C-reactive protein (CRP) is a middle molecule protein that is produced by hepatocytes that is involved in the activity of the innate immune system. Its synthesis can be up-regulated in inflammatory conditions as part of the acute phase response, and prior epidemiological studies have demonstrated an association of higher CRP concentrations with the future development of adverse cardiovascular outcomes.
When paying specific attention to elevated CRP serum levels and CKD progression, the data has been conflicting. Many studies reached different conclusions depending on whether the estimation of GFR was based off of serum creatinine calculations (MDRD, CKD-EPI) or cystatin C measurements. This recent AJKD publication by Mc Causland et al evaluated the TREAT (Trial to Reduce cardiovascular Events with Aranesp Therapy) cohort – 4,038 patients with type 2 diabetes, CKD 3-4 (eGFR 20-60 ml/min), and anemia (Hb <11.0 g/dL) to study CRP elevations. Using the baseline serum CRP concentration, patients were divided into 3 levels: normal (<3 mg/L), mildly elevated (>3.0-<6.9 mg/L) and moderate-markedly elevated (>6.9 mg/L). Roughly half of the patients had baseline CRP concentration at or below the lower limit of detection (<3 mg/L). The primary outcome of interest was development of end-stage renal disease (ESRD), with multiple secondary outcomes including composite cardiovascular outcomes and all-cause mortality.
During the mean follow-up time of 2.2 years, 16% of the TREAT cohort progressed to ESRD. The authors found that patients with CRP levels >6.9 mg/L (moderate-markedly elevated) had 32% greater risk of developing ESRD compared to individuals with CRP <3.0 mg/L (normal). The association of baseline CRP with the development of composite cardiovascular outcomes and all-cause mortality was even stronger, with a 59% increase in the moderate-markedly elevated CRP group compared to the normal group. Interestingly, there was no significant difference in the change in eGFR, with the whole cohort losing 1.8 ml/min/year. Interpreting this simplified conclusion is inherently difficult. The authors appropriately question whether patients with elevated CRP levels may have more comorbid conditions that may require earlier initiation of renal replacement therapy due to an enhanced inflammatory state. An alternate hypothesis suggests that higher CRP levels identify individuals with more comorbidities, leading to overestimation of measured GFR due to lower creatinine generation. The lack of an association with progressive eGFR decline also supports the idea that high CRP levels identify patients with a high comorbidity burden who may require earlier renal replacement therapy rather than a factor that specifically promotes renal functional decline.
Even if clinicians can accept the conclusion at face value, do elevated CRP levels provide a possibility for intervention? Modifiable sources of inflammation (e.g. infection) are easily treated, but other agents that have demonstrated to lower CRP levels include drugs with controversial pleiotropic effects such as sevelamer or the statins. There have been several studies looking at the relationship between sevelamer and CKD progression, none of which has been extraordinarily convincing. Statins in CKD patients have been evaluated in the SHARP trial, although this study focused on lowering LDL rather than CRP levels. Even in the general population, the JUPITER trial demonstrated a reduction in cardiovascular outcomes by targeting patients with CRP levels > 2.0 mg/L by using rosuvastatin. However, this trial was powered by an incredibly high n (17,802 participants), and its controversial result would not be applicable to the CKD population.
Despite the correlation of elevated CRP levels and development of ESRD, causality and clinical interventions to prevent or delay this outcome have not been demonstrated. At best, it seems that serum CRP levels provide us with another prognostic marker (of which there are many) rather than a treatable target for our patients.
Post prepared by Timothy Yau, AJKD Social Media Editor