Mixed Cryoglobulinemic Glomerulonephritis



Mixed Cryoglobulinemic Glomerulonephritis


A. Brad Farris, III, MD





Key Facts


Terminology



  • GN due to immunoglobulins soluble at 37°C, reversibly precipitate with cooling


Etiology/Pathogenesis



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


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


Clinical Issues



  • Proteinuria &/or hematuria


  • Cryoglobulin serum precipitate, typically IgG and IgMκ


  • “Essential mixed cryoglobulinemia syndrome” of vasculitis with cutaneous purpura, urticaria, weakness, & arthralgias


Microscopic Pathology



  • Glomerular mesangial and capillary hypercellularity


  • Glomerular basement membrane duplication


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


Ancillary Tests



  • IgG, IgM, and C3 seen most often on IF


  • Microtubules, rings, and annular structures on EM


  • Many glomerular monocytes/macrophages may be CD68(+)


Top Differential Diagnoses



  • Lupus nephritis, idiopathic MPGN, other GNs


  • Immunotactoid glomerulopathy


  • Thrombotic microangiopathy (TMA)







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.


TERMINOLOGY


Abbreviations



  • Cryoglobulinemic glomerulonephritis (CryoGN)


Synonyms



  • Cryoglobulinemic GN


  • Membranoproliferative GN


  • Essential mixed cryoglobulinemic GN


Definitions



  • 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)


ETIOLOGY/PATHOGENESIS


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)


CLINICAL ISSUES


Presentation



  • “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


Treatment



  • 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


Prognosis



  • 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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunohistochemistry

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

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