Kidney tubule health scores and their associations with incident CKD in women living with HIV.

OBJECTIVES: Individual kidney tubule biomarkers are associated with chronic kidney disease (CKD) risk in people living with HIV (PLWH). Whether a combination of kidney biomarkers can be integrated into informative summary scores for PLWH is unknown. METHODS: We measured eight urine biomarkers of kidney tubule health at two visits over a 3-year period in 647 women living with HIV in the Women's Interagency Health Study. We integrated biomarkers into factor scores using exploratory factor analysis. We evaluated associations between CKD risk factors and factor scores, and used generalized estimating equations to determine associations between factor scores and risk of incident CKD. RESULTS: Factor analysis identified two unique factor scores: a tubule reabsorption score comprising alpha-1-microglobulin, beta-2-microglobulin and trefoil factor-3; and a tubule injury score comprising interleukin-18 and kidney injury molecule-1. We modelled the two factor scores in combination with urine epidermal growth factor (EGF) and urine albumin. Predominantly HIV-related CKD risk factors were independently associated with worsening tubule reabsorption scores and tubule injury scores. During a median follow-up of 7 years, 9.7% (63/647) developed CKD. In multivariable time-updated models that adjusted for other factor scores and biomarkers simultaneously, higher tubule reabsorption scores [risk ratio (RR) = 1.27, 95% confidence interval (CI): 1.01-1.59 per 1 SD higher time-updated score], higher tubule injury scores (RR = 1.36, 95% CI: 1.05-1.76), lower urine EGF (RR = 0.75, 95% CI: 0.64-0.87), and higher urine albumin (RR = 1.20, 95% CI: 1.02-1.40) were jointly associated with risk of incident CKD. CONCLUSIONS: We identified two novel and distinct dimensions of kidney tubule health that appear to quantify informative metrics of CKD risk in PLWH.

Hypertensive nephrosclerosis: wider kidney biopsy indications may be needed to improve diagnostics.

BACKGROUND: Hypertensive nephrosclerosis is the presumed underlying cause in many end-stage kidney disease (ESKD) patients, but the diagnosis is disputed and based on clinical criteria with low diagnostic accuracy. OBJECTIVE: To evaluate and improve the diagnostic process for nephrosclerosis patients. METHODS: We included adults from the population-based HUNT study (n = 50 552), Norwegian CKD patients referred for kidney biopsy 1988-2012 (n = 7261), and unselected nephrology clinic patients (n = 193) used for matching. Decision tree analysis and ROC curve-based methods of optimal cut-offs were used to improve clinical nephrosclerosis criteria. RESULTS: Nephrosclerosis prevalence was 2.7% in the general population, and eGFR decline and risk for kidney-related hospital admissions and ESKD were comparable to patients with diabetic kidney disease. In the biopsy cohort, current clinical criteria had very low sensitivity (0.13) but high specificity (0.94) for biopsy-verified arterionephrosclerosis. A new optimized diagnostic algorithm based on proteinuria (<0.75 g d-1 ), systolic blood pressure (>155 mm Hg) and age (>75 years) only marginally improved diagnostic accuracy (sensitivity 0.19, specificity 0.96). Likewise, there were still false-positive cases with treatable diagnoses like glomerulonephritis, interstitial nephritis and others (40% of all test positive). Decision curve analysis showed that the new criteria can lead to higher clinical utility, especially for patients considering the potential harms to be close to the potential benefits, while the more risk-tolerant ones (harm:benefit ratio < 1:4) should consider kidney biopsy. CONCLUSION: Further improvements of the current clinical criteria seem difficult, so risks and benefits of kidney biopsy could be more actively discussed with selected patients to reduce misclassification and direct treatment.

Biochemical markers of bone turnover and risk of incident hip fracture in older women: the Cardiovascular Health Study.

The relationships of osteocalcin (OC) and C-telopeptide of type I collagen (CTX) with long-term incidence of hip fracture were examined in 1680 post-menopausal women from a population-based study. CTX, but not OC, levels were associated with incident hip fracture in these participants, a relationship characterized by an inverted U-shape. INTRODUCTION: We sought to investigate the relationships of OC, a marker of bone formation, and CTX, a marker of bone resorption, with long-term incidence of hip fracture in older women. METHODS: We included 1680 women from the population-based Cardiovascular Health Study (mean [SD] age 74.5 [5.0] years). The longitudinal association of both markers with incidence of hip fracture was examined using multivariable Cox models. RESULTS: During a median follow-up of 12.3 years, 288 incident hip fractures occurred. Linear spline analysis did not demonstrate an association between OC levels and incident hip fracture. By contrast, increasing levels of CTX up to the middle-upper range were associated with a significantly greater risk of hip fracture (HR = 1.52 per SD increment, 95% CI = 1.10-2.09), while further increases were associated with a marginally non-significant lower risk (HR = 0.80 per SD increment, 95% CI = 0.63-1.01), after full adjustment for potential confounders. In analyses of quartiles, CTX exhibited a similar inverted U-shaped relationship with incident fracture after adjustment, with a significant association observed only for the comparison of quartile 3 to quartile 1 (HR = 1.63, 95% CI = 1.10-2.43). In a subset with available measures, both OC and CTX were inversely associated with bone mineral density of the hip. CONCLUSION: CTX, but not OC, levels were associated with incident hip fracture in post-menopausal women, a relationship characterized by an inverted U-shape. These findings highlight the complex relationship of bone turnover markers with hip fracture risk.

Correlates of T50 and relationships with bone mineral density in community-living older men: the osteoporotic fractures in men (MrOS) study.

PURPOSE: T50 is a novel serum-based marker that assesses the propensity of calcification in serum. Shorter T50 indicates greater propensity to calcify and it has been associated to cardiovascular disease (CVD) and mortality among patients with kidney disease. In the general population, neither the correlates of T50 nor the relationships of T50 with bone mineral density (BMD) are known. METHODS: We performed a nested cross-sectional study selecting 150 individuals at random among participants from the Osteoporotic Fractures in Men (MrOS) Study, a study of community-living older men. We categorized individuals into tertiles of T50 and compared demographics and disease indicators across tertiles. We utilized linear regression to evaluate the cross-sectional association between T50 and hip and spine BMD in multivariable models. RESULTS: Older age was associated with shorter T50. Kidney function tended to be lower in those with shorter T50 and the prevalence of CVD and peripheral arterial disease in those with shorter T50, albeit these findings did not achieve statistical significance. We found no statistically significant associations between T50 and total hip or total spine BMD in either unadjusted or multivariable adjusted models. CONCLUSIONS: T50, a novel indicator of serum calcification propensity, is not associated with BMD in community-living older men. Future larger studies should determine if T50 may give insights to CVD in the general population above and beyond traditional risk factors.

Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial.

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

The association of calcium supplementation and incident cardiovascular events in the Multi-ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Many US adults use calcium supplements to address inadequate dietary intake and improve bone health. However, recent reports have suggested that use of calcium supplements may elevate cardiovascular disease (CVD) risk. In this study, we examined associations between baseline calcium supplement use and incident myocardial infarction (MI) (n = 208 events) and CVD events (n = 641 events) over 10.3 years in men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 6236), with dietary calcium intake at baseline also examined as a supplementary objective. METHODS AND RESULTS: Using Cox proportional hazards models, no compelling associations between calcium intake from supplements or diet and incident CVD events were observed upon multivariate adjustment for potential confounders. An association with lower MI risk was observed comparing those with low levels of calcium supplement use (1-499 mg) to those using no calcium supplements (hazard ratio 0.69, 95% CI 0.48, 0.98, p = 0.039). Relationships were homogeneous by gender, race/ethnicity, or chronic kidney disease. Results were also similar when the analysis was limited to postmenopausal women only. CONCLUSION: Analysis of incident MI and CVD events in the MESA cohort does not support a substantial association of calcium supplement use with negative cardiovascular outcomes.

Fibrosis markers, hip fracture risk, and bone density in older adults.

UNLABELLED: We examined whether blood levels of two markers of fibrosis (transforming growth factor beta one (TGF-ß1) and procollagen type III N-terminal propeptide (PIIINP)) are related to hip fracture risk and to bone mineral density (BMD). TGF-ß1 levels were associated with lower hip fracture risk in women and with lower BMD in men. PIIINP levels were not associated with either outcome. INTRODUCTION: TGF-ß1 serves several roles in bone formation and resorption. A consequence of TGF-ß1 activation is the production of PIIINP, a marker of collagen III deposition. Here, we explore whether these two biomarkers are related to incident hip fracture and bone mineral density (BMD) and whether their associations are modified by systemic inflammation, as measured by C-reactive protein (CRP) levels. METHODS: Participants were from the Cardiovascular Health Study (mean age 78 years; mean follow-up 8.3 years). We included 1681 persons with measured levels of TGF-ß1 (149 hip fractures) and 3226 persons with measured levels of PIIINP (310 hip fractures). RESULTS: Among women, higher TGF-ß1 levels were associated with lower hip fracture risk (HR, per doubling, 0.78 [95 % CI 0.61, 0.91]). Among men, TGF-ß1 levels were associated with hip fracture risk in a non-linear manner, but among those with elevated CRP levels, doubling was associated with increased risk of fracture (HR 2.22 [1.20, 4.08]) (p = 0.02, interaction between low and high CRP and TGF-ß1 on fracture risk). TGF-ß1 levels had no significant association with total hip or total body BMD in women but were significantly associated with lower BMD in men. There were no associations of PIIINP levels with hip fracture risk or BMD in men or women. CONCLUSIONS: TGF-ß1 levels appear to be associated with bone-related phenotypes in a sex-specific manner. The reasons for these differences between men and women regarding TGF-ß1 levels and hip fracture risk and bone density require further investigation.

Association of serum inorganic phosphate with sex steroid hormones and vitamin D in a nationally representative sample of men.

Defects in bone regulatory pathways have been linked to chronic diseases including cardiovascular disease and cancer. In men, a link between bone metabolism and gonadal hormones has been suggested. However, to date, there is lack of evidence on the association between serum inorganic phosphate (Pi) and sex steroid hormones. The objective of this study was to investigate the association between Pi, sex steroid hormones and a known Pi metabolic regulator, vitamin D, in men in the National Health and Nutrition Examination Survey III (NHANES III). From NHANES III, we selected 1412 men aged 20+ who participated in the morning session of Phase I (1988-1991) with serum measurements of Pi, sex hormones, and vitamin D. Multivariable linear regression was used to calculate crude and geometric mean Pi by total and estimated free testosterone and estradiol, sex hormone-binding globulin, androstanediol glucuronide (AAG), and vitamin D. Similar analyses were performed while stratifying by race/ethnicity and vitamin D levels. We found a lack of statistically significant difference in geometric means of Pi across quintiles of concentrations of sex hormones, indicating a tight regulation of Pi. However, Pi levels were inversely associated with calculated free testosterone in non-Hispanic black men, with geometric mean levels of Pi of 1.16 and 1.02 ng/mL for those in the lowest and highest quintiles of free testosterone, respectively (p-trend < 0.05). A similar but weaker pattern was seen between total testosterone and Pi. An inverse association was also seen between AAG and Pi in men with vitamin D concentration below the median (<24.2 ng/mL). No associations were observed among men with vitamin D levels at or above the median. Our findings suggest a weak link among sex hormones, vitamin D, and Pi in men. The observed effects of race/ethnicity and vitamin D indicate a complex association involving various regulators of Pi homeostasis.

Estimating risks of de novo kidney diseases after living kidney donation.

De novo post donation renal diseases, such as glomerulonephritis or diabetic nephropathy, are infrequent and distinct from the loss of GFR at donation that all living kidney donors experience. Medical findings that increase risks of disease (e.g. microscopic hematuria,borderline hemoglobin A1C) often prompt donor refusal by centers. These risk factors are part of more comprehensive risks of low GFR and end-stage renal disease (ESRD) from kidney diseases in the general population that are equally relevant. Such data profile the ages of onset, rates of progression, prevalence and severity of loss of GFR from generically characterized kidney diseases. Kidney diseases typically begin in middle age and take decades to reach ESRD, at a median age of 64. Diabetes produces about half of yearly ESRD and even more lifetime near-ESRD. Such data predict that (1) 10- to 15-year studies will not capture the lifetime risks of post donation ESRD; (2)normal young donors are at demonstrably higher risk than normal older candidates; (3) low-normal predonation GFRs become risk factors for ESRD when kidney diseases arise and (4) donor nephrectomy always increases individual risk. Such population-based risk data apply to all donor candidates and should be used to make acceptance standards and counseling more uniform and defensible.

Higher leptin is associated with hypertension: the Multi-Ethnic Study of Atherosclerosis.

Adipokines are secreted from adipose tissue, influence energy homeostasis and may contribute to the association between obesity and hypertension. Among 1897 participants enrolled in the Multi-Ethnic Study of Atherosclerosis, we examined associations between blood pressure and leptin, tumor necrosis factor-α (TNFα), resistin and total adiponectin. The mean age and body mass index (BMI) was 64.7 years and 28.1, respectively, and 50% were female. After adjustment for risk factors, a 1-s.d.-increment higher leptin level was significantly associated with higher systolic (5.0 mm Hg), diastolic (1.9), mean arterial (2.8) and pulse pressures (3.6), as well as a 34% higher odds for being hypertensive (P<0.01 for all). These associations were not materially different when the other adipokines, as well as BMI, waist circumference or waist-to-hip ratio, were additionally added to the model. Notably, the associations between leptin and hypertension were stronger in men, but were not different by race/ethnic group, BMI or smoking status. Adiponectin, resistin and TNFα were not independently associated with blood pressure or hypertension. Higher serum leptin, but not adiponectin, resistin or TNFα, is associated with higher levels of all measures of blood pressure, as well as a higher odds of hypertension, independent of risk factors, anthropometric measures and other selected adipokines.

Prediction and classification of cardiovascular disease risk in older adults with diabetes.

AIMS/HYPOTHESIS: We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis. METHODS: As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred. RESULTS: The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle-brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima-media thickness modestly improved discrimination (C statistic 0.68; p = 0.002) and classification (net reclassification improvement [NRI] 0.12; p = 0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures. CONCLUSIONS/INTERPRETATION: Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.

Fetuin-A is not associated with mortality in chronic kidney disease.

Fetuin-A is a serum protein that inhibits vascular calcification such that lower levels are associated with a higher prevalence of vascular calcification and mortality risk among end-stage renal disease populations. We analyzed data of 822 persons in the Modification of Diet in Renal Disease study, a randomized, controlled trial of persons with predominantly non-diabetic stage 3-4 chronic kidney disease (CKD). Serum fetuin-A levels were measured in baseline serum. Survival status and cause of death were determined by the National Death Index. Cox proportional hazard models evaluated the association of fetuin-A levels with all-cause and cardiovascular mortality. Glomerular filtration ranged from 13 to 55 ml per min per 1.73 m(2). During a median follow-up of 9.5 years, 25% of persons died from any cause and 12% died from a cardiovascular cause. Compared to the lowest tertile, no association was found between the highest fetuin-A tertile and all-cause or cardiovascular mortality. Similarly, no association was found between fetuin-A as a continuous variable and all-cause or cardiovascular mortality. Our study shows that serum fetuin-A levels are not related to all-cause or cardiovascular mortality among persons with predominantly non-diabetic stage 3 or 4 CKD.

The predictive value of combined hypoalbuminemia and hypocholesterolemia in high functioning community-dwelling older persons: MacArthur Studies of Successful Aging.

OBJECTIVES: To examine the effect of simultaneous hypoalbuminemia and hypocholesterolemia levels on 3- and 7-year rates of mortality and decline in functional status. METHODS: In this cohort study, 937 community-based persons aged 70 to 79 years in 1988, who had high baseline physical and cognitive functioning, were classified into four groups: Group 1 (low albumin, low cholesterol), Group 2 (low albumin, normal cholesterol), Group 3 (normal albumin, low cholesterol) and Group 4 (normal albumin, normal cholesterol) using baseline blood values. Crude and multiply adjusted rates of (1) mortality (2) decline in Rosow-Breslau (RB) functional status, and (3) mortality or decline in RB functional status in 1991 and 1995 were calculated. RESULTS: Group 1 subjects had multiply adjusted relative risks (ARR) of 3.62 and 3.53 for 3-and 7-year mortality compared with Group 4. Group 1 subjects had ARRs of 3.82, 3.02, and 2.67 of 3-year mortality or decline in RB activity scale when compared with Groups 4, 2, and 3, respectively. CONCLUSIONS: Concomitant low serum cholesterol and albumin levels may identify high functioning older persons who are at increased risk of subsequent mortality and functional decline.