Renal involvement in systemic lupus erythematosus is usually exhibited as lupus nephritis, which is a form of immune complex-mediated glomerulonephritis and one of the most severe organ manifestations of systemic lupus erythematosus. The pathogenesis involved glomerular immune complex deposition, which leads to glomerular inflammation and typically shows a “full-house” pattern on immunofluorescence microscopy. Other forms of glomerulonephritis are rarely observed in patients with systemic lupus erythematosus. Pauci-immune crescentic glomerulonephritis is the pattern of injury most commonly observed in patients with antineutrophil cytoplasmic autoantibody-associated glomerulonephritis. The characteristic histological feature of pauci-immune crescentic glomerulonephritis is focal necrotizing and crescentic glomerulonephritis with little or no glomerular staining for immunoglobulin by immunofluorescence microscopy. We report a rare case of antineutrophil cytoplasmic autoantibody-negative pauci-immune crescentic glomerulonephritis in a patient with systemic lupus erythematosus.

© 2022 The Author(s). Published by S. Karger AG, Basel

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease. Renal involvement in SLE is usually exhibited as lupus nephritis (LN), which is a form of immune complex-mediated glomerulonephritis and one of the most severe organ manifestations of SLE. LN can develop in approximately 30% of patients with SLE [1]. Pauci-immune crescentic glomerulonephritis (PICGN) is the pattern of injury most commonly observed with antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis. This may present as granulomatosis with polyangiitis (GPA), microscopic polyangiitis, eosinophilic GPA, or renal limited vasculitis [2]. The characteristic histological feature of PICGN is focal necrotizing and crescentic glomerulonephritis with little or no glomerular staining for Ig by immunofluorescence (IF) microscopy. PICGN is rarely observed in the course of other autoimmune diseases. We report a rare case of ANCA-negative PICGN in a patient with SLE.

A 44-year-old woman presented with multiple joint pains, oral ulcers, malar rash, and alopecia in March 2021. She has no known medical condition prior to presentation and did not use any over-the-counter supplements or traditional medication. Family history was insignificant for any autoimmune disease.

Physical examination revealed vasculitic rash over both lower limbs, right neck lymphadenopathy, and body temperature of 36.5°C. She was normotensive. Other systemic examination findings were unremarkable.

Laboratory tests showed hemoglobin level of 10.3 g/dL, platelet count of 116 × 109/L, and white blood cell count of 3.8 × 109/L with eosinophil count of 1%. Peripheral smear did not show any presence of schistocytes. The renal profile was normal with urea level of 3.6 mmol/L and creatinine level of 46 µmol/L. The serum albumin level was 25 g/L. She also had increased liver enzyme levels: aspartate aminotransferase level of 412/μL and alanine aminotransferase level of 116/μL. C3 level was slightly low (0.8 g/L; normal range, 0.9–1.8), with C4 level of 0.1 g/L (normal range, 0.1–0.4). Moreover, the erythrocyte sedimentation rate was 92 mm/h. Urine analysis revealed 2+ protein and 4+ erythrocyte. The 24-h urine protein level was 0.88 g with total urine volume of 2,500 mL.

Autoimmune serological workup ensued and included the following: antinuclear antibody (IF assay) was positive at 1:1,280 with a homogeneous pattern and positive for dsDNA with titer >400 IU/mL. Antinucleosomes and antihistones were positive. pANCA, cANCA, antimyeloperoxidase, and antiproteinase 3 were all negative (indirect IF and fluoroenzyme immunoassay method). The other autoantibodies to extractable nuclear antigens (Jo-1, Sm, SSA, SSB, Scl-70, centromere protein B, ribosomal P-protein), anti-beta 2 glycoprotein 1, and anti-cardiolipin antibody were negative.

The patient underwent excisional biopsy for right neck lymphadenopathy, and histopathologic examination showed histiocytic necrotizing cervical lymphadenitis, which is suggestive of Kikuchi disease. Right leg skin punch biopsy for vasculitic rash was also performed, and the findings were consistent with cutaneous vasculitis involving small superficial vessels with predominant lymphocytic cell infiltration.

She was diagnosed with SLE and started prednisolone, hydroxychloroquine, and vitamin D analogs. Renal sonography showed 11-cm kidneys with no hydronephrosis. A renal biopsy was performed on June 1, 2021. There were 23 glomeruli in the renal biopsy with two cellular/fibrocellular crescents. There were eight glomeruli with segmental endocapillary hypercellularity, one with global glomerulosclerosis and one with segmental sclerosis. Neutrophilic infiltration is noted in five glomeruli. Focal segmental glomerular capillary wall thickening is observed. Silver staining highlights occasional membrane vacuolation. No necrosis or hyaline deposits were found. There were also focal chronic tubulointerstitial damage and moderate acute interstitial nephritis (Fig. 1). IF examination showed no staining for IgG, IgA, IgM, C1q, C3, kappa, and lambda light chain (Fig. 2, 3).

Periodic acid-Schiff staining of kidney biopsy of the patient shows segmental endocapillary hypercellularity with cellular crescent (original magnification, ×200).

Immunofluorescent microscopic pattern showing lack of staining for IgG, IgM, IgA, and C3.

Immunofluorescent microscopic pattern showing lack of staining for C1q, kappa, and lambda light chain.

Induction treatment was started with monthly intravenous cyclophosphamide 0.75 g/m2 (NIH regime), approximately 1.2 g each cycle in addition to oral prednisolone. She completed a 6-month course of monthly intravenous cyclophosphamide and tapering dose of prednisolone.

At follow-up, her creatinine remains static, and the 24-h urinary proteinuria reduced to 0.14 g. The microscopic hematuria resolved, and the serum albumin and complements level normalized.

This patient fulfilled the 2019 European League against Rheumatism/American College of Rheumatology classification for SLE (six criteria: hematologic, mucocutaneous, musculoskeletal, renal involvement, low C4 level, and presence of anti-dsDNA antibody) [3]. In patients with SLE, LN is the most common kidney complication. The pathogenesis involved glomerular immune complex deposition, which leads to glomerular inflammation and typically exhibits a “full-house” pattern on IF. The International Society of Nephrology and the Renal Pathology Society (ISN/RPS) classify LN based on the location of accumulation of immune complexes in the glomeruli, presence or absence of mesangial or endocapillary proliferation, overall extent of glomerular involvement (focal or diffuse) and glomerular injury (global or segmental), and whether glomerular injury is active (inflammatory) or chronic (sclerotic) [4]. The kidney may also sustain damage by other mechanisms, such as thrombotic microangiopathy. Thus, renal biopsy plays a crucial role in confirming the diagnosis.

The biopsy in our patient revealed PICGN, and ANCA serology was negative. PICGN is a subtype of proliferative glomerulonephritis generally noted in association with conditions such as microscopic polyangiitis and GPA. The pathogenesis that is distinct from all other immune complex-mediated glomerulonephritis cases, namely, immune complex deposition and antiglomerular membrane antibody reaction, cannot be demonstrated. Cases of such pauci-immune crescentic glomerulonephritis occurring in SLE are distinctly rare. Schwartz et al. [5] in 1983 reported 4 cases of SLE with severe active glomerulonephritis in which IF microscopy revealed only minimal deposition of immune reactants. The possibility of cell-mediated rather than antibody/immune complex-mediated glomerular injury is to explain “pauci-immune” proliferative crescentic glomerulonephritis. This would involve the interaction of endothelial cells with lymphocytes, monocytes, and neutrophils, activated to inflict glomerular injury independent of antibodies or immune complexes [6].

More than 90% of patients with PICGN have circulating ANCA. The role of ANCAs in the pathogenesis of glomerulonephritis is not fully understood, although it has been suggested that ANCAs activate neutrophils and monocytes within the glomerular capillaries, resulting in necrotizing glomerular injury. In a small number of patients with PICGN, circulating ANCA was negative, and this subgroup of patients had not been investigated fully, except for a few studies [7, 8].

In light microscopy of PICGN, glomeruli showed segmental glomerular basement membrane breaks, necrosis, and crescents, often at varying stages of organization, ranging from cellular to fibrocellular to fibrous. Unaffected portions of the glomeruli do not show significant proliferation [2]. Renal biopsy of our patient showed endocapillary hypercellularity in 8 of 23 glomeruli, and two glomeruli showed evidence of cellular/fibrocellular crescent. These light microscopic features are more suggestive of LN. However, the IF examination of our patient’s renal biopsy showed negative staining for immunoglobulins. Thus, it does not fulfill the ISN/RPS classification for LN. We concluded that our patient had PICGN in the background of SLE. There is no standard treatment for PICGN in SLE because cases are rare, but the use of the combination of cyclophosphamide and corticosteroids with variable evolution is common [6, 9].

Both cases reported by Akhtar et al. [9] apparently responded to steroid and cyclophosphamide treatment. Three of five patients presented by Charney et al. [6] also responded to therapy. Two received daily cyclophosphamide and prednisolone, and one received not only cyclophosphamide and prednisone but also plasma exchange. Our patient responded well to cyclical IV cyclophosphamide and prednisolone.

The authors thank Dr. Norra Harun, consultant histopathologist, Hospital Tengku Ampuan Afzan, for providing the images in Figures 1–3.

The authors have no ethical conflicts to disclose. Written informed consent was obtained from the patient for publication of this case report, including the histology images. The case report is based entirely on data abstraction from existing medical or laboratory record obtained during patient care without any interventions. Ethical approval was not required for this study in accordance with local/national guidelines.

There are no relevant conflicts of interest to declare.

No funding received.

Chee Eng Chan obtained the history, performed the physical examinations, and obtained investigational report. Tze Jian Ng wrote the initial draft. Mohd Kamil Ahmad and Fariz Safhan Mohamad Nor reviewed the paper and revised it. All the authors read and approved the final manuscript.

All data are included in this article. Further inquiries can be directed to the corresponding author.

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