Treat-to-Target in Lupus Nephritis. What is the Role of the Repeat Kidney Biopsy?

Abstract

Kidney involvement, termed lupus nephritis (LN), develops in 35–60% of patients with systemic lupus erythematosus, often early during the disease course. When not treated promptly and efficiently, LN may lead to rapid and severe loss of kidney function, being the reason why it is considered one of the most severe lupus manifestations. Despite improved pharmacotherapy, 5–20% of LN patients develop end-stage kidney disease within ten years from the LN diagnosis. While the principal ground of LN therapy is prevention of renal function worsening, resembling a race against nephron loss, consensual agreement upon outcome measures and clinically meaningful short- and long-term targets of LN therapy have yet to be determined. Literature points to the importance of inclusion of tissue-based approaches in the determination of those targets, and evidence accumulates regarding the importance of per-protocol repeat kidney biopsies in the evaluation of the initial phase of therapy and prediction of long-term renal prognosis. The latter leads to the hypothesis that the information gleaned from repeat biopsies may contribute to optimised therapeutic decision making, and, therefore, increased probability to attain complete renal response in the short term, and a more favourable renal prognosis within a longer prospect. The multinational project ReBioLup was recently designed to serve as a key contributor to form evidence about the role of per-protocol repeat biopsies in a randomised fashion and aspires to unify the global LN community towards improved kidney and patient survival.

Current Insights on Biomarkers in Lupus Nephritis: A Systematic Review of the Literature

“…In alignment with this aim, urine constitutes an attractive source for sampling, since it is easily obtainable, non-invasive, and theoretically more specific of kidney involvement than peripheral blood. However, it is important to underline the importance of the integration of tissue-based information in fluid-based biomarker research as a strategy to accurately determine the best peripheral molecular readouts for kidney-specific injury [ 171 , 172 ]. In this regard, studies for the identification of biomarkers that could be integrated into the current histopathological classification [ 159 ] for a more granular diagnostic and prognostic stratification of LN patients are needed and form an integral part of the future research agenda in this field.…”

A Histology-Guided Approach to the Management of Patients with Lupus Nephritis: Are We There Yet?

“…The role of repeat kidney biopsy has been increasingly recognized over the past decades as an invaluable tool to assess the histological stratification and adjust immunosuppressive therapy in patients with LN [ 2 ]. Nonetheless, despite the fact that several scenarios in relation to the moment of the repeat biopsy have been described, there is little consensus on the optimal approach [ 50 ].…”

“…A collaborative effort from the Lupus Nephritis Trials Network designed a prospective, randomized, multinational study with the aim to investigate whether a per-protocol repeat kidney biopsy after 12 months from initiation of IS therapy in incident cases of active LN results in treatment changes and, subsequently, in improved long-term outcomes (ReBioLup study, “Per-protocol repeat kidney biopsy in incident cases of lupus nephritis”, ClinicalTrials.gov Identifier: NCT04449991) [ 2 ]. Similarly, we are currently undertaking a randomized, clinical trial with the aim to compare the efficacy of two IS regimens (EUROLUPUS vs. RITUXILUP regimen [ 52 , 53 ]) with complete histological remission (AI of 0) defined as the primary end-point (GLUREDLUP study, “Minimizing Glucocorticoid Administration in Patients With Proliferative Lupus Nephritis”, ClinicalTrials.gov Identifier: NCT05207358).…”

“… The integration of percutaneous kidney biopsy in the management of patients with SLE and renal involvement (adapted after [ 2 , 10 , 30 , 31 , 50 , 79 , 80 ]) (abbreviations: GN, glomerulonephritis; TMA, thrombotic microangiopathy; TIN, tubulo-interstitial nephritis; ATN, acute tubular necrosis; APS, anti-phospholipid syndrome; LN, lupus nephritis; CNI, calcineurin inhibitor; IS, immunosuppression; and RCT, randomized clinical trial). …”

“…Systemic lupus erythematosus (SLE) is the prototype of autoimmune disorders caused by a loss of tolerance to endogenous nuclear antigens triggering an aberrant autoimmune response that determines a broad spectrum of organ manifestations with a wide range of severity [ 1 , 2 ]. Renal involvement occurs in up to two-thirds of patients with SLE, often early during the disease course, and is the most important contributor to the morbidity and mortality of these patients as a consequence of disease activity, target organ damage, and adverse events associated with aggressive immunosuppressive (IS) therapy [ 1 , 3 ].…”