Systemic Lupus Erythematosus With IgA Nephropathy: Challenges in Diagnosis and Management

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which renal involvement is common and prognostically significant. Lupus nephritis (LN) affects up to 60% of adults and remains a major cause of morbidity and renal failure. IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN generally follows a variable course and is often less aggressive [1]. The coexistence of SLE and IgAN is uncommon and creates a diagnostic dilemma, as both conditions can present with proteinuria, hematuria, and impaired renal function. SLE and IgAN share genetic risk factors and similar immune pathways, including B-cell activation and cytokines like IL-6 and interferons that drive inflammation. Complement involvement also overlaps, with SLE activating the classical pathway and IgAN activating the alternative and lectin pathways [2]. The causal relationship between the 2 diseases, or their simple co-occurrence, is a subject of ongoing discussion [2–4]. There is scarcity of specific treatment guidelines for patients with IgAN and SLE.

We report the case of a young woman with SLE who had biopsy-proven immunoglobulin A nephropathy (IgAN). Unlike most cases, in which IgAN follows a mild or indolent course, her presentation was aggressive and required immunosuppression. This highlights that IgAN in SLE can at times behave more like LN.

Case Report

A woman in her early twenties presented with a 2-month history of progressive bilateral leg and facial edema, followed by mild shortness of breath and abdominal distension. She had been diagnosed with SLE in her late teens, complicated by recurrent seizures and an episode of psychosis. She continued to have seizures despite antiepileptic therapy. Her treatment included hydroxychloroquine 200 mg daily and low-dose prednisone.

On admission, she was afebrile, normotensive, and hemodynamically stable and weighed 42 kg. Examination revealed periorbital and facial edema, bilateral lower-extremity pitting edema (3+/3+), reduced breath sounds at the lung bases, and abdominal distension. An oral ulcer with a yellowish slough was noted on the right buccal mucosa.

Laboratory evaluation showed hemoglobin 9.9 g/dL, platelets 120×109/L, serum albumin 2.6 g/dL, and creatinine 1.2–1.4 mg/dL (baseline 0.6–0.8). Urinalysis revealed 3+ protein with numerous dysmorphic red blood cells (RBCs); 24-hour urine confirmed nephrotic-range proteinuria of 4.2 g/day. Anti-nuclear antibody (ANA) was positive (speckled 1: 80, +++), with anti-ribonucleoprotein (RNP) positivity, while anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-dsDNA IgG were negative. Antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin, and β2-glycoprotein I, were negative. Complement testing showed low C3 (0.57 g/L) with normal C4. Viral serologies were negative. The erythrocyte sedimentation rate (ESR) was 36 mm/h and C-reactive protein (CRP) was 8 mg/L. Computed tomography (CT) demonstrated mild ascites and bilateral pleural effusions, while Doppler imaging revealed thrombosis of the right common femoral and great saphenous veins.

Renal biopsy revealed 14 glomeruli with segmental sclerosis and mild mesangial expansion (Figure 1). There was no interstitial fibrosis, crescents, or wire-loop lesions. Immunofluorescence demonstrated dominant mesangial IgA deposits with weaker IgM and C3, while IgG and C1q were absent. Electron microscopy confirmed mesangial electron-dense deposits without subendothelial or subepithelial involvement (Figure 2). The Oxford MEST-C score was M1E0S1T0C0.

Our patient met the EULAR/ACR classification criteria for an SLE diagnosis, achieving a score of 20, without including the renal domain. Other possibilities, such as infection-related glomerulonephritis, ANCA-associated vasculitis, and antiphospholipid-associated nephropathy, were ruled out by serology and pathology. Deep vein thrombosis (DVT) was most likely related to nephrotic-range proteinuria, which is known to increase thrombotic risk. The overall findings supported severe IgAN with SLE.

Treatment was started with prednisone 40 mg daily, mycophenolate mofetil 360 mg twice daily, and ramipril 10 mg for renoprotection. HCQ 200 mg daily was continued, along with vitamin D, calcium, and rivaroxaban.

At the 3-month follow-up, proteinuria had decreased to 0.9 g/day, and urinalysis showed resolution of hematuria with trace protein. Creatinine stabilized at 1.0–1.2 mg/dL. Concurrently, the prednisone dosage was tapered to 5 mg daily. At subsequent visits, she remained seizure-free and clinically stable, with no recurrence of edema or systemic disease flares, and had good tolerance to the therapeutic regimen.

Discussion

The coexistence of SLE and IgAN poses a diagnostic and therapeutic challenge. Renal impairment in lupus is often attributed to LN, but this case illustrates that other nephritides must also be considered. Histopathological assessment is essential to distinguish between them. This raises the question of whether IgA-dominant nephritis in lupus is a distinct subtype of LN or a coincidental coexistence, both of which carry important implications for management. IgAN generally follows a slow and indolent course, with disease activity confined to the kidneys and minimal systemic manifestations, whereas lupus nephritis typically exhibits a relapsing–remitting pattern associated with systemic flares and immune complex-mediated injury [1,5]. The clinical course in our patient suggested that her SLE may have triggered or exacerbated IgAN, complicating its presentation and treatment. The favorable response to immunosuppression, along with improvement in disease activity scores, further supports this observation. This scenario shows that severe IgAN can co-occur with SLE and can be misdiagnosed as LN [2–4]. Management should be guided by the overall clinical context, and our case suggests that IgAN in SLE may merit treatment similar to treatment for LN with immunosuppression, although further studies are needed to confirm this.

Clinically, both LN and IgAN can present with edema, proteinuria, hematuria, and impaired renal function, which makes them appear similar at first. LN is defined by immune complex deposition in mesangium and capillary walls with a ‘full-house’ immunofluorescence pattern, including IgG, IgA, IgM, C1q, and C3. IgAN shows dominant mesangial IgA without C1q and mesangial electron-dense deposits on EM [6]. Some overlap cases report additional IgG or C1q, creating diagnostic ambiguity [3]. Serology can also be misleading: low complement and positive anti-dsDNA, typical of LN, are usually absent in IgAN. Low complement in overlapping scenarios can reflect extra-renal lupus activity rather than LN [2]. The lack of C4 and C1q deposits, which are found in LN, suggests that an alternative pathway of complement activation is involved in the pathogenesis in IgAN [7]. Low C3 has been associated with more severe forms of IgAN, reflecting complement activation through the alternative and lectin pathways that drive mesangial injury and adverse outcomes [2,7]. These findings highlight the importance of integrating clinical and serological data with histopathology to achieve accurate diagnosis and guide management.

Therapeutic decisions in this overlap scenario must be individualized. Most patients with IgAN are managed conservatively, with immunosuppression reserved for progressive or crescentic disease after an adequate trial of supportive therapy. The need for immunosuppression in IgAN is best guided by clinical indicators such as persistent proteinuria, microscopic hematuria, declining eGFR, and histopathological features, including mesangial or endocapillary hypercellularity, segmental sclerosis, tubular atrophy, interstitial fibrosis, or crescents. Only a few reported cases of histologically-confirmed IgAN in patients with inactive lupus have required immunosuppressive treatment [2–5]. In our patient, however, early initiation of immunosuppression was warranted due to severe renal involvement, the presence of M1/S1 lesions known to respond to therapy, and concomitant uncontrolled neuropsychiatric lupus with recurrent seizures. Although cyclophosphamide can be useful for acute neuropsychiatric lupus, especially related seizures, its fertility and toxicity risks makes it less suitable in young females. MMF has shown benefit for long-term seizure control in SLE, making it a safer and more appropriate choice. MMF improves renal outcomes, particularly in non-White populations [8]. While immunosuppression is traditionally considered after 3–6 months of supportive management, recent guidelines advocate for an earlier, integrated approach combining optimized supportive measures with immunosuppressive therapy to minimize ongoing nephron loss and improve long-term outcomes in IgAN [5,8].

Conclusions

The coexistence of SLE and IgA nephropathy poses diagnostic and therapeutic challenges. Renal dysfunction in lupus should not be presumed to represent classical lupus nephritis without histopathological confirmation. This case report shows that lupus activity can trigger or intensify IgA-mediated injury, resulting in an overlapping pattern that responds favorably to immunosuppression. The main challenge in the approach to patients is to estimate the degree of disease activity and predict renal function decline. Therapy should be individualized, and continued surveillance of proteinuria, complement levels, and eGFR is essential, as both IgAN and SLE can relapse even after an initial therapeutic response. Further studies are needed to determine whether IgA-dominant nephritis in lupus is a distinct subtype or a coincidental coexistence within the lupus nephritis spectrum.