What is already known?

Current KDIGO and EULAR guidelines generally classify Class I and II lupus nephritis (LN) as usually nonproliferative lesions with favorable short-term renal findings („benign”), but uncertain long-term histological stability.

What this viewpoint adds?

Histological instability: Retrospective data indicates that Class II LN is often not a stable endpoint but a precursor, with 70% of cases eventually transforming into more aggressive proliferative (Class III/IV) nephritis.

According to the latest KDIGO guidelines, specific kidney-directed immunological therapy for Class I (minimal mesangial) and Class II (mesangial proliferative) lupus nephritis (LN) is specified for cases presenting with significant, nephrotic-range proteinuria. In such cases, to treat ‘lupus podocytopathy,’ the initiation of therapy is recommended based on the analogy of minimal change disease and focal segmental glomerular sclerosis treatment protocols [1], (Figure 1). The EULAR guideline for LN, revised in 2025, does not address Class I/II LN. The position statement issued in 2019 declares that immunological treatment is generally not required, adding that ‘the presence of significant proteinuria should prompt histological reassessment to detect ­proliferative changes that may have been overlooked’ [2].

Overall, the current guidelines classify Class I/II LN as a ‘benign’ lesion, recommending kidney-directed therapy only for nephrotic-range proteinuria, thereby representing a ‘wait-and-watch’ approach from a nephrological perspective [3].

Regarding kidney biopsy indication, besides the unexplained decrease in glomerular filtration rate (GFR), both the KDIGO and EULAR recommendations have maintained the 0.5 g/day proteinuria threshold [1,2]. Although the explicitly stated reason for this threshold is to make the indications for a kidney biopsy more deliberate, it creates a potential issue: if low-grade proteinuria is detected alongside a normal GFR, as lower levels of proteinuria are typically associated with low-class LN not requiring therapy intensification, biopsies may not be performed even in equivocal cases [4]. Such equivocal cases encompass not only a concomitant active urinary sediment (e.g., microscopic hematuria, cellular casts) but also clinical profiles carrying an inherently higher risk of severe LN incidence and progressive disease, such as younger age at onset (pediatric and adult patients aged <30 years), male sex, non-White populations, and persistent serologic activity characterized by hypocomplementemia, and/or elevated anti-dsDNA titers, and/or anti-C1q antibodies [1–3,5].

While large, prospective, randomized controlled trials have not been conducted in patients with Class I/II LN, retrospective studies - based on repeat biopsy findings - indicate a clinically significant probability of histological transformation to a higher class in these patients: an average of 70% if a second biopsy was performed for every Class II LN patient, or an average of 75% if the biopsy was performed according to the clinical course. [3,6–15; Table 1].

The progression from Class I to Class II lupus nephritis marks a definitive shift from minimal mesangial involvement to overt mesangial hypercellularity. In Class I disease immune complexes are strictly confined to the mesangium, usually accompanied by the ‘full house’ pattern with deposition of multiple immunoglobulin classes (IgG, IgM, IgA) and complement components (C3, C1q), but still failing to induce a significant inflammatory response or structural alterations detectable by light microscopy. As the pathology advances to Class II, the increased accumulation of these deposits triggers both a proliferative response in the mesangial cells and an expansion of the surrounding matrix [16–18]. If the underlying systemic inflammation remains uncontrolled, a further transition from Class II to Class III (focal) and IV (diffuse) LN may occur [3,4,19,20].

According to the limited repeat-biopsy literature neither proteinuria nor serological markers (anti-dsDNA and C3/C4) could reliably predict histological transformation from Class I/II LN to proliferative forms [8,9].

The incidence of transformation together with the lack of validated markers to identify this change should raise our awareness of this condition and lead us to question whether the aforementioned liberal approach and patience toward treating Class I/II LN with subnephrotic proteinuria – which reflects an underlying ‘smoldering’ mesangial proliferation in the absence of overt podocytopathy – is appropriate.

In addition, a fundamental inconsistency in the guidelines arises when a kidney biopsy confirms Class I or II LN, when proteinuria is detected above 0.5 g/day, while still below the nephrotic range. In such cases, where kidney-directed immunosuppressive treatment is not required, it remains unclear how to interpret these findings and achieve the proteinuria-based complete remission targets defined for Class III/IV/V LN (proteinuria <0.5 g/day). Are we to assume that immunosuppression administered for extrarenal symptoms, combined with adjunctive treatment, will resolve this?

Further uncertainty arises regarding the management of cases that relapse in Class II form after the treatment of Class III or IV lupus nephritis. Could such an outcome be interpreted either as the unsuccessful treatment of a proliferative form, indicating a need for revision of therapy or as a “benign” residual lesion?

Taken together, these factors represent a ‘gray area’ and an avenue that should be addressed to shift our current paradigms in Class I/II LN and to initiate prospective clinical trials in this patient cohort, focusing on long-term kidney outcomes, protocol or risk-triggered repeat biopsy and biomarkers.

Among the primary renal diseases, IgA nephropathy (IgAN) is considered the classic form of mesangioproliferative glomerulonephritis. On light and electron microscopy IgAN and Class II LN share nearly identical features, such as mesangial cell proliferation, although immunofluorescence reveals predominant IgA deposition in the former and the ‘full house pattern’ in the latter [16–20; Table 2]. Evidence from IgAN shows that mesangioproliferative lesions can carry a poor prognosis on their own, even without the progression to severe proliferative forms that may occur in LN.

Analogous to LN, the proteinuria serves as the primary surrogate endpoint in IgAN, from which long-term outcomes are inferred [21–23].

Although proteinuria is an imperfect follow-up marker in LN, as it is nonspecific for ongoing inflammatory activity, it remains a well-established, reliable prognostic factor [21]. Several novel biomarker candidates show promise in reflecting intraglomerular processes, none are currently validated for routine clinical practice. Furthermore, while repeat kidney biopsy remains the gold standard, its invasiveness can limit its use in routine follow-up. Therefore, in LN, while a holistic monitoring approach – integrating kidney function (eGFR), urinary sediment, complement levels (C3/C4), and serological activity (such as anti-dsDNA and anti-C1q antibodies) – remains irreplaceable, current clinical guidelines continue to define proteinuria-based response targets [1–3,5].

Based on outcome data from large-scale studies in IgAN, improving long-term renal outcomes has required a revision of proteinuria goals, which should now be kept as low as possible to prevent progression to advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) [22]. While LN guidelines remain liberal, recent KDIGO guidelines for IgAN have tightened proteinuria targets, stating that protein excretion ‘should be maintained at a minimum of less than 0.5 g/day (or equivalent) and ideally at less than 0.3 g/day (or equivalent)’ [22].

Considering the pathological similarities between the mesangial forms of SLE kidney involvement and IgAN – and given that proteinuria is a shared surrogate marker – reducing protein excretion through the control of the underlying immune process, besides conservative nephroprotective care, can be a key to delaying renal failure and preventing transformation.

In recent years, the immunological therapies targeting the mesangioproliferative process of IgAN, have evolved significantly. These emerging therapies target pathways already utilized in SLE treatment, such as B-cell-activating factor (BAFF) inhibition, dual BAFF and a proliferation-induced ligand (APRIL) inhibition, complement inhibition and plasma cell inhibition [14,20,23–25, Table 2].

Increasing evidence highlights the benefits of early, effective disease control in SLE [26,27]. Lupus nephritis represents an organ manifestation of SLE rather than an independent disease entity, as emphasized by the updated 2025 EULAR guidelines on SLE with kidney involvement [28]. Taken together, these considerations provide a clear rationale for selecting from the above-mentioned, effective therapies in SLE when Class I/II LN is detected, on the assumption that they can simultaneously control extrarenal manifestations and the underlying mesangial process.

While targeted biologic therapies represent a higher upfront investment, their use in early-stage LN may be cost-effective by preventing insidious damage or histological transformation to proliferative classes. The financial impact is profound: according to US data from Edgecomb et al. (2026), annual healthcare costs for SLE patients with CKD are nearly double those without renal involvement ($59,956 vs. $31,652), and expenditures escalate exponentially with advancing CKD stage, rising from $36,417 in Stage 1 to $152,169 annually in Stage 5 [29]. A paradigm shift toward „proactive” treatment could significantly reduce the long-term healthcare expenditure associated with CKD progression.

This highlights a growing need to reevaluate the diagnostic approach and treatment of Class I/II LN.

‘Time is kidney’: based on data from retrospective studies indicate that mesangioproliferative forms of LN progress to more severe stages in a significant proportion of cases (Table 1, Figure 1). Furthermore, according to data from kidney and cardiovascular outcome trials, addressing even low levels of proteinuria is crucial, as reducing protein excretion is key to delaying CKD progression and reducing cardiovascular risk [22,30].

Coupled with this, the therapeutic successes achieved in IgAN – which shares a similar mesangial pathology – support the premise that arresting the mesangioproliferative process significantly improves long term renal outcomes. Targeted therapies addressing pathways identical to those in IgAN are already part of clinical practice in SLE and carry a ‘rational risk’ relative to the expected clinical benefits and long-term cost-effectiveness [31–33].

Recent advances in immunotherapies (e.g., belimumab, telitacicept) enable the selection of personalized and effective immunosuppressive therapy tailored to the patient’s clinical profile (extrarenal activity, serological profile, degree of proteinuria), balanced with an acceptable safety profile and, in particular, manageable infectious risk [31–33].

In summary, we should be „proactive” in our therapeutic approach to Class I/II LN with subnephrotic-range proteinuria – given that guidelines already recommend specific immunological therapy for nephrotic-range cases – and consider initiating targeted treatment guided by histopathology, proteinuria levels and the patient’s clinical SLE phenotype (Figure 1).

Moreover, although both the 2025 EULAR and 2024 KDIGO LN guidelines emphasize that the 0.5 g/day proteinuria threshold is intended only as a clinical guide for intervention [1,28], this threshold easily becomes a rigid cutoff if lower-class LN is perceived as lacking therapeutic consequences [4]. In contrast by adopting the view that targeted treatments are available and more stringent treatment targets are achievable even in lower-class LN, the proteinuria threshold can more easily evolve into a truly individualized approach.

Therefore, there is a pressing need to collect more data on Class I/II LN and to enroll patients with these classes into prospective studies focusing on both the natural history of the disease and the efficacy of conventional synthetic and targeted immunosuppressive therapies (e.g. B-cell-directed agents, complement inhibitors, and drugs targeting intracellular signaling cascades).