Risk for Chronic Kidney Disease Progression After Acute Kidney Injury: Findings From the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not. OBJECTIVE: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD). DESIGN: Multicenter prospective cohort study. SETTING: United States. PARTICIPANTS: Patients with CKD (n = 3150). MEASUREMENTS: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits. RESULTS: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m2) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m2) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m2 per year) also had CI bounds that included the possibility of no effect. LIMITATIONS: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge. CONCLUSION: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. PRIMARY FUNDING SOURCE: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

Prospective associations of health literacy with clinical outcomes in adults with CKD: findings from the CRIC study.

BACKGROUND: Limited health literacy is associated with significant morbidity and mortality in the general population but the relation of health literacy with long-term clinical outcomes among adults with chronic kidney disease (CKD) is less clear. METHODS: Prospective data from the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3715) were used. Health literacy was assessed with the Short Test of Functional Health Literacy in Adults (dichotomized as limited/adequate). Cox proportional hazards models were used to separately examine the relations of health literacy with CKD progression, cardiovascular event (any of the following: myocardial infarction, congestive heart failure, stroke or peripheral artery disease), and all-cause, cardiovascular and non-cardiovascular mortality. Poisson regression was used to assess the health literacy-hospitalization association. Models were sequentially adjusted: Model 1 adjusted for potential confounders (sociodemographic factors), while Model 2 additionally adjusted for potential mediators (clinical and lifestyle factors) of the associations of interest. RESULTS: In confounder-adjusted models, participants with limited (vs adequate) health literacy [555 (15%)] had an increased risk of CKD progression [hazard ratio (HR) 1.34; 95% confidence interval (CI) 1.06-1.71], cardiovascular event (HR 1.67; 95% CI 1.39-2.00), hospitalization (rate ratio 1.33; 95% CI 1.26-1.40), and all-cause (HR 1.54; 95% CI 1.27-1.86), cardiovascular (HR 2.39; 95% CI 1.69-3.38) and non-cardiovascular (HR 1.27; 95% CI 1.01-1.60) mortality. Additional adjustments for potential mediators (Model 2) showed similar results except that the relations of health literacy with CKD progression and non-cardiovascular mortality were no longer statistically significant. CONCLUSIONS: In the CRIC Study, adults with limited (vs adequate) health literacy had a higher risk for CKD progression, cardiovascular event, hospitalization and mortality-regardless of adjustment for potential confounders.

A Comparative Study of Serum Phosphate and Related Parameters in Chronic Kidney Disease between the USA and Japan.

INTRODUCTION: Recent studies have suggested a higher incidence of cardiovascular disease (CVD) among patients with chronic kidney disease (CKD) in the USA than in Japan. Hyperphosphatemia, a possible risk for CVD, may explain this difference; however, international differences in phosphate parameters in CKD have not been well elaborated. METHODS: By using the baseline data from the USA and the Japanese nation-wide, multicenter, CKD cohort studies; the Chronic Renal Insufficiency Cohort Study (CRIC, N = 3,870) and the Chronic Kidney Disease-Japan Cohort Study (CKD-JAC, N = 2,632), we harmonized the measures and compared clinical parameters regarding phosphate metabolism or serum phosphate, fibroblast growth factor-23 (FGF23), and parathyroid hormone (PTH), in the cross-sectional model. RESULTS: Multivariable linear regression analyses revealed that serum phosphate levels were significantly higher in CRIC across all levels of estimated glomerular filtration rate (eGFR) with the greatest difference being observed at lower levels of eGFR. Serum FGF23 and 25-hydroxy vitamin D (25OHD) levels were higher in CRIC, while PTH levels were higher in CKD-JAC at all levels of eGFR. Adjustments for demographics, 25OHD, medications, dietary intake or urinary excretion of phosphate, PTH, and FGF23 did not eliminate the difference in serum phosphate levels between the cohorts (0.43, 0.46, 0.54, 0.64, and 0.78 mg/dL higher in CRIC within eGFR strata of >50, 41-50, 31-40, 21-30, and ≤20 mL/min/1.73 m2, respectively). These findings were consistent when only Asian CRIC participants (N = 105) were included in the analysis. CONCLUSION: Serum phosphate levels in CRIC were significantly higher than those of CKD-JAC across all stages of CKD, which may shed light on the international variations in phosphate parameters and thus in cardiovascular risk among CKD patients. The key mechanisms for the substantial differences in phosphate parameters need to be elucidated.

Fibroblast Growth Factor 23 and Risk of Hospitalization with Infection in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. METHODS: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. RESULTS: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). CONCLUSIONS: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.

Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease.

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-ß (TGF-ß)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-ß were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-ß, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.

Effects of Sodium Bicarbonate in CKD Stages 3 and 4: A Randomized, Placebo-Controlled, Multicenter Clinical Trial.

RATIONALE & OBJECTIVE: Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and bone outcomes. STUDY DESIGN: Multicenter, randomized, placebo-controlled, clinical trial. SETTING & PARTICIPANTS: 149 patients with CKD stages 3 and 4 between July 2011 and April 2016 at 3 centers in Cleveland, OH, and the Bronx, NY. INTERVENTION: Sodium bicarbonate (0.4 mEq per kg of ideal body weight per day) (n=74) or identical-appearing placebo (n=75). OUTCOMES: Dual primary outcomes were muscle function assessed using sit-to-stand test and bone mineral density. Muscle biopsies were performed at baseline and 2 months. Participants were seen at baseline and 2, 6, 12, and 24 months. RESULTS: Mean baseline serum bicarbonate level was 24.0±2.2 (SD) mEq/L and mean baseline estimated glomerular filtration rate was 36.3±11.2mL/min/1.73m2. Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm during follow-up were 26.4±2.2, 25.5±2.3, 25.6±2.6, and 24.4±2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (P<0.001). Compared to the placebo group, participants randomly assigned to sodium bicarbonate treatment had no significant differences in sit-to-stand time (5 repetitions: P=0.1; and 10 repetitions P=0.07) or bone mineral density (P=0.3). Sodium bicarbonate treatment caused a decrease in serum potassium levels that was of borderline statistical significance (P=0.05). There were no significant differences in estimated glomerular filtration rates, blood pressure, weight, serious adverse events, or levels of muscle gene expression between the randomly assigned groups. LIMITATIONS: Initial mean serum bicarbonate level was in the normal range. CONCLUSIONS: Sodium bicarbonate therapy in patients with CKD stages 3 and 4 significantly increases serum bicarbonate and decreases potassium levels. No differences were found in muscle function or bone mineral density between the randomly assigned groups. Larger trials are required to evaluate effects on kidney function. FUNDING: National Institutes of Health grant. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01452412.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. STUDY DESIGN: Retrospective analysis nested in a cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). EXPOSURE: Years before ESKD. OUTCOMES: Serial FGF-23, PTH, serum phosphate, and serum calcium levels. ANALYTICAL APPROACH: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. RESULTS: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. LIMITATIONS: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. CONCLUSIONS: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Influence of Baseline Diastolic Blood Pressure on Effects of Intensive Compared With Standard Blood Pressure Control.

BACKGROUND: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. METHODS: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. RESULTS: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level (P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57-1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61-0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. CONCLUSIONS: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Lipids, Apolipoproteins, and Risk of Atherosclerotic Cardiovascular Disease in Persons With CKD.

RATIONALE & OBJECTIVE: A large residual risk for atherosclerotic cardiovascular disease (ASCVD) remains in the setting of chronic kidney disease (CKD) despite treatment with statins. We sought to evaluate the associations of lipid and apolipoprotein levels with risk for ASCVD in individuals with CKD. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Adults aged 21 to 74 years with non-dialysis-dependent CKD at baseline enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in 7 clinical study centers in the United States. PREDICTOR: Baseline total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), HDL-C, and apolipoprotein AI (Apo-AI) values stratified into tertiles. OUTCOME: A composite ASCVD event of myocardial infarction or ischemic stroke. ANALYTIC APPROACH: Multivariable Cox proportional hazards regression to estimate the risk for ASCVD for each tertile of lipoprotein predictor. RESULTS: Among 3,811 CRIC participants (mean age, 57.7 years; 41.8% white), there were 451 ASCVD events during a median follow-up of 7.9 years. There was increased ASCVD risk among participants with VLDL-C levels in the highest tertile (HR, 1.28; 95% CI, 1.01-1.64), Apo-B levels in the middle tertile (HR, 1.30; 95% CI, 1.03-1.64), HDL-C levels in the middle and lowest tertiles (HRs of 1.40 [95% CI, 1.08-1.83] and 1.77 [95% CI, 1.35-2.33], respectively), and Apo-AI levels in the middle and lowest tertiles (HRs of 1.77 [95% CI, 1.02-1.74] and 1.77 [95% CI, 1.36-2.32], respectively). LDL-C level was not significantly associated with the ASCVD outcome in this population (HR, 1.00 [95% CI, 0.77-1.30] for the highest tertile). LIMITATIONS: Associations based on observational data do not permit inferences about causal associations. CONCLUSIONS: Higher VLDL-C and Apo-B levels, as well as lower HDL-C and Apo-AI levels, are associated with increased risk for ASCVD. These findings support future investigations into pharmacologic targeting of lipoproteins beyond LDL-C, such as triglyceride-rich lipoproteins, to reduce residual risk for ASCVD among individuals with CKD.

Erythrocytosis is associated with intradialytic hypotension: a case series.

BACKGROUND: For patients with end stage renal disease undergoing hemodialysis, erythrocytosis occurs rarely. Erythrocytosis increases the risk of thrombosis, which is a common complication in hemodialysis patients. The risk of thrombosis may also be increased by hypotension. The purpose of our report is to examine the relationship between intradialytic hypotension and erythrocytosis. CASE PRESENTATION: We present a series of five patients with end stage renal disease and erythrocytosis (peak hemoglobin range 15.2-18.5 g/dL). All were erythropoiesis-stimulating agent naïve and non-smokers. Prior to developing erythrocytosis, each patient developed recurring episodes of intradialytic hypotension over several months. A statistically significant inverse correlation was observed between nadir intradialytic systolic blood pressure and hemoglobin concentration. In the index case, midodrine treatment resulted in resolution of the hypotension and erythrocytosis. Most of the patients had multiple acquired renal cysts, which is a potential source of erythropoietin. Four of the five cases developed arteriovenous dialysis access or deep venous thrombosis. CONCLUSIONS: An association between intradialytic hypotension and erythrocytosis was observed in five cases. We postulate that chronic intermittent hypotension and renal ischemia may lead to erythropoietin secretion, and this cascade could represent a newly recognized cause of secondary erythrocytosis.

Risks of Adverse Events in Advanced CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: People with advanced chronic kidney disease are at risk for the development of end-stage renal disease (ESRD), but also many other adverse outcomes, including cardiovascular disease (CVD) events and death. Determination of risk factors that explain the variability in prognosis and timing of these adverse outcomes can aid patient counseling and medical decision making. STUDY DESIGN: Prospective research cohort. SETTING & PARTICIPANTS: 1,798 participants with estimated glomerular filtration rates (eGFRs)<30mL/min/1.73m2 in the CRIC Study were followed up for a median of 5.5 years. PREDICTORS: Age, race, sex, eGFR, proteinuria, diabetes mellitus, body mass index, ejection fraction, systolic blood pressure, history of CVD, and smoking history. OUTCOMES: ESRD, CVD (congestive heart failure, stroke, myocardial infarction, and peripheral artery disease), and death. RESULTS: Baseline age of the cohort was 60 years, 46% were women, and 46% were African American. Although 52.3% of participants progressed to ESRD during follow-up, the path by which this occurred was variable. For example, predicted 1-year probabilities for a hypothetical 60-year-old white woman with eGFR of 30mL/min/1.73m2, urine protein excretion of 1.8g/d, and no diabetes or CVD (risk characteristics similar to the average participant) were 3.3%, 4.1%, and 0.3%, for first developing CVD, ESRD, and death, respectively. For a 40-year-old African American man with similar characteristics but higher systolic blood pressure, the corresponding 1-year probabilities were 2.4%, 13.2%, and 0.1%. For all participants, the development of ESRD or CVD increased the risk for subsequent mortality, with no differences by patient race or body mass index. LIMITATIONS: The CRIC population was specifically recruited for kidney disease, and the vast majority had seen a nephrologist. CONCLUSIONS: The prognosis and timing of adverse outcomes in chronic kidney disease vary by patient characteristics. These results may help guide the development of personalized approaches for managing patients with advanced CKD.

Change in Measured GFR Versus eGFR and CKD Outcomes.

Measured GFR (mGFR) has long been considered the gold standard measure of kidney function, but recent studies have shown that mGFR is not consistently superior to eGFR in explaining CKD-related comorbidities. The associations between longitudinal changes in mGFR versus eGFR and adverse outcomes have not been examined. We analyzed a subset of 942 participants with CKD in the Chronic Renal Insufficiency Cohort Study who had at least two mGFRs and two eGFRs determined concurrently by iothalamate and creatinine (eGFRcr) or cystatin C, respectively. We compared the associations between longitudinal changes in each measure of kidney function over 2 years and risks of ESRD, nonfatal cardiovascular events, and all-cause mortality using univariate Cox proportional hazards models. The associations for all outcomes except all-cause mortality associated most strongly with longitudinal decline in eGFRcr. Every 5-ml/min per 1.73 m(2) decline in eGFRcr over 2 years associated with 1.54 (95% confidence interval, 1.44 to 1.66; P<0.001) times higher risk of ESRD and 1.23 (95% confidence interval, 1.12 to 1.34; P<0.001) times higher risk for cardiovascular events. All-cause mortality did not associate with longitudinal decline in mGFR or eGFR. When analyzed by tertiles of renal function decline, mGFR did not outperform eGFRcr in the association with any outcome. In conclusion, compared with declines in eGFR, declines in mGFR over a 2-year period, analyzed either as a continuous variable or in tertiles, did not consistently show enhanced association with risk of ESRD, cardiovascular events, or death.

Abrupt Decline in Kidney Function Before Initiating Hemodialysis and All-Cause Mortality: The Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: It is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation. PREDICTORS: The primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR≥30mL/min/1.73m(2) at that time point. OUTCOMES: All-cause mortality within 1 year after initiating hemodialysis therapy. MEASUREMENTS: Multivariable Cox proportional hazards. RESULTS: Among 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76). LIMITATIONS: Relatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data. CONCLUSIONS: Abrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD.

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD.

BACKGROUND: Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, ß-trace protein (BTP), ß2-microglobulin (B2M), and cystatin C, are not well characterized. STUDY DESIGN: Pooled cross-sectional analysis of 3 studies. SETTING & PARTICIPANTS: 3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTORS: Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations. OUTCOMES: Serum creatinine, BTP, B2M, and cystatin C levels. RESULTS: In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C. LIMITATIONS: Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. CONCLUSIONS: Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

Proteinuria, but Not eGFR, Predicts Stroke Risk in Chronic Kidney Disease: Chronic Renal Insufficiency Cohort Study.

BACKGROUND AND PURPOSE: Chronic kidney disease is associated with an increased risk of cardiovascular events. However, the impact of chronic kidney disease on cerebrovascular disease is less well understood. We hypothesized that renal function severity would be predictive of stroke risk, independent of other vascular risk factors. METHODS: The study population included 3939 subjects enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study, a prospective observational cohort. Stroke events were reported by participants and adjudicated by 2 vascular neurologists. Cox proportional hazard models were used to compare measures of baseline renal function with stroke events. Multivariable analysis was performed to adjust for key covariates. RESULTS: In 3939 subjects, 143 new stroke events (0.62 events per 100 person-years) occurred over a mean follow-up of 6.4 years. Stroke risk was increased in subjects who had worse baseline measurements of renal function (estimated glomerular filtration rate and total proteinuria or albuminuria). When adjusted for variables known to influence stroke risk, total proteinuria or albuminuria, but not estimated glomerular filtration rate, were associated with an increased risk of stroke. Treatment with blockers of the renin-angiotensin system did not decrease stroke risk in individuals with albuminuria. CONCLUSIONS: Proteinuria and albuminuria are better predictors of stroke risk in patients with chronic kidney disease than estimated glomerular filtration rate. The impact of therapies targeting proteinuria/albuminuria in individuals with chronic kidney disease on stroke prevention warrants further investigation.

Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: The purpose of this study is to evaluate serum bicarbonate level as a risk factor for renal outcomes, cardiovascular events, and mortality in patients with chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and December 2008. PREDICTOR: Serum bicarbonate level. OUTCOMES: Renal outcomes, defined as end-stage renal disease (either initiation of dialysis therapy or kidney transplantation) or 50% reduction in estimated glomerular filtration rate (eGFR); atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease); congestive heart failure events; and death. MEASUREMENTS: Time to event. RESULTS: Mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m(2), and median serum bicarbonate level was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, 332 experienced an atherosclerotic event, and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal end point was 3% lower per 1-mEq/L increase in serum bicarbonate level (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01). The association was stronger for participants with eGFR >45 mL/min/1.73 m(2) (HR, 0.91; 95% CI, 0.85-0.97; P = 0.004). The risk of heart failure increased by 14% (HR, 1.14; 95% CI, 1.03-1.26; P = 0.02) per 1-mEq/L increase in serum bicarbonate level over 24 mEq/L. Serum bicarbonate level was not associated independently with atherosclerotic events (HR, 0.99; 95% CI, 0.95-1.03; P = 0.6) and all-cause mortality (HR, 0.98; 95% CI, 0.95-1.02; P = 0.3). LIMITATIONS: Single measurement of sodium bicarbonate. CONCLUSIONS: In a cohort of participants with CKD, low serum bicarbonate level was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate levels. There was no association between serum bicarbonate level and all-cause mortality or atherosclerotic events.

Association of cardiac troponin T with left ventricular structure and function in CKD.

BACKGROUND: Serum cardiac troponin T (cTnT) is associated with increased risk of heart failure and cardiovascular death in several population settings. We evaluated associations of cTnT levels with cardiac structural and functional abnormalities in a cohort of patients with chronic kidney disease (CKD) without heart failure. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: Chronic Renal Insufficiency Cohort (CRIC; N=3,243). PREDICTOR: The primary predictor was cTnT level. Secondary predictors included demographic and clinical characteristics, hemoglobin level, high-sensitivity C-reactive protein level, and estimated glomerular filtration rate using cystatin C. OUTCOMES: Echocardiography was used to determine left ventricular (LV) mass and LV systolic and diastolic function. MEASUREMENTS: Circulating cTnT was measured in stored sera using the highly sensitive assay. Logistic and linear regression models were used to examine associations of cTnT level with each echocardiographic outcome. RESULTS: cTnT was detectable in 2,735 (84%) persons; median level was 13.3 (IQR, 7.7-23.8) pg/mL. Compared with undetectable cTnT (<3.0 pg/mL), the highest quartile (23.9-738.7 pg/mL) was approximately 2 times as likely to have LV hypertrophy (OR, 2.43; 95% CI, 1.44-4.09) in the fully adjusted model. cTnT level had a more modest association with LV systolic dysfunction; as a log-linear variable, a significant association was present in the fully adjusted model (OR of 1.4 [95% CI, 1.2-1.7] per 1-log unit; P < 0.001). There was no significant independent association between cTnT level and LV diastolic dysfunction. When evaluated as a screening test, cTnT level functioned only modestly for LV hypertrophy and concentric hypertrophy detection (area under the curve, 0.64 for both), with weaker areas under the curve for the other outcomes. LIMITATIONS: The presence of coronary artery disease was not formally assessed using either noninvasive or angiographic techniques in this study. CONCLUSIONS: In this large CKD cohort without heart failure, detectable cTnT had a strong association with LV hypertrophy, a more modest association with LV systolic dysfunction, and no association with diastolic dysfunction. These findings indicate that circulating cTnT levels in patients with CKD are predominantly an indicator of pathologic LV hypertrophy.

Expert Consensus on the Nephrotoxic Potential of 195 Medications in the Non-intensive Care Setting: A Modified Delphi Method.

INTRODUCTION: Nephrotoxin exposure is significantly associated with acute kidney injury (AKI) development. A standardized list of nephrotoxic medications to surveil and their perceived nephrotoxic potential (NxP) does not exist for non-critically ill patients. OBJECTIVE: This study generated consensus on the nephrotoxic effect of 195 medications used in the non-intensive care setting. METHODS: Potentially nephrotoxic medications were identified through a comprehensive literature search, and 29 participants with nephrology or pharmacist expertise were identified. The primary outcome was NxP by consensus. Participants rated each drug on a scale of 0-3 (not nephrotoxic to definite nephrotoxicity). Group consensus was met if ≥ 75% of responses were one single rating or a combination of two consecutive ratings. If ≥ 50% of responses indicated "unknown" or not used in the non-intensive care setting, the medication was removed for consideration. Medications not meeting consensus for a given round were included in the subsequent round(s). RESULTS: A total of 191 medications were identified in the literature, with 4 medications added after the first round from participants' recommendations. NxP index rating consensus after three rounds was: 14 (7.2%) no NxP in almost all situations (rating 0); 62 (31.8%) unlikely/possibly nephrotoxic (rating 0.5); 21 (10.8%) possibly nephrotoxic (rating 1); 49 (25.1%) possibly/probably nephrotoxic (rating 1.5); 2 (1.0%) probably nephrotoxic (rating 2); 8 (4.1%) probably/definite nephrotoxic (rating 2.5); 0 (0.0%) definitely nephrotoxic (rating 3); and 39 (20.0%) medications were removed from consideration. CONCLUSIONS: NxP index rating provides clinical consensus on perceived nephrotoxic medications in the non-intensive care setting and homogeneity for future clinical evaluations and research.

Probing the Association between Acute Kidney Injury and Cardiovascular Outcomes.

BACKGROUND: Patients hospitalized with AKI have higher subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality than their counterparts without AKI, but these higher risks may be due to differences in prehospitalization patient characteristics, including the baseline level of estimated glomerular filtration rate (eGFR), the rate of prior eGFR decline, and the proteinuria level, rather than AKI itself. METHODS: Among 2177 adult participants in the Chronic Renal Insufficiency Cohort study who were hospitalized in 2013-2019, we compared subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality between those with serum creatinine-based AKI (495 patients) and those without AKI (1682 patients). We report both crude associations and associations sequentially adjusted for prehospitalization characteristics including eGFR, eGFR slope, and urine protein-creatinine ratio (UPCR). RESULTS: Compared with patients hospitalized without AKI, those with hospitalized AKI had lower eGFR prehospitalization (42 versus 49 ml/min per 1.73 m 2 ), faster chronic loss of eGFR prehospitalization (-0.84 versus -0.51 ml/min per 1.73 m 2 per year), and more proteinuria prehospitalization (UPCR 0.28 versus 0.16 g/g); they also had higher prehospitalization systolic BP (130 versus 127 mm Hg; P < 0.01 for all comparisons). Adjustment for prehospitalization patient characteristics attenuated associations between AKI and all three outcomes, but AKI remained an independent risk factor. Attenuation of risk was similar after adjustment for absolute eGFR, eGFR slope, or proteinuria, individually or in combination. CONCLUSIONS: Prehospitalization variables including eGFR, eGFR slope, and proteinuria confounded associations between AKI and adverse cardiovascular outcomes, but these associations remained significant after adjusting for prehospitalization variables.

Effect of Intensive Blood Pressure Control on Kidney Outcomes: Long-Term Electronic Health Record-Based Post-Trial Follow-Up of SPRINT.

BACKGROUND: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values. METHODS: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m 2 and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m 2 , respectively. RESULTS: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was -0.67 ml/min per 1.73 m 2 per year (95% confidence interval [CI], -0.79 to -0.56) in the standard treatment group and -0.96 ml/min per 1.73 m 2 per year (95% CI, -1.08 to -0.85) in the intensive treatment group ( P < 0.001). The slopes were not significantly different during the observation phase: -1.02 ml/min per 1.73 m 2 per year (95% CI, -1.24 to -0.81) in the standard group and -0.85 ml/min per 1.73 m 2 per year (95% CI, -1.07 to -0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70). CONCLUSIONS: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase.