We sincerely thank Sidra Javed for her interest in our article and greatly appreciate her thoughtful and constructive evaluation.

While the availability of biopsy-confirmed lupus nephritis cases and long-term follow-up data represents a major strength of our cohort, the relatively limited sample size, as noted by Javed et al., constitutes an important limitation that may have reduced the robustness and statistical power of our analyses.1

We agree that using CD68+ and CD163+ immunostaining provides a rather simplified view of macrophage subtypes. Still, this approach is practical and commonly used in routine pathology, especially in retrospective studies where advanced molecular methods like transcriptomic profiling or flow cytometry are not available. Although M1 inflammatory and M2 anti-inflammatory properties are prominent, M1/M2 conversion and dominance should be determined rather than oversimplified considerations. A predominance of anti-inflammatory properties can also exacerbate chronic kidney disease by causing fibrosis.2 That said, we fully acknowledge the importance of more detailed analyses, and future studies using these techniques could certainly offer a deeper understanding of macrophage diversity and function in lupus nephritis.

Since a significant portion of our cohort (52% had class III or IV LN) was in advanced stages and no standard immunosuppressive treatments before biopsy due to retrospective design, we believe that we could not find statistical significance between the NIH index and macrophage numbers and types. On the other hand, the number of glomerular CD163+ cells was significantly increased in patients with class III–IV lupus nephritis, whereas the number of interstitial CD68+ cells was significantly elevated in progressive cases of class III–IV lupus nephritis.

Our findings demonstrate an association between endocapillary hypercellularity and increased CD68+ macrophage infiltration that was consistent with previous studies,3 we agree that it remains unclear whether this marker provides prognostic value beyond established clinical parameters such as proteinuria, complement levels, and anti-dsDNA titers. Since our study was not specifically designed to evaluate treatment response, it was not possible to specifically address this aspect in the current data set. We do not have data on serial biopsy results, which would provide an opportunity to analyze associations between macrophage counts and activity and chronicity scores or between macrophage counts and responses to therapies in a longitudinal manner. Furthermore, due to the retrospective design of the study, differences in treatment received before biopsy may affect the results. A recent study using single-cell RNA sequencing and immunostaining analyses showed that patients in the highest tertile of glomerular CD68+ macrophage infiltration were 7.92 times more likely to achieve a clinical response compared with patients in the lowest tertile.4 Furthermore, we propose that the observed association between endocapillary proliferation and the presence of more than seven CD68+ cells per glomerulus may represent a hypothesis-generating finding and provide supportive evidence for the classification of lupus nephritis. Nevertheless, we recognize the importance of this question, and future longitudinal studies integrating histopathologic, immunologic, and therapeutic outcome data will be essential to clarify whether CD68+ macrophage burden can serve as a predictive biomarker for response to immunosuppressive therapy in lupus nephritis.

Quantification of macrophage densities in native kidney biopsies was shown to contribute to risk stratification for progression to end-stage kidney disease irrespective of the primary kidney disorder5; thus, macrophage plasticity may not be specific to SLE. Therefore, a key question remains as to whether macrophages act merely as bystanders within the renal microenvironment or actively contribute to the pathogenesis of tissue injury so we aimed to investigate potential differences in macrophage number and compartmental distribution between immune-mediated (lupus nephritis) and non–immune-mediated (diabetic nephropathy) forms of chronic kidney injury, with the aim of elucidating their respective roles in disease progression.

Our method of cell count was semi-quantitative, while some previous studies used digital computational image softwares.3,6 Thus, the cell numbers in the present study may be underestimated. Indeed, median cell number in previous studies appear to be higher than the present study.6 The treatments used for patients were not standardized, and previous drug exposure may have affected macrophage polarization.7

In summary, we agree with all of your comments. The primary aim of our study was to explore whether macrophages might have a potential role in lupus nephritis, given their involvement in innate immunity and their close relationship with the complement system. In this context; our study should be considered hypothesis-generating, intended to provide preliminary insights and to serve as a basis for future studies with larger cohorts and more detailed macrophage characterization.