Nephrology for the Family Physician - O.I. Bakaliuk 2003

Renal Pathology in Other Diseases
The Kidneys in Cryoglobulinemias

Cryoglobulins are pathological Proteins, most commonly of the immunoglobulin type, that tend to precipitate at temperatures around 37 °C and redissolve upon heating, although cases have been reported where cryoglobulins were detected at temperatures as low as 36 °C (L. Jäger, 1990).

Cryoglobulinemia was first described in 1933 by M.M. Wintrobe and M.V. Bell, and this pathological condition received its name in 1947 (A.B. Lerner, C.J. Watson).

Depending on their constituent components, Three types of cryoglobulins are distinguished: Type I (simple cryoglobulinemia) – cryoglobulins are represented solely by a monoclonal immunoglobulin (more frequently classes M or G, 28% of cases); Type II (mixed cryoglobulinemia) – the cryoprecipitate consists of a single monoclonal immunoglobulin bound to a polyclonal immunoglobulin of a second Class, 26% of cases); Type III – also mixed cryoglobulinemia, but the cryoprecipitate consists exclusively of polyclonal IMMUNOGLOBULINS in various combinations (e.g., Ig class M + Ig class G; Ig class A + Ig class M + Ig class G, 45% of cases).

It is believed (L. Jäger, 1990) that Type I cryoglobulins are typically present in the Blood of patients with lymphoproliferative disorders (multiple myeloma, lymphomas, Waldenström's macroglobulinemia), Type II with Connective Tissue diseases, and Type III with chronic infections and Liver pathology. Clinically, Type I cryoglobulinemia, specifically of the Ig class M or Ig class G type, is the most common. Mixed (polyclonal) cryoglobulinemias of types II and III are caused by The formation of immune complexes in which an Ig class M usually plays The Role of the antigen. Among them, a subtype with a polyclonal rheumatoid factor is distinguished (Ig class M + Ig class G and/or Ig class A, W. Robert et al., 1991), which is associated with chronic inflammatory infectious or autoimmune processes, as well as a subtype with a monoclonal rheumatoid factor (Ig class M, Ig class G, or Ig class A).

From a clinical standpoint, cryoglobulinemias are divided into primary (essential) and secondary.

Primary cryoglobulinemias include cases (29–50%) where the cause of the disease cannot be identified; secondary cases are those where cryoglobulinemia is diagnosed in association with paraproteinemic hemoblastosis (plasmacytoma, Waldenström's macroglobulinemia), lymphoproliferative disorders (Lymphocytic Leukemia, lymphosarcoma), connective tissue diseases (systemic lupus erythematosus, polyarteritis nodosa, rheumatoid Arthritis, Bechterew's disease, Sjögren's syndrome), vasculitis, infectious diseases (bacterial endocarditis, post-streptococcal GN, Syphilis, infectious mononucleosis, Toxoplasmosis, cytomegalovirus mononucleosis, echinococcosis, Lyme arthritis, chronic hepatitis B), and Other forms of pathology (Crohn's disease, sarcoidosis, Pemphigus, erythroderma, Ulcerative Colitis). The majority of these conditions are associated with The production of rheumatoid factor, and all of them are characterized by prolonged antigenic stimulation of The Immune System. Among them, systemic lupus erythematosus and bacterial endocarditis deserve special mention, as cryoglobulinemia in these cases is additionally associated with hypocomplementemia. In most patients, essential cryoglobulinemia is the result of persistent hepatitis B virus infection (M. Meltzer et al., 1996).

For mixed cryoglobulinemias, Skin lesions in the form of hemorrhagic rashes are most characteristic (70%); skin lesions in the form of livedo or urticaria more frequently accompany non-mixed forms. Skin biopsy reveals acute necrotizing vasculitis, and immunofluorescence studies show deposits of immunoglobulins classes M and G, as well as the C₃ component of Complement in the walls of Arteries.

The second most frequent symptom (40–50%) in cryoglobulinemias is joint pain, which is rarely combined with signs of joint inflammation or destruction.

GN as a symptom of cryoglobulinemia is detected in 30–55% of cases. Renal involvement proper determines the prognosis in this form of pathology—the average life expectancy of patients ranges from two weeks to 8.7 years, according to various authors (W. Brand et al., 1999).

Neurological symptoms (25%) consist of numbness, paresthesias, and paresis; symptoms of Central Nervous system dysfunction are relatively rare.

The Clinical presentation of cryoglobulinemias is also characterized by fever, Raynaud's syndrome, hepatosplenomegaly, anemia, and abdominal pain due to intestinal vasculitis. Since it is not always possible to determine the type of cryoglobulinemia through laboratory testing, its leading clinical symptoms are presented below according to type (Table 7).

Table 7. Clinical symptoms of cryoglobulinemia

The Kidneys are predominantly affected in Type II cryoglobulinemia. Currently, Type II cryoglobulinemia is viewed as a non-malignant lymphoproliferative condition resulting from chronic antigenic stimulation by hepatitis C Viruses and characterized by the expansion of a B-lymphocyte clone. This clone is committed to producing a monoclonal immunoglobulin of class M with cryoglobulin and rheumatoid factor properties (V.G. Radchenko et al., 1999). The clinical presentation of renal involvement does not differ from other pathological conditions (varying degrees of lower back pain, edema, dysuria, nocturia). Arterial Hypertension may sometimes precede other clinical manifestations of the disease, but more often the signs of Kidney damage coincide with The Development of purpura. Nephrotic Syndrome develops in 20–25% of cases (M. Campise et al., 1999). Rarely, and typically following significant hypothermia or dehydration, cryoglobulinemia proceeds as subacute GN with rapidly progressive renal failure. Urinary syndrome is characterized by minimal proteinuria and Hematuria. Glomerular changes are caused by the deposition of immune complexes in the glomerular basement membrane, microthrombosis of capillaries (A. Cohen, 1998), and interstitial sclerosis, presenting a picture of proliferative GN.

Characteristic immunological criteria for cryoglobulinemic GN include hypocomplementemia (C₄ fraction) and high titers of rheumatoid factor (R. Misiani et al., 1999).

Diagnosis of cryoglobulinemia is complex and based on a detailed analysis of clinical and anamestic data (role of hypothermia) along with laboratory findings (rapid gelation of blood serum at room temperature, detection of Ig class M + Ig class G cryoglobulins, elevated blood levels of class M immunoglobulins and circulating immune complexes, decreased C₃ complement component, and absence of paraproteins in blood and urine). Some significance is attached to immunofluorescence results—unlike systemic lupus erythematosus, cryoglobulinemia lacks C1q deposits, and unlike acute post-streptococcal GN, it lacks predominant C₃ deposits.

Treating cryoglobulinemias is a challenging task. The principles of therapy include targeting the virus, removing cryoproteins, using pharmacological agents to inhibit inflammatory mediators, and employing cytostatics to reduce the synthesis of pathological proteins.

Interferon-alpha should be considered the optimal Treatment for cryoglobulinemic GN, as it is the only effective agent for HCV infection (1.5–3 million IU subcutaneously, three times a week for 6–24 months; R. Davda et al., 1993). Among newer approaches, the combination of interferon-alpha with ribavirin is worth noting (R. Misiani et al., 1999). Plasmapheresis is also utilized in the therapeutic regimen; corticosteroids (more frequently as pulse therapy) are used in the presence of fever, vasculitis, musculoskeletal syndrome, nephrotic syndrome, or hypocomplementemia. In some cases, interferon is prescribed in combination with NSAIDs.

Cytostatics (chlorambucil, cyclophosphamide) are more commonly used to treat monoclonal cryoglobulinemia associated with myeloma or Waldenström's macroglobulinemia.