Traditional vs. nontraditional risk factor assessment in chronic kidney disease

Chronic kidney disease (CKD), defined as the presence of kidney damage (≥30 mg/day of urinary albumin excretion) or decreased kidney function [glomerular filtration rate (GFR) <60 ml/min] for at least 3 months, is a major independent risk factor for cardiovascular disease (CVD) [1]. In addition to having a lower GFR and a higher albumin excretion, patients with CKD often have a number of traditional and nontraditional CVD risk factors. Traditional risk factors such as hypertension and diabetes are highly prevalent among patients with CKD [2–4] and have been associated with larger increases in CVD risk at earlier stages of CKD progression [5]. Nontraditional risk factors such as C-reactive protein (CRP), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) have been also associated with an increased risk for CVD mortality among patients with CKD [6,7]. Consequently, because the prevalence of these risk factors is high among CKD populations, the risk of CVD mortality is often higher than the risk of progressing to end-stage renal disease (ESRD), making the detection, treatment, and control of CVD risk factors major clinical priorities. The underlying cause for the development of CVD among patients with CKD stems from the chronic and systemic progression of macrovascular atherosclerosis and microvascular dysfunction [8]. Microvascular dysfunction, described as an impairment in the delivery of blood to the heart from disorder in the prearterial, arterial, or capillary networks, has a pathogenesis that is not fully understood but may be due to the presence of traditional CVD risk factors, impaired vasomotor activity, and/or endothelial dysfunction [9,10]. Early detection and diagnosis of microvascular dysfunction is therefore critical to delaying the progression of atherosclerotic CVD for patients living with various stages of CKD. Current approaches to detecting and diagnosing microvascular dysfunction include direct or indirect evaluation of endothelial function via biomarkers known to inhibit nitric oxide (NO) synthesis and/or induce proinflammatory responses [11]. Such markers include ADMA and SDMA, CRP, angiopoietin-2 (Ang-2), and urinary albumin. Laser Doppler flowmetry (LDF), a noninvasive method of estimating blood perfusion within the microcirculation, has also been found to identify endothelial dysfunction in patients with hypertension and ESRD [12,13], yet its ability to estimate blood perfusion for nondialysis patients with CKD is unknown. Ang-2, an inhibitor of the Tie-2 cell signaling pathway, is reported to be higher in patients with CKD and has predicted CVD mortality in patients with ESRD, but has never been assessed nor evaluated in nondialysis patients with CKD. ADMA and SDMA, both inhibitors of NO synthase and regulators of vascular resistance, have been established as important biomarkers for patients with ESRD, but their role in nondialysis patients with CKD is limited and unconfirmed. Therefore, to better understand the role and predictive value of Ang-2, ADMA, SDMA, LDF, and traditional risk factors of CVD on CVD outcomes, additional investigations are needed. In the current issue of the Journal of Hypertension, Nemcsik et al. [14] assessed whether Ang-2, ADMA, SDMA, and LDF predicted CVD morbidity and mortality and all-cause mortality among a sample of 105 nondialysis patients with CKD. The authors found that among the microvascular parameters, Ang-2 and postocclusive reactive hyperemia area (PORHHA), a measure of microvascular dysfunction with LDF, predicted CVD morbidity and mortality univariately, along with traditional risk factors including age, diabetes, brachial pulse pressure, CRP, and baseline CVD. PORHHA, CRP, age, and diabetes remained significant and predictive of CVD mortality in multivariate analyses. From these findings, the authors concluded that PORHHA with LDF seems to provide clinicians with added value when assessing patients with CKD for CVD risk. However, because traditional risk factors surpassed the predictive role of the selected microvascular biomarkers, they concluded that PORHHA with LDF may be used as a supplemental risk assessment for patients with various stages of CKD. The current study by Nemcsik et al.[14] provides important information about the possible roles of traditional vs. nontraditional CVD risk factors in a sample of 105 nondialysis patients with CKD. The study was well documented, had a long median follow-up period (66.6 months), and used a strong methodological study design with appropriate and standardized controls. In addition, the authors used valid and reliable measurement tools, employed appropriate statistical procedures, and addressed issues of confounding with backward elimination procedures. However, despite these strengths, the study is not without limitation. Because the study included a small sample of 105 patients with a post-hoc β = 0.69, the study lacks statistical power. However, an a-priori power analysis performed with G*Power 3.1 [15] indicates that a sample size of 163 would be sufficient to yield a β = 0.80 with a medium ƒ2 = 0.15 at a predetermined alpha level set to P less than 0.05. In addition to lacking statistical power, the study included both log-transformed and nontransformed data in the same multivariate analyses, making the interpretability of the data difficult as both geometric and arithmetic values were assessed. Another limitation of the study was that patients with various stages of CKD were assessed on an aggregate basis without disaggregating the data stage by stage. Although patients with a GFR ≤ 35 ml/min did not differ from patients with a GFR ≥ 35 ml/min, understanding the possible role of the selected functional and microvascular biomarkers and their ability to predict CVD outcomes on stage by stage would have enhanced the value of the findings. Lastly, because the sample included mostly younger patients, the generalizability of the findings to older nondialysis patients with CKD remains limited. In summary, the current study by Nemcsik et al.[14] is the first to assess the predictive value of Ang-2, ADMA, SDMA, LDF, and traditional risk factors of CVD on CVD outcomes in stages 1–5 nondialysis patients with CKD. Despite the study's few limitations, it offers promise for the potential use of LDF as an early assessment tool to detect subclinical endothelial and microvascular dysfunction. Future investigations should confirm and expand upon the findings of Nemcsik et al.[14] in larger more generalizable samples of nondialysis patients with CKD, as new information gained could potentially aid clinicians in detecting and diagnosing macrovascular atherosclerosis at earlier onsets of CKD progression. However, at this time, the evaluation of traditional risk factors should continue to be used in the primary assessment of subclinical macrovascular disease among patients with CKD until confirmatory studies with LDF are published. ACKNOWLEDGEMENTS The author thanks Dr Alberto Zanchetti, editor in chief of the Journal of Hypertension for the opportunity to write this editorial comment. Conflicts of interest There are no conflicts of interest.