Lupus nephritis (LN) affects 35–60% of patients with systemic lupus erythematosus (SLE), and constitutes one of the most severe disease manifestations [Anders HJ et al. Nat Rev Dis Primers 2020; Singh S et al. Am J Med Sci 2009; Pons-Estel GJ et al. Autoimmun Rev 2011; Cervera R et al. Medicine (Baltimore) 2003]. Several factors contribute to renal function impairment in LN, including genetic cargo, nephron endowment, disease activity, drug-induced toxicity and renal flares. Five to 20% of the afflicted patients develop end-stage kidney disease (ESKD) within ten years from the first LN episode. Available therapies induce complete renal remission in only 20–30% of patients after six months of treatment, and even patients who respond to therapy may relapse in 35% of the cases [Houssiau FA. J Am Soc Nephrol 2004; Houssiau FA et al. Arthritis Rheum 2004; Houssiau FA et al. Lupus 2018].
To date, clinical and laboratory tests cannot reliably reflect histopathological findings, and kidney biopsy is indispensable for diagnosis, classification, and exclusion of mimickers. The role of control biopsies after induction therapy is debatable, despite accumulating evidence of discrepancies between clinical and histological responses. In the concrete, several elegant post-treatment biopsy studies have demonstrated persistent activity at the level of tissue despite adequate clinical response, suggesting that intensified immunosuppression may be required in these patients [Zickert A et al. Lupus Sci Med 2014; De Rosa M et al. Kidney Int 2018; Malvar A et al. Nephrol Dial Transplant 2017; Pineiro GJ et al. Am J Nephrol 2016; Arends S et al. Ann Rheum Dis 2012]. However, studies investigating the role of repeat kidney biopsies in treatment evaluation and long-term renal outcome have to date included limited numbers of patients, and varying definitions regarding treatment response and renal outcome. Thus, the concept of a prospective multicentric per-protocol repeat biopsy study to generate evidence for future recommendations for the diagnostic and therapeutic management of LN gains increasing support [Anders HJ. Ann Transl Med 2018].
Several studies have sought to identify predictors of long-term renal prognosis, including routine clinical and serological markers [Gordon C et al. Lupus 2009; Hahn BH et al. Arthritis Care Res (Hoboken) 2012; Bihl GR et al. Nephrol Dial Transplant 2006; Parodis I et al. PLoS 2019]. Proteinuria levels <0.7–0.8 g/day at month 12 after initiation of treatment have been validated in different cohorts as a readily available predictor of favourable long-term renal outcome [Dall'Era M et al. Arthritis Rheumatol 2015; Tamirou F et al. Lupus Sci Med 2015; Ugolini-Lopes MR et al. Lupus Sci Med 2017]. However, while the positive predictive value (PPV) of this target was high, the negative predictive value (NPV) was poor in two of three studies, since most patients not achieving the proteinuria target still had a good long-term outcome [Dall'Era M et al. Arthritis Rheumatol 2015; Tamirou F et al. Lupus Sci Med 2015]. Associations between chronic tissue damage in repeat biopsies and long-term renal function impairment have been demonstrated in European and Hispanic LN populations [Zickert A et al. Lupus Sci Med 2014; Malvar A et al. Nephrol Dial Transplant 2017]. It was recently demonstrated in a retrospective study that a high grade of residual activity in per-protocol repeat biopsies predicted subsequent renal relapse in patients with incident LN, and a high grade of chronic damage in repeat biopsies predicted long-term renal function impairment [Parodis I et al. Rheumatology (Oxford) 2020]. More specifically, NIH activity index scores > 3 predicted subsequent renal flares, whereas NIH chronicity index scores > 3 were associated with renal function deterioration in the long term. It is worth noting that active lesions in glomeruli mostly accounted for the former association with relapses, whereas chronic damage in the tubulointerstitial compartment were found to be a more important contributor to the latter association with long-term renal function.