Thrombotic microangiopathy and kidney damage

Hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are diseases with a similar clinical picture, which is based on thrombotic microangiopathy. The term "thrombotic microangiopathy" defines a clinical and morphological syndrome, manifested by microangiopathic hemolytic anemia and thrombocytopenia, which develops due to occlusion of thrombi containing aggregated platelets and fibrin, vessels of the microcirculatory bed (arterioles, capillaries) of various organs, including kidneys.

Causes of the thrombotic microangiopathy

Thrombotic thrombocytopenic purpura was first described in 1925 by E. Moschowitz in a 16-year-old girl with fever, hemolytic anemia, petechial rash, hemiparesis and kidney damage caused by "hyaline thrombi of terminal arterioles and capillaries". In 1955, S. Gasser et al. Published their observation of thrombocytopenia, Coombs-negative hemolytic anemia and kidney failure in 5 children, calling this symptom complex "hemolytic-uremic syndrome." The term thrombotic microangiopathy was introduced by WS Symmers in 1952 to replace the term "thrombotic thrombocytopenic purpura". However, today it is used not as a name for the disease, but for determining the specific type of microvascular damage (mainly arterioles and capillaries) represented by edema and / or detachment of endothelial cells from the basal membrane, expansion of the subendothelial space with the accumulation of loose membrane-like material in it, the formation of intravascular thrombocyte thrombi in the absence of signs of inflammation of the vascular wall.

Hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura are the most common forms of thrombotic microangiopathy. At the heart of their differentiation are the differences in the predominant localization of the microangiopathic process and the age of the patients. Hemolytic-uremic syndrome is considered as having an infectious nature of the disease of children, manifested mainly by kidney damage, thrombotic thrombocytopenic purpura - as a kind of systemic form of thrombotic microangiopathy, developing in adults and proceeding with a predominant CNS lesion.

However, the clear differentiation of these diseases is complicated by the fact that the development of hemolytic-uremic syndrome is possible in adult patients (neurological manifestations may occur), and patients with thrombotic thrombocytopenic purpura describe severe acute renal failure. In cases where it is difficult to distinguish hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, the use of the term HUS / TGP is acceptable.

The cause of thrombotic microangiopathy is diverse. Isolate infectious forms of hemolytic-uremic syndrome and are not associated with infection, sporadic. Most cases of infectious hemolytic-uremic syndrome (90% in children and about 50% in adults) have intestinal prodrome-a typical associated with diarrhea or post-diarrheal hemolytic-uremic syndrome. The most frequent pathogen in this form of hemolytic uraemic syndrome is E. Coli, producing verotoxin (also known as shiga-like toxin for its structural and functional similarity to type I Shigella dysenteriae toxin, also causing hemolytic-uremic syndrome). Almost 90% of patients with diarrhea + haemolytic uremic syndrome in the economically developed countries are allocated E. Coli serotype 0157: H, but at least 10 more serotypes of this pathogen associated with the development of thrombotic microangiopathy are known. In developing countries, along with E. Coli, the causative agent of the disease is often Shigella dysenteriae I type.

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

Symptoms of the thrombotic microangiopathy

A typical post-diarrheal hemolytic-uremic syndrome is preceded by a prodrome, manifested in the majority of patients with bloody diarrhea lasting from 1 to 14 days (an average of 7 days). By the time of admission to hospital, 50% of patients have already stopped diarrhea. Most children have vomiting, mild fever, intense abdominal pain, imitating the picture of "acute abdomen." Following a diarrheal prodrome, an asymptomatic period of different duration may occur.

Hemolytic-uremic syndrome manifests itself with a sharp pallor, weakness, inhibition, oligoanuria, although in some cases diuresis does not change. Possible development of  jaundice  or dermal purpura.

Most patients develop oliguric acute renal failure, in 50% of cases requiring treatment with glomerulonephritis. However, observations with little or no renal dysfunction have been described.

Diagnostics of the thrombotic microangiopathy

Hemolytic anemia and thrombocytopenia are the main laboratory markers of thrombotic microangiopathy.

Anemia  develops in the period from 1 to 3 weeks from the onset of the disease, in most patients it is significantly expressed and in 75% of cases it requires blood transfusions. In patients with hemolytic uremic syndrome, the average hemoglobin level is 70-90 g / l, although it is possible to rapidly reduce it to 30 g / l. The severity of anemia does not correlate with the degree of acute renal failure. High reticulocytosis, an increase in the level of unconjugated bilirubin, a decrease in the haptoglobin of the blood indicate the presence of hemolysis. The most sensitive marker of hemolysis, directly correlated with its severity, is an increase in LDH levels. However, with thrombotic microangiopathy, the increase in LDH activity is due not only to the release of the enzyme from erythrocytes, but also to ischemic organ damage. The microangiopathic nature of hemolysis in HUS / TTP is confirmed by the negative reaction of Coombs and the detection of deformed, altered erythrocytes (schizocytes) in the peripheral blood smear.

[7], [8], [9], [10], [11], [12]

Treatment of the thrombotic microangiopathy

Treatment of thrombotic microangiopathy involves the use of freshly frozen plasma, the purpose of which is to prevent or limit intravascular thrombus formation and tissue damage, and maintenance therapy aimed at eliminating or limiting the severity of major clinical manifestations. However, the ratio of these treatments for hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura is different.

The basis of treatment of post-diarrheal hemolytic-uremic syndrome is maintenance therapy: correction of water-electrolyte disorders, anemia, renal failure. When expressed manifestations of hemorrhagic colitis in children need parenteral nutrition.

Forecast

The risk of developing a typical haemolytic-uremic syndrome after E. Coli infection has increased many times with the use of antidiarrheal drugs and antibacterial drugs, bloody diarrhea, fever, vomiting and high leukocytosis, especially in young children (up to 2 years) and the elderly.

Post-diarrheal hemolytic-uremic syndrome has a favorable prognosis: in 90% of cases a full recovery occurs. Mortality during an acute episode is 3-5% (a sharp decrease in mortality, which was 50% in the 1960s, was due to significant progress in the treatment of acute renal failure, anemia, arterial hypertension, electrolyte disorders achieved in the last 40 years ). Almost 5% of patients who have experienced an acute stage of the disease develop chronic renal failure or severe extrarenal manifestations, and 40% have a long-term decline in GFR.

Anuria lasting more than 10 days, the need for hemodialysis during the acute stage of the disease, proteinuria, persisting for a year after arresting an acute episode, are associated with a risk of developing chronic renal failure in the future. Morphological risk factors for adverse prognosis for kidney function are focal cortical necrosis, lesion of more than 50% of glomeruli and arteriolar lesion.

There are 2 variants of the course of atypical hemolytic-uremic syndrome

The first is characterized by a pronounced gastrointestinal prodrome, anuric acute renal failure and malignant hypertension. In acute period, high mortality is noted as a result of severe lesions of the gastrointestinal tract and central nervous system. Recovery of kidney function is possible in less than 50% of patients. The second variant is characterized by progressive deterioration of kidney function and neurologic symptoms, reminiscent of thrombotic thrombocytopenic purpura. This form can be hereditary, usually recursive, steadily leading to chronic kidney failure or death.

Acute thrombotic thrombocytopenic purpura in the early 60's was almost a fatal disease with a mortality rate of 90%. However, at the present time, due to early diagnosis, the development of new therapeutic approaches (treatment with freshly frozen plasma), modern methods of intensive therapy, mortality has decreased to 15-30%.

Recurrent episodes of thrombotic thrombocytopenic purpura are repeated at intervals of 4 weeks or more after complete recovery. They need to be distinguished from the continuation of an acute episode after too rapid cessation of the introduction of freshly frozen plasma, which causes a new wave of thrombocytopenia and hemolysis. Currently, the relapse rate has increased to 30%, which is associated with a decrease in mortality during the first acute episode as a result of improved treatment. Relapses are possible after a few months or even years from the onset of the disease. Although the exacerbation responds to treatment, like the first episode, a long-term prognosis in the recurrent form of thrombotic thrombocytopenic purpura is generally unfavorable.

In acute thrombotic thrombocytopenic purpurea, timely treatment with freshly frozen plasma avoids the development of terminal renal failure in the future.

[13], [14], [15], [16]