Supplemental Table 1. Standardized Serum Creatinine Measurements. Supplemental Table 3. Sensitivity Analyses with Additional Mortality Outcomes.

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1 SUPPLEMENTAL MATERIAL Supplemental Table 1. Standardized Serum Creatinine Measurements Supplemental Table 2. List of ICD 9 and ICD 10 Billing Codes Supplemental Table 3. Sensitivity Analyses with Additional Mortality Outcomes. Supplemental Table 4. Sensitivity Analyses by Revascularization Status. Supplemental Figure 1. Creation of the Stage 3 through 5 Sunnybrook Chronic Kidney Disease Cohort. Supplemental Figure 2. Rates of Hospitalization for Interim Cardiovascular Events. Supplemental Figure 3. Time of ESRD or ACM prior to ESRD After Interim Cardiovascular Event Supplemental Figure 4. Rates of Competing Outcomes by Revascularization Status. Supplemental Figure 5. Rates of Competing Outcomes after Interim Heart Failure, Myocardial Infarction and Stroke Events. Supplemental Figure 6. Adjusted Risk of Competing Outcomes After Revascularized Interim CV Events Supplemental Figure 7. Adjusted Risk of Competing Outcomes After Interim Heart Failure, Myocardial Infarction and Stroke Events. S1#

2 Supplemental Figure 8. Adjusted Risk of Competing Outcomes After Revascularized Interim Heart Failure and Myocardial Infarction Events Supplemental Figure 9. Rates of Hospitalization for Interim Cardiovascular Events Either Before or After Progression toesrd. Supplemental Figure 10. Rates of All-Cause Mortality, Either Prior to or After ESRD, Subsequent to Hospitalization Heart Failure, Myocardial Infarction and Stroke. Supplemental Figure 11. Adjusted Risk of All-Cause Mortality, Either Prior to or after ESRD, Subsequent to Interim Cardiovascular Events. S2#

3 Laboratory N* Years Assay type Reference(s) Analyzer(s) IDMS traceable SRM Sunnybrook Modified (kinetic) Jaffe 1-3 Hitachi 911, Hitachi 917,Roche Modular P Yes SRM 914, SRM 967 Gamma Enzymatic -- Kodak Vitros 950 Yes SRM 914 Dynacare TM Gamma Dynacare TM 2008 Modified (kinetic) Jaffe 3-5 Roche Modular Analyzer Yes SRM 914 Canadian Medical Laboratiories TM 514 Prior to 2008 Modified (kinetic) Jaffe 6 Beckman LX20 Yes SRM 914 LifeLabs TM 430 Prior to 2008 Other/unknown** 412 Prior to 2008 Enzymatic -- Ortho No Supplemental Table 1. Standardized Serum Creatinine Measurements. The table provides a summary of the laboratories that provided baseline creatinine values to the Sunnybrook CKD cohort and the assay methodology employed. *N = the number of subjects whose baseline creatinine value was measured by a given laboratory for the time intervals listed. **Other/unknown = 123 creatinine determinations in which a laboratory provider was not listed in the clinical record and 289 values from twelve other community laboratories. IDMS = isotope dilution mass spectrometry, SRM = standard reference material number. S3#

4 Outcome Source Type ICD version Code(s) Validity Ref Heart Failure Myocardial Infarction Stroke, non subarachnoid hemorrhage or infarction FSC Diag DAD Diag Sens: 77%, PPV: 88% DAD Diag 10 I50 Sens: 86%, PPV: 86% FSC Diag DAD Diag 9 410,411 Sens: 89%, PPV: 89% DAD Diag 10 I21 - I23 Sens: 89%, PPV: 87% FSC Diag , , 432.9, 434- DAD Diag , 436 Sens: 92%, PPV: 71% Sens: 75-81%, PPV: 69-87% DAD Diag 10 I61 - I64 E650, E655, E679, E682, G262, G263, Revasc. FSC Proc -- G298, G509, R700, Z434, Z442, Z743, Z744, Z759, Z780, Z781, Z788 All Cause Mortality End-stage Renal Disease ,11 11, RPDB Vital Status Field Sens: 94%, PPV: 100% FSC Proc -- G863, G866, G865, G864, G862, G861, G860, G099, R852, R853, R840, R851, R827, S Supplemental Table 2. List of ICD 9 and ICD 10 Billing Codes. Revasc coronary revascularization codes (angiography, percutaneous coronary interventions or coronary artery bypass grafting); FSC Fee for Service Code; DAD Discharge Abstract Database; Diag Diagnostic code; Proc Procedural Code; RPDB Registered Persons Database; Sens Sensitivity; PPV Positive Predictive Value; Ref reference number. S4#

5 Any CV Event ESRD All Cause Mortality CV-Related Death Non-CV-Related Death ## ## ## ## Main Analysis 5.33 (3.74, 7.58) 4.15 (3.30, 5.23) (8.30, 18.45) 2.13 (1.57, 2.87) Main#Analysis#with#Baseline#Covariates# within#90#days#of#index#date*# 5.32 (3.69, 7.65) 4.27 (3.38, 5.39) (8.46, 19.02) 2.20 (1.63, 2.98) Main#Analysis#with#Age#as#the#Time#Scale**# 4.69 (3.30, 6.67) 4.26 (3.41, 5.32) (7.60, 16.32) 2.30 (1.73, 3.07) Main Analysis in Complete Cases 5.74 (3.82, 8.62) 4.48 (3.22, 6.23) (9.37, 32.06) 2.03(1.32, 3.13) Adjusted#for#Baseline#Traditional#Risk# Factors # Adjusted for Baseline Extended Comorbidity List Main Analysis Within Alternative Interim CV Event and CV-Related Death Definition 5.22 (3.65, 7.46) 4.14 (3.29, 5.21) (8.30, 18.46) 2.12 (1.57, 2.87) 5.31 (3.70, 7.61) 4.18 (3.32, 5.27) (8.17, 18.27) 2.15 (1.59, 2.91) 3.88 (2.51, 5.99) 3.56 (2.76, 4.58) (8.81, 27.68) 2.41 (1.80, 3.22) Supplemental Table 3. Sensitivity Analyses with Additional Mortality Outcomes. The hazard ratios and 95% confidence intervals of competing outcomes when an interim cardiovascular event is analyzed in a time-dependent Cox proportional hazards model are presented. The main analysis is adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart failure, occlusive cardiovascular disease, hypertension, and diabetes history. Sensitivity analysis included: *restricting to patient with baseline covariates available within 90 days of the index date (n=2942) **age as the time-scale rather than time-on-study, complete cases (n=1620), #after adjustment for heavily imputed traditional risk factors such as body-mass index, systolic blood pressure, high-density lipoprotein, and total cholesterol, after adjustment for an extended list of baseline comorbid conditions including history of cancer (n=1162), chronic obstructive pulmonary disease (n=453), dementia (n=164), and S5#

6 after restricting interim CV events to hospitalizations in which the primary diagnosis was heart failure, myocardial infarction or stroke (n=271) and restricting CV-related death to mortality in hospital or within 30 days of a hospitalization in which the primary diagnosis was a CV event (n=75). CV - cardiovascular; ESRD - end-stage renal disease. S6#

7 Any CV Event ESRD ACM Prior to ESRD Revascularized Not Revascularized Revascularized Not Revascularized ## ## ## ## Main Analysis 9.04 (4.10, 19.93) 5.04 (3.49, 7.29) 3.78 (2.22, 6.43) 4.19 (3.30, 5.32) Main#Analysis#with#Baseline#Covariates# within#90#days#of#index#date*# (4.32, 25.24) 5.00 (3.42, 7.30) 3.41 (1.80, 6.44) 4.35 (3.42, 5.53) Main#Analysis#with#Age#as#the#Time#Scale**# 7.60 (3.43, 16.82) 4.46 (3.08, 6.45) 4.02 (2.34, 6.89) 4.28 (3.40, 5.40) Main Analysis in Complete Cases 9.76 (3.02, 31.50) 5.49 (3.62, 8.33) 3.38 (1.56, 7.32) 4.62 (3.29, 6.47) Adjusted#for#Baseline#Traditional#Risk# Factors # Adjusted for Baseline Extended Comorbidity List Main Analysis Within Alternative Interim CV Event Definition 9.67 (4.36, 21.43) 4.91 (3.38, 7.13) 3.77 (2.23, 6.37) 4.18 (3.29, 5.31) 8.97 (4.02, 20.02) 5.03 (3.45, 7.32) 3.79 (2.18, 6.59) 4.22 (3.32, 5.36) 6.09 (2.38, 15.56) 3.68 (2.32, 5.83) 3.04 (1.69, 5.48) 3.61 (2.77, 4.72) Supplemental Table 4. Sensitivity Analyses by Revascularization Status. The hazard ratios and 95% confidence intervals of competing outcomes when an interim cardiovascular event is analyzed in a time-dependent Cox proportional hazards model are presented. The main analysis is adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart failure, occlusive cardiovascular disease, hypertension, and diabetes history. Sensitivity analysis included: *restricting to patient with baseline covariates available within 90 days of the index date (n=2942) **age as the time-scale rather than time-on-study, complete cases (n=1620), #after adjustment for heavily imputed traditional risk factors such as body-mass index, systolic blood pressure, high-density lipoprotein, and total cholesterol, after adjustment for an extended list of baseline co- S7#

8 morbid conditions including history of cancer (n=1162), chronic obstructive pulmonary disease (n=453), dementia (n=164), and after restricting interim CV events to hospitalizations in which the primary diagnosis was heart failure, myocardial infarction or stroke (n=271). ACM- all-cause mortality, CV - cardiovascular; ESRD - end-stage renal disease. S8#

9 Supplemental Figure 1. Creation of the Stage 3 through 5 Sunnybrook Chronic Kidney Disease Cohort. See text for details. S9#

10 (A) # # S10#

11 (B)" " S11#

12 # Supplemental Figure 2. Rates of Hospitalization for Interim Cardiovascular Events. (A) The time-to-hospitalization for cardiovascular events are depicted as incidence functions using the method of Kaplan and Meier, which may overestimate incidence in the presence of competing risks such as death and end-stage renal disease. However, this analysis is congruent with crude rates (presented below) and cause-specific hazard modelling. The number at risk is shown below the plot. (B) The unadjusted crude rates of hospitalization for interim cardiovascular events with 95% confidence intervals are depicted. Note that the numbers of specific events do not sum to 447 because of the possibility of more than one CV event type during a follow-up or hospitalization. Any cardiovascular event: black, heart failure: red, myocardial infarction: blue, stroke: green. Rates are presented per 100 person-time-years with 95% confidence intervals. CV: Cardiovascular, ESRD: End-Stage Renal Disease; N: number of patients. S12#

13 Supplemental Figure 3. Time of ESRD or ACM prior to ESRD After an Interim Cardiovascular Event. The proportion of patients who developed ESRD or suffered ACM prior to ESRD grouped by the time period in which the competing event occurred after the interim CV event is depicted. There were 447 interim CV events. Seventy-six of these patients developed ESRD of which 40 S13#

14 (53%) occurred 90 days after the interim CV event. Similarly, 167 patients with an interim CV event suffered ACM prior to ESRD, of which 134 (80%) occurred 90 days after the interim CV event. CV- cardiovascular; ACM all cause mortality; ESRD End-Stage Renal Disease S14#

15 S15#

16 Supplemental Figure 4. Rates of Competing Outcomes by Revascularization Status. The unadjusted rates of ESRD and all-cause mortality prior to ESRD after revascularized CV events, non-revascularized CV events and without CV events is depicted. Rates are presented per 100 person-time-years with 95% confidence intervals. ACM- all-cause mortality; ESRD - end-stage renal disease S16#

17 S17#

18 Supplemental Figure 5. Rates of Competing Outcomes After Hospitalization Heart Failure, Myocardial Infarction and Stroke. The unadjusted rates of ESRD, all-cause mortality, CV-related death prior to ESRD and non-cv-related death prior to ESRD with and without a heart failure, myocardial infarction or stroke event. Rates are presented per 100 person-time-years with 95% confidence intervals. CV cardiovascular; ESRD - end-stage renal disease S18#

19 S19#

20 Supplemental Figure 6. Adjusted Risk of Competing Outcomes After Revascularized Interim CV Events. Forrest plots depict hazard ratios and 95% confidence intervals for the competing outcomes when a CV event analyzed as a time-dependent covariate in a Cox proportional hazards model. Interim events were partitioned based on revascularization occurring during the interim hospitalization or within 14 days of discharge. The referent group are patients not experiencing an interim event during the study period. The models are adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart failure, occlusive cardiovascular disease, hypertension, and diabetes history. HF: heart failure, MI: myocardial infarction, ESRD: End-Stage Renal Disease, HR: hazard ratio S20#

21 Supplemental Figure 7. Adjusted Risk of Competing Outcomes After Interim Heart Failure, Myocardial Infarction and Stroke Events. Forrest plots depict hazard ratios and 95% confidence intervals for the competing outcomes when an interim heart S21#

22 failure, myocardial infarction, and stroke event is analyzed as a time-dependent covariate in a Cox proportional hazards model. The referent group are patients not experiencing an interim event during the study period. The models are adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart failure, occlusive cardiovascular disease, hypertension, and diabetes history. HF: heart failure, MI: myocardial infarction, ESRD: End-Stage Renal Disease, HR: hazard ratio. S22#

23 S23#

24 Supplemental Figure 8. Adjusted Risk of Competing Outcomes After Revascularized Interim Heart Failure and Myocardial Infarction Events. Forrest plots depict hazard ratios and 95% confidence intervals for the competing outcomes when an interim heart failure and myocardial infarction event analyzed as a time-dependent covariate in a Cox proportional hazards model. Interim events were partitioned based on revascularization occurring during the interim hospitalization or within 14 days of discharge. The referent group are patients not experiencing an interim event during the study period. Stroke events were not analyzed due to small number of events. The p-value for difference between ESRD vs ACM prior to ESRD for revascularized and non-revascularized heart failure events was P=0.73 and P=0.33, respectively. The p-value for difference between ESRD vs ACM prior to ESRD for revascularized and non-revascularized myocardial infarction events was P=0.06 and P=0.99, respectively. The models are adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart failure, occlusive cardiovascular disease, hypertension, and diabetes history. HF: heart failure, MI: myocardial infarction, ESRD: End-Stage Renal Disease, HR: hazard ratio. S24#

25 (A) S25#

26 (B) S26#

27 Supplemental Figure 9. Rates of Hospitalization for Interim Cardiovascular Events Before or After ESRD. (A) The time-tohospitalization for cardiovascular events are depicted as incidence functions using the method of Kaplan and Meier, which may overestimate incidence in the presence of the competing risk of death. However, this analysis is congruent with crude rates (presented below) and cause-specific hazard modelling. The number at risk is shown below the plot. (B) The unadjusted rates of hospitalization for cardiovascular events with 95% confidence intervals are depicted. Note that the numbers of specific events do not sum to because of the possibility of more than one CV event type during a follow-up or hospitalization. Any cardiovascular event: black, heart failure: red, myocardial infarction: blue, stroke: green. Rates are presented per 100 person-time-years with 95% confidence intervals. CV cardiovascular; ESRD - end-stage renal disease; N - number of patients; CHF congestive heart failure; HF heart failure; MI myocardial infarction. S27#

28 S28#

29 Supplemental Figure 10. Rates of All-Cause Mortality After Hospitalization Heart Failure, Myocardial Infarction and Stroke. The unadjusted rates all-cause mortality either before or after ESRD and 95% confidence intervals are depicted in patients with and without an interim CV, heart failure, myocardial infarction or stroke event. Rates are presented per 100 person-time-years with 95% confidence intervals. CV cardiovascular; ESRD - end-stage renal disease; HF - heart failure; MI - myocardial infarction. S29#

30 Supplemental Figure 11. Adjusted Risk of All-Cause Mortality After Interim Cardiovascular Events. Forrest plots depict hazard ratios and 95% confidence intervals for all-cause mortality before or after end-stage renal disease (ESRD) when an interim cardiovascular (CV), heart failure, myocardial infarction or stroke event is analyzed as a time-dependent covariate in a Cox proportional hazards model. The referent group are patients not experiencing an interim event during the study period. The models are adjusted for baseline age, gender, glomerular filtration rate, albuminuria, calcium, phosphate, albumin, bicarbonate, hemoglobin, heart S30#

31 failure, occlusive cardiovascular disease, hypertension, diabetes history and ESRD (modeled as a time-dependent covariate). CV cardiovascular; ESRD - end-stage renal disease; HR - hazard ratio; ACM - all-cause mortality. S31#

32 SUPPLEMENTAL REFERENCES 1.$ Jaffé$M.$Über$den$Niederschlag,$welchen$Pikrinsäure$in$normalem$Harn$erzeugt$und$über$eine$ neue$reaktion$des$kreatinins.$z"eitschrift"fur"physiologische"chemie."1886;10:391m400.$ 2.$ Fabiny$DL,$Ertingshausen$G.$Automated$reactionMrate$method$for$determination$of$serum$ creatinine$with$the$centrifichem.$clin"chem."aug$1971;17(8):696m700.$ 3.$ Bartels$H,$Bohmer$M.$[MicroMdetermination$of$creatinine].$Clin"Chim"Acta."Mar$1971;32(1):81M 85.$ 4.$ Siekmann$L.$Measurement$of$creatinine$in$human$serum$by$isotope$dilution$mass$spectrometry.$ J"Clin"Chem"Clin"Biochem."1985;23:137M144.$ 5.$ Seelig$HP.$Zeitschrift$fur$klinische$Chemie$und$klinische$Biochemie$1969;7(6):581M585.$ 6.$ Heinegard$D,$Tiderstrom$G.$Determination$of$serum$creatinine$by$a$direct$colorimetric$method.$ Clin"Chim"Acta."Feb$12$1973;43(3):305M310.$ 7.$ Quan$H,$Parsons$GA,$Ghali$WA.$Validity$of$information$on$comorbidity$derived$rom$ICDM9MCCM$ administrative$data.$med"care."aug$2002;40(8):675m685.$ 8.$ Deyo$RA,$Cherkin$DC,$Ciol$MA.$Adapting$a$clinical$comorbidity$index$for$use$with$ICDM9MCM$ administrative$databases.$j"clin"epidemiol."jun$1992;45(6):613m619.$ 9.$ Henderson$T,$Shepheard$J,$Sundararajan$V.$Quality$of$diagnosis$and$procedure$coding$in$ICDM10$ administrative$data.$med"care."nov$2006;44(11):1011m1019.$ 10.$ Austin$PC,$Daly$PA,$Tu$JV.$A$multicenter$study$of$the$coding$accuracy$of$hospital$discharge$ administrative$data$for$patients$admitted$to$cardiac$care$units$in$ontario.$am"heart"j."aug$ 2002;144(2):290M296.$ 11.$ Juurlink$DN,$Prevra$C,$Croxford$R.$Canadian"Institute"for"Health"Information"Discharge"Abstract" Database:"a"validation"study.$Toronto,$On.2006.$ 12.$ Fisher$ES,$Whaley$FS,$Krushat$WM,$et$al.$The$accuracy$of$Medicare's$hospital$claims$data:$ progress$has$been$made,$but$problems$remain.$am"j"public"health."feb$1992;82(2):243m248.$ 13.$ Jha$P,$Deboer$D,$Sykora$K,$Naylor$CD$Characteristics$and$Mortality$Outcomes$of$Thrombolysis$ Trial$Participants$and$Nonparticipants:$a$PopulationMBased$Comparison.$J$Am$Coll$Cardiol.$1996;$ 27:$1335M42.$ S32$

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