CRYOGLOBULINEMIA and its pathophysiology
- 1. CRYOGLOBULINEMIA PRESENTER – Dr Gaurav DM Nephrology Resident
- 2. Outline • INTRODUCTION • CLASSIFICATION • HEPATITIS C VS NON-HEPATITIS CRYOGLOBULINEMIA • PATHOGENESIS • CLINICAL FEATURES • MICROSCOPY • INVESTIGATIONS • TREATMENT
- 3. INTRODUCTION • Cryoglobulinemia is defined as the presence of cryoglobulins in the serum, which are immunoglobulins that reversibly precipitate at 4 °C and form a gel when the temperature is 37 °C • Hepatitis C – 80 to 90% of cases • Mixed Cryoglobulinemia represent 60–75% of all cryoglobulinemia's, and are found in connective tissue diseases, and infectious or lymphoproliferative disorders.
- 9. Etiology
- 10. Hepatitis C virus mixed cryoglobulinemia and kidney disease
- 11. Pathogenesis 1. High concentrations of HCV envelope protein E2 in vitro stimulate B-cell expansion via interaction with CD81, a known HCV E2 entry factor 2. IgG-bound HCV specifically drives 3. The clonal expansion of B cells secreting IgM RF 4. Monoclonal B-cell expansion leading to type II MC may evolve into frank B-cell non-Hodgkin lymphoma.(10%) 5. Transformation from polyclonal B-cell proliferation (type III MC) to oligo/monoclonal B cell proliferation (type II MC) and to the overt malignant lymphoma is a multistep process probably requiring multiple mutagenic events
- 15. PURPURIC LESIONS
- 16. Necrosis in patients with Cryoglobulinemia
- 17. Non-HCV mixed cryoglobulinaemic vasculitis • Prevalence reported as approximately 1:100,000 individuals • Idiopathic cryoglobulinemia vasculitis is considered to be a rare disorder, but no recent study has evaluated the prevalence of the disease. • Idiopathic cryoglobulinemia vasculitis appears more common aged 45–65 years, maximum incidence in women • Worse prognostic factors were age (> 60 years) and renal involvement
- 18. • The rates of most clinical and immunological manifestations of MC vasculitis are quite similar in HCV-positive and -negative patients • Renal manifestations are more frequently reported in HCV-negative patients, in 14–63 % of patients • Renal involvement was characterized by microscopic hematuria in all patients, nephrotic range proteinuria in 75% of patients, hypertension in 80% of patients, and renal failure in 85% • Type I cryoglobulinemia develops in the setting of protein-secreting monoclonal gammopathies such as a monoclonal gammopathy of undetermined significance (MGUS) or a B-cell lineage malignancy (eg, multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia)
- 20. CRYOGLOBULINEMIA AND RENAL DISEASE • The first clinical manifestations of type II MC usually appear in the fourth to fifth decade of life. • More common in Women outnumber men • Cryoglobulins are deposited in the mesangium during their trafficking in the glomerulus. • They can also be seen as intense subendothelial IgM deposits by immunofluorescence • Their nephrotoxicity is related to special affinity of the IgMκ RF for cellular fibronectin present in the mesangial matrix • Only the RF isolated from cryoprecipitable type II MC had specific affinity; all the other monoclonal RFs are not able to fix fibronectin
- 21. • Cryoglobulins can also be deposited in the glomerular capillaries as eosinophilic thrombi and this is usually associated with vasculitis and fibrinoid necrosis of the glomeruli • Immune complexes containing HCV antigens have been observed in the mesangium of patients with cryoglobulinaemia leading to mesangial expansion • The presence of HCV-related proteins in the mesangium has been associated with higher proteinuria, possibly reflecting direct mesangialdamage by HCV . • An increased expression of toll-like receptors has been found in the mesangial cells target of HCV-related MPGN, but not non-HCV MPGN.
- 22. Case series • In large series was made by Roccatello et al. (2007), who included 146 patients with cryoglobulinemic nephritis, of whom 87% (N = 127) were HCV positive. • Type II cryoglobulin (IgG/IgMκ) occurred in 74.4% of cases. The remainder had type III cryoglobulins. • A diffuse MPGN was the most common histologic pattern (83%). • Survival at 10 years was about 30% and cardiovascular disease was the cause of death in > 60% of patients; additional causes of death included infections (10%), hepatic failure (19%), and neoplasia (3%). • Poor Prognosis – Elevated Creatinine (>1.5mg/dl), Nephrotic range Proteinuria, Severe Hypertension, >50% crescents or Marked IFTA
- 23. • Cryoglobulinemia PAS-positive findings in skin biopsy deposits can help differentiate type I cryoglobulinemia from other thrombotic vasculopathies • Cryoglobulinemic glomerulonephritis PAS-positive cryo-plugs in capillary lumens are a key diagnostic feature. Other features include chunky, irregular capillary wall deposits, globular intracapillary deposits, and a double-contour appearance of the basement membrane on silver stain PAS-positive intracapillary deposits in the kidney glomeruli can help distinguish between vasculitis associated with infections, medications, or autoimmune diseases not involving cryoglobulins
- 25. Light Microscopy
- 26. A Double-contour Appearance Of The Basement Membrane On Silver Stain
- 29. Treatment • Treatment of cryoglobulinemia depends upon the underlying disorder and upon the severity and nature of involvement • Hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis used to be a severe disease with an estimated five-year mortality rate of 25 percent • • Apart from liver fibrosis, the prognosis of HCV-associated cryoglobulinemic vasculitis is mainly dependent on vasculitic involvement of the kidney, central nervous system, heart, and gastrointestinal tract
- 31. Collection A. 10 to 20 mL of blood is collected and prepared at 37°C without the addition of anticoagulants. The serum is then centrifuged and then refrigerated to allow precipitation of cryoglobulin. B. Type I cryoglobulinemia presents as a precipitate within 24 hours with a 3 to 5-day window. Type II/III present with precipitation approximately 5 to 7 days after initial refrigeration C. Cryocrit in individuals without cryoglobulinemia is close to zero, and a cryocrit greater than 0.5 to 1 percent or concentration over 50 mcg/mL is significant. D. In type II, cryocrit is between 2 to 7 percent, while type III holds to around 1 to 3 percent Predictive measure for cryoglobulinemia is based on the measurement of cryoglobulin coupled with a low C4 complement level. This combination is typical of cryoglobulinemia syndromes
- 34. Management
- 38. Therapy
- 41. • Two RCTs have demonstrated the superiority of rituximab monotherapy as compared with conventional immunosuppressive therapy (i.e., corticosteroids, azathioprine, cyclophosphamide, methotrexate, and plasma exchange) for the treatment of HCV- associated cryoglobulinemic vasculitis
- 42. Rituximab • Rituximab interferes with synthesis of cryoglobulins, monoclonal IgM, and renal deposition of immune complexes. • An important pathogenetic feature of mixed cryoglobulinemia (including cryoglobulinemic GN) is chronic stimulation of B lymphocytes by HCV and widespread autoantibody synthesis related to HCV-induced lowering of the cell activation threshold. • Potential regimens include rituximab (375 mg/m2 weekly for 4 weeks, or 2 doses of 1 g given 14 days apart) with or without corticosteroids
- 43. Thank You