Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, is independently associated with proteinuria in HIV infection in a cross-sectional study of HIV-infected women in the Women’s Interagency HIV Study. We estimated the percent difference in urine protein excretion and odds of proteinuria (200 mg/g and higher) associated with two versus one or no APOL1 risk allele using linear and logistic regression, respectively. Of 1285 women successfully genotyped, 379 carried one and 80 carried two risk alleles. Proteinuria was present in 124 women; 78 of whom had proteinuria confirmed on a second sample. In women without prior AIDS, two risk alleles were independently associated with a 69% higher urine protein excretion (95% CI: 36%, 108%) and 5-fold higher odds of proteinuria (95% CI: 2.45, 10.37) versus one or no risk allele. No association was found in women with prior AIDS. Analyses in which women with impaired kidney function were excluded and proteinuria was confirmed by a second urine sample yielded similar estimates. Thus, APOL1 risk alleles are associated with significant proteinuria in HIV-infected persons without prior clinical AIDS, independent of clinical factors traditionally associated with proteinuria. Trials are needed to determine whether APOL1 genotyping identifies individuals who could benefit from earlier intervention to prevent overt renal disease.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
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.
Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality.
We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index.
Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043).
In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.
All-cause Mortality; Cardiovascular Mortality; Dialysis Outcomes; Indoxyl Sulfate; P-cresol Sulfate; Uremic Solutes
African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans.
Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
Setting & Participants
Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls.
Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes.
APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1.
The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001).
Non-pooled GWAS have not been performed in AA nondiabetic nephropathy.
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.
African American; APOL1; CFH; end-stage renal disease; FIND; FSGS; hypertension
Nephrotic syndrome is one of the most commonly diagnosed kidney diseases in childhood and its progressive forms can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). There have been few longitudinal studies among a multi-ethnic cohort to determine potential risk factors influencing disease susceptibility, treatment response, and progression of nephrotic syndrome. Temporal relationships cannot be studied through cross-sectional study design. Understanding the interaction between various factors is critical to developing new strategies for treating children with kidney disease. We present the rationale and the study design of a longitudinal cohort study of children with nephrotic syndrome, the Insight into Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT) study. The specific aims are to determine: 1) socio-demographic, environmental, and genetic factors that influence disease susceptibility; 2) rates of steroid treatment resistance and steroid treatment dependence, and identify factors that may modify treatment response; 3) clinical and genetic factors that influence disease susceptibility and progression to CKD and ESRD; and 4) the interaction between the course of illness and socio-demographic, environmental, and clinical risk factors.
INSIGHT is a disease-based observational longitudinal cohort study of children with nephrotic syndrome. At baseline, participants complete questionnaires and provide biological specimen samples (blood, urine, and toenail clippings). Follow-up questionnaires and repeat biological specimen collections are performed annually for up to five years.
The proposed cohort will provide the structure to test various risk factors predicting or influencing disease susceptibility, treatment response, and progression to CKD among children with nephrotic syndrome.
ClinicalTrials.gov Identifier NCT01605266.
Children; Nephrotic syndrome; Cohort; Chronic kidney disease; FSGS; Minimal change disease; Study protocol
Increased acid excretion may promote renal injury. To evaluate this in African Americans with hypertensive nephrosclerosis, we studied the association between the net endogenous acid production and progression of kidney disease in 632 patients in the AASK trial. Protein and potassium intakes were estimated from 24-hour urea nitrogen and potassium excretion, and used to estimate net endogenous acid production, averaged over 2 years, approximating routine intake. The link between net endogenous acid production and the I125iothalamate glomerular filtration rate (iGFR) and time to end stage renal disease or doubling of serum creatinine was analyzed using mixed models and Cox proportional hazards regressions. The trend in higher net endogenous acid production was significantly associated with a faster decline in iGFR over a median of 3.2 years. After adjustment for age, body mass index, baseline iGFR, urine protein to creatinine ratio and randomized treatment group, the trend in higher net endogenous acid production remained significantly associated with a faster decline in iGFR at a rate 1.01 mL/min/1.73 m2 per year faster in the highest to the lowest quartile. However, in time to event analyses over a median of 7.7 years, the adjusted hazard ratio (1.10) for composite renal events per 25 mEq/day higher net endogenous acid production was not significant. Hence, our findings implicate endogenous acid production as a potential modifiable risk factor for progressive kidney disease.
Cystatin C has been proposed as an alternative marker of kidney function among HIV-infected persons in whom serum creatinine is affected by extra-renal factors.
In this cross-sectional study, we compared estimated glomerular filtration rates (eGFR) using serum creatinine versus cystatin C between 150 HIV-uninfected and 783 HIV-infected men. We evaluated the prevalence of chronic kidney disease (CKD; eGFR<60 mL/min/1.73 m2) and examined the influence of extra-renal factors on GFR-estimates among HIV-infected men.
Estimated GFRSCR was similar by HIV serostatus, but eGFRCYSC was lower in HIV-infected men. A higher proportion of HIV-infected men were classified as having CKD when using eGFRCYSC versus eGFRSCR (7% vs. 5%, P<0.01). In HIV-infected individuals without CKD, eGFRSCR was higher than eGFRCYSC while it was lower than eGFRCYSC in persons with CKD. In HIV-infected men, older age, proteinuria, and prior clinical AIDS were inversely associated with both GFR-estimates. Higher serum albumin levels and ACE-inhibitor/ARB use were associated with lower eGFRSCR. HIV viral load, hepatitis C co-infection, and serum alkaline phosphatase were inversely associated with eGFRCYSC.
Among HIV-uninfected and HIV-infected men of similar social risk behaviors, GFR estimates differed by biomarker and kidney function level. Estimated GFRCYSC classified a larger proportion of HIV-infected men with CKD compared to eGFRSCR. Differences between these GFR-estimating methods may be due to the effects of extra-renal factors on serum creatinine and cystatin C. Until GFR-estimating equations are validated among HIV-infected individuals, current GFR estimates based on these biomarkers should be interpreted with care in this patient population.
HIV; kidney disease; serum creatinine; cystatin C; glomerular filtration rate; Multicenter AIDS Cohort Study
Polymorphisms in the MYH9 and adjacent APOL1 gene region demonstrate a strong association with non-diabetic kidney disease in African-Americans. However, it is not known to what extent these polymorphisms are present in other ethnic groups. To examine the association of genetic polymorphisms in this region with chronic kidney disease (CKD; estimated glomerular filtration rate <60 ml/min/1.73 m2) in individuals of European ancestry, we examined rs4821480, an MYH9 single-nucleotide polymorphism (SNP) recently identified as associated with kidney disease in African-Americans, in 13 133 participants from the Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities (ARIC) Study. In addition, we further interrogated the MYH9/APOL1 gene region using 282 SNPs for association with CKD using age-, sex- and center-adjusted models and performed a meta-analysis of the results from both studies. Because of prior data linking rs4821480 and kidney disease, we used a P-value of <0.05 to test the association with CKD. In the meta-analysis, rs4821480 (minor allele frequency 4.45 and 3.96% in FHS and ARIC, respectively) was associated with higher CKD prevalence in participants free of diabetes (odds ratio 1.44; 95% confidence interval 1.15–1.80; P = 0.001). No other SNPs achieved significance after adjusting for multiple testing. Results utilizing directly genotyped data confirmed the results of the primary analysis. Recently identified APOL1 risk variants were also directly genotyped, but did not account for the observed MYH9 signal. These data suggest that the MYH9 polymorphism rs4821480 is associated with an increased risk of non-diabetic CKD in individuals of European ancestry.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
P-selectin is released by activated platelets and endothelium contributing to inflammation and thrombosis. We evaluated the association between soluble P-selectin and atherosclerotic cardiovascular disease (ASCVD) in dialysis patients.
We measured soluble P-selectin in serum from 824 incident dialysis patients. Using Cox proportional hazards models, we modeled the association of P-selectin levels with ASCVD events, cardiovascular mortality and sudden cardiac death.
After adjustment for demographics, comorbidity and traditional cardiovascular risk factors, higher P-selectin levels were associated with increased risk of ASCVD and cardiovascular mortality among males (p = 0.02 and p = 0.01, respectively), but not females (p = 0.52 and p = 0.31, respectively; p interaction = 0.003), over a median of 38.2 months. Higher P-selectin was associated with a greater risk of sudden cardiac death among males (p = 0.05). The associations between increasing P-selectin and cardiovascular mortality as well as sudden cardiac death in males persisted after adjustment for C-reactive protein, interleukin-6, serum albumin and platelet count (p = 0.01 and p = 0.03, respectively). The risk for sudden cardiac death was more than 3 times greater for males in the highest tertile of soluble P-selectin compared with the lowest tertile after adjustment (HR: 3.19; 95% CI: 1.18 – 8.62; p = 0.02).
P-selectin is associated with ASCVD, cardiovascular mortality and sudden cardiac death among male dialysis patients.
Cardiovascular disease; Dialysis; End-stage renal disease; Inflammation; Sudden cardiac death; P-selectin
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
Genome-wide association studies linked single-nucleotide polymorphisms (SNPs) at the MYH9 locus to chronic kidney disease among African-Americans, particularly glomerular diseases such as HIV nephropathy and idiopathic focal and segmental glomerulosclerosis (FSGS). However, these MYH9 SNPs are intronic, and despite extensive sequencing, a causal variant remains elusive. To investigate the role of MYH9 in kidney disease, we selectively deleted Myh9 from mouse podocytes and found that mutant C57BL/6 mice did not develop renal insufficiency or proteinuria compared to control littermates, even when the mice were aged for 9 months. To explain the surprisingly normal phenotype, we considered genetic redundancy with the paralog Myh10 in podocytes, but we found that Myh10 was not expressed in podocytes in Myh9-deficient or control mice. We tested whether Myh9 podocyte deletion predisposed mice to glomerulopathy in response to injury by doxorubicin hydrochloride (Adriamycin), and we found that Myh9 podocyte-deleted mice developed proteinuria and glomerulosclerosis, while control mice were resistant. In summary, Myh9 podocyte deletion in C57BL/6 mice results in susceptibility to experimental doxorubicin hydrochloride glomerulopathy. We review evidence that MYH9 dysfunction in humans results in similar susceptibility and place our data, the first examination of Myh9 kidney disease in experimental animals, in the context of recent findings in human kidney disease, including the role of APOL1.
Background. Anaemia worsens as kidney function declines. Both conditions are associated with increased mortality. Serum cystatin C is purportedly a more sensitive marker of kidney disease and a better predictor of mortality than serum creatinine. However, studies suggest that extrarenal factors also influence cystatin C levels.
Methods. We determined whether estimates of glomerular filtration rate [estimated glomerular filtration rate (eGFR)] based on serum cystatin C alone or in combination with serum creatinine were superior to those based on serum creatinine in recognizing impaired kidney function in the setting of anaemia in a sub-sample of the Third National Health and Nutrition Examination Survey of the USA consisting of 6734 participants, 20 years or older.
Results. The prevalence of moderate to severe kidney disease (eGFR 15–59 mL/min/1.73 m2) among anaemic persons was 15–16% when based on serum creatinine alone (eGFRSCR) or combined with cystatin C (eGFRSCR + CYSC); this estimate increased to nearly 25% when kidney function was estimated by cystatin C (eGFRCYSC). The adjusted odds ratios of kidney disease in anaemic versus non-anaemic persons were slightly higher with eGFRCYSC than eGFRSCR and eGFRSCR + CYSC in younger adults [odds ratio (OR) = 5.22, 95% confidence interval (CI): 2.23, 12.17], women (OR = 5.34, 95% CI: 2.36, 12.06) and those with elevated C-reactive protein (CRP) (OR = 7.36, 95% CI: 1.98–27.36).
Conclusions. Impaired kidney function was common in individuals with anaemia. Among anaemic individuals, the prevalence estimate for kidney disease was notably higher when kidney function was estimated by cystatin C alone compared with the estimations by serum creatinine alone or in combination with serum cystatin C. eGFRCYSC may be particularly helpful in identifying kidney disease in the setting of anaemia among younger persons, women and those with elevated CRP. Regardless of which renal biomarker is used, our study suggests that an evaluation for underlying kidney disease should be considered in the standard workup of anaemia.
anaemia; chronic kidney failure; creatinine; cystatin C; glomerular filtration rate
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 was to determine the association of urine output with mortality, quality of life (QOL) and inflammation in incident hemodialysis patients.
Nationally representative prospective cohort study
Setting & Participants
734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998, follow-up until December 2004.
Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained by questionnaires at baseline and year 1.
Outcomes & Measurements
Primary outcomes were all-cause and cardiovascular (CVD) mortality, analyzed using Cox regression adjusted for demographic, clinical and treatment characteristics. Secondary outcomes were QOL, inflammation (CRP and interleukin-6 [IL-6] levels) and erythropoietin (EPO) requirements.
617/734 (84%) participants reported urine output at baseline and 163/579 (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 (Hazard Ratio [HR], 0.70; 95% Confidence Interval [CI], 0.52-0.93; p=0.02) and a trend towards lower CVD 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 CRP (p=0.02) and IL-6 (p=0.03) levels. Importantly, EPO dose was 12,000 units/week lower in those with urine output at year 1 compared with those without (p=0.001).
Urine volume was measured in only a subset of patients (42%) but was in agreement with self-report (p<0.001).
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. Development of methods to assess and preserve RKF is important and may improve dialysis care.
End-stage Renal Disease; Hemodialysis; Residual Kidney Function; Mortality; Quality of Life; Inflammation
To characterize the distribution of blood pressure (BP), prevalence and risk factors for hypertension in pediatric chronic kidney disease (CKD), we conducted a cross-sectional analysis of baseline BP's in 432 children (mean age 11y; 60% male; mean glomerular filtration rate [GFR] 44 ml/min/1.73m2) enrolled in the Chronic Kidney Disease in Children cohort study. BP's were obtained using an aneroid sphygmomanometer. GFR 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 pre-hypertensive (BP 90-95th percentile); 68% of subjects with elevated SBP were taking antihypertensive medications. For diastolic BP, 14% were hypertensive, and 9% were pre-hypertensive; 53% of subjects with elevated DBP were taking antihypertensive medications. 54% 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 CKD, absence of antihypertensive medication use, and elevated serum potassium. Among subjects receiving antihypertensive treatment, uncontrolled BP was associated with male sex, shorter CKD duration and absence of ACE inhibitor or ARB use.
37% of children with CKD had either elevated systolic or diastolic BP, and 39% of these were not receiving antihypertensives, indicating that hypertension in pediatric CKD may be frequently under- or even un-treated. Treatment with ACE inhibitors or ARB's may improve BP control in these patients.
kidney disease; children; adolescents; hypertension; blood pressure; ACE inhibitors
Recent breakthroughs in genomics have led to a critical reappraisal of factors once thought to initiate common complex forms of kidney disease. The tenet that diabetes mellitus and hypertension routinely initiate kidney disease whenever blood glucose concentrations or systemic blood pressures reach critical levels for prolonged periods is falling from favor, although it remains important to control hypertension and hyperglycemia to slow nephropathy progression and prevent cardiovascular disease. Many patients with systemic diseases that may potentially involve their kidneys never develop nephropathy. In addition, severe forms of several common kidney diseases cluster tightly in families. This manuscript discusses the existence of differential nephropathy susceptibility based on an individual's genetic make-up, in the context of environmental exposures. Novel genetic analysis methods and recently identified major kidney disease susceptibility genes are discussed, including novel perspectives for categorizing complex forms of nephropathy based on the expanding spectrum of MYH9-associated disease. Genetic screening, gene-environment and gene-gene interactions are also addressed.
African American; chronic kidney disease; focal segmental glomerulosclerosis; hypertension; genetics; MYH9
Previous studies have shown that, in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations.
Phenotypic and genotypic data were obtained from African American (AA; total number of individuals (N)=1004), American Indian (AI; N=883), European American (EA; N=537), and Mexican American (MA; N=1634) individuals from the Family Investigation of Nephropathy and Diabetes. Nonparametric linkage analysis, using an average of 4,404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM.
Statistically significant evidence for linkage was observed on chromosomes 4q21.1 (LOD=3.13; genome-wide p=0.04) in AA. In addition, a total of eleven regions showed suggestive evidence for linkage (estimated at LOD>1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD=2.02) and 22q12.3 (LOD=2.38) in AA, 2p11.1 (LOD=2.23) in AI, 6p12.3 (LOD=2.77) in EA, and 13q21.1 (LOD=2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD>1.71 have been identified in previously published studies.
The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA, 6p in EA, 2p in AI, and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
FIND; Type 2 Diabetes; linkage analysis; ethnicity
Stroke is the third most common cause of cardiovascular disease death in patients on dialysis; however, characteristics of cerebrovascular disease, including clinical subtypes and subsequent consequences, have not been well described.
Prospective national cohort study, the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study.
Settings & Participants
1,041 incident dialysis patients treated in 81 clinics, enrolled from 10/95–7/98, followed until 12/31/2004.
Time from dialysis initiation.
Outcomes & Measurements
Cerebrovascular disease events were defined as non-fatal (hospitalized stroke, carotid endarterectomy) and fatal (stroke death) events after dialysis initiation. Stroke subtypes were classified using standardized criteria from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) system. Incidence of cerebrovascular event subtypes were analyzed using time-to-event analyses accounting for competing risk of death. Clinical outcomes after stroke were abstracted from medical records.
A total of 165 participants experienced a cerebrovascular event with an overall incidence of 4.9 per 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. The median time from onset of symptoms to first stroke evaluation was 8.5 hours (25th and 75th percentiles 1, 42 hours), with only 56% of patients successfully escaping death, nursing home, or a skilled nursing facility.
Relatively small sample size limits power to determine risk factors.
Cerebrovascular disease is common in dialysis patients, is identified late, and carries a significant risk of morbidity and mortality. Stroke etiologic subtypes on dialysis are multifactorial, suggesting risk factors may change the longer one has ESRD. Further studies are needed to address the poor prognosis through prevention, early identification, and treatment.
Cerebrovascular disease; Stroke; Dialysis; Prognosis; Epidemiology
Deaths of participants and losses to follow-up pose challenges for defining outcomes in epidemiologic studies. The authors compared several definitions of incident chronic kidney disease (CKD) in terms of incidence, agreement, and risk factor associations. They used data from 14,873 participants in the community-based, multicenter, biracial Atherosclerosis Risk in Communities Study (1987–1999). The estimated glomerular filtration rate (eGFR) was based on serum creatinine at baseline and the 3- and 9-year follow-up visits. Hospitalizations were ascertained continuously. The authors compared 4 definitions of incident CKD: 1) low eGFR (<60 mL/minute/1.73 m2); 2) low and declining (≥25%) eGFR; 3) an increase in serum creatinine (≥0.4 mg/dL) at 3- or 9-year follow-ups; and 4) CKD-related hospitalization or death. From these definitions, they identified 1,086, 677, 457, and 163 cases, respectively. There was relatively good agreement among definitions 1–3, but definition 4 identified mostly different cases. Risk factor associations were consistent across definitions for hypertension and lipids. Diabetes showed weaker associations with definition 1 (incidence rate ratio = 1.5, 95% confidence interval: 1.2, 1.7) than with definition 4 (incidence rate ratio = 6.3, confidence interval: 4.4, 8.9). Associations with gender differed in direction and magnitude across definitions. Case definition can impact relative risk estimates for CKD risk factors.
cohort studies; diagnostic techniques and procedures; incidence; kidney diseases
Clinical practice guidelines were established to improve the diagnosis and management of chronic kidney disease (CKD), but the extent, determinants, and cost implications of guideline adherence and variation in adherence have not been evaluated.
Settings & Participants
Nationally representative sample of 301 U.S. primary care physicians and nephrologists
Provider and patient characteristics
Outcomes & Measurements
Guideline adherence was assessed as present if physicians recommended at least 5 of 6 clinical tests prescribed by the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (KDOQI) guidelines for a hypothetical patient with newly identified CKD. We also assessed patterns and cost of additional non-recommended tests for the initial clinical evaluation of CKD.
Most of the 86 family medicine, 89 internal medicine, and 126 nephrology physicians practiced greater than 10 years (54%), were in non-academic practices (76%), spent greater than 80% of their time performing clinical duties (78%), and correctly estimated kidney function (73%). Overall, 35% of participants were guideline adherent. Compared to nephrologists, internal medicine and family physicians had lower odds of adherence for all recommended testing (Odds Ratio (OR) [95% CI]:0.6[0.3–1.1] and 0.3[0.1–0.6], respectively). Participants practicing greater than 10 years had lower odds of ordering all recommended testing compared to participants practicing less than 10 years (OR[95% CI]: 0.5[0.3–0.9]). Eighty-five percent of participants recommended additional tests, which resulted in a 23% increased total per patient cost of the clinical evaluation.
Recommendations for a hypothetical case scenario may differ from that of actual patients.
Adherence to the recommended clinical testing for the diagnosis and management of CKD was poor and additional testing was associated with substantially increased cost of the clinical evaluation. Improved clarity, dissemination, and uptake of existing guidelines are needed to improve quality and decrease costs of care for patients with CKD.
chronic kidney disease; primary care providers; guidelines; KDOQI; cost
Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase–signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease study.
Prospective cohort study.
Setting & Participants
764 White (n=518) and Black (n=246) participants from 79 dialysis centers.
SNPs in JAK3, STAT4, and STAT6 selectedusing a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent.
Outcomes and Measurements
Cox proportional hazards models were used to estimate unadjusted and multivariable adjusted hazard ratios (HR) for incident cardiovascular disease events after dialysis initiation associated with each race-specific SNP.
Two European tag SNPs (rs3212780 and rs3213409) were associated with new cardiovascular disease events in White patients in JAK3, with unadjusted HR 1.92 (p<0.001) and 1.82 (p=0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in White patients with unadjusted HR 2.09 (p<0.001) and in Black patients with HR 2.07 (p=0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis.
This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary.
Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.
dialysis; cardiovascular diseases; inflammation; genes
Thiazides, recommended as first-line anti-hypertensive therapy, are associated with an increased risk of diabetes. Thiazides also lower serum potassium. To determine if thiazide-induced diabetes is mediated by changes in potassium, we analyzed data from 3,790 non-diabetic participants in the Systolic Hypertension in Elderly Program (SHEP), 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. 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 [HR]) with chlorthalidone was 2.07 (95% Confidence Interval [CI], 1.51–2.83; p<0.001). After adjustment for change in serum potassium, the risk was significantly reduced (HR, 1.54, 95% CI, 1.09–2.17; p=0.01); the extent of risk attenuation (41%; 95% CI, 34–49%) is 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%–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.
Hypertension; Diabetes; Thiazide Diuretics; Chlorthalidone; Hypokalemia; Potassium
Apolipoprotein E polymorphisms (APOE) have been associated with lowered glomerular filtration rate (GFR) and chronic kidney disease (CKD) with e2 allele conferring risk and e4 providing protection. However, few data are available in non-European ethnic groups or in a population-based cohort.
The authors analyzed 5,583 individuals from the Third National Health and Nutrition Examination Survey (NHANES III) to determine association with estimated GFR by the Modification of Diet in Renal Disease (MDRD) equation and low-GFR cases. Low-GFR cases were defined as GFR <75 ml/min/1.73 m2; additionally, GFR was analyzed continuously.
In univariate analysis, the e4 allele was negatively associated with low-GFR cases in non-Hispanic whites, odds ratio (OR): 0.76, 95% confidence interval (CI): 0.60, 0.97. In whites, there was a significant association between increasing APOE score (indicating greater number of e2 alleles) and higher prevalence of low-GFR cases (OR: 1.21, 95%CI: 1.01, 1.45). Analysis of continuous GFR in whites found the e4 allele was associated with higher levels of continuous GFR (β-coefficient: 2.57 ml/min/1.73 m2, 95%CI: 0.005, 5.14); in non-Hispanic blacks the e2 allele was associated with lower levels of continuous GFR (β-coefficient: -3.73 ml/min/1.73 m2, 95%CI: -6.61, -0.84). APOE e2 and e4 alleles were rare and not associated with low-GFR cases or continuous GFR in Mexican Americans.
In conclusion, the authors observed a weak association between the APOE e4 allele and low-GFR cases and continuous GFR in non-Hispanic whites, and the APOE e2 allele and continuous GFR in non-Hispanic blacks, but found no association with either measure of kidney function in Mexican Americans. Larger studies including multiethnic groups are needed to determine the significance of this association.
The prevalence of obesity (body mass index (BMI) ≥30 kg/m2) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (ρ = −0.042, P = 1.6×10−7). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = −3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = −4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.
Obesity is about 1.5-fold more prevalent in African Americans than European Americans. To determine whether genetic background may contribute to this observed disparity, we scanned the genomes of African Americans, searching for genomic regions where obese individuals have a difference from the average proportion of African ancestry. By examining genetic data from more than 15,000 African Americans, we show that the proportion of European ancestry is inversely correlated with BMI. In obese individuals, we detect two loci with increased African ancestry on chromosome X (Xq13.1 and Xq25) and one locus with increased European ancestry on chromosome 5 (5q13.3). The 5q13.3 and Xq25 regions both contain genes that are known to be involved in appetite regulation. Our results suggest that genetic factors may contribute to the difference in obesity prevalence between African Americans and European Americans. Further studies of the regions may identify the causative variants affecting susceptibility to obesity.