Double Trouble: Dual Positivity for Antiglomerular Basement Membrane Antibody and proteinase-3-antineutrophil Cytoplasmic Antibody Presenting as Rapidly Progressive Glomerulonephritis

Abstract

Antiglomerular basement membrane (anti-GBM) disease and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are uncommon causes of rapidly progressive glomerulonephritis. Their coexistence, termed double-positive disease, is rare and associated with severe renal and pulmonary manifestations. A 27-year-old male came with complaints of inflammatory polyarthralgia followed by progressive dyspnea and hemoptysis. Investigations revealed azotemia, active urinary sediment with proteinuria, bilateral pulmonary infiltrates, and dual seropositivity for anti-GBM antibodies and proteinase-3-ANCA. A diagnosis of double-positive vasculitis with pulmonary-renal syndrome was made. The treatment of the patient started with intravenous methylprednisolone, therapeutic plasma exchange, and intravenous cyclophosphamide, followed by oral glucocorticoids. Renal function improved significantly, with serum creatinine decreasing from 2.44 mg/dL at presentation to 1.42 mg/dL at discharge. The patient remained clinically stable during follow-up. Double-positive anti-GBM and ANCA disease represents a distinct clinical entity with overlapping features of both conditions. Early recognition and aggressive immunosuppressive therapy can result in favorable renal outcomes.

INTRODUCTION

Small-vessel vasculitis is characterized by a heterogeneous group of immune-mediated diseases representing necrotizing inflammation of arterioles, capillaries, and venules.[1] Among these, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and anti–glomerular basement membrane (anti-GBM) disease are uncommon but important causes of rapidly progressive glomerulonephritis (RPGN).[1,2] Individually, both entities are rare; however, their coexistence, termed double-positive disease, is increasingly recognized in clinical practice. This disorder poses unique diagnostic and therapeutic challenges, as it shares clinical, serological, and prognostic features of both diseases.[3,4] Patients having such a disorder frequently present with severe renal involvement and pulmonary hemorrhage, often manifesting as pulmonary–renal syndrome.[3,4] Compared with isolated anti-GBM disease, double-positive patients may demonstrate better odds of initial kidney recovery, but unlike classic anti-GBM disease, they retain a significant risk of relapse similar to AAV. Early diagnosis and timely initiation of aggressive immunosuppressive therapy, including plasma exchange, are therefore crucial to improving outcomes. We report a case of a 27-year-old male with double-positive anti-GBM and proteinase-3 (PR3)-AAV who responded favorably to early aggressive treatment.

CASE REPORT

A 27-year-old male with no known comorbidities presented with intermittent inflammatory arthralgias involving various small and large joints such as hands, wrists, knees, ankles, and shoulders for 2 months. The arthralgias were associated with early morning stiffness lasting more than 1 h. There was no history of joint swelling, deformity, skin rash, photosensitivity, oral ulcers, or Raynaud phenomenon.

One month later, he developed progressive dyspnea on exertion accompanied by a dry cough and a single episode of hemoptysis. There were no febrile episodes, night sweats, weight loss, hematuria, oliguria, recent upper respiratory tract infection, or exposure to nephrotoxic drugs. He was a nonsmoker and had no history of alcohol intake or substance abuse.

He had been empirically initiated on antitubercular therapy at another center based on radiological suspicion of pulmonary tuberculosis; however, treatment was discontinued after 1 week due to suspected drug-induced hepatitis. He was later on referred to the higher center for further management.

On examination, the patient was pale and tachypneic. Blood pressure recorded was 148/94 mmHg, pulse rate 96 beats/min, respiratory rate 22 breaths/min, and SpO₂ 92% on room air. Body mass index was 16.4 kg/m². Chest examination revealed bilateral fine basal crackles. Cardiovascular, abdominal, and neurological examinations were unremarkable. There was no peripheral edema, rash, or synovitis.

Investigations

Laboratory evaluation revealed normocytic normochromic anemia with hemoglobin of 8.9 g/dL. Serum creatinine was raised to 2.44 mg/dL, with blood urea of 78 mg/dL. Urinalysis showed proteinuria (2+), microscopic hematuria, and an active urinary sediment with dysmorphic red blood cells. Twenty-four–hour urinary protein excretion was 1.6 g/day.

Ultrasonography of the kidneys demonstrated normal-sized kidneys with increased cortical echogenicity and preserved corticomedullary differentiation. High-resolution computed tomography of the thorax was suggestive of bilateral patchy and confluent consolidations with surrounding ground-glass opacities, suggestive of alveolar hemorrhage.

Sputum examination was negative for acid-fast bacilli and a cartridge-based nucleic acid amplification test, effectively excluding pulmonary tuberculosis. Serological evaluation was positive for anti-GBM antibodies and PR3 ANCA. Antinuclear antibodies, anti–double-stranded DNA antibodies, complement levels, and viral serology were within normal limits.

Diagnosis

Based on the clinical presentation, radiological findings, active urinary sediment, and blood workup positive for both anti-GBM antibodies and PR3-ANCA, a diagnosis of RPGN due to double-positive anti-GBM and AAV with pulmonary involvement was established.

Management

The treatment started with intravenous methylprednisolone 500 mg daily for three consecutive days; after that, the patient was shifted on oral prednisolone at a dose of 40 mg/day. Given the presence of pulmonary involvement and impaired renal function, therapeutic plasma exchange was performed for five sessions on alternate days. Induction immunosuppression was achieved with intravenous cyclophosphamide 500 mg administered with mesna for uroprotection.

Following therapy, the patient demonstrated significant clinical and biochemical improvement. Dyspnea resolved, hemoptysis did not recur, and oxygen saturation normalized. Renal function improved, with serum creatinine decreasing to 1.42 mg/dL. He was continued on oral glucocorticoids with a gradual taper, along with antiproteinuric therapy. A second dose of intravenous cyclophosphamide was administered 2 weeks later. At follow-up, he remained clinically stable with preserved renal function, and serial laboratory parameters remained stable over subsequent visits [Table 1].

Table 1.

Laboratory parameters in follow-up visits of patient

	March 2025	April 2025	May 2025	June 2025
Test	Result
Hemoglobin	10.7 gm/dl	12.8 gm/dl	13.6 gm/dl	14.9 gm/dl
Total Leukocyte Count (TLC)	6500/ul	6800/ul	6700/ ul	8800/ ul
Platelet Count	211,000/ul	205,000/ul	237,000/ul	269,000/ul
Creatinine	1.00 mg/dl	1.02 mg/dl	0.97 mg/dl	1.04 mg/dl
Urea	29 mg/dl	21 mg/dl	31 mg/dl	32 mg/dl
Sodium (Na)	136 mmol/L	137 mmol/L	139 mmol/L	139 mmol/L
Potassium (K)	4.43 mmol/l	4.05 mmol/l	4.78 mmoll	4.86 mmol/l
Urine Routine	Protein 1+ RBC 5-6. Pus 2-3. Casts not detected	Protein 2+ RBC 8-10. Pus 6-8, Casts not detected	Protein 2+, RBC 1-2. Pus 1-2. Casts not detected	Protein 3+, RBC 3-4. Pus 1-2, Casts not detected
Urine Protein Creatinine Ratio (UPCR)	6.3	7.2	7	7.25

DISCUSSION

Anti-GBM disease and AAV are individually rare, with reported annual incidences of approximately 1–2 per million and 15–20 per million population, respectively.[2,3] The concurrrence of anti-GBM antibodies and ANCA has been reported in up to 30%–40% of patients with anti-GBM disease, most commonly with myeloperoxidase-ANCA, although PR3-ANCA positivity has also been described.[4]

The pathogenesis of double-positive disease remains incompletely understood. One proposed mechanism suggests that ANCA-mediated neutrophil activation leads to GBM damage, exposing cryptic antigens and triggering anti-GBM antibody formation.[4]

Compared with isolated anti-GBM disease, double-positive patients have a higher likelihood of renal recovery if treated early, particularly when dialysis is not required at presentation.[3,4] However, unlike classic anti-GBM disease, they are prone to disease relapse, reflecting the AAV component. Consequently, long-term follow-up is essential.

Current international guidelines recommend induction therapy with high-dose steroids and cyclophosphamide or rituximab for severe AAV. Plasmapheresis is recommended in cases of severe renal impairment or pulmonary hemorrhage.[5]

Our patient benefited from early recognition and prompt initiation of combined therapy, resulting in meaningful renal recovery and resolution of pulmonary manifestations.

CONCLUSION

Double-positive anti-GBM and AAV is a rare but clinically significant cause of pulmonary–renal syndrome and RPGN. Awareness of this entity and rapid aggressive treatment with immunosuppression and plasma exchange are critical in improving renal and patient survival.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.