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иппт. Kidney damage in mixed cryoglobulinemia. Kurmanova G. M., Imangali M., Alipbayeva A., Malikova A., Isbulat L

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НазваниеKidney damage in mixed cryoglobulinemia. Kurmanova G. M., Imangali M., Alipbayeva A., Malikova A., Isbulat L
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Имя файлаAtlnaticus Cryoglobulinemia_what_is_that.docx

Подборка по базе: Biomarkers of dalayed graft function as a form of acute kidney i.

Kurmanova G.M., Imangali M., Alipbayeva A., Malikova A., Isbulat L.
Abstract. Mixed cryoglobulinemia (MC) is a disease in which circulating cryoprecipitating immune complexes are detected in the blood serum and which is manifested by a classical triad of symptoms: purpura, weakness, arthralgia. Etiopathogenesis of MC is characterized by polyclonal activation of lymphocytes. Hepatitis C plays a causal role in the activation of this process along with environmental and genetic factors. In this case, a clinical example of MC with kidney damage is given.

Key words: Cryoglobulinemia, Viral hepatitis B, Viral hepatitis C, kidney damage in mixed cryoglobulinemia.


Mixed cryoglobulinemia (MC) – refers to the presence of circulating cryoprecipitable immune complexes in the blood and manifests clinically by a classical Meltzer’s triad if purpura, weakness and joint syndrome. MC is characterized by variable organ involvement including skin lesion (orthostatic purpura, ulcers, urticaria), glomerulonephritis, peripheral neuropathy, diffuse vasculitis and less, frequently, interstitial lung involvement and endocrine disorders, in the background of chronic hepatitis. Some patient may develop lymphatic and hepatic malignancies, usually as late complications. [8] The etiopathogenesis of MC is the syndrome of polyclonal activation of lymphocytes. Hepatitis C virus (HCV) infection is approved to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency (HIV) infection or primary Sjögren syndrome. Diagnosis is based on clinical and laboratory findings. Differential diagnosis include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren

syndrome. The first-line treatment of MC should focus on eradication of HCV. The general prognosis is poorer in patients with renal diseases, liver failure, lymphoproliferative disease. [9]

Cryoglobulinemia what is that

What infections calls 1,2,3 types of cryoglobulinemia ?
Cryoglobulins are serum immunoglobulins that precipitate when cooled at 27°C and redissolve when rewarming. Сryoglobulinemia is a clinical syndrome that results from systemic inflammation caused by cryoglobulin-containing immune complexes. [1]
Cryoglobulins differ in their composition :
Type I-In compostition we can find monoclonal IgG, IgA or IgM. Associated diseases : multiple myeloma (IgG, IgM), Chronic lymphosytic leukemia, Waldenstrom macroglobilinemia, Idiopathic monoclonal gammopathy, Lymphoproliferative disorders.
Type II-Polyclonal IgG and monoclonal IgM (with rheumatoid factor activity). Disorders are : Hepatitis C, Hepatitis B, HIV ; Neoplasms ;
Type III-Polyclonal IgG and polyclonal IgM. Disorders : Infections : viral (hepatitis B and C, Epstein-Barr, cytomegalovirus ; Autoimmune disorders( SLE), Chronic liver disorders. [1]

Types II and III are also referred to as mixed cryoglobulinemia, represent 80% of all cryoglobulins.
Comparison of clinical and laboratory findings between type I and mixed cryoglobulinemia (type II/III) [5]

Type I

Mixed cryoglobulinemia (type II/III)

Main clinical findings




Skin ulcers






Peripheral neuropathy






Involvement of lungs, heart, GI tract, and central nervous system

Almost never

Rare (∼5%)

Hyperviscosity syndrome

Occasionally; usually in IgM isotype and when M-protein is >4 g/dL

Rarely; never in type III

Laboratory findings

Cryoglobulin composition

Monoclonal Ig’s (usually IgG or IgM)

Type II: monoclonal IgM with RF activity plus polyclonal IgG;Type III: polyclonal IgM with RF activity plus polyclonal IgG


Above 5%; can reach more than 50%

Less than 5%

Complement assays

May be decreased

Decreased (mainly C4)

RF activity

Occasionally increased


Epidemiology of II type mixed cryoglobulinemia.

Hepatitis C is a main cause of apprearance of mixed cryoglobulinemia.

Hepatitis C virus (HCV) infection is a major health problem. The World Health Organization (WHO) estimates that at least 150–170 million people, approximately 3% of the world's population, are chronically infected.  In some large cohort studies, up to 74% of patients experienced HCV-EHMs of different severity, from perceived to disabling conditions. [2]

HCV infection represents the cause of MC in roughly 90-95% of cases. The disease expression is variable, ranging from mild symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). [3]

HCV role

  • At the patients infected with HCV, the frequency of identification of a cryoglobulinemia varies from 34% to 54%

  • At the admixed cryoglobulinemia HCV infection markers in a blood find in 63-76% of cases

  • In cryoprecipitates — in 75-99% of cases

  • HCV-PHK is found the PCR method not only in Serum of patients with a cryoglobulinemia, but also in highly concentrated form in cryoprecipitates. May be faulse-negative results of markers in serology.



Mortality and morbidity in individuals with cryoglobulinemia often depend on concomitant disease (eg, lymphoproliferative disorder, viral hepatitis); for example, the prognosis in patients with chronic hepatitis C depends on their response to treatment; manifested by their decrease in viral rate. The overall prognosis is worse in persons with concomitant renal disease, lymphoproliferative disease, or plasma cell disorders. Mean survival is approximately 50% at 10 years after diagnosis. [7]

Morbidity due specifically to cryoglobulinemia may be significant, with infection and cardiovascular disease being major considerations. Hepatic failure may result from chronic viral hepatitis.

Sex- and age-related demographics

The female-to-male ratio is 3:1. The mean age reported is 42-52 years.
Main extra hepatic manifestations of hepatitis C Virus infection: tentative classification according to the strength of the association. [3]

Table 1 Main extra hepatic manifestations of hepatitis C Virus infection: tentative classification according to the strength of the association.

A. Significant prevalence, consistent pathogenetic data and “ex-adjuvantibus” criteria

Mixed cryoglobulinaemia/cryoglobulinaemic vasculitis

B-cell NHL

B. Higher prevalence than controls

Type 2 diabetes mellitus type 2

Insulin resistance


Renal insufficiency


Cognitive impairment


Impaired quality of life

Cardiovascular disorders (i.e. stroke, ischemic heart disease)

Sicca syndrome


Auto-antibody production (i.e. cryoglobulins, rheumatoid factor, and antinuclear, anticardiolipin, anti-thyroid and anti-smooth muscle antibodies)

Monoclonal gammopathies

Immune thrombocytopenia

Porphyria cutanea tarda

Lichen planus

C. Possible association




Chronic polyradiculoneuropathy

Lung alveolitis

D. Anecdotal association



Polyarteritis nodosa


Mooren corneal ulcer

Erythema nodosum

E. Association with antiviral treatment (interferon alpha)




Impaired quality of life



Skin vasculitis

Peripheral neuropathy

NHL, non-Hodgkin's lymphoma; SS, Sjögren's syndrome; PM/DM, polymyositis/dermatomyositis; PAN, polyarteritis nodosa.



The process of cryoprecipitation is not entirely understood and probably differs between type I and type II/III. In type I, the monoclonal component undergoes crystallization and aggregation, which is dependent on temperature and concentration.Although the definition of cryoglobulins is precipitation at cold temperatures, this process can occur at room temperature at high cryoglobulin concentrations. This probably explains why distal extremities (lower temperatures) and kidneys (increase in concentration as a result of ultrafiltration) are major sites of pathology. In type II/III cryoglobulinemia, cryoprecipitation takes place in the setting of immune complex formation between polyclonal IgG and IgM with RF activity and complement fixation. Cryoprecipitation cannot be induced by the IgM or IgG components separately and requires specific antigen-avidity IgG molecules. This underscores the unique properties of cryoglobulins and explains the high incidence of HCV as a cause. [5]

Tissue injury

The mechanism of cryoglobulin pathogenicity is best described for HCV-associated cryoglobulinemia. HCV drives a clonal B-cell expansion, which secretes a monoclonal IgM that binds to polyclonal IgG molecules, which defines a RF. The IgM interacts with anti-HCV IgG to form immune complexes. These immune complexes bind via a C1q to C1q receptors to receptor on endothelial cells, which promotes inflammatory cell recruitment and produces vasculitis. In contrast, the underlying pathogenesis of cryoglobulins in type I is small blood vessel occlusion with minimal inflammatory response [5]


HCV is able to bind and penetrate into the renal parenchymal cells via the CD81 and SR-B1 receptors. HCV RNA has been found in mesangial cells, tubular epithelial cells, and endothelial cells of glomerular and tubular capillaries. HCV-related granular protein deposits located in the mesangium were found to be related to higher degrees of proteinuria.[4]

Mixed cryoglobulins are serum proteins reversibly precipitating in 4 °C.é Polyclonal immunoglobulin G (IgG) is bound to another immunoglobulin, which is an antiglobulin and acts as an anti-IgG rheumatoid factor (RF). In type II MC, the antiglobulin is monoclonal, whereas in type III MC, it is polyclonal. MC may be associated with infections, systemic autoimmune diseases, lymphoproliferative disorders and HCV infection. HCV is known to be the cause of 80%-90% of MC. In general, HCV is associated with type II MC, however it has also been reported to be associated with type III MC. The pathophysiological mechanism of HCV-related MC probably involves E2-CD81 interaction. The E2 protein of HCV interacts with CD81, the cellular receptor for HCV that is required for infection of hepatocytes. CD81 is also expressed on B lymphocytes and the E2-CD81 interaction leads to monoclonal proliferation of B lymphocytes and eventually HCV-related MC.[4]

Cryoglobulins are deposited in the glomerular capillaries and mesangium and they appear as intense subendothelial IgM deposits by immunofluorescence microscopy. Cryoglobulins are also usually associated with histologic signs of vasculitis and downstream fibrinoid necrosis. Cryoglobulin associated nephrotoxicity is suggested to be due to affinity of the IgM-RF for cellular fibronectin in the mesangial matrix. Cryoglobulins may also induce endothelitis via anti-endothelial activity and complement activation leading to increased expression of VCAM-1 and platelet aggregation. Actually cryoglobulinemic vasculitis is a systemic vasculitis that involves mostly small-sized arteries and veins in which immune complexes composed of RF, IgG, HCV RNA and complements are deposited on endothelial surfaces. Unlike the pattern seen in cutaneous vasculitis, HCV RNA is not the predominant component in immune complexes of kidney lesions.

Toll-like receptors (TLR) may also have a role in HCV-associated renal injury. TLR3 expression was found to be increased in the mesangial cells of patients with HCV-related MPGN. TLR4 is constitutively expressed by podocytes. Glomerular expressions of TLR4 and fibronectin were found to be upregulated in a murine model of cryoglobulinemic glomerulonephritis. [4]

Here is the case of patient with mixed cryoglobulinemia, probably lined with hepatitis C.

Complaints at admission :

  • Shortness of breath during physical load,in a horizontal position

  • Cough: unproductive, mucous sputum.

  • Swelling to belly, face

  • Pain in right side

  • Pain in the knee and elbow joints

  • Dizziness

  • Weakness

  • Fast fatigability

  • Temperature 37-38° C without sweat and chills

  • Nosebleed

  • Rash on the back, the lumbar region, on the anterior surface of the tibia

Anamnesis morbi

In June 2017, there were swelling of the lower limbs, face, shortness of breath during physical exertion and at rest, headaches, nosebleeds.Articular syndrome worries for 10 years . She did not apply for medical help. She was treated independently, took Nonsteroidal anti-inflammatory drugs, diuretics.In early October, sharply increased temperature 37-38 C ° for 2 weeks. Cough with phlegm, pain in the right side, dizziness, headaches. Independently took Ceftriaxone 1.0 g 2 p / d No. 4, Cavinton Tb, Aspirin Tb.

In December, there were edema of the lower extremities, face. Independently took Hypothiazide tablets.In connection with the deterioration of the condition was delivered to the City Clinical Hospital No. 7, an ultrasound of the Abdominal cavity was performed.Given the effusion to the right, the intoxication syndrome is directed to the City Clinical Hospital No. 1 in the pulmonology department with a diagnosis of bilateral lower lobar pneumonia, complicated by pleurisy, chronic bronchitis. He was hospitalized in an emergency.
Anamnesis vitae

She grew and developed according to age.Viral hepatitis, tuberculosis denies
Skin and venereal diseases are denied.
Professional harmfulness-denies.
Bad habits deny, passive smoker.
Was conducted an ectopic pregnancy 16 years ago, closed craniocerebral injury, accident about 4 years ago.Arterial hypertension max rise 160/100, adaptation 100/70 (anaprilin). In 24 years of pneumonia with left-sided pleurisy, received in-patient treatment in the Scientific Research Institute ofCardiology.Heredity the father was ill with Arterial Hypertension, death from a heart attack, the aunt was ill with cirrhosis of the liver, the grandmother was ill with heart disease.She is divorced.Medical abortion 2 times. Receiving Contraceptive (rigevidone) for 7 years about 5 years ago.Has allergy to the penicillin series.
Objective status at admission

  • General condition: severe severity due to edema, anemia, respiratory failure, intoxication.

  • consciousness clear.

  • The figure is correct, normosthenic.

  • Skin and visible mucous sclera icteric coloration, dry and warm.

  • Rash on the back, the lumbar region, on the anterior surface of the tibia

  • Subcutaneous fat expressed moderately Cicada, the uniform distribution.

  • Skin turgor saved.

  • Muscle tone is maintained.

  • Peripheral lymph nodes not enlarged, not palpable.

  • Pronounced swelling of the lower extremities, face and stomach.

Character of rash
A rash that does not disappear with pressure, detectable in the form of a dense elevation above the skin surface.

Reserves of dark pigmented spots

Respiratory system
Breathing self. The shape of the chest normal. The movement of the thorax during respiration: a part of the two halves is not the same, right behind in the act of respiration.

Palpation of the thorax: voice tremor will be conducted for all lung fields with not the same intensity.

Percussion of the lungs: dullness of sound right in n/right on. The borders of lung is not changed.

Auscultation of the lungs vesicular breathing, reschooling in n/a on the right, moist rales in n/on the left. NPV 23 min, Saturation 96%
Cardiovascular system

Auscultation: heart sounds are muffled, regular rhythm, heart rate 88 beats/min AP 130/80 mmHg
Gastrointestinal tract

Tongue wet clean. On palpation the abdomen is soft, painful in the left hypochondrium, increased in volume due to edema of the anterior abdominal wall, anasarca. The liver and spleen are difficult to percutiebat. Chair regular.
Urogenital system

The kidneys are not changed, the symptom tapping negative on both sides. Urination free, painless.
Muscle and bone-articular system

are advanced, the tone is preserved, muscle is painless.
Endocrine system

The thyroid gland is not enlarged.


The first method of diagnostics is general blood analysis, there is hypohemoglobinemia, low level of hematocrit, erythrocytopenia, leukocytopenia, high level of ESR. On the base of general blood analysis patient has anemia III degree, that’s why was done two hemotransfusions with erythrocytes mass 350ml and 260 ml, and level of HGB increased until 89g/l.







57 g/l

52 g/l

72 g/l

89 g/l

























In biochemical blood analysis is hypoalbuminemia, but with normal level of general protein. Also, she had increased bilirubin level, low iron level.

Biochemical blood analysis














Total protein










Total bilirubin



Direct bilirubin





In general urine analysis all indexes are normal, but our patient had anasarca, peripheral edema and hypoalbuminemia, therefore, in general urine analysis should be found protein, that’s why laboratory analysis is not appropriate. Because of edema we start to treat with diuretics, bit it were not effective. Then we start to treat with glucocorticosteroids, Prednisolone 40mg per oral, and in 3 days edema disappeared.

Additional investigations as blood analysis form markers HBV and HCV are negative, blood analysis for HIV is negative, rheumatoid factor was 32.7 where normal level until 18, in coagulogram all level indicators decreased. So our patient had pronounced edematous syndrome, no signs of portal hypertension, and it does not fit into the picture of liver cirrhosis. Edema is hypoproteinemic, but level of general protein is normal, with hypoalbumiemia. She had many systemic manifestations, where we think about viral hepatitis C which leads to anemia and glomerulonephritis.

In our patient we found main clinical manifestations of cryoglobuline vasculitis, as weakness, arthralgy, hyperpigmentation, sense of neuropathy, mesangiokapillar glomerulonephritis, anasarca- hypoproteinurea.

The diagnosis of our patient is liver cirrhosis, stage of subcompensation, with systemic manifestations of HCV, mixed cryoglobulinemia syndrome-cryoglobulinemic vasculitis-glomerulonephritis, triad Meltzer (rash, weakness, articular syndrome), rheumatoid factor, sensory neuropathy (ulnar nerve), anemia of mixed origin (iron deficiency and hypoplastic).

Diagnosis approved (Monti и соавт. 1995):

  • More than 2 signs from Meltzer's triad (hemorrhagic purpura, delicacy, an arthralgia)

  • Systemacity of a lesion: dermal implications, a lesion of kidneys, a liver and existence of peripheric neuropathy (allows to estimate extent of advance of a vasculitis)

  • Positive rheumatoid factor in blood serum – character high level

  • Blood analysis on markers of a virus of hepatitis B and C, PCR on HCV-PHK,

  • at negative result – research on other infections capable to cause a syndrome

And answer to the treatment with glucocorticoids was good.

For the future etiological treatment should be done PCR to hepatitis, and then should be treated with antiviral therapy.
Conclusion: this case shows a typical example of hepatitis C with mixed cryoglobulinemia. Prognosis: kidney failure with cirrhosis of the liver (would allow to live for many years), mortality due to kidneys for 7 years to 70%
References :

1) Fred F. Ferri M.D. F.A.C.P.-Clnical advisor. 2017 p332-333
2) Cacoub, P., Renou, C., Rosenthal, E. et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d’Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l’Hepatite C. Medicine. 2000; 79: 47–56

3)Patrice Сacoub, Laura Gragnani, Cloe Comarmond, Anna Linda Zignego Extrahepatic manifestations of chronic hepatitis C virus infection- December 15, 2014 Volume 46, Supplement 5, Pages S165–S173

4) Hepatitis C virus associated glomerulopathies, Abdullah Ozkok and Alaattin Yildiz World J Gastroenterol. 2014 Jun 28; 20(24): 7544–7554.

5) How I treat cryoglobulinemia, Eli Muchtar, Hila Magen and Morie A. Gertz, Blood 2017 129:289-298

6) Cryoglobulinemia in chronic hepatitis C: clinical aspects and response to treatment with interferon alpha and ribavirin [Table 4]

7) Cryoglobulinemia ,Colin C Edgerton, MD Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Clinical Assistant Professor, Department of Medicine, Uniformed Services University (Updated: Dec 18, 2017) [MedScape]

  1. Ferri C. Zignego AL,Pileri SA. Cryoglobulins (review) J Clin Pathol 2012;

  1. Gorevic PD, Kassab HJ, Levo Y, Kohn R, Meltzer M, Franklin E. Mixed Cryoglobulinemia. Am J Med 2012;

Резюме. Смешанная криоглобулинемия (СК) - заболевание, при котором в сыворотке крови выявляют циркулирующие криопреципитирующие иммунные комплексы и которые проявляется классической триадой симптомов: пурпурой, слабостью, артралгиями. Этиопатогенез СК характеризуется поликлональной активацией лимфоцитов. Гепатит С играет причинную роль в активации данного процесса наряду с окружающими и генетическими факторами. В данном случае приводится клинический пример СК с поражением почек.

Ключевые слова : Криоглобулинемия, Вирусный гепатит В, Вирусный гепатит С, поражение почек при смешанной криоглобулинемии.

Түйін. Аралас криоглобулинемия (АК) – криопреципитацияланатын иммундық комплекстердің қан сарысуында табылуымен және классикалық триада симптомдары пурпура, әлсіздік, артралгиямен сипатталатын ауру. АК этиопатогенезі поликлоналді лимфоциттерінің күшеюімен сипатталады. Осы механизмнің күшеюіне қоршаған орта, генетикалық факторлармен қатар гепатит С да әсер етеді. Мысалда АК кезіндегі бүйрек зақымдануы сипатталған клиникалық жағдайда берілген.

Түйінді сөздер: Криоглобулинемия, Вирусты гепатит В, Вирусты гепатит С, аралас криоглобулинемия кезіндегі бүйрек зақымдануы.

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