Marie Evans

Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis

IMPORTANCE Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed. OBJECTIVE To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis. DATA SOURCES Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014. STUDY SELECTION Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease. DATA EXTRACTION AND SYNTHESIS Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed. MAIN OUTCOMES AND MEASURES Kidney failure (treatment by dialysis or kidney transplant). RESULTS During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02). CONCLUSIONS AND RELEVANCE Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.

Warfarin, Kidney Dysfunction, and Outcomes Following Acute Myocardial Infarction in Patients With Atrial Fibrillation

IMPORTANCE Conflicting evidence exists regarding the association between warfarin treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney disease (CKD) and atrial fibrillation. OBJECTIVE To study outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS Observational, prospective, multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry (2003-2010), which includes all Swedish hospitals that provide care for acute cardiac diseases. Participants included consecutive survivors of an acute myocardial infarction (MI) with atrial fibrillation and known serum creatinine (N = 24,317), including 21.8% who were prescribed warfarin at discharge. Chronic kidney disease stages were classified according to estimated glomerular filtration rate (eGFR). MAIN OUTCOMES AND MEASURES (1) Composite end point analysis of death, readmission due to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these 2 outcomes within 1 year from discharge date. RESULTS A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30-60: event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15-30: event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR≤15: event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR, 1.10 (95% CI, 0.86-1.41); eGFR>30-60 event rate, 6.8 for warfarin vs 6.3 for no warfarin; HR, 1.04 (95% CI, 0.81-1.33); eGFR>15-30 event rate, 9.3 for warfarin vs 10.4 for no warfarin; HR, 0.82 (95% CI, 0.48-1.39); eGFR≤15 event rate, 9.1 for warfarin vs 13.5 for no warfarin; HR, 0.52 (95% CI, 0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9592 events) for event rates per 100 person-years: eGFR>60 event rate, 32.1 for warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR>30-60 event rate, 53.6 for warfarin vs 69.0 for no warfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR>15-30 event rate, 90.2 for warfarin vs 117.7 for no warfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR≤15 event rate, 86.2 for warfarin vs 138.2 for no warfarin; HR, 0.55 (95% CI, 0.37-0.83). CONCLUSIONS AND RELEVANCE Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.

Acute kidney injury after coronary artery bypass grafting and long-term risk of end-stage renal disease.

Background— Acute kidney injury (AKI) is a common complication after coronary artery bypass grafting (CABG) and is associated with adverse outcomes. However, the relationship between AKI after CABG and the long-term risk of end-stage renal disease (ESRD) is unknown. Methods and Results— This study included 29 330 patients who underwent primary isolated CABG in Sweden between 2000 and 2008. AKI was classified according to the Acute Kidney Injury Network (AKIN) classification: stage 1, >0.3 mg/dL (>26 &mgr;mol/L) or 50% to 100% increase; stage 2, 100% to 200% increase; and stage 3, >200% increase from the preoperative to postoperative serum creatinine level. Cox proportional hazards regression analysis was used to calculate hazard ratios with 95% confidence intervals for ESRD in AKIN stage 1 and stage 2 to 3. Postoperative AKI occurred in 13% of patients. During a mean follow-up of 4.3±2.4 years, 123 patients (0.4%) developed ESRD, including 50 (1.6%) in AKIN stage 1, 29 (5.2%) in AKIN stage 2 to 3, and 44 (0.2%) without AKI after CABG. After multivariable adjustment, the hazard ratio for ESRD was 2.92 (95% confidence interval, 1.87–4.55) for AKIN stage 1 and 3.81 (95% confidence interval, 2.14–6.79) for AKIN stage 2 to 3. Conclusions— This nationwide study of patients who underwent CABG found that a small increase in the postoperative serum creatinine level was associated with an almost 3-fold increase in the long-term risk of ESRD after adjustment for a number of confounders, including preoperative renal function.

No survival benefit from early-start dialysis in a population-based, inception cohort study of Swedish patients with chronic kidney disease

Abstract.  Evans M., Tettamanti G., Nyrén O., Bellocco R., Fored C.M., Elinder C.‐G. (Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Karolinska Institutet, Stockholm, Sweden; University of Milano‐Bicocca, Milan, Italy; Karolinska Institutet, Stockholm, Sweden) No survival benefit from early‐start dialysis in a population‐based, inception cohort study of Swedish patients with chronic kidney disease. J Intern Med 2010; 269: 289–298.

Acetaminophen, aspirin and progression of advanced chronic kidney disease

BACKGROUND Although many studies have investigated the possible association between analgesic use (acetaminophen and aspirin) and the development of chronic kidney disease (CKD), the effect of analgesics on the progression of established CKD of any cause has not yet been investigated. METHODS In this population-based Swedish cohort study, we investigated the decline over 5-7 years in estimated glomerular filtration rate (eGFR) among 801 patients with incident, advanced CKD (serum creatinine >3.4 mg/dL for men, >2.8 mg/dL for women for the first time) and with different analgesic exposures. Lifetime analgesic use and current regular use were ascertained through in-person interviews at inclusion while data on analgesic use during the follow-up was abstracted from the medical records at the end of the study period. A linear regression slope, based on their eGFR values during the follow-up, provided a summary of within-individual change. In the final multivariate analyses, a linear mixed effects model was implemented to assess the relation of analgesic use and change in eGFR over time. RESULTS The progression rate for regular users of acetaminophen was slower than that for non-regular users (regular users progressed 0.93 mL/min/1.73 m(2) per year slower than non-regular users; 95% CI 0.03, 1.8). For regular users of aspirin, the progression rate was significantly slower than that for non-regular users (regular users progressed 0.80 mL/min/1.73 m(2) per year slower than non-regular users; 95% CI 0.1, 1.5). Different levels of lifetime cumulative dose of acetaminophen and aspirin did not significantly affect the progression rate. CONCLUSION We suggest that single substance acetaminophen and aspirin may be safe to use by patients with diagnosed advanced CKD stage 4-5 without an adverse effect on the progression rate of the disease.

Glomerular filtration rate-estimating equations for patients with advanced chronic kidney disease

BACKGROUND Renal function is often estimated using one of several glomerular filtration rate (GFR) estimating equations. However, there is no consensus which estimating equation performs best in patients with advanced renal failure. METHODS We compared the performance of five different estimated GFR (eGFR) equations [Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease (CKD) Epidemiology collaboration (CKD-EPI) and Mayo Clinic and Lund-Malmö] with measured GFR (plasma iohexol clearance) in 2098 referred CKD patients with mGFR <30 mL/min/1.73 m(2). RESULTS There were 398 patients with an mGFR ≤ 10 mL/min/1.73 m(2), 1974 with a measured GFR (mGFR) 11-20 mL/min/1.73 m(2) and 749 patients with mGFR 21-30 mL/min/1.73 m(2). Across the entire range, the median bias of eGFR was lowest for the Lund-Malmö equation (0.7 mL/min/1.73 m(2)), followed by the CKD-EPI (1.2 mL/min/1.73 m(2)), the MDRD (1.6 mL/min/1.73 m(2)), Mayo Clinic equation (1.7 mL/min/1.73 m(2)) and Cockcroft-Gault equation (4.6 mL/min/1.73 m(2)). The best accuracy within 30% of mGFR was also for Lund-Malmö (76%), while it was similar for CKD-EPI, MDRD and Mayo (65-67%). The Cockcroft-Gault had the worst accuracy of only ∼54%.The median bias was stable across mGFR categories, while the accuracy within 30% of mGFR became worse with decreasing mGFR. All equations performed best among patients with hereditary kidney diseases and tubulointerstitial disease. Accuracy was generally worse for patients >65 years of age and for those with diabetic nephropathy. CONCLUSIONS In patients with advanced renal failure, the GFR-estimating equations show reasonably good performance on the population level. On the individual patient level, they are inaccurate, especially in elderly patients and those with diabetic nephropathy.

Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality

Current guidelines for chronic kidney disease (CKD) recommend using albuminuria as well as estimated glomerular filtration rate (eGFR) to stage CKD. However, CKD progression is solely defined by change in eGFR with little regard to the risk implications of change in albuminuria. This is an observational study from the Stockholm CREAtinine Measurements (SCREAM) project, a health care utilization cohort from Stockholm, Sweden, with laboratory measures from 2006-2011 and follow-up through December 2012. Included were 31,732 individuals with two or more ambulatory urine albumin to creatinine ratio (ACR) tests. We assessed the association between change in ACR during a baseline period of 1, 2, or 3 years and end-stage renal disease (ESRD) or death. Using a 2-year baseline period, there were 378 ESRD events and 1712 deaths during a median of 3 years of follow-up. Compared to stable ACR, a 4-fold increase in ACR was associated with a 3.08-times (95% confidence interval 2.59 to 3.67) higher risk of ESRD while a 4-fold decrease in ACR was associated with a 0.34-times (0.26 to 0.45) lower risk of ESRD. Similar associations were found in people with and without diabetes mellitus, with and without hypertension, and also when adjusted for the change in eGFR during the same period. The association between change in ACR and mortality was weaker: ACR increase was associated with mortality, but the relationship was largely flat for ACR decline. Results were consistent for 1-, 2-, and 3-year ACR changes. Thus, changes in albuminuria are strongly and consistently associated with the risk of ESRD and death.

Time in Therapeutic Range and Outcomes After Warfarin Initiation in Newly Diagnosed Atrial Fibrillation Patients With Renal Dysfunction

Background It is unknown whether renal dysfunction conveys poor anticoagulation control in warfarin‐treated patients with atrial fibrillation and whether poor anticoagulation control associates with the risk of adverse outcomes in these patients. Methods and Results This was an observational study from the Stockholm CREatinine Measurements (SCREAM) cohort including all newly diagnosed atrial fibrillation patients initiating treatment with warfarin (n=7738) in Stockholm, Sweden, between 2006 and 2011. Estimated glomerular filtration rate (eGFR; mL/min per 1.73 m2) was calculated from serum creatinine. Time‐in‐therapeutic range (TTR) was assessed from international normalized ratio (INR) measurements up to warfarin cessation, adverse event, or end of follow‐up (2 years). Adverse events considered a composite of intracranial hemorrhage, ischemic stroke, myocardial infarction, or death. During median 254 days, TTR was 83%, based on median 21 INR measurements per patient. TTR was 70% among patients with eGFR <30, around 10% lower than in those with normal renal function. During observation, adverse events occurred in 4.0% of patients, and those with TTR ≤75% were at higher adverse event risk. This was independent of patient characteristics, comorbidities, number of INR tests, days exposed to warfarin, and, notably, independent of eGFR: adjusted odds ratio (OR) 1.84 (95% CI, 1.41–2.40) for TTR 75% to 60% and adjusted OR 2.09 (1.59–2.74) for TTR <60%. No interaction was observed between eGFR and TTR in association to adverse events (P=0.2). Conclusion Severe chronic kidney disease (eGFR <30) patients with atrial fibrillation have worse INR control while on warfarin. An optimal TTR (>75%) is associated with lower risk of adverse events, independently of underlying renal function.

The Stockholm CREAtinine Measurements (SCREAM) project: protocol overview and regional representativeness

Background We here describe the construction of the Stockholm CREAtinine Measurement (SCREAM) cohort and assess its coverage/representativeness of the Stockholm county in Sweden. SCREAM has the principal aims to estimate the burden and consequences of chronic kidney disease (CKD) and to identify inappropriate drug use (prescription of nephrotoxic, contraindicated or ill-dosed drugs). Methods SCREAM is a repository of laboratory data of individuals, residing or accessing healthcare in the region of Stockholm, who underwent creatinine assessments between 2006–11. Laboratory tests were linked to administrative databases with complete information on socioeconomic status, demographic data, healthcare utilization, diagnoses, vital status and dispensed prescription medicines. Results SCREAM identified 1 118 507 adult Stockholm citizens with available creatinine tests between 2006–11. This corresponded to 66% of the complete population in the region. Geographical coverage was uniform, ranging between 62 and 72% throughout its 26 municipalities. Population coverage was higher across older age strata (50% coverage for age range 18–44 years, >75% for 45–64 years and >90% coverage for ≥65 years). Of note, 97 and 98% of all individuals with a diagnosis of diabetes mellitus or cardiovascular disease, respectively, were captured by SCREAM. Further, 89% of all deaths registered in the period occurred in individuals with a creatinine test undertaken. Conclusion SCREAM represents the largest cohort to estimate the burden and healthcare implications of CKD in Sweden. The coverage and representativeness of the region of Stockholm was high and in accordance to both the commonness of creatinine assessment, and the medical indications for creatinine testing. The inclusion of individuals who sought medical care and had a creatinine test undertaken resulted in a slight over-representation of elderly and comorbid patients.

Occupational Lead Exposure and Severe CKD: A Population-Based Case-Control and Prospective Observational Cohort Study in Sweden

BACKGROUND The role of low-level lead exposure in the cause of chronic kidney disease (CKD) is unsettled. STUDY DESIGN Case-control study and prospective observational cohort study. SETTING & PARTICIPANTS 926 cases with incident severe CKD (serum creatinine > 3.4 mg/dL for men and > 2.8 mg/dL for women for the first time) and 998 population controls were included. Cases represented nearly all patients with incident severe CKD in Sweden during 2 years. Cases also were followed up prospectively for 7-9 years. Exposed and nonexposed cases were compared with regard to rate of change in estimated glomerular filtration rate (eGFR) and renal survival. PREDICTOR Lead exposure was assessed using the expert rating method. OUTCOMES & MEASUREMENTS Associations between lead exposure and risk of CKD, adjusted for factors associated with this outcome, were analyzed using multivariable logistic regression modeling, whereas links to the rate of change in eGFR were analyzed in mixed-effects multivariable models based on up to 6 measurements. Renal survival in relation to lead exposure was analyzed in a Cox proportional hazards model. RESULTS The adjusted OR for incident severe CKD was 0.97 (95% CI, 0.68-1.38) in lead-exposed compared with nonexposed participants. The OR for individuals with the highest average exposure (>0.0075 mg/m(3)) was 1.09 (95% CI, 0.64-1.85). ORs for CKD caused by glomerulonephritis, nephrosclerosis, and diabetic nephropathy did not differ importantly. In patients with CKD ever exposed and most exposed to lead, eGFRs changed by -4.27 and -3.39 mL/min/1.73 m(2)/y compared with -4.55 mL/min/1.73 m(2)/y in nonexposed patients, respectively. LIMITATIONS Only native Swedes were included, which may limit generalizability. Blood lead was not measured to confirm the validity of the expert rating method. CONCLUSION Our data provide no evidence of an important role of low-level occupational lead exposure in the cause or progression of severe CKD.