Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study.

RATIONALE & OBJECTIVE: Safe analgesic choices are limited in chronic kidney disease (CKD). We conducted a comparative analysis of harm from opioids versus nonsteroidal anti-inflammatory drugs (NSAIDs) in CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,939 patients with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURES: 30-day analgesic use reported at annual visits. OUTCOMES: A composite outcome of 50% glomerular filtration rate reduction and kidney failure requiring kidney replacement therapy (KRT), as well as the outcomes of kidney failure requiring KRT, hospitalization, and pre-kidney failure death. ANALYTICAL APPROACH: Marginal structural models with time-updated exposures. RESULTS: Participants were followed up for a median of 6.84 years, with 391 (9.9%) and 612 (15.5%) reporting baseline opioid and NSAID use, respectively. Time-updated opioid use was associated with the kidney disease composite outcome, kidney failure with KRT, death (HRs of 1.4 [95% CI, 1.2-1.7], 1.4 [95% CI, 1.1-1.7], and 1.5 [95% CI, 1.2-2.0], respectively), and hospitalization (rate ratio [RR], 1.7; 95% CI, 1.6-1.9) versus opioid nonusers. Similar results were found in an analysis restricted to a subcohort of participants reporting ever using other (nonopioid and non-NSAID) analgesics or tramadol. Time-updated NSAID use was associated with increased risk for the kidney disease composite (HR, 1.2; 95% CI, 1.0-1.5) and hospitalization (RR, 1.1; 95% CI, 1.0-1.3); however, these associations were not significant in the subcohort. The association of NSAID use with the kidney disease composite outcome varied by race, with a significant risk in blacks (HR, 1.3; 95% CI, 1.0-1.7). NSAID use was associated with lower risk for kidney failure with KRT in women and individuals with glomerular filtration rate<45mL/min/1.73m2 (HRs of 0.63 [95% CI, 0.45-0.88] and 0.77 [95% CI, 0.59-0.99], respectively). LIMITATIONS: Limited periods of recall of analgesic use and potential confounding by indication. CONCLUSIONS: Opioid use had a stronger association with adverse events than NSAIDs, with the latter's association with kidney disease outcomes limited to specific subgroups, notably those of black race.

Patterns of NSAIDs Use and Their Association with Other Analgesic Use in CKD.

BACKGROUND AND OBJECTIVES: Avoiding nonsteroidal anti-inflammatory drugs is important for safe CKD care. This study examined nonsteroidal anti-inflammatory drug use patterns and their association with other analgesic use in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Chronic Renal Insufficiency Cohort Study is an observational cohort study that enrolled 3939 adults ages 21-74 years old with CKD between 2003 and 2008 using age-based eGFR inclusion criteria. Annual visits between June of 2003 and December of 2011 were organized into 15,917 visit-pairs (with an antecedent and subsequent visit) for 3872 participants with medication information. Demographics, kidney function, and clinical factors were ascertained along with report of nonsteroidal anti-inflammatory drug or other analgesic use in the prior 30 days. RESULTS: In our study, 24% of participants reported nonsteroidal anti-inflammatory drug use at baseline or at least one follow-up study visit. Having a 10 ml/min per 1.73 m2 higher eGFR level at an antecedent visit was associated with higher odds of starting nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 1.44; 95% confidence interval, 1.34 to 1.56). Seeing a nephrologist at the antecedent visit was associated with lower odds of starting or staying on nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87 and odds ratio, 0.61; 95% confidence interval, 0.46 to 0.81, respectively). Starting and stopping nonsteroidal anti-inflammatory drugs were both associated with higher odds of increasing the number of other analgesics (odds ratio, 1.52; 95% confidence interval, 1.25 to 1.85 and odds ratio, 1.78; 95% confidence interval, 1.39 to 2.28, respectively) and higher odds of increasing the number of opioid analgesics specifically (odds ratio, 1.92; 95% confidence interval, 1.48 to 2.48 and odds ratio, 1.46; 95% confidence interval, 1.04 to 2.03, respectively). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use is common among patients with CKD but less so among those with worse kidney function or those who see a nephrologist. Initiation or discontinuation of nonsteroidal anti-inflammatory drugs is often associated with supplementation with or replacement by, respectively, other analgesics, including opioids, which introduces possible drug-related problems when taking these alternative analgesics.

Loss of executive function after dialysis initiation in adults with chronic kidney disease.

The association of dialysis initiation with changes in cognitive function among patients with advanced chronic kidney disease is poorly described. To better define this, we enrolled participants with advanced chronic kidney disease from the Chronic Renal Insufficiency Cohort in a prospective study of cognitive function. Eligible participants had a glomerular filtration rate of 20 ml/min/1.73m2 or less, or dialysis initiation within the past two years. We evaluated cognitive function by a validated telephone battery at regular intervals over two years and analyzed test scores as z scores. Of 212 participants, 123 did not transition to dialysis during follow-up, 37 transitioned to dialysis after baseline, and 52 transitioned to dialysis prior to baseline. In adjusted analyses, the transition to dialysis was associated with a significant loss of executive function, but no significant changes in global cognition or memory. The estimated net difference in cognitive z scores at two years for participants who transitioned to dialysis during follow-up compared to participants who did not transition to dialysis was -0.01 (95% confidence interval -0.13, 0.11) for global cognition, -0.24 (-0.51, 0.03) for memory, and -0.33 (-0.60, -0.07) for executive function. Thus, among adults with advanced chronic kidney disease, dialysis initiation was associated with loss of executive function with no change in other aspects of cognition. Larger studies are needed to evaluate cognition during dialysis initiation.

Atrial Fibrillation and Risk of ESRD in Adults with CKD.

BACKGROUND AND OBJECTIVES: Atrial fibrillation frequently complicates CKD and is associated with adverse outcomes. Progression to ESRD is a major complication of CKD, but the link with atrial fibrillation has not been fully delineated. In this study, we examined the association of incident atrial fibrillation with the risk of ESRD in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied participants in the prospective Chronic Renal Insufficiency Cohort Study without atrial fibrillation at entry. Incident atrial fibrillation was identified by study visit ECGs, self-report, and hospital discharge diagnostic codes, with confirmation by physician adjudication. ESRD through 2012 was ascertained by participant self-report, medical records, and linkage to the US Renal Data System. Data on potential confounders were obtained from self-report, study visits, and laboratory tests. Marginal structural models were used to study the potential association of incident atrial fibrillation with risk of ESRD after adjustment for time-dependent confounding. RESULTS: Among 3091 participants, 172 (5.6%) developed incident atrial fibrillation during follow-up. During mean follow-up of 5.9 years, 43 patients had ESRD that occurred after development of incident atrial fibrillation (11.8/100 person-years) compared with 581 patients without incident atrial fibrillation (3.4/100 person-years). In marginal structural models with inverse probability weighting, incident atrial fibrillation was associated with a substantially higher rate of ESRD (hazard ratio, 3.2; 95% confidence interval, 1.9 to 5.2). This association was consistent across important subgroups by age, sex, race, diabetes status, and baseline eGFR. CONCLUSIONS: Incident atrial fibrillation was associated with higher risk of developing ESRD in CKD. Additional study is needed to identify potentially modifiable pathways through which atrial fibrillation was associated with a higher risk of progression to ESRD. More aggressive monitoring and treatment of patients with CKD and atrial fibrillation may improve outcomes in this high-risk population.

Traditional and non-traditional risk factors for incident peripheral arterial disease among patients with chronic kidney disease.

BACKGROUND: The risk of peripheral arterial disease (PAD) is higher in patients with chronic kidney disease (CKD) compared with those without. However, reasons for this increased risk are not fully understood. METHODS: We studied risk factors for incident PAD among 3169 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Patients with CKD aged 21-74 years were recruited between 2003 and 2008 and followed for a median of 6.3 years. Incident PAD was defined as a new onset ankle-brachial index (ABI) of <0.9 or confirmed clinical PAD. RESULTS: In a multivariate-adjusted model, older age, female sex, non-Hispanic Black, current smoking, diabetes, higher pulse pressure, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were significantly associated with the increased risk of incident PAD. After adjustment for these traditional risk factors as well as use of medications and CRIC Study clinic sites, the following baseline novel risk factors were significantly associated with risk of incident PAD [hazard ratio and 95% confidence interval (CI) for a one standard deviation (SD) higher level]: log[C-reactive protein (CRP)] (1.16, 1.06-1.25, P < 0.001), white blood cell count (1.09, 1.01-1.18, P = 0.03), fibrinogen (1.15, 1.06-1.26, P = 0.002), log(myeloperoxidase) (1.12, 1.03-1.23, P = 0.01), uric acid (0.88, 0.80-0.97, P = 0.01), glycated hemoglobin (1.16, 1.05-1.27, P = 0.003), log(homeostatic model assessment-insulin resistance) (1.21, 1.10-1.32, P < 0.001) and alkaline phosphatase (1.15, 1.07-1.24, P < 0.001). CONCLUSIONS: Among patients with CKD, inflammation, prothrombotic state, oxidative stress, glycated hemoglobin, insulin resistance and alkaline phosphatase are associated with an increased risk of PAD, independent of traditional risk factors.

Relation of serum lipids and lipoproteins with progression of CKD: The CRIC study.

BACKGROUND AND OBJECTIVES: Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective cohort study in adults (n=3939) with CKD aged 21-74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR). RESULTS: Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m(2); 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories. CONCLUSIONS: In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.

Urinary sodium is a potent correlate of proteinuria: lessons from the chronic renal insufficiency cohort study.

BACKGROUND: While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied. METHODS: We measured 24-hour urinary sodium, potassium and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure, demographics, hemoglobin A1c and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria. RESULTS: Our data demonstrated that urinary sodium (+1 SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (ß = 0.29, p < 0.0001), with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (ß = 0.13, R(2) = 0.35, p < 0.0001). CONCLUSIONS: An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.

Factors associated with depressive symptoms and use of antidepressant medications among participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC Studies.

BACKGROUND: Depressive symptoms are correlated with poor health outcomes in adults with chronic kidney disease (CKD). The prevalence, severity, and treatment of depressive symptoms and potential risk factors, including level of kidney function, in diverse populations with CKD have not been well studied. STUDY DESIGN: Cross-sectional analysis. SETTINGS & PARTICIPANTS: Participants at enrollment into the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies. CRIC enrolled Hispanics and non-Hispanics at 7 centers in 2003-2007, and H-CRIC enrolled Hispanics at the University of Illinois in 2005-2008. MEASUREMENT: Depressive symptoms measured by Beck Depression Inventory (BDI). PREDICTORS: Demographic and clinical factors. OUTCOMES: Elevated depressive symptoms (BDI score ≥11) and antidepressant medication use. RESULTS: Of 3,853 participants, 27.4% had evidence of elevated depressive symptoms and 18.2% were using antidepressant medications; 31.0% of persons with elevated depressive symptoms were using antidepressants. The prevalence of elevated depressive symptoms varied by level of kidney function: 23.6% for participants with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) and 33.8% of those with eGFR <30 mL/min/1.73 m(2). Lower eGFR (OR per 10-mL/min/1.73 m(2) decrease, 1.10; 95% CI, 1.04-1.17), and non-Hispanic black race (OR, 1.42; 95% CI, 1.16-1.74) were each associated with increased odds of elevated depressive symptoms after controlling for other factors. In regression analyses incorporating BDI score, whereas female sex was associated with greater odds of antidepressant use, Hispanic ethnicity, non-Hispanic black race, and higher urine albumin levels were associated with decreased odds of antidepressant use (P < 0.05 for each). LIMITATIONS: Absence of clinical diagnosis of depression and use of nonpharmacologic treatments. CONCLUSIONS: Although elevated depressive symptoms were common in individuals with CKD, use of antidepressant medications is low. Individuals of racial and ethnic minority background and with more advanced CKD had a greater burden of elevated depressive symptoms and lower use of antidepressant medications.

Risk factors for peripheral arterial disease among patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have an increased risk for developing peripheral arterial disease (PAD). The aim of this study was to examine the cross-sectional association between novel risk factors and prevalent PAD in patients with CKD. A total of 3,758 patients with estimated glomerular filtration rates of 20 to 70 ml/min/1.73 m(2) who participated in the Chronic Renal Insufficiency Cohort (CRIC) study were included in the present analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, gender, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, estimated glomerular filtration rate, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios for a 1-SD higher level of risk factors were 1.18 (95% confidence interval [CI] 1.08 to 1.29) for log-transformed high-sensitivity C-reactive protein, 1.18 (95% CI 1.08 to 1.29) for white blood cell count, 1.15 (95% CI 1.05 to 1.25) for fibrinogen, 1.13 (95% CI 1.03 to 1.24) for uric acid, 1.14 (95% CI 1.02 to 1.26) for glycosylated hemoglobin, 1.11 (95% CI 1.00 to 1.23) for log-transformed homeostasis model assessment of insulin resistance, and 1.35 (95% CI 1.18 to 1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in patients with CKD.

Hemodynamic correlates of proteinuria in chronic kidney disease.

BACKGROUND AND OBJECTIVES: Brachial artery measures of BP are associated with increasing degrees of proteinuria. Whether central measures of BP or vascular stiffness are associated with increased risk of proteinuria in patients with chronic kidney disease (CKD) is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Measurements of central and brachial artery BP, and aortic pulse wave velocity (PWV) were performed in a cross-sectional cohort of patients with CKD (n = 2144) from the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased risk of proteinuria. Multivariate analysis stratified by diabetes included age, ethnicity, gender, estimated glomerular filtration rate (GFR), waistline, smoking, heart rate, and medications to evaluate the relationship of hemodynamic factors and proteinuria. RESULTS: Brachial artery systolic BP (SBP) was important as an explanatory factor for variations in proteinuria among both diabetics (R(2) = 0.40, P < 0.0001) and non diabetics (R(2) = 0.38, P < 0.001). Measures of peripheral pulse pressure (PP), central SBP, and central pulse pressure added little to the explained variation in proteinuria beyond brachial artery SBP, whereas PWV as a measure of vascular stiffness incrementally accounted for a significant portion of variation in proteinuria beyond that explained by brachial artery SBP in diabetics (R(2) = 0.42, P < 0.001) but not non diabetics. CONCLUSIONS: Brachial artery SBP and PWV are both associated with variations in proteinuria in patients with CKD.