Mixed Cryoglobulinemic Glomerulonephritis

Mixed Cryoglobulinemic Glomerulonephritis

A. Brad Farris, III, MD

High-power view of a PAS stain shows hyaline, refractile “pseudothrombi” image (also known as PAS-positive “coagulum”), and glomerular basement membrane duplication image in a case of cryoglobulinemic GN.

High-power EM of cryoglobulinemic GN shows curved microtubular structures image and rings image. Without a history of cryoglobulinemia, this might be interpreted as immunotactoid glomerulopathy.



  • Cryoglobulinemic glomerulonephritis (CryoGN)


  • Cryoglobulinemic GN

  • Membranoproliferative GN

  • Essential mixed cryoglobulinemic GN


  • GN due to specific proteins (immunoglobulins) that are soluble at 37°C and reversibly precipitate at cold temperatures

  • Originally described by Meltzer, Franklin, McCluskey, and colleagues (1966)


Infectious Agents

  • Hepatitis C virus (HCV) comprises ≥ 30% of mixed cryoglobulinemias

    • It was once unknown that HCV caused these cases, & these cases were once termed “essential mixed cryoglobulinemias”

Type II Mixed Cryoglobulinemia

  • Renal disease typically occurs with type II mixed cryoglobulinemia & not usually with type I or III

    • Monoclonal component is almost always IgM with kappa light chain (IgMκ)



  • “Essential mixed cryoglobulinemia syndrome”

    • Systemic vasculitis with cutaneous purpura, urticaria, weakness, & arthralgias

      • Biopsy shows leukocytoclastic vasculitis

    • 10-60% of cases have renal disease

  • Proteinuria

    • 1/5 have nephrotic-range proteinuria or nephrotic syndrome

  • Hematuria

    • Some have microscopic hematuria

    • ˜ 25% of patients have acute nephritic syndrome with hypertension, increased serum creatinine, proteinuria, and macroscopic hematuria

    • < 5% of patients develop oliguric or anuric renal failure

  • Renal dysfunction

    • Mild renal insufficiency may be present, but serum creatinine is typically normal

  • Hypertension

    • Commonly occurs & may be rather severe

  • Splenomegaly

Laboratory Tests

  • Cryoglobulin precipitate, typically IgG and IgMκ, detectable as a “cryocrit” or percent of serum composed of precipitate

    • Best detected when blood specimen is maintained at 37°C until clotting is completed

  • C4 (early complement component) low and C3 normal or slightly decreased

  • Serum antibodies against HCV or HCV RNA in most patients


  • Surgical approaches

    • Renal transplantation uncommonly performed because of usual indolent nature

    • May recur in transplant

  • Adjuvant therapy

    • Plasmapheresis for relief of acute exacerbation of renal disease

    • Cryofiltration, whereby patient’s plasma is cooled, precipitating out cryoglobulins, and then rewarmed and reinfused

  • Drugs

    • Corticosteroids

      • Aggressive immunosuppressive therapy (pulse methylprednisolone followed by oral steroids and cyclophosphamide) only used with caution to prevent hepatitis C reactivation; typically only used in patients with severe acute vasculitis and multisystem manifestations

    • Cytotoxic immunosuppressive drugs

      • Cyclophosphamide (Cytoxan)

    • Interferon-α

      • Used to treat hepatitis C virus-associated cryoglobulinemia

    • Ribavirin

    • Rituximab


  • Typically more indolent than idiopathic MPGN

  • Progression to ESRD uncommon, occurring in around 10% of cases (usually in 5-10 years)

  • Death may result from infections, cardiovascular disease, and systemic effects of vasculitis


Histologic Features

  • Glomeruli

    • Diffuse intracapillary hypercellularity with glomerular capillary loop occlusion

      • Leukocytes, particularly monocytes, compose the hypercellularity

    • Eosinophilic, refractile-appearing PAS(+) hyaline deposits fill capillary lumina

      • Known as “intraluminal thrombi” or perhaps more properly “pseudothrombi” since they are not actually composed of fibrin

      • Also called PAS(+) coagulum by some pathologists

    • Glomerular basement membrane (GBM) diffusely thickened, appreciated most readily on PAS or Jones stain

    • Reduplication or “tram tracking” of GBM

    • Crescents (also known as extracapillary proliferation)

    • Mild or marked mesangial proliferation associated with cases having heavy proteinuria and renal failure

  • Tubulointerstitium

    • Interstitial fibrosis and tubular atrophy is usually mild/localized

    • Erythrocyte casts in tubular lumina, particularly during acute episodes

  • Vessels

    • Vasculitis of small- and medium-sized arteries and arterioles (20-25% of cases)

    • Intimal and medial fibrinoid necrosis

    • Intraluminal glassy or refractile deposits in arterioles as they are in glomerular capillary loops

    • Intimal fibrosis eventually replaces areas of fibrinoid necrosis



Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Mixed Cryoglobulinemic Glomerulonephritis

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