Sage Journals: Discover world-class research

Abstract

Introduction

Lupus podocytopathy (LP) is an under-recognized pathological manifestation in patients with systemic lupus erythematosus (SLE). Despite being a distinct entity, current American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) guidelines do not include specific recommendations about LP, contributing to uncertainty regarding its diagnosis and treatment. This systematic review aims to synthesize the available literature on LP from case reports, case series and retrospective cohort studies to better characterize its clinical course, thereby informing clinical decision-making.

Material and methods

A systematic search of EMBASE and MEDLINE was conducted to identify relevant studies. Eligible studies included case reports, case series, and cohort studies reporting SLE patients who had biopsy-proven lupus podocytopathy without features of class III, IV, or V lupus nephritis. Demographic characteristics, clinical presentations, relevant laboratory and pathology results, treatment and outcomes were studied.

Results

This systematic review included 26 studies (18 case reports/small series and 8 cohorts), analyzing 19 individual cases and 240 cohort patients with LP. Most patients were young females, and LP was often part of the initial lupus manifestation with nephrotic-range proteinuria. Minimal change disease (MCD) was the predominant pathology. Patients with LP had an overall favorable outcome with treatment employing systemic steroid and steroid-sparing agents.

Conclusions

LP is an uncommon but distinct manifestation of SLE with overall favorable outcome with treatment using systemic steroid and steroid-sparing agents.

Keywords

Systemic lupus erythematosus podocytopathy minimal change disease focal segmental glomerulosclerosis nephrotic syndrome

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and immune-complex deposition leading to multiorgan inflammation.¹ Kidney involvement in SLE, known as lupus nephritis (LN), is one of the most severe complications, affecting a large number of patients and significantly impacting prognosis.² Approximately 50% of patients with SLE develop LN, and up to 10% progress to end-stage renal disease (ESRD).^3–5 LN typically presents with hematuria, proteinuria, and declining renal function, and is a major contributor to SLE morbidity and mortality. Immune-mediated renal injury in LN is usually diagnosed by classic biopsy findings of immune complex-mediated glomerulonephritis with a “full house” pattern on immunofluorescence (IgG, IgA, IgM, C3, and C1q). The Society of Nephrology/Renal Pathology Society (ISN/RPS) classification divides lupus nephritis into six classes based on the location and extent of immune complex deposition and glomerular injury.⁶ Nephrotic syndrome in SLE is typically associated with focal, diffuse (Class III/IV) or membranous (Class V) LN. However, in rare cases, patients with SLE develops nephrotic syndrome without typical immune-complex deposition. Over the years, scattered reports have described SLE patients with nephrotic syndrome whose kidney biopsies reveal pathology resembling minimal change disease (MCD) and/or focal segmental glomerulosclerosis (FSGS). These observations prompt speculation into whether such pathology represents coincidental finding or a lupus-related mechanism. By the early 1980s, researchers began to identify these cases as a unique type of lupus-related kidney disease, distinct from common lupus nephritis.⁷ This led to the concept of lupus podocytopathy (LP), a term now used to describe a unique renal pathology in SLE characterized clinically by nephrotic syndrome with pathological features resembling primary MCD or FSGS rather than classic immune-complex LN.^8–10 In LP, light microscopy of the renal biopsy usually shows normal glomeruli, minimal mesangial proliferation, or FSGS lesions, typically without the endocapillary proliferation, necrosis, or crescents seen in active LN.^9,11,12 Immunofluorescence is negative or shows only mesangial immune complex deposition, and no subendothelial or subepithelial immune complex deposition. Electronic microscopic examination reveals diffuse podocyte foot process effacement, similar to changes in MCD.¹³ LP is relatively rare, accounting for roughly 1 to 2%^13,14 of nephrotic patients with SLE. It seems to represent a non-immune-complex podocyte injury in the setting of SLE. The severe foot process effacement observed in LP suggests a mechanism similar to idiopathic podocytopathy (as seen in primary MCD/FSGS). It has been hypothesized that SLE-related immune dysregulation such as circulating permeability factors, cytokine dysregulation (notably interleukin-13 and other lymphokines), and T-cell dysfunction could trigger podocyte damage, mirroring the pathogenesis of idiopathic MCD.^12,15–20 This contrasts with proliferative LN (classes III/IV) and membranous LN (class V), where immune complexes drive leukocyte infiltration, capillary wall damage, and complement-mediated injury.

Due to its rarity, diagnosing LP can be challenging and is often delayed or missed. Clinicians might incorrectly attribute severe proteinuria to more common proliferative or mambranous LN or to unrelated primary kidney diseases, delaying accurate diagnosis and appropriate care. To accurately diagnose LP, clinicians need to have a high suspicion and obtain a kidney biopsy with electron microscopy. A further challenge is that current official guidelines and classification systems did not officially include LP. For instance, the widely used ISN/RPS lupus nephritis classification and the ACR/EULAR SLE criteria include various types of LN but not lupus podocytopathy as a distinct class.^6,21 Without clear guidelines, clinicians rely mainly on individual case reports and expert opinions, leading to uncertainty in how to best manage LP patients.

Current treatment approaches for LP primarily involve glucocorticoids, which often successfully reduce proteinuria^22,23 and can lead to remission. However, relapses are common, and there is no standard recommendation on the use of other immunosuppressants, particularly for steroid-resistant or relapsing cases.^22,24

Due to these gaps, a systematic review of existing literature on LP is essential. Consolidating clinical evidence from various reports will enhance awareness, improve diagnostic accuracy, and guide more effective treatment. Ultimately, a clearer understanding of LP can lead to its inclusion in official guidelines, ensuring better patient care and outcomes.

Material and methods

This systematic review was registered on PROSPERO with identifier CRD420251050644. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.²⁵

Search strategy

Two reviewers (QW, BB) systematically searched electronic databases (MEDLINE and EMBASE) for articles published in English before May 12^th, 2025, about lupus podocytopathy. The keywords and the search strategy used for the literature search are provided in Supplemental Table S1 and S2. Two reviewers (QW, BB) independently screened titles and abstracts of the articles identified in the literature search. Then, the reviewers retrieved the full texts and assessed for inclusion based on the eligibility criteria. A third reviewer (KS) reviewed the articles when there was uncertainty, and disagreements were resolved after discussion between the three reviewers.

Eligibility criteria

The inclusion criteria were¹: Patients of any age or sex with a diagnosis of SLE²; Kidney biopsy-confirmed lupus podocytopathy which was defined as MCD/FSGS on light microscopy with or without mesangial proliferation, with electron microscopy (EM) showing foot process effacement (FPE), and absence of proliferative features typical of lupus nephritis (LN). The exclusion criteria were¹: Articles with patients not meeting ACR/EULAR or Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE²; Renal biopsy with significant immune deposits in subepithelial or subendothelial regions³; Studies in which EM was not performed; However, studies in which EM data were available for most patients but missing in a small minority were eligible for inclusion, provided that those cases met predefined substitute criteria⁴; LP with co-existing LN class III, IV or V on the same biopsy; Cases classified as class II LN were included only if meeting LP criteria (EM with FPE, unless EM was unavailable)⁵; Cases with no follow-up data⁶; Review articles, animal studies, non-English articles. We included case reports, case series, and cohort studies fulfilling our criteria. Letters to editors were also included if fulfilled the criteria and reported information for the patients. Cohort studies would partially be excluded if some of the cases do not meet the criteria – for example, if some of the patients had pure LP and some had co-existing LV class III, IV or V, then only patients with pure LP would be included in this review.

Quality assessment

Two reviewers (QW, RS) independently reviewed each included study to assess the quality using Joanna Briggs Institute (JBI) tools. We used JBI case report checklists and JBI case series checklists²⁶ for the included case reports, case series and cohort studies. Since our study focused on the characteristics of the LP population without a comparator, we determined that the JBI checklist for cohort studies was not appropriate. Any disagreements that occurred during the assessment were resolved after mutual discussion.

Data extraction

Data extraction was performed by using Rayyan.²⁷ The reviewers (QW, RS, BB, KS, MJ) extracted data from the included studies into two separate standardized spreadsheets for the case reports and case series/cohort studies.

The following data were extracted for case reports: gender, age, history of prior LN, initial presentation, whether LP was part of the initial presentation, SLE history at the time of LP diagnosis, baseline kidney function, prior SLE treatment, extra-renal features, laboratory test results, renal biopsy findings, treatment, response, relapse, and outcomes.

The following data were extracted for case series and cohort studies: total patients number, age (mean or range), percentage of female patients, percentage of nephrotic syndrome, laboratory tests, history of prior LN, renal biopsy findings, treatment, response, relapse rate, and outcomes.

Data analysis

Data were summarized descriptively. Meta-analysis was not performed. Relevant clinical information was summarized in tables. To address variations in proteinuria from different studies, we integrated both 24-h urine protein measurements and spot urine protein creatinine ratio (UPCR) values with standardized conversion to gram/day, in order to estimate a weighted average daily proteinuria.

For case reports, data from pediatric and adult patients’ data were analyzed separately. For cohort studies, data from pediatric and adult populations were not analyzed separately as only one cohort consisted solely of pediatric patients, while two other cohorts included a mix of both age groups. We used Rstudio to calculate p-values for pooled data when necessary. Categorical variables, were compared using Fisher’s exact test in this study.

To address variations in proteinuria from different studies, we integrated both 24-h urine protein measurements and spot urine protein creatinine ratio (UPCR) values with standadized conversion to gram/day, in order to estimate weighted average daily proteinuria.

Results

Data selection

Our search protocol identified 307 records. One additional study was identified through manual searching based on its thematic connection to a previously included article. After removing duplicates, 223 records remained. We excluded 142 records based on title and abstract review. The full texts of 35 articles were assessed for eligibility. Among these reports, 3 studies were reviews of a few cases lacking sufficient detail on LP, 3 lacked treatment or renal outcome data, 1 was published in a non-English language, 1 did not meet the SLE classification criteria, 1 described dense deposits in the capillary wall suggestive of subendothelial or subepithelial pathology rather than LP, and 1 was a duplicate study of the same cohort focusing on different aspects. Ultimately, 26 studies met the inclusion criteria and were included in the final systematic review.^{11,12,15,24,28–49} Among these 26 studies, 18 were case reports, letter to editor with sufficient data, or case series with 2 cases, 8 studies were retrospective cohort studies or case series of more than 5 cases with aggregated data.

The steps of literature review and selection was generated by PRISMA Flow Diagram⁵⁰ and is shown in Figure 1.

Figure 1.

PRISMA flow diagram for literature review and selection process.

Case reports

A total of 19 patients were identified from case reports and small case series. The median age was 23 years (range 3–46) and 84% were female. Six out of 19 were pediatric patients and 13 were adult patients. Baseline characteristics are summarized in Supplemental Table S3.

Presentation

Among the 19 patients included in case reports, 5% (n = 1) had a prior history of LN class III-V. LP was the initial presentation of SLE in 68% (n = 13) of the cases. Nephrotic range of proteinuria was reported in 84% (n = 16) of the patients at the presentation. Serologic testing showed positive anti–double-stranded DNA (dsDNA) antibodies in 58%, low complement 3 (C3) in 32%, and low complement 4 (C4) in 26% of patients (Table 1).

Table 1.

Baseline characteristics, clinical manifestations, diagnostic findings, management, and outcomes of lupus podocytopathy in individual case reports, stratified by age groups.

Variable	Pediatric (n = 6)	Adult (n = 13)
Median age (range)	13 years (3-14)	25 years (22-46)
Female (%)	83.3% (n = 5)	84.6% (n = 11)
LP as initial SLE presentation	66.7% (n = 4)	69.2% (n = 9)
Nephrotic-range proteinuria	100% (n = 6)	76.9% (n = 10)
Mean 24-hr proteinuria	Not calculated (reporting format varied)	12.4 g/day (n = 12)^a
Positive anti-dsDNA (%)	50% (n = 3)	53.8% (n = 7)
Low C3 (%)	16.7% (n = 1)	38.5% (n = 5)
Low C4 (%)	16.7% (n = 1)	30.8% (n = 4)
Histopathology	MCD: 100% (n = 6)	MCD: 38.5% (n = 5); FSGS: 23.0% (n = 3); unclear: 38.5% (n = 5)
Systemic steroid use	100% (n = 6)	100% (n = 13)
Steroid-sparing agent used	50% (n = 3)	69.2% (n = 9); MMF most common
Achieved CR or PR	83.3% (n = 5); 4 CR, 1 PR	92.3% (n = 12); 11 CR, 1 PR
No response to therapy	0	7.7% (n = 1)
Relapse	0	15.4% (n = 2)
Progression to LN	16.7% (n = 1)	0
Dialysis required	0	15.4% (n = 2, 1 temporary, 1 long-term)

LP: lupus podocytopathy, SLE: systemic lupus erythematosus, C3: complement 3, C4: complement 4, MCD: minimal change disease, FSGS: focal segmental glomerulosclerosis, LN: lupus nephritis, MMF: mycophenolate mofetil, CR: complete remission, PR: partial remission.

^aUPCR was converted to estimated 24-h protein excretion using the formula: UPCR (g/g) × 1 g/day in adult patients.

Among the 6 pediatric patients, 66.7% (n = 4) patients had LP as the initial presentation of lupus. The other 2 patients had LP 3 and 7 years after diagnosis of lupus respectively. All patients had nephrotic range proteinuria. DsDNA was positive in 50% (n = 3) patients, 2 had negative dsDNA and 1 was not mentioned. The mean 24-h urine protein was not calculated as some reports used spot urine protein creatinine ratio (UPCR) and some used gram per day. Low C3 was observed in 16.7% (n = 1) patients and low C4 was observed in 16.7% (n = 1) patients.

Among the 13 adult patients, 69.2% (n = 9) patients had LP as the initial presentation of lupus. Of the remaining 4 patients, one developed LP 10 years after a diagnosis of SLE, one after 6 months, and another after 3 years.^36,39,42 The fourth patient had a history of discoid lupus diagnosed 10 years earlier and developed features suggestive of SLE during follow-up, although a formal diagnosis was not established.⁴⁵ DsDNA was positive in 53.8% (n = 7) of the patients. Low C3 and C4 were observed in 38.5% (n = 5) and 30.8% (n = 4) of the patients, respectively (Table 1). Mean 24-h proteinuria was 11.58 g. UPCR and 24-h urine protein data were appropriately converted and pooled for analysis.

Pathology

Histopathologic patterns were consistent with MCD or MCD-like in 57.9% of the patients, FSGS in 15.8%, and unclear or unspecified patterns in 26.3% due to lack of detail or ambiguous descriptions in biopsy reports (Table 1).

In the pediatric population, all patients (n = 6) had MCD pathology, whereas in the adult population, only 38% (n = 5) had MCD.

Treatment and outcome

All patients received systemic steroids. A total of 69% (n = 13) were treated with at least one steroid-sparing agent, excluding those who had received such agents prior to the diagnosis of LP, among which 61% (n = 8) received mycophenolate.

In the pediatric population, all patients (n = 6) received systemic steroids, and 50% (n = 3) received at least one steroid-sparing agent in the initial presentation. 83.3% (n = 5) of the patients achieved complete or partial remission, among which 66.7% (n = 4) achieved complete remission (CR) and 16.7% (n = 1) achieved partial remission (PR) while 1 patient was marked as “clinical stable” without enough details to specify. Time to remission varied among patients and is summarized in Table S3. None of the 6 patients experienced clinical relapse. One patient developed into LN class IV after 2 years which required systemic steroid and mycophenolate mofetil and the histology of this patient was MCD. No patients ended up requiring dialysis (Table 1).

In the adult population, all patients (n = 13) received systemic steroids, 69.2% (n = 9) received and at least one steroid-sparing agent in the initial presentation. 92.3% (n = 12) of the patients achieved CR or PR, among which 84.6% (n = 11) patients achieved CR and 7.7% (n = 1) achieved PR while 7.7% (n = 1) had no response. Time to remission was summarized in Table S3. Relapse occurred in 15.4% (n = 2) patients. 15.4% (n = 2) required dialysis, one temporary and one long-term (Table 1).

For both pediatric and adult patients, the time course of response to therapy, when available, was relatively rapid, with most patients experiencing CR or PR within several weeks up to 3 to 5 months. Unfortunately, the length of remission is difficult to assess, since duration of follow up was only up to 1 year in most reported patients (Table S3).

Cohort studies

Eight cohort studies were included. We excluded patients with biopsy findings consistent with ISN/RPS class III, IV, or V lupus nephritis at the time of LP diagnosis. For some cohorts, only a subset of patients met the inclusion criteria for this systematic review, and these data were subsequently re-aggregated. Nearly all the patients had EM demonstrating FPE. In one cohort study, EM was not available for a small number of patients (n = 9). In these cases, the presence of mesangial immune deposits on immunofluorescence, and the presence of nephrotic syndrome were used as a substitute.³⁰

Altogether 240 patients were included. The median age was at 29 with 87.7% females from 209 patients of 7 studies. One cohort did not specify age and gender in podocytopathy group.

Among the 8 cohorts, 1 consisted only of pediatric population, 5 included only adult patients, and the other 2 cohorts had a combination of adult and pediatric patients. Baseline characteristics are summarized in Supplemental Table S4.

Presentation

Among these 240 patients, 95.0% (n = 228) had nephrotic range proteinuria. The weighted average proteinuria was 6.2 g/day (Table 2).

Table 2.

Baseline characteristics, clinical manifestations, diagnostic findings, management, and outcomes of lupus podocytopathy in retrospective cohort studies.

Category	Findings
Characteristics
Age (median)	29
Female	87.7%
Clinical manifestation
Nephrotic-range proteinuria	95.0% (n = 228)
Weighted average proteinuria	6.2 g/day
Pathology
MCD or MCD-like	42.5% (n = 102)
FSGS	17.9% (n = 43)
MsP	37.9% (n = 91)
LN class I	4.6% (n = 11)
Notes	Histologic definitions varied across studies; some patterns were overlapping or ambiguously reported.
Treatment and outcome
Systemic steroid use	98.8% (n = 237)
Steroid-sparing agents	Data not aggregated due to reporting heterogeneity; agents included MMF, CYC, AZA, CNI, rituximab. See Supplemental Table S4
CR rate	73.3% (n = 176)
CR + PR rate	94.6% (n = 227)
No response rate	5.4% (n = 13)
Relapse rate (4 studies, n = 208)	52.9% (n = 110)
MCD CR + PR rate (4 studies, n = 92)	98.9% (n = 91)
FSGS CR + PR rate (4 studies, n = 39)	84.6% (n = 33); p = .003
MCD CR rate (4 studies, n = 92)	84.8% (n = 78)
FSGS CR rate (4 studies, n = 39)	51.3% (n = 20); p = .0001
Progression to LN	8.3% (n = 20)
ESRD/HD/Advanced renal failure	1.3% (n = 3)

MCD: Minimal change disease, FSGS: focal segmental glomerulosclerosis, MsP: mesangial proliferation, LN: lupus nephritis, MMF: Mycophenolate Mofetil, CYC: cyclophosphamide, AZA: azathioprine, CNI: Calcineurin Inhibitor, CR: complete remission, PR: partial remission, ESRD: end-stage renal disease, HD: hemodialysis.

Pathology

Among these 240 cases, MCD-like lesions were reported in 42.5% (n = 102), FSGS in 17.9% (n = 43), and mesangial proliferation in 37.9% (n = 91) of the patients. Eleven patients were reported as having LN class I (Table 2). Notably, the included studies lacked uniformity in histologic classification. While some referred to findings as lupus nephritis (LN) class II, others used the broader term mesangial proliferation (MsP) to describe similar features. Certain studies categorized LN class I as a distinct subtype, whereas others interpreted such findings as minimal change disease (MCD) or MCD-like pathology. Additionally, while some studies considered MCD and MsP as separate histologic patterns, others suggested that they may coexist within the same biopsy specimen. These overlapping and inconsistently defined classifications were often not clearly described in the original reports. Moreover, in the study by Wang et al.⁴⁶ only LP patients with mesangial proliferative (MsP) patterns were included, while those with other histologic subtypes such as FSGS were excluded. As a result, the overall proportions summarized in this review may not accurately reflect the true distribution of histologic patterns in the overall LP population.

Treatment and outcomes

All studies reported glucocorticoid therapy as the mainstay. 98.8% (n = 237) of the patients received different kinds of systemic steroids. Steroid sparing agents include mycophenolate mofetil (MMF), cyclophosphamide (CYC), azathioprine (AZA), cyclosporine, tacrolimus, and rituximab. We were not able to aggregate data regarding the percentage of patients who received steroid sparing agents for their LP due to the heterogeneity of the studies. Details of the use of steroid-sparing agents for each study were summarized in Supplemental Table S4.

Among the 240 patients, 94.6% (n = 227) achieved complete or partial response and 5.4% (n = 13) patients had no response. Four studies reported relapse rates. Among the 208 patients, 52.9% (n = 110) patients experienced relapse during the follow-up time period. Four out of eight studies reported remission rates in MCD and FSGS separately and among these patients, 33 out of 39 FSGS patients achieved CR or PR with remission rate of 84.6%, while 91 out of 92 MCD patients achieved CR or PR with 98.9% remission rate (p = .003) (Table 2).

Among these 240 patients, 20 patients developed into LN. Three patients developed into end stage renal disease (ESRD)/advanced renal failure/hemodialysis (HD) dependent eventually.

Discussion

This systematic review summarized data from case reports, case series and retrospective cohort studies focusing on LP. Among the 19 patients from case reports, more than half had LP as part of the initial presentation of SLE and most of them had a favorable outcome with only one patient developing LN and two requiring dialysis. Compared with LN, LP appears to have a more benign course and outcome.

There is no standard classification or definition of LP in current International Society of Nephrology (ISN)/Renal Pathology Society classification (RPS) guidelines. In 2016, Bomback and Markowitz⁵¹ proposed diagnostic criteria for lupus podocytopathy (Table 3).

Table 3.

Proposed criteria for diagnosis of lupus podocytopathy.

Domain	Defining Features
Clinical	1. Meeting ACR SLE classification criteria; 2. Nephrotic syndrome
Light microscopy	1. Normal glomeruli or FSGS; 2. Absence of endocapillary proliferation, necrosis, and/or crescents (mesangial proliferation may be present)
Immunofluorescence microscopy	1. Deposits absent or limited to mesangium
Electron microscopy	1. Extensive foot process effacement (typically >70%); 2. Deposits absent or limited to mesangium

SLE: systemic lupus erythematosus, ACR: American College of Rheumatology, FSGS: Focal Segmental Glomerulosclerosis.

Table based on previously proposed diagnostic criteria by Bomback and Markowitz.⁵¹

Podocytes are specialized epithelial cells that serve as a critical filtration barrier in glomeruli.⁵² When injured, they lose their actin cytoskeleton structure and undergo effacement of foot processes which leads to filtration impairment and result in significant proteinuria. Key proteins such as nephrin anchor the cytoskeleton to the slit diaphragm and maintain podocyte shape and adhesion. Pathways including nephrin phosphorylation and actin polymerization have been shown to be central to podocyte motility and injury response.⁵³ Wiggins⁵⁴ proposed the podocyte depletion hypothesis in 2007, suggesting that the outcome of glomerular injury depends on the extent of podocyte depletion, regardless of the nature of the initial insult (immune, toxic, infectious, ischemic, or otherwise).

Meliambro et al.⁵⁵ summarized different mechanisms of podocyte injury, including genetic causes; circulating factors such as nephrin autoantibodies; immune-mediated pathways including tumor necrosis factor (TNF) signaling, inflammatory cytokines (e.g., interleukins), and complement activation; as well as mechanical and metabolic stress and viral infections. More specifically, the study by Bruggeman et al.⁵⁶ identified tumor necrosis factor receptor 2 (TNFR2) expression on podocytes and its association of podocyte and kidney injury in mice. Complement activation has been shown to play a role in podocyte injury by activating cytokines, proteases, oxidants, altering cytoskeleton and slit diaphragm proteins.⁵⁷

Watts et al. (2022)¹² identified autoantibodies against nephrin, which is a component of the podocyte slit diaphragm in approximately 30% of patients with MCD. These antibodies were present during active disease and diminished with remission. Renal biopsies also showed punctate IgG deposits colocalizing with nephrin, supporting an autoimmune mechanism of MCD. Hengel et al.⁵⁸ later confirmed that anti-nephrin autoantibodies can cause actin and cytoskeletal alterations via phosphorylation of nephrin, which suggested the direct pathogenicity of these autoantibodies. Notably, in their study, 44% of MCD patients and 9% of primary FSGS patients had antinephrin autoantibodies. No patient with LN was found to have anti-nephrin autoantibodies. However, Chugh and Clement⁵⁹ proposed a different perspective, as these antibodies have not induced foot process effacement in animal models. They argued that antinephrin autoantibodies may reflect a secondary immune response to podocyte injury rather than a primary cause. Epitope mapping would be needed to prove this concept.

SLE is a systemic autoimmune disorder associated with dysregulation of both the innate immune system and the adaptive immune system with autoantibody production and cytokine activation.⁶⁰ Previous studies have shown that the podocytopathy rate was higher in lupus population compared to general population,¹⁷ suggesting a potential pathophysiological link between lupus-related immune dysregulation and podocyte injury.¹⁷ However, the exact mechanism remains unclear.

We propose several potential mechanisms linking SLE to podocyte injury. First, SLE has been shown to increase the production of reactive oxygen species (ROS),⁶¹ which can contribute to downstream podocyte stress and damage.⁶² Second, complement activation, a known feature of SLE,⁶⁰ has also been implicated in podocyte injury.⁵⁷ Finally, the presence of diverse autoantibodies and proinflammatory cytokines in SLE may interact with podocyte surface receptors, triggering signaling cascades that lead to further cellular injury.⁶²

The predominant renal manifestation of LP is nephrotic range proteinuria. In this review, almost all patients presented with nephrotic range proteinuria with average 24-h protein of 6.2 g/day. In the study by Wang et al.,⁴⁶ patients with podocytopathy had significantly higher proteinuria than those without, suggesting that proteinuria severity is linked to the degree of podocyte effacement—a hallmark of LP. They also commented that podocytopathy is more likely to be the initial lupus presentation than LN without podocytopathy, which aligns with the findings of our systematic review.

In our study, patients with LP overall showed a favorable response to steroids and steroid sparing agents, with a high remission rate. Notably, the FSGS subtypes tended to have a lower remission rate compared to the MCD subtypes. While there are no current guidelines for the treatment of LP, the studies involved have used systemic steroid, and steroid-sparing agents including mycophenolate, cyclophosphamide, azathioprine, cyclosporin, tacrolimus, and rituximab with good response.

Additionally, more than half of the patients experienced at least one relapse of LP requiring treatment. Relapse data were reported in 4 of the 8 included studies. In the study of Bonelli et al.³⁰ the researchers analyzed therapies at the time of diagnosis and did not identify any specific agent associated with a reduced risk of relapse. In another study, Xia et al.²⁴ was able to identify acute kidney injury (AKI) as an independent risk factor for kidney relapse. Overall, the available data were insufficient to draw meaningful conclusions regarding the impact of specific therapies on relapse prevention because most studies did not report outcomes explicitly for these agents.

Nevertheless, emerging studies have demonstrated that certain immunosuppressive agents may have protective effects on podocytes, thereby reducing proteinuria. Calcineurin Inhibitors (CNI) have been demonstrated to block the phosphatase activity of calcineurin, which dephosphorylates synaptopodin, and thus maintain the stability of the actin cytoskeleton in podocytes and reduce proteinuria.^63–65 Among these agents, volclosporin has a more sustainable profile with no requirement to monitor blood levels.⁶⁵ Additionally, MMF has also been shown to have a direct effect on the transcriptome of podocytes via non-immunologic pathways, potentially reducing proteinuria.⁶⁶ However, whether these agents can reduce relapse rate warrants further clinical investigation.

Futher more, the review by Meliambro et al.⁵⁵ pointed out several emerging targets and interventions for podocytopathies, although not specifically for LP. These include Apolipoprotein L (APOL)-targeted therapies (Inaxaplin), JAK–STAT pathway inhibitors (Baricitinib), endothelin receptor antagonists (Sparsentan), TRPC channel inhibitors, complement inhibitors and mitochondrial-targeted therapies.

There are several limitations of this systematic review. First, there is inconsistency in the definition of lupus podocytopathy (LP). While LP is generally characterized by proteinuria with significant podocyte foot process effacement in the absence of endocapillary proliferation or substantial subendothelial or subepithelial immune complex deposits, there is no universally accepted cutoff for the degree of foot process effacement required for diagnosis. As a result, although most patients included had diffuse FPE, the extent varied. In a small subset of patients from a single study, patients with any degree of PFE were included. While this may reflect real-world reporting, it introduced variability into the study. Second, while mesangial proliferation and mesangial immune complex deposition are typically considered acceptable within the spectrum of LP, some studies also included cases with mild subepithelial deposits, further contributing to variability in histologic definitions. Third, as mentioned above, studies lacked uniformity in histologic classification and there were overlaps between different subtypes. Fourth, one study specifically included masengial proliferative LP which makes the proportion of each subtype not represent the real population. Fifth, although nearly all patients had EM confirmed FPE, there was a small subset of patients (n = 9) whose EM was not available and the study used substitute clinical criteria, which may introduce potential misclassification. Sixth, two of the studies mixed pediatric and adult populations, which may have introduced heterogeneity due to age-related differences in disease presentation, treatment response, and histologic patterns. Seventh, in some studies, the use of steroid-sparing agents was not clearly reported. For instance, while the authors listed the number of patients who received each specific agent, it was unclear whether these treatments overlapped in individual patients. As a result, the total number of patients who received any steroid-sparing agent could not be reliably determined. Eighth, while some studies defined complete and partial remission according to established criteria, for example, proteinuria <0.5 g/day with near-normal GFR for complete remission; and ≥50% reduction in proteinuria to <3 g/day for partial remission, many did not specify the criteria used or used different criterias. Ninth, while some studies specified whether or not patients were off steroid-sparing agents during and after remission, others provided less detailed information.

Conclusions

LP is a distinct and under-recognized renal manifestation of SLE. It is characterized clinically by nephrotic-range proteinuria and pathologically by podocyte effacement in the absence of proliferative lupus nephritis features. Our systematic review, which included published case reports, case series and retrospective cohort studies, demonstrated that LP tends to be the initial presentation of SLE and generally responds well to treatment with systemic corticosteroids and steroid-sparing agents.

Patients with MCD pathology tend to achieve higher remission rates compared to those with FSGS. Although relapse is common, only a small proportion of patients progress to classical LN or ESRD requiring dialysis.

The pathogenesis of LP remains poorly understood, but podocyte injury and effacement appear to be driven by immunologic pathways, inflammatory cytokines, and complement activation. While current treatment strategies remains unclear, overall patients responded to systemic steroid and steroid-sparing agents. There are emerging therapies targeting podocytes for podocytopathies, although not specifically for LP.

Given the difference in clinical presentation and outcomes between LP and traditional LN, early histological diagnosis through kidney biopsy is essential to guide appropriate treatment strategies.

Supplemental material

Supplemental material - Lupus podocytopathy: A systematic review of clinical evidence from cases and cohorts

Supplemental material for Lupus podocytopathy: A systematic review of clinical evidence from cases and cohorts by Qi Wang, Bismah Basharat, Kefang Sun, Roshan Subedi, Massiel Jimenez Artiles and Stanley Ballou in Lupus

Footnotes

Author contributions

Qi Wang designed the search strategy, performed literature screening, quality assessment, data extraction, and wrote the original draft of the manuscript. Bismah Basharat contributed to literature screening and data extraction, and participated in manuscript review and editing. Kefang Sun assisted with literature screening and data extraction, drafted the introduction section, and contributed to manuscript review and editing. Roshan Subedi contributed to quality assessment and data extraction, and participated in manuscript review and editing. Massiel Jimenez Artiles participated in data extraction and manuscript review and editing. Stanley Ballou provided senior supervision and critical revision of the manuscript. All authors approved the final version of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical considerations

This study is based on previously published literature and does not involve any new studies with human participants or animals performed by any of the authors.

We confirm that the manuscript is original, has not been submitted elsewhere, and complies with the journal’s guidelines. All authors meet authorship criteria.

ORCID iD

Qi Wang

Supplemental material

Supplemental material for this article is available online.

References

Hoi

Igel

Mok

, et al. Systemic lupus erythematosus. Lancet 2024; 403(10441): 2326–2338.

Dang

, et al. Lupus nephritis: new progress in diagnosis and treatment. J Autoimmun 2022; 132: 102871.

Almaani

Meara

Rovin

. Update on lupus nephritis. Clin J Am Soc Nephrol 2017; 12(5): 825–835.

Somers

Marder

Cagnoli

, et al. Population-based incidence and prevalence of systemic lupus erythematosus: the Michigan lupus epidemiology and surveillance program. Arthritis Rheumatol 2014; 66(2): 369–378.

Seligman

Lum

Olson

, et al. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med 2002; 112(9): 726–729.

Bajema

Wilhelmus

Alpers

, et al. Revision of the international society of Nephrology/Renal Pathology society classification for lupus nephritis: clarification of definitions, and modified national institutes of health activity and chronicity indices. Kidney Int 2018; 93(4): 789–796.

Abuelo

Esparza

Garella

. Steroid-dependent nephrotic syndrome in lupus nephritis. Response to chlorambucil. Arch Intern Med 1984; 144(12): 2411–2412.

Okai

Soejima

Suzuki

, et al. [A case report of lupus nephritis associated with minimal change nephrotic syndrome--comparison of various histological types of 67 cases with lupus nephritis]. Nihon Jinzo Gakkai Shi 1992; 34(7): 835–840.

Dube

Markowitz

Radhakrishnan

, et al. Minimal change disease in systemic lupus erythematosus. Clin Nephrol 2002; 57(2): 120–126.

10.

Hertig

Droz

Lesavre

, et al.

SLE and idiopathic nephrotic syndrome: coincidence or not?

Am J Kidney Dis 2002; 40(6): 1179–1184.

11.

Kraft

Schwartz

Korbet

, et al. Glomerular podocytopathy in patients with systemic lupus erythematosus. J Am Soc Nephrol 2005; 16(1): 175–179.

12.

Chen

Wang

, et al. Clinical-morphological features and outcomes of Lupus podocytopathy. Clin J Am Soc Nephrol 2016; 11(4): 585–592.

13.

Oliva-Damaso

Payan

Oliva-Damaso

, et al. Lupus podocytopathy: an overview. Adv Chron Kidney Dis 2019; 26(5): 369–375.

14.

Parikh

Almaani

Brodsky

, et al. Update on Lupus Nephritis: Core curriculum 2020. Am J Kidney Dis 2020; 76(2): 265–281.

15.

Chaudhury

Rajarajan

Yousuf

, et al. Lupus podocytopathy: an important differential diagnosis of nephrotic syndrome in systemic lupus erythematosus. Indian J Nephrol 2016; 26(4): 284–287.

16.

VDB

Aten

Chand

, et al. Interleukin-4 and interleukin-13 act on glomerular visceral epithelial cells. J Am Soc Nephrol 2000; 11(3): 413–422.

17.

Sakhi

Moktefi

Bouachi

, et al. Podocyte injury in Lupus nephritis. J Clin Med. 2019; 8(9): 1340.

18.

Maeda

Abdi

Tsokos

. The role of podocytes in lupus pathology. Curr Rheumatol Rep 2024; 27(1): 10.

19.

Liu

Wen

Peng

, et al. Immune podocytes in the immune microenvironment of lupus nephritis. Mol Med Rep. 2023; 28(5): 204.

20.

Chen

. Lupus podocytopathy: a distinct entity of lupus nephritis. J Nephrol 2018; 31(5): 629–634.

21.

Aringer

Costenbader

Daikh

, et al. 2019 European league against Rheumatism/American college of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019; 71(9): 1400–1412.

22.

Kidney Disease Improving Global Outcomes KDIGO Lupus Nephritis Work Group . KDIGO 2024 clinical practice guideline for the management of LUPUS NEPHRITIS. Kidney Int 2024; 105(1s): S1–s69.

23.

Sammaritano

Askanase

Bermas

, et al. American college of Rheumatology (ACR) guideline for the screening, treatment, and management of Lupus nephritis. Arthritis Rheumatol 2024.

24.

Xia

Deng

Zhuang

, et al. Risk factors for acute kidney injury and kidney relapse in patients with lupus podocytopathy. Clin Kidney J 2024; 17(6): sfae148.

25.

Moher

Liberati

Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097.

26.

Munn

Barker

Moola

, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth 2020; 18(10): 2127–2133.

27.

Ouzzani

Hammady

Fedorowicz

, et al. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016; 5(1): 210.

28.

Abdelnabi

. Is podocytopathy another image of renal affection in p-SLE? Pediatr Rheumatol Online J 2021; 19(1): 57.

29.

Aly

Zeng

Acharya

, et al. Delayed onset minimal change disease as a manifestation of Lupus podocytopathy. Clin Pract 2021; 11(4): 747–754.

30.

Bonelli

Sciascia

Calatroni

, et al. Clinical presentation, outcomes and risk of relapses of lupus podocytopathy in a multicentre Italian cohort. J Nephrol 2025; 38(2): 643–653.

31.

Deshpande

. Minimal change nephrotic syndrome in a child with systemic lupus erythematosus. Indian J Nephrol 2023; 33(5): 381–383.

32.

Doğantan

Günay

Taşkın

, et al. Two faces of lupus nephritis? Answers. Pediatr Nephrol 2021; 36(7): 2109–2111.

33.

Dominguez Davalos

De La Flor

Bedia Castillo

, et al. An unusual case of nephrotic range proteinuria in a short-standing type 1 diabetic patient with newly diagnosed systemic lupus erythematosus: a case report and literature review. Med Sci 2024; 12(4): 74.

34.

Fujinaga

Nishino

Mizutani

, et al. Transition from lupus podocytopathy to diffuse proliferative lupus nephritis without proteinuria in childhood-onset systemic lupus erythematosus. Clin Nephrol 2017; 87(4): 217–219.

35.

Iwazu

Akimoto

Izawa

, et al. Accelerated recovery from nephrotic syndrome with acute renal failure by double filtration plasmapheresis in a patient with lupus podocytopathy. Clin Exp Nephrol 2012; 16(3): 485–489.

36.

Khan

Mohammadrezaei

Aslam

, et al. Lupus podocytopathy: a rare cause of nephrotic syndrome in patients with systemic lupus erythematosus. J Community Hosp Intern Med Perspect 2023; 13(5): 57–60.

37.

Kurihara

Terai

Yabe

, et al. Tacrolimus induction therapy for nephrotic syndrome caused by minimal mesangial lupus nephritis with lupus podocytopathy: a case-based review. Am J Case Rep 2022; 23: e937201.

38.

Zeng

, et al. Lupus podocytopathy and antiphospholipid syndrome in a child with SLE: a case report and literature review. Front Pediatr 2022; 10: 950576.

39.

Lionaki

Liapis

Vallianou

, et al. The various forms of nephrotic syndrome in a patient with systemic lupus erythematosus. Case Rep Nephrol 2020; 2020: 7869216.

40.

Liu

Murray

Tomaszewski

. Lupus podocytopathy superimposed on diabetic glomerulosclerosis: a case report. Medicine (Baltim) 2021; 100(37): e27077.

41.

Lopez Vasquez

Bembry

Mesa

, et al. Lupus podocytopathy-case series and review. Lupus 2022; 31(8): 1017–1019.

42.

Oliveira

Sala

Freitas

, et al. Refractory diffuse podocytopathy. Journal of Nephropathology. 2023; 12(2): e17314.

43.

Paramalingam

Wong

Dogra

, et al. Recurrent podocytopathy in a patient with systemic lupus erythematosus. Sage Open Med Case Rep 2017; 5: 2050313x17695997.

44.

Pilania

Jindal

Sandesh

, et al. Chylous ascites and podocytopathy as the presentation of childhood lupus-an unusual occurrence. Lupus 2019; 28(2): 244–248.

45.

Shea-Simonds

Cairns

Roufosse

, et al. Lupus podocytopathy. Rheumatology 2009; 48(12): 1616–1618.

46.

Wang

Chen

, et al. Mesangial proliferative lupus nephritis with podocytopathy: a special entity of lupus nephritis. Lupus 2018; 27(2): 303–311.

47.

Wang

Song

, et al. Podocyte involvement in lupus nephritis based on the 2003 ISN/RPS system: a large cohort study from a single centre. Rheumatology 2014; 53(7): 1235–1244.

48.

Zeng

Jiang

, et al. Lupus podocytopathy complicated with multiple organ injuries in a patient with severe lupus. Ann Palliat Med 2019; 8(5): 763–768.

49.

Doğantan

Günay

Taşkın

, et al. Two faces of lupus nephritis? Questions. Pediatr Nephrol 2021; 36(7): 2107–2108.

50.

Haddaway

Page

Pritchard

, et al. PRISMA2020: an R package and shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and open Synthesis. Campbell Syst Rev 2022; 18(2): e1230.

51.

Bomback

Markowitz

. Lupus podocytopathy: a distinct entity. Clin J Am Soc Nephrol 2016; 11(4): 547–548.

52.

Quaggin

Kreidberg

. Development of the renal glomerulus: good neighbors and good fences. Development 2008; 135(4): 609–620.

53.

Garg

. A review of podocyte biology. Am J Nephrol 2018; 47(Suppl 1): 3–13.

54.

Wiggins

. The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int 2007; 71(12): 1205–1214.

55.

Meliambro

Campbell

. Podocyte-targeted therapies - progress and future directions. Nat Rev Nephrol 2024; 20(10): 643–658.

56.

Bruggeman

Drawz

Kahoud

, et al. TNFR2 interposes the proliferative and NF-κB-mediated inflammatory response by podocytes to TNF-α. Lab Invest 2011; 91(3): 413–425.

57.

Nangaku

Shankland

Couser

. Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 2005; 16(5): 1195–1204.

58.

Hengel

Dehde

Lassé

, et al. Autoantibodies targeting Nephrin in podocytopathies. N Engl J Med 2024; 391(5): 422–433.

59.

Chugh

Clement

. Idiopathic minimal change nephrotic syndrome: a podocyte mystery nears the end. Am J Physiol Ren Physiol 2023; 325(6): F685–F694.

60.

Fortuna

Brennan

. Systemic lupus erythematosus: epidemiology, pathophysiology, manifestations, and management. Dent Clin 2013; 57(4): 631–655.

61.

Kienhöfer

Boeltz

Hoffmann

. Reactive oxygen homeostasis - the balance for preventing autoimmunity. Lupus 2016; 25(8): 943–954.

62.

Nagata

. Podocyte injury and its consequences. Kidney Int 2016; 89(6): 1221–1230.

63.

Kale

Shelke

Lei

, et al. Voclosporin: unique chemistry, pharmacology and toxicity profile, and possible options for implementation into the management of Lupus nephritis. Cells 2023; 12(20): 2440.

64.

Ashinze

Mafua

Banerjee

, et al. Voclosporin: a comprehensive review of its role as a novel calcineurin inhibitor in the management of systemic lupus erythematosus. Medicine (Baltim) 2025; 104(25): e42858.

65.

Ponticelli

Reggiani

Moroni

. Old and new calcineurin inhibitors in lupus nephritis. J Clin Med 2021; 10(21): 4832.

66.

Abo Zed

SED

Hackl

Bohl

, et al. Mycophenolic acid directly protects podocytes by preserving the actin cytoskeleton and increasing cell survival. Sci Rep 2023; 13(1): 4281.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.16 MB