Diabetes Metab J.  2023 May;47(3):415-425. 10.4093/dmj.2022.0177.

The Ratio of Estimated Glomerular Filtration Rate Based on Cystatin C and Creatinine Reflecting Cardiovascular Risk in Diabetic Patients

• Khang AR
• Lee MJ
• Yi D
• Kang YH

• KMID: 2542518
• DOI: http://doi.org/10.4093/dmj.2022.0177

Abstract

Background
The ratio of estimated glomerular filtration rate (eGFR) based on cystatin C and creatinine (eGFR_{cystatin C}/eGF_Rcreatinine ratio) is related to accumulating atherosclerosis-promoting proteins and increased mortality in several cohorts.
Methods
We assessed whether the eGFR_{cystatin C}/eGFR_creatinine ratio is a predictor of arterial stiffness and sub-clinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, who were followed up during 2008 to 2016. GFR was estimated using an equation based on cystatin C and creatinine.
Results
A total of 860 patients were stratified according to their eGFR_{cystatin C}/eGF_Rcreatinine ratio (i.e., <0.9, 0.9–1.1 [a reference group], and >1.1). Intima-media thickness was comparable among the groups; however, presence of carotid plaque was frequent in the <0.9 group (<0.9 group, 38.3%; 0.9–1.1 group, 21.6% vs. >1.1 group, 17.2%, P<0.001). Brachial-ankle pulse wave velocity (baPWV) was faster in the <0.9 group (<0.9 group, 1,656.3±333.0 cm/sec; 0.9–1.1 group, 1,550.5±294.8 cm/sec vs. >1.1 group, 1,494.0±252.2 cm/sec, P<0.001). On comparing the <0.9 group with the 0.9–1.1 group, the multivariate-adjusted odds ratios of prevalence of high baPWV and carotid plaque were 2.54 (P=0.007) and 1.95 (P=0.042), respectively. Cox regression analysis demonstrated near or over 3-fold higher risks of the prevalence of high baPWV and carotid plaque in the <0.9 group without chronic kidney disease (CKD).
Conclusion
We concluded that eGFR_{cystatin C}/eGFR_creatinine ratio <0.9 was related to an increased risk of high baPWV and carotid plaque in T2DM patients, especially, those without CKD. Careful monitoring of cardiovascular disease is needed for T2DM patients with low eGFR_{cystatin C}/eGFR_creatinine ratio.

Keyword

Atherosclerosis; Creatinine; Cystatin C; Diabetes mellitus; type 2; Glomerular filtration rate; Vascular stiffness

Figure

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  Fig. 1 The prevalence of (A) brachial-ankle pulse wave velocity ≥1,550 cm/sec and (B) carotid plaque according to estimated glomerular filtration rate (eGFR)cystatin C/eGFRcreatinine ratio. aP<0.001, bP<0.01.

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  Fig. 2 The prevalence of (A) brachial-ankle pulse wave velocity ≥1,550 cm/sec and (B) carotid plaque according to tertile of cystatin C. aP<0.001, bP<0.01, cP<0.05.

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  Fig. 3 Graphs of Cox proportional hazards regression models showing the cumulative hazard function for (A) brachial-ankle pulse wave velocity ≥1,550 cm/sec and (B) carotid plaque according to estimated glomerular filtration rate (eGFR)cystatin C/eGFRcreatinine ratio. T2DM, type 2 diabetes mellitus.

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Reference

1. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, et al. Lifetime risks of cardiovascular disease. N Engl J Med. 2012; 366:321–9.

2. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007; 116:85–97.

3. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003; 108:2154–69.

4. 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.

5. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004; 15:1307–15.

6. Coresh J, Astor B, Sarnak MJ. Evidence for increased cardiovascular disease risk in patients with chronic kidney disease. Curr Opin Nephrol Hypertens. 2004; 13:73–81.

7. Soveri I, Berg UB, Bjork J, Elinder CG, Grubb A, Mejare I, et al. Measuring GFR: a systematic review. Am J Kidney Dis. 2014; 64:411–24.

8. Perkins BA, Nelson RG, Ostrander BE, Blouch KL, Krolewski AS, Myers BD, et al. Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol. 2005; 16:1404–12.

9. Seronie-Vivien S, Delanaye P, Pieroni L, Mariat C, Froissart M, Cristol JP, et al. Cystatin C: current position and future prospects. Clin Chem Lab Med. 2008; 46:1664–86.

10. Shlipak MG, Matsushita K, Arnlov J, Inker LA, Katz R, Polkinghorne KR, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013; 369:932–43.

11. Peralta CA, Katz R, Sarnak MJ, Ix J, Fried LF, De Boer I, et al. Cystatin C identifies chronic kidney disease patients at higher risk for complications. J Am Soc Nephrol. 2011; 22:147–55.

12. Grubb A, Lindstrom V, Jonsson M, Back SE, Ahlund T, Rippe B, et al. Reduction in glomerular pore size is not restricted to pregnant women: evidence for a new syndrome: ‘Shrunken pore syndrome’. Scand J Clin Lab Invest. 2015; 75:333–40.

13. Grubb A. Shrunken pore syndrome: a common kidney disorder with high mortality: diagnosis, prevalence, pathophysiology and treatment options. Clin Biochem. 2020; 83:12–20.

14. Oberg CM, Lindstrom M, Grubb A, Christensson A. Potential relationship between eGFRcystatin C/eGFRcreatinine-ratio and glomerular basement membrane thickness in diabetic kidney disease. Physiol Rep. 2021; 9:e14939.

15. Herou E, Dardashti A, Nozohoor S, Zindovic I, Ederoth P, Grubb A, et al. The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-ratio. Scand J Clin Lab Invest. 2019; 79:167–73.

16. Xhakollari L, Grubb A, Jujic A, Bachus E, Nilsson PM, Leosdottir M, et al. The Shrunken pore syndrome is associated with poor prognosis and lower quality of life in heart failure patients: the HARVEST-Malmo study. ESC Heart Fail. 2021; 8:3577–86.

17. Negi SI, Nambi V. The role of carotid intimal thickness and plaque imaging in risk stratification for coronary heart disease. Curr Atheroscler Rep. 2012; 14:115–23.

18. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010; 121:505–11.

19. Ohkuma T, Ninomiya T, Tomiyama H, Kario K, Hoshide S, Kita Y, et al. Brachial-ankle pulse wave velocity and the risk prediction of cardiovascular disease: an individual participant data meta-analysis. Hypertension. 2017; 69:1045–52.

20. Katakami N, Osonoi T, Takahara M, Saitou M, Matsuoka TA, Yamasaki Y, et al. Clinical utility of brachial-ankle pulse wave velocity in the prediction of cardiovascular events in diabetic patients. Cardiovasc Diabetol. 2014; 13:128.

21. Ankle Brachial Index Collaboration, Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008; 300:197–208.

22. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S49–73.

23. Nyman U, Grubb A, Larsson A, Hansson LO, Flodin M, Nordin G, et al. The revised Lund-Malmo GFR estimating equation outperforms MDRD and CKD-EPI across GFR, age and BMI intervals in a large Swedish population. Clin Chem Lab Med. 2014; 52:815–24.

24. Grubb A, Horio M, Hansson LO, Bjork J, Nyman U, Flodin M, et al. Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Clin Chem. 2014; 60:974–86.

25. Levin A, Stevens PE, Bilous RW, Coresh J, De Francisco AL, De Jong PE, Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group, et al. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013; 3:1–150.

26. de Boer IH, Katz R, Cao JJ, Fried LF, Kestenbaum B, Mukamal K, et al. Cystatin C, albuminuria, and mortality among older adults with diabetes. Diabetes Care. 2009; 32:1833–8.

27. Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009; 20:1813–21.

28. Astor BC, Hallan SI, Miller ER 3rd, Yeung E, Coresh J. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. Am J Epidemiol. 2008; 167:1226–34.

29. Bello AK, Hemmelgarn B, Lloyd A, James MT, Manns BJ, Klarenbach S, et al. Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. Clin J Am Soc Nephrol. 2011; 6:1418–26.

30. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010; 375:2073–81.

31. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004; 351:1285–95.

32. Gargiulo R, Suhail F, Lerma EV. Cardiovascular disease and chronic kidney disease. Dis Mon. 2015; 61:403–13.

33. Purde MT, Nock S, Risch L, Medina Escobar P, Grebhardt C, Nydegger UE, et al. The cystatin C/creatinine ratio, a marker of glomerular filtration quality: associated factors, reference intervals, and prediction of morbidity and mortality in healthy seniors. Transl Res. 2016; 169:80–90.

34. Almen MS, Bjork J, Nyman U, Lindstrom V, Jonsson M, Abrahamson M, et al. Shrunken pore syndrome is associated with increased levels of atherosclerosis-promoting proteins. Kidney Int Rep. 2018; 4:67–79.

35. Lund U, Rippe A, Venturoli D, Tenstad O, Grubb A, Rippe B. Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys. Am J Physiol Renal Physiol. 2003; 284:F1226–34.

36. Ellison DH, Loffing J. Thiazide effects and adverse effects: insights from molecular genetics. Hypertension. 2009; 54:196–202.

37. 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.

38. Koenig W, Twardella D, Brenner H, Rothenbacher D. Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate. Clin Chem. 2005; 51:321–7.

39. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen C, Newman AB, et al. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol. 2005; 45:268–71.

40. Shlipak MG, Katz R, Sarnak MJ, Fried LF, Newman AB, Stehman-Breen C, et al. Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease. Ann Intern Med. 2006; 145:237–46.

41. Huang R, Gu J, Cao Q, Ma J, Gu W, Fan Z. The association between serum cystatin C and carotid intima-media thickness in metabolic syndrome patients with normal estimated glomerular filtration rate. Clin Chim Acta. 2015; 448:170–3.