Cryoglobulinemic nephritis


Type II mixed cryoglobulinemia almost exclusively causes "cryoglobulinemic nephritis", a disease characterized by different morphological lesions, generally related to different mechanisms of cryoglobulin deposition, with correspondingly different clinical syndromes. 

Morphological pattern Clinical syndrome Immunohistological pattern Cryoglobulin deposition mechanism
Membranoproliferative exudative with thrombi Acute nephritic syndrome Intraluminal thrombi Acute massive precipitation
Membranoproliferative exudative without thrombi Nephrotic syndrome Diffuse parietal Chronic deposition
Lobular membranoproliferative Nephrotic syndrome Peripheral lobular Chronic deposition
Mesangioproliferative Urinary abnormalities Mesangial Initial stage of mesangial deposition


Fig. 1-2. The most common morphological picture is a membranoproliferative exudative glomerulonephritis, characterized by variable degrees of mesangial proliferation and massive intracapillary leukocyte (mainly monocyte-macrophage) accumulation.


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Fig. 3-4. The intense hypercellularity, due to inflammatory cells filling the capillary lumina, is evident at higher magnification. Nephrotic syndrome accompanies generally these forms. 


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Fig. 5. By immunohistochemistry, the massive accumulation of monocyte-macrophages (CD68 positive cells) is evident. This type of glomerular infiltration is rather specific of cryoglobulinemic nephritis, more intense than in other exudative nephritis, such as  acute post-streptococcal GN and diffuse lupus nephritis.


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Fig. 6. ICAM-1 likely mediates monocyte recruitment. 


Fig. 7. VCAM-1 is instead completely negative in the glomerular tuft. A similar VCAM-1 behavior has been found in acute post-streptococcal GN and is very different from that observed in ANCA-associated renal vasculitis

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Rastaldi MP, Ferrario F, et al. J Am Soc Nephrol 2000; 11: 2036-2043, with permission

Fig. 8. Glomerular basement membranes are diffusely and markedly thickened, and frequently show huge subendothelial deposits. 

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Fig. 9. In some cases subepithelial "hump-like" deposits are evident, undistinguishable from those found in acute post-streptococcal GN and in some forms of idiopathic MPGN.


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Fig. 10. Diffuse double contours are highlighted by silver staining. 


Fig. 11. At higher magnification the extension of the double contours is evident. 

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Fig. 12-13. As clearly evidenced by immunohistochemistry, monocyte interposition characterizes the double contour of cryoglobulinemic GN, whereas in idiopathic MPGN this space is occupied by mesangial cells. 


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Fig. 14-15. IgG and IgM granular deposits along the capillary walls are observed by immunofluorescence, probably due to chronic deposition of IgG-IgM cryoglobulins.


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D'Amico G. Kidney Int 1998; 54: 650-671, with permission

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Fig. 16. Huge subendothelial deposits and double contours of the capillary wall are found by electron microscopy. The picture is similar to idiopathic MPGN. (x 1700)

Fig. 17-18. Electron microscopy shows that monocyte-macrophages are likely involved in the degradation of immune deposits. In fact they are found in close proximity to the subendothelial deposits and their cytoplasm contains electrondense material. (x 1700-x 2800)


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Fig. 19-20. Capillary thickening is due to double contours, electrondense deposits, and presence of monocyte-macrophages (that show intense phagocytosis). (x 2800-x 4600)


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Fig. 21. Macrophages containing electrondense material are frequently found also in the capillary lumina. (x 8000)

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Fig. 22. Also mesangial cells are involved in phagocytosis, as witnessed by their foamy appearance. (x 2800)

Fig. 23-24. Ultrastructural examination shows in some cases that deposits have a randomly arranged microtubular structure. (x 6000-x 13000)


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Fig. 25. By high resolution electron microscopy this type of deposition appears completely different from amyloid fibrils. (x 22000)


Fig. 26-27. In about one third of cases the deposits completely fill the capillary lumina (endoluminal thrombi). This picture is caused by acute precipitation of circulating cryoglobulins, and is clinically expressed by acute nephritic syndrome.


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Fig. 28-29. Thrombi are amorphous, eosinophilic and PAS-positive.


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Fig. 30. Huge thrombi can be found in some cases. 

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Fig.31. "Intermediate" pictures, with membranoproliferative exudative GN, subendothelial deposits and rare scattered endoluminal thrombi, can be observed. Although suggestive for cryoglobulinemic GN, these features can also be found in diffuse lupus nephritis.  

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Fig. 32. Monocyte endocapillary accumulation is massive even in these cases. 

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D'Amico G. Kidney Int 1998; 54: 650-671, with permission


Fig 33-34. By immunohistochemistry, macrophage behavior looks different from that observed in ANCA-associated renal vasculitis: few macrophages are acutely activated (27E10 positivity) and the proliferation marker PCNA is almost completely negative.


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Fig. 35-36. IgG and IgM positive endoluminal thrombi are evident by immunofluorescence.


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D'Amico G, Colasanti G, et al. Kidney Int 1989; 35: 1004-1014, with permission

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Fig. 37-38. "Intermediate" pictures show by immunofluorescence both subendothelial deposits and scattered thrombi.


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 Fig. 39-40. Huge endocapillary electrondense deposits are observed by electron microscopy. (x 1700-x 4600)


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Fig. 41. A cut artifact causes the irregular appearance of the thrombus. (x 4600)


Fig. 42-43. Even thrombi can have a structured aspect. (x 22000)


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Fig. 44. Electron microscopy shows monocyte-macrophages in close proximity to the endoluminal thrombi. (x 8000)

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 Fig. 45-46. In 20% of cases mesangial proliferation and lobular mesangial sclerosis characterize a picture which is similar to idiopathic type I MPGN, and is clinically associated to nephrotic syndrome. Even in these cases monocyte-macrophages are present in high numbers at glomerular level.


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Fig. 47-48. Monocyte-macrophages are clearly detected at higher magnification.


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Fig. 49. By immunohistochemistry the entity and the location of monocyte-macrophages (CD68 positive cells) can be precisely detected. 

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Fig. 50. The lobular pattern is caused by microaneurismatic dilations of the glomerular basement membrane, similar to other lobular/nodular nephritis (type I MPGN, diabetic GS, amyloidosis, light chain deposition disease).

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Fig. 51.The microaneurisms are more evident by silver staining. 

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Fig. 52-53. The so-called "peripheral lobular" IgG and IgM deposits, likely due to chronic cryoglobulin deposition, are evident by immunofluorescence. The picture is similar to idiopathic MPGN.


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 Fig. 54-55. Electron microscopy examination confirms the prevailing mesangial proliferation, always associated to monocyte-macrophage infiltration. (x 3600)


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Fig. 56-57. In some cases, characterized by segmental mesangial proliferation and mild exudation, diagnosis can be difficult.


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Fig. 58. Even in these mild cases, double contours of the capillary wall are evident by silver staining. 

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Fig. 59. Immunohistochemistry shows a certain number of monocyte-macrophages, suggesting the diagnosis of cryoglobulinemic nephritis. 

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Fig. 60-61. Pure mesangial pictures can also be found, with only mild and segmental mesangial proliferation, without exudation, clinically accompanied by urinary abnormalities.


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D'Amico G. Kidney Int 1998; 54: 650-671, with permission

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Fig. 62 - 63. Immunofluorescence allows the correct diagnosis, showing a mild segmental IgG and IgM deposition.


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D'Amico G. Kidney Int 1998; 54: 650-671, with permission

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Fig. 64-65. Although these pictures can mainly represent early cases, we have found a mild mesangial proliferation also in repeat biopsies, after the complete disappearance of thrombi and exudative lesions.


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Fig. 66-67. Disappearance of endoluminal thrombi in these cases was confirmed by immunofluorescence.


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I biopsy

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Fig.68. Segmental glomerulosclerosis is a rare finding in cryoglobulinemic glomerulonephritis. Actually the disease usually does not progress to end stage renal failure. 



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Fig 69. A massive interstitial leukocyte infiltration is not uncommon in cryoglobulinemic GN. 


Fig. 70-71. Segmental rounded interstitial foci of leukocytes can also be frequently observed. They never show a periglomerular accumulation and the Bowman's capsule is invariably intact, in contrast to what happens in necrotizing-extracapillary glomerulonephritis (ANCA-associated vasculitis, anti-GBM antibody disease, HS nephritis, IgA GN).

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Fig.72-73. Not only T-lymphocytes (CD3), but also B-lymphocytes (CD20) participate to these interstitial inflammatory foci. This peculiar B-lymphocyte participation might be related to the B-cell proliferation induced by the Hepatitis C Virus.


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Fig. 74. In these foci of leukocyte infiltration monocyte-macrophages are very few or completely absent. 


Fig. 75-76. In about one third of cases a vasculitis of small size arteries is present, characterized by vessel wall necrosis and intra- and peri-vascular leukocyte infiltration. A similar arteritis is found in ANCA-associated vasculitis, anti-GBM antibody disease, HS nephritis and in rare cases of lupus nephritis.


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Fig.77. The peri-vascular participation of monocyte-macrophages can be detected by immunohistochemistry. 


Fig.78-79. Other cases are characterized by a massive arteriolar thrombosis, with complete occlusion of the vascular lumen, similar to the thrombotic microangiopathy of lupus nephritis.


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Fig. 80. A vasculitis of large size arteries is not rare, with massive vessel wall necrosis and perivascular inflammatory reaction, similar to that of ANCA-associated vasculitis.


Fig. 81-82. In arteritis fibrin intensely stains the vessel walls.


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Fig. 83-84. Arteritis evolves to concentric proliferation and sclerosis with almost complete lumen occlusion. Arteritis is probably at the basis of the very severe, almost untreatable arterial hypertension commonly found in cryoglobulinemic patients.


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