In this cross-sectional study, we noted that FPG, 2-h PG and hs-CRP were all independently associated with DKD in T2DM; Moreover, the associations of the 2-h PG as well as FPG with DKD were modified by hs-CRP; with hs-CRP increasing, the strengths of the association between blood glucose and DKD linearly rose, especially when hs-CRP values were higher than 3 mg/L. To the best of our knowledge, this is the first time the association between blood glucose and DKD was found to be modified by hs-CRP in T2DM.
Hyperglycemic burden has been recognized to be the most important risk factor for DKD in diabetes. Of the other risk factors of DKD, hs-CRP, an inflammatory biomarkers, might be one of the correlators of DKD[18–20], though few studies do not approve of this view . In one recent cohort study, Lili Liu and his colleagues followed 3924 individuals with impaired fasting glucose or diabetes for 5 years and revealed reduction in hs-CRP levels was associated with the decreased risk of DKD in these participants. A recent animal study also showed that hs-CRP could bind to FcγRII on apoptotic cells and exacerbate epithelialmesenchymal transition via the Wnt/β-catenin and ERK1/2 signal paths, which could promote the development of diabetic kidney disease. This present study enriched the knowledge on their relationship.
Among their relationship, our current study presented one interesting and clinically valuable finding that the associations of both FPG and 2-h PG with DKD were modified by hs-CRP. In practice, only a subset of patients with DM develops DKD even if they have higher level of blood glucose. Previous studies have demonstrated that there might be a strong effect of genetic susceptibility to influence development of DKD in both animal [25–27] and human beings [28, 29]. Gurley and his colleagues found a marked triggering of immune and inflammatory gene expression profiles in the mice with DM was associated with susceptibility to development of DKD. Given the fact that hs-CRP is one of the inflammatory biomarkers, the aforementioned findings, at least partly, support our current results that hs-CRP modified the association of blood glucose and DKD.
Findings from this investigation might be of great clinical significance. ACCORD trial indicates intensive hypoglycemic therapy with lower A1C target (e.g., less than 6% vs. 7–8%) has been associated with a reduction in DKD but at the cost of more hypoglycemic events and an increase in total and cardiovascular disease-related mortality[30, 31]. Thus intensive hypoglycemic therapy should be avoided to prevent hypoglycemia in the process of hypoglycemic treatment. The findings from present study indicated the effect of hyperglycemia on DKD might be small in patients with DM and lower hs-CRP value, such as those with hs-CRP < 3 mg/L. Thus to avoid hypoglycemia, intensive hypoglycemic therapy might be unnecessary for these individuals from the perspective of prevention of DKD and the findings in ACCORD trial. These subjects, i.e. those with hs-CRP < 3 mg/L, account for a larger proportion in this study (68%).
For patients with higher hs-CRP, such as those with hs-CRP higher than 3 mg/L, on the basis of hypoglycemic therapy, anti-inflammatory therapy may be a wise choice in view of the fact that the effect of hyperglycemia on DKD was lower as hs-CRP value became low, i.e. lower intensity of inflammation. One animal experiment showed adding a statin to a background of ACE inhibition and angiotensin II receptor blockade therapy normalized proteinuria and provided better renoprotection than a dual RAS blockade in rats with overt diabetic nephropathy . Apart from lipid-regulating effects, statins also interfere with prenylation of Ras and Rho family small GTP-binding proteins, leading to block of the activation of signaling pathways and transcription factors, which regulate inflammatory and fibrogenic genes related to renal disease progression. Pentoxifylline is a possible nonselective inhibitor of inflammatory mediators. In a prospective, randomized, placebo controlled trial enrolled macroalbuminuric patients with type 2 diabetes, after 6 months, patients treated with pentoxifylline had a significant reduction in albuminuria compared with placebo. Thus, based on these research results, our finding suggests on the top of hypoglycemic therapy anti-inflammation might provide a way to manage DKD for subjects with DM and a higher hs-CRP value, i.e. higher inflammatory response.
The cut-off point of hs-CRP, i.e. 3 mg/L, identified in present study is in line with the upper limit of normal value of hs-CRP used in our clinical practice. This adds the robustness of our findings. In terms of the effect modification of hs-CRP on relationship between 2 h-PG and DKD, a cut-off point of hs-CRP 2.4 mg/L was found, which is close to 3 mg/L, and a sampling error cannot be excluded. When we divided the participants into two groups based on the cut-off point 3.0 mg/L, there was no a significant association between 2 h-PG and DKD in those with hs-CRP value less than 3 mg/L, while there existed a significant relationship in the counterparts, i.e. those with hs-CRP value higher than 3 mg/L.
Several limitations should be considered in our study. First, the cross-sectional design prevents us from making causal inferences in this study. Therefore, prospective studies are warranted to confirm our findings. Second, blood glucose levels fluctuate over time and the single measure was used in this study. Nevertheless, not only the relationship between FPF and DKD was modified by hs-CRP, but the association of 2-h PG with DKD was also similarly influenced, which increases the robustness of our finding. Third, the LIE assumption regarding the effect modification of hs-CRP on the relationship between FPF and DKD appeared to be invalid, whereas it was valid in terms of association of 2-h PG with DKD. Whether such a discrepancy is attributed to sampling error is worth of verifying in future study. Finally, we adjusted many potential confounders in the multivariable model, however other residual confounders may still exist in this investigation.