This prospective study demonstrated the usefulness of uVCAM-1 as a biomarker of disease activity and treatment response in LN. We assessed the uVCAM-1 levels at baseline and after 4, 8 and 12 months in 31 active and 31 inactive LN patients, without other significant SLE activity (SLEDAI-2K median 2; 25th -75th percentiles 0–4). The uVCAM-1 levels were elevated in patients with active compared to inactive LN at the baseline. A significant correlation was found between uVCAM-1 levels and renal activity scores, C3 and C4 levels, anti-dsDNA, UPCR and hematuria. The levels of uVCAM-1 dropped significantly in patients with active LN who went into remission and significantly increased in patients who went into activity.
In LN, urinary biomarkers may be more specific for renal damage than serum biomarkers, particularly in SLE patients with active systemic disease (7). Besides that, obtaining urine for laboratory testing is much easier and less invasive, making it an ideal biological sample for a disease that requires repetitive screening. Nevertheless, it is unlikely that uVCAM-1 will entirely replace kidney biopsy in the diagnostic process since it cannot help in differentiating LN classes neither provides information about the presence of nephropathy secondary to antiphospholipid syndrome or other etiologies.
The uVCAM-1 levels were significantly higher in patients with active LN. We have also demonstrated during the follow-up, a tendency to higher levels of uVCAM-1 in patients with partial renal response compared to complete renal response, which further reinforces this relationship. These results are in agreement with previous studies demonstrating elevated uVCAM-1 levels in patients with active LN (12, 19–21).
Moreover, the uVCAM-1 levels consistently correlated with several renal activity scores, like renal SLEDAI, renal SLAM-R and renal SLICC. Serum levels of complements and anti-dsDNA as well as UPCR levels also showed a significant correlation with uVCAM-1.
The VCAM-1 is an adhesion molecule involved in trafficking of inflammatory cells and lymphocytes. The increase of VCAM-1 was verified not only in the endothelium, but also in cortical tubules and glomeruli of murine lupus nephritis models (35). VCAM-1 was also elevated in the urine of mice with experimentally induced immune nephritis, showing a good correlation with disease activity (18) and the strains that developed more severe kidney disease also had higher urinary VCAM-1 levels (36). VCAM-1 expression increased significantly in the kidney of patients with LN, as detected by immunohistochemical and computer-imaging analyses techniques (17, 37). These findings suggest that elevated levels of uVCAM-1 in LN reflect increased of it production within the kidney as a consequence of active inflammation.
The ROC curve of uVCAM-1 demonstrated an AUC of 0.84 for all the participants and a cutoff of 47.2 ng/mgCr yielded a good sensitivity (74.2%) and specificity (74.2%) for the diagnosis of active LN. In our study, high uVCAM-1 levels reflected the presence of LN in SLE patients at least in the same way (C4 levels) or even better (C3 levels and anti-dsDNA antibodies) than clinical markers in widespread use. When combined with traditional LN biomarkers (C3, C4 and anti-dsDNA), uVCAM-1 increased sensitivity from 90.3–96.8%.
In agreement with the work from MoK CC et al (20), we observed no difference between uVCAM-1 levels and nephritis class (proliferative with or without membranous vs pure membranous). We decide not to include patients with class I and II nephritis, which were not associated with VCAM-1 elevation in previous studies (14, 20). Some studies showed that elevated uVCAM-1 is not specific for SLE. It appears to be a marker of renal injury since other types of inflammatory nephritis (anti-neutrophil cytoplasmic antibodies-associated glomerulonephritis, for instance) also showed elevated levels of uVCAM-1 (12, 13). Therefore, patients with class V LN who had a sufficient degree of inflammation to fulfill the activity criteria would also be expected to have a significant increase in uVCAM-1 levels. A previous study that found higher levels of uVCAM-1 in proliferative classes did not compare them against pure class V, but with a group formed together with class II (38). This finding remains to be confirmed in larger numbers of patients displaying each of these histological subtypes.
Variations of uVCAM-1 levels were found to reflect renal disease activity in LN patients. Besides that, effective LN therapy reduced uVCAM-1 levels over the time, emphasizing the role of uVCAM-1 as a valuable biomarker in LN follow-up. Among patients who reactivated nephritis during follow-up, uVCAM-1 levels were not found to be predictive of flare. However, the peak was at the time of the flare, thus uVCAM-1 levels may provide supporting evidence in cases where the diagnosis of a renal flare is suspected. This may be especially important in cases whose traditional biomarkers are not helpful to identify LN activity, for instance, in patients with residual hematuria or proteinuria, anti-dsDNA permanently positive or who have deficiencies of complement components.
This study has some potential limitations. The first is not having uVCAM-1 assessments at shorter time intervals. Therefore, we cannot rule out elevation of uVCAM-1 levels closer to the nephritis flare. However, it is unlikely that a patient with inactive disease will be reevaluated in a period shorter than four months in clinical practice. Other limitation is that some measurements were based on a relatively small group of patients (only seven reactivated LN) and our study may not have enough power to be conclusive at this point. In this study we were also unable to compare the performance of uVCAM-1 with proteinuria regarding the diagnosis of LN. As proteinuria was one of the parameters considered in our definition of active LN, we could not examine it as an independent marker in comparison with uVCAM-1 in the diagnosis of active LN. For the same reason, this study does not allow conclusions about the usefulness of monitoring uVCAM-1 in patients with chronic residual proteinuria