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Mixed cryoglobulinemia and kidney damage

Medical expert of the article

Urologist, oncourologist
, medical expert
Last reviewed: 04.07.2025

Mixed cryoglobulinemia is a special type of systemic small vessel vasculitis characterized by the deposition of cryoglobulins in the vessel wall and most often manifested by skin lesions in the form of purpura and renal glomeruli.

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Causes mixed cryoglobulinemia

Currently, the term "essential cryoglobulinemia" should be considered conditional, since the cause of mixed cryoglobulinemia is clearly established - these are viral infections. In the vast majority of cases, cryoglobulinemia is associated with HCV, and the role of other viruses (Epstein-Barr, hepatitis A and B) is less significant. In patients infected with HCV, the frequency of detection of cryoglobulinemia varies from 34 to 54%. In mixed cryoglobulinemia, markers of HCV infection are detected in the blood in 63-76% of cases, and in cryoprecipitates - in 75-99% of cases.

HCV is believed to stimulate the proliferation of a specific clone of B lymphocytes that produces polyclonal (IgM) or monoclonal (IgMic) rheumatoid factor. Binding of the latter in the blood or in situ to IgG (in HCV infection, IgG exhibits the properties of antibodies to HCV) leads to the formation of type II cryoglobulins, the deposition of which in the wall of small vessels, including glomerular capillaries, is accompanied by the consumption of complement components, inducing damage to the vascular wall and the development of inflammation.

It turned out that monoclonal IgMic rheumatoid factor of mixed cryoglobulins has the ability to bind to fibronectin of the mesangial matrix of glomeruli, which explains the high nephritogenicity of type II cryoglobulins. Kidney damage is noted in both types of mixed cryoglobulinemia, but in type II - 3 times more often.

Unlike type III, in which renal manifestations are nonspecific, type II with monoclonal IgMic develops glomerulonephritis with special morphological features, allowing it to be considered as a separate variant of glomerulonephritis - cryoglobulinemic.

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Pathogenesis

Morphologically, cryoglobulinemic glomerulonephritis is a variant of mesangiocapillary glomerulonephritis associated almost exclusively with type II mixed cryoglobulinemia and characterized by features that distinguish it from both idiopathic mesangiocapillary glomerulonephritis type I and diffuse proliferative lupus nephritis. These include:

  • Massive infiltration of the glomeruli by leukocytes, predominantly monocytes/macrophages, causing pronounced endocapillary proliferation.
  • The presence of so-called "intraluminal" thrombi in the glomerular capillaries - amorphous eosinophilic PAS-positive deposits of varying size, adjacent to the inner surface of the capillary wall and often completely obstructing the lumen of the capillaries. The immunofluorescence method revealed the presence of cryoglobulins identical to circulating ones in the composition of these intracapillary deposits. Electron microscopy reveals a fibrillar or microtubular structure of these deposits, identical to that of the cryoprecipitate obtained from the same patient in vitro.
  • Double-walled glomerular basement membrane due to interposition of monocytes/macrophages between the glomerular basement membrane and endothelial cells or newly formed membrane-like material. Double-walled glomerular basement membrane is more pronounced in cryoglobulinemic glomerulonephritis than in mesangiocapillary glomerulonephritis, where it results from interposition of mesangial cells. About 30% of patients with cryoglobulinemic glomerulonephritis have features of vasculitis of small and medium-sized arteries, characterized by fibrinoid necrosis and monocytic infiltration of the vessel wall. Renal vasculitis may occur in the absence of glomerular involvement and often correlates with the severity of purpura or vasculitis of the mesenteric arteries.

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Symptoms mixed cryoglobulinemia

Symptoms of mixed cryoglobulinemia include the development of cryoglobulinemic vasculitis, which is observed in 50-67% of patients, on average after 15 years of HCV infection. Cryoglobulinemic vasculitis most often develops in women, in most cases at the age of 40-50 years. Symptoms of cryoglobulinemic vasculitis are characterized by significant polymorphism. The most common are palpable purpura on the skin of the lower extremities, sometimes with ulceration, arthralgia, Raynaud's syndrome, and peripheral polyneuropathy. Abdominal pain syndrome (leading in some cases to surgical interventions) and hepatosplenomegaly are also characteristic. Sjögren's syndrome and lymphadenopathy are observed less often.

Kidney damage in mixed cryoglobulinemia

Glomerulonephritis is the most common visceritis, observed in 35-50% of patients with mixed cryoglobulinemia. Symptoms of mixed cryoglobulinemia and kidney damage usually appear several months or years after the first signs of the disease (purpura, arthralgia), but in some patients glomerulonephritis is combined with extrarenal symptoms already at the onset of cryoglobulinemia. In rare cases, the development of glomerulonephritis precedes other manifestations of mixed cryoglobulinemia (nephritic mask). The renal process manifests itself as acute nephritic syndrome in about a quarter of patients, nephrotic syndrome in 20%, and more than 50% have moderate urinary syndrome, manifested by proteinuria and erythrocyturia. In less than 5% of patients, glomerulonephritis from the very beginning acquires a rapidly progressive course or debuts as oliguric acute renal failure. Patients with cryoglobulinemic glomerulonephritis experience early and, in most cases, severe arterial hypertension, the complications of which (acute myocardial infarction, stroke) can cause death in patients.

The course of glomerulonephritis in mixed cryoglobulinemia is variable. Almost a third of patients, especially in the presence of acute nephritic syndrome, achieve remission of the renal process within a period of several days to several weeks. In most cases, a stable course of nephritis with minimal urinary syndrome and normal renal function is noted. In 20% of patients, glomerulonephritis acquires a wave-like course with frequent relapses of acute nephritic syndrome, coinciding, as a rule, with an exacerbation of vasculitis and a relapse of extrarenal symptoms. Progression of cryoglobulinemic glomerulonephritis with the development of terminal renal failure is rarely noted (10% of cases), as a rule, in patients with constantly high or increasing cryoglobulinemia. It is believed that the severity of renal damage in cryoglobulinemic vasculitis usually does not correlate with the level of cryoglobulinemia, however, in the study of NA. Mukhina, L.V. Kozlovskaya established a high frequency of rapidly progressive glomerulonephritis and nephrotic syndrome with a high level of type II cryoglobulins (more than 1 mg/ml).

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Forms

Cryoglobulins are serum immunoglobulins that have the property of reversible cold precipitation. Depending on the composition, there are 3 types of cryoglobulins.

  • Type I cryoglobulins are monoclonal immunoglobulins, predominantly of the IgM class; this type of cryoglobulin, found in multiple myeloma or Waldenstrom's disease, rarely causes kidney damage.
  • Cryoglobulins of types II and III are mixed, since they consist of at least 2 immunoglobulins, one of which (polyclonal IgG) acts as an antigen, and the other, which is an antibody, is an immunoglobulin bound to it (anti-IgG), usually of the IgM class, which has rheumatoid factor activity. The composition of cryoglobulins in type II includes monoclonal IgM (containing mainly one type of light chains - k), in type III - polyclonal (containing k- and X-light chains).

Mixed cryoglobulinemia types II and III can develop in a number of infectious and autoimmune diseases, and in this case it is called secondary mixed cryoglobulinemia. Until recently, in about 30% of patients, it was not possible to establish a connection between cryoglobulinemia and another pathology, which led to the emergence of the term "essential cryoglobulinemia". Essential cryoglobulinemia was described by M. Meltzer in 1966 as a syndrome including general weakness, purpura, arthralgia (Meltzer's triad) in combination with cryoglobulinemia type II.

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Diagnostics mixed cryoglobulinemia

Laboratory diagnostics of mixed cryoglobulinemia

Diagnosis of mixed cryoglobulinemia involves detection of cryoglobulins in the blood serum (cryocrit level over 1%). IgM rheumatoid factor is often detected in high titer. Cryoglobulinemic vasculitis is characterized by a decrease in the total hemolytic activity of complement CH50, C4 and Clq components with a normal content of C3, a decrease in which is typical for non-cryoglobulinemic mesangiocapillary glomerulonephritis.

Of great diagnostic value is the detection of hepatitis C markers in the blood serum: HCV antibodies and HCV RNA.

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Treatment mixed cryoglobulinemia

For the treatment of active cryoglobulinemic glomerulonephritis (acute nephritic and/or nephrotic syndrome with rapid development of renal failure), immunosuppressive therapy (a combination of glucocorticoids and cytostatics) and plasmapheresis (cryopheresis) should be prescribed.

  • Treatment of mixed cryoglobulinemia with glucocorticoids begins with intravenous administration of ultra-high doses (1 g of methylprednisolone) for 3 days, followed by a transition to oral administration of prednisolone at 1 mg/kg of body weight per day for 4 weeks, after which the drug dose is gradually reduced to a maintenance dose, which is maintained for several months. Cyclophosphamide is prescribed at a dose of 2 mg/kg of body weight per day for at least 4 months or as pulse therapy at 800-1000 mg intravenously at intervals of 3-4 weeks until acute nephritic or nephrotic syndromes are relieved. The dose of cyclophosphamide depends on the state of renal function: if the creatinine content in the blood is more than 450 μmol/l, it is reduced by 50%.
  • Plasmapheresis or cryoapheresis is performed 3 times a week for 2-3 weeks only in combination with active immunosuppressive therapy, which helps to avoid the development of rebound syndrome, which is possible after the termination of the procedures due to an increase in cryocrit.

Currently, the approach to the treatment of cryoglobulinemic vasculitis, including glomerulonephritis, has changed, which was facilitated by the identification of a link between cryoglobulinemia and HCV infection. It is believed that etiotropic treatment of mixed cryoglobulinemia, aimed at eradication of the virus, will lead to the disappearance of cryoglobulinemia and the clinical manifestations of vasculitis caused by it. For this purpose, it is recommended to prescribe alpha-interferon drugs as monotherapy or in combination with ribavirin. Preferably, long-term (for 12 months) treatment with alpha-interferon drugs at a dose of 5 million IU daily in combination with ribavirin (1000-1200 mg/day).

A number of studies on the effectiveness of antiviral drugs in HCV-associated cryoglobulinemic vasculitis have shown that they improve the course of the skin process, lead to the elimination of HCV markers, a decrease in the cryocrit level and an increase in CH-50, but do not affect the activity of glomerulonephritis and do not prevent its progression.

In addition, the positive effect was short-lived. Discontinuation of therapy resulted in relapses of viremia and was accompanied by a high frequency of exacerbations of cryoglobulinemic vasculitis in the next 3-6 months. In this regard, antiviral therapy is recommended for patients with HCV-associated cryoglobulinemic nephritis with severe urinary syndrome without renal dysfunction or with initial signs of renal failure. Patients with active HCV-associated cryoglobulinemic nephritis, manifested by acute nephritic or nephrotic syndromes and rapidly increasing renal failure, are indicated for glucocorticoids and cytostatic drugs in combination with plasmapheresis.

Forecast

There are 2 groups of prognostic criteria for cryoglobulinemic glomerulonephritis associated with the hepatitis C virus: clinical and morphological.

  • Clinical factors of unfavorable prognosis of mixed cryoglobulinemia include age over 50 years, male gender, combination of HBV and HCV infection, signs of viral replication, liver cirrhosis, recurrent cutaneous purpura, arterial hypertension, blood creatinine concentration of more than 130 μmol/l at the onset of the disease, hypocomplementemia, cryocrit level of more than 10%.
  • Morphological signs of nephritis such as intracapillary thrombi, severe monocytic infiltration of the glomeruli, and acute vasculitis of the intrarenal arteries are associated with an unfavorable prognosis of mixed cryoglobulinemia.

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