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Published in: BMC Nephrology 1/2019

Open Access 01-12-2019 | Hypertension | Research article

Complement C3 and incident hospitalization due to chronic kidney disease: a population-based cohort study

Authors: Xue Bao, Yan Borné, Iram Faqir Muhammad, Christina-Alexandra Schulz, Margaretha Persson, Marju Orho-Melander, Kaijun Niu, Anders Christensson, Gunnar Engström

Published in: BMC Nephrology | Issue 1/2019

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Abstract

Background

Circulating C3 has been associated with diabetes and hypertension, which are the leading causes of chronic kidney disease (CKD). C3 activation is considered to contribute to several renal diseases. Here we examined whether elevated C3 concentration is associated with hospitalization due to CKD in the general population, and whether this relationship is mediated by factors such as diabetes and hypertension.

Methods

Baseline plasma C3 was quantified in 4552 participants, without previous hospital admission due to CKD, from the Malmö Diet and Cancer cohort study. Incidence of first hospitalization due to CKD (main diagnosis) was investigated in relation to C3 levels using Cox proportional hazards regression models after a mean follow-up of 19.2 ± 4.16 years. Traditional risk factors of CKD including diabetes, blood pressure, C-reactive protein and baseline renal function were considered in adjustments and sensitivity analyses.

Results

During the follow-up period, 94 subjects were admitted to hospital due to CKD. After multivariate adjustment, the hazard ratios (95% confidence interval) for hospitalization from CKD across quartiles of C3 were 1.00 (reference), 1.68 (0.69, 4.13), 2.71 (1.15, 6.39), and 3.16 (1.36, 7.34) (p for trend = 0.003). Results were generally consistent across different sensitivity analyses.

Conclusions

These findings indicate that C3 is associated with incidence of first hospitalization due to CKD in the general population. The observed relationship cannot be entirely attributed to hyperglycemia and hypertension.
Literature
1.
go back to reference James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet. 2010;375:1296–309.CrossRef James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet. 2010;375:1296–309.CrossRef
2.
go back to reference Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–72.CrossRef Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–72.CrossRef
3.
go back to reference Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2011;80:572–86.CrossRef Herzog CA, Asinger RW, Berger AK, Charytan DM, Diez J, Hart RG, et al. Cardiovascular disease in chronic kidney disease. A clinical update from kidney disease: improving global outcomes (KDIGO). Kidney Int. 2011;80:572–86.CrossRef
4.
go back to reference Di Angelantonio E, Chowdhury R, Sarwar N, Aspelund T, Danesh J, Gudnason V. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. BMJ. 2010;341:c4986.CrossRef Di Angelantonio E, Chowdhury R, Sarwar N, Aspelund T, Danesh J, Gudnason V. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. BMJ. 2010;341:c4986.CrossRef
5.
go back to reference Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.CrossRef Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.CrossRef
6.
go back to reference Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20:34–50.CrossRef Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20:34–50.CrossRef
7.
go back to reference McGeer PL, Lee M, McGeer EG. A review of human diseases caused or exacerbated by aberrant complement activation. Neurobiol Aging. 2017;52:12–22.CrossRef McGeer PL, Lee M, McGeer EG. A review of human diseases caused or exacerbated by aberrant complement activation. Neurobiol Aging. 2017;52:12–22.CrossRef
8.
go back to reference Sahu A, Lambris JD. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol Rev. 2001;180:35–48.CrossRef Sahu A, Lambris JD. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol Rev. 2001;180:35–48.CrossRef
9.
go back to reference Wlazlo N, van Greevenbroek MM, Ferreira I, Feskens EJ, van der Kallen CJ, Schalkwijk CG, et al. Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM study. Diabetes Care. 2014;37:1900–9.CrossRef Wlazlo N, van Greevenbroek MM, Ferreira I, Feskens EJ, van der Kallen CJ, Schalkwijk CG, et al. Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM study. Diabetes Care. 2014;37:1900–9.CrossRef
10.
go back to reference Engström G, Hedblad B, Berglund G, Janzon L, Lindgarde F. Plasma levels of complement C3 is associated with development of hypertension: a longitudinal cohort study. J Hum Hypertens. 2007;21:276–82.CrossRef Engström G, Hedblad B, Berglund G, Janzon L, Lindgarde F. Plasma levels of complement C3 is associated with development of hypertension: a longitudinal cohort study. J Hum Hypertens. 2007;21:276–82.CrossRef
11.
go back to reference Borne Y, Muhammad IF, Lores-Motta L, Hedblad B, Nilsson PM, Melander O, et al. Complement C3 associates with incidence of diabetes, but no evidence of a causal relationship. J Clin Endocrinol Metab. 2017;102:4477–85.CrossRef Borne Y, Muhammad IF, Lores-Motta L, Hedblad B, Nilsson PM, Melander O, et al. Complement C3 associates with incidence of diabetes, but no evidence of a causal relationship. J Clin Endocrinol Metab. 2017;102:4477–85.CrossRef
12.
go back to reference Li X, Ding F, Zhang X, Li B, Ding J. The expression profile of complement components in podocytes. Int J Mol Sci. 2016;17:471.CrossRef Li X, Ding F, Zhang X, Li B, Ding J. The expression profile of complement components in podocytes. Int J Mol Sci. 2016;17:471.CrossRef
13.
go back to reference Zhou W, Marsh JE, Sacks SH. Intrarenal synthesis of complement. Kidney Int. 2001;59:1227–35.CrossRef Zhou W, Marsh JE, Sacks SH. Intrarenal synthesis of complement. Kidney Int. 2001;59:1227–35.CrossRef
14.
go back to reference Tang S, Zhou W, Sheerin NS, Vaughan RW, Sacks SH. Contribution of renal secreted complement C3 to the circulating pool in humans. J Immunol. 1999;162:4336–41.PubMed Tang S, Zhou W, Sheerin NS, Vaughan RW, Sacks SH. Contribution of renal secreted complement C3 to the circulating pool in humans. J Immunol. 1999;162:4336–41.PubMed
15.
go back to reference Thurman JM. Complement in kidney disease: core curriculum 2015. Am J Kidney Dis. 2015;65:156–68.CrossRef Thurman JM. Complement in kidney disease: core curriculum 2015. Am J Kidney Dis. 2015;65:156–68.CrossRef
16.
go back to reference Berglund G, Elmstahl S, Janzon L, Larsson SA. The Malmo diet and Cancer study. Design and feasibility J Intern Med. 1993;233:45–51.PubMed Berglund G, Elmstahl S, Janzon L, Larsson SA. The Malmo diet and Cancer study. Design and feasibility J Intern Med. 1993;233:45–51.PubMed
17.
go back to reference Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmo, Sweden. Diabet Med. 2000;17:299–307.CrossRef Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects. Results from a cross-sectional study in Malmo, Sweden. Diabet Med. 2000;17:299–307.CrossRef
18.
go back to reference Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.PubMed Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.PubMed
19.
go back to reference Schulz CA, Persson M, Christensson A, Hindy G, Almgren P, Nilsson PM, et al. Soluble Urokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based Malmo diet and Cancer study. Kidney Int Rep. 2017;2:239–47.CrossRef Schulz CA, Persson M, Christensson A, Hindy G, Almgren P, Nilsson PM, et al. Soluble Urokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based Malmo diet and Cancer study. Kidney Int Rep. 2017;2:239–47.CrossRef
20.
go back to reference Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367:20–9.CrossRef Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367:20–9.CrossRef
21.
go back to reference Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRef Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRef
22.
go back to reference Qureshi AR, Evans M, Stendahl M, Prutz KG, Elinder CG. The increase in renal replacement therapy (RRT) incidence has come to an end in Sweden-analysis of variations by region over the period 1991-2010. Clin Kidney J. 2013;6:352–7.CrossRef Qureshi AR, Evans M, Stendahl M, Prutz KG, Elinder CG. The increase in renal replacement therapy (RRT) incidence has come to an end in Sweden-analysis of variations by region over the period 1991-2010. Clin Kidney J. 2013;6:352–7.CrossRef
23.
go back to reference Kidney Disease. Improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and Management of Chronic Kidney Disease. Kidney Int. 2013;3:1–150.CrossRef Kidney Disease. Improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and Management of Chronic Kidney Disease. Kidney Int. 2013;3:1–150.CrossRef
24.
go back to reference Kohl M, Plischke M, Leffondre K, Heinze G. PSHREG: a SAS macro for proportional and nonproportional subdistribution hazards regression. Comput Methods Prog Biomed. 2015;118:218–33.CrossRef Kohl M, Plischke M, Leffondre K, Heinze G. PSHREG: a SAS macro for proportional and nonproportional subdistribution hazards regression. Comput Methods Prog Biomed. 2015;118:218–33.CrossRef
25.
go back to reference Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.CrossRef Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.CrossRef
26.
go back to reference Gabrielsson BG, Johansson JM, Lonn M, Jernas M, Olbers T, Peltonen M, et al. High expression of complement components in omental adipose tissue in obese men. Obes Res. 2003;11:699–708.CrossRef Gabrielsson BG, Johansson JM, Lonn M, Jernas M, Olbers T, Peltonen M, et al. High expression of complement components in omental adipose tissue in obese men. Obes Res. 2003;11:699–708.CrossRef
27.
go back to reference Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ. Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int. 2000;58:293–301.CrossRef Muntner P, Coresh J, Smith JC, Eckfeldt J, Klag MJ. Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int. 2000;58:293–301.CrossRef
28.
go back to reference Kohagura K, Kochi M, Miyagi T, Kinjyo T, Maehara Y, Kinjyo K, et al. Hypertriglyceridemia accompanied by increased serum complement component 3 and proteinuria in non-nephrotic chronic kidney disease. Clin Exp Nephrol. 2014;18:453–60.CrossRef Kohagura K, Kochi M, Miyagi T, Kinjyo T, Maehara Y, Kinjyo K, et al. Hypertriglyceridemia accompanied by increased serum complement component 3 and proteinuria in non-nephrotic chronic kidney disease. Clin Exp Nephrol. 2014;18:453–60.CrossRef
29.
go back to reference Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015;64:1886–97.CrossRef Tsai S, Clemente-Casares X, Revelo XS, Winer S, Winer DA. Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases? Diabetes. 2015;64:1886–97.CrossRef
30.
go back to reference James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint National Committee (JNC 8). JAMA. 2014;311:507–20.CrossRef James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint National Committee (JNC 8). JAMA. 2014;311:507–20.CrossRef
31.
go back to reference Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011;80:1231–8.CrossRef Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, et al. Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study. Kidney Int. 2011;80:1231–8.CrossRef
32.
go back to reference Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339:1448–56.CrossRef Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies. N Engl J Med. 1998;339:1448–56.CrossRef
33.
go back to reference Muscari A, Antonelli S, Bianchi G, Cavrini G, Dapporto S, Ligabue A, et al. Serum C3 is a stronger inflammatory marker of insulin resistance than C-reactive protein, leukocyte count, and erythrocyte sedimentation rate: comparison study in an elderly population. Diabetes Care. 2007;30:2362–8.CrossRef Muscari A, Antonelli S, Bianchi G, Cavrini G, Dapporto S, Ligabue A, et al. Serum C3 is a stronger inflammatory marker of insulin resistance than C-reactive protein, leukocyte count, and erythrocyte sedimentation rate: comparison study in an elderly population. Diabetes Care. 2007;30:2362–8.CrossRef
34.
go back to reference Ajjan R, Grant PJ, Futers TS, Brown JM, Cymbalista CM, Boothby M, et al. Complement C3 and C-reactive protein levels in patients with stable coronary artery disease. Thromb Haemost. 2005;94:1048–53.CrossRef Ajjan R, Grant PJ, Futers TS, Brown JM, Cymbalista CM, Boothby M, et al. Complement C3 and C-reactive protein levels in patients with stable coronary artery disease. Thromb Haemost. 2005;94:1048–53.CrossRef
35.
go back to reference Kojima C, Takei T, Ogawa T, Nitta K. Serum complement C3 predicts renal arteriolosclerosis in non-diabetic chronic kidney disease. J Atheroscler Thromb. 2012;19:854–61.CrossRef Kojima C, Takei T, Ogawa T, Nitta K. Serum complement C3 predicts renal arteriolosclerosis in non-diabetic chronic kidney disease. J Atheroscler Thromb. 2012;19:854–61.CrossRef
36.
go back to reference Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87.CrossRef Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87.CrossRef
37.
go back to reference Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, et al. C3 glomerulopathy: consensus report. Kidney Int. 2013;84:1079–89.CrossRef Pickering MC, D'Agati VD, Nester CM, Smith RJ, Haas M, Appel GB, et al. C3 glomerulopathy: consensus report. Kidney Int. 2013;84:1079–89.CrossRef
38.
go back to reference Zhang J, Wang Y, Zhang R, Li H, Han Q, Guo R, et al. Implication of decreased serum complement 3 in patients with diabetic nephropathy. Acta Diabetol. 2018;55:31–9.CrossRef Zhang J, Wang Y, Zhang R, Li H, Han Q, Guo R, et al. Implication of decreased serum complement 3 in patients with diabetic nephropathy. Acta Diabetol. 2018;55:31–9.CrossRef
Metadata
Title
Complement C3 and incident hospitalization due to chronic kidney disease: a population-based cohort study
Authors
Xue Bao
Yan Borné
Iram Faqir Muhammad
Christina-Alexandra Schulz
Margaretha Persson
Marju Orho-Melander
Kaijun Niu
Anders Christensson
Gunnar Engström
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2019
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-019-1248-7

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