What are the types of cryoglobulinemic glomerulonephritis?

Types of Cryoglobulinemic Glomerulonephritis

Cryoglobulinemic glomerulonephritis is classified into two main types based on the immunoglobulin composition: Type I (monoclonal) and Type II/III (mixed cryoglobulinemia), with only Type I and II cryoglobulinemias considered associated with monoclonal immunoglobulins and causing renal disease. 1

Classification by Cryoglobulin Type

Type I Cryoglobulinemia

• Contains monoclonal immunoglobulin only (typically IgM or IgG) 2
• Associated with lymphoproliferative disorders such as multiple myeloma, Waldenström macroglobulinemia, or B-cell lymphomas 2
• Characterized by immunoglobulin thrombi in arterioles and glomerular capillaries that exhibit crystalline structure or periodicity on electron microscopy 1
• Can present with intravascular cryoglobulin thrombi or endovasculitis affecting blood vessels 1

Type II Mixed Cryoglobulinemia (Most Common Renal Type)

• Composed of monoclonal IgM (usually IgMκ) acting as rheumatoid factor bound to polyclonal IgG 3
• Accounts for 74.4% of cryoglobulinemic glomerulonephritis cases 4
• Strongly associated with hepatitis C virus infection (87% of cases) 4
• The monoclonal IgM component specifically targets the polyclonal IgG, forming immune complexes 3

Type III Mixed Cryoglobulinemia

• Contains polyclonal IgM bound to polyclonal IgG 2, 3
• Less commonly causes glomerulonephritis compared to Type II 4
• Also associated with HCV infection and autoimmune diseases 2

Histopathologic Classification

Membranoproliferative Pattern (Most Common)

• Diffuse membranoproliferative glomerulonephritis occurs in approximately 80-83% of cases 1, 4
• Characterized by large deposits filling capillary lumens with fibrillar or crystalloid structure on electron microscopy 3
• Massive monocyte infiltration creates prominent exudative component 3
• Double-contoured glomerular basement membrane appearance due to peripheral monocyte interposition 3

Crystalline Variant (Cryocrystalglobulinemic Glomerulonephritis)

• Rare variant characterized by immunoglobulin thrombi with crystalline structure in arterioles and glomerular capillaries 1
• Exhibits crystalline structure or periodicity on electron microscopy 1
• Crystallization in periphery can be precipitated by cold exposure, resulting in small-vessel occlusion and thrombosis 1

Crescentic/Rapidly Progressive Pattern

• Can present as rapidly progressive glomerulonephritis with crescent formation 5
• Immune complex-type RPGN with granular deposits of IgA, IgG, and C3 5
• Occluding protein thrombi in glomerular capillary loops 5

Ultrastructural Features

Microtubular Deposits

• Cryoglobulinemic glomerulonephritis features microtubular immunoglobulin deposits with hollow centers 1
• Microtubules have large diameters ranging from 17-52 nm, distinguishing them from fibrils 1
• Organized in parallel arrays visible on electron microscopy 1

Anatomic Distribution

• Lesions mainly involve glomeruli but can occasionally affect blood vessels 1
• Intravascular cryoglobulin thrombi or endovasculitis may be present 1
• Subendothelial deposits predominate in immune complex deposition 5

Clinical Presentation Patterns

Acute Nephritic Syndrome (15%)

• Characterized by acute onset with hematuria and renal impairment 1
• Massive monocyte infiltration distinguishes it from idiopathic MPGN 3

Nephrotic Syndrome (20%)

• Proteinuria >3 g/24h with edema and hypoalbuminemia 1
• Some patients show mixed nephrotic and nephritic features 1

Isolated Proteinuria with Microscopic Hematuria (30%)

• Most common presentation with proteinuria <3 g/24h 1
• Usually accompanied by microscopic hematuria 1

Acute Renal Failure (10%)

• Rapid decline in kidney function, sometimes with oligoanuria (5%) 1
• May require plasmapheresis and immunosuppression 5

Important Clinical Caveats

• Type I and II are the only cryoglobulin types considered associated with monoclonal immunoglobulins in the context of MGRS (Monoclonal Gammopathy of Renal Significance) 1
• HCV genotype 1b is more frequent than genotype 2 (55% vs 43%) in cryoglobulinemic glomerulonephritis 4
• Age, serum creatinine level, and proteinuria at onset independently predict risk for severe renal failure 4
• Cardiovascular disease accounts for >60% of deaths, reflecting improved survival with modern therapies 4
• Renal biopsy is mandatory in any patient with urinary abnormalities or unexplained renal impairment to determine histologic pattern and guide therapy 1