Background

Whether elevations in levels of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin [NGAL] and kidney injury molecule 1 [KIM-1]) are associated with future risk of kidney disease has not been investigated.

Study design

1:1 nested case-control study.

Setting & participants

686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).

Predictor

NGAL and KIM-1 were measured at baseline, expressed as log-transformed continuous variables, and categorized into deciles.

Outcomes

Kidney function was estimated by cystatin C level using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD stage 3 was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) and an eGFR decrease >1 mL/min/1.73 m(2) per year, and rapid kidney function decrease was defined as decrease ≥3 mL/min/1.73 m(2) per year.

Measurements

Cases were defined as persons with eGFR >60 mL/min/1.73 m(2) who subsequently developed incident CKD stage 3 and/or had rapid kidney function decrease by the MESA year-5 visit. Controls were matched for age, sex, race, diabetes, and baseline eGFR. We adjusted for age, hypertension, and presence of albuminuria (albumin-creatinine ratio ≥30 mg/g).

Results

Of 343 cases, 145 had incident CKD stage 3, 141 had rapid kidney function decrease, and 57 had both. Mean eGFR for controls was 81 ± 10 mL/min/1.73 m(2) at baseline and 80 ± 10 mL/min/1.73 m(2) at follow-up compared with 82 ± 13 and 58 ± 10 mL/min/1.73 m(2) for cases. Each doubling of KIM-1 level (in picograms per milliliter) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD stage 3 and/or rapid kidney function decrease. Compared with the lowest 90%, the highest decile of KIM-1 level was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (in nanograms per milliliter) were not associated with incident CKD stage 3 and/or rapid kidney function decrease (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL levels were standardized for urine creatinine.

Limitations

The case-control design limits the ability to account for persons who died or were not available for follow-up.

Conclusions

Urinary KIM-1 level is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk of CKD.

Background

African Americans and patients with chronic kidney disease (CKD) are at high risk for clinical heart failure (HF). In this study, we aimed to determine the association of markers of kidney disease with subclinical HF (by echocardiogram) and risk of clinical HF among a large, well-characterized community-based cohort of African American patients. We also examined whether the association of markers of kidney disease with HF was attenuated with adjustment for echocardiographic measures.

Methods

We studied participants in the Jackson Heart Study, a large community-based cohort of African Americans. Estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) were measured at baseline. We tested the association of eGFR and urine ACR with left ventricular mass (LVM), left ventricular ejection fraction (LVEF) and physician-adjudicated incident HF.

Results

Among the 3332 participants in the study, 166 (5%) had eGFR <60 mL/min/1.73 m² and 405 (12%) had urine ACR ≥30 mg/g. In models adjusted for demographics, comorbidity and the alternative measure of kidney disease, lower eGFR and higher urine ACR were associated with higher LVM {β-coefficient 1.54 [95% confidence interval (CI) 0.78-2.31] per 10 mL/min/1.73 m² decrease in eGFR and 2.87 (95% CI 1.85-3.88) per doubling of urine ACR}. There was no association of eGFR and urine ACR with LVEF [β-coefficient -0.12 (95% CI -0.28-0.04) and -0.11 (95% CI -0.35-0.12), respectively]. There was no association of eGFR with the risk of incident HF [HR 1.02 (95% CI 0.91-1.14) per 10 mL/min/1.73 m² decrease], while there was a significant association of urine ACR [HR 2.22 (95% CI 1.29-3.84) per doubling of urine ACR]. This association was only modestly attenuated with adjustment for LVM [HR 1.95 (95% CI 1.09-3.49)].

Conclusions

Among a community-based cohort of African Americans, lower eGFR and higher ACR were associated with higher LVM. Furthermore, higher urine ACR was associated with incident HF, which was not entirely explained by the presence of left ventricular disease.

Recent evidence has demonstrated the importance of kidney function in healthy aging. We examined the association between kidney function and change in cognitive function in 3,907 participants in the Cardiovascular Health Study who were recruited from 4 US communities and studied from 1992 to 1999. Kidney function was measured by cystatin C-based estimated glomerular filtration rate (eGFRcys). Cognitive function was assessed using the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test, which were administered up to 7 times during annual visits. There was an association between eGFRcys and change in cognitive function after adjustment for confounders; persons with an eGFRcys of less than 60 mL/minute/1.73 m(2) had a 0.64 (95% confidence interval: 0.51, 0.77) points/year faster decline in Modified Mini-Mental State Examination score and a 0.42 (95% confidence interval: 0.28, 0.56) points/year faster decline in Digit Symbol Substitution Test score compared with persons with an eGFRcys of 90 or more mL/minute/1.73 m(2). Additional adjustment for intermediate cardiovascular events modestly affected these associations. Participants with an eGFRcys of less than 60 mL/minute/1.73 m(2) had fewer cognitive impairment-free life-years on average compared with those with eGFRcys of 90 or more mL/minute/1.73 m(2), independent of confounders and mediating cardiovascular events (mean difference = -0.44, 95% confidence interval: -0.62, -0.26). Older adults with lower kidney function are at higher risk of worsening cognitive function.

Vitamin D deficiency is prevalent in 25% of Americans. However, 25(OH)D may not be an accurate measure of vitamin D because the majority (85%-90%) of 25(OH)D is bound to vitamin D binding protein (VDBP), which varies by over 30% across individuals. Free 25(OH)D may be a better measure, but it is difficult to measure accurately and precisely. The existing free 25(OH)D estimating equation does not include VDBP phenotypes; therefore, new equations that include this variable may be more accurate. A total of 370 participants in the Health, Aging, and Body Composition Study, a cohort of healthy community-dwelling individuals aged 70-79 years old, underwent VDBP and vitamin D metabolite [25(OH)D, 24,25(OH)2D, 1,25(OH)2D, free 25(OH)D] measurements and were randomly allocated into equation development (two out of three) and internal validation (one out of three) groups. New equations were developed with multiple linear regression and were internally validated with Bland-Altman plots. The mean age was 75 ± 3 years, 53% were female, and the mean measured free 25(OH)D was 5.37 ± 1.81 pg/mL. Three equations were developed. The first equation included albumin, 25(OH)D3, 25(OH)D2, VDBP, 1,25(OH)2D3, and 24,25(OH)2D3. The second equation included all variables in Eq. (1) plus VDBP phenotypes. The third equation included albumin, 25(OH)D3, intact parathyroid hormone, and 1,25(OH)2D3. In internal validation, all three new equations predicted free 25(OH)D values within 30% and 15% of the measured free 25(OH)D concentrations in 76%-80% and 48%-52% of study participants, respectively. Equation (2) was the most precise, with a mean bias of 0.06 (95% limits of agreement -2.41 to 2.30) pg/mL. The existing equation estimated free 25(OH)D within 30% and 15% of measured free 25(OH)D in 43% and 22% of participants, respectively. Free 25(OH)D can be estimated with clinically available biomarkers as well as with more laboratory-intensive biomarkers with moderate precision. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

AIMS: Among persons with prevalent heart failure (HF), iron deficiency has been linked to HF admissions, and intravenous iron replacement improves HF outcomes. Recent studies in persons with chronic kidney disease (CKD) demonstrate that iron deficiency is associated with incident HF. This study aimed to determine the relationship of iron status with incident HF in community-dwelling older adults irrespective of their kidney function. METHODS: In this case-cohort study, 1,006 Cardiovascular Health Study participants (785 from the random sub-cohort [including 193 HF cases] and 221 additional HF cases [N = 414 total HF cases]) aged ≥ 65 years without HF (41% with CKD), we used weighted Cox models to evaluate associations of iron status with incident HF. Participants were categorized based on quartiles of transferrin saturation and ferritin as iron replete (27.3%), functional iron deficiency (7.7%), iron deficiency (11.8%), mixed iron deficiency (5.6%), high iron (9.3%) and non-classified (38.1%), consistent with prior studies. RESULTS: Compared to older persons who were iron replete, those with iron deficiency were at higher risk of incident HF (HR 1.47; 1.02-2.11) in models adjusting for demographics, HF risk factors, and estimated glomerular filtration rate. Other iron categories did not associate with incident HF. The relationship of iron deficiency with incident HF did not differ by CKD status (interaction P value 0.2). CONCLUSIONS: Among community-dwelling elders, iron deficiency is independently associated with incident HF, an association that was similar irrespective of CKD status. Our findings support conduct of clinical trials of iron replacement for prevention of HF in older adults with iron deficiency.

Rationale & objective

Urinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes.

Study design

Observational cohort.

Setting & participants

We analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m² and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline.

Outcomes

The primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation).

Analytical approach

We used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration).

Results

During a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr.

Limitations

Cohort excluded patients with diabetes and overall had low levels of albuminuria.

Conclusions

1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.

Background and objectives

Although a peritoneal equilibration test yields data on three parameters (4-hour dialysate/plasma creatinine, 4- to 0-hour dialysate glucose, and 4-hour ultrafiltration volume), all studies have focused on the prognostic value of dialysate/plasma creatinine for patients undergoing peritoneal dialysis. Because dialysate 4- to 0-hour glucose and ultrafiltration volume may be superior in predicting daily ultrafiltration, the likely mechanism for the association of peritoneal equilibration test results with outcomes, we hypothesized that they are superior to dialysate/plasma creatinine for risk prediction.

Design, setting, participants, & measurements

We examined unadjusted and adjusted associations of three peritoneal equilibration test parameters with all-cause mortality, technique failure, and hospitalization rate in 10,142 patients on peritoneal dialysis treated between January 1, 2007 and December 31, 2011 in 764 dialysis facilities operated by a single large dialysis organization in the United States, with a median follow-up period of 15.8 months; 87% were treated with automated peritoneal dialysis.

Results

Demographic and clinical parameters explained only 8% of the variability in dialysate/plasma creatinine. There was a linear association between dialysate/plasma creatinine and mortality (adjusted hazards ratio per 0.1 unit higher, 1.07; 95% confidence interval, 1.02 to 1.13) and hospitalization rate (adjusted incidence rate ratio per 0.1 unit higher, 1.05; 95% confidence interval, 1.03 to 1.06). Dialysate/plasma creatinine and dialysate glucose were highly correlated (r=-0.84) and yielded similar risk prediction. Ultrafiltration volume was inversely related with hospitalization rate but not with all-cause mortality. None of the parameters were associated with technique failure. Adding 4- to 0-hour dialysate glucose, ultrafiltration volume, or both did not result in any improvement in risk prediction with dialysate/plasma creatinine alone.

Conclusions

This analysis from a large contemporary cohort treated primarily with automated peritoneal dialysis validates dialysate/plasma creatinine as a robust predictor of outcomes in patients treated with peritoneal dialysis.

BACKGROUND: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail. METHODS: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables. RESULTS: Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function. CONCLUSIONS: Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.

Objective

To describe ethnic and sex differences in the prevalence and determinants of fatty liver in a multiethnic cohort.

Patients and methods

We studied participants of the Multi-Ethnic Study of Atherosclerosis who underwent baseline noncontrast cardiac computed tomography between July 17, 2000, and August 29, 2002, and had adequate hepatic and splenic imaging for fatty liver determination (n=4088). Fatty liver was defined as a liver/spleen attenuation ratio of less than 1. We compared the prevalence and severity of fatty liver, in 4 ethnicities (white, Asian, African American, and Hispanic), and the factors associated with fatty liver in each ethnicity, stratifying by obesity and metabolic syndrome. Multivariable ordinal logistic regression was used to determine the effect of cardiometabolic risk factors on the prevalence of fatty liver in different ethnicities.

Results

The prevalence of fatty liver varied significantly by ethnicity (African American, 11%; white, 15%; Asian, 20%; and Hispanic, 27%; P<.001). Although African Americans had the highest prevalence of obesity, a smaller percentage of obese African Americans received a diagnosis of fatty liver than did other ethnicities (African American, 17%; white, 31%; Asian, 37%; and Hispanic 39%; P<.001). Hispanics had the highest prevalence of fatty liver, including the obese and metabolic syndrome population. An increase in insulin resistance predicted a 2-fold increased prevalence of fatty liver in all ethnicities after multivariable adjustment.

Conclusion

African Americans have a lower prevalence and Hispanics have a higher prevalence of fatty liver than do other ethnicities. There are distinct ethnic variations in the prevalence of fatty liver even in patients with the metabolic syndrome or obesity, suggesting that genetic factors may play a substantial role in the phenotypic expression of fatty liver.

Background

Serum fibroblast growth factor-23 (FGF-23) is associated with cardiovascular disease (CVD), yet the mechanisms remain uncertain. Our objective was to determine whether higher FGF-23 concentrations are associated with arterial stiffness.

Methods

In this cross-sectional study, serum FGF-23 concentrations were measured in 5977 participants without known CVD in the Multi-Ethnic Study of Atherosclerosis. The primary outcomes of interest were large (LAE) and small artery elasticity (SAE), pulse pressure and ankle-brachial index (ABI) > 1.30. LAE and SAE were measured by pulse contour analysis of the radial artery. Pulse pressure was measured with an automated sphygmomanometer using the average of two resting blood pressure measurements. ABI was calculated as the ratio of the ankle and brachial systolic blood pressures.

Results

Serum FGF-23 concentrations were not significantly associated with LAE [relative difference (RD) per doubling: 0%; 95% confidence interval (CI): -2-1%], SAE (RD per doubling: 0%; 95% CI: -3-2%), pulse pressure (β per doubling: 0.44; 95% CI: -0.31-1.19), or a high ABI (odds ratio per doubling: 1.14; 95% CI: 0.84-1.55). Findings were similar irrespective of chronic kidney disease status.

Conclusions

Higher serum FGF-23 concentrations are not associated with arterial stiffness, as measured by pulse pressure, LAE, SAE or high ABI, in a community-based population without CVD.