Risk Of Focal Segmental Glomerulosclerosis Research Articles

Has APOL1 kidney disease treatment been hiding in plain sight?

Two coding variants of APOL1 account for much of the excess risk of focal segmental glomerulosclerosis in people of recent West African ancestry. There is an unmet need of treatment for apolipoprotein L1 kidney disease. In this issue, Sula Karreci etal. reported that lisinopril reduced proteinuria and glomerulosclerosis in a mouse model of apolipoprotein L1-induced focal segmental glomerulosclerosis, in a genotype-specific manner. By contrast, hydralazine and dapagliflozin had no effect. This study highlights the potential therapeutic utility of angiotensin-converting enzyme inhibitor in apolipoprotein L1 kidney disease.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.

MeSsAGe risk score: tool for renal biopsy decision in steroid-dependent nephrotic syndrome.

A lack of consensus exists as to the timing of kidney biopsy in children with steroid-dependent nephrotic syndrome (SDNS) where minimal change disease (MCD) predominates. This study aimed at examining the applicability of a biomarker-assisted risk score model to select SDNS patients at high risk of focal segmental glomerulosclerosis (FSGS) for biopsy. Fifty-five patients with SDNS and biopsy-proven MCD (n = 40) or FSGS (n = 15) were studied. A risk score model was developed with variables consisting of age, sex, eGFR, suPAR levels and percentage of CD8+ memory T cells. Following multivariate regression analysis, total risk score was calculated as sum of the products of odds ratios and corresponding variables. Predictive cut-off point was determined using receiver operator characteristics (ROC) curve analysis. Plasma suPAR levels in FSGS patients were significantly higher, while percentage of CD45RO+CD8+CD3+ was significantly lower than in MCD patients and controls. ROC analysis suggests the risk score model with threshold score of 16.7 (AUC 0.84, 95% CI 0.72-0.96) was a good predictor of FSGS on biopsy. The 100% PPV cut-off was >24.0, while the 100% NPV was <13.3. A suPAR and CD8+ memory T cell percentage-based risk score model was developed to stratify SDNS patients for biopsy and for predicting FSGS.

An investigation ofAPOL1risk genotypes and preterm birth in African American population cohorts

Two genetic variants in apolipoprotein L1 (APOL1) are associated with increased risk of focal segmental glomerulosclerosis as well as other glomerular phenotypes. These risk variants are common in individuals of African ancestry but absent in other racial groups. Yet, the majority of individuals with two APOL1 risk alleles [high-risk (HR) genotype] do not have renal disease. It is critical to identify environmental and secondary genetic influences that, when combined with these alleles, lead to kidney disease. In a recent study of black children with glomerular disease enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) and Chronic Kidney Disease in Children Study (n = 104), we found that subjects with an HR genotype had a 4.6-fold increase in the odds of preterm birth as compared to those with a low risk (LR) genotype [odds ratio 4.6 (CI 1.4-15.5)]. There are known racial disparities in preterm birth, which itself is a known risk factor for chronic kidney disease and focal segmental glomerulosclerosis. Thus, we questioned whether an HR APOL1 genotype is associated with prematurity in the general African American population. We analyzed two publically available genetic datasets of preterm birth in African Americans, including 867 infants and 519 mothers from the Gene Environment Association Studies (GENEVA) study of preterm delivery and 960 mothers from the Boston Medical Center genome-wide association study of preterm birth. We performed multivariable analyses testing for association between HR APOL1 and birth outcomes. In both studies, there was no association between HR APOL1 in mothers and prematurity, gestational age or birthweight. Additionally, in the GENEVA study, we saw no association between infant HR APOL1 and prematurity, gestational age or birthweight. From these data, we conclude that the previously observed association between HR APOL1 and prematurity is specific to those with glomerular disease, suggesting prematurity may act as an additional risk factor in APOL1-associated renal disease.

Ethnic Differences in Childhood Nephrotic Syndrome.

Nephrotic syndrome is a common glomerular disease in children with significant variability in both incidence and steroid responsiveness among various ethnic groups. The average incidence of nephrotic syndrome is 2–16.9 per 100,000 children worldwide. Understanding the variability by ethnicity may point to potential factors leading to nephrotic syndrome, which remains elusive, and may highlight factors accounting for differences in medication response. The emerging role of genetic factors associated with steroid responsive and steroid-resistant forms of nephrotic syndrome within an ethnic group can provide insight into potential biological mechanisms leading to disease. For example, among African-Americans, the risk variants in APOL1 are associated with a more than 10-fold increase in risk of focal segmental glomerulosclerosis and high-risk carriers have a twofold greater risk of progression to end-stage renal disease. Ongoing collaborative studies should consider capturing data on self-reported ethnicity to understand differences in incidence and outcomes. In the future, the availability of whole-genome data will provide an excellent opportunity for new clinical and translational research in childhood nephrotic syndrome and lead to a better understanding of the disease.

APOL1nephropathy: from gene to mechanisms of kidney injury

The contribution of African ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein L1 (APOL1). The APOL1 variants appear at a high allele frequency in populations of West African ancestry as a result of apparent adaptive selection of the heterozygous state. Heterozygosity protects from infection with Trypanosoma brucei rhodesiense. This review will describe the role of the approaches in population genetics for the description of APOL1-associated nephropathies and draw inferences as to the biologic mechanisms from genetic epidemiology findings to date. Modifier loci can influence APOL1 risk for the development of kidney disease. 'Second hits', both viral and non-viral, may explain the discrepancy between the remarkably high odds ratios and the low lifetime risks of kidney disease in two allele carriers of APOL1 risk variants. Therapeutic strategies for APOL1-associated nephropathies will require the prevention and treatment of these 'second hits' and the development of drugs to protect the APOL1 downstream renal injury pathways.

MYH9 and APOL1 are both associated with sickle cell disease nephropathy

Renal failure occurs in 5-18% of sickle cell disease (SCD) patients and is associated with early mortality. At-risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The myosin, heavy chain 9, non-muscle (MYH9) and apolipoprotein L1 (APOL1) genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. We genotyped 26 single nucleotide polymorphisms (SNPs) in MYH9 and 2 SNPs in APOL1 (representing the G1 and G2 tags) in 521 unrelated adult (18-83 years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Seven SNPs in MYH9 and one in APOL1 remained significantly associated with proteinuria after multiple testing correction (P < 0·0025). An MYH9 risk haplotype (P = 0·001) and the APOL1 G1/G2 recessive model (P < 0·0001) were strongly associated with proteinuria, even when accounting for the other. Glomerular filtration rate was negatively correlated with proteinuria (P < 0·0001), and was significantly predicted by an interaction between MYH9 and APOL1 in age-adjusted analyses. Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk.

The association between angiotensin-converting enzyme insertion/deletion gene variant and risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis

The association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism with the risk of focal segmental glomerulosclerosis (FSGS) is still controversial. A meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and FSGS susceptibility. We performed a predefined literature search and selection of eligible relevant studies to collect data from electronic databases. In total, 12 articles were identified for the analysis of the association between ACE I/D gene polymorphism and FSGS risk. One report included an investigation in Arab and Jewish populations separately. Thus, there were seven reports in Asians, two in Caucasians, one in Africans, two in Arabs and one in Jews. In Asians, there was a markedly positive association between the D allele or DD genotype and FSGS susceptibility (p = 0.008; p = 0.002), and the II genotype may play a protective role against FSGS onset (p = 0.002). However, a link between ACE I/D gene polymorphism and FSGS risk was not found in Caucasians, Africans, Arabs or Jews (Caucasians: D: p = 0.11, DD: p = 0.19, II: p = 0.70; Africans: D: p = 0.40, DD: p = 0.49, II: p = 0.61; Arabs: D: p = 0.34, DD: p = 0.10, II: p = 0.42; Jews: D: p = 0.90, DD: p = 0.97, II: p = 0.83). The D allele or DD homozygosity may become a significant genetic molecular marker for the onset of FSGS in Asians, but not for Caucasians, Africans, Arabs or Jews.

Variation in APOL1 Gene May Contribute to High Rates of Kidney Disease in African Americans

1. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329:841–845. ### Study Hypothesis African Americans have much higher rates of kidney failure than those of European ancestry. Previous genetic studies found variation at or near the MYH9 gene to be associated with increased risk of focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD), but the causal mutations in MYH9 were not identified. The authors hypothesized that the kidney disease risk alleles might be located in a genomic region larger than previously thought, due to a strong signal of natural selection in the region containing the MYH9 and APOL1 genes.1 ### How Was the Hypothesis Tested? Sequence data from the 1000 Genomes Project was used to identify polymorphisms with large frequency differences between Africans and Europeans. These variants, together with some additional single-nucleotide polymorphisms of biological relevance, were genotyped using Sequenom technology. Initial association analyses were done comparing 205 African Americans with biopsy-proven …

Genetic Variation In MYH9 Is Associated with Sickle Cell Disease Nephropathy

AbstractAbstract 1648 Background:Renal failure occurs in 5–18% of sickle cell disease (SCD) patients and is a major risk factor for early mortality. However, there is no established method of identifying SCD patients that are at high risk of developing this outcome prior to the appearance of proteinuria, and its pathobiology is not well understood. The non-muscle myosin heavy chain ll-A (MYH9) gene, which encodes the heavy chain of myosin II-A in the podocyte cytoskeleton, has been identified as driving the high risk of focal segmental glomerulosclerosis (FSGS) and end-stage renal disease in African Americans. Methods:We genotyped 26 single nucleotide polymorphisms (SNPs) in the MYH9 gene in 521 unrelated adult (18 – 83 years) SCD patients who had been screened for proteinuria. Logistic regression was used to determine if the SNPs predicted risk for proteinuria among the patients. Results:Of 521 adult SCD patients studied, 140 had proteinuria, while 381 did not. On average, subjects with proteinuria were 6 years older than subjects without proteinuria (p<0.0001). The odds of having proteinuria increased by 1.04 (4.2%) for every one year increase in age, starting at age 18. We found association with proteinuria for 8 SNPs in MYH9, with nominal p values ranging from 0.025 to 0.0001. Two of these SNPs (rs5756129 and rs1005570) had been previously associated with FSGS in African-Americans without SCD (Kopp et al., 2008). Five SNPs remained significant after correcting for multiple testing (p < 0.003) using the method described by Li and Ji (2005), and a risk haplotype significantly associated with proteinuria (p=0.001) was identified. The frequency of proteinuria among individuals who were homozygous for the risk genotype ranged from 40–50% for each of the five SNPs remaining significant after adjusting for multiple testing, while the risk of proteinuria for individuals who did not have that genotype ranged from 20–30%. Glomerular filtration rate was negatively correlated with proteinuria (r = -0.25, p < 0.0001) but was not itself associated with MYH9 SNPs. Although we tested for association of proteinuria with the two most significant BMPR1B SNPs found by Nolan et al. (2007), neither were associated with proteinuria or GFR in age-adjusted analysis of our cohort, although we did observe nominal evidence for association of a different BMPR1B SNP with proteinuria in our data set (rs1434536, p=0.004, age adjusted). To further investigate a possible connection between BMPR1B and MYH9, we performed regression analyses including BMPR1B SNPs (rs1434536, rs2240036 and rs4145993) and the MYH9 haplotype in the models and controlled for age. In these analyses, the MYH9 risk haplotype remained a significant predictor of proteinuria and was only borderline associated with GFR. None of the BMPR1B SNPs were associated with proteinuria or GFR when the MYH9 haplotype was included in the model, suggesting that MYH9 is likely the more important contributor to these processes in our data set. Conclusion:Our data provide additional support for the role of MYH9 in renal dysfunction among African Americans. A specific haplotype appears to be associated with increased risk for proteinuria among patients with SCD. The association of MYH9 with renal dysfunction in SCD provides insight into the pathophysiology of this process and may lead to early identification of patients at risk and, ultimately, to new modes of therapeutic intervention. Disclosures:De Castro:GlycoMimetics: . Telen:GlycoMimetics: Consultancy, clinical trial sponsorship.

The May-Hegglin anomaly in a kidney transplant recipient.

We report a 37-year-old renal transplanted patient with thrombocytopaenia. He had May–Hegglin anomaly (MHA) inherited from his father, who died due to myocardial infarction subsequent to two renal transplantations. At the age of 15 years, proteinuria was found, but he was not biopsied. In 1982, he underwent splenectomy because of trauma. In 1989, when he was 17, renal function was found to be decreased. Five years later, he started haemodialysis and at 24 years he underwent live related kidney transplantation. Serum creatinine was always found stable around 1.9 mg/dl on cyclosporine, azathioprine and steroids. Automated blood count reported a number of platelets around 8000/μl with a mean volume of 20.3 fl (normal range 7.2– 11.1 fl). However, blood cell counters have a defined volume window for platelet counting and large macrothrombocytes are classified as red blood cells, meaning that platelet number is underestimated (Figure 1). The true value of platelets after count with the microscope was around 30 000/μl. He was completely asymptomatic, without any bleeding tendency. MHA is a rare autosomal dominant platelet disorder, characterized by macrothrombocytopaenia and granulocyte inclusion bodies. The mutation involves the MYH9 gene, localized in chromosome 22q, which encodes a heavy chain of non-muscle myosin IIA. MYH9-related hereditary macrothrombocytopaenia disorders include: MHA, Ebstein, Fechtner and Sebastian syndromes, which are characterized by nephritis, hearing loss and cataract [1]. In 1992, Nel et al. [2] reported two cases of MHA incidentally discovered in a patient and his brother during investigation for end-stage renal failure and workup for renal transplantation. Alhindawi and Al-Jbour [3] described an association between Epstein syndrome and chronic nephropathy. Recently, Singh et al. [4] suggested that MYH9 gene alterations are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans.

CKD in MYH9-Related Disorders

MYH9-related disorders are rare causes of chronic kidney disease (CKD) presenting as chronic glomerulonephritis and derive from mutations of the MYH9 gene, which encodes for the nonmuscle myosin heavy chain IIA. These disorders are autosomal dominant and include May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes. Diagnosis of these disorders is made first in early childhood because of the characteristic peripheral-blood smear findings of thrombocytopenia, giant platelets, and variably detected basophilic cytoplasmic inclusion bodies in leukocytes. CKD typically develops later in adulthood and may progress to end-stage renal disease. MYH9-related disorders may be associated with deafness and cataract; hence, Alport syndrome becomes important in the differential diagnosis. However, the autosomal dominance pattern of inheritance and characteristic peripheral-blood smear findings in the former help differentiate the two conditions. New evidence suggests that MYH9 gene alterations also are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans. The purpose of this review is to focus on the known, but rarely recognized association of MYH9-related disorders with CKD and highlight the recent discoveries related to the MYH9 gene that may explain the reason for a high CKD burden in African Americans.