Diagnosis and treatment of hemolytic uremic syndrome in children Photo is illustrative. From open sources. >> Sergey Baiko, Associate Professor of the 1st Department of Children's Diseases, Belarusian State Medical University,

Diagnosis and treatment of hemolytic uremic syndrome in children

The photo is illustrative. From open sources.

>> Sergey Baiko, Associate Professor of the 1st Department of Children's Diseases of the Belarusian State Medical University, Ph.D. Sciences.

Hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure (ARF) in young children. Every year, 20 to 30 patients with this pathology are admitted to the Republican Center for Pediatric Nephrology and Renal Replacement Therapy, 75% of them need renal replacement therapy (RRT).

HUS is a clinical and laboratory symptom complex, including microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI).

The triggering factor for the development of the disease is most often Escherichia coli, which produces Shiga-like toxin (Stx), a typical manifestation of the disease is diarrhea (HUS D+), often bloody. In 10–15% of cases, HUS may occur without diarrhea (HUS D–). AKI is observed in 55-70% of cases. Sources of human infection with Shigatoxin-producing E. coli (STEC) are milk, meat, and water; contacts with infected animals, people and their secretions are also dangerous.

HUS refers to thrombotic microangiopathies characterized by thrombosis of the renal vessels. The modern classification (see Table 1) excludes the concepts of HUS D+ and D–, and contains options depending on the cause of the disease: typical (tHUS), atypical (aHUS), caused by Streptococcus pneumoniae (SPA-HUS).

When a child is admitted to a hospital and until the etiological cause of HUS is identified, the terms HUS D+ and D– can be used. However, further clarification of the HUS variant is required: STEC-HUS, SPA-HUS, etc.

The most common form among all HUS variants (90–95% of cases) is tHUS; it is associated with diarrhea and Shigatoxin of enterohemorrhagic strains of E. coli (STEC-HUS), less often with Shigella dysenteriae type I.

HUS not associated with diarrhea and Shigatoxin includes a heterogeneous group of patients in whom the etiological significance of infection with bacteria that produce Shigatoxin and Shiga-like toxins is excluded. Subdivided into options:

SPA-HUS – caused by Streptococcus pneumoniae, which produces neuraminidase;
atypical HUS is caused by genetic defects in the proteins of the complement system (factor H (CFH), I (CFI), B (CFB), membrane cofactor protein (MCP), thrombomodulin (THBD), complement C3 fraction) or the presence of antibodies to them (to the factor H (CFHR 1/3));
secondary HUS – may accompany systemic lupus erythematosus, scleroderma, antiphospholipid syndrome; develop when taking antitumor, antiplatelet drugs, immunosuppressants;
cobalamin C deficient HUS (methylmalonic aciduria).

The clinical classification of HUS is based on the severity of the disease:

mild degree – a triad of symptoms (anemia, thrombocytopenia, AKI) without violations of the rate of urination;

medium degree – the same triad, complicated by convulsive syndrome and (or) arterial hypertension, without violations of the rate of urination;
severe – triad in combination with oligoanuria (or without it), when dialysis therapy is necessary; triad on the background of oligoanuria with arterial hypertension and (or) convulsive syndrome, requiring dialysis.

The manifestation of typical HUS is noted mainly between the ages of 6 months and 5 years. Atypical has an early onset (perhaps even in the neonatal period) associated with mutations in the CFH and CFI genes (mean age of first presentation is 6 months and 2 months, respectively). When the gene encoding MCP is mutated, HUS always debuts after a year.

In North America and Western Europe, STEC-HUS in 50–70% of cases is a consequence of E. coli infection, serotype O157:H7.

It has a unique biochemical property (no sorbitol fermentation) that makes it easy to distinguish it from other fecal E. coli. Many other E. coli serotypes (O111:H8; O103:H2; O121; O145; O104:H4; O26 and O113) also cause STEC-HUS. In Asia and Africa, the main cause of HUS is Shigella dysenteriae, serotype I.

Over the past 10 years, there have been no cases of HUS caused by Shigella dysenteriae, serotype I in Belarus.

After exposure to enterohemorrhagic E. coli, 38–61% of patients develop hemorrhagic colitis and only 10–15% of those infected develop HUS. The overall incidence of STEC-HUS in European countries is different: 1.71 cases per year per 100,000 children under 5 years old and 0.71 cases under 15 years old in Germany; 2 and 0.7 respectively in the Netherlands; 4.3 and 1.8 in Belgium; 0.75 and 0.28 in Italy.

The incidence of HUS in Belarus is one of the highest in Europe: an average of 4 cases (from 2.7 to 5.3) per 100,000 children under the age of 5 and 1.5 (1–2) under 15 years of age. The largest number of cases is registered in Vitebsk, Grodno regions and Minsk; the smallest – in Brest and Gomel. The peak is observed in the warm season (May-August).

STEC-HUS is characterized by the presence of a prodromal period in the form of diarrhea. The median time between E. coli infection and disease onset is three days (range one to eight). It begins, as a rule, with cramping pains in the abdomen and non-bloody diarrhea. Within 1-2 days, in 45-60% of cases, the stool becomes bloody. Vomiting is observed in 30-60% of cases, fever in 30%, leukocytosis is determined in the blood. X-ray examination with a barium enema allows you to see the picture of "fingerprints", indicating swelling and hemorrhage in the submucosal layer, especially in the region of the ascending and transverse colon. Arterial hypertension in the acute period of HUS (occurs in 72% of cases) is associated with hyperhydration and activation of the renin-angiotensin-aldosterone system, is characterized by a persistent course and is difficult to treat.

Increased risk factors for HUS after E. coli infection include bloody diarrhea, fever, vomiting, leukocytosis, extreme age groups, female gender, use of antibiotics that depress intestinal motility. STEC-HUS is not a benign disease – 50-75% of patients develop oligoanuria, require dialysis, 95% of cases have red blood cell transfusions, and 25% have nervous system damage, including stroke, seizures, and coma. Because dialysis is available and intensive care centers are available, infant and young child mortality has declined. However, up to 5% of patients die in the acute phase of HUS.

Streptococcus pneumoniae infection is associated with 40% of cases of non-shigatoxin-associated HUS and 4.7% of all episodes of HUS in children in the United States. Neuraminidase, formed by the bacteria S. pneumoniae, removing sialic acids from cell membranes, exposes the Thomsen-Friedenreich antigen, exposing it to circulating immunoglobulins M. Further binding of the latter to this new antigen on platelets and endothelial cells leads to platelet aggregation and damage to the endothelium. The disease is usually severe, accompanied by respiratory distress syndrome, neurological disorders and coma; lethality reaches 50%.

Of the drugs most often cause secondary HUS, antitumor (mitomycin, cisplatin, bleomycin and gemcitabine), immunotherapeutic (cyclosporine, tacrolimus, OKT3, quinidine) and antiplatelet drugs (ticlopidine and clopidogrel). The risk of developing HUS after using mitomycin is 2–10%. The onset of the disease is delayed, one year after the start of therapy. The prognosis is unfavorable, mortality within 4 months reaches 75%.

The literature describes cases of post-transplant HUS. It may occur in patients who have never had the disease before (de novo) or in whom it was the primary cause of ESRD (recurrent post-transplant HUS). De novo post-transplant HUS can be triggered by calcineurin inhibitors or humoral rejection (C4b positive). This form of HUS after kidney transplantation occurs in 5–15% of patients receiving cyclosporine A and approximately 1% of those using tacrolimus.

HUS during pregnancy sometimes develops as a complication of preeclampsia. In some, the variant is life-threatening, accompanied by severe thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and liver damage (HELLP syndrome). In such situations, emergency delivery is indicated – it is followed by a complete remission.

Postpartum HUS mostly appears within 3 months after delivery. The outcome is usually unfavorable, mortality is 50-60%.

Atypical HUS, caused by genetic defects in the proteins of the complement system, is characterized by a triad of main features, accompanied by an undulating and relapsing course.This form may be sporadic or family (the disease is marked more than one family member and the impact of STX is excluded). The forecast for agius is unfavorable: 50% of cases proceeds with the development of terminal renal failure or irreversible damage to the brain, mortality in the acute phase reaches 25%.

Laboratory diagnostics and criteria Micrangiopathic hemolysis during Gus is characterized by:

reduced hemoglobin and haptoglobin levels;
an increase in lactate dehydrogenase (LDH), the free hemoglobin of plasma and bilirubin (mostly indirect), reticulocytes;
appearance of schizocytosis in peripheral blood (more than 1%),
Negative Cumbas reaction (lack of anti-raspiel antibodies).

Thrombocytopenia is diagnosed with the number of peripheral blood platelets less than 150 €109 / l. The coating level of platelets by more than 25% of the initial (even within the age norm) indicates increased consumption and reflects the development of Guses.

The level of serum creatinine, the calculated flushing filtration rate allow you to determine the OPP stage (see Table 2).
* For calculating the estimated speed of glomerular filtration, the Schwarz formula is used.

** In the absence of initial creatinine levels, it is possible to use the upper limit of the norm for the appropriate age of the child to assess its increase.

*** In children up to 1 year, Oliguria is determined by reducing the dilution rate of less than 1 ml / kg / h.

To identify the transition of the preenal OPP in the renal or first stage, the levels of neutrophilic gelatinase-associated lipocaline (NGAL) in the blood and (or) urine are determined. The degree of increasing NGAL reflects the severity of the OPP.

Early marker of lowering the speed of glomerular filtration – cystatin with blood.

The "Stec-Gus" diagnosis is confirmed by the release of E. coli in the cultures of the child's feces (for the diagnosis of E. coli O157, a medium with sorbitol is used). Antigens E. coli O157 and shigatoxine are detected by the polymerase chain reaction in the samples of the chair.

To confirm the infectious nature, the Guses use serological tests for antibodies to shigatoxin or to lipopolisaccharides of E. coli enterohemorrhagic strains. Early diagnosis involves the use of express tests to identify antigens E. coli O157: H7 and shigatoxin in a chair.

To eliminate sepsis, the C-jet protein, prokalcitonin, blood prepression, is determined.

All patients need to investigate the C3 and C4-fraction of the blood complement to assess the severity and ways to activate it, and in some cases – to confirm the atypical flow of Gus.

If a child has no diarrhea in the prodromal period, first of all, the development of SPA-GUS should be excluded.

Available or previously transferred diseases that are most often caused

S. Pneumoniae: Pneumonia, Otitis, Meningitis. To identify the pathogen, culture tests of blood, liquor and (or) express diagnosis of S. pneumoniae antigens in the urine are carried out.

In patients with HUS who have neurological symptoms (convulsive syndrome, depression of consciousness, coma), the activity of blood metalloproteinase that cleaves von Willebrand factor multimers (ADAMTS-13) is evaluated to exclude thrombotic thrombocytopenic purpura (TTP). TTP is characterized by neurological symptoms, low platelet levels (30×109/l), absence or moderate azotemia (blood creatinine no more than 150–200 µmol/l), fever, and a decrease in ADAMTS-13 activity by less than 10% (before plasma therapy).

The development of the HUS symptom complex in an infant under 6 months of age requires the exclusion of methylmalonic aciduria. If this pathology is suspected, the levels of amino acids – isoleucine, valine, methionine and threonine are analyzed; the content of acylcarnitines and homocysteine in the patient's blood, renal excretion of homocysteine and organic acids – methylmalonic, 3-hydroxypropionic, 3-hydroxy-n-valeric, methylcitric, propionylglycine are determined. A molecular genetic study confirms the diagnosis if mutations are detected in the MUT, MMAA, MMAB, MMACNS, MMADHC, MCEE genes.

The list of diagnostic procedures for the diagnosis of HUS includes basic manipulations, which in most cases are sufficient to verify the diagnosis, and additional ones necessary for rare variants of the disease and complications.

complete blood count (platelet count, leukocyte count, ESR – if possible, with the calculation of the percentage of schistocytes);
acid-base state;
biochemical blood test (the levels of total protein, albumin, creatinine, urea, alanine aminotransferase, aspartate aminotransferase, LDH, total and direct bilirubin, glucose, potassium, sodium, chlorine, calcium, C-reactive protein are determined);
general urinalysis (if available);
coagulogram;
determination of blood group (according to AB0 systems) and Rh factor;
direct Coombs test (anti-erythrocyte antibody level);
Examination of feces by express methods to detect Shigatoxin (types I and II) and E. coli O157 antigens and (or) isolation of cultures of Shigatoxin containing E. coli on special media (with sorbitol for E. coli O157:H7) or their detection DNA in stool samples;
analysis of feces for pathogenic intestinal flora;
Ultrasound of the kidneys and bladder.

in biochemical analysis – the study of cystatin C, haptoglobin, procalcitonin, presepsin;
for a coagulogram – detection of levels of soluble fibrin-monomeric complexes, D-dimers;
determination of proteins of the blood complement system – C3 and C4;
study of the levels of factors H, I, MCP (CD46) in the blood;
calculation of levels of blood homocysteine, methylmalonic acid (blood and urine) ± molecular genetic study to detect mutations in the MMACHC gene;
control of NGAL levels in blood and urine;
pregnancy test (should be done in all teenage girls with HUS or TTP);
determination of the activity of ADAMTS-13 and antibodies to ADAMTS-13 in the blood;
The search for antibodies to shigatoxin and (or) Lipopolisaccharides Stec in the serum in 7-14 days from the beginning of the diarrhea (re-in 7-10 days);
Determination of autoantiboders to the factor H in the blood;
Molecular genetic study to identify the mutations of genes encoding the proteins of the complement system;
Ultrasound kidneys with an assessment of the renal blood flow and the state of the bladder.

Indicators that allow differential diagnostics are listed in Table 3.

The key to successful children with Gus is an early diagnosis of the disease and the timely beginning of supportive treatment.

Treatment

There is no TGUS therapy with proven effectiveness. During the acute phase, it is necessary extremely supportive. A complex of medical measures includes etiotropic, imprint, pathogenetic and replacement renal therapy.

Briefly about Gus's therapy – in Table 4.

Cases of practice

This conclusion allowed the patient on October 11 to put the patient into a leaf of the renal transplant, and on December 8 of the next year, he successfully performed a transplantation of donor kidney. For more than 2.5 years, a satisfactory transplant function is preserved.