This is the first study to identify an association between proliferative LN on index biopsies and IFTA progression on clinically indicated repeat biopsies. Previous studies have shown an association between proliferative LN and moderate-severe IFTA on a single kidney biopsy [4, 6, 16], but no studies to date have demonstrated an association between proliferative LN on index biopsies and IFTA on clinically indicated repeat biopsies. To our knowledge, only two studies by Pagni et al. and Kwon et al. investigated possible factors related to IFTA on repeat biopsy. Pagni et al. found a correlation between class IV LN and severity of interstitial fibrosis on the same repeat biopsies, but the study didn’t evaluate the association between proliferative LN on index biopsies and the progression of IFTA [8]. Kwon et al. found that a high renal component of systemic lupus erythematosus disease activity index (SLEDAI) was associated with IFTA progression, but the study didn’t investigate the association between classification of LN and IFTA progression [9]. The association between proliferative LN on index biopsies and IFTA progression further suggests that patients with LN who develop severe IFTA are more likely to have more severe glomerular disease at the initial presentation.
Prior studies have proposed several possible mechanisms for glomerular-interstitial disease interaction. First, the deposition of immune complexes can occasionally fill the capillary loops and lead to subsequent complement activation, damaging the glomerular microvasculature and causing interstitial ischemia. Second, the increased protein filtration and proteinuria from damaged basal membrane results in inflammation and cytotoxic injury to the tubules and interstitium. Third, some autoimmune antibodies, such as anti-cytoplasmic antibodies that target immunogenic antigen vimentin expressed in LN with tubulointerstitial lesions, might also play a role [17, 18]. Persistent inflammatory damage leads to cytokine release, macrophage activation, increased fibroblast function, and, eventually, IFTA.
While questions remain regarding the complex relationship between glomerular and tubulointerstitial lesions in LN patients, our results are consistent with prior studies showing high rates of worsening tubulointerstitial lesions on clinically indicated repeat biopsies (49% in this study versus previously reported 35–55% rate of progression) [7–10]. Similarly, we did not identify correlations between demographic or laboratory parameters and IFTA progression, and commonly tested biomarkers have been shown to be insufficient to assess LN activity. Apart from clinically indicated repeat biopsies when patients have active or recurrent LN, several prior studies investigating repeat kidney biopsies post-treatment or protocol repeat biopsies have demonstrated a discordance between clinical and histological activity during long-term follow-up, with persistent LN activity including interstitial inflammation and scarring among patients who have achieved a complete renal response to treatment [12–14, 19]. Taken together, these findings underscore the need to identify non-invasive biomarkers associated with IFTA progression.
This study also has several treatment implications. The association between proliferative LN and IFTA progression, together with underlying glomerular-interstitial interaction, provide a strong rationale to consider the use of combination regimens with recently approved agents, voclosporin and belimumab, as the induction treatments in patients with proliferative LN to minimize progression [20, 21]. Currently, a combination regimen with belimumab or voclosporin is recommended for LN patients with inadequate responses after several months of standard induction therapy [22, 23]. The potential use of anti-fibrotic medications targeting pro-fibrotic cytokines and subsequent fibrosis pathways in patients with LN should also be investigated [24].
This study has several limitations due to its retrospective nature and a relatively small sample size. The records of patients enrolled in this study were obtained over a period of more than fifteen years, and clinical data recording was not consistent over time. As a result, some important data, such as indications for each repeat biopsy, SLEDAI, and the NIH activity and chronicity scores, were not consistently available and were not evaluated. For the same reasons, a central review of kidney biopsies with a more detailed evaluation of the IFTA and TII was not performed. The study sample included patients with relatively preserved kidney function at the time of index biopsy. As a result, detecting the significance of several variables might be underpowered due to a relatively small number of progressors in this cohort. The effects of different induction therapies and medication adherence on IFTA progression could also not be assessed due to the retrospective design.
The major strength of this study is the real-world experience of LN patients from two large, urban tertiary care centers with homogeneity of treatment at the time of index biopsy. Another strength is the large proportion of racially and ethnically diverse patients, with the majority of patients self-identifying as Hispanic or Latino and Black or African American.
In conclusion, this study revealed that proliferative LN was associated with IFTA progression on repeat kidney biopsy and identified LN patients who are at higher risk of tubulointerstitial scarring. Our study also provides insight into the complex relationship between glomerular and tubulointerstitial disease progression in patients with LN and lays the foundation for future prospective studies investigating novel markers of interstitial damage and worse kidney outcomes.