Rulan S. Parekh

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39–0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.

APOL1 risk variants, race, and progression of chronic kidney disease.

BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Blood Pressure in Children with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children Study

To characterize the distribution of blood pressure (BP), prevalence, and risk factors for hypertension in pediatric chronic kidney disease, we conducted a cross-sectional analysis of baseline BPs in 432 children (mean age 11 years; 60% male; mean glomerular filtration rate 44 mL/min per 1.73 m2) enrolled in the Chronic Kidney Disease in Children cohort study. BPs were obtained using an aneroid sphygmomanometer. Glomerular filtration rate was measured by iohexol disappearance. Elevated BP was defined as BP ≥90th percentile for age, gender, and height. Hypertension was defined as BP ≥95th percentile or as self-reported hypertension plus current treatment with antihypertensive medications. For systolic BP, 14% were hypertensive and 11% were prehypertensive (BP 90th to 95th percentile); 68% of subjects with elevated systolic BP were taking antihypertensive medications. For diastolic BP, 14% were hypertensive and 9% were prehypertensive; 53% of subjects with elevated diastolic BP were taking antihypertensive medications. Fifty-four percent of subjects had either systolic or diastolic BP ≥95th percentile or a history of hypertension plus current antihypertensive use. Characteristics associated with elevated BP included black race, shorter duration of chronic kidney disease, absence of antihypertensive medication use, and elevated serum potassium. Among subjects receiving antihypertensive treatment, uncontrolled BP was associated with male sex, shorter chronic kidney disease duration, and absence of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. Thirty-seven percent of children with chronic kidney disease had either elevated systolic or diastolic BP, and 39% of these were not receiving antihypertensives, indicating that hypertension in pediatric chronic kidney disease may be frequently under- or even untreated. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may improve BP control in these patients.

Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study.

BACKGROUND Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients, but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study is to determine the association of urine output with mortality, quality of life (QOL), and inflammation in incident hemodialysis patients. STUDY DESIGN Nationally representative prospective cohort study. SETTING & PARTICIPANTS 734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998; follow-up until December 2004. PREDICTOR Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained using questionnaires at baseline and year 1. OUTCOMES & MEASUREMENTS Primary outcomes were all-cause and cardiovascular mortality, analyzed using Cox regression adjusted for demographic, clinical, and treatment characteristics. Secondary outcomes were QOL, inflammation (C-reactive protein and interleukin 6 levels), and erythropoietin (EPO) requirements. RESULTS 617 of 734 (84%) participants reported urine output at baseline, and 163 of 579 (28%), at year 1. Baseline urine output was not associated with survival. Urine output at year 1, indicating preserved RKF, was independently associated with lower all-cause mortality (HR, 0.70; 95% CI, 0.52-0.93; P = 0.02) and a trend toward lower cardiovascular mortality (HR, 0.69; 95% CI, 0.45-1.05; P = 0.09). Participants with urine output at baseline reported better QOL and had lower C-reactive protein (P = 0.02) and interleukin 6 (P = 0.03) levels. Importantly, EPO dose was 12,000 U/wk lower in those with urine output at year 1 compared with those without (P = 0.001). LIMITATIONS Urine volume was measured in only a subset of patients (42%), but agreed with self-report (P < 0.001). CONCLUSIONS RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation, and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. The development of methods to assess and preserve RKF is important and may improve dialysis care.

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

Despite intensive anti-hypertensive 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 non-muscle 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 association of sudden cardiac death with inflammation and other traditional risk factors

Despite the frequency of cardiovascular death in dialysis patients, few studies have prospectively measured sudden cardiac death in these individuals. Here, we sought to determine the frequency of sudden cardiac death and its association with inflammation and other risk factors among the CHOICE (Choices for Healthy Outcomes In Caring for ESRD) cohort of 1,041 incident dialysis patients. Sudden cardiac death was defined as that occurring outside of the hospital with an underlying cardiac cause from death certificate data. Over a median 2.5 years of follow-up, 22% of all mortality in this cohort was due to sudden cardiac death. Using Cox proportional hazards, we found that the highest tertiles of high-sensitivity C-reactive protein and of IL-6 were each associated with twice the risk of sudden cardiac death compared to their lowest tertiles when adjusted for demographics, comorbidities and laboratory factors. A decrement in serum albumin was associated with a 1.35 times increased risk for sudden cardiac death in the highest compared to the lowest tertile. These findings were robust and consistent when accounting for competing risks of death from other causes. Hence, we found that sudden cardiac death is common among patients with end stage renal disease and that inflammation and malnutrition significantly increased its occurrence independent of traditional cardiovascular risk factors.

Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: The Family Investigation of Nephropathy and Diabetes (FIND)

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.

Cerebrovascular disease incidence, characteristics, and outcomes in patients initiating dialysis: the choices for healthy outcomes in caring for ESRD (CHOICE) study.

BACKGROUND Stroke is the third most common cause of cardiovascular disease death in patients on dialysis therapy; however, characteristics of cerebrovascular disease, including clinical subtypes and subsequent consequences, have not been well described. STUDY DESIGN Prospective national cohort study, the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. SETTINGS & PARTICIPANTS 1,041 incident dialysis patients treated in 81 clinics enrolled from October 1995 to July 1998, followed up until December 31, 2004. PREDICTOR Time from dialysis therapy initiation. OUTCOMES & MEASUREMENTS Cerebrovascular disease events were defined as nonfatal (hospitalized stroke and carotid endarterectomy) and fatal (stroke death) events after dialysis therapy initiation. Stroke subtypes were classified by using standardized criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system. The incidence of cerebrovascular event subtypes was analyzed by using time-to-event analyses accounting for competing risk of death. Clinical outcomes after stroke were abstracted from medical records. RESULTS 165 participants experienced a cerebrovascular event with an overall incidence of 4.9 events/100 person-years. Ischemic stroke was the most common (76% of all 200 events), with cardioembolism subtype accounting for 28% of the 95 abstracted ischemic events. Median time from onset of symptoms to first stroke evaluation was 8.5 hours (25th and 75th percentiles, 1 and 42), with only 56% of patients successfully escaping death, nursing home, or skilled nursing facility. LIMITATIONS Relatively small sample size limits power to determine risk factors. CONCLUSIONS Cerebrovascular disease is common in dialysis patients, is identified late, and carries a significant risk of morbidity and mortality. Stroke etiologic subtypes on dialysis therapy are multifactorial, suggesting risk factors may change the longer one has end-stage renal disease. Additional studies are needed to address the poor prognosis through prevention, early identification, and treatment.

APOL1 Variants Associate with Increased Risk of CKD among African Americans

Although case-control studies suggest that African Americans with common coding variants in the APOL1 gene are 5-29 times more likely than those individuals without such variants to have focal segmental glomerulosclerosis, HIV-associated nephropathy, or ESRD, prospective studies have not yet evaluated the impact of these variants on CKD in a community-based sample of African Americans. Here, we studied whether the APOL1 G1 and G2 risk alleles associate with the development of CKD and progression to ESRD by analyzing data from 3067 African Americans in the Atherosclerosis Risk in Communities Study who did not have CKD at baseline. Carrying two risk alleles associated with a 1.49-fold increased risk of CKD (95% CI=1.02 to 2.17) and a 1.88-fold increased risk of ESRD (95% CI=1.20 to 2.93) compared with zero or one risk allele; associations persisted after adjusting for European ancestry. Among participants who developed CKD, those participants with two risk alleles were more likely to progress to ESRD than their counterparts with zero or one risk allele (HR=2.22, 95% CI=1.01 to 4.84). In conclusion, APOL1 risk variants are risk factors for the development of CKD and progression from CKD to ESRD among African Americans in the general population.

Changes in Serum Potassium Mediate Thiazide-Induced Diabetes

Thiazides, recommended as first-line antihypertensive therapy, are associated with an increased risk of diabetes. Thiazides also lower serum potassium. To determine whether thiazide-induced diabetes is mediated by changes in potassium, we analyzed data from 3790 nondiabetic participants in the Systolic Hypertension in Elderly Program, a randomized clinical trial of isolated systolic hypertension in individuals aged ≥60 years treated with chlorthalidone or placebo. Incident diabetes was defined by self-report, antidiabetic medication use, fasting glucose ≥126 mg/dL, or random glucose ≥200 mg/dL. The mediating variable was change in serum potassium during year 1. Of the 459 incident cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the unadjusted incidence rates of diabetes per 100 person-years were 6.1 and 3.0 in the chlorthalidone and placebo groups, respectively. In year 1, the adjusted diabetes risk (hazard ratio) with chlorthalidone was 2.07 (95% CI: 1.51 to 2.83; P<0.001). After adjustment for change in serum potassium, the risk was significantly reduced (hazard ratio: 1.54; 95% CI: 1.09 to 2.17; P=0.01); the extent of risk attenuation (41%; 95% CI: 34% to 49%) was consistent with a mediating effect. Each 0.5-mEq/L decrease in serum potassium was independently associated with a 45% higher adjusted diabetes risk (95% CI: 24% to 70%; P<0.001). After year 1, chlorthalidone use was not associated with increased diabetes risk. In conclusion, thiazide-induced diabetes occurs early after initiating treatment and appears to be mediated by changes in serum potassium. Potassium supplementation might prevent thiazide-induced diabetes. This hypothesis can and should be tested in a randomized trial.