Journal of Kidney

How do I Deal with Cryoglobulinemia?

Fabian Holder^{* *}Correspondence: Fabian Holder, Editorial Office, Journal of Kidney, Belgium, Email:

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Introduction

Cryoglobulinemia is a condition in which cryoglobulins are present in the bloodstream. Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures lower than normal body temperature (37°C) and then rehydrate. This finding was initially made in a patient with multiple myeloma in 1933. Cryoglobulins were discovered to be globulins that emerged in various disorders when the word "cryoglobulin" was created in 1947. Cryoglobulinemia can be asymptomatic without causing end-organ damage and is often detected as a result of a routine laboratory test. Cryoglobulins that induce end-organ damage by precipitating in tiny to medium-sized blood vessels are typically referred to as cryoglobulinemic vasculitis. Cryoglobulinemia is classified using a technique that was devised more than 40 years ago. It has the benefit of connecting with pathogenicity and clinical symptoms, which vary depending on the kind. The cryoglobulins in type I cryoglobulinemia are monoclonal Immunoglobulins (Igs), most commonly of the IgG or IgM isotypes, with IgA or free immunoglobulin light chains being rare. 4 In the context of protein-secreting monoclonal gammopathies, type I cryoglobulinemia occurs. Only 40% of individuals have Monoclonal Gammopathy of Undetermined Significance (MGUS), whereas the other 60% have a B-cell malignancy (e.g., Multiple Myeloma (MM), Waldenström Macroglobulinemia (WM), or Chronic Lymphocytic Leukaemia (CLL). Patients with MGUS and those with B-cell malignancies have similar amounts of Type I cryoglobulin.

The cryoglobulins in type II cryoglobulinemia are a combination of monoclonal IgM and polyclonal IgG with Rheumatoid Factor (RF) activity. In up to 90% of patients, this is linked to Hepatitis C Virus (HCV) infection. Geographic differences exist, with greater incidence of HCV infection in the Mediterranean area. Other infections (mostly HIV and Hepatitis B Virus (HBV), Connective Tissue Diseases (CTDs), and lymphoproliferative disorders can also produce type II cryoglobulinemia.

Approximately 10% of patients have no discernible reason (termed essential mixed cryoglobulinemia). Polyclonal IgM with RF activity and polyclonal IgG describe Type III.

Pathogenesis

Cryoprecipitate
The process of cryoprecipitate is not well known, and type I and type II/III cryoprecipitate are likely to differ. The monoclonal component of type I undergoes crystallization and aggregation, which is temperature and concentration-dependent. Although cryoglobulins are defined as proteins that precipitate at low temperatures, this process can also happen at room temperature with high cryoglobulin concentrations. This explains why the disease is more common in the distal extremities (lower temperatures) and kidneys (concentration rise due to ultrafiltration). Cryoprecipitation occurs in type II/III cryoglobulinemia in the context of immunological complex formation between polyclonal IgG and IgM with RF activity and complement fixation. IgM and IgG components alone cannot cause cryoprecipitate; particular antigen-avidity IgG molecules are required.

Tissue Injury
For HCV-associated cryoglobulinemia, the mechanism of cryoglobulin pathogenicity is better defined. HCV causes clonal B-cell growth, which produces monoclonal IgM molecules that attach to polyclonal IgG molecules, forming an RF. Immune complexes are formed when IgM interacts with anti-HCV IgG. These immune complexes link to endothelial cells' C1q receptors, which enhances inflammatory cell recruitment and causes vasculitis. The etiology of cryoglobulins in type I, on the other hand, is tiny blood vessel blockage with a limited inflammatory response.

Diagnosis and Laboratory Evaluation
Cryoglobulinemia is diagnosed by looking for common clinical signs and symptoms in the presence of cryoglobulins in the blood. Incorrect sample processing might result in false-negative findings. To minimize precipitation, samples should be moved and centrifuged at 37°C before serum extraction. Precipitation at 1 to 4°C normally occurs within hours in type I; samples should be kept for 7 days since precipitation in mixed types might be delayed. If the test for cryoglobulin is negative but the index of suspicion remains high, the test should be repeated after contacting the laboratory to check that the sample was handled properly. If cryoglobulins are found, the cryoconite (the relative volume of the precipitate expressed as a percentage of total serum volume) should be reported if feasible. Type I has the highest cryoconite level, while type III has the lowest (it can be more than 50% in type I and less than 5% in type II/III). Although increased cryoconite has been found to enhance the incidence of symptomatic illness, the correlation between cryoconite and clinical symptoms is poor. In a few investigations, the cryoconite was found to be predictive. Overall, cryoconite should be used just for diagnosis because the cryoconite and treatment response have a weak relationship.

Management

Treatment is limited to symptomatic conditions and focuses on the underlying problem. Bone marrow aspiration and/or biopsy, as well as relevant imaging investigations, are all part of a comprehensive hematologic examination. Because of the low occurrence, high-quality information on the best treatment option for the underlying condition is scarce. As a result, most suggestions are based on professional opinion and the best available data.

It is imperative to educate patients on avoiding exposure to the cold by wearing gloves when using the freezer or refrigerator, wearing warm clothes in air-conditioned facilities, and relocating to a warmer climate during the winter months. Foot and leg care is important to prevent wound complications. Diabetic foot care guidelines can be followed for this purpose (e.g., checking the feet every day, wearing shoes and socks at all times, and trimming toenails gently). Cryoglobulinemia is a very uncommon clinical condition. Because the presence of cryoglobulins in the serum aids diagnosis, it's crucial to be aware of its clinical range. End-organ damage and repeated relapses make treatment difficult.

Without any developing illness-specific therapies, all therapeutic approaches are now geared to either cure the underlying disease or provide immunosuppression. Because cryoglobulinemia is a varied illness in terms of signs and origin, it's difficult to come up with a set of universal care guidelines, even though there are some parallels in therapy techniques, as previously mentioned. There is a scarcity of high-quality data, particularly for the rarer cryoglobulinemia subtypes.