^3,5,10

Another measure of disparity in nephrotic syndrome is the pattern of response to therapy and morphologic changes seen on kidney biopsy. In a study of children seen in a single health facility in the southern United States, Kim et al¹¹ showed that steroid-resistant nephrotic syndrome (SRNS) is 3 times more common among African Americans compared with whites. In addition, a recent study from Canada showed that although nephrotic syndrome is more common in South Asian children, they are less likely to have a frequently relapsing or steroid-dependent course.³ Another study showed that more severe histologic patterns, such as focal segmental glomerulosclerosis (FSGS), are more common in African Americans compared with the rest of the population.⁴ In summary, there is clearly health disparity in childhood nephrotic syndrome, which is driven by multiple genetic, biological, and environmental factors. In this review, we discuss the genetic drivers of the disparity.

Cause and Classification of Nephrotic Syndrome

The precise cause of nephrotic syndrome remains unclear in most cases, and most patients are therefore classified as having idiopathic nephrotic syndrome. In the few cases for which the cause can be established, it is often secondary to a primary disease process, such as metabolic disease or infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). Nephrotic syndrome may also occur secondary to exposure to heavy metals and other toxins, maladaptive responses such as hyperfiltration in single kidneys, and obesity. A small percentage of cases are due to mutations in single genes (monogenic nephrotic syndrome), and mutations in more than 50 genes have been identified as causes of nephrotic syndrome.^12–14 The causes of nephrotic syndrome also vary with age. Most cases in the first 3 months of life are referred to as congenital nephrotic syndrome, and almost 80% are due to single gene defects.¹⁵ After the first year of life and through the first decade of life, idiopathic type predominates. Secondary causes increase after the first decade of life.

Studies performed in the 1970s by the International Study of Kidney Disease in Children (ISKDC) consortium showed that irrespective of pathologic changes in the kidney, the single most important predictor of long-term kidney function is the response to treatment with corticosteroids and other immunosuppressive agents.^16,17 It is these landmark findings that led to the classification of nephrotic syndrome based on response to therapy. Using this schema, patients are classified broadly as having either steroid-sensitive nephrotic syndrome (SSNS) or SRNS. Kidney biopsies from most children with SSNS will show minimal change disease histology, whereas a majority of patients with SRNS will have other more severe histologic patterns, such as FSGS and membranous nephropathy, among others.^16–18

In children, ~80% of patients will have SSNS and therefore have an excellent prognosis. The proportion of patients with SSNS decreases with age, such that <50% of adults with nephrotic syndrome will have a steroid-sensitive course.² Conversely, SRNS is found in ~20% of children with nephrotic syndrome. SRNS is associated with a worse prognosis and increased risk for progression to end-stage kidney disease.^2,14,19 SRNS is the second most common cause of early-onset chronic kidney disease, accounting for 10.4% of all cases.¹⁹

Genetic Basis of Health Disparity in Nephrotic Syndrome

Recent advances in genomic technology have started to provide insight into the biological basis of some of the disparities described in the previous sections. For example, studies conducted in the last 20 years have identified mutations in more than 50 genes as causes of nephrotic syndrome in different populations.^12,13 These studies in aggregate showed that the driving mechanisms of some cases of nephrotic syndrome are likely structural defects of the podocytes and other components of the glomerular filtration barrier. In addition to revealing the mechanisms of how these mutations cause disease, findings from these studies have also shown that these rare genetic defects may predict the pattern of response to therapy and post-transplantation course. Monogenic nephrotic syndrome is known to be in the severe end of the spectrum of nephrotic syndrome in that >95% of children with monogenic nephrotic syndrome will be therapy resistant and the majority will progress to end-stage kidney disease within 10 years of diagnosis.^12,13 However, they are less likely to have disease recurrence after kidney transplantation.^20–23 Some studies have shown that mutations may cluster in certain populations, thereby partially explaining the higher risk for the disease and pattern of therapy response in these populations, whereas the prevalence of mutations in other populations is extremely rare.^8,11,24 One would expect a higher incidence of monogenic nephrotic syndrome in the African American population because they are more severely affected. However, studies from multiple cohorts seem to suggest that although the prevalence of monogenic nephrotic syndrome in some populations may be as high as 30%, the prevalence in African American children is probably <5%.^12,24 The reason for this is unclear; one possible explanation may be that SRNS in African American children may be a predominantly polygenic disease.

Although there are multiple studies of hereditary nephrotic syndrome, there are few population-level studies that can explain the genetic basis of health disparity in the more common idiopathic and nonfamilial nephrotic syndrome. In a landmark study in 2010, the genetic basis for the high prevalence of FSGS variants in nephrotic syndrome in African Americans was established when disease risk alleles G1 and G2 in the gene encoding apolipoprotein 1 (APOL1) were shown to confer 10 times the odds of developing FSGS in a population of African descent.²⁵ APOL1 G1 and G2 confer protection against trypanosome infection but predispose individuals to kidney disease later in life. Since then, the G1 and G2 alleles have been associated with other chronic kidney diseases, such as HIV-associated nephropathy and sickle cell disease nephropathy, among others.^26–28 In a recent study of African-American children with glomerular disease in the Chronic Kidney Disease in Children (CKiD) Study and Nephrotic Syndrome Study Network (NEPTUNE) cohorts, Ng et al²⁹ reported that 46% of children in this cohort had APOL1 high-risk genotypes (G1G1, G1G2, and G2G2). We found a similar prevalence of high-risk APOL1 genotype in our cohort of African American patients with SRNS, suggesting that APOL1 is probably the major driver of severe glomerular disease in African American children.^29,30 However, it should be noted that only ~25% of African American children with a high-risk APOL1 genotype go on to develop chronic kidney disease, implying that there are disease modifiers that may protect or aggravate APOL1-associated disease.²⁷ Some of the candidate modifiers that have been reported include the gene encoding glutathione-S-transferase-μ1 (GSTM1) and, more recently, ubiquitin D (UBD).³¹

More recently, we focused on the identification of genetic risk factors for childhood-onset SSNS with the broad objective of identifying drivers of disparities in disease prevalence and clinical course. Using genome-wide exome chip analysis and the strategy of extreme phenotyping, for which sex- and race/ethnicity-matched adults are compared with children with SSNS, we identified variants in HLA-DQA1 as risk alleles for SSNS in South Asian children.³² To determine whether these variants are race specific, we genotyped cohorts of children of European descent and African American children for these variants. We showed that the HLA-DQA1 risk variants are also associated with SSNS in these children, suggesting that the locus is most likely a cosmopolitan risk allele and is unlikely to be the explanation for the disparity in incidence and prevalence of SSNS in different populations (Table 1). In a follow-up study, we and others showed that in African American children, APOL1 is not a risk factor for SSNS, and HLA-DQA1 is not a risk locus for SRNS (Table 2).³⁰ We therefore showed for the first time that the pattern of therapy response in nephrotic syndrome could be delineated by genotyping for these 2 risk loci.

Table 1.

HLA-DQA1 and Risk for Childhood Steroid-Sensitive Nephrotic Syndrome

	Allele Frequency: HLA-DQA1
Race	Cases	Controls	P
South Asian	0.67	0.49	1.2 × 10−6
White	0.82	0.46	1.4 × 10−17
African American	0.72	0.42	5.7 × 10−17

Data source: Adeyemo et al.³⁰

Table 2.

Association of HLA-DQA1 and APOL1 Loci With Different Subtypes of Nephrotic Syndrome in African American Children

	Allele Frequency			P
Gene Variant (SNP)	SSNS	SRNS	Controls	SSNS vs Controls	SRNS vs Controls
HLA-DQA1 (rs1129740)	0.72	0.45	0.42	5 × 1011	0.6
HLA-DQA1 (rs1071630)	0.72	0.45	0.39	5 × 1011	0.6
APOL1 G1 (rs73885319, rs60910145)	0.23	0.378	0.226	0.9	0.0004
APOL1 G2 (rs71785313)	0.12	0.18	0.13	0.6	0.16

Abbreviations: rs, reference single-nucleotide polymorphism; SNP, single-nucleotide polymorphism; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome.

Data source: Adeyemo et al.³⁰

Most of the risk loci that have been identified to date are in common variants (minor allele frequency > 3%), and most of the loci explain only a small fraction of the risk for nephrotic syndrome.³¹ The implication of this is that there likely exist other genetic variants, such as rare variants and copy number variations, that may directly influence disease risk and pattern of response to therapy. Further studies will require large sample sizes and concerted collaborative efforts among investigators around the world.

Conclusions

Advances in genomics and discoveries of genes mutated in hereditary nephrotic syndrome have provided strong evidence that nephrotic syndrome is a disease of the podocytes. Complex disease risk loci identified for FSGS, childhood SSNS, and other glomerular diseases have greatly improved our understanding of the genetic architecture of the disease and largely improved our understanding of disease mechanisms. However, there is still a need for investigations to continue along this line to identify risk loci that are acting in concert with environmental factors to explain disparities in disease incidence, severity, and pattern of response to therapy. Findings from such studies have the potential to lead to identification of population-specific novel biomarkers and promising therapeutic targets.