Supplemental Material Appendix Supplementary Table 1 Supplementary Table 2 Figure 1 Figure 2. Appendix Box. The SAS code for the simulations

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1 Supplemental Material Appendix Supplementary Table 1 Supplementary Table 2 Figure 1 Figure 2 Appendix Box. The SAS code for the simulations 1. The SAS code for the simulation model with a constant standard deviation (SD) is as following: do i=1 to 1400; kidney_fcn=max(1, 50+15*rannor(0)); igfr=max(1, kidney_fcn+5*rannor(0)); CrCl=max(1, kidney_fcn*1.13+7*rannor(0)); Output ; end ; 2. The SAS code for the simulation model with a constant coefficient of variation (CV) is as following: do i=1 to 1400; 1

2 kidney_fcn=max(1, 50+15*rannor(0)); igfr=max(1, kidney_fcn*( *rannor(0)); CrCl=max(1, kidney_fcn*1.13*( *rannor(0)); Output ; end ; 3. The SAS code for the simulation model with a uniform distribution of true kidney function from 20 to 80 ml/min/1.73m 2 (i.e. instead of bell-shaped distribution, the distribution is rectangle-shaped) is as following: do i=1 to 1400; kidney_fcn=50-sqrt(3)*15+sqrt(12)*15*ranuni(0); igfr=max(1, kidney_fcn+5*rannor(0)); CrCl=max(1, kidney_fcn*1.13+7*rannor(0)); Output ; end ; 2

3 Supplementary Table 1. Quotes from textbooks and review articles regarding enhanced creatinine secretion Reference Content Basis for statement Inker LA, Perrone RD: Assessment of kidney function, In: UpToDate, section editor: Sterns RH, Aug 27, 2014 Inker LA, Perrone RD: Calculation of the creatinine clearance, In: UpToDate, section editor: Sterns RH, Dec 04, 2015 In reality, a reduction in GFR results in increased tubular creatinine secretion that blunts the rise in serum creatinine. As the GFR falls, the rise in the serum creatinine is partially opposed by enhanced proximal tubular creatinine secretion. The increase in creatinine secretion as GFR falls can limit the interpretation of the creatinine clearance. However, tubular secretion by the organic cation secretory pathways in the proximal tubule accounts for approximately 10 to 20 percent of urinary creatinine in patients with a normal GFR and a progressively higher percentage as the GFR falls. However, the increase in creatinine secretion will result in the creatinine Doolan PD, Alpen EL, Theil GB: A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Am J Med 32:65-79, 1962 Kim KE, Onesti G, Ramirez O, Brest AN, Swartz C: Creatinine clearance in renal disease: a reappraisal. Br Med J 4:11-14, 1969 Levey AS: Measurement of renal function in chronic renal disease. Kidney Int 38: , 1990 Petri M, Bockenstedt L, Colman J, Whiting-O Keefe Q, Fitz G, Sebastian A, Hellmann D: Serial assessment of glomerular filtration rate in lupus nephropathy. Kidney Int 34: , 1988 van Acker BA, Koomen GC, Koopman MG, de Waart DR, Arisz L: Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate. Lancet 340: , 1992 Doolan PD, Alpen EL, Theil GB: A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Am J Med 32:65-79, 1962 Kim KE, Onesti G, Ramirez O, Brest AN, Swartz C: Creatinine clearance in renal disease: a reappraisal. Br Med J 4:11-14, 3

4 clearance being a progressively greater overestimate of the GFR Levey AS: Measurement of renal function in chronic renal disease. Kidney Int 38: , 1990 Petri M, Bockenstedt L, Colman J, Whiting-O Keefe Q, Fitz G, Sebastian A, Hellmann D: Serial assessment of glomerular filtration rate in lupus nephropathy. Kidney Int 34: , 1988 van Acker BA, Koomen GC, Koopman MG, de Waart DR, Arisz L: Creatinine clearance during cimetidine administration for measurement of glomerular filtration rate. Lancet 340: , 1992 Israni AK, Kasiske BL: Laboratory assessment of kidney disease: glomerular filtration rate, urinalysis, and proteinuria. In: Brenner & Rector's The kidney, 9th ed., edited by Brenner BM, Philadelphia, Elsevier Saunders, 2011, pp Lafyette RA, Perrone RD, Levey AS: Laboratory Evaluation of Renal Function. In: Diseases of the Kidney, 6th The tendency for tubular secretion to rise proportionally with declining levels of kidney function, for example, decreases the usefulness of creatinine clearance determinations as accurate reflections of GFR in patients with kidney disease. Although the overestimation of GFR by creatinine clearance is not clinically significant in individuals with normal GFR, in patients with renal disease and decreased GFR the overestimation is proportionally greater and is not Levey AS, Perrone RD, Madias NE: Serum creatinine and renal function. Annu Rev Med 39: ,

5 ed., edited by Schrier RW, Gottschalk CW, Philadelphia, Lippincott Williams & Wilkins, 1996, pp Levey AS, Perrone RD, Madias NE: Serum creatinine and renal function. Annu Rev Med 39: , 1988 Levey AS: Measurement of renal function in chronic renal disease. Kidney Int 38: , 1990 predictable. However, because of the increasing contribution of creatinine secretion to creatinine clearance as GFR declines, creatinine clearance might fall minimally or even remain stable despite a decline in GFR. When GFR first declines, tubular secretion is augmented, stabilizing the serum level. Hence, clearance due to tubular secretion rises; consequently, creatinine clearance (Ccr) declines more slowly than GFR, and the ratio of Ccr to GFR rises. Thereafter, as GFR declines further, tubular secretion increases further, but not in proportion to the increase in serum level. Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 2: , 1982 Hilton PJ, Roth Z, Lavender S, Jones NF: Creatinine clearance in patients with proteinuria. Lancet 2: , 1969 Kim KE, Onesti G, Ramirez O, Brest AN, Swartz C: Creatinine clearance in renal disease: a reappraisal. Br Med J 4:11-14, 1969 Modification of Diet in Renal Disease Study Group. Prepared by Levey AS, Berg RL, Gassman JJ, Hall PM, Walker WG: Creatinine filtration, secretion and excretion during progressive renal disease. Kidney Int 36(suppl 27):S73-S80, 1989 Walser M, Drew HH, LaFrance ND: Creatinine measurements often yield false estimation of progression in chronic renal 5

6 Mandayam S, Mitch WE: Dietary Factors in the treatment of chronic kidney disease. In: Diseases of the Kidney & Urinary Tract, 8th ed., edited by Schrier RW, Philadelphia, Lippincott Williams & Wilkins, 2007, pp Pearlman AM, Gonin JM: Evaluation of Kidney Function: Biochemical and Nuclear Medicine Tests. In: Handbook of Nephrology & Hypertention, 5th ed., edited by Wilcox CS, Tisher CC, Philadelphia, Lippincott Williams & Wilkins, 2004, pp Perrone RD, Madias NE, Levey AS: Serum creatinine as an index of renal function: new insights into old concepts. The 24-hour endogenous creatinine clearance usually exceeds inulin clearance, because of tubular secretion of creatinine, but with advanced CKD, values of creatinine clearance and GFR become numerically closer, even through the percentage difference between creatinine clearance and GFR will increase. Tubular secretion of creatinine normally accounts for 10-40% of that excreted, but this percentage increases in those with chronic renal insufficiency disease. Thus, creatinine clearance systematically overestimates the GFR, particularly in chronic renal insufficiency. However, as the GFR falls, the ratio of creatinine to inulin clearance increases because of an increased tubular secretion of creatinine. failure. Kidney Int 43: , 1988 Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 2: , 1982 Lubowitz H, Slatopolsky E, Shankel S, et al: Glomerular filtration rate: determination in patients with chronic renal disease. JAMA 199: , 1967 Mitch WE: Measuring the rate of progression of renal insufficiency. The Progressive Nature of Renal Disease. New York: Churchill Livingston, 1992, pp 203 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 39:S1, 2002 Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 2: ,

7 Clin Chem 38: , 1992 Bennett WM, Porter GA: Endogenous creatinine clearance as a clinical measure of glomerular filtration rate. Br Med J 4:84-86, 1971 Dodge WF, Travis LB, Daeschner CW: Comparison of endogenous creatinine clearance with inulin clearance. Am J Dis Child 113: , 1967 Hilton PJ, Roth Z, Lavender S, Jones NF: Creatinine clearance in patients with proteinuria. Lancet 2: , 1969 Kassirer JP: Clinical evaluation of kidney function-glomerular function. N Engl J Med 285: , 1971 Kim KE, Onesti G, Ramirez O, Brest AN, Swartz C: Creatinine clearance in renal disease. A reappraisal. Br Med J 4:11-14, 1969 Lavender S, Hilton PJ, Jones NF: The measurment of glomerular filtration rate in renal disease. Lancet 2: , 1969 Miller BF, Winkler AW: The renal excretion of endogenous creatinine in man. Comparison with exogenous creatinine and inulin. J Clin Invest 17:31-40, 1938 Shannon J: The renal excretion of creatinine in man. J Clin Invest 14: ,

8 Reiser IW, Porush JG: Evaluation of Renal Function. In: Massry & Glassock s Textbook of nephrology, 3rd ed., edited by Massry SG, Glassock RJ, Baltimore Williams & Wilkins, 1995, pp Schwartz GJ, Furth SL: Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatr Nephrol 22: , 2007 Shoskes DA, McMahon AW: Renal Physiology and Pathophysiology. In: Campbell-Walsh Urology, 10th ed., edited by Kavoussi LR, Partin AW, Novick AC, Peters CA, Philadelphia, Elsevier Saunders, 2012, pp Toto RD: Conventional measurement of renal function utilizing serum creatinine, creatinine clearance, inulin and para-aminohippuric acid clearance. Curr With renal failure, however, this fortuitous relationship no longer exists because tubular secretion of creatinine assumes a greater percentage of the excreted load and the percentage error reflected by the noncreatinine chromogens diminishes as the serum creatinine increases. Whereas urinary creatinine contributed by tubular secretion does not normally exceed 10%, this fraction rises greatly during chronic renal insufficiency, and creatinine clearance may greatly exceed GFR, particularly at low levels of GFR. As GFR falls, tubular secretion of creatinine increases; so, plasma creatinine may not change noticeably until there has been a significant drop in GFR. Creatinine clearance overestimates true GFR, on average, by 10% to 20%. This becomes even more important as GFR declines, because tubular secretion increases in response to increasing serum creatinine levels and may contribute up to 35% of all creatinine removal at GFR levels of 40-80ml/min. In patients with renal insufficiency the fractional secretion of creatinine increases substantially; therefore, the error in overestimating GFR increases as fractional creatinine secretion increases. Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 2: , 1982 Levey AS: Measurement of renal function in chronic renal disease. Kidney Int 38: , 1990 Levey AS, Perrone RD, Madias NE: Serum creatinine and renal function. Annu Rev Med 39: , 1988 Arant BS Jr, Edelmann CM Jr, Spitzer A. The congruence of creatinine and inulin clearances in children: Use of the Thchnicon autoanalyzer. J Pediatr 81: , 1972 Doolan PD, Alpen EL, Theil GB: A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Am J Med 32:65-79, 1962 Lemann J, Bidani AK, Bain RP, Lewis EJ, Rohde RD, and the Collaborative Study Group of Angiotensin Converting Enzyme Inhibition in Diabetic Nephropathy: Use of the serum creatinine to estimate glomerular filtration rate in health and early diabetic 8

9 Opin Nephrol Hypertens 4: ; discussion , 1995 Walser M: Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis 32:23-31, 1998 The ratio of creatinine clearance (Ccr) to simultaneously determined GFR (Ccr/GFR) is almost always greater than unity and increases with decreasing GFR to a maximum average of approximately 1.7 at a GFR of approximately 20ml/min. nephropathy. Am J Kidney Dis 16: , 1990 Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 2: , 1982 Bennett WM, Porter GA: Endogenous creatinine clearance as a clinical measure of glomerular filtration rate. Br Med J 4:84-86, 1971 Brown SC, O Reilly PH: Glomerular filtraiton rate measurment: A neglected test in urological practice. Br J Urol 75: , 1995 Doolan PD, Alpen EL, Theil GB: A clinical appraisal of the plasma concentration and endogenous clearance of creatinine. Am J Med 32:65-79, 1962 Kim KE, Onesti G, Ramirez O, Brest AN, Swartz C: Creatinine clearance in renal disease. A reappraisal. Br Med J 4:11-14, 1969 Lavender S, Hilton PJ, Jones NF: The measurment of glomerular filtration rate in renal disease. Lancet 2: , 1969 Luke DR, Halstenson CE, Opsahl JA, Matzke GR: Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther 48: ,

10 Van Lente F, Suit P: Assessment of renal function by serum creatinine and creatinine clearance: Glomerular filtration rate estimated by four procedures. Clin Chem 35: ,

11 Supplementary Table 2. Baseline characteristics of the study population Characteristic N=1342 Age (years) 56.2 ± 12.2 Male gender, % 56.7% Race/Ethnicity, % Non-Hispanic white 42.3% Non-Hispanic black 36.8% Hispanic 14.0% Others 6.9% Creatinine clearance (CrCl) (ml/min/1.73m 2 ) 52.1 ± 25.8 Iothalamate measured glomerular filtration rate (igfr) 48.0 ± 19.9 (ml/min/1.73m 2 ) CrCl/iGFR, mean ± SD 1.13 ± 0.46 CrCl/iGFR, median (IOR) 1.09 (0.88, 1.32) Physical examinations Body mass index (kg/m 2 ) 31.3 ± 6.8 Body surface area (m 2 ) 2.0 ± 0.3 Systolic blood pressure (mmhg) 129 ± 22 Diastolic blood pressure (mmhg) 73 ± 13 Self-reported comorbidities, % Diabetes, % 48.3% Cardiovascular disease, % 26.4% Peripheral vascular disease, % 5.7% Stroke, % 8.0% Current smoking, % 11.2% Laboratory results Serum creatinine (mg/dl) 1.70 ± 0.56 BUN (mg/dl) 29 ± 13 Albumin (g/dl) 3.9 ± 0.5 Hematocrit (%) 37.4 ± 4.9 Triglyceride (mg/dl) 155 ± 112 LDL cholesterol (mg/dl) 103 ± 36 Fasting glucose (mg/dl) 113 ± 49 Hemoglobin A1C (%) 6.6 ± 1.6 hs-crp (mg/l) [median (IQR)] 2.2 ( ) 24-hrs urine albumin (mg/24 hrs) [median (IQR)] 84 (11-643) 11

12 Supplementary Figure 1. A. B. (A) Relationship between CrCl/iGFR ratio and igfr, (B) Relationship between CrCl/iGFR ratio and CrCl (The line shown through the scatterplot is from LOESS) 12

13 Supplementary Figure 2. Mean=1.13 Relationship between CrCl/iGFR ratio and mean of CrCl and igfr (The line shown is from LOESS) 13

Validity of the use of Schwartz formula against creatinine clearance in the assessment of renal functions in children

Validity of the use of Schwartz formula against creatinine clearance in the assessment of renal functions in children *H W Dilanthi 1, G A M Kularatnam 1, S Jayasena 1, E Jasinge 1, D B D L Samaranayake