Described by Wintrobe et al in 1933, cryoglobulinemias are abnormal plasma proteins that precipitate or form a cold gel.
Lerner and Watson showed in 1947 that immunoglobulins (Ig) were included in their composition and Lospalluto et al., In 1962, that they may belong to one or more classes and have rheumatoid factor activity. In 1974, Brouet et al established the classification of cryoglobulins.
Type I cryoglobulins are composed of an isolated IgM monoclonal Ig more often than IgG or IgA, or exceptionally a monoclonal light chain. A Type I IgG cryoglobulin may have antibody activity against polyclonal IgG. Type II cryoglobulins are composed of monoclonal Ig and polyclonal IgG. This monoclonal Ig has antibody activity against polyclonal IgGs. The monoclonal component is a kappa IgM, or rarely an IgG or IgA. Type III cryoglobulins are composed of one or more classes of polyclonal Ig. Cryoglobulins of types II and III are said to be mixed. They have rheumatoid factor activity and are immune complexes.
Recently, immunoblotting or two-dimensional electrophoresis analysis has described type II / III cryoglobulins, in which polyclonal IgGs are associated with oligoclonal IgM. The appearance of a type II / III cryoglobulin could mark a stage between type III and type II: the age of hepatitis is higher and the level of cryoglobulin is higher in patients with cryoglobulin type II.
Non-immunoglobulin elements, such as beta-1C, lipoproteins, ribonucleic acid (RNA) from hepatitis C virus (HCV) can participate in the composition of mixed cryoglobulins.
Cryoglobulins are demonstrated in a variety of circumstances.
Type I cryoglobulins are observed in the usually malignant lymphoproliferative syndromes, particularly Waldenström macroglobulinemia, multiple myeloma, but also in benign monoclonal gammopathies.
Type II cryoglobulins are found mainly in HCV infections but also in myeloma, Waldenström macroglobulinemia, other non-Hodgkin’s lymphoma, some of which appear to be HCV-induced, and various autoimmune diseases -immune, including systemic lupus erythematosus, rheumatoid arthritis and Sjögren’s syndrome.
Type III cryoglobulinemia occurs in a variety of circumstances: acute or chronic viral infections (infectious mononucleosis, hepatitis C), bacterial and parasitic infections (acute poststreptococcal glomerulonephritis, subacute endocarditis, syphilis, leprosy, autoimmune diseases type II cryoglobulinemia) and cancers.
Cryoglobulinemia type III, and more rarely type II cryoglobulinemia, may occur in the absence of detectable cause.They are then called essential. Type III cryoglobulin is detected in more than 4% of apparently healthy subjects over 60 years of age. But the appearance of lymphoma or other malignant disease in the years following the discovery of mixed cryoglobulinemia is not exceptional.
The frequency of each type of cryoglobulinemia is difficult to define. It is evaluated differently, in the series reported in the literature, according to the specialty and the recruitment of the different teams. Cryoglobulins of type III are certainly the most frequent, cryoglobulins type I and II much rarer. In the Brouet et al series, for example, 25% of patients have type I cryoglobulin, 25% type II cryoglobulin, and 50% Type III cryoglobulin.
The clinical signs of cryoglobulinaemia should be distinguished from those induced by the causative condition. Some are related to plasma hyperviscosity, others to the deposition of cryoglobulin in the vascular walls. The syndrome of hyperviscosity is rare observation. It occurs during type I cryoglobulinemia and exceptionally type II cryoglobulinemia.Deposition of immune complexes accounts for most of the manifestations of type II and III cryoglobulinemias.
The clinical manifestations of cryoglobulinemia are varied. Cryoglobulinaemia can remain completely asymptomatic, which is common in types III. In contrast, Type I and Type II cryoglobulinemia are sometimes responsible for a rapidly fatal multivisceral disease, but this is rare. They occur at any age in adults, but preferentially between 40 and 65 years;they are twice as common in women than in men. All the organs can be affected during a cryoglobulinemia, but the frequency of the different symptoms (depending on the mode of recruitment of the patients) is difficult to evaluate, the large series of the literature combining various types of cryoglobulins: Meltzer triad 14-30% (see below), purpura 60-80%, neuropathy 8-27%, joint damage 5-22%, Raynaud phenomenon 4.5-37%, nephropathy 4.5-37% of the cases.These figures probably overestimate the reality, as asymptomatic forms may go unnoticed or not included in some studies.
In mixed mixed cryoglobulinemia alone, the prevalence of renal involvement is also difficult to assess for the reasons set out above. Several series of literature combine type II cryoglobulinemias with type III cryoglobulinemias.
Others are purely nephrological, or have a broad nephrological predominance. The criteria for kidney damage vary from one series to another. Systematic screening for urinary abnormalities is not always performed. However, in a multi-center, multidisciplinary Italian study involving 913 patients, the prevalence of renal signs was 35% in type II cryoglobulinemia and 15% in type III cryoglobulinemia, close to those observed in the Brouet et al. al.
To our knowledge, no work has been dedicated specifically to possible renal lesions of type III cryoglobulinemias.practice, observation of a type III cryoglobulinemia and glomerulonephritis in the same patient is commonplace, but the disorder responsible for cryoglobulinemia alone can explain in most cases, if not renal lesions. In any event, if they exist, the renal lesions due to the presence only in the serum of a type III cryoglobulin are exceptional. They will not be discussed later.
Ultimately, only renal manifestations of cryoglobulinemia type II have been the subject of numerous publications. Being the most frequent, they will be described first. A separate chapter is devoted to renal manifestations of type I cryoglobulinaemia.
Type II Cryoglobulinemias and Nephropathies:
The first manifestations of type II cryoglobulinaemia generally occur between 50 and 60 years, with extremes of 14 to 85 years. Women are two to three times more often affected than men, but the difference is less marked if only kidney damage is taken into account. The largest series have been reported in Italy, France, Spain, Israel and New York.
Renal Symptomatology, Hemodynamic and Volemic Abnormalities:
In more than half of the cases, renal involvement is revealed by arterial hypertension, microscopic hematuria and proteinuria without nephrotic syndrome. In the absence of biological examination of the urine, high blood pressure passes for a long time essential, and urinary abnormalities are unknown. In 20% of cases, renal involvement is manifested by impure nephrotic syndrome, and in other cases by a nephritic syndrome that is more often subacute than acute with proteinuria, hypoalbuminemia, abundant or macroscopic microscopic haematuria (“dirty broth” urine or red), hypertension often poorly tolerated with pulmonary edema and renal insufficiency. Kidney failure can be severe.Anuria is possible. In these cases, the clinical picture associates nephritic syndrome with rapidly progressive glomerulonephritis syndrome.
Regardless of the mode of presentation, hypertension affects more than 80% of patients.
Renal signs are present in the initial assessment of cryoglobulinemia in half of the cases. In other cases, a delay of a few months to more than 10 years separates them from extrarenal manifestations. Finally, it is not unusual for a type II cryoglobulinemia to be revealed by isolated nephropathy and the diagnosis can only be evoked after the immunomorphological examination of the renal biopsy.
The evolution of nephropathy is unpredictable.
In about a quarter of cases, it is enamelled by the occurrence of one or more outbreaks spread over more than 15 years and manifested by a nephritic syndrome. They are usually contemporaneous with an accentuation of extrarenal symptoms.
Death may occur during one of these outbreaks in a multi-organ failure table resistant to all treatments.
This unfavorable trend concerns about 5% of cases.
In one third of cases, partial or complete remission occurs spontaneously or after treatment. This is possible even after severe renal thrust. However, it is more frequent (50% of cases) when the symptomatology is limited to proteinuria and / or hematuria.
In other cases, kidney damage does not evolve or not for many years. High blood pressure is the most worrying manifestation.
Nephropathy leads to 10-15% of patients with chronic kidney disease, followed by hemodialysis after several years of development. In the series of 116 patients in the Milan group published in 1985, the actuarial survival was 70% at 10 years after the onset of the disease and 64% after the diagnosis of cryoglobulinemia, renal survival of 68 and 48% respectively , whereas all patients had severe glomerular lesions proved by renal anatomical examination. The death occurred 170 ± 120 months after the first signs of the disease, and 29 ± 34 months after diagnosis. Renal insufficiency had pejorative prognostic ignorance. The prognosis is worse in a series of 105 patients published 10 years later by the same group. Overall survival was 49% 10 years after renal biopsy.
Following a follow-up of 131 months after the first signs of cryoglobulinemia and 72 months after renal biopsy, 42 patients died of cardiovascular, hepatic or infectious disease, 15 depend on an extrarenal form of treatment, two are in complete remission and 15 in only renal remission. Risk factors for death or dialysis are age greater than 50 years, purpura, splenomegaly, cryocrite greater than 10%, C3 less than 54 mg / dL and serum creatinine greater than 136 ímol / L. Renal insufficiency should no longer influence the prognosis in the affluent countries as such, because of the possibilities of extrarenal treatment. In fact, kidney failure is rarely the leading cause of death. This is mainly due to hemodynamic disorders, multivisceral vasculitis, malignancy, hepatopathy and infections. The life and renal prognosis is much more severe in patients co-infected with the human immunodeficiency virus (HIV), with poor survival of 6.1 months.
Hemodynamic and volemic abnormalities:
Hemodynamic disorders respond to various mechanisms often entangled without it being possible to specify the precise responsibility of each one.
Blood pressure is often very high and difficult to control. Over a period of years, it favors the occurrence of hypertrophic or dilated cardiomyopathy with important disorders of left ventricular compliance and atherosclerosis that can affect all the territories, in particular the coronary arteries. Hypertension is due in part to water-related inflation associated with glomerular lesions. This explanation is insufficient because the diuretics alone do not usually control it.
Water-based inflation can be major when a nephritic syndrome, nephrotic syndrome, or combination of both occurs.The weight gain can then exceed 10 kg. Water-based inflation is sometimes underestimated when general signs of vasculitis have led to weight loss. It is manifested by generalized swelling of the four limbs and the face, as in acute post-infectious glomerulonephritis, effusions in the serous, mainly pleural, and an increase in hypertension which is usually poorly tolerated, with acute edema or subacute lung. Chronic liver disease promotes ascites. Again, hypervolemia is not the only explanation for edema and effusion. They can withstand severe hydrosodic depletion until signs of hypovolemia (orthostatic arterial hypotension, functional increase in renal insufficiency). They are also not explained by hypoalbuminemia. The usually dramatic effect on edema and effusion resistant to hydrosodic depletion of corticosteroids, as an intravenous or oral bolus, suggests that there is a significant disturbance of capillary permeability due to activation of endothelial cells and macrophages by cryoglobulin and increased cytokine production.
Renal signs and haemodynamic disorders may be the only manifestations of type II cryoglobulinemia, but in the majority of cases they occur at the same time as extrarenal manifestations or afterwards.
The most frequent extrarenal manifestations constitute the triad described in 1966 by Meltzer and Franklin: purpura, arthralgia and asthenia.
Signs of skin:
Purpura is the most frequent symptom (70-93% of cases). It predominates in the lower limbs and can go up to the buttocks and the abdomen. It usually spares the upper body. It is made of petechiae and sometimes of purpuric papules.
Some elements may be necrotic. These elements may be confluent, especially in the lower third of the leg and the ankle. It evolves in pulses parallel to other clinical signs. After several flares, purpura leaves sequelae in the form of ocher spots, livedo, and sometimes ulcers. It can be pruriginous and painful. It would be caused or aggravated by exposure to cold in 30% of cases. Like all vascular purpuras, it is increased by orthostatism. Skin necrosis predominates in the supra-alopear regions and may also interest the toes, fingers, nose and ears. They are infrequent in type II cryoglobulinemias. Fifty percent of patients describe Raynaud’s syndrome.
The cutaneous signs are associated with each other. They can evolve for years, even several decades, without appearing severe visceral manifestations or alteration of the general state.
Signs of joints:
Arthralgia affects about half of the patients. They are symmetrical and fixed. They mainly concern the hands, feet and knees, less often the hips and elbows. The joints are usually cold or not very inflammatory. Joint destruction can occur after several years of evolution.
Neurological attacks are infrequent (5 to 30% of cases), but are of particular gravity because they are liable to leave serious consequences. They are mainly manifested by peripheral neuropathy, which is more often sensitive than motor, symmetrical or not, with paresthesia or anesthesia in the affected territories and an alteration in the rates of nerve conduction. Central nervous system damage has been exceptionally reported. In our experience, they are in a context of serious mortal multiviscal attacks.
Their impact is variously appreciated: 3 to 43% depending on the series and the criteria chosen. Thus, CT and X-ray showed interstitial pneumonitis in 78% of cases, which is minimal in more than half. Respiratory function tests and blood gas analysis revealed anomalies in 35% of cases. They are manifested by dyspnea, cough and pleural effusions, exceptionally by hemoptysis and asthma.
The occurrence of respiratory distress requiring assisted ventilation is rare. This can lead to death, in a table of uncontrollable pulmonary haemorrhage (personal observations).
The possible mechanisms of respiratory disorders are numerous and difficult to disentangle during the patient’s lifetime. The scanner can be very useful here. Pleural effusions often play an important part; their abundance is underestimated by clinical and simple radiography. Pulmonary edema is common; it may be related to the conjunction of hypervolaemia, capillary permeability disorder and left ventricular dysfunction in long-standing hypertensive patients. Finally, hemoptysis causes a pulmonary haemorrhagic edema or pulmonary vasculitis which has been shown at autopsy to be discussed in some cases.
They affect 2 to 20% of the patients. They are manifested by abdominal pain and transit disorders. Vasculitis lesions are found at the autopsy. Evolving by flare-ups followed by remissions, like other signs, they lead exceptionally to surgery.
Cryoglobulinaemia may not cause any change in the general condition, but it is almost constant in patients suffering from symptomatic nephropathy. Asthenia is one of the elements of the triad of Meltzer and Franklin. Curiously, it is rarely mentioned, whereas it is frequent and intense. It is often attributed to depressive syndrome. Anorexia is common; the weight loss passes unnoticed when it is masked by edema due to nephropathy. The temperature is normal in the absence of infectious complications.
The diagnosis of cryoglobulinemia is based on the detection of cryoglobulin in the serum.
Blood should ideally be taken from a patient on an empty stomach and in a room maintained at 37 ° C. It is placed in an oven at 37 ° C. and also centrifuged at 37 ° C. The collected serum is then placed at 4 ° C. The precipitation temperature is between + 4 and + 36 ° C. (usually between 25 and 30 ° C.). The search for the cryoglobulin is carried out after 8 days of storage, the precipitation being a slow phenomenon. But it is important to know, for emergencies, that it is sometimes detectable within 24 hours.
After purification, the cryoglobulin level is evaluated in grams per liter (g / L) or, after centrifugation at 4 ° C. of the serum in a hematocrit tube, in percentage (cryocrite), and its composition is defined. Cryoglobulins usually redissolve at 37 ° C. and recover their property of precipitating with cold after heating at 56 ° C. However, some of them, pyroglobulins, irreversibly precipitate at this temperature.
Cryocrite is between 1 and more than 70%, the serum level of cryoglobulin is less than 1 to more than 20 g / L; the highest rates are observed in type I cryoglobulinemia secondary to myeloma and the lowest in type III cryoglobulinemia. A high cryocrite may cause hyperviscosity syndrome. The rate of cryoglobulin has no prognostic value for the majority of authors; however, a high cryocrite is associated with an unfavorable prognosis for some. A correlation between clinical improvement and decrease in cryoglobulin levels has been described. But in everyday practice, it is remembered that the rate of cryoglobulin can vary significantly in a given patient, without any change in the clinical situation.
The electrophoresis and the immunoelectrophoresis of the serum, carried out at 37 ° C., demonstrate the monoclonal compound.
Hypocomplementemia is common in symptomatic type II cryoglobulinemias. It focuses on C1q, C4 and CH50. C4 is lowered in 81% of type II cryoglobulinemia (and 64% of type III cryoglobulinemia).
The serum of patients with mixed cryoglobulinemia has rheumatoid factor activity. The other biological signs are inconstant and non-specific. Moderate anemia is common. Hypergammaglobulinemia and elevation of CRP (C reactive protein) are common. On the other hand, despite the inflammatory syndrome, the sedimentation rate is often close to zero.
Renal biopsy reveals a very characteristic, and sometimes specific, set of lesions.
Examination by optical microscopy:
The most common glomerular lesion is focal or diffuse endocapillary proliferation. This consists mainly of monocytes activated in very large numbers, sometimes neutrophils, and by T lymphocytes in particular CD8. In the most exudative forms, amorphous eosinophilic and PAS positive deposits (periodic Schiff staining) are found along the internal slope of the basal membrane of the glomerular capillaries. These deposits can occupy all the light of a capillary loop and thus achieve an “intraluminal thrombus”. The association of massive monocytic infiltration with thrombi is very evocative of type II cryoglobulinemia.
The glomerular basement membranes are thickened, with a double contour appearance emphasized by the silver impregnation. This aspect is due to interposition of mesangial matrix, cytoplasm of monocytes, and deposits between the basement membrane outside, and a basal neomembran within, in close contact with these deposits. The whole, endocapillar proliferation and double contours, realizes a particular membranoproliferative glomerulonephritis.
In some patients, monocytic infiltration is much less marked and thrombi are lacking. Elsewhere, it is completely absent and the glomerular lesions are merely moderate mesangial proliferation, usually segmental. An aspect of lobular glomerulonephritis may also be observed with predominant mesangial proliferation and marked hypertrophy of the mesangial matrices with little or no visible deposition.
Curiously, glomerular lesions usually do not evolve towards glomerulosclerosis, and the transformation of glomeruli into “sealing loaves”, even after years of evolution, is not frequent. Necrosis of glomerular capillary loops and extracapillary proliferation are rare. The latter is almost always segmental and affects only a small number of glomeruli. Thrombi can disappear completely. Glomerular lesions of thrombotic microangiopathy have been described in two patients.
Vasculitis of the interlobular arteries and associated arterioles is present in one third of the cases. It is characterized by fibrinoid necrosis of the wall, and perivascular infiltration by macrophage monocytes, which may constitute a granuloma. Arterial light is sometimes obstructed. These lesions evolve towards the sclerosis of the wall.
In the acute phase of renal disease, the interstitium is infiltrated by macrophage monocytes and T lymphocytes, mainly CD8, and B sometimes clustered. On late biopsies, fibrosis is usually discrete.
The deposits fix the antibodies directed against the constituents of the cryoglobulin, the anti-IgM, the anti-IgG, the light anti-chains much more often than the anti-C3, and sometimes the anti-C1q, anti-C4 and antifibrinogen sera. However, one or more components of the cryoglobulin may not be revealed. Deposits can take three aspects:
– voluminous deposits filling the lumen of the glomerular capillaries (thrombi);
– scanty and segmental granular deposits in the capillary wall, in the subendothelial position;
– abundant and diffuse granular deposits of the same topography.
The same glomerulus often contains thrombi and granular deposits. These same deposits are encountered in the walls and arterial lumen in a third of the cases.
Examination by electron microscopy:
The deposits are electronically dense and appear either amorphous or organized. Organized deposits form microtubules of 100 to 1000 nm in length and 30 nm in diameter on average. In cross-section, they appear as rings with a light center and the periphery of which is underlined by an inconsistent covering of protein material with little osmiophilicity, which can be arranged in points. The microtubules may be randomly dispersed or clustered together.The ultrastructure of the deposits is identical to that of cryoprecipitate in the same patient. These deposits are found in the lumen of the capillary loops and in the subendothelial regions, rarely in the mesangial areas,
in the subepithelial regions and in the monocyte macrophages. Such structures may be encountered outside the cryoglobulinemia. The cytoplasm of endothelial cells, mesangial, rarely podocytes, occasionally contains crystals of various forms which could be composed of denatured cryoglobulins. Electron microscopy confirms that endocapillary proliferation is essentially due to an influx of macrophage monocytes, whereas the proliferation of mesangial cells is usually discrete or absent. The monocytes-macrophages are filled with large protein vacuoles devoid of crystalline structure. The cells, when they are in great number, participate in the occlusion of the glomerular capillaries. Their cytoplasm is also interposed, with mesangial material and deposits, between the native basal membrane and the endothelial cells, from which they are separated by a basal neomembrane, and participates in the double contour appearance of the glomerular capillary loops. But this phenomenon is not as marked as in the so-called primitive membranoproliferative glomerulonephritis.
The pathogenic role of type II cryoglobulins is demonstrated in several experimental models and strongly suggested by clinical findings.
Type II cryoglobulins taken from patients with renal involvement and injected after solubilization into the peritoneum of a mouse induce a membranoproliferative glomerulonephritis. A hybridoma derived from a MRLMpJ- / lpr-lpr mice synthesizes an IgG3 possessing cryoglobulin and rheumatoid factor activity. Intraperitoneal administration of this hybridrome to an MRL / BAL B mouse induces cutaneous vasculitis and membranoproliferative glomerulonephritis very similar to that observed in human pathology, with infiltration by polymorphonuclear cells, mesangial proliferation, mesangial and subendothelial deposits in wire loop accompanied by thrombi. Cryoglobulin activity is related to the constant part of the alpha 3 chain. Renal lesions develop independently of rheumatoid factor activity. These two models allowed us to study the dynamics of deposition.
Mechanisms of deposition of cryoglobulin:
Cryoglobulin is deposited first in the mesangial cells and then in the subendothelial regions. The volume of the mesangial deposits increases rapidly, which results in a filling of the lumen of the glomerular capillary loops. In electron microscopy, there is continuity between mesangial, subendothelial and thrombi deposits.
The mechanisms responsible for the deposition are imperfectly known.
The concentration of plasma proteins during their passage through the capillary loops is a plausible explanation for their deposition in the glomerulus. Similarly, plasma levels of cryoglobulin are likely to play a role. In the same patient, renal manifestations disappear or subside when the serum level of cryoglobulin decreases, and vice versa.
However, it is not unusual to see the symptoms disappear under the effect of a corticoid treatment, or spontaneously, in the absence of a significant change in the level of the cryoglobulin.
There is a biochemical affinity between type II cryoglobulins and some matrix and cellular proteins. The kappa IgMs of type II cryoglobulins bind in vitro to one of the important components of the basal membrane and the mesangial matrix, fibronectin. The kappa-fibronectin IgM complex binds polyclonal IgGs in solution. In contrast, kappa IgM in patients with Waldenström disease who have no cryoglobulin activity have no affinity for fibronectin.
Anomalies of cryoglobulin purification:
Role of macrophages:
Abnormalities in the purification of type II cryoglobulins are observed in patients with severe nephropathy. Compared with patients without nephropathy, the half-life of radiolabelled cryoglobulins is increased, their uptake by the liver and the spleen decreases, their degradation by macrophages slowed, while the opsonization capacity of these is normal.
One of the main characteristics of renal lesions is the massive infiltration of the floccus by monocytes-macrophages.
The intensity of this infiltration is closely correlated with the expression of the MCP I gene and the MCP I protein. Moreover, this is maximum in the immediate vicinity of cryoglobulin deposits. MCP I is a cytokine with specific chemotactic activity on monocytes-macrophages. It is produced (in vitro) by mesangial cells, endothelial cells and proximal convoluted tubule cells. Different cytokines and aggregated IgG stimulate the synthesis in vitro.
Finally, activated macrophages produce many cytokines that activate renal resident cells, as well as lysosomal enzymes and oxygen free radicals that cause cellular and matrix alterations.
Role of hepatitis C virus:
HCV plays a central role in type II cryoglobulinemia.
Until recently, mixed cryoglobulins were attributed to various bacterial, autoimmune, particularly hepatobiliary or malignant disorders. They can actually be encountered during bacterial endocarditis, rheumatoid arthritis, Sjögren’s syndrome, mainly non-Hodgkin’s lymphoma, Waldenström disease, rarely chronic lymphocytic leukemia and myeloma.In 30% of mixed cryoglobulinemia (types II and III), no cause was identified and cryoglobulinemia was considered essential. Then the idea prevailed that the antibody activity of kappa IgM was directed not against polyclonal IgG alone but against an antigen-antibody complex, the antigen being hepatitis B virus (HBV) and playing an important pathogenic role. However, most investigators have not found an association between HBV and type II cryoglobulinemia.
The central role of HCV was demonstrated in the early 1990s. The serum of patients with type II cryoglobulinemia contains anti-HCV antibodies in 87 to 100% of the cases, and messenger RNA (mRNA ) coding for HCV in 71 to 100% of cases.
In addition, HCV-coding mRNA is concentrated up to 1000 times in cryoprecipitate, and cryoprecipitate contains 94% of antibodies to HCV. But in half of the patients, these are only detectable after elimination of the rheumatoid factor. In contrast, 20% to 54% of patients with hepatitis C are carriers of asymptomatic mixed type III cryoglobulin in 90% of cases, type II with a higher concentration and usually symptomatic in 9-35% of patients. remaining cases.
The role of HCV in the occurrence of nephropathy is further suggested by demonstrating, in a short series, mRNA coding for HCV in the serum and cryoprecipitate of all patients with nephropathy, This is undetectable in the absence of nephropathy.
The prevalence of genotype 2a / III is significantly greater in patients with mixed cryoglobinemia than in controls (41% versus 15%), coinciding with a subgroup of patients with clinical and biological signs of liver disease (85%). . Co-infection with hepatitis G virus is common, but does not appear to play a primary role.
There is a genetic predisposition to the occurrence of cryoglobulinemia in patients with HCV. This would be more frequent in subjects with HLA DR3, DR7, DR11 and B8 alleles.
HCV can infect T and B lymphocytes and indirectly induce clonal proliferation, although it does not have reverse transcriptase or oncogenes. There is a clear association between HCV and non-Hodgkin’s lymphomas of low or intermediate grade, HCV-associated lymphomas with very specific clinical and histological characteristics. Clearly, the monotypic character of the kappa IgM of type II cryoglobulins is the product of a monoclonal proliferation B. Medullary biopsy revealed low grade lymphoma in 38% of type II cryoglobulinemia.
Until the late 1980s, the treatment included variable dose corticosteroid therapy (1/4 to 1 mg / kg / day) and / or cyclophosphamide or chlorambucil treatment regimen has been validated by controlled trials, difficult to carry out in this infrequent affection and of capricious evolution. Intravenous boluses of methylprednisolone at the dose of 1 g, repeated three times, were added to the meningeal renal form due to nephrotic or nephritic syndrome with rapidly evolving renal failure. The rate of serum creatinine decreased in the first week of treatment, and the rate of proteinuria in the first month. At the same time, more than 70% of the patients disappeared or faded in less than 1 week.Hypocomplementemia decreased and the rate of cryoglobulinemia decreased. These treatments were given for short periods, interrupted between outbreaks.
The survival of patients undergoing such a therapeutic regimen was 93% at 1 year.
Plasma exchanges are also credited with high efficacy, but not compared to the much less expensive bolus methylprednisolone. However, they should be prescribed when life-threatening conditions are threatened in the short term, either as a first-line treatment or after failure of the treatments described above. It is essential to realize them in a room whose temperature is carried above that which causes the cryoprecipitation.
The demonstration in the early 1990s of a causal relationship between HCV and type II cryoglobulins led to the treatment of HCV with interferon alpha. As early as 1987, prior to the discovery of HCV, work by Bonono et al suggested that interferon alpha, at a dose of 3 million units (MU) per day, could improve clinical symptomatology and permanently decrease cryocrite.
Numerous isolated cases and a prospective, randomized, cross-over trial suggest that treatment with interferon alpha is likely to result in:
– a regression of the general and renal signs which can go as far as complete remission;
– the marked disappearance or reduction of the level of cryoglobulin;
– a disappearance of the viral RNA from the circulation, but the probability of relapse is strong when the treatment is stopped.
A prospective, randomized trial comparing interferon therapy at a dose of 3 MU three times weekly for 24 weeks to no treatment in a group of 53 patients, most of whom had only moderate renal impairment showed:
– that the viral mRNA disappears from the serum of 15 patients out of 25 treated, and persists in the controlled patients;
– a clinical response only occurs if the viral mRNA has disappeared from the serum;
– the serum creatinine level decreases significantly in responders and increases or stays unchanged in control subjects;
– a relapse occurs constantly at the end of treatment.
A prospective study using the same therapeutic regimen in a group of 34 patients with more severe nephropathy revealed little difference in results: significant reduction in proteinuria and non – significant serum creatinine, relapse at cessation of treatment, enhancement if viral RNA remains detectable.
A retrospective study from 1985 studied the effects of 3 MU of interferon alpha administered daily for 3 months and then every 2 days for the next 9 months in 31 consecutive patients. Complete clinical and biological remission (cryocrite < 10% of baseline) was observed in 62% of patients with mean follow-up of 33 months (3 to 100 months). A secondary elevation of liver enzymes, indicative of disease activity, occurred in all patients with a cumulative dose of less than 621 MU, and only in 8% of those who received a higher dose. The two predictors of a sustained response are a cumulative dose of high interferon and the presence in the serum of the only anti-C22 antibody. Isolated cases of cryoglobulinemias remaining severely symptomatic despite conventional treatment and remission after doses up to 10 MU / d have been reported. Overall, there appears to be a consensus in favor of a dose of 4.5 to 6 MU three times a week for 6 months and then for the responders 3 MU for another 6 months with a very gradual the following 6 months.
The addition of ribavirin to interferon significantly improves the long-term efficacy of treatment of hepatitis C. A recent preliminary study and isolated observation suggest that it would be the same in type II cryoglobulinemia. But the side effects of ribavirin (anemia, rash …) are currently a major obstacle to its use in patients with renal insufficiency.Interferon regularly induced rejection of organ allografts, four liver transplant patients suffering from hepatitis C and membranoproliferative glomerulonephritis secondary to type II cryoglobulinemia, with renal insufficiency and nephritic syndrome, were treated with ribavirin alone at dose of 1 g / d. In all four cases, the renal symptomatology regressed or disappeared under treatment, while the viral load remained constant. Interruption of treatment resulted in relapse. A worsening of the clinical manifestations of cryoglobulinemia, particularly neurological, at the start of treatment with interferon, has been reported several times.
Practical attitude to serious kidney forms:
Pending the results of randomized prospective trials, it appears wise to begin treatment of the most acute and severe renal forms (nephritic syndromes, rapidly progressive renal failure, life-threatening extrarenal manifestations) by intravenous bolus methylprednisolone (or plasma exchange), followed by corticosteroids with cyclophosphamide or chloraminophene per os, and postpone possible interferon therapy. The main risk of such an attitude would be hepatic.The occurrence of clinically significant worsening of hepatitis C, triggered by the corticosteroid and immunosuppressive treatment of nephropathy associated with type II cryoglobulinemia, appears to be low, except in a particular case. Similarly, deaths occurring early in the course of development are very rarely linked to hepatitis C. However, remissions of severe renal manifestations have also been observed after treatment with conventional interferon alone or in combination.
Symptomatic treatment of renal manifestations of cryoglobulinemia is of considerable importance in the most serious forms. High blood pressure and hydrosodic retention, often responsible for overall heart failure, require high doses of loop diuretics, associated vasodilators, and strict water restriction.
Hemofiltration and extrarenal treatment should not be implemented too late. Frequent anorexia is responsible for undernutrition which should be controlled if necessary by enteral or parenteral nutrition. The prevention of nosocomial or opportunistic infection is a constant concern.
Treatment of B lymphomas complementing the evolution of type II cryoglobulinemia is the responsibility of hematology.
Nephropathies and Cryoglobulinemias Type I:
In the Brouet et al series, the prevalence of renal signs in type I cryoglobulinemias is 25%. Paradoxically, the number of documented publications of type I cryoglobulinemia with renal involvement is less than 20, most describing only one or two cases. Furthermore, the information provided in the published large series does not allow the described kidney damage to be linked to any of the three types of cryoglobulins. It is accepted that renal manifestations are less frequent in type I cryoglobulinemia than in type II. In fact, it is rare for a patient with type I cryoglobulinemia to be admitted to nephrology.
The symptomatology is often modeled on that observed during type II cryoglobulinaemias: abundant proteinuria, nephrotic syndrome, high blood pressure, hydrosodic inflation, usually moderate renal insufficiency. Anuria is possible, possibly caused by hypothermia during surgery. A hyperviscosity syndrome can be observed, which could explain some kidney failure that it would be hazardous to document by biopsy in this situation. The hypocomplemia is inconstant. The renal evolution is often favorable after treatment of the causal haemopathy whose nature fixes the prognosis. The combination of corticoidplasmapheresis and chemotherapy is sometimes of remarkable immediate efficacy on renal signs, in the most serious forms and hyperviscosity syndromes. However, death may occur early in a multifactorial pattern that is refractory to treatment or infectious complications.
Histological lesions vary from one observation to another. The most commonly described lesion is a membranoproliferative glomerulonephritis which may be segmental. Cell proliferation is made of mesangial cells and polynuclear cells.
But these lesions were described at a time when monocyte-macrophage cells infiltrating floccus were not recognized.A recent observation indicates the presence of foam cells in the floccus, and others a segmental and focal extracapillary proliferation.
Diffuse obliteration of all glomerular capillary loops by thrombi, without cell proliferation, similar to that described in Waldenström’s macroglobulinemia, may be encountered. The association of membranoproliferative glomerulonephritis and thrombi, as well as lesions of arteriolar angiitis have been published. Immunofluorescence studies with anti-chains, anti-chains and C3-anti-chains show complement and monoclonal immunoglobulin in subendothelial regions, thrombi, and sometimes in arterioles.
Electron microscopic examination shows subendothelial deposits, dense to electrons, less often mesangial and extramembrane, as well as thrombi. The deposited material can appear as 80 Å diameter fibrils, curved or rectilinear, in bundles of 700 to 2000 Å thick in the lumens of the glomerular capillary loops and in the cytoplasm of the macrophages infiltrating the floccus. Rhomboid crystals are occasionally observed in the mesangium, endothelial cells and podocytes. In one case, the deposits looked like fingerprints.