Measuring systemic levels of C components and C activation products, in addition to studying C3, C4 and CH50 , may be useful to predict diagnosis, disease activity and/or prognosis for C-associated diseases, including some kidney diseases [3, 6]. However, as a background characteristic, renal function may be impaired in patients with CKD, particularly in elderly patients, and the effects on evaluations of C components and C activation products have remained unclear. We therefore investigated whether residual renal function may affect measurements of serum or plasma levels of C components and C activation products in CKD patients without active glomerulonephritis, excluding patients with end-stage renal disease (ESRD) on dialysis.
In the present study, both serum and plasma Ba levels correlated inversely with Cin and eGFR as markers of renal function, but neither serum nor plasma levels of C5a or sC5b-9 correlated with Cin or eGFR. In contrast, levels of C3, C4 and CH50 in both serum and plasma samples were within standard ranges and did not correlate with renal function. Concerning differences between plasma and serum levels, serum levels of Ba, C5a and sC5b-9 were significantly higher than plasma levels as in a previous report, although that study included only healthy subjects .
From our results associated with renal function according to CKD characterizations, we observed significant increases in serum and plasma levels of Ba in patients with Cin<60 or Cin<30 compared with Cin≥60 or Cin≥30, respectively. Although plasma C5a levels in Cin<60 patients were also slightly but significantly higher than that in Cin≥60 patients, the range of C5a levels was almost within standard levels as reported from a study of healthy Japanese individuals . No other significant differences were identified between other pairs of groups. When measuring plasma and serum levels of Ba, C5a, sC5b-9, C3, C4 and CH50 under various pathological conditions, Ba as a fragment of factor B, a C activation product of the alternative pathway in complement activation system might be affected by background renal function. However, other levels appear unaffected.
The C system is a key system to maintain host heath and provide a strong defense against foreign materials [1, 3]. In contrast, uncontrolled activation of the C system can develop and enhance various pathological conditions [15, 16]. Maintaining a balance between activation and inhibition of the C system is considered important. In the field of nephrology, the C system is presently known to be associated with the pathogenic mechanisms underlying conditions such as aHUS and C3G and progression of renal injuries to both glomeruli and the interstitium in kidney diseases [15, 17, 18, 3]. In addition, development of anti-C agents has recently been proceeding. Some agents such as C1-inhibitors and anti-C5 antibodies have become clinically available and others with exact targets in the C system are in clinical or preclinical trials [19, 2, 20]. At the current stage of development of anti-C agents, development of biomarkers associated with the C system might also be much more important than a few decades ago. Moreover, C activation products were recently reported to assist in diagnosing and/or determining the severity of disease activity. In the field of nephrology, the usefulness of C5a and sC5b-9 is under discussion  and we have also tried to identify biomarkers in peritoneal dialysate to predict the prognosis of peritoneal dialysis-related peritonitis [21, 22], but these issues remain unclear.
Around the world, including in Japan, numbers of elderly patients and patients with CKD are increasing . Renal function is reported to gradually decreased and fall to CKD in aged populations . ESRD due to nephrosclerosis has therefore also increased in Japan in recent decades . However, in most published reports investigating levels of C products, assessment of or adjustment for background renal function was not considered when evaluating the results, even in studies with aged patients. The present study evaluated GFR using Cin as well as eGFR, because Cin offers a more accurate method compared with creatinine clearance, and has usually been positioned as a gold standard for evaluating renal function . Our results suggest that evaluation of Ba levels and plasma C5a levels should be considered with baseline renal function, whereas measurement of serum levels of sC5b-9 and serum C5a might not be clinically relevant in CKD in the absence of active glomerulonephritis. Why only serum and plasma levels of Ba showed correlations with renal function remains unclear. Hypothetically, because the molecular weights of Ba (~33 kDa)  are much smaller than those of C3, C4 and sC5b-9 (~190 kDa, ~187 kDa, and >1000 kDa) [27, 28, 21], Ba might have more influence on decreased GFR than the others. As another hypothesis, an early stage of an alternative pathway in the C activation system might be enhanced in patients with advanced CKD because of decreased blood pH and/or increased uremic toxins [29, 30]. However, later points of C regulation might be expected to effectively work to stop the terminal pathway of the C system. As a limitation to this study, the sample number was small and patients who had developed ESRD requiring dialysis therapies were not included. Whether the baseline levels of Ba in serum/plasma of CKD patients were adequate in this study remains unclear. In future, a larger-scale study is warranted to clarify this issue.
In the present study, we observed that both serum and plasma levels of Ba increased depending on renal function without active glomerulonephritis, particularly in CKD G4 and G5 patients, but sC5b-9 was not affected by renal function in those patients. In conclusion, among advanced CKD patients, we suggested that Ba, but not sC5b-9, may need to considered when measuring and analyzing levels of C products in blood samples.