- Email: [email protected]
Postsurgical inflammatory response is not associated with increased serum cystatin C values
Clinical Biochemistry 43 (2010) 1138–1140
Contents lists available at ScienceDirect
Clinical Biochemistry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c l i n b i o c h e m
Postsurgical inflammatory response is not associated with increased serum cystatin C values Torbjörn Åkerfeldt, Johanna Helmersson, Anders Larsson ⁎ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 14 April 2010 Received in revised form 23 June 2010 Accepted 1 July 2010 Available online 1 August 2010 Keywords: Cystatin C C-reactive protein Glomerular filtration rate Human Inflammation Surgery
a b s t r a c t Objectives: Cystatin C is used both as a glomerular filtration (GFR) marker and a cardiovascular risk marker. There are several studies showing an association between cystatin C and inflammatory markers and it has been suggested that the inflammatory response in itself could result in elevated cystatin C levels. The aim of this study was to evaluate if an induced inflammatory response has an effect on cystatin C levels in humans. Materials and methods: CRP and cystatin C were analyzed in serum samples from orthopedic surgery patients (n = 29). The patients were sampled prior to surgery and four and thirty days after surgery. Results: The surgery induced a pronounced CRP elevation on day four, median 137.3 (interquartile range 104.1–178.2) mg/L compared to 1.94 (1.20–8.70) mg/L before surgery, P b 0.001, but no significant difference in cystatin C levels before and four and thirty days after surgery could be seen. Conclusions: The orthopedic surgery-induced inflammatory response does not cause changes in cystatin C levels. © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Serum or plasma creatinine is the most widely used marker for estimating glomerular filtration rate (GFR) in clinical practice. GFR is often calculated from plasma creatinine using Cockcroft-Gault [1], Modification of Diet in Renal Disease (MDRD) study or CDK-EPI equations [2,3]. The ideal GFR marker should be an endogenous substance, which is produced at a constant rate and is cleared only via glomerular filtration without secretion or reabsorbtion by the tubular cells. Serum cystatin C has been proposed as a new and superior GFR marker to creatinine. The protein is a cystein protease inhibitor with a molecular mass of 13 kDa [4]. A meta-analysis has also indicated that cystatin C is superior to plasma creatinine as a marker for estimation of renal function [5]. Despite the common use, creatinine has serious limitations as marker for renal function. Creatinine is influenced by factors such as gender, age, muscle mass, physical activity and diet [6]. It is also insensitive for detecting small decreases in GFR, in the so-called creatinine-blind GFR area [7]. In comparison with creatinine, cystatin C is a rather new GFR marker. This means that there are fewer studies on other factors apart from GFR that may affect the cystatin C results. Thyroid function clearly affects cystatin C values [8] but there are also reports showing that cystatin C is associated or affected by
⁎ Corresponding author. Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Fax: +46 18 552562. E-mail address: [email protected] (A. Larsson).
inflammation. Stevens et al showed that higher C-reactive protein (CRP) were associated with higher levels of cystatin C [9]. At the same time other studies have not been able to demonstrate an association between CRP and cystatin C [10] Also, Ridker et al., found an association in a cross-sectional analysis, but no longitudinal association [11]. The question is thus whether this is a direct affect of CRP or if it is the inflammation, which is detected by CRP elevation, that leads to reduced kidney function and decreased GFR. The aim of the present study was to evaluate if an orthopedic surgery-induced inflammatory response had an effect on cystatin C levels. We used an elective surgery model as this allows sampling from the same patient with and without inflammatory activity in a standardized fashion [12]. The inflammatory response after orthopedic surgery is much more pronounced than the inflammatory response usually associated with increased risk of cardiovascular disease.
Materials and methods Patient samples and assays Elective orthopedic patients (n=29, 13 males and 16 females) undergoing surgery at the Uppsala University Hospital were included in the study. The mean age of the patients was 67 years (range 45–80 years). Fourteen of the patients had knee surgery and fifteen of the patients had hip arthroplasty. The study was approved by the local ethical board at Uppsala University and all patients signed an informed consent prior to inclusion in the study.
0009-9120/$ – see front matter © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2010.07.004
T. Åkerfeldt et al. / Clinical Biochemistry 43 (2010) 1138–1140
Cystatin C assay Serum cystatin C (reagent: 1014, Gentian, Moss, Norway) were analyzed on an Architect Ci8200® analyzer (Abbott, Abbot Park, IL, USA). The total analytical imprecision of the cystatin C method was 1.1% at 1.25 mg/L and 1.4% at 5.45 mg/L. The equation used for calculating GFR in mL/min/1.73 m2 from the cystatin C results in mg/ mL was y = 79.901x− 1.4389 [13].
1139
decreased at thirty days after surgery, 5.08 (2.10–11.15) mg/L, compared to four days after surgery (Fig. 2). Linear correlations between cystatin C and CRP Cystatin C and CRP concentrations were positively correlated prior to surgery (R = 0.44, P = 0.019) and four days after surgery (R = 0.37, P = 0.058) but not thirty days after surgery (R = 27, P = 0.20).
CRP assay
Discussion
Serum CRP (reagent: 6K2601) were analyzed on an Architect Ci8200 analyzer (Abbott Laboratories, Abbott Park, IL, USA). The CRP assay had a total coefficient of variation of 0.8% at 8 mg/L and the assay calibrator was traceable to CRM 470. Lower limit of detection for the CRP assay was 0.2 mg/L.
Glomerular filtration rate (GFR) is generally accepted as the best overall indicator of renal function and is therefore a valuable marker for renal disease. It is important that GFR markers are able to detect not only severe kidney disease but also at the earliest, most treatable stages. Early recognition of low GFR would be an important clinical advance allowing early treatment thus preventing patients from progressing to end-stage renal failure. Cystatin C has been proposed to be superior to creatinine for detecting minor decrease in kidney function (60–90 mL/min/1.73 m2) [14]. Both plasma creatinine and cystatin C can provide rapid test results. Creatinine has been used for GFR estimations since the beginning of the last century. This means that we have a lot of knowledge on substances or conditions other than GFR that may influence the creatinine values. Cystatin C is in comparison with creatinine a very new GFR marker and we may thus lack knowledge on conditions that may cause erroneous eGFR based on cystatin C. One such are is the effect of inflammation. Indeed, a cross-sectional linear association between CRP and cystatin C before surgery could be seen in this study which is in line with several reports showing an association between inflammation and cystatin C [15–18]. It is also well known that chronic inflammatory diseases are associated with atherosclerosis and increased risk for cardiovascular disease and mortality [19–21]. A generalized atherosclerosis will also affect the kidneys resulting in atherosclerosis in the glomeruli and reduced kidney function which will result in increased cystatin C values and reduced estimated GFR. Elective surgery is a suitable human inflammation model that has been used in a number of studies. In elective surgery, the patients usually have a low inflammatory response prior to surgery. The surgical procedure induces a standardized in time tissue injury that is shown by a rapid CRP increase. The inflammation subsides and CRP is usually normalized within a month. The median cystatin C value before surgery was 0.97 mg/L (GFR = 83.5 mL/min/1.73 m2). Thus, the patient group had slightly reduced estimated GFR. The patients have reached an age that is associated with increased cystatin C levels as cystatin C increases with age due to reduced kidney function. There was no significant increase in cystatin C levels as could have been
Statistics Serum cystatin C and CRP values were skewed distributed according to Shapiro–Wilks test (W b 0.95) and were log-transformed to reach normal distribution. Cystatin C and CRP before surgery and 4 and 30 days after surgery were tested with repeated-measures analysis of variance and paired t-tests or Pearson's correlation analysis. Figures were prepared in Excel 2000 (Microsoft Corporation, Seattle, WA, USA). Statistics were performed with Stata 10.1 (Stata Corporation, Collage Station, TX, USA) and Statistica 7.1 (StatSoft, Tulsa, OK, USA). Descriptive statistics were reported as median and IQR (interquartile range). We regarded p b 0.05 as statistically significant throughout the text. Results Cystatin C and eGFR Median cystatin C values prior to surgery were 0.97 (0.86–1.23) mg/L) corresponding to a median estimated GFR (eGFR) of 83.5 (59.3–99.3) mL/min/1.73 m2. Cystatin C levels did not differ significantly four days after surgery, 1.05 (0.84–1.26) mg/L (eGFR 74.5 [57.3–102.7] mL/min/1.73 m2), or thirty days after surgery, 1.11 (0.94–1.24) mg/L (eGFR 69.3 [59.0–87.4] mL/min/1.73 m2), compared to prior to surgery (Fig. 1). CRP Median CRP values prior to surgery was 1.94 (1.20–8.70) mg/L. CRP concentrations were increased at four days after surgery, 137.3 (104.1–178.2) mg/L, compared to before surgery. CRP values were
Fig. 1. Cystatin C in individual patients before (n = 29), four days (n = 29) and 30 days (n = 24) after orthopedic surgery. The horizontal bars indicate median values. P for difference 0.17 (repeated-measures analysis of variance).
Fig. 2. CRP in individual patients before, four days and 30 days after orthopedic surgery. The horizontal bars indicate median values. P for difference b 0.001 (repeated-measures analysis of variance). P (before surgery vs. day 4) b0.001, P (day 4 vs. day 30) b 0.001, P (day 30 vs. before surgery) = 0.059.
1140
T. Åkerfeldt et al. / Clinical Biochemistry 43 (2010) 1138–1140
expected if the inflammation in itself caused increased cystatin C levels. A limitation of the study is the number of patients included (n = 29). Orthopedic surgery is a common procedure. The main problem in this setting is to get samples on day 30. Rather than having a high proportion of missing data on day 30, we limited the study group. This study indicates that orthopedic surgery-induced inflammation does not directly cause increased cystatin C levels but there may still exist a cross-sectional association between inflammation and cystatin C in many patient groups as inflammation is associated with reduced kidney function. Acknowledgments This study was supported by the Uppsala University Hospital Research Fund. We thank Christine Leo Swenne and Lena Gunningberg for organizing the blood sample collection. References [1] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [2] Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–54. [3] Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, et al. Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant 2010;25:449–57. [4] Grubb AO. Cystatin C-properties and use as diagnostic marker. Adv Clin Chem 2000;35:63–99. [5] Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40:221–6. [6] Hsu CY, Chertow GM, Curhan GC. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 2002;61:1567–76.
[7] Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:269–78. [8] Karawajczyk M, Ramklint M, Larsson A. Reduced cystatin C-estimated GFR and increased creatinine-estimated GFR in comparison with iohexol-estimated GFR in a hyperthyroid patient: A case report. J Med Case Reports 2008;2:66. [9] Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75: 652–60. [10] Al-Malki N, Heidenheim PA, Filler G, Yasin A, Lindsay RM. Cystatin C levels in functionally anephric patients undergoing dialysis: the effect of different methods and intensities. Clin J Am Soc Nephrol 2009;4:1606–10. [11] Rifkin DE, Katz R, Fried LF, Kestenbaum B, Jenny NS, Newman AB, et al. Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. Nephron Clin Pract 2010;115:c114–21. [12] Bastian D, Tamburstuen MV, Lyngstadaas SP, Reikeras O. Systemic and local cytokine kinetics after total hip replacement surgery. Eur Surg Res 2008;41: 334–40. [13] Flodin M, Jonsson AS, Hansson LO, Danielsson LA, Larsson A. Evaluation of Gentian cystatin C reagent on Abbott Ci8200 and calculation of glomerular filtration rate expressed in mL/min/1.73 m(2) from the cystatin C values in mg/L. Scand J Clin Lab Invest 2007;67:560–7. [14] Roos JF, Doust J, Tett SE, Kirkpatrick CM. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children—a meta-analysis. Clin Biochem 2007;40:383–91. [15] Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75: 652–60. [16] Filiopoulos V, Vlassopoulos D. Inflammatory syndrome in chronic kidney disease: pathogenesis and influence on outcomes. Inflamm Allergy Drug Targets 2009;8: 369–82. [17] Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 2009;30:2838–44. [18] Larsson A, Helmersson J, Hansson LO, Basu S. Serum cystatin C is associated with other cardiovascular risk markers and cardiovascular disease in elderly men. Int J Cardiol 2008;125:263–4. [19] Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049–60. [20] van Zonneveld AJ, de Boer HC, van d V, Rabelink TJ. Inflammation, vascular injury and repair in rheumatoid arthritis. Ann Rheum Dis 2010;69(Suppl 1):i57–60. [21] Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 2009;30:2838–44.
Contents lists available at ScienceDirect
Clinical Biochemistry j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c l i n b i o c h e m
Postsurgical inflammatory response is not associated with increased serum cystatin C values Torbjörn Åkerfeldt, Johanna Helmersson, Anders Larsson ⁎ Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
a r t i c l e
i n f o
Article history: Received 14 April 2010 Received in revised form 23 June 2010 Accepted 1 July 2010 Available online 1 August 2010 Keywords: Cystatin C C-reactive protein Glomerular filtration rate Human Inflammation Surgery
a b s t r a c t Objectives: Cystatin C is used both as a glomerular filtration (GFR) marker and a cardiovascular risk marker. There are several studies showing an association between cystatin C and inflammatory markers and it has been suggested that the inflammatory response in itself could result in elevated cystatin C levels. The aim of this study was to evaluate if an induced inflammatory response has an effect on cystatin C levels in humans. Materials and methods: CRP and cystatin C were analyzed in serum samples from orthopedic surgery patients (n = 29). The patients were sampled prior to surgery and four and thirty days after surgery. Results: The surgery induced a pronounced CRP elevation on day four, median 137.3 (interquartile range 104.1–178.2) mg/L compared to 1.94 (1.20–8.70) mg/L before surgery, P b 0.001, but no significant difference in cystatin C levels before and four and thirty days after surgery could be seen. Conclusions: The orthopedic surgery-induced inflammatory response does not cause changes in cystatin C levels. © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction Serum or plasma creatinine is the most widely used marker for estimating glomerular filtration rate (GFR) in clinical practice. GFR is often calculated from plasma creatinine using Cockcroft-Gault [1], Modification of Diet in Renal Disease (MDRD) study or CDK-EPI equations [2,3]. The ideal GFR marker should be an endogenous substance, which is produced at a constant rate and is cleared only via glomerular filtration without secretion or reabsorbtion by the tubular cells. Serum cystatin C has been proposed as a new and superior GFR marker to creatinine. The protein is a cystein protease inhibitor with a molecular mass of 13 kDa [4]. A meta-analysis has also indicated that cystatin C is superior to plasma creatinine as a marker for estimation of renal function [5]. Despite the common use, creatinine has serious limitations as marker for renal function. Creatinine is influenced by factors such as gender, age, muscle mass, physical activity and diet [6]. It is also insensitive for detecting small decreases in GFR, in the so-called creatinine-blind GFR area [7]. In comparison with creatinine, cystatin C is a rather new GFR marker. This means that there are fewer studies on other factors apart from GFR that may affect the cystatin C results. Thyroid function clearly affects cystatin C values [8] but there are also reports showing that cystatin C is associated or affected by
⁎ Corresponding author. Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Fax: +46 18 552562. E-mail address: [email protected] (A. Larsson).
inflammation. Stevens et al showed that higher C-reactive protein (CRP) were associated with higher levels of cystatin C [9]. At the same time other studies have not been able to demonstrate an association between CRP and cystatin C [10] Also, Ridker et al., found an association in a cross-sectional analysis, but no longitudinal association [11]. The question is thus whether this is a direct affect of CRP or if it is the inflammation, which is detected by CRP elevation, that leads to reduced kidney function and decreased GFR. The aim of the present study was to evaluate if an orthopedic surgery-induced inflammatory response had an effect on cystatin C levels. We used an elective surgery model as this allows sampling from the same patient with and without inflammatory activity in a standardized fashion [12]. The inflammatory response after orthopedic surgery is much more pronounced than the inflammatory response usually associated with increased risk of cardiovascular disease.
Materials and methods Patient samples and assays Elective orthopedic patients (n=29, 13 males and 16 females) undergoing surgery at the Uppsala University Hospital were included in the study. The mean age of the patients was 67 years (range 45–80 years). Fourteen of the patients had knee surgery and fifteen of the patients had hip arthroplasty. The study was approved by the local ethical board at Uppsala University and all patients signed an informed consent prior to inclusion in the study.
0009-9120/$ – see front matter © 2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2010.07.004
T. Åkerfeldt et al. / Clinical Biochemistry 43 (2010) 1138–1140
Cystatin C assay Serum cystatin C (reagent: 1014, Gentian, Moss, Norway) were analyzed on an Architect Ci8200® analyzer (Abbott, Abbot Park, IL, USA). The total analytical imprecision of the cystatin C method was 1.1% at 1.25 mg/L and 1.4% at 5.45 mg/L. The equation used for calculating GFR in mL/min/1.73 m2 from the cystatin C results in mg/ mL was y = 79.901x− 1.4389 [13].
1139
decreased at thirty days after surgery, 5.08 (2.10–11.15) mg/L, compared to four days after surgery (Fig. 2). Linear correlations between cystatin C and CRP Cystatin C and CRP concentrations were positively correlated prior to surgery (R = 0.44, P = 0.019) and four days after surgery (R = 0.37, P = 0.058) but not thirty days after surgery (R = 27, P = 0.20).
CRP assay
Discussion
Serum CRP (reagent: 6K2601) were analyzed on an Architect Ci8200 analyzer (Abbott Laboratories, Abbott Park, IL, USA). The CRP assay had a total coefficient of variation of 0.8% at 8 mg/L and the assay calibrator was traceable to CRM 470. Lower limit of detection for the CRP assay was 0.2 mg/L.
Glomerular filtration rate (GFR) is generally accepted as the best overall indicator of renal function and is therefore a valuable marker for renal disease. It is important that GFR markers are able to detect not only severe kidney disease but also at the earliest, most treatable stages. Early recognition of low GFR would be an important clinical advance allowing early treatment thus preventing patients from progressing to end-stage renal failure. Cystatin C has been proposed to be superior to creatinine for detecting minor decrease in kidney function (60–90 mL/min/1.73 m2) [14]. Both plasma creatinine and cystatin C can provide rapid test results. Creatinine has been used for GFR estimations since the beginning of the last century. This means that we have a lot of knowledge on substances or conditions other than GFR that may influence the creatinine values. Cystatin C is in comparison with creatinine a very new GFR marker and we may thus lack knowledge on conditions that may cause erroneous eGFR based on cystatin C. One such are is the effect of inflammation. Indeed, a cross-sectional linear association between CRP and cystatin C before surgery could be seen in this study which is in line with several reports showing an association between inflammation and cystatin C [15–18]. It is also well known that chronic inflammatory diseases are associated with atherosclerosis and increased risk for cardiovascular disease and mortality [19–21]. A generalized atherosclerosis will also affect the kidneys resulting in atherosclerosis in the glomeruli and reduced kidney function which will result in increased cystatin C values and reduced estimated GFR. Elective surgery is a suitable human inflammation model that has been used in a number of studies. In elective surgery, the patients usually have a low inflammatory response prior to surgery. The surgical procedure induces a standardized in time tissue injury that is shown by a rapid CRP increase. The inflammation subsides and CRP is usually normalized within a month. The median cystatin C value before surgery was 0.97 mg/L (GFR = 83.5 mL/min/1.73 m2). Thus, the patient group had slightly reduced estimated GFR. The patients have reached an age that is associated with increased cystatin C levels as cystatin C increases with age due to reduced kidney function. There was no significant increase in cystatin C levels as could have been
Statistics Serum cystatin C and CRP values were skewed distributed according to Shapiro–Wilks test (W b 0.95) and were log-transformed to reach normal distribution. Cystatin C and CRP before surgery and 4 and 30 days after surgery were tested with repeated-measures analysis of variance and paired t-tests or Pearson's correlation analysis. Figures were prepared in Excel 2000 (Microsoft Corporation, Seattle, WA, USA). Statistics were performed with Stata 10.1 (Stata Corporation, Collage Station, TX, USA) and Statistica 7.1 (StatSoft, Tulsa, OK, USA). Descriptive statistics were reported as median and IQR (interquartile range). We regarded p b 0.05 as statistically significant throughout the text. Results Cystatin C and eGFR Median cystatin C values prior to surgery were 0.97 (0.86–1.23) mg/L) corresponding to a median estimated GFR (eGFR) of 83.5 (59.3–99.3) mL/min/1.73 m2. Cystatin C levels did not differ significantly four days after surgery, 1.05 (0.84–1.26) mg/L (eGFR 74.5 [57.3–102.7] mL/min/1.73 m2), or thirty days after surgery, 1.11 (0.94–1.24) mg/L (eGFR 69.3 [59.0–87.4] mL/min/1.73 m2), compared to prior to surgery (Fig. 1). CRP Median CRP values prior to surgery was 1.94 (1.20–8.70) mg/L. CRP concentrations were increased at four days after surgery, 137.3 (104.1–178.2) mg/L, compared to before surgery. CRP values were
Fig. 1. Cystatin C in individual patients before (n = 29), four days (n = 29) and 30 days (n = 24) after orthopedic surgery. The horizontal bars indicate median values. P for difference 0.17 (repeated-measures analysis of variance).
Fig. 2. CRP in individual patients before, four days and 30 days after orthopedic surgery. The horizontal bars indicate median values. P for difference b 0.001 (repeated-measures analysis of variance). P (before surgery vs. day 4) b0.001, P (day 4 vs. day 30) b 0.001, P (day 30 vs. before surgery) = 0.059.
1140
T. Åkerfeldt et al. / Clinical Biochemistry 43 (2010) 1138–1140
expected if the inflammation in itself caused increased cystatin C levels. A limitation of the study is the number of patients included (n = 29). Orthopedic surgery is a common procedure. The main problem in this setting is to get samples on day 30. Rather than having a high proportion of missing data on day 30, we limited the study group. This study indicates that orthopedic surgery-induced inflammation does not directly cause increased cystatin C levels but there may still exist a cross-sectional association between inflammation and cystatin C in many patient groups as inflammation is associated with reduced kidney function. Acknowledgments This study was supported by the Uppsala University Hospital Research Fund. We thank Christine Leo Swenne and Lena Gunningberg for organizing the blood sample collection. References [1] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41. [2] Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–54. [3] Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, et al. Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant 2010;25:449–57. [4] Grubb AO. Cystatin C-properties and use as diagnostic marker. Adv Clin Chem 2000;35:63–99. [5] Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 2002;40:221–6. [6] Hsu CY, Chertow GM, Curhan GC. Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 2002;61:1567–76.
[7] Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:269–78. [8] Karawajczyk M, Ramklint M, Larsson A. Reduced cystatin C-estimated GFR and increased creatinine-estimated GFR in comparison with iohexol-estimated GFR in a hyperthyroid patient: A case report. J Med Case Reports 2008;2:66. [9] Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75: 652–60. [10] Al-Malki N, Heidenheim PA, Filler G, Yasin A, Lindsay RM. Cystatin C levels in functionally anephric patients undergoing dialysis: the effect of different methods and intensities. Clin J Am Soc Nephrol 2009;4:1606–10. [11] Rifkin DE, Katz R, Fried LF, Kestenbaum B, Jenny NS, Newman AB, et al. Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. Nephron Clin Pract 2010;115:c114–21. [12] Bastian D, Tamburstuen MV, Lyngstadaas SP, Reikeras O. Systemic and local cytokine kinetics after total hip replacement surgery. Eur Surg Res 2008;41: 334–40. [13] Flodin M, Jonsson AS, Hansson LO, Danielsson LA, Larsson A. Evaluation of Gentian cystatin C reagent on Abbott Ci8200 and calculation of glomerular filtration rate expressed in mL/min/1.73 m(2) from the cystatin C values in mg/L. Scand J Clin Lab Invest 2007;67:560–7. [14] Roos JF, Doust J, Tett SE, Kirkpatrick CM. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children—a meta-analysis. Clin Biochem 2007;40:383–91. [15] Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, et al. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 2009;75: 652–60. [16] Filiopoulos V, Vlassopoulos D. Inflammatory syndrome in chronic kidney disease: pathogenesis and influence on outcomes. Inflamm Allergy Drug Targets 2009;8: 369–82. [17] Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 2009;30:2838–44. [18] Larsson A, Helmersson J, Hansson LO, Basu S. Serum cystatin C is associated with other cardiovascular risk markers and cardiovascular disease in elderly men. Int J Cardiol 2008;125:263–4. [19] Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 2005;352:2049–60. [20] van Zonneveld AJ, de Boer HC, van d V, Rabelink TJ. Inflammation, vascular injury and repair in rheumatoid arthritis. Ann Rheum Dis 2010;69(Suppl 1):i57–60. [21] Klingenberg R, Hansson GK. Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J 2009;30:2838–44.