Study protocol for systematic review to identify the risk...

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Study protocol for systematic review to identify the risk factors of development and progression of chronic kidney disease Objective To identify the risk factors for disease development and progression in each stage of chronic kidney disease (CKD). Inclusion Criteria Study type

We will include studies examining the risk factors for initiation, development, or progression of CKD.

Studies of either cohort or case-control design will be eligible to enter our systematic review, but studies of cross-sectional design will not be eligible.

Eligible studies should have collected repeated information which could evaluate the change in renal function.

Participants

Eligible studies should include participants older than 18 years of age. Participants with CKD stage 1-5 at baseline, or participants without CKD at baseline, will be

eligible. Outcome measures

Eligible studies should have reported at least one of the following outcomes: decline in renal function, or end-stage renal disease (ESRD).

ESRD is defined as the need for dialysis therapy or kidney transplantation. Publication type

Full-length articles in peer-reviewed journals will be eligible.

There is no restriction on language of publication.

Data extraction

Two investigators (Wan-Chuan Tsai, Hon-Yen Wu) will independently perform data extraction. The following information will be extracted and entered into databases: details of the study design, location and published year of study, patient demographic characteristics (age, sex, and ethnicity), numbers of patients enrolled and excluded, the CKD stages at baseline and follow-up, duration of study, study outcomes, identified risk factors and their adjusted effect size, as well as other covariates adjusted in the regression models. We will identify the CKD stages at baseline and follow-up

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according to renal function measures. The stages of CKD are defined by the K/DOQI Clinical Practice Guidelines according to the glomerular filtration rate (GFR) and evidence of kidney damage.1 Patients will be classified according to the following criteria: stage 5 (GFR <15 ml/min), stage 4 (GFR 15–29 ml/min), stage 3 (GFR 30–59 ml/min), stage 2 (kidney damage with a GFR of 60–89 ml/min), and stage 1 (kidney damage with a GFR >90 ml/min). Participants of GFR ≥ 60 ml/min and without kidney damage are designated as stage 0. Patients with the requirement of renal replacement therapy are designated as ESRD. When the relevant information regarding design or outcomes is unclear, or when doubt exists for duplicate publications, the original authors will be contacted to obtain the necessary information. Disagreements between the two authors will be resolved by discussion. If the disagreement persists, two other senior investigators (Yu-Sen Peng, Kuo-Liong Chien) will be consulted to attain consensus. Quality Assessment

The methodological quality and risk of bias of the eligible studies will be evaluated independently by two investigators (Wan-Chuan Tsai, Hon-Yen Wu) using the Newcastle-Ottawa Scale.2,3 Disagreements between the two authors will be resolved by discussion. If the disagreement persists, two other senior investigators (Yu-Sen Peng, Kuo-Liong Chien) will be consulted to attain consensus.

Data Synthesis and Analysis

All data from each eligible study will be extracted and entered into a computer database using a spreadsheet software (Microsoft Excel 2010; Microsoft Corp, Redmond, WA, USA). Categorical variables will be presented as frequencies or percentages and continuous variables as mean values, unless stated otherwise. Data from all the included studies will be synthesized narratively. An exploratory meta-analysis will be performed where feasible to pool hazard ratios (HRs) of a specific risk factor for a specific outcome, from studies with the same baseline and follow-up stages of CKD. The pooled estimates of HR and 95% confidence interval (CI) of risk factors for development or progression of CKD will be calculated using the method of the DerSimonian and Laird random-effects model while heterogeneity of treatment effects across studies will be assessed with I2, the Cochrane Q-test, and the Galbraith plot method.3,4 Publication bias will be examined with the funnel plot method, the Begg's adjusted rank correlation test, and the Egger's regression asymmetry test.5,6 Sensitivity analyses will be conducted by the same methods after omission of data from specific studies, such as studies with a different population or large sample size that might dominate the pooled effect sizes. Two-sided P ≤ 0.05 is considered statistically significant. Statistical analyses will be performed with Stata software (version 11.1, StataCorp LP, College Station, TX, USA).

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Search Strategies We will search the following electronic databases: MEDLINE PubMed Scopus Cochrane Library We search additional studies in the reference lists of all identified publications, including relevant meta-analyses and systematic reviews. MEDLINE: Search using the Ovid interface from the earliest available date of indexing through 15 Oct 2012: (1) Kidney Failure, Chronic/ or chronic kidney disease.mp. or Renal Insufficiency, Chronic/; (2) Risk Factors/; (3) Disease Progression/; (4) Cohort Studies/; (5) Case-Control Studies/; (6) 4 or 5; (7) 1 and 2 and 3 and 6. PubMed: Search using the NCBI interface from the earliest available date of indexing through 15 Oct 2012: (("kidney failure, chronic"[MeSH Terms]) OR ("renal insufficiency, chronic"[MeSH Terms])) AND ("risk factors"[MeSH Terms]) AND ("disease progression"[MeSH Terms]) AND (("cohort studies"[MeSH Terms]) OR ("case-control studies"[MeSH Terms])) Scopus: Search using the Elsevier interface from the earliest available date of indexing through 15 Oct 2012: ("kidney failure, chronic" OR "renal insufficiency, chronic") AND "risk factors" AND "disease progression" AND ("cohort studies" OR "case-control studies") Cochrane Library: Searched using the Wiley interface from the earliest available date of indexing through 15 Oct 2012: ("kidney failure, chronic" OR "renal insufficiency, chronic") AND "risk factors" AND "disease progression" AND ("cohort studies" OR "case-control studies")

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References 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification,

and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266. 2. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the

quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf.

3. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration. http://www.cochrane-handbook.org.

4. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med. 1988;7:889-894.

5. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-1101.

6. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-634.

Supplementary References : References of studies included in the systematic review 1. Locatelli F, Marcelli D, Comelli M, et al. Proteinuria and blood pressure as causal

components of progression to end-stage renal failure. Northern Italian Cooperative Study Group. Nephrol Dial Transplant. 1996;11:461-467.

2. Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 1997;51:1908-1919.

3. Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754-762.

4. Boaz M, Biro A, Katzir Z, Smetana S. Patterns of dietary intake and serum lipids interact with proteinuria as risk factors for progression of chronic renal failure. Ren Fail. 1998;20:383-390.

5. Regalado M, Yang S, Wesson DE. Cigarette smoking is associated with augmented progression of renal insufficiency in severe essential hypertension. Am J Kidney Dis. 2000;35:687-694.

6. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomatic isolated microscopic haematuria: long-term follow-up. QJM. 2004;97:739-745.

7. Evans M, Fryzek JP, Elinder CG, et al. The natural history of chronic renal failure: results from an unselected, population-based, inception cohort in Sweden. Am J Kidney Dis. 2005;46:863-870.

8. Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F, Zoccali C. Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol. 2005;16:2449-2455.

9. Shankar A, Klein R, Klein BE. The association among smoking, heavy drinking, and chronic kidney disease. Am J Epidemiol. 2006;164:263-271.

10. Brantsma AH, Atthobari J, Bakker SJL, De Zeeuw D, De Jong PE, Gansevoort RT. What predicts progression and regression of urinary albumin excretion in the nondiabetic population? J Am Soc Nephrol. 2007;18:637-645.

11. Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic kidney disease. Am J Med. 2007;120:280 e281-287.

12. Hemmelgarn BR, Culleton BF, Ghali WA. Derivation and validation of a clinical index for prediction of rapid progression of kidney dysfunction. QJM. 2007;100:87-92.

13. Ozsoy RC, van der Steeg WA, Kastelein JJP, Arisz L, Koopman MG. Dyslipidaemia as predictor of progressive renal failure and the impact of treatment with atorvastatin.

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Nephrol Dial Transplant. 2007;22:1578-1586. 14. Imai E, Horio M, Yamagata K, et al. Slower decline of glomerular filtration rate in the

Japanese general population: a longitudinal 10-year follow-up study. Hypertens Res. 2008;31:433-441.

15. Yoshida T, Takei T, Shirota S, et al. Risk factors for progression in patients with early-stage chronic kidney disease in the Japanese population. Intern Med. 2008;47:1859-1864.

16. Levin A, Djurdjev O, Beaulieu M, Er L. Variability and risk factors for kidney disease progression and death following attainment of stage 4 CKD in a referred cohort. Am J Kidney Dis. 2008;52:661-671.

17. Agarwal R. Blood pressure components and the risk for end-stage renal disease and death in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:830-837.

18. Bash LD, Erlinger TP, Coresh J, Marsh-Manzi J, Folsom AR, Astor BC. Inflammation, hemostasis, and the risk of kidney function decline in the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2009;53:596-605.

19. Bolignano D, Lacquaniti A, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:337-344.

20. Fried LF, Katz R, Cushman M, et al. Change in cardiovascular risk factors with progression of kidney disease. Am J Nephrol. 2009;29:334-341.

21. Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol. 2009;20:1069-1077.

22. Ryu S, Chang Y, Woo H-Y, et al. Time-dependent association between metabolic syndrome and risk of CKD in Korean men without hypertension or diabetes. Am J Kidney Dis. 2009;53:59-69.

23. Bash LD, Astor BC, Coresh J. Risk of incident ESRD: a comprehensive look at cardiovascular risk factors and 17 years of follow-up in the Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis. 2010;55:31-41.

24. Kuo HW, Tsai SS, Tiao MM, Liu YC, Lee IM, Yang CY. Analgesic use and the risk for progression of chronic kidney disease. Pharmacoepidemiology and Drug Safety. 2010;19:745-751.

25. Obi Y, Kimura T, Nagasawa Y, et al. Impact of age and overt proteinuria on outcomes of stage 3 to 5 chronic kidney disease in a referred cohort. Clin J Am Soc Nephrol. 2010;5:1558-1565.

26. Chien KL, Lin HJ, Lee BC, Hsu HC, Lee YT, Chen MF. A prediction model for the risk of incident chronic kidney disease. Am J Med. 2010;123:836-846 e832.

27. Hoefield RA, Kalra PA, Baker P, et al. Factors associated with kidney disease progression and mortality in a referred CKD population. Am J Kidney Dis.

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2010;56:1072-1081. 28. Agarwal R, Light RP. Patterns and prognostic value of total and differential leukocyte

count in chronic kidney disease. Clin J Am Soc Nephrol. 2011;6:1393-1399. 29. De Nicola L, Chiodini P, Zoccali C, et al. Prognosis of CKD patients receiving

outpatient nephrology care in Italy. Clin J Am Soc Nephrol. 2011;6:2421-2428. 30. Khedr A, Khedr E, House AA. Body mass index and the risk of progression of chronic

kidney disease. J Ren Nutr. 2011;21:455-461. 31. O'Seaghdha CM, Hwang SJ, Bhavsar NA, et al. Lower urinary connective tissue

growth factor levels and incident CKD stage 3 in the general population. Am J Kidney Dis. 2011;57:841-849.

32. Shastri S, Katz R, Shlipak MG, et al. Cystatin C and albuminuria as risk factors for development of CKD stage 3: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis. 2011;57:832-840.

33. Sugiura T, Wada A. Resistive index predicts renal prognosis in chronic kidney disease: results of a 4-year follow-up. Clin Exp Nephrol. 2011;15:114-120.

34. Wang F, Zhang L, Zuo L, Liu L, Wang H. Mortality and renal function decline among a community-based Chinese population with normal or mildly impaired renal function. Nephrol Dial Transplant. 2011;26:2847-2852.

35. Wu IW, Hsu KH, Lee CC, et al. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant. 2011;26:938-947.

36. Shankar A, Sun L, Klein BE, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011;80:1231-1238.

37. Iseki K, Iseki C, Kinjo K. C-reactive protein is a predictor for developing proteinuria in a screened cohort. Nephron Clin Pract. 2011;117:c51-56.

38. Baek SD, Baek CH, Kim JS, Kim SM, Kim JH, Kim SB. Does stage III chronic kidney disease always progress to end-stage renal disease? A ten-year follow-up study. Scand J Urol Nephrol. 2012;46:232-238.

39. Cheng HT, Huang JW, Chiang CK, Yen CJ, Hung KY, Wu KD. Metabolic syndrome and insulin resistance as risk factors for development of chronic kidney disease and rapid decline in renal function in elderly. J Clin Endocrinol Metab. 2012;97:1268-1276.

40. Pereira AC, Carminatti M, Fernandes NM, et al. Association between laboratory and clinical risk factors and progression of the predialytic chronic kidney disease. J Bras Nefrol. 2012;34:68-75.

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Supplementary Table 1. Identified risk factors with their adjusted effect sizes for CKD development and progression.

Author Year Baseline

CKD stage Study endpoint Risk factors for CKD development and progression (effect size) Measure of effect size

Locatelli1 1996 3-5 Doubling of creatinine or ESRD Creatinine (2.18), proteinuria (1.50), calcium (0.78), underlying nephropathya Hazard ratio

Hunsicker2,3 1997 3-4 Slope of decline in GFR Proteinuria (-1.09), PKD (-3.50), transferrin (0.01), black (-1.50), MAP (-0.04), HDL (0.03) β coefficient

Hunsicker2,3 1997 4-5 Slope of decline in GFR Proteinuria (-0.97), PKD (-1.88), transferrin (0.01) β coefficient

Hunsicker2,3 1997 4-5 ESRD or death Proteinuria (0.41), PKD (0.58), transferrin (-0.01),GFR (-0.17) β coefficient

Boaz4 1998 3-5 Slope of 1/creatinine Dietary pattern (-0.001), lipid (-0.001), proteinuria (-0.002) β coefficient

Regalado5 2000 1-2 Slope of 1/creatinine Smoking (4.38), proteinuria (2.86), black (2.40), age (1.99) Standard score

Regalado5 2000 1-2 Change in creatinine clearance Smoking (4.36), proteinuria (2.02), black (1.99), mean BP (1.97) Standard score

Chow6 2004 1-2 GFR < 60 ml/min; proteinuria > 0.5 g/day; or

hypertension

Proteinuria (2.04), GFR (2.02), uric acid (1.02) Hazard ratio

Evans7 2005 4-5 ESRD Age (0.72), male (1.59), diabetes (1.24), GFR (2.27) Hazard ratio

Ravani8 2005 2-5 ESRD or death ADMA (1.20), hemoglobin (0.78), proteinuria (1.33), GFR (0.91) Hazard ratio

Shankar9 2006 0-2 GFR < 60 ml/min Current smoking (1.97), heavy drinking (1.99) Odds ratio

Brantsma10 2007 0-2 Progression in albuminuria MAP (1.91), fasting glucose (1.09), antihypertensive drugs (0.70) Odds ratio

Gooch11 2007 0-5 GFR decrease ≥ 15 ml/min Use of NSAID (1.29), use of COX-2 inhibitor (1.25) Odds ratio

Hemmelgarn12 2007 0-5 GFR decline ≥ 25% in 2 years Age (1.00), cardiovascular disease (1.50), diabetes (1.90), gout (1.50), anti-emetic drugs (2.90) Odds ratio

Ozsoy13 2007 1-4 GFR decline > 5 ml/min/year or ESRD Apolipoprotein B (2.63), type of renal disease (3.04), MAP (1.54), proteinuria (1.67) Odds ratio

Imai14 2008 0-5 GFR decline in 10 years Hypertension, proteinuria, GFR Stratified by age and sex

Yoshida15 2008 1-2 Slope of decline in GFR Proteinuria (-0.30), smoking (-0.24), hypertension (-0.20), HDL (-0.22) β coefficient

Levin16 2008 4-5 ESRD Age (0.91), male(1.49), GFR(0.75), systolic BP (1.02), diastolic BP (1.05), hemoglobin (0.94), phosphate (1.02),

PTH (1.28), proteinuria (1.49), use of ACEI/ARB (0.78)

Hazard ratio

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Supplementary Table 1. Continued.



Agarwal17 2009 1-5 ESRD Systolic BP (6.37) Hazard ratio

Bash18 2009 0-2 GFR < 60 ml/min Leukocyte count (1.30), fibrinogen (1.25), von Willebrand factor (1.46), factor VIIIc (1.39), albumin (0.63) Hazard ratio

Bolignano19 2009 2-4 Doubling of creatinine or ESRD Urinary NGAL (1.03), serum NGAL (1.02), GFR (0.97) Hazard ratio

Fried20 2009 0-3 Creatinine increase ≥ 0.3 mg/dL in 3 years Fibrinogen (1.38), factor VIII (1.38), HDL (0.80), triglyceride (1.21), interleukin-6 [0.04], factor VIII [0.05] Please see footnoteb

Hallan21 2009 0-4 ESRD Age (1.72), male (2.22), low physical activity (1.71), diabetes (1.80), systolic BP (1.16), HDL (0.90),

antihypertensive drugs (2.38), GFR (65.6), albuminuria (47.5)

Hazard ratio

Ryu22 2009 0 GFR < 60 ml/min Metabolic syndrome (1.99/1.75), triglyceride (1.44/1.71), HDL (2.23/2.03) Hazard ratioc

Bash23 2010 0-5 ESRD GFR (141.68), black (2.47), age (1.60), male (1.49), diabetes (6.10), systolic BP (1.44), CAD (1.60), BMI (1.13),

smoking (former/current:1.64/1.93), triglyceride (1.68)

Hazard ratio

Kuo24 2010 1-5 ESRD Use of acetaminophen (2.92), use of aspirin (1.96), use of NSAID (1.56), use of rofecoxib (1.98) Hazard ratio

Obi25 2010 3-5 ESRD Age (0.67), proteinuria (4.97) Hazard ratio

Chien26 2010 0-2 GFR < 60 ml/min Age (1.08), BMI (1.06), diastolic BP (1.02), diabetes (1.44), stroke (3.46), postprandial glucose (1.00),

HbA1c (1.18), proteinuria (5.57), uric acid (1.18)

Relative risk

Hoefield27 2010 3-5 ESRD Age (0.98), diastolic BP (1.02), hemoglobin (0.98), phosphate (2.17), proteinuria (1.08), stage of CKD (18.82) Hazard ratio

Agarwal28 2011 0-5 ESRD or death Granulocyte (1.67), monocyte (1.52) Hazard ratio

De Nicola29 2011 3-5 ESRD Age (0.94), proteinuria (3.17/2.02)d, phosphate (1.59), BMI (0.97), cardiovascular event (1.27), hemoglobin (1.27) Hazard ratio

Khedr30 2011 3-5 Slope of decline in GFR GFR (-0.08), proteinuria (-0.61), diabetic nephropathy (-0.96), use of ACEI/ARB (1.01) β coefficient

O'Seaghdha31 2011 0 CKD stage 3 Urinary connective tissue growth factor (0.33) Odds ratio

Shastri32 2011 0-2 CKD stage 3 Microalbuminuria (1.57), cystatin C (1.37) Incidence rate ratio

Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Proteinuria (5.06), resistive index (2.98), GFR (2.26), systolic BP (1.90) Hazard ratio

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Wang34 2011 0-5 GFR decrease ≥ 20% Albuminuria (1.79), uric acid (1.25), age (1.35) Odds ratio

Wu35 2011 1-5 GFR decrease ≥ 50% or ESRD P-cresyl sulphate (1.04), indoxyl sulphate (1.03) Hazard ratio

Shankar36 2011 0-2 GFR < 60 ml/min Tumor necrosis factor-α receptor 2 (2.49), leukocyte count (1.98), interleukin-6 (1.57) Hazard ratio

Iseki37 2011 0 Dipstick proteinuria ≥ 1+ C-reactive protein (1.43) Hazard ratio

Baek38 2012 3 GFR < 30 ml/min Microalbuminuria (1.99), macroalbuminuria (3.06), microscopic hematuria (2.07), CKD stage 3B (2.99) Hazard ratio

Cheng39 2012 1-3 GFR decrease > 3 ml/min/year Metabolic syndrome (1.39), insulin resistance (1.16), glucose (1.58) Hazard ratio

Cheng39 2012 1-3 Incident CKD Metabolic syndrome (1.93), triglyceride (1.95), glucose (2.24) Hazard ratio

Pereira40 2012 3-5 ESRD Diabetic nephropathy (4.42) Hazard ratio

Abbreviations. ACEI, angiotensin converting enzyme inhibitor; ADMA, asymmetrical dimethylarginine; ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood

pressure; CAD, coronary artery disease; CKD, chronic kidney disease; COX-2, cyclooxygenase-2; ESRD, end-stage renal disease; GFR, glomerular filtration rate, HbA1c,

hemoglobin A1c; HDL, high-density lipoprotein cholesterol; MAP, mean arterial pressure; NGAL, neutrophil gelatinase-associated lipocalin; NSAID, non-steroidal

anti-inflammatory drug; PKD, polycystic kidney disease; PTH, parathyroid hormone.

Note.

See supplementary references for studies included in the systematic review. a Nephroangiosclerosis vs interstitial nephritis (3.55), PKD vs interstitial nephritis (2.47). b ( ), Odds ratio; [ ],β coefficient. c Hazard ratios (standard/time-dependent). d The association between proteinuria and outcome was stratified by CKD stage 3/4.

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Supplementary Table 2. Summary for Newcastle-Ottawa quality assessment scale of studies included in the systematic review.

Author Year Selection Comparability Outcome/exposure

1 2 3 4 1 1 2 3

Locatelli1 1996 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆

Hunsicker2,3 1997 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Hunsicker2,3 1997 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Boaz4 1998 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Regalado5 2000 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Chow6 2004 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Evans7 2005 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Ravani8 2005 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Shankar9 2006 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Brantsma10 2007 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Gooch11 2007 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Hemmelgarn12 2007 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Ozsoy13 2007 ☆ ☆ ☆ ☆ ☆ ☆ ☆ ☆

Imai14 2008 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Yoshida15 2008 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Levin16 2008 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Agarwal17 2009 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Bash18 2009 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Bolignano19 2009 ☆ ☆ ☆ ☆ ☆ ☆ ☆ ☆

Fried20 2009 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Hallan21 2009 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Ryu22 2009 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆

Bash23 2010 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Kuo24 2010 ☆ ☆ ☆ ☆ ☆☆ ☆

Obi25 2010 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Chien26 2010 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Hoefield27 2010 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Agarwal28 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

De Nicola29 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Khedr30 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

O'Seaghdha31 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Shastri32 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Sugiura33 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

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Author Year Selection Comparability Outcome/exposure

1 2 3 4 1 1 2 3

Wang34 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Wu35 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Shankar36 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Iseki37 2011 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Baek38 2012 ☆ ☆ ☆ ☆

☆ ☆

Cheng39 2012 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Pereira40 2012 ☆ ☆ ☆ ☆ ☆☆ ☆ ☆ ☆

Note. See supplementary references for studies included in the systematic review. A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome/exposure categories, and a maximum of two stars can be given for the Comparability category.

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Supplementary Table 3. Adjusted effect sizes and results of statistical tests of major risk factors for CKD development and progression.

Risk factor Author Year Baseline

CKD stage Study endpoint Definition of the risk factor Effect size 95% CI P value Measure of effect size

Proteinuria Locatelli1 1996 3-5 Doubling of creatinine or ESRD Baseline proteinuria (g/day) 1.50 1.26-1.79 Hazard ratio

Proteinuria Hunsicker2,3 1997 3-4 Slope of decline in GFR Baseline log proteinuria (g/day) -1.09 <0.001 β coefficient

Proteinuria Hunsicker2,3 1997 4-5 Slope of decline in GFR Baseline log proteinuria (g/day) -0.97 <0.001 β coefficient

Proteinuria Hunsicker2,3 1997 4-5 ESRD or death Baseline log proteinuria (g/day) 0.41 0.001 β coefficient

Proteinuria Boaz4 1998 3-5 Slope of 1/creatinine Baseline proteinuria (g/day) -0.002 0.003 β coefficient

Proteinuria Regalado5 2000 1-2 Slope of 1/creatinine Baseline UPCR (mg/mg) 2.86 0.004 Standard score

Proteinuria Regalado5 2000 1-2 Change in creatinine clearance Baseline UPCR (mg/mg) 2.02 0.04 Standard score

Proteinuria Chow6 2004 1-2 Composite endpointsa Baseline proteinuria (0.1 g/day) 2.04 1.13-3.68 0.02 Hazard ratio

Proteinuria Ravani8 2005 2-5 ESRD or death Baseline proteinuria (g/L) 1.33 1.16-1.52 <0.001 Hazard ratio

Proteinuria Ozsoy13 2007 1-4 GFR decline > 5 ml/min/year or ESRD Baseline proteinuria (1 g/day) 1.67 1.28-2.18 Odds ratio

Proteinuria Imai14 2008 0-5 GFR decline in 10 years Baseline dipstick proteinuria ≥ 1+ <0.001 Stratified by age, sex

Proteinuria Yoshida15 2008 1-2 Slope of decline in GFR Baseline dipstick proteinuria ≥ 1+ -0.30 0.01 β coefficient

Proteinuria Levin16 2008 4-5 ESRD Baseline proteinuria (1 g/day) 1.49 1.15-1.92 0.01 Hazard ratio

Proteinuria Hallan21 2009 0-4 ESRD Baseline UACR (male > 300 mg/g; female > 200 mg/g) 47.5 19.8-109.0 <0.001 Hazard ratio

Proteinuria Obi25 2010 3-5 ESRD Baseline UPCR ≥ 1 g/g or dipstick proteinuria ≥ 2+ 4.97 2.23-11.1 <0.001 Hazard ratio

Proteinuria Chien26 2010 0-2 GFR < 60 ml/min Baseline proteinuria (≥ 100 mg/dL) 5.57 2.64-11.76 <0.001 Relative risk

Proteinuria Hoefield27 2010 3-5 ESRD Baseline proteinuria (1 g/day) 1.08 1.01-1.14 0.01 Hazard ratio

Proteinuria De Nicola29 2011 3 ESRD Baseline proteinuria (≥ 0.5 g/day) 3.17 1.76-5.72 <0.01 Hazard ratio

Proteinuria De Nicola29 2011 4 ESRD Baseline proteinuria (≥0.5 g/day) 2.02 1.41-2.88 0.01 Hazard ratio

Proteinuria De Nicola29 2011 5 ESRD Baseline proteinuria (≥ 0.5 g/day) 1.13 0.73-1.76 0.59 Hazard ratio

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Proteinuria Khedr30 2011 3-5 Slope of decline in GFR Baseline proteinuria > 0.5 g/day or UACR > 30 mg/mmol -0.61 0.02 β coefficient

Proteinuria Shastri32 2011 0-2 CKD stage 3 Baseline UACR (male > 17 µg/mg; female > 25 µg/mg) 1.57 1.19-2.07 Incidence rate ratio

Proteinuria Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Baseline UPCR ≥ 1 g/g 5.06 2.95-8.51 <0.001 Hazard ratio

Proteinuria Wang34 2011 0-5 GFR decrease ≥ 20% Baseline UACR (male ≥ 20 mg/g; female ≥ 30 mg/g) 1.79 1.02-3.15 Odds ratio

Proteinuria Baek38 2012 3 GFR < 30 ml/min Baseline UACR between 30 mg/g and 300 mg/g 2.99 1.04-3.85 0.001 Hazard ratio

Proteinuria Baek38 2012 3 GFR < 30 ml/min Baseline UACR > 300 mg/g 3.06 1.94-4.84 <0.001 Hazard ratio

Proteinuria Pereira40 2012 3-5 ESRD Baseline proteinuria (mg) 1.25 0.45-3.43 0.67 Hazard ratio

Male Regalado5 2000 1-2 Slope of 1/creatinine Male vs female 0.20 -0.17-0.13 >0.05 Standard score

Male Regalado5 2000 1-2 Change in creatinine clearance Male vs female 1.37 -0.04-0.23 >0.05 Standard score

Male Evans7 2005 4-5 ESRD Male vs female 1.59 1.35-1.88 Hazard ratio

Male Brantsma10 2007 0-2 Progression in albuminuria Male vs female 1.00 0.84-1.19 Odds ratio

Male Brantsma10 2007 0-2 Regression in albuminuria Male vs female 0.63 0.52-0.77 Odds ratio

Male Yoshida15 2008 1-2 Slope of decline in GFR Male vs female 0.78 β coefficient

Male Levin16 2008 4-5 ESRD Male vs female 1.49 1.26-1.76 <0.001 Hazard ratio

Male Hallan21 2009 0-4 ESRD Male vs female 2.22 1.49-3.31 <0.001 Hazard ratio

Male Bash23 2010 0-5 ESRD Male vs female 1.49 1.10-2.01 Hazard ratio

Male Hoefield27 2010 3-5 ESRD Male vs female 1.07 0.74-1.54 0.70 Hazard ratio

Male De Nicola29 2011 3-5 ESRD Male vs female 1.18 0.94-1.48 0.16 Hazard ratio

Male Wang34 2011 0-5 GFR decrease ≥ 20% Female vs male 1.24 0.85-1.82 Odds ratio

Diabetes Evans7 2005 4-5 ESRD Type 1 or type 2 diabetes 1.24 1.02-1.51 Hazard ratio

Diabetes Hemmelgarn7 2007 0-5 GFR decline ≥ 25% in 2 years Type 1 or type 2 diabetes 1.90 1.60-2.20 Odds ratio

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Diabetes Levin16 2008 4-5 ESRD Type 1 or type 2 diabetes 0.82 0.56-1.21 0.30 Hazard ratio

Diabetes Hallan21 2009 0-4 ESRD Type 1 or type 2 diabetes 1.80 1.11-2.90 0.02 Hazard ratio

Diabetes Bash23 2010 0-5 ESRD Fasting glucose ≥ 126 mg/dL, non-fasting glucose ≥ 200

mg/dL, self-reported physician diagnosis of diabetes, or

use of oral hypoglycemic drugs or insulin

6.10 4.57-8.13 Hazard ratio

Diabetes Hoefield27 2010 3-5 ESRD Type 1 or type 2 diabetes 1.37 0.91-2.08 0.10 Hazard ratio

Diabetes Chien26 2010 0-2 GFR < 60 ml/min Type 2 diabetes 1.44 1.02-2.03 0.04 Relative risk

Diabetes De Nicola29 2011 3-5 ESRD Type 1 or type 2 diabetes 1.19 0.93-1.52 0.17 Hazard ratio

Diabetes Khedr30 2011 3-5 Slope of decline in GFR Type 1 or type 2 diabetes -0.96 0.01 β coefficient

Diabetes Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Type 1 or type 2 diabetes 1.33 0.81-2.18 0.25 Hazard ratio

Diabetes Wang34 2011 0-5 GFR decrease ≥ 20% Fasting glucose ≥ 7.0 mmol/L, 2-h glucose ≥ 11.1

mmol/L, or medical record-confirmed diabetes

1.21 0.85-1.74 Odds ratio

Diabetes Pereira40 2012 3-5 ESRD Type 1 or type 2 diabetes 4.42 1.47-13.24 0.01 Hazard ratio

Age Regalado5 2000 1-2 Slope of 1/creatinine Age (1 year) 1.99 0.047 Standard score

Age Evans7 2005 4-5 ESRD Age ≥ 65 years 0.72 0.57-0.90 Hazard ratio

Age Brantsma10 2007 0-2 Progression in albuminuria Age (10 years) 1.19 1.10-1.29 Odds ratio

Age Brantsma10 2007 0-2 Regression in albuminuria Age (10 years) 0.95 0.86-1.04 Odds ratio

Age Hemmelgarn1

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2007 0-5 GFR decline ≥ 25% in 2 years Age > 75 years 1.00 1.00-1.10 Odds ratio

Age Yoshida15 2008 1-2 Slope of decline in GFR Age ≥ 60 years 0.49 β coefficient

Age Levin16 2008 4-5 ESRD Age (5 years) 0.91 0.89-0.94 <0.001 Hazard ratio

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Age Bolignano19 2009 2-4 Doubling of creatinine or ESRD Age (1 year) 1.00 0.98–1.02 0.47 Hazard ratio

Age Hallan21 2009 0-4 ESRD Age (10 years) 1.72 1.48-1.99 <0.001 Hazard ratio

Age Bash23 2010 0-5 ESRD Age ≥ 55 years 1.60 1.21-2.10 Hazard ratio

Age Obi25 2010 3-5 ESRD Age (10 years) 0.67 0.49-0.92 0.01 Hazard ratio

Age Chien26 2010 0-2 GFR < 60 ml/min Age (1 year) 1.08 1.07-1.10 <0.001 Relative risk

Age Hoefield27 2010 3-5 ESRD Age (1 year) 0.98 0.97-0.99 0.03 Hazard ratio

Age De Nicola29 2011 3-5 ESRD Age (5 years) 0.94 0.90-0.98 <0.01 Hazard ratio

Age Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Age ≥ 60 years 0.77 0.46-1.31 0.34 Hazard ratio

Age Wang34 2011 0-5 GFR decrease ≥ 20% Age (5 years) 1.35 1.22-1.50 Odds ratio

Age Pereira40 2012 3-5 ESRD Age (1 year) 0.98 0.94-1.01 0.24 Hazard ratio

BP Hunsicker2,3 1997 3-4 Slope of decline in GFR MAP (mmHg) -0.04 0.03 β coefficient

BP Regalado5 2000 1-2 Change in creatinine clearance Mean BP (mmHg) 1.97 0.049 Standard score

BP Brantsma10 2007 0-2 Progression in albuminuria Change in MAP (10 mmHg) 1.91 1.72-2.12 Odds ratio

BP Ozsoy13 2007 1-4 GFR decline > 5 ml/min/year or ESRD MAP (10 mmHg) 1.54 1.14-2.08 Odds ratio

BP Imai14 2008 0-5 GFR decline in 10 year Mean BP > 106 mmHg (male, age 50-79 years) <0.05 Stratified by age, sex

BP Yoshida15 2008 1-2 Slope of decline in GFR BP ≥ 130/85 mmHg or use of antihypertensive drugs -0.20 0.045 Beta coefficients

BP Levin16 2008 4-5 ESRD Systolic BP (5 mmHg) 1.02 1.001-1.04 0.04 Hazard ratio

BP Levin16 2008 4-5 ESRD Diastolic BP (5 mmHg) 1.05 1.01-1.09 0.01 Hazard ratio

BP Agarwal17 2009 1-5 ESRD BP > 150/90 mmHg 6.37 1.36-30.0 Hazard ratio

BP Hallan21 2009 0-4 ESRD Systolic BP (10 mmHg) 1.16 1.07-1.25 <0.001 Hazard ratio

BP Chien26 2010 0-2 GFR < 60 ml/min Diastolic BP (mmHg) 1.02 1.00-1.03 0.02 Relative risk

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BP Hoefield27 2010 3-5 ESRD Diastolic BP (mmHg) 1.02 1.00-1.04 0.01 Hazard ratio

BP Hoefield27 2010 3-5 ESRD Systolic BP (mmHg) 1.00 0.99-1.01 0.60 Hazard ratio

BP De Nicola29 2011 3-5 ESRD BP ≥ 130/80 mmHg 1.10 0.77-1.55 0.60 Hazard ratio

BP Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Systolic BP ≥ 140 mmHg 1.90 1.12-3.22 0.02 Hazard ratio

BP Sugiura33 2011 1-5 GFR decrease ≥ 20 ml/min or ESRD Diastolic BP ≥ 90 mmHg 0.94 0.54-1.63 0.82 Hazard ratio

BP Wang34 2011 0-5 GFR decrease ≥ 20% Systolic BP (10 mmHg) 1.09 0.99–1.19 Odds ratio

BP Cheng39 2012 1-3 GFR decrease > 3 ml/min/year BP ≥ 130/85 mmHg 0.94 0.67-1.33 0.73 Odds ratio

BP Cheng39 2012 1-3 Incident CKD BP ≥ 130/85 mmHg 0.88 0.51-1.54 0.66 Odds ratio

Abbreviations. BP, blood pressure; CI, confidence interval; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MAP, mean arterial pressure;

UACR, urine albumin to creatinine ratio; UPCR, urine protein to creatinine ratio.

Note.

See supplementary references for studies included in the systematic review. a Composite endpoints of GFR < 60 ml/min, proteinuria > 0.5 g/day, and hypertension.

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Supplementary Table 4. Studies adopted outcomes that could be classified into a specific range of CKD stages.

Author Year Country Follow-up

(months)

Participant

number

Age

(years)

Sex, female

(%)

Baseline

CKD stage

Follow-up CKD

stage Risk factors for CKD development and progression

O'Seaghdha31 2011 USA 200 63.9 60.0 0 3 Urinary connective tissue growth factor

Iseki37 2011 Japan 24 8926 49.6 41.6 0 1-5 C-reactive protein

Ryu22 2009 Korea 46 10685 37.0 0.0 0 3-5 Metabolic syndrome, triglyceride, HDL

Shastri32 2011 USA 56 5422 61.0 51.5 0-2 3 Microalbuminuria, cystatin C

Shankar9 2006 USA 60 4898 62.3 56.0 0-2 3-5 Current smoking, heavy drinking

Bash18 2009 USA 174 14854 54.4 54.8 0-2 3-5 Leukocyte count, fibrinogen, von Willebrand factor, factor VIIIc, albumin

Chien26 2010 Taiwan 26 5168 51.2 36.7 0-2 3-5 Age, BMI, diastolic BP, diabetes, stroke, postprandial glucose, HbA1c, proteinuria, uric acid

Shankar36 2011 USA 180 4926 58.4 55.3 0-2 3-5 Tumor necrosis factor-α receptor 2, leukocyte count, interleukin-6

Obi25 2010 Japan 38 461 67.0 38.0 3-5 ESRD Age, proteinuria

Hoefield27 2010 UK 26 1325 65.1 36.3 3-5 ESRD Age, diastolic BP, hemoglobin, phosphate, proteinuria, stage of CKD

De Nicola29 2011 Italy 60 1248 67.0 42.6 3-5 ESRD Age, proteinuria, phosphate, BMI, cardiovascular event, hemoglobin

Pereira40 2012 Brazil 57 211 65.4 51.2 3-5 ESRD Diabetic nephropathy

Evans7 2005 Sweden 24 920 35.3 4-5 ESRD Age, male, diabetes, GFR

Levin16 2008 Canada 31 4231 66.8 42.5 4-5 ESRD Age, male, GFR, systolic BP, diastolic BP, hemoglobin, phosphate, PTH, proteinuria, use of ACEI/ARB

Hallan21 2009 Norway 124 65589 50.1 53.2 0-4 ESRD Age, male, low physical activity, diabetes, systolic BP, antihypertensive drugs, HDL, GFR, albuminuria

Bash23 2010 USA 192 15324 54.0 55.0 0-5 ESRD GFR, black, age, male, diabetes, systolic BP, CAD, BMI, smoking, triglyceride

Agarwal17 2009 USA 84 218 68.4 4.1 1-5 ESRD Systolic BP

Kuo24 2010 Taiwan 19163 51.6 50.1 1-5 ESRD Use of acetaminophen, use of aspirin, use of NSAID, use of rofecoxib

Baek38 2012 Korea 142 347 64.0 44.1 3 4-5 Microalbuminuria, macroalbuminuria, microscopic hematuria, CKD stage 3B

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Abbreviations. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CKD,

chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate, HbA1c, hemoglobin A1c; HDL, high-density lipoprotein cholesterol; NSAID, non-steroidal

anti-inflammatory drug; PTH, parathyroid hormone.

Note. See supplementary references for studies included in the systematic review.

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Supplementary Figure 1. Funnel plots for assessment of publication bias among studies included in the exploratory meta-analysis. (A) male sex, (B) proteinuria > 1 g/day, and (C) diabetes, for the outcome of progression from chronic kidney disease stage 3-5 to end-stage renal disease.

Supplementary Figure 2. Galbraith plots for assessment of heterogeneity among studies included in the exploratory meta-analysis. (A) male sex, (B) proteinuria > 1 g/day, and (C) diabetes, for the outcome of progression from chronic kidney disease stage 3-5 to end-stage renal disease

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