A 60-year-old female was admitted from a renal outpatient clinic for investigation of acute kidney injury and a diffuse constellation of symptoms. She had intermittent haematuria for 1 week prior to her visit, small and large joint aches, increasing peripheral oedema, two discreet episodes of epistaxis and had noticed a purpuric rash spreading over her lower shins and heels bilaterally for the prior 3 days. Her blood pressure in clinic was 149/99. Her urinalysis was 3+ positive for protein and her urinary protein:creatinine ratio was found to be 516. Past medical history was notable only for culture-negative cutaneous tuberculosis treated in 2013. The patient's initial blood tests on arrival and subsequent vasculitic screen are summarised in table 1.
An echocardiogram was normal, suggesting there was no coexistent heart failure. A renal biopsy demonstrated mesangiocapillary glomerulonephritis with multifocal extraglomerular necrotising vasculitis. Immunofluorescence demonstrated large amounts of IgM and IgG in a granular distribution along capillary walls. Electron microscopy demonstrated endocapillary hypercellularity with scattered subendothelial irregular electron-dense deposits and dark electron-dense areas with fine granularity rather than an ordered clear structure. This was in keeping with immunocomplex membranoproliferative glomerulonephritis secondary to cryoglobulinaemia.
This patient's cryoglobulins precipitated out of serum over 6 h, and immunofixation suggested type 1 due to a monoclonal IgMk paraprotein. Low levels of C4 were detected, and there was no rheumatoid factor detected in the cryocrit.
A bone marrow aspirate and trephine was performed to exclude underlying myeloproliferative disease, which demonstrated only reactive marrow. A CT TAP was performed to investigate for underlying malignancy which could be driving the cryoglobulinaemia. This demonstrated a small area of small bowel thickening in the duodenum, and small pleural effusions. This region of bowel was biopsied endoscopically; however, no luminal abnormality could be seen. The biopsy returned as normal.
A bronchoscopy was performed to exclude any active tuberculosis due to her history and abnormal CT thorax findings. This showed unremarkable lavage. There were no acid fast bacilli on Ziehl-Neelsen staining.
Our patient's renal function and oedema continued to worsen. On admission, she was commenced on frusemide 80 mg i.v. b.d., but due to her worsening oedema and newly developing oliguria, a decision was made to commence regular ultrafiltration. In light of her progressive renal dysfunction, and now worsening vasculitic rash, she was commenced on triple immunosuppression with alternative day plasma exchange (with IVIG 5 g), prednisolone (1 mg/kg/day) and rituximab (375 mg/m2 in weekly doses; 600 mg given).
Therapy for type 1 cryoglobulinaemia is unclear, but it has been suggested this should have similarities to that which one would apply to a B-cell disorder, given this is most often the underlying cause. There are small case series suggesting rituximab is safe in mixed cryoglobulinaemia alone or in combination, and at least one trial has suggested it has superior efficacy to cyclophosphamide in a mixed cryoglobulinaemic population including cryo globulinaemic vasculitis. What little evidence does exist for type 1 cryoglobulinaemia suggests rituximab is safe and effective. This is supported by longer-term registry data suggesting rituximab is both effective and well tolerated.
The trial data from ANCA-associated vasculitis suggest cyclophosphamide and rituximab have similar side effect profiles. We felt that we would not be putting our patient unduly at risk by choosing rituximab under the circumstances.
Two days after the initial dose of rituximab, she developed acute respiratory distress and was found to be in florid pulmonary oedema (fig. 1). This was managed successfully by ultrafiltration. She received a second dose of rituximab 1 week later, and within 24 h developed tonic-clonic seizures, severe hypertension (averaging 170/100) and a further episode of flash pulmonary oedema necessitating intubation and ventilation.
On extubation, she was encephalopathic and hyperreflexic. MRI of the head revealed subcortical white matter high T2 and FLAIR signal in the occipital and posterior parietal lobes consistent with PRES (fig. 2). She was loaded with phenytoin (500 mg i.v.), and blood pressure was noted to be 200/100. This was controlled with increasing her oral antihypertensive agents. Repeat bronchoscopy and BAL demonstrated active neutrophils, consistent with ARDS, but no evidence of infection.
She did not receive any further rituximab but continued with plasma exchange, i.v. immunoglobulin and prednisolone. Her repeat cryoglobulin levels decreased but remained detectable despite alternate day plasma exchange for 2 weeks, prompting the initiation of cyclophosphamide (500 mg i.v.).
There have been no further seizures, and her encephalopathy completely resolved over the course of 10 days. Following 1 dose of cyclophosphamide, the cryoglobulin titre fell to undetectable levels. All immunosuppression and plasma exchange were thus discontinued; the cryoglobulin remains undetectable at 8 months of follow-up. Her creatinine has stabilised at 160 micromol/l giving our patient an estimated GFR of 30 ml/min/1.73 m2 and a protein:creatinine ratio of 219.