Association of Urinary Dickkopf-3 Levels with Cardiovascular Events and Kidney Disease Progression in Systolic Blood Pressure Intervention Trial.

BACKGROUND: Urinary Dickkopf-3 (uDKK3) is a tubular epithelial-derived profibrotic protein secreted into the urine under tubular stress. It is associated with kidney disease progression in persons with chronic kidney disease (CKD) and diabetes, and post-operative and contrast-associated acute kidney injury (AKI). We explored associations of uDKK3 with cardiovascular disease (CVD), kidney and mortality outcomes within the subset of Systolic Blood Pressure Intervention Trial (SPRINT) participants with non-diabetic CKD. METHODS: We included 2,344 participants with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at baseline. We used Cox proportional hazards models to evaluate associations of uDKK3 with CVD (acute decompensated heart failure, myocardial infarction, acute coronary syndrome, stroke or CVD death), kidney outcomes (incident end stage kidney disease [ESKD], incident AKI, and eGFR decline ≥30%), and all-cause mortality. We used linear mixed models to examine the association of uDKK3 with annual percentage change in eGFR. Models were adjusted for demographic and clinical characteristics, eGFR and albuminuria. RESULTS: Over a median follow up of 3.5 years, there were 292 CVD, 73 ESKD, 183 AKI, 471 eGFR decline, and 228 mortality events. In multivariable models without adjustment for eGFR and albuminuria, uDKK3 was strongly associated with CVD, ESKD, AKI, eGFR decline ≥30%, and mortality. However, after further adjustment for eGFR and albuminuria, uDKK3 was no longer associated with risks for composite CVD (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.92-1.23), ESKD (0.80; 0.62-1.02), AKI (1.01; 0.85-1.21), eGFR decline >30% (0.88; 0.79-0.99) or mortality (1.02; 0.87-1.20). For the linear eGFR change outcome, higher uDKK3 also had no association in the fully adjusted model (-0.03; -0.41-0.36). CONCLUSIONS: Among individuals with hypertension and non-diabetic CKD, higher uDKK3 appeared to have associations with a greater risk of CVD events, incident ESKD, incident AKI, eGFR decline ≥30%, and mortality, but was not independent of eGFR and albuminuria.

Plasma proenkephalin A and incident chronic kidney disease and albuminuria in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Plasma proenkephalin A (PENK-A) is a precursor of active enkephalins. Higher blood concentrations have been associated with estimated glomerular filtration rate (eGFR) decline in European populations. Due to the significant disparity in incident chronic kidney disease (CKD) between White and Black people, we evaluated the association of PENK-A with incident CKD and other kidney outcomes among a biracial cohort in the U.S. METHODS: In a nested cohort of 4,400 participants among the REasons for Geographic And Racial Differences in Stroke, we determined the association between baseline PENK-A concentration and incident CKD using the creatinine-cystatin C CKD-EPI 2021 equation without race coefficient, significant eGFR decline, and incident albuminuria between baseline and a follow-up visit 9.4 years later. We tested for race and sex interactions. We used inverse probability sampling weights to account for the sampling design. RESULTS: At baseline, mean (SD) age was 64 (8) years, 49% were women, and 52% were Black participants. 8.5% developed CKD, 21% experienced ≥ 30% decline in eGFR and 18% developed albuminuria. There was no association between PENK-A and incident CKD and no difference by race or sex. However, higher PENK-A was associated with increased odds of progressive eGFR decline (OR: 1.12; 95% CI 1.00, 1.25). Higher PENK-A concentration was strongly associated with incident albuminuria among patients without diabetes mellitus (OR: 1.29; 95% CI 1.09, 1.53). CONCLUSION: While PENK-A was not associated with incident CKD, its associations with progression of CKD and incident albuminuria, among patients without diabetes, suggest that it might be a useful tool in the evaluation of kidney disease among White and Black patients.

Tubule dysfunction and injury and future risk of sepsis-associated acute kidney injury.

BACKGROUND: Novel biomarkers can quantify both kidney tubule function, including proximal tubule reabsorptive (urine α-1 microglobulin (uα1m)) and tubule protein synthesis capacities (urine uromodulin (uUMOD)), and tubular injury (urine neutrophil gelatinase-associated lipocalin (uNGAL)). In a blood pressure trial, we reported that lower reabsorptive and synthetic protein capacity at times of health predicted future risk of acute kidney injury (AKI), but most AKI was related to hemodynamic causes in this trial. Associations between tubular function and injury and future AKI related to other causes is unknown. MATERIALS AND METHODS: We performed a case-control study in REGARDS, a population-based cohort study, among participants who provided urine at the baseline visit. We matched each septic AKI case by age, sex, race, and time from baseline to hospital admission 1 : 1 to a participant with sepsis who did not develop AKI (controls). Using conditional logistic regression, we evaluated the associations of uα1m, uUMOD, urine ammonium, and uNGAL with septic AKI. RESULTS: Mean age was 69 ± 8 years, 44% were female, and 39% were Black participants. Median baseline eGFR among cases and controls was 73 (55, 90) and 82 (65, 92) mL/min/1.73m2, and median albuminuria was 19 (8, 87) vs. 9 (5, 22) mg/g, respectively. No independent associations were observed between the tubule function or injury markers and subsequent risk of septic AKI once models were adjusted for baseline albuminuria, estimated glomerular filtration rate, and other risk factors. CONCLUSION: Among community participants, tubule function and injury markers at times of health were not independently associated with future risk of septic AKI.

Urine Uromodulin, Kidney Tubulointerstitial Fibrosis, and Furosemide Response.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IFTA) are common findings on biopsy in chronic kidney disease (CKD) and strongly predictive of kidney failure. IFTA is poorly correlated with estimated glomerular filtration rate (eGFR) and albuminuria, the most common metrics of kidney disease. Thus, IFTA is prognostically important, yet its presence and severity are invisible to the clinician except when kidney biopsies are obtained. OBJECTIVES: To investigate 1) the cross-sectional association between urine uromodulin (uUMOD) and IFTA, and 2) to determine whether uUMOD levels were associated with diuretic response after a furosemide stress test. METHODS: We performed logistic regression to evaluate the association between uUMOD and fibrosis. We used linear regression models to assess the association of uUMOD with urine output. RESULTS: Among 52 participants, the mean age was 42 ± 16 years, 48% were women, 23% had diabetes, and the median eGFR was 56 ml/min/1.73m2. The mean uUMOD concentration was 5.1 (8.4) mcg/mL. Each halving of uUMOD was associated with 1.74 higher odds (95% CI 1.10, 2.75) of grade 2 or 3 fibrosis. However, this association was no longer significant after adjusting for baseline eGFR and albuminuria. Each halving of urine uromodulin was associated with a decreased response to furosemide. This association was also no longer significant after adjusting for baseline eGFR and albuminuria. CONCLUSION: In a population of individuals with a wide range of kidney function undergoing clinically indicated kidney biopsies, we did not find an association between uUMOD and interstitial fibrosis or response to loop diuretics after adjusting for eGFR and albuminuria.

Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity.

RATIONALE & OBJECTIVE: Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. PREDICTORS: eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). OUTCOME: All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). ANALYTICAL APPROACH: Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. RESULTS: Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). LIMITATIONS: Included only Black and White persons in the United States. CONCLUSION: Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. PLAIN-LANGUAGE SUMMARY: Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

Markers of Kidney Tubule Dysfunction and Major Adverse Kidney Events.

BACKGROUND: Serum creatinine and albuminuria are primary markers of glomerular function and injury, respectively. Tubular secretion, acid-base homeostasis, protein reabsorption, among other tubular functions, are largely ignored. This mini-review aimed to discuss how two tubular functions, secretion, and acid-base homeostasis are associated with major adverse kidney events (MAKEs). SUMMARY: Proximal tubular secretion is an essential function that allows the elimination of endogenous substances and drugs. Recently discovered endogenous markers in urine and plasma allow a noninvasive way of assessing tubular secretion markers. Several studies have found an association between these markers and a higher risk of chronic kidney disease (CKD) progression and mortality. In a study we recently performed among patients with CKD and at risk of cardiovascular events, lower tubular secretion was associated with an increased risk of acute kidney injury and metabolic acidosis, independent of baseline eGFR and albuminuria. The kidney tubules also play a crucial role in acid-base homeostasis. Although the standard clinical assessment of acidosis consists of measuring serum bicarbonate, urinary ammonium excretion decreases before over metabolic acidosis. Urinary ammonium excretion is associated with CKD progression, a higher risk of kidney failure, and an increased mortality risk, independent of baseline eGFR and albuminuria. KEY MESSAGES: Novel biomarkers of kidney tubular health consistently associate with MAKEs, above and beyond baseline eGFR, albuminuria, and other CKD risk factors. Tubular markers may provide new opportunities to improve kidney prognosis, drug dosing, and monitoring for adverse events.

Risk Factors for Incident CKD in Black and White Americans: The REGARDS Study.

RATIONALE & OBJECTIVE: Little information exists on the incidence of and risk factors for chronic kidney disease (CKD) in contemporary US cohorts and whether risk factors differ by race, sex, or region in the United States. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 4,198 Black and 7,799 White participants aged at least 45 years, recruited from 2003 through 2007 across the continental United States, with baseline estimated glomerular filtration rate (eGFR)>60mL/min/1.73m2 and eGFR assessed again approximately 9 years later. EXPOSURES: Age, sex, race (Black or White), region ("stroke belt" or other), education, income, systolic blood pressure, body mass index, diabetes, coronary heart disease, hyperlipidemia, smoking, and albuminuria. OUTCOMES: (1) eGFR change and (2) incident CKD defined as eGFR<60mL/min/1.73m2 and≥40% decrease from baseline or kidney failure. ANALYTICAL APPROACH: Linear regression and modified Poisson regression were used to determine the association of risk factors with eGFR change and incident CKD overall and stratified by race, sex, and region. RESULTS: Mean age of participants was 63±8 (SD) years, 54% were female, and 35% were Black. After 9.4±1.0 years of follow-up, CKD developed in 9%. In an age-, sex-, and race-adjusted model, Black race (ß =-0.13; P<0.001) was associated with higher risk of eGFR change, but this was attenuated in the fully adjusted model (ß=0.02; P=0.5). Stroke belt residence was independently associated with eGFR change (ß =-0.10; P<0.001) and incident CKD (relative risk, 1.14 [95% CI, 1.01-1.30]). Albuminuria was more strongly associated with eGFR change (ß of-0.26 vs-0.17; P=0.01 for interaction) in Black compared with White participants. Results were similar for incident CKD. LIMITATIONS: Persons of Hispanic ethnicity were excluded; unknown duration and/or severity of risk factors. CONCLUSIONS: Established CKD risk factors accounted for higher risk of incident CKD in Black versus White individuals. Albuminuria was a stronger risk factor for eGFR decrease and incident CKD in Black compared with White individuals. Living in the US stroke belt is a novel risk factor for CKD.

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial.

Rational & Objective: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain. Study Design: Longitudinal subgroup analysis of clinical trial participants. Setting & Participants: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposure: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline. Outcome: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality. Analytical Approach: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality. Results: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m2 (P for interaction < 0.001). Limitations: Persons with diabetes and proteinuria >1 g/d were excluded. Conclusions: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

Lipid accumulation product, visceral adiposity index and risk of chronic kidney disease.

BACKGROUND: Lipid accumulation product (LAP) and visceral adiposity index (VAI) are novel, non-imaging markers of visceral adiposity that are calculated by using body mass index (BMI), waist circumference (WC) and serum lipid concentrations. We hypothesized that LAP and VAI are more strongly associated with adverse kidney outcomes than BMI and WC. METHODS: Using data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we used multivariable logistic regression to evaluate associations of LAP, VAI, BMI and WC with incident chronic kidney disease (CKD), (incident eGFR < 60 ml/min/1.73m2 and > 25% decline). RESULTS: Among the overall cohort of 27,550 participants, the mean baseline age was 65 years; 54% were women; and 41% were African American. After a median of 9.4 years (IQR 8.6, 9.9) of follow-up, a total of 1127 cases of incident CKD were observed. Each two-fold higher value of VAI (OR 1.12, 95% CI 1.04, 1.20), LAP (OR 1.21, 95% CI 1.13, 1.29), WC (OR 2.10, 95% CI 1.60, 2.76) and BMI (OR: 2.66, 95% CI 1.88, 3.77), was associated with greater odds of incident CKD. CONCLUSIONS: LAP and VAI as measures of visceral adiposity are associated with higher odds of incident CKD but may not provide information beyond WC and BMI.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Associations of High-Sensitivity Troponin and Natriuretic Peptide Levels With Serious Adverse Events in SPRINT.

Background Assessing the risk of serious adverse events (SAEs) during hypertension treatment is important for understanding the benefit-harm trade-offs of lower blood pressure goals. It is unknown whether high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) provide information about SAEs. Methods and Results In SPRINT (Systolic Blood Pressure Intervention Trial), hs-cTnT and NT-proBNP were measured at baseline in 8828 (94.3%) and 8836 (94.4%) participants, respectively. Multivariable Cox proportional hazards models were used to evaluate hs-cTnT and NT-proBNP associations with a composite of SPRINT's SAEs of interest: hypotension, syncope, bradycardia, acute kidney injury, electrolyte abnormalities, and injurious falls. Elevations in hs-cTnT and NT-proBNP were associated with increased composite SAE risk (hazard ratio [HR] per 2-fold higher hs-cTnT: 1.15; 95% CI, 1.06‒1.25; HR per 2-fold higher NT-proBNP: 1.09; 95% CI, 1.05‒1.14). Compared with both hs-cTnT and NT-proBNP in the lower tertiles, both biomarkers in the highest tertile was associated with increased composite SAE risk (HR, 1.56; 95% CI, 1.32‒1.84). Composite SAE risk was higher in the intensive-treatment group than in the standard-treatment group for participants with both biomarkers in the lower tertiles, but similar between treatment groups for participants with both biomarkers in the highest tertile (P for interaction=0.008). Conclusions Elevations in hs-cTnT and NT-proBNP individually and in combination are associated with higher composite SAE risk in SPRINT. The differential impact of blood pressure treatment on SAE risk across combined biomarker categories may have implications for identifying individuals with more favorable benefit-harm profiles for intensive blood pressure lowering.

Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT.

BACKGROUND: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. METHODS: Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). RESULTS: At baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). CONCLUSIONS: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.

RATIONALE & OBJECTIVE: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI). STUDY DESIGN: Observational cohort nested in a clinical trial. SETTING & PARTICIPANTS: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m2 at baseline. EXPOSURE: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1-microglobulin (A1M) and ß2-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH). OUTCOME: Longitudinal changes in eGFR and risk of AKI. ANALYTICAL APPROACH: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression. RESULTS: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively). LIMITATIONS: The factors require validation in other settings. CONCLUSIONS: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes?

CONTEXT: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used. OBJECTIVE: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes. DESIGN: Case cohort study from the Cardiovascular Health Study. SETTING: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years. OUTCOMES: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations. RESULTS: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk. CONCLUSIONS: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.

Is Tubular Dysfunction a Risk Factor for AKI?

Tubular functions are critical for homeostasis maintenance. However, tubular function markers are not typically assessed in routine clinical care. Recent research by our group has revealed that tubular dysfunction at baseline is a risk factor for subsequent acute kidney injury (AKI), independent of estimated glomerular filtration rate and albuminuria. Here, we describe the underlying hypotheses and biological insights and contrast the changes in tubule function versus injury both before and after an AKI episode.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury.

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and ß-2-microglobulin [ß2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.