Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

A generalized covariate-adjusted top-scoring pair algorithm with applications to diabetic kidney disease stage classification in the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: The growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification. However, standard TSP methods do not accommodate covariates that could heavily influence feature selection for the top-scoring pair. Herein, we propose a covariate-adjusted TSP method, which uses residuals from a regression of features on the covariates for identifying top scoring pairs. We conduct simulations and a data application to investigate our method, and compare it to existing classifiers, LASSO and random forests. RESULTS: Our simulations found that features that were highly correlated with clinical variables had high likelihood of being selected as top scoring pairs in the standard TSP setting. However, through residualization, our covariate-adjusted TSP was able to identify new top scoring pairs, that were largely uncorrelated with clinical variables. In the data application, using patients with diabetes (n = 977) selected for metabolomic profiling in the Chronic Renal Insufficiency Cohort (CRIC) study, the standard TSP algorithm identified (valine-betaine, dimethyl-arg) as the top-scoring metabolite pair for classifying diabetic kidney disease (DKD) severity, whereas the covariate-adjusted TSP method identified the pair (pipazethate, octaethylene glycol) as top-scoring. Valine-betaine and dimethyl-arg had, respectively, ≥ 0.4 absolute correlation with urine albumin and serum creatinine, known prognosticators of DKD. Thus without covariate-adjustment the top-scoring pair largely reflected known markers of disease severity, whereas covariate-adjusted TSP uncovered features liberated from confounding, and identified independent prognostic markers of DKD severity. Furthermore, TSP-based methods achieved competitive classification accuracy in DKD to LASSO and random forests, while providing more parsimonious models. CONCLUSIONS: We extended TSP-based methods to account for covariates, via a simple, easy to implement residualizing process. Our covariate-adjusted TSP method identified metabolite features, uncorrelated from clinical covariates, that discriminate DKD severity stage based on the relative ordering between two features, and thus provide insights into future studies on the order reversals in early vs advanced disease states.

The Otago Exercise Program compared to falls prevention education in Zuni elders: a randomized controlled trial.

BACKGROUND: When a Zuni elder sustains a fall-related injury, the closest tribal skilled nursing facility is 100 miles from the Pueblo and no physical therapy services are available. Thus, fall prevention strategies as a primary intervention to avert injurious falls and preserve aging in place are needed. The objective of the study is to compare the effectiveness of a community health representative (CHR)-delivered, culturally-adapted Otago Exercise Program (OEP) fall prevention program compared to the standard of care education-based fall risk management. METHODS: "Standing Strong in Tribal Communities: Assessing Elder Falls Disparity" is mixed-methods research with a randomized controlled trial. The CHRs will be trained to deliver the culturally-adapted OEP trial and offer advantages of speaking "Shiwi" (Zuni tribal language) and understanding Zuni traditions, family structures, and elders' preferences for receiving health information. Focus groups will be conducted to assure all materials are culturally appropriate, and adapted. A physical therapist will train CHRs to screen elders for falls risk and to deliver the OEP to the intervention group and education to the control group. Up to 400 Zuni elders will be screened by the CHRs for falls risk and 200 elders will be enrolled into the study (1:1 random allocation by household). The intervention is 6 months with measurements at baseline, 3, 6 and 12 months. The primary outcome is improved strength and balance (timed up and go, sit to stand and 4 stage balance test), secondary outcomes include falls incidence, self-efficacy using Attitudes to Falls-Related Interventions Scale, Medical Outcomes Study Short Form 12 (SF-12v2) and Self-Efficacy for Managing Daily Activities. DISCUSSION: Fall prevention for Zuni elders was identified as a tribal priority and this trial is built upon longstanding collaborations between the investigative team, Zuni tribal leaders, and multiple tribal health programs. Delivery by the CHRs make this model more acceptable, and thus, more sustainable long term. This study has the potential to change best practice for elder care in tribal and rural areas with limited access to physical therapist-delivered fall prevention interventions and aligns with tribal goals to avert fall-related injury, reduce healthcare disparity, and preserve elder's independence. TRIAL REGISTRATION: NCT04876729.

Early Patient-Centered Outcomes Research Experience With the Use of Telehealth to Address Disparities: Scoping Review.

BACKGROUND: Health systems and providers across America are increasingly employing telehealth technologies to better serve medically underserved low-income, minority, and rural populations at the highest risk for health disparities. The Patient-Centered Outcomes Research Institute (PCORI) has invested US $386 million in comparative effectiveness research in telehealth, yet little is known about the key early lessons garnered from this research regarding the best practices in using telehealth to address disparities. OBJECTIVE: This paper describes preliminary lessons from the body of research using study findings and case studies drawn from PCORI seminal patient-centered outcomes research (PCOR) initiatives. The primary purpose was to identify common barriers and facilitators to implementing telehealth technologies in populations at risk for disparities. METHODS: A systematic scoping review of telehealth studies addressing disparities was performed. It was guided by the Arksey and O'Malley Scoping Review Framework and focused on PCORI's active portfolio of telehealth studies and key PCOR identified by study investigators. We drew on this broad literature using illustrative examples from early PCOR experience and published literature to assess barriers and facilitators to implementing telehealth in populations at risk for disparities, using the active implementation framework to extract data. Major themes regarding how telehealth interventions can overcome barriers to telehealth adoption and implementation were identified through this review using an iterative Delphi process to achieve consensus among the PCORI investigators participating in the study. RESULTS: PCORI has funded 89 comparative effectiveness studies in telehealth, of which 41 assessed the use of telehealth to improve outcomes for populations at risk for health disparities. These 41 studies employed various overlapping modalities including mobile devices (29/41, 71%), web-based interventions (30/41, 73%), real-time videoconferencing (15/41, 37%), remote patient monitoring (8/41, 20%), and store-and-forward (ie, asynchronous electronic transmission) interventions (4/41, 10%). The studies targeted one or more of PCORI's priority populations, including racial and ethnic minorities (31/41, 41%), people living in rural areas, and those with low income/low socioeconomic status, low health literacy, or disabilities. Major themes identified across these studies included the importance of patient-centered design, cultural tailoring of telehealth solutions, delivering telehealth through trusted intermediaries, partnering with payers to expand telehealth reimbursement, and ensuring confidential sharing of private information. CONCLUSIONS: Early PCOR evidence suggests that the most effective health system- and provider-level telehealth implementation solutions to address disparities employ patient-centered and culturally tailored telehealth solutions whose development is actively guided by the patients themselves to meet the needs of specific communities and populations. Further, this evidence shows that the best practices in telehealth implementation include delivery of telehealth through trusted intermediaries, close partnership with payers to facilitate reimbursement and sustainability, and safeguards to ensure patient-guided confidential sharing of personal health information.

American Indian chronic Renal insufficiency cohort study (AI-CRIC study).

BACKGROUND: Chronic kidney disease (CKD) is an increasing epidemic globally that is associated with adverse health outcomes including end stage kidney disease (ESKD), cardiovascular disease (CVD), and death. American Indians (AIs) have a higher prevalence of CKD than most other racial/ethnic groups, due in part to a high prevalence of type 2 diabetes. Other genetic and environmental factors not yet identified may also contribute to the disproportionate burden of CKD in AIs. METHOD: We will establish 3 clinical centers to recruit AIs from the Southwest United States (US) to expand the Chronic Renal Insufficiency Cohort (CRIC) study. We will follow the current CRIC protocol for kidney and cardiovascular measures and outcomes, which include ambulatory monitoring of kidney function and the use of mobile health technologies for CVD sub-phenotyping, and compare the outcomes in AIs with those in other racial/ethnic groups in CRIC. DISCUSSION: AI-CRIC will identify the role of various risk factors for rapid loss of kidney function among AIs of the Southwest US. In addition, to better understand the natural history of CKD and CVD in this high-risk population, we will identify unique risk factors for CKD and CVD progression in AIs. We will also compare event rates and risk factors for kidney and cardiovascular events in AIs with the other populations represented in CRIC.

Impact of Isolyte Versus 0.9% Saline on Postoperative Event of Acute Kidney Injury Assayed by Urinary [TIMP-2] × [IGFBP7] in Patients Undergoing Cardiac Surgery.

OBJECTIVE: Administration of excess chloride in 0.9% normal saline (NS) decreases renal perfusion and glomerular filtration rate, thereby increasing the risk for acute kidney injury (AKI). In this study, the effect of NS versus Isolyte use during cardiac surgery on urinary levels of tissue inhibitor of metalloproteinase 2 and insulin-like growth factor-binding protein 7 [TIMP-2] × [IGFBP7] and postoperative risk of AKI were examined. DESIGN: Prospective, randomized, and single-blinded trial. SETTING: Single university medical center. PARTICIPANTS: Thirty patients over 18 years without chronic renal insufficiency or recent AKI undergoing elective cardiac surgery. INTERVENTIONS: Subjects were randomized to receive either NS or Isolyte during the intraoperative period. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in urinary levels of [TIMP2] × [IGFBP7] from before surgery to 24 hours postoperatively. Secondary outcomes included serum creatinine pre- and postoperatively at 24 and 48 hours, serum chloride pre- and postoperatively at 24 and 48 hours, need for dialysis prior to discharge, and arterial pH measured 24 hours postoperatively. Sixteen patients received NS and 14 patients received Isolyte. Three patients developed AKI within the first 3 postoperative days, all in the NS group. The authors found increases in [TIMP-2] × [IGFBP7] in both groups. However, the difference in this increase between study arms was not significant (p = 0.92; -0.097 to 0.107). CONCLUSION: The authors observed no change in urinary [TIMP-] × [IGFBP7] levels in patients receiving NS versus Isolyte during cardiac surgery. Future larger studies in patients at higher risk for AKI are recommended to evaluate the impact of high- versus lower-chloride solutions on the risk of postoperative AKI after cardiac surgery.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

PERFORMANCE OF A1C VERSUS OGTT FOR THE DIAGNOSIS OF PREDIABETES IN A COMMUNITY-BASED SCREENING.

OBJECTIVE: Reliable identification of individuals at risk for developing diabetes is critical to instituting preventative strategies. Studies suggest that the accuracy of using hemoglobin A1c as a sole diagnostic criterion for diabetes may be variable across different ethnic groups. We postulate that there will be lack of concordance between A1c and the oral glucose tolerance test (OGTT) for diagnosing prediabetes across Hispanic and non-Hispanic white (NHW) populations. METHODS: A total of 218 asymptomatic adults at risk for type 2 diabetes (T2D) were assessed with A1c and OGTT for the diagnosis of prediabetes. Glucose homeostasis status was assigned as no diabetes (A1c <5.7% [39 mmol/mol]), prediabetes (A1c 5.7 to 6.4% [46 mmol/mol]), and T2D (A1c >6.4% [46 mmol/mol]). Inclusion criteria were age >18 years and at least one of the following: a family history of diabetes, a history of gestational diabetes, Hispanic ethnicity, non-Caucasian race, or obesity. Subjects received a fasting 75-g OGTT and A1c on the same day. Bowker's test of symmetry was employed to determine agreement between the tests. RESULTS: Data from 99 Hispanic patients and 79 NHW patients were analyzed. There was no concordance between A1c and OGTT for Hispanic (P = .002) or NHW individuals (P = .003) with prediabetes. CONCLUSION: A1c is discordant with OGTT among Hispanic and NHW subjects for the diagnosis of prediabetes. Sole use of A1c to designate glycemic status will result in a greater prevalence of prediabetes among Hispanic and NHW New Mexicans. ABBREVIATIONS: A1c = hemoglobin A1c BMI = body mass index CDC = Centers for Disease Control CI = confidence interval FPG = fasting plasma glucose NHW = non-Hispanic white OGTT = oral glucose tolerance test T2D = type 2 diabetes WHO = World Health Organization.

Heritability of serum sodium concentration: evidence for sex- and ethnic-specific effects.

Serum sodium concentration is the clinical index of systemic water balance. Although disordered water balance is common and morbid, little is known about genetic effects on serum sodium concentration at the population level. Prior studies addressed only participants of European descent and either failed to demonstrate significant heritability or showed only modest effect. We investigated heritability of serum sodium concentration in large cohorts reflecting a range of races/ethnicities, including the Framingham Heart Study (FHS, non-Hispanic Caucasian), the Heredity and Phenotype Intervention Heart Study (HAPI, Amish Caucasian), the Jackson Heart Study (JHS, African American), the Strong Heart Family Study (SHFS, American Indian), and the Genetics of Kidney Disease in Zuni Indians Study (GKDZI, American Indian). Serum sodium was transformed for the osmotic effect of glucose, and participants with markedly elevated glucose or reduced estimated glomerular filtration rate (eGFR) were excluded. Using a standard variance components method, incorporating covariates of age, glucose, and eGFR, we found heritability to be high in African American and American Indian populations and much more modest in non-Hispanic Caucasian populations. Estimates among females increased after stratification on sex and were suggestive among female participants in FHS (0.18 ± 0.12, P = 0.057) and male participants in JHS (0.24 ± 0.16, P = 0.067) and statistically significant among female participants in JHS (0.44 ± 0.09, P = 1 × 10 ⁻7), SHFS (0.59 ± 0.05, P = 9.4 × 10⁻46), and GKDZI (0.46 ± 0.15, P = 1.7 × 10⁻4), and male participants in HAPI (0.18 ± 0.12, P = 0.03) and SHFS (0.67 ± 0.07, P = 5.4 × 10⁻²6). Exclusion of diuretic users increased heritability among females and was significant in all cohorts where data were available. In aggregate, these data strongly support the heritability of systemic water balance and underscore sex and ethnicity-specific effects.

Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

Diabetes status modifies the efficacy of home-based kidney care for Zuni Indians in a randomized controlled trial.

BACKGROUND: Home-Based Kidney Care (HBKC) is a pragmatic treatment approach that addresses patient preferences and cultural barriers to healthcare. We previously reported the results of a clinical trial of HBKC vs. usual care in a cohort of Zuni Indians in New Mexico. This study investigated the potential for differential efficacy of HBKC vs. usual care according to type 2 diabetes (T2DM) status. METHODS: We analyzed the data from all individuals who participated in a randomized clinical trial that compared HBKC to usual care among patients with CKD, and assessed whether the effect of the HBKC intervention affected the subset of patients with T2DM differently than those individuals without T2DM. We used linear regression models to estimate the effect of HBKC on improvement in Patient Activation Measure (PAM) total scores within the groups of participants defined by T2DM status, and to compare the effects between these two groups. We used generalized estimating equations (GEE) to account for household clustering. RESULTS: The original study enrolled 63 participants into the HBKC group, and 62 into the usual care. Ninety-eight of these individuals completed the 12-month intervention, 50 in the HBKC group and 48 in the usual care group. The present study compared the intervention effect in the 56 participants with T2DM (24 participants in the HBKC group and 32 in usual care) to the intervention effect in the 42 participants without T2DM (26 participants in the HBKC group and 16 in usual care). Those with T2DM who received the HBKC intervention experienced an average increase in PAM total scores of 16.0 points (95% Confidence Interval: 8.8-23.1) more than those with T2DM who were in the usual care group. For those without T2DM, the intervention had essentially no effect, with those who received the HBKC intervention having an average PAM total scores that was 1.4 points (95% C.I.: -12.4 to 9.6) lower than those who received usual care. There was a significantly different HBKC treatment effect by T2DM status (p = 0.02). CONCLUSION: This secondary analysis suggests that the effectiveness of this HBKC intervention on increasing patient activation is most notable among those CKD patients who also have T2DM.

Heritability of measures of kidney disease among Zuni Indians: the Zuni Kidney Project.

BACKGROUND: The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes. STUDY DESIGN: A community-based participatory research approach was used to recruit family members of individuals with kidney disease. SETTING & PARTICIPANTS: The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs. PREDICTOR OUTCOMES & MEASUREMENTS: Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was >or=0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria. RESULTS: Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes. LIMITATIONS: Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions. CONCLUSIONS: Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations.

Mitochondrial DNA deletion and sarcopenia.

PURPOSE: Accumulation of mitochondrial DNA deletions and the resultant impaired oxidative phosphorylation may play a pathogenic role in the mediation of age-related sarcopenia. METHODS: Twenty four participants of the New Mexico Aging Process Study were classified as normal lean (n = 15) or sarcopenic (n = 9) based on body composition determined by Dual Energy x-ray Absorptiometry. Complex I and Complex IV activities were measured in the skeletal muscle samples obtained from gastrocnemius muscle. A two-stage nested polymerase chain reaction strategy was used to identify the mitochondrial DNA deletions in the entire mitochondrial genome in the skeletal muscle samples. RESULTS: Although Complex I activity was not significantly different (5.5 +/- 0.9 vs. 4.6 +/- 0.7 mU/mg protein, P > 0.05), Complex IV activity was higher in sarcopenic subjects (1.4 +/- 0.3 vs. 1.0 +/- 0.1 mU/mg protein, P < 0.05). Mitochondrial DNA deletions were mostly located in the region of Complex I and spanned from nicotinamide adenine dinucleotide dehydrogenase 1 to nicotinamide adenine dinucleotide dehydrogenase 6. Deletions in the 8,577-10,407 bp and 10,233-11,249 bp regions were associated with a significant decrease in Complex I activity (P < 0.05 and P = 0.02, respectively). Total cumulative deletion, defined as the sum of individual length of deletions in a subject, was comparable in subjects with and without sarcopenia (1760 +/- 726 vs. 1782 +/- 888 bp, P > 0.05). The magnitude of mitochondrial DNA deletion, however, correlated positively with lean body mass (r = 0.43, P < 0.05). CONCLUSION: Thus, mitochondrial DNA deletions are common in elderly subjects and are negatively related to Complex I activity. The positive association between mitochondrial DNA deletions and lean body mass needs to be confirmed by studies in a larger study population.

Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis.

BACKGROUND: CD14 is a key molecule in innate immunity that mediates cell activation and signaling in response to endotoxin and other bacterial wall-derived components. CD14 protein exists in soluble (sCD14) and membrane-bound forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) therapy are not known. We hypothesized that increased sCD14 levels in HD patients are associated with proinflammatory cytokine activation and increased mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study, a cohort derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area. PREDICTORS: sCD14 levels in serum. OUTCOMES: 33-month mortality. RESULTS: Mean sCD14 level was 7.24 +/- 2.45 microg/mL. Tumor necrosis factor alpha level was the strongest correlate of sCD14 level (r = +0.24; P < 0.001), followed by interleukin 6 level (r = +0.18; P = 0.002), serum ferritin level (r = +0.21; P < 0.001), total iron-binding capacity (r = -0.19; P < 0.001), body mass index (r = -0.15; P = 0.008), vintage (r = +0.14; P = 0.01), low-density lipoprotein cholesterol level (r = +0.13; P = 0.03), and body fat (r = -0.11; P = 0.06). During the 33-month follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders, including serum tumor necrosis factor alpha, C-reactive protein, and interleukin 6 levels, showed that compared with the lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 microg/mL) were associated with greater death risk (hazard ratio, 1.94; 95% confidence interval, 1.01 to 3.75; P = 0.04). LIMITATIONS: Survivor bias in combined incident/prevalent studies. CONCLUSIONS: Increased sCD14 level is related positively to markers of inflammation and negatively to nutritional status and is an independent predictor of mortality in long-term HD patients. Additional studies are needed to examine the usefulness of sCD14 level in risk stratification and the clinical decision-making process in HD patients.

Soluble CD14 levels, interleukin 6, and mortality among prevalent hemodialysis patients.

BACKGROUND: CD14 is a pattern-recognition receptor that has a central immunomodulatory role in proinflammatory signaling in response to a variety of ligands, including endotoxin. CD14 protein is present in 2 forms: soluble (sCD14) and membrane bound. Here, we studied the implications of increased sCD14 levels in hemodialysis patients. We hypothesized that sCD14 level increase may link to cytokine activation and protein-energy wasting, predisposing to increased mortality risk. STUDY DESIGN: Prospective observational study of prevalent hemodialysis patients. SETTING & PARTICIPANTS: 211 prevalent hemodialysis patients, median age of 65 years, with 29 months of vintage dialysis time followed up for mortality for a median of 31 months. PREDICTORS: Tertiles of baseline circulating sCD14 levels corresponding to less than 2.84, 2.85 to 3.62, and greater than 3.63 microg/mL. OUTCOME: The major outcome of interest was all-cause mortality. MEASUREMENTS: sCD14 and endotoxin, together with other markers of inflammation and protein-energy wasting. RESULTS: Median sCD14 level was 3.2 microg/mL (25th to 75th percentile, 2.7 to 3.9). sCD14 level correlated positively with C-reactive protein, interleukin 6, endotoxin, and pentraxin 3 levels and negatively with serum albumin level, muscle mass, and handgrip strength. Patients with increased sCD14 levels had lower body mass index and increased prevalence of muscle atrophy. Patients within the highest sCD14 tertile had a crude morality hazard ratio of 1.94 (95% confidence interval, 1.13 to 3.32) that persisted after adjustment for multiple confounders (hazard ratio, 3.11; 95% confidence interval, 1.49 to 6.46). In patients with persistent inflammation, the presence of a concurrent sCD14 level increase gradually increased mortality risk, but this effect was less than multiplicative and failed to show a statistical interaction. LIMITATIONS: Those inherent to an observational study. CONCLUSIONS: sCD14 level is associated with inflammation and protein-energy wasting in hemodialysis patients. It is a strong and independent predictor of mortality that warrants further assessment in the clinical setting regarding its usefulness as a complementary prognosticator to other general inflammatory markers.

Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations-significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes Research Group.

BACKGROUND: 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. METHODS: 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. Non-parametric linkage analysis, using an average of 4404 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. RESULTS: Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 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. CONCLUSIONS: 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.

Bone and body composition response to testosterone therapy vary according to polymorphisms in the CYP19A1 gene.

PURPOSE: To evaluate the influence of single nucleotide polymorphisms (SNPs) of CYP19A1 on the response and susceptibility to side effects from testosterone therapy. This is a prospective, single-arm study of men with low-morning serum testosterone (<10.68 nmol/l) administered testosterone cypionate 200 mg intramuscularly every 2 weeks for 18 months. METHODS: We measured areal bone mineral density (aBMD) and body composition by dual energy X-ray absorptiometry, tibial volumetric BMD and geometry by peripheral quantitative computer tomography, bone turnover markers by enzyme-linked immunosorbent assay, testosterone, and estradiol by liquid-chromatography/mass-spectroscopy, genotyping by microarray, CYP19A1 expression by quantitative polymerase chain reaction, hematocrit and prostate-specific antigen (PSA). RESULTS: We enrolled 105 men (40-74-years-old). SNPs rs1062033 and rs700518 were associated with significant differences in outcomes at 18 months. The GG genotype in rs1062033 had significant increase in whole body aBMD, but had significant decrease in tibial bone size compared to the CG and CC genotypes. Body composition analysis showed that the CC genotype of rs1062033, and the AA genotype of rs700518, had significant increase in total lean and appendicular lean mass compared to CG and GG, and AG and GG, respectively. The GG genotype of rs700518 had significant increase in PSA (GG = 105.8 ± 23.3% vs. AG + AA = 53.4 ± 11.3%, p = 0.046) while hematocrit changes were comparable among genotypes. CYP19A1 expression was highest in GG genotype in both SNPs. CONCLUSIONS: For the first time, we demonstrated that CYP19A1 SNPs influence response to testosterone therapy in hypogonadal men, highlighting the importance of genetic profiling in therapeutics even for common clinical conditions.