Low prevalence of apolipoprotein L1 gene variants in Black South Africans with hypertension-attributed chronic kidney disease
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Variants in apolipoprotein L1 (APOL1) gene were shown to be associated with higher rates of nondiabetic kidney disease in black patients compared with white patients. Frequencies of these variants differ substantially in African populations, suggesting that their contribution to kidney disease might differ. We determined the frequency and association of (APOL1) risk alleles with markers of kidney disease in black South Africans with hypertension-attributed chronic kidney disease (CKD) and their first-degree relatives. Black patients with hypertension-attributed CKD with an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m2 were included, together with their first-degree relatives. G1 (rs60910145 and rs73885319) and G2: rs71785313 single nucleotide polymorphisms were genotyped by restriction fragment length polymorphism. Similar to previous association studies, we mainly tested recessive genetic models. The allele frequencies of both the G1 and G2 (APOL1) risk alleles were similar amongst all the groups. There was no difference in the two-risk-allele frequency in CKD patients (10%) compared to controls (8.6%), p = 0.790. Carriage of two (APOL1) risk alleles (vs. zero or one risk allele) was not a predictor of hypertension-attributed CKD (OR, 0.85; 95% CI, 0.25 - 2.83; p = 0.790). Patients with CKD and first-degree relatives with and without (APOL1) risk alleles had statistically indistinguishable blood pressures, creatinine and HDL-cholesterol levels. Apolipoprotein L1 risk variants are present in black South Africans with similar frequencies between CKD patients, first-degree relatives, and healthy controls. The lack of association of these variants with hypertension-attributed CKD in this population needs to be explored further in studies with larger sample sizes.
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Inducible nitric oxide synthase gene polymorphisms are associated with a risk of nephritis in Henoch-Schönlein purpura children.

Henoch-Schönlein purpura (HSP) is the most common form of systemic small-vessel vasculitis in children, and HSP nephritis (HSPN) is a major complication of HSP and is the primary cause of morbidity and mortality. Previous studies have suggested that inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of HSP. In this study, we performed a detailed analysis to investigate the potential association between iNOS polymorphisms and the risk of HSP and the tendency for children with HSP to develop HSPN in a Chinese Han population. A promoter pentanucleotide repeat (CCTTT)n and 10 functional single-nucleotide polymorphisms (SNPs) from 532 healthy controls and 513 children with HSP were genotyped using the MassARRAY system and GeneScan. The results suggested that the allelic and genotypic frequencies of the rs3729508 polymorphism were nominally associated with susceptibility to HSP. In addition, there was a significant difference in the allelic distribution of the (CCTTT)12 repeats and rs2297518 between the HSP children with and without nephritis; the HSP children with nephritis exhibited a significantly higher frequency of the (CCTTT)12 repeats and A allele of rs2297518 than the HSP children without nephritis (P FDR = 0.033, OR = 1.624, 95% CI = 1.177-2.241 and P FDR = 0.030, OR = 1.660, 95% CI = 1.187-2.321, respectively). CONCLUSION: Our results support that iNOS polymorphisms are associated with the risk of HSP and may strongly contribute to the genetic basis of individual differences in the progression to nephritis among children with HSP in the Chinese Han population. What is Known: • The etiology of HSP is unknown, but the genetic factors may play an important role in the pathogenesis of HSP. • iNOS could contribute to the development and clinical manifestations of HSP, and this has not been studied extensively so far. What is New: • Our results support that iNOS polymorphisms not only are associated with HSP risk but also strongly contribute to the genetic basis of individual differences in the progression of HSP to nephritis among Chinese Han children.

Trends in Disparity by Sex and Race/Ethnicity for the Leading Causes of Death in the United States-1999-2010.

CONTEXT: Temporal trends in disparities in the leading causes of death within and between US demographic subgroups indicate the need for and success of interventions to prevent premature death in vulnerable populations. Studies that report recent trends are limited and outdated. OBJECTIVE: To describe temporal trends in disparities in death rates by sex and race/ethnicity for the 10 leading causes of death in the United States during 1999-2010. DESIGN: We used underlying cause of death data and population estimates from the National Vital Statistics System to calculate age-adjusted death rates for the 10 leading causes of death during 1999-2010. We measured absolute and relative disparities by sex and race/ethnicity for each cause and year of death; we used weighted linear regression to test for significance of trends over time. RESULTS: Of the 10 leading causes of death, age-adjusted death rates by sex and race/ethnicity declined during 1999-2010 for 6 causes and increased for 4 causes. But sex and racial/ethnic disparities between groups persisted for each year and cause of death. In the US population, the decreasing trend during 1999-2010 was greatest for cerebrovascular disease (-36.5%) and the increasing trend was greatest for Alzheimer disease (52.4%). For each sex and year, the disparity in death rates between Asian/Pacific Islanders (API) and other groups varied significantly by cause of death. In 2010, the API-non-Hispanic black disparity was largest for heart disease, malignant neoplasms, cerebrovascular diseases, and nephritis; the API-American Indian/Alaska Native disparity was largest for unintentional injury, diabetes mellitus, influenza and pneumonia, and suicide; and the API-non-Hispanic white disparity was largest for chronic lower respiratory diseases and Alzheimer disease. CONCLUSIONS: Public health practitioners can use these findings to improve policies and practices and to evaluate progress in eliminating disparities and their social determinants in vulnerable populations.

Longitudinal changes in hematocrit in hypertensive chronic kidney disease: results from the African-American Study of Kidney Disease and Hypertension (AASK).

BACKGROUND: Anemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association. METHODS: We followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I(125) iothalamate) in place of eGFR. RESULTS: At baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m(2). For example, the absolute decline in hematocrit per 10 mL/min/1.73 m(2) decline in longitudinal eGFR was -3.7, -1.3 and -0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m(2), respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m(2)). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR-hematocrit association did not differ by body mass index, serum albumin or C-reactive protein. CONCLUSIONS: Men, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m(2)) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race.

BACKGROUND: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis. METHODS: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure. RESULTS: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased. CONCLUSIONS: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Rethinking hypertensive kidney disease: arterionephrosclerosis as a genetic, metabolic, and inflammatory disorder.

PURPOSE OF REVIEW: Hypertension is the attributed cause of approximately 30% of end-stage kidney disease cases in the United States, but there has been controversy as to whether benign hypertension is a cause of chronic kidney disease. RECENT FINDINGS: The histology of chronic kidney disease attributed to nonmalignant hypertension is arterionephrosclerosis, with pathology in the terminal branches of the interlobular arteries, together with global glomerulosclerosis. The identification of coding region variants in APOL1, encoding apolipoprotein L1, has opened a new perspective on this debate. These variants are restricted to populations of recent African descent and are strongly associated with clinically diagnosed arterionephrosclerosis, particularly when there is moderate-grade or high-grade proteinuria or progression to more advanced levels of kidney dysfunction. Nevertheless, not all African Americans with hypertension who progress to end-stage kidney disease have two APOL1 risk variants, and individuals of European and Asian descent also manifest arterionephrosclerosis. Further, we do not understand the mechanisms by which APOL1 initiates pathology in the renal microcirculation. SUMMARY: APOL1 nephropathy comprises a disease spectrum (perhaps with distinct endophenotypes), including focal segmental glomerulosclerosis, collapsing glomerulopathy, and arterionephrosclerosis. The terms hypertensive kidney disease and hypertensive nephrosclerosis have outlived their usefulness. It may be time to use the established, etiologically neutral term, arterionephrosclerosis, to consider whether this is a disease rather than a pathologic description, and to determine the causal role of various clinical correlates including aging, obesity, hyperlipidemia, smoking, chronic inflammation, and oxidative stress.

Hypertension-misattributed kidney disease in African Americans.

Lipkowitz et al. extend the African American Study of Kidney Disease and Hypertension to the level of genetic epidemiology, in a case-control study design. Analysis of genotypes at the APOL1 kidney disease risk region supports a paradigm shift in which genetic risk is proximate to both kidney disease and hypertension. The findings mandate urgency in clarifying mechanisms whereby APOL1 region risk variants interact with environmental triggers to cause progressive kidney disease accompanied by dangerous hypertension.

Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK).

Oxidative stress is acknowledged to play a role in kidney disease progression. Genetic variants that affect the capacity to handle oxidative stress may therefore influence the outcome of kidney disease. We examined whether genetic variants of the GSTM1 gene, a member of a superfamily of glutathione S-transferases, influence the course of kidney disease progression in participants of the African American Study of Kidney Disease (AASK) trial. Groups with and without the common GSTM1 null allele, GSTM1(0), differed significantly in the time to a glomerular filtration rate (GFR) event or dialysis (P = 0.04) and in the time to GFR event, dialysis, or death (P = 0.02). The hazard ratios (HR) for the time to a GFR event or dialysis in those with two or one null allele relative to those possessing none were 1.88 [95% confidence interval (CI), 1.07 to 3.30, P = 0.03] and 1.68 (95% CI, 1.00 to 2.84, P < 0.05), respectively. For the time to GFR event, dialysis, or death, the HR for two null alleles was 2.06 (95% CI, 1.20 to 3.55, P = 0.01) and for one null allele 1.70 (95% CI, 1.02 to 2.81, P = 0.04). We demonstrated that GSTM1 directly regulates intracellular levels of 4-hydroxynonenal (4-HNE) in vascular smooth muscle cells. Furthermore, we showed that renal 4-HNE levels and GSTM1 are both increased after reduction of renal mass (RRM) in the mouse. We conclude that GSTM1 is normally upregulated in chronic kidney disease (CKD) in a protective response to increased oxidative stress. A genetic variant that results in loss of GSTM1 activity may be deleterious in CKD.

Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans.

Despite intensive antihypertensive therapy there was a high incidence of renal end points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the nonmuscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers, were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dl during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.

The impact of race and ethnicity on disease severity in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) can result in comorbidities and high disease severity. The aim of this study was to evaluate the effects of age, sex, race, ethnicity, cost of hospitalization, length of stay, and payor source on SLE disease severity scores. DESIGN: Epidemiological study. SETTING: Hospital discharge data were obtained from the DFW Hospital Council (DFWHC), for 65,535 patients hospitalized in the North Texas Dallas-Fort Worth (DFW) Metropolitan Statistical Area (MSA) from 1999-2005 with at least one autoimmune disease. PATIENTS: Of the 65,535 autoimmune patients, 14,829 patients had SLE as a diagnosis. The sample was assessed for disease severity according to the SLE comorbidity Index. MAIN OUTCOME: Disease severity, SLE comorbidities. RESULTS: SLE patients were younger and more than five times more likely to have multiple autoimmune diseases. More than one third of Hispanic patients were on Medicaid or self-pay and more likely to have higher disease severity. Race (Caucasian), sex (female), and payor source (PPO/POS) predicted lower disease severity scores. SLE was predictive of eight of the fourteen SLE-CI diseases, with greatest effects observed for nephritis (OR = 3.30, P < .0001), chronic renal failure (OR = 3.36, P < .0001), pericarditis (OR = 3.2, P < .0001), and pleuritis (OR = 2.06, P < .0001). Non-Caucasian patients were more likely to have chronic renal failure, nephritis, congestive heart failure, pericarditis and pleuritis. CONCLUSIONS: The comorbidities that exist in SLE vary according to ethnicity. It is paramount for physicians to be cognizant of these disparities and make appropriate referrals.

ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai.

ITGAM was recently found to be associated with systemic lupus erythematosus (SLE) in populations of not only European ancestry, but also in Hispanic- and African-Americans, Mexicans and Colombians. The risk alleles in the gene, however, were found to be monomorphic in two Asian populations examined: Japanese and Korean. In this study, using a collection of 910 SLE patients and 2360 controls from Chinese living in Hong Kong, analyzed by both genome-wide association and direct sequencing, we confirmed the association of the same risk alleles in ITGAM with the disease. These findings were further replicated in the Thai population with 278 patients and 383 ethnicity- and geography-matched controls. Subphenotype stratification analyses showed significantly more involvement of the gene in patients with renal nephritis and neurological disorders. Although our results support a pivotal role by rs1143679 (R77H) in disease association, our data also suggests an additional contribution from rs1143683, another non-synonymous polymorphism in this gene (A858V). Therefore, despite the low-allele frequencies of the risk alleles of the gene in our two Asian populations, ITGAM was confirmed to be a risk factor related to disease susceptibility and probably severe manifestations of SLE.

Causes of end-stage renal failure in black patients starting renal replacement therapy.

In the United States, blacks are more frequently diagnosed than whites with end-stage renal failure (ESRF) from primary hypertension or diabetic nephropathy. We performed a validation retrospective case-note study of all blacks with ESRF who started renal replacement therapy (RRT) at three teaching hospitals in London, England, during 1991 to 1995 to investigate and validate the causes of primary renal disease using standard criteria. We identified 144 black patients with a mean age of 52.0 +/- 16.0 (SD) years; 59% were men and 32% had renal histological data. One hundred forty-four whites who were matched for age, sex, and onset of RRT (42% with renal histological data) underwent a similar validation exercise. Before the validation, the principal working diagnosis in the black patients had been diabetic nephropathy in 35% (89%, type 2; 11%, type 1); primary hypertension, 19%; glomerulonephritis (GN), 18%; and uncertain cause, 15%. After validation analysis, this changed to diabetes, 38% (16% biopsy proven); uncertain, 24%; GN, 20%; and primary hypertension, only 10% (28% biopsy proven). Among the uncertain cases (n = 34), 19 patients had hypertension, but this could not be established as the primary disease; 94% of all blacks had hypertension, accelerated in 21%. Among whites, only 3.5% had primary hypertension, and this proportion was not changed by the validation study. Type 2 diabetes is the most common single cause of ESRF in black patients in London, and although hypertension is more common and more severe in blacks, the proportion of renal failure attributed to primary hypertension is overestimated, and the diagnosis is often made using inadequate criteria.

Environmental factors predicting nephritis in systemic lupus erythematosus.

OBJECTIVES: To evaluate social class, ethnic origin, and various endocrine variables as potential risk factors in the development of nephritis in patients with systemic lupus erythematosus (SLE). METHODS: A cross-sectional survey was carried out of all outpatients with SLE attending the lupus Clinic of St Thomas's Hospital from March to October 1992 using retrospective survival data. The main outcome measure was the duration of SLE before the onset of nephritis. RESULTS: Two hundred and ninety six women and 11 men were studied; the male patients were excluded from the analysis. Univariate analysis showed an increased risk of nephritis in patients with SLE of West Indian origin with 54 v 19% with nephritis at five years, in patients of lower social class, in patients who did not drink alcohol, and in those with a history of fetal loss after the onset of lupus. No significant effect of the age of onset of SLE, use of oral contraceptives, normal pregnancy, or smoking was seen. Multivariate analysis showed that ethnic origin did not influence the risk of nephritis independently of social class. CONCLUSIONS: Factors associated with socioeconomic deprivation may increase disease severity in patients with SLE.