Cryoglobulinaemic Glomerulonephritis

Cryoglobulinaemic glomerulonephritis is an immune complex glomerulonephritis caused by cryoglobulins, immunoglobulins that precipitate in the cold and redissolve on rewarming. Type I is monoclonal (IgM or IgG; associated with myeloma, Waldenström macroglobulinaemia and lymphoma). Type II is mixed, with a monoclonal IgM kappa rheumatoid factor bound to polyclonal IgG. Type III is mixed with polyclonal IgM and IgG.

Types II and III account for most cases, and hepatitis C virus infection accounts for 80 to 90% of mixed cryoglobulinaemia worldwide; other causes are hepatitis B, HIV, systemic lupus erythematosus, Sjögren syndrome, lymphoproliferative disease and idiopathic disease. Kidney involvement occurs in 20 to 35% of patients with mixed cryoglobulinaemia, usually as a membranoproliferative glomerulonephritis.

Pathophysiology. Cryoglobulin complexes deposit in glomeruli and small vessels, activating the classical complement cascade (low C4 and CH50, relatively normal C3) and recruiting monocytes, producing endocapillary proliferation, intraluminal hyaline "thrombi" (precipitated cryoglobulin) and basement membrane double contours.

• Meltzer triad: palpable purpura (lower limbs, recurrent), arthralgia and weakness.
• Kidney: nephritic or nephrotic syndrome, microscopic haematuria, proteinuria, hypertension, acute kidney injury (about 20%) or rapid progression with crescents.
• Peripheral neuropathy (mononeuritis multiplex or sensory polyneuropathy), skin ulcers, Raynaud phenomenon, livedo, digital ischaemia (type I).
• Hepatic disease from hepatitis C, sicca symptoms, lymphadenopathy, and hyperviscosity in type I (headache, visual loss, bleeding).

Red flags

• Rapid loss of kidney function or oliguria.
• Digital gangrene, skin necrosis, gastrointestinal ischaemia or pulmonary haemorrhage.
• Hyperviscosity symptoms (confusion, stroke, visual change).
• Hepatic decompensation or coexisting hepatitis B or HIV.

• Cryoglobulins: warm syringes and tubes to 37°C from collection to the laboratory; serum stored at 4°C for 7 days; cryocrit quantifies (type I above 5%); characterisation by immunofixation. Repeat testing if negative with a high index of suspicion.
• Complement: low C4 with variable C3; rheumatoid factor strongly positive in types II and III.
• Hepatitis C RNA and antibody, hepatitis B surface antigen, HIV, antinuclear antibodies, anti-Ro and anti-La, protein electrophoresis, immunofixation, free light chains, full blood count, liver tests, creatinine, urine microscopy and protein:creatinine ratio.
• Kidney biopsy: membranoproliferative pattern with endocapillary proliferation, monocyte infiltration, and intraluminal hyaline thrombi; immunofluorescence with IgM, IgG and C3; electron microscopy with organised fibrillar or microtubular deposits (cryoglobulin crystals); skin biopsy showing leucocytoclastic vasculitis.
• Bone marrow biopsy and imaging for lymphoproliferative disease; liver assessment (elastography) in hepatitis C.

Differential diagnosis

• Membranoproliferative glomerulonephritis from other causes (hepatitis C without cryoglobulin, C3 glomerulopathy), ANCA vasculitis, lupus nephritis, IgA vasculitis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, light chain disease.

Hepatitis C-associated disease: antiviral therapy

• Glecaprevir and pibrentasvir 300 mg and 120 mg orally daily for 8 weeks (no dose adjustment for kidney failure); alternative sofosbuvir and velpatasvir 400 mg and 100 mg daily for 12 weeks. Sustained virological response is achieved in over 95% and clears cryoglobulins in 60 to 90%.
• With severe or rapidly progressive kidney disease, vasculitis with ulcers or neuropathy, give immunosuppression with the antiviral.

Immunosuppression for severe disease (organ- or life threatening)

• Rituximab 375 mg/m² intravenously weekly for 4 doses, or 1 g on days 1 and 15; with methylprednisolone 500 mg to 1 g intravenously daily for 3 days, then prednisolone 0.5 to 1 mg/kg daily (maximum 60 mg) tapered over 8 to 12 weeks.
• Plasma exchange (3 to 5 litres or 60 mL/kg, 3 to 7 sessions over 2 weeks, warmed fluid and extracorporeal circuit) for hyperviscosity, rapidly progressive glomerulonephritis, or life threatening vasculitis.
• Cyclophosphamide intravenously 15 mg/kg (12.5 mg/kg at age 60 to 70; 10 mg/kg over 70) every 2 weeks for 3 doses if rituximab is contraindicated.

Non-hepatitis C disease

• Hepatitis B: entecavir 0.5 mg daily (renal adjustment) or tenofovir alafenamide 25 mg daily.
• Lymphoproliferative or plasma cell clone: clone directed therapy with haematology (rituximab based chemoimmunotherapy; bortezomib based regimens for type I).
• Autoimmune: treat the underlying disease. Idiopathic mixed disease: rituximab with steroids.

Supportive care

• Avoid cold exposure (keep extremities warm), treat ulcers and neuropathic pain (gabapentin 100 mg after dialysis or at night, maximum 300 mg).
• Blood pressure below 130/80 mmHg; ramipril 2.5 mg daily to 10 mg daily; sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin.
• Prophylaxis during immunosuppression: co-trimoxazole 480 mg daily, proton pump inhibitor, hepatitis B screening and entecavir prophylaxis if core antibody positive.

Monitoring. Hepatitis C RNA at 12 weeks after treatment; cryocrit, C4, rheumatoid factor, creatinine, urine protein:creatinine ratio monthly for 3 months, then every 3 months; relapse in 30 to 50% after rituximab alone.

Referral and escalation. Nephrology, hepatology and rheumatology; haematology for type I; intensive care for hyperviscosity or vasculitic crisis.

Special groups

• Pregnancy: avoid direct acting antivirals (limited data), cyclophosphamide and mycophenolate; treat after delivery unless disease is severe.
• Transplant recipients: hepatitis C can be treated with direct acting antivirals; cryoglobulinaemic glomerulonephritis may recur.