Lupus nephritis (LN) affects 20–60% of patients with Systemic Lupus Erythematosus (SLE)1,2 and progresses to end-stage kidney disease (ESKD) in 10% of them.3 Recent clinical trials4,5 have spurred a new interest in early multi-targeted treatment strategies aimed at achieving higher rates of complete remission and facilitating quicker steroid withdrawal. This approach is supported by recent guidelines.1

However, this new paradigm carries the risk of overtreating specific subgroups of LN patients who could achieve high remission rates with standard dual therapy (i.e. steroids and mycophenolate). Conversely, identifying high risk patients who require combined treatment regimens is crucial. Since the clinical and histological features required to guide this stratification are not clearly characterized,6 we examined a cohort of patients with newly diagnosed LN from our center to assess these possible predictors.

Our cohort achieved an overall response rate (CR and PR) of 91.4% after 104 weeks of follow-up. While pivotal trials such as ALMS8 and Euro-lupus9 achieved high remission rates using MMF or cyclophosphamide, a significant subset of patients still fails to respond, increasing the risk of End-Stage Kidney Disease (ESKD).

Recent trials for belimumab,5 voclosporin,4 and obinutuzumab10 have reported notable CR rates of 43%, 41%, and 46.4%, respectively, within relatively short follow-up periods (52–104 weeks). Consequently, KDIGO LN guidelines1 propose a multi-target induction therapy combining steroids, mycophenolic acid analogs, and either a calcineurin inhibitor or belimumab as a first-line alternative to traditional dual therapy. These recommendations are also reflected in the Spanish GLOSEN guidelines,11 which emphasize early immunosuppression intensification if proteinuria does not decrease by at least 25% within the first three months.

Our institution standard of care is based on steroids and MMF. However, additional treatment was needed in 51.4% of patients in our cohort, mainly in patients with persistently higher proteinuria at 12 weeks, which is consistent with GLOSEN recommendations, and lower chronicity index in the biopsy at debut, according to the exploratory multivariable analysis. When comparing groups at 104 weeks, the rate of CR was higher in the ST group than in the TI group. This difference should be interpreted with caution, as it likely reflects indication bias, as patients in the TI group were escalated because of inadequate early response according to GLOSEN criteria, making direct efficacy comparisons between groups inappropriate.

Our exploratory findings suggest that, within this small cohort, in patients presenting with persistently higher proteinuria at 12 weeks and a low chronicity index in the biopsy at debut, clinicians should consider a more proactive approach based on triple therapy schemes. Conversely, patients with low grade proteinuria and a higher chronicity index may not require triple therapy, especially if the activity index is low.

The finding regarding chronicity indices is puzzling and counterintuitive, given that greater chronicity and lower activity are generally associated with worse long-term renal prognosis. A higher chronicity index at the time of diagnosis may reflect a predominantly fibrotic, ‘burnt-out’ lesion with reduced ongoing immune-mediated injury, rather than an actively inflamed glomerulus. Accordingly, clinicians may have been less inclined to intensify therapy in this subgroup. The prognostic value of chronicity indices has been assessed in previous studies focused on the role of repeat biopsies to guide the immunosuppression.12 It is important to emphasize that this finding should not be interpreted as suggesting that chronicity is a favorable prognostic marker. Rather, it may identify a specific subgroup of patients in whom the dominant histological process at presentation is chronic and irreversible, and in whom the incremental benefit of treatment intensification may be limited. This hypothesis is exploratory and requires prospective validation in larger cohorts.

Similarly, higher proteinuria at diagnosis and at 12 weeks may serve as a surrogate marker of increased immunological activity and, accordingly, current guidelines recommend its use as an indicator for treatment intensification.1,11,13

Similar findings were observed when evaluating predictors of complete remission. In the exploratory multivariable analysis, higher baseline proteinuria showed a trend toward a lower likelihood of achieving complete remission at 104 weeks, whereas the histological activity index was not independently associated with this outcome. Although these results should be interpreted with caution due to the limited sample size and the exploratory nature of the analysis, they suggest that baseline proteinuria may help identify patients who require closer monitoring and earlier consideration of treatment intensification.

In this study, we described the primary predictors of treatment intensification in a real-world cohort of patients with lupus nephritis. We identified histological and clinical biomarkers that may help define a “low-risk” subgroup, suitable for standard therapy with corticosteroids and MMF. These “low-risk” patients were good responders and could benefit from less intense immunosuppression regimens.

We also observed encouraging results regarding steroid use, as prednisone was discontinued in 11 patients and was maintained at low doses in the rest, which could mitigate risks of genomic-mediated adverse events such as infections, hypertension, diabetes, and osteoporosis.14

Several limitations to our study must be acknowledged: First, the retrospective design of the study precludes causal inference, although it is worth noting that our data is consistent with findings from published clinical trials and retrospective cohorts. Second, the small sample size represents a major limitation restricting the generalisability of our conclusions and the significance of the multivariable analysis - this is particularly relevant to the counterintuitive chronicity index finding, which is difficult to interpret reliably in an underpowered dataset. Third, the TI group was heterogeneous, comprising patients who received agents with distinct mechanisms of action (belimumab or calcineurin inhibitors), selected at the treating clinician's discretion. Although no significant difference in time to TI was identified between patients receiving tacrolimus and those receiving belimumab, the study was underpowered to detect meaningful differences within this subgroup. Fourth, the non-randomized allocation to ST or TI groups introduces an indication bias, as patients perceived as having more severe or refractory disease were preferentially escalated. Although baseline eGFR and proteinuria differences were not statistically significant, baseline proteinuria was higher in TI group, so residual confounding cannot be excluded. Given the sample size, a propensity score analysis was not feasible; however, the primary aim of this study was to identify predictors of treatment intensification rather than to compare the efficacy of both strategies, which limits the impact of this bias on the main results. Fifth, the use of 12-week proteinuria as a predictor of treatment intensification is subject to partial incorporation bias, as proteinuria trajectory informs the clinical decision to escalate per GLOSEN guidelines. However, the escalation criterion is based on relative reduction rather than absolute value, which partially mitigates this concern. Results should nonetheless be interpreted with appropriate caution. Finally, the higher remission rates observed in our cohort compared to clinical trials may be attributed to the inclusion of all LN patients initiating follow-up within the specified period, rather than only those with worse prognosis. In fact, the median eGFR at LN onset was above 100ml/min/1.73m2, and only 24.3% of patients presented an eGFR below 60ml/min/1.73m2. Keeping this in mind is essential for the interpretation of our findings, although this limitation is also present in various LN clinical trials.4,9,10

In conclusion, patients with mild presentations of lupus nephritis may be candidates for dual therapy with mycophenolate and low-dose steroids. Close monitoring of proteinuria during the first months, together with careful interpretation of histological activity and chronicity indices, may help identify patients who require earlier treatment intensification. These findings should be considered hypothesis-generating and warrant validation in larger prospective cohorts.

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  Paul Hernandez-Velasco: Methodology, Investigation, Validation, Writing – original draft, Data curation.

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  Celia Gonzalez-Garcia: Methodology, Data curation, Investigation, Validation, Writing – original draft.

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  Maria Galindo: Conceptualization, Writing – review & editing, Supervision.

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  Enrique Morales: Conceptualization, Supervision, Writing – original draft, Writing – review & editing.

The study was conducted according to the Declaration of Helsinki. The Institutional Review Board statement was waived given this study involved retrospective review of patient charts. Informed consent was waived due to the retrospective nature of the study.

Data will be shared upon request.

This research has not received any specific funding from public sector agencies, commercial organizations or non-profit organizations.

The authors of this manuscript have no conflicts of interest to disclose that could influence the results or the interpretation of their manuscript.