Michael G. Shlipak

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

Elevations of Inflammatory and Procoagulant Biomarkers in Elderly Persons With Renal Insufficiency

Background—Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. Methods and Results—The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged ≥65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level ≥1.3 mg/dL in women and ≥1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P <0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. Conclusion—Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis.

BACKGROUND Acute kidney injury (AKI) is common in hospitalized patients. The impact of AKI on long-term outcomes is controversial. STUDY DESIGN Systematic review and meta-analysis. SETTING & PARTICIPANTS Persons with AKI. SELECTION CRITERIA FOR STUDIES MEDLINE and EMBASE databases were searched from 1985 through October 2007. Original studies describing outcomes of AKI for patients who survived hospital discharge were included. Studies were excluded from review when participants were followed up for less than 6 months. PREDICTOR AKI, defined as acute changes in serum creatinine level or acute need for renal replacement therapy. OUTCOMES Chronic kidney disease (CKD), cardiovascular disease, and mortality. RESULTS 48 studies that contained a total of 47,017 participants were reviewed; 15 studies reported long-term data for patients without AKI. The incidence rate of mortality was 8.9 deaths/100 person-years in survivors of AKI and 4.3 deaths/100 patient-years in survivors without AKI (rate ratio [RR], 2.59; 95% confidence interval, 1.97 to 3.42). AKI was associated independently with mortality risk in 6 of 6 studies that performed multivariate adjustment (adjusted RR, 1.6 to 3.9) and with myocardial infarction in 2 of 2 studies (RR, 2.05; 95% confidence interval, 1.61 to 2.61). The incidence rate of CKD after an episode of AKI was 7.8 events/100 patient-years, and the rate of end-stage renal disease was 4.9 events/100 patient-years. LIMITATIONS The relative risk for CKD and end-stage renal disease after AKI was unattainable because of lack of follow-up of appropriate controls without AKI. CONCLUSIONS The development of AKI, defined as acute changes in serum creatinine level, characterizes hospitalized patients at increased risk of long-term adverse outcomes.

Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients

Context Renal insufficiency increases the risk for cardiovascular disease, but whether it affects survival after myocardial infarction is unknown. Contribution This large cohort study of Medicare beneficiaries hospitalized between April 1994 and July 1995 revealed the following: 1-year postmyocardial infarction mortality for no, mild, and moderate renal insufficiency was 24%, 46%, and 66%, respectively. Moderate renal insufficiency was more common in black and male patients and in patients with diabetes or previous stroke. Patients with moderate renal insufficiency received aspirin, -blockers, thrombolytic therapy, angiography, and angioplasty less often than patients with mild or no renal insufficiency. Implications Patients with moderate renal insufficiency have increased mortality after myocardial infarction. They also get fewer effective treatments for myocardial infarction, which may explain the higher death rate. The Editors Patients with end-stage renal disease who require dialysis have markedly increased mortality after myocardial infarction compared with other patients. One-year mortality in these patients is approximately 60% (1-3). After myocardial infarction, these patients are also unlikely to receive aggressive therapy, such as thrombolytic therapy and primary angioplasty, although these treatments have been associated with improved survival in these patients (4). Patients with renal insufficiency have a greater risk for cardiovascular disease events (5, 6), but the association between mild and moderate renal insufficiency and survival after myocardial infarction has not been evaluated in-depth (1, 7). Two earlier studies have included measures of renal function in prediction models for death after myocardial infarction. Normand and colleagues (8) incorporated both blood urea nitrogen and creatinine levels into a multivariate prediction model for 30-day mortality after myocardial infarction. Jacobs and colleagues included urea nitrogen levels as one of seven categories of predictors for death after hospital admission for acute coronary syndromes (9). However, studies have not compared survival after myocardial infarction among patients with and without renal insufficiency. In addition, the use of medical treatments and procedures after myocardial infarction among patients with and without renal insufficiency, and their association with survival, has not been studied. We hypothesized that patients with mild and moderate renal insufficiency would have substantially greater 1-year mortality than patients with no renal insufficiency. We also hypothesized that patients with renal insufficiency would be less likely to receive therapeutic interventions known to improve survival after myocardial infarction, such as -blockers, aspirin, angiotensin-converting enzyme (ACE) inhibitors, thrombolytic therapy, and primary angioplasty. Using data from the Cooperative Cardiovascular Project, we evaluated the treatment of patients with no renal insufficiency and patients with mild and moderate renal insufficiency. We also determined the independent association of renal insufficiency with survival after myocardial infarction. Methods Patients The Cooperative Cardiovascular Project collected data from all elderly (age 65 years) Medicare beneficiaries who were admitted between April 1994 and July 1995 to an acute-care hospital and discharged with the diagnosis of acute myocardial infarction (International Classification of Diseases, Ninth Revision, diagnosis code 410) (10). The diagnosis was confirmed by review of the medical records for each patient and required a serum creatine kinaseMB index greater than 5%; an elevated serum lactate dehydrogenase level with lactate dehydrogenase-1 greater than or equal to lactate dehydrogenase-2; or two of the following three criteria: chest pain, serum creatine kinase level more than twice the normal value, or electrocardiographic evidence of acute myocardial infarction (11). A total of 139 567 patients had confirmed myocardial infarction. Only the initial hospitalization for myocardial infarction during the period of evaluation was included. We excluded 6790 patients with severe renal insufficiency (serum creatinine level 4.0 mg/dL [354 mol/L]) or estimated creatinine clearance less than 0.17 mL/sec. We also excluded 10 570 patients (8.1%) for whom information on body weight was not available to estimate creatinine clearance. Measurements Within the Cooperative Cardiovascular Project, trained medical record abstracters collected the following data for each patient: date and location of hospitalization, demographic characteristics, comorbid conditions, severity of illness measures, electrocardiogram findings, laboratory values, results from invasive and noninvasive cardiac studies, contraindications to therapy, in-hospital treatments, and discharge medications (9). The reliability of the data abstraction process has been demonstrated (10, 12). We classified renal function using both the admission serum creatinine level and the estimated creatinine clearance. We defined no renal insufficiency as a serum creatinine level less than 1.5 mg/dL (<132 mol/L), mild renal insufficiency as a serum creatinine level between 1.5 and 2.4 mg/dL (132 to 212 mol/L), and moderate renal insufficiency as a serum creatinine level between 2.5 and 3.9 mg/dL (221 to 345 mol/L). We estimated creatinine clearance by using the CockroftGault equation (13) and divided patients into tertiles. Data on serum creatinine levels were available for all patients. Data on mortality during the first year after hospital admission were obtained from Social Security Administration records. Statistical Analysis We compared the characteristics and treatments of patients with no renal insufficiency, mild renal insufficiency, and moderate renal insufficiency using analysis of variance and chi-square tests. We compared the proportions of patients treated with -blockers among all patients in each category of renal function and in just the patients without relative contraindications to -blockers (previous heart failure, diabetes, chronic obstructive pulmonary disease, and pulmonary edema at presentation). We compared use of ACE inhibitors among all patients and then restricted the comparison to patients with hypertension or diabetes. For thrombolytic therapy, we compared treatment as a proportion of all patients treated and as a proportion of ideal patients treated. Ideal candidates were defined by ST-segment elevation or left bundle-branch block on the electrocardiogram; onset of chest pain within 6 hours of presentation; age of 80 years or younger; and the absence of peptic ulcer disease, chronic liver disease, metastatic cancer, and terminal illness (14). To determine the association of renal function with survival after myocardial infarction, we constructed KaplanMeier curves for the three groups of serum creatinine levels (and the tertiles of creatinine clearance); statistical significance was assessed by using the log-rank test. We repeated these analyses within subgroups of patients who presented without pulmonary edema or cardiogenic shock (Killip class I and class II) to determine whether the association of renal function with 1-year survival persisted among patients with less severe myocardial infarctions. We used Cox proportional-hazards models to determine whether mild and moderate renal insufficiency were independent predictors of 1-year mortality (15). These models were adjusted for patient demographic characteristics (age, sex, race, rural or urban setting, and region of the United States); comorbid conditions (history of diabetes mellitus, hypertension, hypercholesterolemia, tobacco use, congestive heart failure, stroke, peripheral vascular disease, angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, chronic obstructive pulmonary disease, dementia, inability to ambulate, depression, and incontinence); severity of clinical presentation (Killip class, electrocardiogram findings, heart rate, mean arterial blood pressure, alertness and orientation according to the Glasgow coma scale, duration of chest pain, and blood urea nitrogen level [< 30 mg/dL; <10.7 mmol/L as urea or 30 mg/dL; 10.7 mmol/L as urea]); hospital characteristics (capability to do coronary angiography and revascularization; volume of myocardial infarction admissions); in-hospital treatments (aspirin, -blockers, ACE inhibitors, thrombolytic therapy, intravenous nitroglycerin, coronary angiography, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft surgery); and discharge medications (aspirin, -blockers, calcium-channel blockers, and ACE inhibitors). We evaluated the inclusion of a categorical variable for each hospital (n = 4200) in a 10% sample of our data set, but it had little effect on the association of renal function with survival after myocardial infarction. We also checked for violations of linearity by examining augmented models, which included quadratic terms for continuous predictors. We tested the validity of the proportional hazards assumption by determining whether the risk estimates for the renal function categories varied significantly over time. Because we found a significant interaction of the risk for renal function over time, we elected to explore stratified models over time. We separately evaluated the association of our renal function categories with survival after myocardial infarction for the following time intervals: months 1, 2 to 3, 4 to 6, 7 to 9, and 10 to 12. Because the association of renal insufficiency with mortality was the same for months 7 to 9 and 10 to 12, we combined these follow-up intervals. We confirmed that there were no residual violations of the proportional hazards assumption within each time strata by again testing for the presence of an interaction of each renal function predictor with time in predicting mor

Markers of Inflammation, Coagulation, and Renal Function Are Elevated in Adults with HIV Infection

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.

Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals

OBJECTIVES This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events. BACKGROUND End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear. METHODS We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women. RESULTS An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine. CONCLUSIONS Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease

Context Cystatin C concentration approximates glomerular filtration rate (GFR) more precisely than creatinine concentration. Can it identify people without known kidney disease who have increased risks for cardiovascular disease? Contribution In this longitudinal study involving 3659 elderly persons without known kidney disease (estimated GFR 60 mL/min per 1.73 m2), increasing cystatin C concentration was associated with increased risks for death, stroke, myocardial infarction, heart failure, and progression to chronic kidney disease. Associations were much stronger for cystatin C than for creatinine. Cautions Albuminuria was not measured; some patients may have been misclassified as having no kidney disease. Implications Among elderly persons, cystatin C concentration may be a better biomarker for adverse outcomes than serum creatinine concentration. The Editors Chronic kidney disease is a worldwide health problem that carries a substantial risk for cardiovascular morbidity and death. Chronic kidney disease has been defined as a creatinine-based estimated glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 (1), which represents a loss of more than half of normal kidney function. An estimated GFR less than 60 mL/min per 1.73 m2 has been strongly associated with cardiovascular risk and death (2). However, surprisingly little evidence supports an association of kidney function with adverse clinical events at GFR levels of 60 mL/min per 1.73 m2 or greater (1). The absence of risk associated with an estimated GFR of 60 mL/min per 1.73 m2 or greater may reflect a biological threshold effectthat milder reductions of actual GFR are clinically inconsequentialor may be due to inherent limitations of serum creatinine for estimating GFR (35). Cystatin C is an alternative serum measure of kidney function that approximates direct measures of GFR (for example, iothalamate clearance) more precisely than creatinine, because its serum concentrations are independent of muscle mass and do not seem to be affected by age or sex (68). Cystatin C is a 122amino acid, 13-kDa protein that is a member of a family of competitive inhibitors of lysosomal cysteine proteinases. Its functions include involvement in extracellular proteolysis, modulation of the immune system, and antibacterial and antiviral activities. Cystatin C has several properties that make it a good candidate marker of GFR, including a constant production rate regulated by a housekeeping gene expressed in all nucleated cells, free filtration at the glomerulus, complete reabsorption and catabolism by the proximal tubules with no reabsorption into the bloodstream, and no renal tubular secretion (6). Among elderly persons who do not meet standard criteria for chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2), many participants in the Cardiovascular Health Study (CHS) have elevated cystatin C concentrations (1.0 mg/L). We hypothesized that cystatin C would be an important prognostic factor for risk for death, cardiovascular disease, and incident chronic kidney disease, whereas estimated GFR and creatinine would be unable to distinguish levels of risk. Our goal was to determine whether elevated cystatin C concentrations in patients with normal estimated GFR could define a state of preclinical kidney disease. Methods Description of the Cohort The Cardiovascular Health Study (CHS) is a community-based, longitudinal study of adults 65 years of age and older at baseline (9). Enrollment began in 1989, with annual visits thereafter. The study recruited persons from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania, with the following inclusion criteria: 1) older than 65 years of age, 2) not institutionalized, 3) expected to remain in the current community for 3 years or longer, 4) not receiving active treatment for cancer, and 5) gave written informed consent without requiring a proxy respondent. The study design, quality control procedures, laboratory methods, and blood pressure measurement procedures have been published previously (9, 10). Our analysis includes 4663 CHS participants who attended the 19921993 annual visit and who had measurements of creatinine and cystatin C concentrations. We excluded 274 participants because creatinine concentration was not available or cystatin C concentration could not be measured due to inadequate serum specimens. Follow-up for events continued until 30 June 2002 with a median of 9.3 years (maximum of 10.1 years). Kidney Function Measurements We measured all assays on fasting plasma specimens that were stored at 70C. We measured cystatin C concentration by using a BNII nephelometer (Dade Behring Inc., Deerfield, Illinois) that utilized a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring Inc.) (11). The assay range is 0.195 mg/L to 7.330 mg/L. The reference ranges for young, healthy individuals and healthy persons older than 50 years of age are reported to be 0.53 mg/L to 0.92 mg/L and 0.58 mg/L to 1.02 mg/L, respectively (12). We measured serum creatinine concentration by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), a colorimetric method. The mean coefficient of variation was 1.94% (creatinine level range, 102.5 mol/L [1.16 mg/dL] to 344.8 mol/L [3.90 mg/dL]). We calculated the estimated GFR from serum creatinine by using the modified 4-variable version of the Modification of Diet in Renal Disease (MDRD) formula (13). We indirectly calibrated the creatinine levels in our study with those from the Cleveland Clinic laboratorythe core laboratory of the MDRD trialas previously described (14, 15). As recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) group, we defined chronic kidney disease on the basis of an estimated GFR less than 60 mL/min per 1.73 m2 (1). Secondary Predictors We chose demographic characteristics (age, sex, and race); traditional cardiovascular risk factors (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol levels, presence of diabetes and hypertension, current smoking, height, weight, and physical activity); C-reactive protein level; and prevalent heart failure, myocardial infarction, or stroke as adjustment variables for all analyses. We defined hypertension by a seated blood pressure average of 140/90 mm Hg or greater or a history of treated hypertension. We determined the presence of diabetes by clinical history of diabetes, use of hypoglycemic agent or insulin, or fasting glucose level of 7.0 mmol/L or greater (126 mg/dL). We adjudicated the self-report of prevalent myocardial infarction, stroke, and heart failure as previously described (16). Outcomes Follow-up visits occurred by telephone every 6 months and in person annually. The primary outcomes included in our study were all-cause death, cardiovascular death, noncardiovascular death, incident heart failure, stroke, and myocardial infarction. A CHS outcome assessment committee adjudicated these events. We identified deaths by review of obituaries, medical records, death certificates, the Centers for Medicare & Medicaid Services health care utilization database for hospitalizations, and household contacts. We have actively followed all persons through clinical visits, telephone calls, or surveillance of death registries. We defined cardiovascular death as death caused by coronary heart disease, heart failure, peripheral vascular disease, or cerebrovascular disease (16). Methods used to diagnose incident heart failure, stroke, and myocardial infarction have been previously described (1719). We also compared the rate of progression to incident chronic kidney disease at the 19961997 examination among participants with estimated GFR greater than 60 mL/min per 1.73 m2 at baseline (19921993). Unlike the primary outcomes that occurred on specific dates during follow-up, incident chronic kidney disease was a discrete outcome that could only occur at the time of the 19961997 examination when we measured follow-up creatinine concentration. Statistical Analysis Our analysis began by separating the cohort into persons with and without estimated GFR less than 60 mL/min per 1.73 m2 at the 19921993 clinical visit. We compared the mean cystatin C concentration, creatinine concentration, and estimated GFR within each stratum and Pearson correlations among the 3 measures. We used a Fisher 2-sample Z-test for correlations to determine whether the correlations of cystatin C with estimated GFR and creatinine differed between persons with and persons without chronic kidney disease. We limited our next analyses to participants without chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2). We compared the distributions of creatinine and cystatin C concentrations graphically. We used penalized smoothing splines (P-splines) to depict the association of each measure with mortality risk across the full range in the subcohort without chronic kidney disease (20). Results are similar to smoothing splines with a knot at each data point but are computationally simpler. We used multivariate Cox proportional hazards models to compare the association of cystatin C and creatinine concentrations as linear variables (per SD) with each outcome. Evaluations of incident heart failure, stroke, and myocardial infarction excluded participants with prevalent disease. We tested for a nonlinear association by adding a quadratic term to each model, but these were not statistically significant. We verified the proportional hazards assumption by using graphical methods, as well as formal hypothesis testing. To test for proportionality of hazards, we used KaplanMeier curves. The graph of the survival function versus the survival time resulted in parallel curves. Similarly, the graph of the log(log(survival)) versus log(survival time) also resulted in parallel lines. We also used tests and

Postoperative Biomarkers Predict Acute Kidney Injury and Poor Outcomes after Pediatric Cardiac Surgery

Acute kidney injury (AKI) occurs commonly after pediatric cardiac surgery and associates with poor outcomes. Biomarkers may help the prediction or early identification of AKI, potentially increasing opportunities for therapeutic interventions. Here, we conducted a prospective, multicenter cohort study involving 311 children undergoing surgery for congenital cardiac lesions to evaluate whether early postoperative measures of urine IL-18, urine neutrophil gelatinase-associated lipocalin (NGAL), or plasma NGAL could identify which patients would develop AKI and other adverse outcomes. Urine IL-18 and urine and plasma NGAL levels peaked within 6 hours after surgery. Severe AKI, defined by dialysis or doubling in serum creatinine during hospital stay, occurred in 53 participants at a median of 2 days after surgery. The first postoperative urine IL-18 and urine NGAL levels strongly associated with severe AKI. After multivariable adjustment, the highest quintiles of urine IL-18 and urine NGAL associated with 6.9- and 4.1-fold higher odds of AKI, respectively, compared with the lowest quintiles. Elevated urine IL-18 and urine NGAL levels associated with longer hospital stay, longer intensive care unit stay, and duration of mechanical ventilation. The accuracy of urine IL-18 and urine NGAL for diagnosis of severe AKI was moderate, with areas under the curve of 0.72 and 0.71, respectively. The addition of these urine biomarkers improved risk prediction over clinical models alone as measured by net reclassification improvement and integrated discrimination improvement. In conclusion, urine IL-18 and urine NGAL, but not plasma NGAL, associate with subsequent AKI and poor outcomes among children undergoing cardiac surgery.

Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study.

Background— Previous studies have associated reduced hemoglobin levels with increased adverse events in heart failure. It is unclear, however, whether this relation is explained by underlying kidney disease, treatment differences, or associated comorbidity. Methods and Results— We examined the associations between hemoglobin level, kidney function, and risks of death and hospitalization in persons with chronic heart failure between 1996 and 2002 within a large, integrated, healthcare delivery system in northern California. Longitudinal outpatient hemoglobin and creatinine levels and clinical and treatment characteristics were obtained from health plan records. Glomerular filtration rate (GFR; mL · min−1 · 1.73 m−2) was estimated from the Modification of Diet in Renal Disease equation. Mortality data were obtained from state death files; heart failure admissions were identified by primary discharge diagnoses. Among 59 772 adults with heart failure, the mean age was 72 years and 46% were women. Compared with that for hemoglobin levels of 13.0 to 13.9 g/dL, the multivariable-adjusted risk of death increased with lower hemoglobin levels: an adjusted hazard ratio (HR) of 1.16 and 95% confidence interval (CI) of 1.11 to 1.21 for hemoglobin levels of 12.0 to 12.9 g/dL; HR, 1.50 and 95% CI, 1.44 to 1.57 for 11.0 to 11.9 g/dL; HR, 1.89 and 95% CI, 1.80 to 1.98 for 10.0 to 10.9; HR, 2.31 and 95% CI, 2.18 to 2.45 for 9.0 to 9.9; and HR, 3.48 and 95% CI, 3.25 to 3.73 for <9.0 g/dL. Hemoglobin levels ≥17.0 g/dL were associated with an increased risk of death (adjusted HR, 1.42; 95% CI, 1.24 to 1.63). Compared with those with a GFR ≥60 mL · min−1 · 1.73 m−2, persons with a GFR <45 mL · min−1 · 1.73 m−2 had an increased mortality risk: adjusted HR, 1.39 and 95% CI, 1.34 to 1.44 for 30 to 44; HR, 2.28 and 95% CI, 2.19 to 2.39 for 15 to 29; HR, 3.26 and 95% CI, 3.05 to 3.49 for <15; and HR, 2.44 and 95% CI, 2.28 to 2.61 for those on dialysis. Relations were similar for the risk of hospitalization. The findings did not differ among patients with preserved or reduced systolic function, and hemoglobin level was an independent predictor of outcomes at all levels of kidney function. Conclusions— Very high (≥17 g/dL) or reduced (<13 g/dL) hemoglobin levels and chronic kidney disease independently predict substantially increased risks of death and hospitalization in heart failure, regardless of the level of systolic function. Randomized trials are needed to evaluate whether raising hemoglobin levels can improve outcomes in chronic heart failure.

Multiple loci associated with indices of renal function and chronic kidney disease

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m2) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10−8) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.