The Prognostic Value of High-Sensitivity CRP in the East Asian Population

Corresponding Author

The link between chronic kidney disease (CKD) and cardiovascular disease (CVD) has long been recognized in medical research.¹ Currently, there is an increasing prevalence of CKD globally, inevitably leading to a greater burden of cardiovascular complications if modifiable risk is left unaddressed.^2,3 Chronic inflammation is characteristic of those with CKD and plays a key role in the complex pathological mechanism that underpins CVD in this patient group.¹

Historically, the rates of CVD in East Asian countries have been less than in Western countries; however, incidence is now increasing. Most CVD burden has been attributed to high systolic blood pressure, increased low-density lipoprotein cholesterol, dietary risks, tobacco use, and air pollution, with high body mass index and high fasting plasma glucose rapidly rising as risk factors.⁴ The prevalence of associated metabolic conditions such as obesity, hypercholesterolemia, hypertension, and diabetes mellitus are also increasing.^5,6 Several factors have been implicated in this epidemiological shift. Industrialization and urbanization of many areas have seen an increase in air pollution, which is linked to increased systemic inflammation. It has also led to lifestyle changes, shifting toward less physical activity, intake of more processed foods,⁷ and an increase in the prevalence of tobacco smoking,⁴ further contributing to the inflammatory milieu.

C-reactive protein (CRP) is a circulating pentameric plasma protein produced mainly by the liver in response to inflammation and infection. So-called high-sensitivity C-reactive protein (hs-CRP) denotes an alternative method of measuring circulating plasma CRP, where assays of greater analytical sensitivity detect very low concentrations of this acute phase protein with accuracy and precision. It has been identified as a key biomarker associated with numerous inflammatory conditions, including CVD.⁸ Moreover, it is a noninvasive test that requires a blood sample and laboratory testing with a specialized assay.⁹ Despite recognition of hs-CRP as a prognostic marker in cardiovascular disease and CKD, it is not yet widely used in clinical practice, despite being available on many automated clinical laboratory analyzers.¹⁰

In this issue of JACC: Asia, Kong et al¹¹ explore the link between hs-CRP, as a marker of chronic inflammation, to help predict incident CVD and major adverse cardiac events in those with CKD, specifically in an East Asian population that is typically under-represented in medical research.¹² This is important given the recognized ethnic differences in cardiovascular clinical epidemiology and clinical outcomes between Asian and non-Asian cohorts.13, 14, 15 Ethnic differences in responsiveness to various drug treatments (eg, antithrombotics) and the implications for efficacy and safety have led to description of the so-called East Asian Paradox.¹⁶ Hence, such data on biomarkers and the implications in East Asian populations are welcomed.

To summarize the results, Kong et al¹¹ found that almost universally, those with atherosclerotic CVD had higher baseline levels of hs-CRP than those without. They conclude that there was a significant association between increasing hs-CRP levels and incidence of both CVD and CKD. Around three-quarters of papers included in their review established a correlation between raised hs-CRP in those with known CVD and the incidence of major adverse cardiovascular events. As expected in a large systematic review of this nature, it was acknowledged that there was significant heterogeneity in statistical reporting and threshold hs-CRP values that need to be considered with the interpretation of these results.

Their findings are broadly consistent with other published works from other geographical cohorts on this topic. There is clear evidence that demonstrates an increased risk of coronary heart disease with incremental increases in CRP.^17,18 hs-CRP has been shown to influence the risk of cardiovascular complications independent of other traditional factors such as hyperlipidemia and smoking.¹⁹ The work reported by Kong et al¹¹ specifically addresses the utility of hs-CRP in the East Asian population and expands on the work of others focused on a Western population.^20,21

The question remains how this can be applied to clinical practice. hs-CRP testing is widely available; however, it is not yet part of routine testing for patients with CKD. Whereas the causal pathway of CVD involves a complex interplay of factors, including inflammation, atherosclerosis, and lifestyle choices, CRP is a widely recognized marker of inflammation, and its prognostic and predictive role in CKD patients remains debated. The sensitivity and specificity of CRP for CVD risk stratification are not ideal, due to the nature of CKD itself (uremic toxins) and its associated complications (catheters). In addition, others have reported that adding CRP to traditional risk assessment models (eg, the Framingham Risk Score) does not significantly improve the ability to predict who will develop CVD.²²

The mechanisms underpinning the association of CRP and cardiovascular risk are complex and multifactorial. It would also be incorrect to assume CRP is solely a marker of inflammation. Circulating native CRP exists as a pentamer, which dissociates into tissue-bound monomeric CRP, which is a proinflammatory isoform capable of activating immune cells.²³ At present, however, there are no routinely available clinical assays that measure circulating monomeric CRP, which exists bound to cell surfaces, so it is impractical to assess the prognostic significance of monomeric CRP in the clinical setting.

Moreover, a change in testing culture is often required to introduce a new laboratory investigation into routine clinical practice effectively.²⁴ In hospital practice, hs-CRP has no advantage in those with significant inflammation that would be detected with traditional CRP assays. Use should therefore be avoided in those in a heightened inflammatory state for example, during periods of acute infection.

Lifestyle modifications such as exercise and smoking cessation reduce hs-CRP levels and lead to a reduced risk of CVD.25, 26, 27, 28 Although these lifestyle modifications are already routinely recommended to those wishing to reduce their cardiovascular risk.

Whereas the utility of CRP as a biomarker for prognostication is debatable, it has shown promise as a therapeutic target that would aim to reduce risk.

Studies have shown that drugs that target inflammatory pathways and reduce hs-CRP correlate with a reduction in cardiovascular risk.²⁹ Possible therapeutic agents that have been studied include statins, angiotensin receptor blockers, and antidiabetic drugs.30, 31, 32 In addition, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome]) trial has found that canakinumab, a monoclonal antibody against interleukin-1β, reduced levels of hs-CRP and observed a reduction in recurrent cardiovascular events in those with a history of myocardial infarction.³³ Clazakizumab has similarly been identified as a possible therapy for cardiovascular event reduction for those on hemodialysis and is undergoing study.³⁴ Whereas research so far has demonstrated encouraging results for these novel agents, they have not yet translated into routine clinical use in patients with CKD.

There is a risk of oversimplifying the complex pathways that lead to CVD when examining biomarkers in isolation. This should not be forgotten when applying hs-CRP to clinical practice. The use of hs-CRP in quantifying CVD should be considered alongside the known and novel prognostic markers as part of a comprehensive cardiovascular risk assessment. As precision medicine gains ground, CRP can be used along with novel cardiac-specific biomarkers and multiomics in East Asian cohorts, given their unique epidemiological profiles.

Kong et al¹¹ have summarized important work that has previously been undertaken on this topic, suggesting hs-CRP is an important biomarker for CVD and CKD in this previously under-represented population. This emphasizes the need for further work on this topic for widespread implementation of testing, as well as the inclusion of a Southeast Asian population in studies of therapeutic agents. This work specifically focuses on the role of hs-CRP in the context of CKD; however, it highlights the potential for hs-CRP to prognosticate in those with end-stage renal disease and receiving renal replacement therapy, who are at significantly increased risk of adverse cardiovascular events. There is some published work looking specifically at this topic, but this would be an area for more work to be undertaken.³⁵

There are notable limitations and therefore suggestions for further work in this area. The reported systematic review used baseline CRP results and would benefit from longitudinal studies to evaluate the significance of dynamic changes in CRP over time. Further, it is unclear from the report if the hs-CRP assays used included only validated clinical laboratory assays and/or research assays, which have not been clinically validated. Future research should focus on validated assays only, hence ensuring standardization in measurement. In addition, the incorporation of hs-CRP results into multivariate clinical prediction algorithms may improve accuracy of prediction, while taking account clinical findings and comorbidities associated with inflammation, CKD and CVD. Recent advances in artificial intelligence and machine learning also offer the opportunity to incorporate blood-based biomarkers into multivariate models for risk prediction.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.