Per-protocol Repeat Kidney Biopsy in Incident Cases of Lupus Nephritis

Study rationale

Lupus nephritis (LN) affects 35-60% of patients with systemic lupus erythematosus (SLE), and constitutes one of the most severe disease manifestations. 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.

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. 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.

Several studies have sought to identify predictors of long-term renal prognosis, including routine clinical and serological markers. 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. 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 (Tamirou et al. 2015; Ugolini-Lopes et al. 2017). Associations between chronic tissue damage in repeat biopsies and long-term renal function impairment have been demonstrated in European and Hispanic LN populations (Piñeiro et al. 2016). 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. 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 (Parodis et al. 2020).

Study objectives

The objectives of the project will be

• to determine the percentage of LN patients in histopathological remission after 12 months of standard of care immunosuppression;
• to correlate histological and immunological (immune deposits) response to therapy with clinical response;
• to evaluate whether therapeutic decisions steered by the results of a per-protocol repeat kidney biopsy improve renal outcomes compared with a matched control group of patients who did not undergo repeat kidney biopsy.
• to generate data on how to evaluate response to therapy in pure membranous LN (ISN/RPS class V), as well as the value of the information retrieved from repeat kidney biopsies in portending long-term renal prognosis in this LN subset.

Study design

Patients with an incident biopsy-proven proliferative or membranous LN, or combinations thereof, selected to be initiated at standard of care immunosuppressive therapy with either MMF or EURO-Lupus IV CYC (combined with GCs and ACE inhibitors/ARBs) will be enrolled in this prospective study. Add-on therapies on the top of the aforementioned regimens will be allowed. At baseline, patients will be randomised 1:1 to either undergo or not undergo a per-protocol repeat kidney biopsy at month 12 from baseline. After randomisation, the patients will be followed for one year within the frame of REBIOLUP Part I, which is observational. Inclusion of patients participating in other investigator-initiated or pharmaceutical industry-driven therapeutic trials will be made possible, provided that those trials do not last more than 12 months. At month 12, REBIOLUP patients will enter into Part II, which is interventional and an interval of ± 1 month is allowed.

In patients with 2003 ISN/RPS class III/IV (± V) at baseline and an NIH activity index score > 3 (cut-off based on a recent proof-of-concept retrospective analysis) in the repeat kidney biopsy, the immunosuppressive therapy will be intensified based on the physician's and patient's shared decision (see recommendations below). In cases of pure membranous nephritis (ISN/RPS class V) at baseline which transformed to ISN/RPS class III/IV (± V) in the repeat biopsy, the same algorithm will be applied.

In patients with pure membranous (2003 ISN/RPS class V) LN in the repeat biopsy, individual assessment of the biopsy should steer the decision of treatment.

Patients who have not undergone a repeat biopsy will be treated according to standard clinical parameters. Percentages of complete renal response at month 24 and renal impairment at month 60 will be compared between the two study arms.

Patients randomised to the control arm (i.e. to not undergo per-protocol repeat biopsy) who underwent a repeat kidney biopsy upon clinical indication approximately at month 12 from baseline, e.g. due to primary non-response or worsening, will be analysed in the control arm (as per intention) for the primary analysis, and, additionally, together with the patients in the interventional arm in a secondary analysis.

Statistical power calculation and number of subjects needed

The anticipated frequency of CRR at month 24 in patients of the "no repeat biopsy" arm is 40%. The investigators consider that a difference of 20% in favour of the "repeat biopsy" arm would be clinically meaningful (i.e. a frequency of 60% CRR at month 24). To detect such a difference, with an α level of 0.05 and a power of 0.80, a number of 98 patients per arm is required. In order to take an anticipated 5% drop-out proportion into account, 206 patients with incident proliferative [2003 ISN/RPS class III/IV (A or A/C)] lupus nephritis will need to be enrolled. Patients with incident active membranous LN (2003 ISN/RPS class V) will also be enrolled in REBIOLUP; however, the target number of patients per arm will be based on proliferative cases only, since power calculation has been based on data from studies of proliferative LN.

Based on an anticipated yearly inclusion rate of 3-5 patients per year per centre, i.e. 6-10 patients during a 2-year period, approximately 20-30 centres of LN expertise will need to participate in the study.