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In this meta-analysis of 16 studies, investigators evaluated the use of cystatin C, alone or with creatinine, to calculate the estimated glomerular filtration rate (eGFR). Measurement of cystatin C improved the prediction of outcomes in chronic kidney disease. The estimated glomerular filtration rate (eGFR) is the clinical standard for the assessment of kidney function. 1 – 3 The eGFR thresholds for the definition and staging of chronic kidney disease are based on risk, 3 but measurement of creatinine to determine the eGFR has limitations in risk prediction, particularly in patients with reduced muscle mass. 4 Cystatin C has received much attention as an alternative filtration marker with stronger and more linear risk relationships than creatinine. 5 – 7 Several studies have suggested that the addition of cystatin C measurements to creatinine measurements in calculating the eGFR significantly improves the risk classification for death, cardiovascular . . .

Globally, nearly 10% of the population has chronic kidney disease (CKD), defined as a glomerular filtration rate less than 60 mL/min/1.73 m2 and/or a urinary albumin to creatinine ratio greater than 30 mg/g (3 mg/mmol). Persons with CKD have a substantially high risk of cardiovascular disease. Indeed, most persons with CKD are far more likely to develop a cardiovascular event than to progress to end-stage kidney disease. Although early detection and staging of CKD could help prevent its cardiovascular consequences, current rates of testing for CKD are very low, even among high-risk populations such as persons with diabetes, hypertension and cardiovascular disease. In this review, we first describe the need to test for both estimated glomerular filtration rate and albuminuria among persons at high risk of CKD in order to properly stage CKD and enhance cardiovascular risk stratification. We then discuss how detection and staging for CKD could help prioritise patients at high risk of atherosclerotic cardiovascular disease and heart failure who could derive the largest benefit from cardiovascular preventive interventions. In addition, we discuss the central role of CKD detection and staging in the initiation of cardiorenal preventive therapies, such as the sodium–glucose cotransporter 2 inhibitors, which have shown overwhelming evidence of cardiorenal protection. We conclude by discussing strategies to overcome historical barriers to CKD detection and treatment.

(See the article by Kalayjian et al, on pages 1796–1805, and the editorial commentary by Dubé and Sattler, on pages 1783–1785.) Background. Human immunodeficiency virus (HIV) replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection. Methods. For persons 45–76 years of age, levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, D-dimer, and cystatin C were compared in 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study and 5386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study. For persons 33–44 years of age, hsCRP and IL-6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study. Results. hsCRP and IL-6 levels were 55% (P<.001) and 62% (P<.001) higher among HIV-infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL-6, D-dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (P<.001 , for each), among HIV-infected participants. HIV-infected participants receiving antiretroviral therapy who had HIV RNA levels ≤400 copies/mL had levels higher (by 21% to 60%) (P<.001) than those in the general population, for all biomarkers. Conclusions. hsCRP, IL-6, D-dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways, to guide potential interventions.

Assessing glomerular filtration rate (GFR) is critical for diagnosis, staging, and management of kidney disease. However, accuracy of estimated GFR (eGFR) is limited by large errors (>30% error present in >10–50% of patients), adversely impacting patient care. Errors often result from variation across populations of non-GFR determinants affecting the filtration markers used to estimate GFR. We hypothesized that combining multiple filtration markers with non-overlapping non-GFR determinants into a panel GFR could improve eGFR accuracy, extending current recognition that adding cystatin C to serum creatinine improves accuracy. Non-GFR determinants of markers can affect the accuracy of eGFR in two ways: first, increased variability in the non-GFR determinants of some filtration markers among application populations compared to the development population may result in outlying values for those markers. Second, systematic differences in the non-GFR determinants of some markers between application and development populations can lead to biased estimates in the application populations. Here, we propose and evaluate methods for estimating GFR based on multiple markers in applications with potentially higher rates of outlying predictors than in development data. We apply transfer learning to address systematic differences between application and development populations. We evaluated a panel of 8 markers (5 metabolites and 3 low molecular weight proteins) in 3,554 participants from 9 studies. Results show that contamination in two strongly predictive markers can increase imprecision by more than two-fold, but outlier identification with robust estimation can restore precision nearly fully to uncontaminated data. Furthermore, transfer learning can yield similar results with even modest training set sample size. Combining both approaches addresses both sources of error in GFR estimates. Once the laboratory challenge of developing a validated targeted assay for additional metabolites is overcome, these methods can inform the use of a panel eGFR across diverse clinical settings, ensuring accuracy despite differing non-GFR determinants.

ABSTRACT BACKGROUND Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown. OBJECTIVE To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants. Design The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older. PARTICIPANTS 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m 2 were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003. MAIN MEASURES The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol. KEY RESULTS During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD. CONCLUSIONS Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

Cystatin C is a cysteine protease inhibitor that is freely filtered by the glomerulus and is therefore a measure of renal function. In this study of elderly persons, the serum cystatin C level was a better predictor of the risk of death and cardiovascular disease than was the serum creatinine level. Cystatin C is a useful alternative measure of renal function, as well as an effective prognostic tool. In this study of elderly persons, the serum cystatin C level was a better predictor of the risk of death and cardiovascular disease than was the serum creatinine level. The presence of renal dysfunction in elderly persons has been associated with an increased risk of death among healthy persons in outpatient care 1 , 2 and among those with several clinical factors, including heart failure, 3 acute hospitalization, 4 inpatient surgery, 5 , 6 and acute myocardial infarction. 7 , 8 However, the primary clinical tool for measuring renal function, the serum creatinine level, is insensitive for the detection of moderate reductions in renal function and is affected by factors unrelated to renal function, such as age, sex, race, and lean muscle mass. Creatinine-based equations to estimate the glomerular filtration rate (GFR) have been derived to compensate . . .

Background Cystatin C is a well-validated marker of glomerular filtration rate in chronic kidney disease. Higher plasma concentrations of cystatin C are associated with worse clinical outcomes in heterogenous populations of critically ill patients and may be superior to creatinine in identifying kidney injury in critically ill patients. We hypothesized that elevated levels of plasma cystatin C in patients with acute respiratory distress syndrome (ARDS) would be associated with mortality risk. Methods In a retrospective study, cystatin C was measured by nephelometry on plasma obtained at enrollment from 919 patients in the Fluid and Catheter Treatment Trial. Multivariable logistic regression was performed testing the association between quartiles of cystatin C and 60-day mortality. Analyses were stratified by acute kidney injury (AKI) status identified in the first 7 days after enrollment by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Results Cystatin C was significantly higher among those patients who died compared to those who survived to 60 days [1.2 (0.9–1.9) mg/L vs. 0.8 (0.6–1.2) mg/L, p  < 0.001]. Compared to the lower three quartiles, subjects in the highest quartile of cystatin C had a significantly higher odds of death at 60 days [OR 1.8 (1.2–2.6), p  = 0.003 in adjusted analyses]; the odds of death incrementally rose in higher cystatin C quartiles compared to the lowest quartile (OR 1.1, 1.8, and 2.5). In adjusted analyses stratified by AKI status, compared to subjects in the lower three quartiles, subjects in the highest quartile of cystatin C with AKI had a significantly higher odds of death at 60 days both in participants with AKI [OR 1.6 (1.0–2.4), p  = 0.048] and those without AKI [OR 2.4 (1.2–5.0), p  = 0.017]. In adjusted analyses, there was no significant association between sex-stratified baseline creatinine quartiles and mortality. Conclusions Higher plasma levels of cystatin C on enrollment were strongly associated with mortality at 60 days in patients with ARDS with and without AKI identified by creatinine-based definitions. Compared to creatinine, cystatin C may be a better biomarker of kidney function in patients with ARDS and therefore identify patients with multiple organ failure at higher risk of death.

We previously demonstrated that assessment of the duration of AKI, in addition to magnitude of rise in creatinine alone, adds prognostic information for long-term survival. We evaluated whether post-operative kidney injury biomarkers in urine collected immediately after cardiac surgery associate with duration of serum creatinine elevation. We studied 1199 adults undergoing cardiac surgery in a prospective cohort study (TRIBE-AKI) and examined the association between the levels of five urinary biomarkers individually at 0-6 hours after surgery: interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver fatty acid binding protein (L-FABP) and albumin with duration of serum creatinine-based AKIN criteria for AKI (0 (no AKI), 1-2, 3-6, ≥7 days). Overall, 407 (34%) patients had at least stage 1 AKI, of whom 251 (61.7%) had duration of 1-2 days, 118 (28.9%) had duration 3-6 days, and 38 (9.3%) had duration of ≥7 days. Higher concentrations of all biomarkers (per log increase) were independently associated with a greater odds of a longer duration of AKI; odds ratios and 95% confidence intervals using ordinal logistic regression were the following: IL-18: 1.22, 1.13-1.32; KIM-1: 1.36, 1.21-1.52; albumin 1.20, 1.09-1.32; L-FABP 1.11, 1.04-1.19; NGAL 1.06, 1.00-1.14). AKI duration of 7 days or longer was associated with a 5-fold adjusted risk of mortality at 3 years. There was an independent dose-response association between urinary levels of injury biomarkers immediately after cardiac surgery and longer duration of AKI. Duration of AKI was also associated with long term mortality. Future studies should explore the potential utility of these urinary kidney injury biomarkers to enrich enrollment of patients at risk for longer duration of AKI into trials of interventions to prevent or treat post-operative AKI.

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/1.73m 2 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.

Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that reduced errors in estimation between Black participants and non-Black participants.