Membranoproliferative Glomerulonephritis and Mixed Cryoglobulinemia as a Form of Presentation of Visceral Leishmaniasis.

BACKGROUND Visceral leishmaniasis (VL) is an endemic systemic disease in the Mediterranean countries, including Spain. This vector-borne infection can present with several clinical presentations, from asymptomatic to severe forms. Renal impairment is frequently described in VL but is usually mild and related to interstitial nephritis, being that glomerular involvement is rarely found. CASE REPORT We describe a case of a 69-year-old Spanish male presenting with subacute renal failure due to membranoproliferative glomerulonephritis and mixed cryoglobulinemia accompanied by other autoimmune features (hypocomplementemia, antinuclear and antiDNA antibodies). No hepatosplenomegaly was found with abdominal ultrasound. Hepatotropic viruses and human immunodeficiency virus serological markers were negatives. We initially suspect the presence of an autoimmune disease and the patient was treated with steroids without improvement. After an extensive study including renal and bone marrow biopsy, a correct diagnosis of visceral leishmaniasis was made, and treatment with liposomal amphotericin B was initiated, achieving renal function recovery and normalization of immunological manifestations. CONCLUSIONS Renal involvement can be an important feature of VL and it might be associated with increased morbidity and mortality. The association between mixed cryoglobulinemia and renal involvement in VL have rarely been described. VL is frequently associated with diverse autoimmune manifestations and it can be initially misdiagnosed, which could lead to fatal consequences. The role of the immune system in the formation of cryoglobulins are discussed. In our case, an autoimmune disease was initially suspected, and starting treatment with steroids pulses was initiated. However, the presence of mixed cryoglobulinemia in this patient who was hepatitis C serological marker negative and who had poor renal function recovery after immunosuppressive treatment made us suspect other pathologies. The presence of cryoglobulinemia with renal disease in endemic areas of Leishmania should make us exclude this infection before starting immunosuppressive treatment.

The development of mixed cryoglobulinemia in Capillaria hepatica-infected mice is associated with the capillaria antigen-induced selective proliferation of splenic B-1a cells in response to interleukin-5 stimulation.

Chronic infection by pathogens such as hepatitis C virus induces monoclonal or oligoclonal proliferation of B cells, which produce IgM rheumatoid factor, leading to the development of mixed cryoglobulinemia (MC). Antigen-driven lymphoproliferation is essential to the onset of MC; however, the underlying mechanism is largely unknown. Herein, we show that type II MC is induced by Capillaria hepatica infection through a mechanism in which splenic B-1a cells reacting to C. hepatica-specific antigen selectively proliferate, producing IgM rheumatoid factor under co-stimulation of the specific worm antigen and IL-5. In vitro assays using B-1a cells from infected mice showed that stimulation by C. hepatica soluble fraction promoted the proliferation of B-1a cells and the secretion of IgM, which reacted with the 75-kDa antigen in the soluble fraction. The severity of MC was correlated with the increase in serum IL-5 levels in the infected mice. Furthermore, i.p. injection of the soluble worm fraction caused MC without an inflammatory response in IL-5 transgenic mice, indicating that IL-5 is critical for the development of MC. These results indicate that the selective proliferation of IgM rheumatoid factor-secreting B-1a cells is induced by co-stimulation by the specific pathogen antigen and IL-5 in the development of MC in C. hepatica-infected mice.

Cryoglobulinemic purpura in visceral leishmaniasis.

Visceral leishmaniasis may present with cytopenias along with the formation of many autoantibodies and, rarely, with the presence of mixed cryoglobulinemia, type II, resembling an autoimmune disease. The syndrome of mixed cryoglobulinemia is characterized by the triad of purpura, arthralgias, and asthenia, in conjunction with cryoglobulins in the serum. In this article mixed cryoglobulinemia, type II, was diagnosed in a negative for hepatitis B or C patient suffering from visceral leishmaniasis. Antimicrobial therapy against leishmania eliminated the cryoglobulin titer, as well as the clinical manifestations of cryoglobulinemia. The role of the immune system and the type of immune response for the formation of cryoglobulins are discussed.

Leg ulcers in active lepromatous leprosy associated with cryoglobulinaemia.

A 40-year-old male agricultural labourer presented with active lepromatous leprosy and painful leg ulcers of 2 months' duration. Biopsy from the ulcer showed nonspecific changes. Raised erythrocyte sedimentation rate and positive rheumatoid factor made us suspect underlying cryoglobulinaemia. Presence of cryoprecipitate in the serum, demonstration of cryoglobulins by serum electrophoresis and raised cryocrit were compatible with cryoglobulinaemia as the cause of atypical leg ulcers in this case. The ulcers healed with bed rest, aspirin and specific anti-leprosy treatment. Though 95% of lepromatous leprosy patients can have cryoglobulinaemia, the presence of atypical ulcers as seen in our patient has not previously been related to the presence of cryoglobulinaemia.

Leg ulcers in active lepromatous leprosy associated with cryoglobulinaemia

A 40-year-old male agricultural labourer presented with active lepromatous leprosy and painful leg ulcers of 2 months' duration. Biopsy from the ulcer showed nonspecific changes. Raised erythrocyte sedimentation rate and positive rheumatoid factor made us suspect underlying cryoglobulinaemia. Presence of cryoprecipitate in the serum, demonstration of cryoglobulins by serum electrophoresis and raised cryocrit were compatible with cryoglobulinaemia as the cause of atypical leg ulcers in this case. The ulcers healed with bed rest, aspirin and specific anti-leprosy treatment. Though 95 per cent of lepromatous leprosy patients can have cryoglobulinaemia, the presence of atypical ulcers as seen in our patient has not previously been related to the presence of cryoglobulinaemia.

Crioglobulinemia: estudo imunoquímico de três pacientes / Cryoglobulinemia: immunochemical study of three patients

As crioglobulinas säo proteínas que se precipitam ao a frio e podem ser encontradas em várias doenças humanas. Sua detecçäo e estudo imunoquímico podem ser úteis para o diagnóstico e compreensäo de muitos estados patológicos. Säo descritos três diferentes casos de crioglobulenemia, cada um representativo dos tipos clássicos de Brouet. Um paciente apresentava crioglobulinemia do tipo I e linfoma plasmocitóide; näo tinha sintomas de criobulinemia propriamente ditos, a despeito dos altos níveis de crioglobulinas circulantes (IgG 3 K monoclonal). O paciente com crioglobulinemia do tipo II, crioglobulinemia essencial mista (IgM lambida monoclonal e IgG policlonais) era portador de leishmaniose mucocutânea. Näo foram encontradas hiperviscosidade sérica ou cristalocrioglobulinas em nenhum do casos. A temperatura de crioprecipitaçäo situou-se sempre abaixo de 20 graus e a concentraçäo das hipocrioglobulinas foi diferentes das respctivas crioglobulinas em dois pacientes, näo havendo relatos na literatura sobre este tipo de achado