Mixed cryoglobulinemia and kidney damage

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

[1], [2], [3], [4], [5], [6]

Causes of the mixed cryoglobulinemia

At present, 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 incidence of cryoglobulinemia varies from 34 to 54%. With mixed cryoglobulinemia markers of HCV infection in the blood are detected in 63-76% of cases, and in cryoprecipitate - in 75-99% of cases.

HCV is believed to stimulate the proliferation of a particular clone of B-lymphocytes producing a polyclonal (IgM) or monoclonal (IgMic) rheumatoid factor. Binding of the latter in blood or in situ with IgG (with HCV IgG infection shows 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 in the glomerulus capillaries, is accompanied by the consumption of complement components, inducing damage to the vascular walls and the development of inflammation.

It turned out that the monoclonal IgMic rheumatoid factor of mixed cryoglobulins has the ability to bind to fibronectin of the mesangial matrix of the 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.

In contrast to type III, in which renal manifestations are non-specific, type II with monoclonal IgMic develops glomerulonephritis with special morphological features that make it possible to treat it as a separate variant of glomerulonephritis - cryoglobulinemic.

[7], [8], [9], [10], [11]

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 glomeruli by leukocytes, mainly monocytes / macrophages, which cause pronounced endocapillary proliferation.
• The presence of so-called "intraluminal" thrombi in the glomerular capillaries - amorphous eosinophilic PAS-positive deposits of different sizes, adjacent to the inner surface of the capillary wall and often completely obturating the lumen of the capillaries. Immunofluorescence method revealed the presence of cryoglobulins, identical to circulating, in the composition of these intracapillary deposits. Electron microscopy reveals fibrillar or microtubule structure of these deposits, identical to that of cryoprecipitate obtained from the same patient in vitro.
• The two-contour of the glomerular basement membrane due to the interposition of monocytes / macrophages between the glomerular basement membrane and the endothelial cells or newly formed membrane-like material. The two-contouring of the glomerular basal membrane in cryoglobulinemic glomerulonephritis is more pronounced than in mesangiocapillary glomerulonephritis where it appears as a result of mesangial cell interposition. About 30% of patients with cryoglobulinemic glomerulonephritis have signs of vasculitis of small and medium-sized arteries characterized by fibrinoid necrosis and monocytic vessel wall infiltration. Renal vasculitis is possible in the absence of glomerular lesions and often correlates with the severity of purpura or vasculitis of the mesenteric arteries.

[12], [13], [14], [15], [16], [17], [18], [19], [20]

Symptoms of the mixed cryoglobulinemia

Symptoms of mixed cryoglobulinemia consist in the development of cryoglobulinemic vasculitis, which occur in 50-67% of patients, on average after 15 years of HCV infection. Cryoglobulinemic vasculitis  often develops in women, in most cases at the age of 40-50 years. Symptoms of cryoglobulinemic vasculitis differ significantly in polymorphism. The most commonly noted palpable purpura on the skin of the lower extremities, sometimes with ulceration, arthralgia, Raynaud's syndrome, peripheral polyneuropathy. Characterized by abdominal pain syndrome (which in some cases leads to surgical interventions), hepatosplenomegaly. Less commonly observed is Sjogren's syndrome, lymphadenopathy.

Kidney damage in mixed cryoglobulinemia

Glomerulonephritis  is the most common visceritis seen 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 in the onset of cryglobulinemia. In rare cases, the development of glomerulonephritis is ahead of other manifestations of mixed cryoglobulinemia (nephritic mask). The renal process manifests with acute nephritic syndrome in about a quarter of patients, nephrotic in 20%, and more than 50% have a moderate urinary syndrome, manifested by proteinuria and erythrocyric. Less than 5% of patients glomerulonephritis from the outset acquires a rapidly progressive course or debuts with oliguric acute renal failure. In patients with cryoglobulinemic glomerulonephritis, early and in most cases severe arterial hypertension is noted, complications of which (acute myocardial infarction, stroke) can cause death of patients.

The course of glomerulonephritis in mixed cryoglobulinemia is variable. Almost a third of patients, especially in the presence of acute syndrome, achieve remission of the kidney process in the period from several days to several weeks. In most cases, a stable course of nephritis is noted with minimal urinary syndrome and normal renal function. In 20% of patients, glomerulonephritis acquires an undulating course with frequent recurrences of acute cold syndrome, which coincide, as a rule, with exacerbation of vasculitis and relapse of extrarenal symptoms. Progression of cryoglobulinemic glomerulonephritis with the development of terminal renal failure is rare (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 NA study. Mukhina, L.V. Kozlovskaya established a high incidence of rapidly progressive glomerulonephritis and nephrotic syndrome with a high level of cryoglobulin type II (more than 1 mg / ml).

Forms

Cryoglobulins are serum immunoglobulins with the property of reversible cold precipitation. Depending on the composition, 3 types of cryoglobulins are isolated.

• Class I cryoglobulins include monoclonal immunoglobulins of predominantly IgM class; This type of cryoglobulin, detected with multiple myeloma or Waldenstrom disease, rarely causes kidney damage.
• Cryoglobulins II and III are mixed, because they consist of at least 2 immunoglobulins, one of which (polyclonal IgG) acts as an antigen, and the other, an antibody, is an associated immunoglobulin (anti-IgG), usually a class IgM, which has rheumatoid factor activity. The composition of cryoglobulins of type II includes monoclonal IgM (containing predominantly one type of light chain-k), while type III contains polyclonal (containing k- and X-light chains).

Mixed cryoglobulinemia type II and III can develop with a variety of infectious and autoimmune diseases, and in this case it is called secondary mixed cryoglobulinemia. Until recently, about 30% of patients failed to establish a cryoglobulinemia relationship with another pathology, leading to the emergence of the term "essential cryoglobulinemia". Essential cryoglobulinemia was described by M. Meltzer in 1966 as a syndrome involving general weakness, purpura, arthralgia (Meltzer's triad) in combination with type II cryoglobulinemia.

[21], [22], [23], [24], [25], [26]

Diagnostics of the mixed cryoglobulinemia

Laboratory diagnosis of mixed cryoglobulinemia

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

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

[27], [28], [29]

Treatment of the mixed cryoglobulinemia

To treat active cryoglobulinemic glomerulonephritis (acute and / or nephrotic syndrome with rapid development of renal failure) immunosuppressive therapy (combination of glucocorticoids and cytostatics), plasmapheresis (cryoapheresis) should be prescribed.

• Treatment of mixed cryoglobulinemia with glucocorticoids begins with intravenous administration of ultrahigh doses (1 g of methylprednisolone) for 3 days, followed by a transition to the intake of prednisolone by 1 mg / kg of body weight per day for 4 weeks, after which the dose of the drug is gradually reduced to a supporting, which is preserved for several months. Cyclophosphamide is prescribed at a dose of 2 mg / kg of body weight per day for a period of at least 4 months or in the form of pulse therapy at 800-1000 mg intravenously at 3-4-week intervals until relief of acute or nephrotic syndromes. The dose of cyclophosphamide depends on the state of kidney function: when creatinine levels in the blood exceed 450 μmol / l, it is reduced by 50%.
• Plasmapheresis or cryoapheresis is carried out 3 times a week for 2-3 weeks only in combination with active immunosuppressive therapy, which avoids the development of the "rebound" syndrome, which is possible after cessation of procedures due to the growth of cryocrit.

Currently, the approach to the treatment of cryoglobulinemic vasculitis, including glomerulonephritis, has changed, which was facilitated by the identification of the connection 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 a-interferon preparations in the form of monotherapy or in combination with ribavirin. Preferably long-term (within 12 months) treatment with a-interferon preparations at a dose of 5 million IU daily in combination with ribavirin (1000-1200 mg / day).

A number of studies on the efficacy of antiviral drugs in cryoglobulinemic vasculitis associated with HCV have shown that they improve the course of the skin process, lead to the elimination of HCV markers, a decrease in cryocrit 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. The termination of therapy resulted in recurrence of viremia and was accompanied by a high incidence of exacerbations of cryoglobulinemic vasculitis in the next 3-6 months. In this regard, antiviral therapy is recommended for patients with HCV-associated cryoglobulinemia nephritis with severe urinary syndrome without impaired renal function or with initial signs of renal insufficiency. Patients with active associated with HCV cryoglobulinemic nephritis, manifested acute or nephrotic syndrome and rapidly increasing renal failure, showed glucocorticoids and cytotoxic drugs in combination with plasmapheresis.

Forecast

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

• The clinical factors of the unfavorable prognosis of mixed cryoglobulinemia include age over 50 years, male sex, combination of HBV and HCV infection, signs of viral replication, liver cirrhosis, recurrent skin purpura, hypertension, creatinine concentration in the blood, more than 130 μmol / l in the onset of the disease, hypocompletenemia, the level of cryocrit more than 10%.
• With unfavorable prognosis of mixed cryoglobulinemia, such morphological signs of nephritis as intracapillary thrombi, severity of monocytic glomerular infiltration and acute vasculitis of the intrarenal arteries are associated.

[30], [31]