Background/Purpose: Biomarkers of renal response in patients with systemic lupus erythematosus (SLE) may provide clues to pathogenesis and drive translation to treatment.  This study was initiated to evaluate the association between renal activity and the changes in erythrocyte bound complement C4d product (EC4d), anti-C1q, anti-dsDNA antibodies and low complement.

Methods: The study enrolled 289 SLE patients (mean age 40 years, 92% females) meeting the 1982 ACR classification criteria.  All patients were evaluated at one time point as part of a cross-sectional study and a subset of 34 patients (mean age 34 years, 94% female) were followed monthly for an average of 9 months. Among patients enrolled in the cross sectional study, the presence of proteinuria was defined by the renal domain on the SELENA-SLEDAI (increase >0.5 g thus implies active and not chronic proteinuria). For the longitudinal study, proteinuria was defined using the random protein to creatinine ratio (expressed as g/g). Complement protein levels (C3 and C4) were determined using immunoturbidimetry, antibodies to anti-C1q and anti-dsDNA were determined by ELISA and EC4d was determined using flow cytometry (expressed as mean fluorescence intensity [MFI]). Statistical analyses consisted of non-parametric tests, and Chi-square tests. Longitudinal changes in urine protein as a function of the change in the biomarkers were evaluated using generalized linear mixed models effects using random intercept and fixed slopes.

Results: Among 289 SLE, 12% presented with proteinuria at the time of the clinical assessment. Higher EC4d levels were observed in the SLE patients who presented with proteinuria compared to those who did not (median 21 MFI [Interquartile range, IQR: 15-29] vs 12 MFI [IQR: 7-22], p<0.01). Abnormal EC4d levels (>20 MFI) were found in 62% of patients with proteinuria compared to 27% of patients without (p<0.001). In contrast, the presence of the low complement component of the SELENA-SLEDAI domain was not significantly different between the groups (53% versus 36% p=0.08). Neither Anti-C1q nor anti-dsDNA antibodies differentiated between the two groups at baseline.  Among the 34 SLE patients followed monthly, a decrease in EC4d levels to lower than 20 MFI was associated with a concomitant decrease of 0.7 g/g urine protein to creatinine ratio (p=0.0018) (Table). Similarly, the decrease in anti-C1q levels to lower than 80 units was accompanied by decreased proteinuria (p=0.0015). Normalization of low complement or loss of anti-dsDNA was non-significantly associated with proteinuria (p>0.19). In multivariate analysis both EC4d and anti-C1q were independently associated with proteinuria (p<0.01).

Conclusion: These data suggest that longitudinal changes in EC4d and anti-C1q levels track with   changes in proteinuria. EC4d correlates more strongly with proteinuria than traditional measures of complement.

Table: Mixed model effect estimates