Hypocomplementaemic urticarial vasculitis with mesangioproliferative glomerulonephritis, interstitial nephritis and absent immune staining

A 62-year-old male with a history of chronic episodic urticaria, recent hypertension and past smoking (4.8 pack-years) was referred to the hospital after presenting to his general practitioner with progressive dyspnoea, fatigue and night sweats. He reported a 15-year history of weekly, transient, non-pruritic, urticarial plaques over the entire body and angioedema affecting the lips and tongue. Angioedema was reported to occur monthly and was responsive to antihistamines with episodes lasting 24 h. There were no obvious environmental or medication exposures identified. On examination, blood pressure was 190/84 mmHg, and there was bilateral pitting oedema below the knees. An erythematous non-scaly unilateral plaque measuring 2 cm was present on the right shoulder. Laboratory investigations found normocytic anaemia (Hb 72 g/L) and acute kidney injury (creatinine 231 μmol/L). Previous baseline creatinine prior to presentation was normal at 90 μmol/L. Urinalysis showed proteinuria (protein/creatinine ratio 240 mg/mmol) and active sediment (erythrocytes >500 × 106/L). A renal tract ultrasound found normal sized kidneys with no evidence of obstruction. Investigations for glomerulonephritis showed hypocomplementaemia (C3 0.32 g/L; C4 < 0.08 g/L) and positive antinuclear antibodies (1:80, speckled pattern). Serologic testing was negative for antibodies against extractable nuclear antigen, double-stranded DNA, glomerular basement membrane, myeloperoxidase, proteinase-3, rheumatoid factor and beta 2 glycoprotein. Hepatitis B, hepatitis C, HIV serology and cryoglobulins were negative. Spirometry revealed a moderate obstructive defect (FEV1 2.32 L, 65% of predicted). A kidney biopsy was performed. By light microscopy, the predominant finding was a patchy mild to moderate interstitial nephritis, with the inflammatory infiltrate including lymphocytes, histiocytes and some eosinophils (Fig. 1A). There was generalised dilatation of tubules, with some tubules containing degenerate blood. Examination of glomeruli found mild mesangial expansion and hypercellularity in some glomeruli. Capillary loops were patent, and there was no endocapillary proliferation or crescents. By silver stain, there were no double contours or basement membrane spikes. Notably, the immunohistochemistry panel was all negative, including for IgG, IgM, C3c, C4d and C1q (Fig. 1B). Electron microscopy confirmed mesangial hypercellularity and revealed numerous mesangial and subendothelial immune-type deposits, some characterised by parallel curvilinear bands with a fingerprint-like pattern (Fig. 1C,D). Electron microscopy findings confirmed the presence of deposits, which is suggestive of a false negative of the immunohistochemistry panel. No immunofluorescence was performed. After a dermatology review, a skin biopsy was performed. By light microscopy, there was moderate dermal neutrophilia, consistent with neutrophilic urticaria. Direct immunofluorescence was performed and did not reveal staining for IgG, IgM, IgA, C3, C4 or C1q. There was no histological evidence of vasculitis. The features in this case of urticaria, glomerulonephritis and hypocomplementaemia raised the possibility of hypocomplementaemic urticarial vasculitis (HUV), a rare form of small vessel vasculitis that causes multi-organ dysfunction. Further serological testing revealed markedly reduced C1q (<12 mg/L, NR 118–244 mg/L) and very high-level anti-C1q antibody level (>100 U/mL, above the quantifiable limit of the assay), establishing a diagnosis of HUV, based on the criteria proposed by Schwartz et al., fulfilling both major criteria (chronic urticarial exanthema and hypocomplementaemia) and two minor criteria (glomerulonephritis, positive C1q antibodies).1 Interestingly, the skin biopsy findings in this case of neutrophilic urticaria have been associated in previous studies with systemic disease including HUV.2 Furthermore, obstructive pulmonary disease, as was noted in the present case, is also a feature of HUV and is associated with a poorer prognosis.3 A recent review of renal pathology in HUV patients with kidney involvement showed that the commonly observed patterns are membranoproliferative (35%), mesangioproliferative (21%) and membranous (19%) glomerulonephritis.4 HUV with renal involvement is usually characterised by a full-house pattern of immunostaining,4 hence the absence of immunostaining, as well as the predominance of tubulointerstitial inflammation, in our case are atypical. Optimal therapy in HUV with kidney involvement is unclear; however, aggressive immune suppression, including high dose of corticosteroids, is commonly deployed.4, 5 The patient was treated with three doses of methylprednisolone 500 mg daily, followed by oral prednisolone 60 mg daily and weaned for a total duration of 2 years. Mycophenolate mofetil 750 mg twice a day was prescribed as a steroid sparing agent, which was subsequently ceased after 10 months of treatment due to neutropenia. After 12 months of treatment, the patient had improvement of kidney function with a new baseline creatinine of 120 μmol/L and resolution of proteinuria and haematuria. The data that support the findings of this study are available from the corresponding author upon reasonable request.