TY - JOUR
AU - Juutilainen,, Auni
AB - Abstract Cryoglobulinaemia is a rare condition characterized by serum immunoglobulins or immunocomplexes which precipitate at temperatures below 37°C and redissolve on warming. Cryoglobulinaemic vasculitis develops in ~ 15% of patients positive for cryoglobulin serology and is often associated with an underlying infectious, autoimmune or lymphoproliferative disease. We describe a case of cryoglobulinaemic vasculitis, which manifested as purpura and rapidly deteriorating renal function in a patient with chronic lymphocytic leukaemia and coexistent parvovirus infection. This case illustrates the complex pathophysiology of cryoglobulinaemic renal injury, and suggests that infection may serve as a trigger in the presence of other pathophysiological factors. chronic lymphocytic leukaemia, cryoglobulinaemia, parvovirus, renal failure Background The symptoms of cryoglobulinaemic vasculitis include characteristic purpura, Raynaud’s syndrome, acrocyanosis, livedo reticularis, ecchymosis, skin ulcerations, and even ischaemic necrosis or gangrene. Arthralgias, weakness, peripheral neuropathy, and renal, cardiac and liver manifestations are frequently encountered [1]. Cryoglobulinaemias are classified into three types according to the immunoglobulin composition. Type I cryoglobulin consists typically of monoclonal IgM, does not activate complement in vitro, leads to symptoms of hyperviscosity and is associated to an underlying lymphoproliferative disease. Type II and III cryoglobulins comprise either monoclonal or polyclonal IgM–rheumatoid factor–IgG complexes, represent mixed cryoglobulinaemias, are associated with many infectious or systemic diseases, and cause small or medium vessel vasculitis frequently with multiple organ involvement [1]. Case report Our patient is a 70-year-old man with a 10-year history of chronic lymphocytic leukaemia (CLL) treated twice with chlorambucil. The latest treatment was finished 12 months ago in a stable clinical situation. In January, he developed an episode of fever passing with 4-day amoxicillin treatment. Periodical epistaxis occurred. A month later, he was admitted to hospital for oedema in hands and legs, and dyspnoea at rest. Cardiac markers and echocardiogram were normal. Chest radiograph demonstrated pleural effusion, and lung CT ground-glass opacity. Laboratory examinations revealed elevated serum amino terminal pro-brain-type natriuretic peptide (1213 ng/dL), hypersedimentation (erythrocyte sedimentation rate 91 mm/h), anaemia (haemoglobin 8.9 g/dL), elevated leucocyte count (72.4 × 109/L) and platelet count (385 × 109/L). Three weeks ago, plasma creatinine had been normal (87 μmol/L), but on admission to hospital, it was elevated (223 μmol/L; estimated glomerular filtration rate 25 mL/min/1.73 m2) increasing up to 467 μmol/L within 6 days. Most strikingly, his fingers, lower extremities and nail beds were coloured with bluish purpura (Figure 1). Fig. 1 Open in new tabDownload slide Cryoglobulinaemic vasculitis manifested as skin lesions and renal injury. (A) Purpura of the nail beds. (B) Leucocytoclastic vasculitis, extravasation of erythrocytes (original magnification × 100). (C) Multiple, rounded hyalin thrombi within the glomerular lumen (original magnification × 200). (D) The hyalin thrombi contain IgA (immunofluorescence micrograph, original magnification × 200). Fig. 1 Open in new tabDownload slide Cryoglobulinaemic vasculitis manifested as skin lesions and renal injury. (A) Purpura of the nail beds. (B) Leucocytoclastic vasculitis, extravasation of erythrocytes (original magnification × 100). (C) Multiple, rounded hyalin thrombi within the glomerular lumen (original magnification × 200). (D) The hyalin thrombi contain IgA (immunofluorescence micrograph, original magnification × 200). Further investigations revealed haematuria and mild proteinuria (800 mg/day). Serum protein level was low (5.8 g/dL). Serum IgM was slightly elevated 303 mg/dL (reference range, 54–300 mg/dL), but IgA and IgG were normal. There was no detectable paraprotein in serum, but urine contained free kappa light chain (150 mg/day). Puumala virus, anti-nuclear, anti-basement membrane and anti-neutrophil cytoplasmic antibodies were negative. Lupus anti-coagulant was positive, but phospholipid antibodies were negative. Hepatitis B and C (HCV), cytomegalovirus and human immunodeficiency virus (HIV) infections were excluded. Parvovirus antibodies (IgM and IgG) were positive, and when tested 9 weeks later, parvovirus nucleic acid test was positive. The test for serum cryoglobulins was positive. Kidney biopsy revealed hyaline thrombi in glomerular capillaries with most prominent infiltration of IgA followed by IgG, IgM and more kappa than lambda light chains. The biopsy from the skin lesion with a necrotic centre demonstrated a leucocytoclastic vasculitis (Figure 1). Since the patient’s kidney function deteriorated rapidly, he was treated with methylprednisolone 1 g/day for 3 days and with intravenous cyclophosphamide (700 mg). Repeated cryoglobulin analysis was now clearly positive. C4 complement was very low (< 20 μg/mL), and C3 was below the reference (480 μg/mL). The rheumatoid factor, analysed 9 weeks after the disease outbreak, was 12.5 IU/mL (reference range 0–14 IU/mL). Haemodialysis and nine plasmaphereses improved the status. Dyspnoea resolved, oedema withdrew, and purpura of the nail beds and lower extremities alleviated. The treatment was continued with cyclophosphamide, methylprednisolone and rituximab. Rituximab (800 mg) was discontinued after 3-week weekly infusions since the leucocytes remained high. Alemtuzumab (30 mg subcutaneously, three times a week) effectively decreased leucocyte count, but the test for cryoglobulins remained positive, and the patient was permanently dependent on haemodialysis. Discussion Infiltration of leukaemic cells to renal parenchyma is observed in 63–90% of CLL patients at autopsy [2], but clinical renal manifestations are uncommon. CLL-associated cryoglobulinaemia and glomerulonephritis are a rare phenomenon [3]. In the case of our patient, the rapidly progressing loss of kidney function concomitantly with the skin manifestations led to the diagnosis of cryoglobulinaemic vasculitis with clinical picture of type II cryoglobulinaemia. Renal manifestations of cryoglobulinaemia are often preceded by other clinical symptoms of cryoglobulinaemia, which may also occur concomitantly or even subsequently to renal failure. End-stage renal disease develops infrequently [4]. The typical histopathological feature of renal involvement of cryoglobulinaemia is the presence of massive intracapillary and subendothelial immunoglobulin aggregates, which may almost obliterate the glomerular lumina. The typical intraluminal deposits are usually associated with the findings of diffuse proliferative, membranoproliferative, or focal and segmental glomerulonephritis. In CLL patients, glomerulonephritis is caused by cryoglobulins or monoclonal immunoglobulins without cryoglobulinaemia and complement activation. In the absence of cryoglobulinaemia, the intracapillary hyaline deposits may be related to fibrillar glomerulopathy as a rare complication in CLL patients [5]. In our patient, the intraluminal precipitates were prominent, and their immunohistological pattern was exceptional, occupied by IgA with lesser amounts of usually predominant IgG, IgM and C3. When a patient with symptomatic cryoglobulinaemia is encountered, one should seek for underlying conditions like lymphoproliferative diseases characterized with paraproteinaemia. Chronic lymphocytic leukaemia likely served as the aetiological factor in our patient. Of infectious diseases, HCV is the most common cause for type II cryoglobulinaemia, but also other infectious aetiologies (chronic hepatitis B, HIV, Epstein–Barr virus, cytomegalovirus, subacute bacterial endocarditis, tuberculosis and Borrelia burgdorferi) should be considered [6]. A few have reported a connection between parvoviral infection and cryoglobulinaemia [7]. In our CLL patient, antibodies and nucleic acid test for parvovirus were positive, offering an alternative aetiology for the cryoglobulinaemic vasculitis. However, parvovirus infection was not likely the primary cause of cryoglobulinaemic vasculitis, but served as a trigger for the clonal activity of B cells. Treatment of cryoglobulinaemic vasculitis should be based on the clinical symptoms and the underlying disease. Parvoviral disease may resolve spontaneously or require treatment with immunoglobulins [7,8]. In lymphoproliferative diseases, the prime strategy is to restrain the clonal B-cell activity, e.g. with rituximab, although positive outcome is not always obtained. Alemtuzumab has been reported to induce remission in non-malignant type I cryoglobulinaemia [9], and it efficiently reduced leucocyte count in our CLL patient. However, restoration of renal function was not achieved in our patient with the combination of lymphoproliferative malignancy and presumable parvovirus infection behind the cryoglobulinaemic vasculitis. Conflict of intereststatement. None declared. References 1 Tedeschi A , Baratè C , Minola E , et al. Cryoglobulinemia , Blood Rev , 2007 , vol. 21 (pg. 183 - 200 ) Google Scholar Crossref Search ADS PubMed WorldCat 2 Da’as N , Polliack A , Cohen Y , et al. Kidney involvement and renal manifestations in non-Hodgkin’s lymphoma and lymphocytic leukemia: a retrospective study in 700 patients , Eur J Haematol , 2001 , vol. 67 (pg. 158 - 164 ) Google Scholar Crossref Search ADS PubMed WorldCat 3 Favre G , Courtellemont C , Callard P , et al. Membranoproliferative glomerulonephritis, chronic lymphocytic leukemia, and cryoglobulinemia , Am J Kidney Dis , 2010 , vol. 55 (pg. 391 - 394 ) Google Scholar Crossref Search ADS PubMed WorldCat 4 Saadoun D , Sellam J , Ghillani-Dalbin P , et al. Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia , Arch Intern Med , 2006 , vol. 166 (pg. 2101 - 2108 ) Google Scholar Crossref Search ADS PubMed WorldCat 5 Schneider R , Lugassy G , Schlesinger M , et al. Fibrillar glomerulopathy associated with chronic lymphocytic leukaemia , Nephrol Dial Transplant , 1996 , vol. 11 (pg. 1352 - 1355 ) Google Scholar Crossref Search ADS PubMed WorldCat 6 Cohen Tervaert JW , Van Paassen P , Damoiseaux J . Type II cryoglobulinemia is not associated with hepatitis C infection: the Dutch experience , Ann NY Acad Sci , 2007 , vol. 1107 (pg. 251 - 258 ) Google Scholar Crossref Search ADS PubMed WorldCat 7 Chiche L , Grados A , Harlé JR , et al. Mixed cryoglobulinemia: a role for parvovirus b19 infection , Clin Infect Dis , 2010 , vol. 50 (pg. 1074 - 1075 ) Google Scholar Crossref Search ADS PubMed WorldCat 8 Lidar M , Lipschitz N , Langevitz P , et al. The infectious etiology of vasculitis , Autoimmunity , 2009 , vol. 42 (pg. 432 - 438 ) Google Scholar Crossref Search ADS PubMed WorldCat 9 Chu D , Stevens M , Gladstone DE . Severe, refractory, non-malignant type I cryoglobulinemia treated with alemtuzumab , Rheumatol Int , 2007 , vol. 27 (pg. 1173 - 1175 ) Google Scholar Crossref Search ADS PubMed WorldCat © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org Oxford University Press
TI - Cryoglobulinaemia and rapidly deteriorating renal function in chronic lymphocytic leukaemia
JF - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gfq701
DA - 2011-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/cryoglobulinaemia-and-rapidly-deteriorating-renal-function-in-chronic-JQPi9o7Y8S
SP - 1101
EP - 1103
VL - 26
IS - 3
DP - DeepDyve
ER -