CKD EVIDENCE TABLES - ALL CHAPTERS

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1 CKD EVIDENCE TABLES - ALL CHAPTERS CHAPTER 3-CKD GUIDELINE CONTENTS: 3.1. INVESTIGATION OF CKD 3.2. FACTORS AFFECTING THE BIOLOGICAL AND ANALYTICAL VARIABILITY OF GFR ESTIMATED FROM MEASUREMENT OF SERUM CREATININE 3.3. DETECTION OF BLOOD AND PROTEIN IN THE URINE 3.4. URINARY ALBUMIN:CREATININE AND PROTEIN:CREATININE RATIOS, AND THEIR RELATIONSHIP TO 24 HOUR URINARY PROTEIN 3.5. INDICATIONS FOR RENAL ULTRASOUND IN THE EVALUATION OF CKD 3.1. INVESTIGATION OF CKD What is the best diagnostic test to measure renal function in routine clinical practice? Ref ID: 4148 Froissart M, Rossert J, Jacquot C et al. Predictive performance the modification diet in renal disease and Cockcrt-Gault equations for estimating renal Patient characteristics Intervention Comparison Length followup Study type Evidence level Crosssectional study Diagnosti c test 1b + 1 centre, Numb er patient s N= 2095 Inclusion criteria Patients referred to Dept. Physiology. None stated. Exclusion criteria Renal replacement, < 18 years old. Black (N=83) were excluded to ensure statistical relevance. 2 equations for estimating GFR: 4 variable MDRD study equation GFR = 186 X Gold Standard: 51 Cr-EDTA GFR No. Not applica ble Test correlation Bias Precision ( 1 SD the mean difference) funding Not stated Page 1 377

2 function. J Am Soc Nephrol. 2005; 16: France 61.1 Population baseline characteristics: N total 2095 N CKD 1933 N kidney donors 162 % male 58.5 Mean age 52.8 Mean weight, kg 70.7 Mean height, cm 167 Mean BSA, m Mean BMI, kg/m Mean plasma 1.69 creatinine, mg/dl Mean GFR, ml/min/1.73m 2 S cr X age X (if female) Cockcrt-Gault = [140 age] X weight/ S cr X 72 (X 0.85 if female) and corrected for BSA. No Procedure: Blood samples for determination creatinine concentration were obtained at the same time as the GFR measurement (Cr- EDTA). Serum creatinine was determined by a modified kinetic Jaffe colorimetric method (Bayer RA-XT and Konelab 20). 5 point calibration for creatinine was used by supplementing the sample with precise amounts creatinine hydrochloride Procedure: Patients were i.v. injected with 3.5 MBq 51 Cr-EDTA (1.8 MBq if GFR < 30 ml/min or weight < 40 kg). Timed blood and urine samples were collected and radioactivity was determined (Packard Cobra gamma counter). Accuracy (percentag e estimates with 30% the measured GFR) Sensitivity Specificity Page 2 377

3 Effect size Test Correlation The MDRD (r=0.910) and Cockcrt-Gault equation (r=0.894) correlated highly with the measured Cr-EDTA GFR. Bias In the whole study group (N=2095), the MDRD equation underestimated the measured GFR (-0.99 ml/min per 1.73 m 2, p=0.001)- a significant, but not clinically important bias. The Cockcrt-Gault equation overestimated the GFR (1.94 ml/min per 1.73 m 2, p<0.0001)-statistically significant, but not clinically important. Bias was greater for the MDRD equation (-6.2 ml/min per 1.73 m 2 ) than the Cockcrt-Gault equation (-0.3 ml/min per 1.73 m 2 ) in with a measured GFR > 90 ml/min per 1.73 m 2. The MDRD equation was less biased than the Cockcrt-Gault equation in with Stage 3, 4, or 5 CKD. The MDRD equation was significantly less biased than the Cockcrt-Gault equation when were analyzed by age (< or > 65 years) and gender (p<0.0001) Accuracy The MDRD equation was more accurate than the Cockcrt-Gault equation (92% versus 88%) in people with GFR > 60 ml/min per 1.73 m2). The trend continued in people with GFR < 60 ml/min per 1.73 m2. (82% MDRD versus 69% Cockcrt-Gault). Precision Neither equation was very precise (MDRD 13.7 versus Cockcrt-Gault 15.4 ml/min per 1.73 m 2 ) in the overall study. However, the MDRD was consistently more precise than the Cockcrt-Gault in kidney donors and also in stratified by GFR range (Stage 1-5 CKD). Sensitivity Sensitivity for the MDRD equation was similar to the Cockcrt-Gault equation, except in people with Stages 4 and 5 CKD. The MDRD equation (78.9%) was more sensitive than the Cockcrt-Gault equation (67.6%) in stage 4 CKD. The MDRD equation (64.8%) was more sensitive than the Cockcrt-Gault equation (43%) in stage 5 CKD. Specificity Both MDRD and Cockcrt-Gault equations had similar specificities across the 5 stages CKD (approx. 90%). Ref ID: 190 Hallan S, Asberg A, Lindberg M et al. Validation the Modification Diet in Renal Disease formula for estimating GFR with special Study type Evidence level cross sectional study Diagnostic test Ib + Number Total N=219 Patient characteristics Intervention Comparison Length follow-up Inclusion criteria 219 referred for Cr-EDTA plasma clearance between May, 1996 and May, Reasons for referral: evaluation CKD, evaluation potential kidney donors, evaluation scheduled for nephrotoxic chemotherapy. 8 interventions, but only results reported for MDRD and Cockcrt- Gault 51 Cr-EDTA plasma clearance. No. n/a Bias Accuracy Precision (the width between the 95% funding Not stated Page 3 377

4 emphasis on calibration the serum creatinine assay. American Journal Kidney Diseases. 2004; 44(1): centre in Norway Exclusion criteria Not stated Population characteristics N 219 Mean age (SD) 56.3 (17.2) % Female 51.1 % Caucasian 99.5 Mean Weight (SD), 71.0 (15.4) kg Mean Height (SD), m (0.104) Mean serum creatinine (SD) mg/dl Mean measured Cr- EDTA clearance (SD), ml/min per 1.73 m 2 Mean egfr MDRD (ml/min per 1.73 m 2 ) Mean egfr Cockcrt-Gault (ml/min per 1.73 m 2 ) (1.899) 49.8 (42.4) MDRD study equation GFR = 186 X S cr X age X (if female) Cockcrt- Gault equation = (140 age) X weight / [72 X S cr X BSA X 0.85 (if female)] No Procedure: 51 Cr EDTA was injected intravenously and three timed blood samples were obtained 3, 4, 5 h postinjection. limits agreement. A large width means a low precision.) Procedure Serum creatinine was measured by the kinetic Jaffe method using a Hitachi 917 instrument. Three tests were carried out to ensure creatinine was calibrated equally with Page 4 377

5 the original MDRD study. Effect size Bias The MDRD equation was the most biased (2275 arbitrary units), while the Cockcrt-Gault equation was the least biased (630 arbitrary units) all eight equations tested. Re-calibration the MDRD equation (calibration II) for calibrated serum creatinine decreased the bias to 320 arbitrary units. Precision The MDRD equation was the most precise (58 ml/min per 1.73 m 2 width between the 95% limits agreement) while the Cockcrt-Gault equation was the least precise (95 ml/min per 1.73 m 2 width between the 95% limits agreement) all 8 equations. Re-calibration the MDRD equation (calibration II) for calibrated serum creatinine resulted in lower precision (73 ml/min per 1.73 m 2 width between the 95% limits agreement) than the uncalibrated MDRD equation. Accuracy Neither the MDRD nor the Cockcrt-Gault equation had very high accuracy. However, the MDRD equation was significantly more accurate (62% accurate within 30% the measured Cr-EDTA GFR) than the Cockcrt-Gault equation (48.8 % accurate within 30% the measured igfr, p < 0.01). Ref ID: 36 Levey AS, Coresh J, Greene T et al. Using standardized serum creatinine values in the modification diet in renal disease study equation for estimating glomerular filtration rate. Annals Internal Medicine. 2006; 145(4): Study type Evidence level Analysis RCT Diagnosti c test 1b + 15 centres, country not stated Numb er patient s N= centre s, countr y not stated Patient characteristics Intervention Comparison Length followup Inclusion criteria Adults with CKD participating in the MDRD trial (No inclusion criteria stated) Exclusion criteria Not stated Population baseline characteristics: 60% male 12% African American Mean age: 50.6 yrs Mean weight: 79.6 kg 4 equations for estimating GFR: Re-expressed 4 variable MDRD study equation GFR = 175 X standardized S cr X age X (if black) X (if Gold Standard: GFR as determined from the urinary clearance 125 I- iothalamate after subcutaneou s infusion Not applica ble Bias ( median difference measured minus estimated GFR) Precision ( R 2 value from regression model) funding Page Grants from National Institute Diabetes and Digestive and Kidney Diseases

6 Mean body surface area: 1.91 m 2 Mean arterial pressure: 99.4 mm Hg Mean dietary protein intake 0.99 g/kg per day Mean GFR: 39.8 ml/min per 1.73m 2 Mean creatinine clearance 48.6 ml/min per 1.73m 2 Mean standardized serum creatinine concentration micromol/l or 2.14 mg/dl Subgroup Analysis by GFR range Overall study > 90 ml/min per 1.73m 2 : 2% ml/min per 1.73m 2 : 13.9% ml/min per 1.73m 2 : 45.9% ml/min per 1.73m 2 : 28.6% < 15 ml/min per 1.73m 2 : 9.6% Causes CKD: 6% diabetes 32% glomerular disease 22% polycystic kidney disease 7% tubulointerstitial disease 40% unknown cause female) Re-expressed 6 variable MDRD study equation GFR = X standardized S cr X age x SUN X albumin X 1.18 (if black) X (if female) Cockcrt-Gault equation adjusted for body surface area GFR = [140 age] X weight X 0.85 (if female) X 1.73/72 standardized S cr X BSA Cockcrt-Gault equation adjusted for bias and body surface area GFR = 0.8 X [140 age] X weight X 0.85 (if female) X 1.73/72 standardized S cr X BSA No Caveat: Investigators do not state if urine 125 I- iothalamate was reassayed in 2004 (when serum creatinine was reassayed and standardized. If not, the gold standard results are 10 years older than the serum creatinine measurement s. Accuracy ( the percentage estimates with 30% the measured GFR) Sensitivity Specificity Positive predictive value Negative predictive value Area under the ROC curve N= 1628 Caveats Serum creatinine samples from the Page 6 377

7 Effect size MDRD study were reassayed on the same instrument (Beckman Synchron CX3) in a central laboratory in 2004 (ten years after the MDRD trial ended). The Beckman assay was calibrated to the Roche/Hitachi P module Creatinase Plus enzymatic asay, traceable to an isotopedilution MS assay. The 4 and 6 variable MDRD equations were reexpressed for use with this standardized serum creatinine assay, but the Cockcrt-Gault equation was not reexpressed because the original serum creatinine samples were not available for calibration. Bias In the overall study, both the 4 and 6 variable MDRD equations were less biased than the Cockcrt-Gault equation adjusted for body surface area (0.2 vs ml/min per 1.73m 2 ). In subgroup analysis, both the 4 variable MDRD and the Cockcrt-Gault equations underestimated the GFR in people with a GFR > 90 ml/min per 1.73m 2 (-3.0 vs ml/min per 1.73m 2 ). The 6 variable MDRD did not underestimate the GFR in this subgroup (0.4 ml/min per 1.73m 2 ). Accuracy In the overall study, both the 4 and 6 variable MDRD equations were more accurate than the Cockcrt-Gault equation adjusted for body surface area [90% accuracy (95% CI 89 to 91) vs 60% accuracy (95% CI 58 to 62)]. Accuracy decreased for all equations in subgroup analysis people with a GFR > 90 ml/min per 1.73m 2. The 4 variable MDRD (78% accuracy; 95% CI 59 to 97), 6 variable MDRD (73%; 95% CI 51 to 95), Cockcrt-Gault equation adjusted for body surface area (56%; 95% CI 44 to 68), and the Cockcrt-Gault Page 7 377

8 equation adjusted for bias and body surface area (83%; 95% 51 to 98) Precision Both the 4 and 6 variable MDRD equations were more precise than the two Cockcrt-Gault equations adjusted for body surface area or body surface area and bias. 4 variable MDRD equation [R 2 = (95% CI to 0.893)]; 6 variable MDRD equation [R 2 = (95% CI to 0.901)]; Cockcrt-Gault equation adjusted for body surface area [R 2 = (95% CI to 0.849)]; Cockcrt-Gault equation adjusted for body surface area and bias [R 2 = (95% CI to 0.849)] GFR Equation Sensitivity Specificity Positive Negative Predictive Value Area under ROC curve * Predictive Value 4-variable MDRD variable MDRD Cockcrt-Gault p<0.001 Cockcrt-Gault adjusted for bias p< * Cutf value for a measured GFR < 60 ml/min per 1.73m 2 : Both the 4 and 6 variable MDRD equations had greater sensitivity (97%) than the Cockcrt-Gault equation (85%). All four equations had similar positive predictive values (94%) Both the 4 and 6 variable MDRD equations had better negative predictive values (80%) than the Cockcrt-Gault equation (53%). Both the 4 and 6 variable MDRD equations were significantly better tests than the Cockcrt Gault equations (Area under the ROC curve vs , p < 0.001) 4 variable MDRD is simpler to use than the 6-variable MDRD equation Ref ID: 154 Poggio ED, Wang X, Greene T et al. Performance the modification diet in renal disease and Cockcrt-Gault equations in the Study type Evidence level Crosssectional study Diagnostic test Ib + Number Total N=1285 CKD N = 828 Kidney Donor Patient characteristics Intervention Comparison Length follow-up Inclusion criteria 1285 out (18 years or older) with or without CKD who had SCr values measured between Jan., 1996 and Dec., Exclusion criteria Not stated 2 interventions MDRD study equation GFR = 186 X S cr igfr measured from renal clearance 125 I iothalamate. n/a Bias Test Correlation Accuracy funding Not stated Page 8 377

9 estimation GFR in health and in chronic kidney disease. Journal the American Society Nephrology. 2005; 16(2): No. centres not stated Group N=457 Population characteristics Tota l CKD Nond iabeti c CKD Diab etic CKD Kidn ey Dono rs N Mean age % Fema le % Nonbl ack race Mean Weig ht (Kg) Mean BSA (m 2 ) Mean seru m creati nine (mg/d L) Mean meas ured igfr (ml/mi n per 1.73 m 2 ) Mean egfr MDR X age X (if female) X (if black) Cockcrt- Gault equation GFR = (140 age) X weight / [72 X S cr X BSA X 0.85 (if female)] No Procedure Serum creatinine was measured by the Jaffe method using a Hitachi 747 or No Procedure: 125 I iothalamate was injected subcutaneou sly and two timed urine collections were obtained. Blood samples were drawn before and after each urine collection. Mean GFR was calculated from two consecutive clearance values and corrected to standard BSA. Page 9 377

10 D (ml/mi n per 1.73 m 2 ) Mean egfr Cock crt- Gault (ml/mi n per 1.73 m 2 ) Effect size Bias In the whole CKD group (N=828), the MDRD equation was superior to the Cockcrt-Gault equation in terms bias. The MDRD equation slightly underestimated the measured igfr, while the Cockcrt Gault equation significantly overestimated the GFR (-0.5 vs. 3.5 ml/min per 1.73 m 2, p < 0.001). The MDRD equation was also significantly less biased than the Cockcrt-Gault equation in the nondiabetic CKD (N=579) subgroup, the diabetic CKD (N=249) subgroup, and in people with a measured GFR < 30 ml/min per 1.73 m 2 (N=546) (p < in each group). The MDRD and Cockcrt-Gault equations were significantly more biased in people with GFR > 60 ml/min per 1.73 m 2 (N=117). The MDRD equation underestimated the measured igfr, while the Cockcrt Gault equation significantly overestimated the GFR (-3.5 vs. 7.9 ml/min per 1.73 m 2, p < 0.001). The equations were also biased, but to a lesser extent in with GFR ml/min per 1.73 m 2. In the kidney donor control group (N=459), the Cockcrt-Gault equation was superior to the MDRD equation in terms bias (1.9 vs ml/min per 1.73 m 2, p < 0.001). Test Correlation In the CKD population, both the MDRD (R=0.90) and Cockcrt-Gault equations (R=0.89 ) correlated highly with measured 125 I iothalamate GFR. In the kidney donor control group, neither the MDRD equation (R=0.36) nor the Cockcrt-Gault equation (R=0.41 ) correlated highly with measured 125 I iothalamate GFR. Accuracy In the whole CKD group (N=828), the MDRD equation was significantly more accurate (71% accurate within 30% the measured igfr) than the Cockcrt-Gault equation (60% accurate within 30% the measured igfr, p < 0.001). The MDRD equation was also significantly more accurate than the Cockcrt-Gault equation in the nondiabetic CKD (74% vs. 63%, p<0.001) subgroup, the diabetic CKD (63% vs,. 53%, p<0.05) subgroup, and in people with a measured GFR < 30 ml/min per 1.73 m 2 (68% vs. 54%, p < 0.001). There was no statistically significant difference in accuracy between the MDRD and Cockcrt-Gault equations in people with GFR ml/min per 1.73 m 2, GFR > 60 ml/min per 1.73 m 2, or in the kidney donor control group. Ref ID: 145 Page

11 Ibrahim H, Mondress M, Tello A et al. An alternative formula to the Cockcrt- Gault and the modification diet in renal diseases formulas in predicting GFR in individuals with type 1 diabetes. Journal the American Society Nephrology. 2005; 16(4): Study type Evidence level Retrospective analysis the Diabetes Control and Complications randomised controlled trial (DCCT) Diagnostic test II + Retrospective analysis Number Total N = 1286 Patient characteristics Intervention Comparison Length follow-up Inclusion criteria Patients (13 to 39 years old) with Type I diabetes enrolled in the DCCT with a serum creatinine < 1.2 mg/dl, blood pressure < 140/90 mm Hg (normotensive). Exclusion criteria Patients with < 2 year study participation and with GFR < 60 ml/min per 1.73 m 2 or GFR > 350 ml/min per 1.73 m 2. Population characteristics at closeout the DCCT: N = 1286 Years from baseline analysis to closeout: 6.3 ± 1.7 Mean age: 33.5 ± 7 % male: 55 % white: 97 Duration diabetes: 12 years ± 4.8 Mean Albumin: 3.9 g/dl ± 0.3 Mean Albumin excretion rate: 50.1 mg/d ± 346 % hypertension: 11.3 % haemoglobin A1c: 8.3 ± 1.6 % current smoker: 24.8 Mean Serum creatinine: 0.85 mg/dl ± 0.14 Mean iothalamate GFR: 122 ml/min per 1.73 m 2 ± 23 Mean Cockcrt-Gault creatinine clearance: 116 ml/min per 1.73 m 2 ± 21 Mean MDRD estimated GFR: 110 ml/min per 1.73 m 2 ± 19 Subgroup analysis by sex and GFR 2 interventions MDRD study equation GFR = 186 X S cr X age X (if female) X (if black) Cockcrt- Gault equation GFR = [1.73 X (140 age) X weight X (0.85 if female)] / [72 X S cr X BSA] No Procedure Serum creatinine was measured by the Jaffe method using a Beckman igfr measured from renal clearance 125 I iothalamate. No Procedure: Renal clearance 125 I iothalamate was measured from four consecutively timed urine collections and five serum samples bracketing these urine collections. CV among the four clearance periods was 11.7%. Analysis the DCCT participants at closeout Bias Precision Accuracy funding Not stated Page

12 range. CXR. The CV for measurement was 2% and the calibration creatinine was identical to the calibration creatinine by the NHANES III and very similar (correlation coefficient ) to that the MDRD study. Effect size Bias In the whole study group, both the Cockcrt-Gault and MDRD equations underestimated the GFR. The Cockcrt-Gault equation was less biased than the MDRD equation (-6 versus -22 ml/min per 1.73 m 2 ). In subgroup analysis men with GFR < 120 ml/min per 1.73 m 2, the Cockcrt-Gault equation was less biased than the MDRD equation (-12 versus -22 ml/min per 1.73 m 2 ). Similarly, in women with GFR < 120 ml/min per 1.73 m 2, the Cockcrt-Gault equation was less biased than the MDRD equation (-17 versus -30 ml/min per 1.73 m 2 ). This underestimation the GFR means that these formulas are less likely to miss people with early impairments in renal function. In subgroup analysis men and women with GFR > 120 ml/min per 1.73 m 2, both the Cockcrt-Gault and MDRD equations overrestimated the GFR. In men with GFR > 120 ml/min per 1.73 m 2, the MDRD equation was less biased than the Cockcrt-Gault equation (± 2 versus ± 5 ml/min per 1.73 m 2 ). Similarly, in women with GFR > 120 ml/min per 1.73 m 2, the MDRD equation was less biased than the Cockcrt-Gault equation (+3 versus +10 ml/min per 1.73 m 2 ). This overestimation GFR means that some people will be erroneously labelled as hyperfilterers, a risk factor for initiation CKD. Precision In the whole study group and in the subgroup analyses, the MDRD equation was generally more precise than the Cockcrt-Gault equation. (R 2 =0.17 vs. 0.09; men with GFR < 120 ml/min per 1.73 m 2 ). Accuracy In men with a GFR < 120 ml/min per 1.73 m 2, the Cockcrt-Gault equation was significantly more accurate than the MDRD equation (92% estimates falling within 30% igfr vs 82% estimates falling within 30% igfr, p<0.0001) In women with a GFR < 120 ml/min per 1.73 m 2, the Cockcrt-Gault equation was significantly more accurate than the MDRD equation (87% estimates falling Page

13 within 30% igfr vs 70% estimates falling within 30% igfr, p<0.0001) In men with a GFR > 120 ml/min per 1.73 m 2, the MDRD equation was significantly more accurate than the Cockcrt-Gault equation (97% estimates falling within 30% igfr vs 87% estimates falling within 30% igfr, p<0.0001) In women with a GFR > 120 ml/min per 1.73 m 2, the MDRD equation was significantly more accurate than the Cockcrt-Gault equation (92% estimates falling within 30% igfr vs 83% estimates falling within 30% igfr, p=0.0007) Ref ID: 884 Burkhardt H, Hahn T, Gretz N et al. Bedside estimation the glomerular filtration rate in hospitalized elderly. Nephron Clinical Practice. 2005; 101(1):c1-c8. Patient characteristics Intervention Comparison Length followup Study type Evidence level Crosssectional study Diagnosti c test 1b (no creatinin e calibratio n) 1 centre, Germany Numb er patient s N= 61 Inclusion criteria Elderly (60 years +) in an acute care geriatric ward with no advanced impairment renal function (serum creatinine > 177 micromol/l). Stable condition. Exclusion criteria Urinary incontinence, mental illness, serum creatinine increase on the day the test. Population baseline characteristics: 52 % male Mean age: 74.6 yrs Mean BMI: 24.3 kg/m 2 Mean inulin clearance: 96.3 ml/min Mean serum creatinine: 93.2 micromol/l % non-insulin-dependent diabetes: 45.9 % hypertensive: 52.4 Reasons for treatment: CVD (n=42), pulmonary disorders (n= 17), infectious disease (n=12), malignomas (n=11), musculoskeletal disorder and falls (n=11), 5 equations for estimating GFR: 6 variable MDRD study equation GFR = 170 X S cr X age x serum urea X albumin X BSA/1.73 X (if female). Note: authors de-normalised the equation for BSA to facilitate comparison with other equations Cockcrt-Gault equation = [140 age] X weight/ S cr X 72 X (0.85 if female) Baracskay = 88 + Gold Standard: inulin clearance N= 61 Procedure: 5 g inulin was iv injected and five timed blood samples were measured using a modified betafructosidase method. Not applica ble Bias defined as the mean difference between two methods (Bland Altman) Precision defined as the range the limits agreement (mean difference ± 2 SD differences ) Area under the ROC curve Subgroup analysis by GFR and funding Not stated Page

14 neurological disorders (n=20), and depression (n=6) (54/S cr ) (1.06 X age) diabetes Geriatric Centre Mannheim formula (GCM) = 88/Scr + (1.5 x weight) -117 Creatinine clearance No. 61 Procedure: Serum creatinine was determined by the kinetic Jaffe method on a Crea plus, Hitachi 717 system. Effect size Bias In an elderly population with no advanced renal impairment (N=61), all 5 equations underestimated the measured GFR. The 6 variable MDRD equation was the least biased (19.8 ml/min (95% CI ), while the Cockcrt Gault equation significantly underestimated the GFR (39.7 ml/min (95% CI ). In subgroup analysis elderly with a measured GFR < 90 ml/min (n=30), all 5 equations had less bias, again the 6 variable MDRD equation was the least biased (3.7 ml/min (95% CI ). In subgroup analysis elderly diabetic (n=28), all 5 equations had more bias, and performed poorly in predicting GFR. Precision The GCM (111.8 (95% CI ), Cockcrt-Gault (112 (95% CI ), and the 6-variable MDRD equations (115.3 (95% CI ) all had similar precision. In subgroup analysis elderly with a measured GFR < 90 ml/min (n=30), precision improved for all 5 equations. In subgroup analysis elderly diabetic (n=28), all 5 equations had poor precision. Area under the ROC At a cutf limit 90 ml/min, the Cockcrt-Gault (area under the ROC = 0.894), MDRD (0.851) and GCM (0.871) equations all had good diagnostic accuracy. Both the Baracskay equation and creatinine concentration had significantly poorer diagnostic accuracy (0.778 and 0.739, respectively) Page

15 At a cutf limit 60 ml/min, the MDRD had the highest diagnostic accuracy (0.976) and this was significantly higher than creatinine clearance (0.852, p=0.021) or the Baracskay equation (AUC=0.761, p=0.034). The Cockcrt-Gault equation had a lower diagnostic accuracy (AUC = 0.866) than the MDRD (no p value given). Ref ID: 166 Christensson AG, Grubb AO, Nilsson JA et al. Serum cystatin C advantageous compared with serum creatinine in the detection mild but not severe diabetic nephropathy. Journal Internal Medicine. 2004; 256(6): Patient characteristics Intervention Comparison Length followup Study type Evidence level crosssectional study Diagnosti c test 1b 1 centre, Sweden Numb er patient s N = 123 Inclusion criteria: Type 1 and Type 2 diabetics. No other inclusion data stated. Exclusion criteria Not stated Population baseline characteristics: Type Diabetes Type 1 Type 2 p- value N Median Age, years 45 (30-76) 61 (48-72) < Males/females 27/14 56/ Median disease duration, years Median 51 Cr- EDTA clearance (ml/min per 1.73 m 2 ) Median S- cystatin C (mg/l) Median S- creatinine (micromole/l) 25 (13-42) 102 (26-153) 0.95 ( ) 86 (69-179) 9 (5-33) 97 (18-134) 1.03 ( ) 81 (52-280) NS < NS NS NS Median urinary 20 (3-11 ( interventions: Cystatin C concentration Creatinine concentration N= 123 Procedure Serum cystatin C was measured by an automated particleenhanced turbidimetric assay on undiluted samples on a Cobra Mira Plus instrument. Serum creatinine was measured Gold Standard: GFR as determined from 51 Cr- EDTA clearance N= 123 Procedure 3.7 MBq 51 Cr-EDTA was injected intravenously and four blood samples were withdrawn at min postinjection. Plasma was measured for activity and clearance was normalised to Not applica ble Test correlation Area under the ROC curve funding Swedish Medical Research Council, Lund Universit y Faculty Medicine, Research Funds Region Skane, Swedish Heart Lung Foundati on, and the Research Fund and the Cancer Research Fund Malmo Universit y Hospital Page

16 albumin (microgram/,mi n) 3175) 2892) NS enzymatically m 2 body surface area. Effect size Test Correlation No age adjustment: In type 1 and 2 diabetics (N=123), cystatin C correlated significantly higher with 51 Cr-EDTA clearance compared to serum creatinine concentration (r=0.817 vs. r=0.678, p=0.0132). Age adjustment When the estimations were performed with age adjustment, there was no statistical difference between cystatin C and creatinine concentration correlation with 51 Cr-EDTA clearance (r= and 0.680, respectively). In subgroup analysis type 1 diabetics, there was no statistical difference between cystatin C and creatinine concentration correlation with 51 Cr-EDTA clearance (r=0.43 vs. 0.38, p=0.783). In subgroup analysis type 2 diabetics, there was no statistical difference between cystatin C and creatinine concentration correlation with 51 Cr-EDTA clearance (r=0.59 vs. 0.63, p=0.372). ROC Analysis Test Area under ROC curve Cystatin C concentration * Creatinine concentration * Cystatin C concentration ** Creatinine concentration ** * Cutf value for a measured 51 Cr-EDTA clearance < 80 ml/min per 1.73m 2 ** Cutf value for a measured 51 Cr-EDTA clearance < 60 ml/min per 1.73m 2 At a cut-f value < 60 ml/min per 1.73 m 2 The diagnostic accuracy cystatin C was significantly greater than creatinine concentration ( vs , p=0.042). In subgroup analysis 34 individuals with 51 Cr-EDTA clearance > 40 ml/min per 1.73 m 2, the diagnostic accuracy cystatin C was statistically greater than creatinine concentration ( vs , p=0.035). Ref ID: 267 Harmoinen A, Lehtimaki T, Korpela M et al. Diagnostic accuracies plasma creatinine, cystatin C, and Study type Evidence level Study type Crosssectional Diagnosti Numb er patient s N = 112 Patient characteristics Intervention Comparison Length followup Inclusion criteria Adults referred for 51 Cr-EDTA clearance. No other criteria stated. Exclusion criteria Not stated 4 interventions: Cystatin C Gold Standard: GFR as determined from 51 Cr- EDTA Not applica ble Test correlation Area under the ROC curve funding Not stated Page

17 glomerular filtration rate calculated by the Cockcrt-Gault and Levey (MDRD) formulas. Clinical Chemistry. 2003; 49(7): c test 1b - (no creatinin e calibratio n) 1 centre, Finland Population baseline characteristics: 49.1% male Mean age: 57.0 yrs BMI range: 15.2 to 42.4 kg/m 2 51 Cr-EDTA clearance range: 5 to 109 ml/min per 1.73m 2 Causes CKD: 24.1% diabetic nephropathy 17.9% rheumatoid arthritis-related disease 17.9% chronic glomerulonephritis concentration Creatinine concentration MDRD study equation GFR = 186 X S cr X age X (if female) Cockcrt-Gault equation GFR = [140 age] X weight / [a X S cr ] clearance No. 112 Procedure Plasma 51 Cr- EDTA clearance was assessed by the single injection method. where a = 0.8 for men and 0.85 for women No. 112 Procedure Serum cystatin C was measured turbidimetrically on a Hitachi 704 instrument. Serum creatinine was measured enzymatically on the same instrument. Page

18 Effect size Test Correlation All tests correlated well with the measured 51 Cr-EDTA clearance and the correlation coefficients did not differ statistically from one another. Test Correlation coefficient (r) Cystatin C concentration Creatinine concentration variable MDRD equation Cockcrt-Gault equation ROC Analysis Test Area under ROC curve (SE) * Cystatin C concentration (0.0173) Creatinine concentration (0.0246), p= variable MDRD equation (0.0105) Cockcrt-Gault equation (0.0071) * Cutf value for a measured 51 Cr-EDTA clearance < 80 ml/min per 1.73m 2 Cystatin C, the 4-variable MDRD equation and the Cockcrt-Gault equation all had high diagnostic accuracies (AUC) and were not statistically different from each other. The diagnostic accuracy cystatin C was significantly greater than creatinine concentration ( vs , p=0.042). In subgroup analysis 34 individuals with 51 Cr-EDTA clearance > 40 ml/min per 1.73 m 2, the diagnostic accuracy cystatin C was statistically greater than creatinine concentration ( vs , p=0.035). Ref ID: 1082 Hojs R, Bevc S, Ekart R et al. Serum cystatin C as an endogenous marker renal function in with mild to moderate impairment kidney function. Nephrology Dialysis Transplantation. 2006; 21(7):1855- Study type Evidence level Crosssectional study Diagnosti c test 1b - (no creatinin e calibratio n) 1 centre, Numb er patient s N = 164 No. ITT 164 Patient characteristics Intervention Comparison Length followup Inclusion criteria Adults with CKD stages 2-3 (GFR ml/min per 1.73m 2 ) referred for 51 Cr EDTA clearance because suspected/established renal disease Exclusion criteria Patients with CKD Stages 1, 4, or 5 Population baseline characteristics: 52.4% male Age range: 14 to 86 years 4 interventions: Serum cystatin C concentration Serum creatinine concentration 4 variable MDRD study equation GFR = 186 X Gold Standard: GFR determined from 51 Cr EDTA clearance No. 164 Not applica ble Bias defined as the mean difference between estimated and measured GFR. Test Correlation Precision Page funding Not stated

19 1862. Slovenia Mean age: 57.5 yrs Mean weight: 77.5 kg Mean height: 168 cm Mean 51 Cr EDTA clearance: 57 ml/min/1.73 m 2 (SD ± 18) Mean serum cystatin C concentration: 1.74 mg/l (SD ± 0.81) Mean serum creatinine concentration: 149 micromol/l (SD ± 64) S cr X age X (if female) Cockcrt-Gault equation adjusted for body surface area GFR = [140 age] X weight/ [0.815 X S cr ] Correction factor 0.85 for females Procedure GFR estimated from a single 51 Cr EDTA injection and three blood samples taken after parenteral application the marker. defined as the width the standard deviation the mean difference Sensitivity Specificity Area under the ROC curve No. 164 Procedure Serum creatinine was measured according to Jaffe without deproteinization. Serum cystatin C was measured by the particle-enhanced immunonephelometric method. Subgroup analysis by sex Effect size Test Correlation In the overall study, serum cystatin C concentration had the highest statistically significant correlation with 51 Cr EDTA clearance (R = 0.753, p<0.0001), and this correlation was upheld in the male population subset (R=0.732, p < ) or the female population subset (R=0.793, p < ). The 4 variable MDRD equation was also highly correlated with 51 Cr EDTA clearance (R = 0.716, p<0.0001), and this correlation was upheld in the male Page

20 population subset (R=0.705, p < ) or the female population subset (R=0.724, p < ). Serum creatinine concentration (R = 0.628, p<0.0001) and the Cockcrt-Gault equation (R = 0.515, p<0.0001) had lower correlations with 51 Cr EDTA clearance. Bias The Cockcrt-Gault equation was less biased than the MDRD equation (0.6 ml/min per 1.73m 2, p=0.79 vs ml/min per 1.73m 2, p<0.001). The MDRD equation significantly underestimated the GFR. Precision The MDRD equation (SD the mean difference = ml/min/1.73 m 2 ) was significantly more precise than the Cockcrt-Gault equation (SD the mean difference = ml/min/1.73 m 2 ), p < Test Sensitivity (%) Specificity (%) Area under ROC curve * Cystatin C ± Creatinine concentration ± 0.030, p = variable MDRD equation ± 0.026, p=0.574 Cockcrt-Gault equation ± 0.039, p= * Cutf value for a measured GFR < 60 ml/min per 1.73m 2 and p value relative to cystatin C In the overall study, serum cystatin C had significantly higher diagnostic accuracy (AUC = ± 0.022) than creatinine concentration (0.850 ± 0.030, p = 0.029) or the Cockcrt-Gault equation (0.753 ± 0.039, p=0.0001). Cystatin C had the highest sensitivity (94.6%). The MDRD equation was also a good test and the diagnostic accuracy the MDRD equation (AUC = ± 0.026, p=0.574) was not significantly different from cystatin C. In male, the Cockcrt and Gault equation (AUC = ± 0.05, p=0.03) had significantly lower diagnostic accuracy than cystatin C, MDRD equation, or creatine concentration. In female, the Cockcrt and Gault equation (AUC = ± 0.06, p=0.001) and creatine concentration (AUC = ± 0.044, p=0.04) both had significantly lower diagnostic accuracies than cystatin C (AUC = ± 0.032) or the MDRD equation (AUC = ± 0.046, p=0.115). Ref ID: 263 Lamb EJ, Webb MC, Simpson DE et al. Estimation glomerular filtration rate in older with chronic renal Study type Evidence level Study type crosssectional Diagnosti Numb er patient s N = 52 No. ITT 52 No. Patient characteristics Intervention Comparison Length followup Inclusion criteria Caucasians aged 68 and older with CKD (mild or moderate renal insufficiency GFR < 80 ml/min per 1.73 m 2 ). 6 interventions: all normalised to BSA Creatinine clearance Gold Standard: GFR as determined from 51 Cr- EDTA Not applica ble Test correlation Bias Precision funding Southeast Regional NHS Project Grant Page

21 insufficiency: is the modification diet in renal disease formula an improvement? Journal the American Geriatrics Society. 2003; 51(7): c test 1b (no creatinin e calibratio n) centre s 1 centre, Kent, UK Exclusion criteria Renal replacement therapy, renal transplant recipients, people unable to give informed consent due to cognitive impairment. Population baseline characteristics: Characteristic N Mean (SD) Age (4.9) Weight, kg (15.3) BSA, m (0.24) Serum creatinine, (78) micromol/l 51 Cr-EDTA clearance, ml/min per 1.73 m 2 Cockcrt- Gault clearance, ml/min per 1.73 m 2 MDRD clearance, ml/min per 1.73 m 2 Abbreviated MDRD clearance, ml/min per 1.73 m 2 Jelliffe bedside clearance, ml/min per 1.73 m 2 Creatinine clearance, (17.8) (16.3) (22.9) (23.3) (15.7) (26.2) Baracskay clearance = [9091/S cr ] 1.06[age] Jelliffe bedside clearance = {98 16[(age-20)/20]/(S cr X 0.011)} X [0.90 if female] MDRD equation GFR = 170 X [S cr X 0.011] X age X [S ur X 2.801] X [S Alb X 0.1] X [0.762 if female] X [1.180 if black] Abbreviated MDRD study equation GFR = 186 X [S cr X 0.011] X age X (if female) X [1.210 if black] Cockcrt-Gault equation GFR = [140 age] X weight / [S cr X 0.792] X [0.85 if female] clearance No. 52 Procedure Plasma 51 Cr- EDTA clearance was assessed by the single injection method and three blood samples. Scheme and the East Kent Hospitals NHS Trust Internal Project Grant Scheme Page

22 ml/min per 1.73 m 2 Baracskay clearance, ml/min per 1.73 m (22.7) No. 52 Procedure Patients provided blood samples and 24-h urine collections. Serum and urinary creatinine and serum urea were measured enzymatically on a Vitros analyzer. Creatinine assay was calibrated with values traceable to the HPLC reference procedure. Effect size Test Correlation From log-log regression analysis, Cockcrt-Gault (R 2 =0.84), MDRD (R 2 =0.84), abbreviated MDRD (R 2 =0.83) and Jelliffe (R 2 =0.81) were highly correlated to the measured 51 Cr-EDTA clearance. Creatinine clearance (R 2 =0.73) and the Baracskay formula (R 2 =0.56) were poorly correlated to the measured 51 Cr-EDTA clearance. Bias Only creatinine clearance and the Baracskay formula were unbiased in estimating GFR. Both MDRD equations overestimated the GFR, while the Cockcrt-Gault and Jelliffe equations significantly underestimated GFR. Mean bias compared with 51 Cr-EDTA clearance was lowest for creatinine clearance [-1.2% ml/min/1.73 m 2, (95% CI ), NS], followed by the Baracskay equation [-3.9% ml/min/1.73 m 2, (95% CI ), NS], MDRD [8.0% ml/min/1.73 m 2, (95% CI ), p<0.001], abbreviated MDRD [8.1% ml/min/1.73 m 2, (95% CI ), p<0.001], Cockcrt-Gault [-10.4% ml/min/1.73 m 2, (95% CI to -6.1), p<0.001], and Jelliffe [-20.2% ml/min/1.73 m 2, (95% CI to ), p<0.001]equations. Precision Precision (defined as the standard deviation differences between the measured 51 Cr-EDTA clearance and the formulaic estimate) was highest for the Cockcrt-Gault equation (7.9 ml/min per 1.73 m 2 ). The MDRD (9.8 ml/min per 1.73 m 2 ) and Jelliffe (9.0 ml/min per 1.73 m 2 ) equations were also relatively precise. Ref ID: 1551 Study type Evidence level Number Patient characteristics Intervention Comparison Length follow-up funding Page

23 Rigalleau V, Lasseur C, Perlemoine C et al. Estimation glomerular filtration rate in diabetic subjects: Cockcrt formula or modification diet in renal disease study equation? Diabetes Care. 2005; 28(4): Crosssectional study 1b - (no creatinin e calibratio n) N=160 diabetic participants (N=50 T1D, N=110 T2D) Inclusion: diabetic attending clinical unit, both male and female and T1D or T2D GFR as calculated by: Cockcrt- Gault compared with GFR calculated by MDRD GFR measured by an isotope method (Cr- EDTA) N/A Correlation with isotopic GFR, sensitivity, specificity, bias, accuracy Not stated Effect size *GFR estimation Mean isotopic GFR was overestimated by Cockcrt-Gault (p<0.05 vs. isotopic GFR) and the mean MDRD equation underestimated GFR (p<0.001 vs. isotopic GFR) *Correlation Both estimations were well correlated to isotopic GFR; Cockcrt-Gault formula r=0.74 (p<0.0001); MDRD equation r=0.81 (p<0.0001), NS between r values. *Bias (the Bland-Altman procedure) The bias for the MDRD equation was the estimation minus GFR, this was negatively correlated to the mean (r=-0.54, p<0.001). For the Cockcrt-Gault this was not the case (r=0.04, NS). *Accuracy (ROC curve analysis) The ROC curve analysis showed that the maximum diagnostic accuracy the Cockcrt-Gault formula for the diagnosis moderate renal failure (< 60 ml/min per 1.73 m2) was lower than the MDRD equation (Cockcrt-Gault formula AUC 0.868, cutf limit 56.5; MDRD equation AUC 0.927, cutf limit 54.7; p<0.05). This was mainly due to a better sensitivity the MDRD equation estimation (Cockcrt-Gault formula sensitivity 77.9% and specificity 78.4%; MDRD equation sensitivity 91.9% and specificity 78.4%). Severe renal failure: For the diagnosis severe renal failure (< 30 ml/min per 1.73 m2) the maximum diagnostic accuracy the Cockcrt-Gault formula was lower than that the MDRD equation (Cockcrt-Gault formula AUC 0.883, cutf limit 43.9; MDRD equation AUC 0.962, cutf limit 42.4; p<0.0001), because improved sensitivity and specificity (Cockcrt-Gault formula sensitivity 78.9% and specificity 84.4%; MDRD equation sensitivity 94.7% and specificity 90.2%). Renal insufficiency: For the renal insufficient participants (N=87) both the formulas overestimated GFR (both p< vs. isotopic GFR), the overestimation was more pronounced with the Cockcrt-Gault formula (p< vs. the MDRD equation). For the renal insufficiency participants the correlation with isotopic GFR was lower for the Cockcrt-Gault formula (Cockcrt-Gault formula r=0.57, p<0.001; MDRD equation r=0.78, p<0.0001; p<0.01 between r values). The Cockcrt-Gault formula over estimated high values GFR (according to the Bland Altman procedure), r=0.38, p< For the MDRD equation this was Page

24 not the case (r=0.07, NS). Ref ID: 1327 Study type Evidence Rigalleau V, Lasseur C, Perlemoine C et al. A simplified Cockcrt-Gault formula to improve the prediction the glomerular filtration rate in diabetic. Diabetes & Metabolism. 2006; 32(1): level Crosssectional study Diagnostic test Ib - (no creatinine calibration) 1 centre, France Number Total N=200 No. ITT 200 Patient characteristics Intervention Comparison Length follow-up Inclusion criteria adult diabetic studied between Jan., 2001 and Jan., Kidney failure or damage defined by an isotopic GFR < 90 ml/min/1.73m 2 and microalbuminuria above 30 mg/24 h. Exclusion criteria Dialysis, nephrotic proteinuria (> 3g/24 h), or clinical edema Population characteristics N 200 Mean age (SD) 63.0 (13.6) % Female 60 % Type 1 Diabetes 31 Mean Weight (SD), 76.5 (14.2) kg Mean Height (SD), 166 (8) cm Mean BMI (SD) 27.5 (4.7) % HbA 1c (SD) 8.6 (1.6) Mean serum 146 (79) creatinine (SD) micromole/l Mean measured Cr (34.9) EDTA clearance (SD), ml/min per 1.73 m 2 Mean egfr MDRD 51.0 (24.3) (SD), ml/min per 1.73 m 2 Mean egfr Cockcrt-Gault (SD), ml/min per 1.73 m 2 Mean egfr Modified Cockcrt-Gault (SD), 61.2 (35.6) 60.0 (29.9) 3 interventions MDRD study equation GFR = 186 X S cr X age X (if female) X (if black) Cockcrt- Gault equation = (140 age) X weight X K / [S cr ] ;where K=1.23 for men and 1.04 for women Modified Cockcrt- Gault equation = (140 age) X 76 X K / [S cr ] ;where K=1.23 for men and 1.04 for women 51 Cr-EDTA renal clearance. No. 200 n/a Bias Accuracy AUC Test correlation funding Not stated Page

25 ml/min per 1.73 m 2 No. 200 Procedure All were studied in the morning after a light breakfast. Serum creatinine was measured by the Jaffe method using an Olympus AU 640 instrument. Effect size Bias In the diabetic patient population (N=200), the MDRD equation underestimated the measured GFR (-1.2 ml/min/1.73 m 2 ), while both the Cockcrt-Gault (+4.5) and modified Cockcrt-Gault (+4.6) equations overestimated the GFR. Test Correlation The modified Cockcrt-Gault equation was significantly more highly correlation with measured Cr-EDTA GFR than the original Cockcrt-Gault equation (r=0.83 vs. 0.75, p<0.05). The MDRD was also highly correlated with measured Cr-EDTA GFR (r=0.82, p=0.068 vs. CG). AUC In diabetic with a measured Cr-EDTA GFR between ml/min/1.73 m 2 (n=119), the MDRD equation had a significantly higher diagnostic accuracy (AUC =0.920) than the Cockcrt-Gault equation (AUC=0.866, p<0.05 vs MDRD). The modified Cockcrt-Gault equation also had significantly higher diagnostic accuracy (AUC=0.921) than the original Cockcrt-Gault equation (AUC=0.866, p<0.05 vs CG ) In diabetic with a measured Cr-EDTA GFR between ml/min/1.73 m 2 (n=52), the MDRD equation had a significantly higher diagnostic accuracy (AUC =0.930) than the Cockcrt-Gault equation (AUC=0.891, p<0.05 vs MDRD). The modified Cockcrt-Gault equation also had significantly higher diagnostic accuracy (AUC=0.942) than the original Cockcrt-Gault equation (AUC=0.891, p<0.05 vs CG ) Accuracy The th -90 th percentiles percentage absolute differences between predicted and measured GFR were lower for the MDRD than for the Cockcrt-Gault, with the modified Cockcrt-Gault being intermediate. Thus, MDRD was more accurate. Page

26 Ref ID: 110 Bicik Z, Bahcebasi T, Kulaksizoglu S et al. The efficacy cystatin C assay in the prediction glomerular filtration rate. Is it a more reliable marker for renal failure? Clinical Chemistry & Laboratory Medicine. 2005; 43(8): Study type Evidence level Study type Crosssectional Diagnostic test II - 24 h creatinine as reference 1 centre in Turkey Number Total N = 244 No. ITT 244 Patient characteristics Intervention Comparison Length follow-up Inclusion criteria Healthy adults (controls) and adults with hypertension (average blood pressure higher than 140/90 mm Hg on two occasions) or type II diabetes. Exclusion criteria 11 subjects excluded for inaccurate urine collections. Patients undergoing dialysis. Population baseline characteristics: Type II Hypertension Control Diabetes N Mean Age 45.3 ± ± ± 6.4 Sex (F/M) 44/40 48/36 45/39 Median Creatinine (range), micromole/l 106 ( ) 106 ( ) 79.5 (53 106) Median Cystatin C (range), mg/l Median Creatinine clearance (range), ml/min Mean Fasting Blood sugar, mmol/l 1.2 ( ) 81.5 ( ) 1.1 ( ) 84.9 ( ) 0.7 ( ) ( ) 5.9 ± ± ± 0.3 Cystatin C concentration Creatinine concentration No. 244 Procedure Serum cystatin C concentration was measured with a particleenhanced turbidimetric immunoassay (DACO-Cys- C) on a Cobas Mira Plus instrument. Serum creatinine was measured enzymatically 24-h urinary creatinine clearance = urine creatinine x 24-h urine volume/[serum creatinine 1440 min] No. 244 Caveat: authors discuss the value inulin clearance or radioisotopic GFR and state that these tests give better results than 24-h creatinine clearance. No explanation as to why they chose 24 h creatinine clearance Not applicable Test correlation Sensitivity Specificity Positive predictive value Negative predictive value Area under the ROC curve funding Not stated Page

27 All diabetics were on moderately restrictive protein diets and received insulin (N=16) or oral antidiabetic medication (remainder). None received anticoagulants or NSAIDS. Incipient nephropathy with microalbuminuria (N=72) and overt nephropathy with overt proteinuria (N=12). on a Hitachi 747 instrument. Most hypertensive (N=63) were newly diagnosed and did not take antihypertensive medication. ACE inhibitors (N=3), calcium antagonists (N=2), indapamide diuretics (N=8). Microalbuminuria (N=82), overt proteinuria (N=2) Effect size Test Correlation Hypertensive Group: Cystatin C and creatinine concentration were highly correlated (0.92, p<0.05). Cystatin C concentration and 24-h creatinine clearance were significantly correlated (-0.87, p< 0.05). Diabetic Group: Cystatin C and creatinine concentration were highly correlated (0.97, p<0.05). Cystatin C concentration and 24-h creatinine clearance were significantly correlated (-0.90, p< 0.05). Healthy Controls: Cystatin C and creatinine concentration were highly correlated (0.94, p<0.05). The correlation between cystatin C concentration and 24-h creatinine clearance was significantly weak (-0.61, p< 0.05). ROC Analysis Whole Study Group Test Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Area under ROC curve Cystatin C * 91 * 90 * 70 * 96 * concentration Creatinine * 91 * 91 * 72 * 94 * 0.949, NS concentration Cystatin C ** 80 ** 96 ** 100 ** 86 ** concentration Creatinine concentration ** 68 ** 82 ** 86 ** 75 ** 0.626, p=0.01 * Cutf value for a measured 24 h creatinine clearance < 60 ml/min ** Cutf value for a measured 24 h creatinine clearance < 80 ml/min Page

28 In the whole study group, cystatin C (AUC = 0.813) had a statistically significant higher diagnostic accuracy than creatinine concentration (AUC = 0.626) in with a 24 h creatinine clearance between ml/min. There was no statistical difference between the diagnostic accuracies cystatin C and creatinine concentration in with a 24 h creatinine clearance < 60 ml/min. Mild Diabetic Nephropathy Subgroup (microalbuminuria) Test Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Cystatin C * 90 * 90 * 87 * 92 concentration Creatinine * 94 * 90 * 86 * 88 concentration Cystatin C ** 92 ** 94 ** 94 ** 88 concentration Creatinine concentration ** 72 ** 76 ** 76 ** 75 * Cutf value for a measured 24 h creatinine clearance < 60 ml/min ** Cutf value for a measured 24 h creatinine clearance < 80 ml/min The sensitivity, specificity, positive predictive values, and negative predictive values cystatin C were significantly higher than creatinine concentration in with diabetic nephropathy and microalbuminuria with a 24 hour creatinine clearance between ml/min. Hypertension with microalbuminuria Test Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Cystatin C * 40 * 96 * 85 * 80 concentration Creatinine * 100 * 93 * 90 * 86 concentration Cystatin C ** 81 ** 96 ** 82 ** 86 concentration Creatinine concentration ** 50 ** 93 ** 78 ** 75 * Cutf value for a measured 24 h creatinine clearance < 60 ml/min ** Cutf value for a measured 24 h creatinine clearance < 80 ml/min The sensitivity, specificity, positive predictive values, and negative predictive values cystatin C were significantly higher than creatinine concentration in with hypertension and microalbuminuria with a 24 hour creatinine clearance between ml/min. Ref ID: 872 Study type Evidence Number Patient characteristics Intervention Comparison Length follow-up funding Page