|Year : 2019 | Volume
| Issue : 2 | Page : 71-74
Summary of 'Hemolytic uremic syndrome in a developing country: Consensus guidelines'
Sushmita Banerjee1, Jyoti Sharma2
1 Department of Pediatrics, Calcutta Medical Research Institute, Kolkata, West Bengal, India
2 Renal Unit, King Edward Memorial Hospital, Pune, Maharashtra, India
|Date of Web Publication||4-Dec-2019|
Renal Unit, King Edward Memorial Hospital, Pune - 411 011, Maharashtra
Source of Support: None, Conflict of Interest: None
Hemolytic uremic syndrome (HUS) is a common cause of acute kidney injury in children and has implications of irreversible renal damage. The management depends on the etiology of HUS. Guidelines for India have been formulated to arrive at the etiology with an algorithmic approach based on the epidemiology and the constraints of facilities available for investigations and therapy in the region. Anti-Factor H antibody-associated illness accounts for over half the cases of atypical HUS (aHUS) in Indian children, and prompt plasma exchange and immunosuppression are recommended to lower antibody levels. Since access to eculizumab is limited, the management of other forms of aHUS relies on plasma therapy. Indications for biopsy and concerns around kidney transplantation are highlighted. A brief comparison with current guidelines from other regions has been made.
Keywords: Anti-Factor H antibody, eculizumab, hemolytic uremic syndrome, plasma exchange
|How to cite this article:|
Banerjee S, Sharma J. Summary of 'Hemolytic uremic syndrome in a developing country: Consensus guidelines'. Asian J Pediatr Nephrol 2019;2:71-4
| Introduction|| |
Hemolytic uremic syndrome (HUS) is a significant cause of acute kidney injury (AKI) in children. Prompt diagnosis and management may limit irreversible renal damage. Guidelines on management of HUS in India (and other developing countries) were developed recently, since the epidemiology of HUS in Indian children is different, diagnostic facilities for some forms are limited, and eculizumab, currently the standard of care for atypical HUS (aHUS) in the developed world, is expensive and not easily available.
| Diagnosis|| |
The guidelines recommend that the following should be present for a diagnosis of HUS: (i) microangiopathic hemolytic anemia, defined by anemia (hemoglobin <10 g/dl and hematocrit <30%) and fragmented red cells on peripheral smear (schistocytes ≥2%) with either elevated lactate dehydrogenase (LDH); >450 IU/l) or undetectable haptoglobin; (ii) thrombocytopenia (platelets <150,000/μl); and (iii) AKI, defined as increase in serum creatinine by 50% over baseline level.
Partial forms may present with AKI and hypertension without thrombocytopenia and anemia, and the diagnosis is then established only by renal histology showing thrombotic microangiopathy (TMA).
| Differential Diagnosis|| |
Disseminated intravascular coagulation should be excluded in children with sepsis or malignancy. Common infections that mimic or trigger HUS, e.g., malaria, leptospirosis, and dengue, should also be excluded. Thrombotic thrombocytopenic purpura (TTP) is rare in childhood but should be considered when there are persistent thrombocytopenia and predominant neurological features. Congenital TTP (Upshaw–Schulman syndrome) may present in neonates with MAHA and jaundice or in children with unexplained and predominant thrombocytopenia. Samples should be stored for levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif (ADAMTS13) activity and anti-ADAMTS13 antibodies; these samples are processed if other etiological screens are negative.
| Etiological Evaluation|| |
Current classifications of HUS are based on etiology. This is important as etiology determines management and prognosis. A child should be suspected to have Shiga toxin associated HUS (STEC HUS) when HUS occurs within 2–3 weeks of bloody diarrhea and/or occurs during a known outbreak of STEC HUS in patients above 6 months of age. The diagnosis is confirmed by detection of Shiga toxin-producing serotypes of Escherichia coli or Shigella spp. by stool culture and demonstration of either fecal Shiga toxin (by ELISA or polymerase chain reaction) or serum immunoglobulin M antibodies to serogroup-specific lipopolysaccharide (by ELISA or passive hemagglutination assay). At present, such facilities are not readily available in the country, and experts emphasize the need to set up specialized laboratories for these investigations.
Pneumococcal HUS is associated with suspected or confirmed invasive pneumococcal disease and a positive Coombs test. HUS may also be associated with or triggered by practically any infective agent, i.e., viruses, bacteria, or rickettsia and may occur in association with a number of diseases, such as systemic lupus erythematosus, malignancy, malignant hypertension, stem cell and organ transplantation, and some medications (quinine and calcineurin inhibitors). Investigations should be planned, based on clinical presentation, to exclude these primary causes.
Cobalamin deficiency accounts for a small (~ 6%–8%) proportion of patients. Features may include failure to thrive, feeding difficulties, neurological abnormalities, and megaloblastic anemia. Diagnosis is based on demonstration of elevated total blood homocysteine levels and confirmed by genetic screening.
A diagnosis of aHUS is made when infection-associated, cobalamin-associated and secondary forms of HUS have been excluded based on the clinical and laboratory features. It should be considered when there is an insidious onset of the illness, partial presentation, recurrent disease, or positive nonsynchronous family history. Atypical HUS is characterized by dysregulation of the alternative complement pathway. Complement C3 levels may be low but are not specific for aHUS. About 40% patients have a pathogenic variant in genes encoding regulatory proteins of the alternative complement pathway (factor H [FH], factor I, CD46, factor B, and C3) or rearrangements of genes encoding FH-related proteins. Mutations in genes outside the complement pathway might be associated with aHUS phenotype, e.g., mutations in DGKE (diacylglycerol kinase-ε) that have been identified in patients with aHUS presenting in the first 2-years of life, PLG (plasminogen) and more recently, INF (informin) and vitronectin (vitronectin). HUS associated with antibodies to FH (anti-FH >150 AU/ml) is an acquired cause of aHUS comprising a distinct subgroup of patients. Anti-FH antibody-associated illness constitutes ~50% of pediatric patients with aHUS in India.
Investigations for Etiology in Children with aHUS
Due to the high prevalence of anti-FH antibodies in aHUS patients in India, all patients should be screened, as soon as possible, for these antibodies by ELISA. Blood levels for complement regulatory factors (FH, factor I, and factor B) may be tested, and flow cytometry for expression of membrane cofactor protein (MCP, CD46) on neutrophils (when available). The experts recommend genetic screening for patients who do not show anti-FH antibodies, young age, family history of asynchronous HUS, relapsing HUS or refractory disease, and prior to renal transplantation. The methods recommended are next-generation sequencing (NGS) for CFH, CFI, CFB, C3, CD46, THBD, and DGKE, and for rearrangements (copy number variations) of CFHR1-CFHR5 by multiplex ligation-dependent probe amplification. Sanger sequencing should be used to validate variants identified on NGS. The findings will help guide physicians regarding the prognosis and risk of relapses and recurrence after transplantation and enable genetic counseling.
| Management|| |
Supportive management is the basis of therapy in all forms of HUS. In children with STEC infection, fluid therapy should be carefully adjusted, i.e., hypovolemia should be corrected promptly, but fluid overload is avoided once AKI sets in. Plasma exchange (PEX) is considered for patients with severe neurological or cardiac involvement. Infections or the primary disease should be treated appropriately. Plasma and blood products should preferably be avoided in pneumococcal HUS, and washed red cells and platelets should be used, if necessary. Early dialysis should be instituted when required. Patients with cobalamin deficiency HUS respond to therapy with parenteral hydroxycobalamin. Betaine is recommended since it helps methylate homocysteine to methionine; folate is used as adjunctive therapy. Specific therapy allows renal recovery and prevents relapses. PEX has no role in these cases.
The guidelines suggest that platelet transfusions should be avoided unless the platelet count is <10,000/μl or to enable vascular catheter insertion. Blood transfusion is recommended for patients with hemoglobin <6 g/dl or hemodynamic instability. All patients require follow-up for at least 5 years for hypertension, proteinuria, and estimation of glomerular filtration rate.
The aim of therapy for patients with anti-FH antibody-associated HUS is reduction of antibody titers. The guidelines recommend prompt initiation of PEX within 24-hr of diagnosis. PEX (60–75 ml/kg; with fresh frozen plasma as the exchange fluid) should be administered daily until hematological remission and then tapered over 4–6 weeks. Immunosuppressive therapy is initiated with prednisolone 1 mg/kg/day for 1 month, followed by the administration on alternate days for 1 month, tapered every 2 weeks thereafter to a dose of 0.2–0.3 mg/kg on alternate days that is continued for 10–12 months. Induction therapy includes intravenous (IV) cyclophosphamide (500 mg/m2 once in 4 weeks) for five doses, initiated once hematological remission is achieved or IV rituximab (375 mg/m2, repeated after 7 days). Maintenance of immunosuppression with azathioprine or mycophenolate mofetil for 18–24 months and tapering doses of oral prednisolone is recommended to decrease the risk of relapses. Antibody titers should be monitored closely between days 7 and 28 and then every 3–6 months. Elevated titer (>1500 AU/ml) during the first 12–24 months is associated with an increased risk of relapse. Relapses follow minor infections in the initial 2 years. Therapy with azathioprine or mycophenolate mofetil and tapering doses of prednisolone is useful in significant reduction of this risk. Therapy with the complement inhibitor, eculizumab, is suggested in the following situations: (i) lack of remission despite 7–10 PEX, (ii) life-threatening features (seizures and cardiac dysfunction), (iii) complications due to PEX or vascular access, and (iv) inherited defect in complement regulation.
For managing patients withaHUS without anti-FH antibodies, especially when eculizumab is not available, prompt initiation of PEX is recommended in a protocol similar to that for anti-FH-associated illness. Subsequently, maintenance therapy with plasma infusions is instituted when complement gene mutations are suspected or confirmed. Therapy with PEX might not be useful in patients with DGKE mutations.
A renal biopsy should be performed: (i) if response to therapy is unsatisfactory, (ii) to determine extent of renal damage and help in prognosis, and (iii) to distinguish between causes of allograft dysfunction, including recurrence of HUS. Rarely, the diagnosis of HUS is first made when renal histology reveals TMA in children presenting with unexplained AKI or subacute renal dysfunction and hypertension.
| Transplantation|| |
Patients with HUS show variable risk of recurrent disease in the allograft. The risk of recurrence is high in patients with dysregulation of the alternative complement pathway, while those with STEC-HUS and abnormalities in membrane-anchored (CD46) and intracellular (DGKE) proteins have low risk. Donors and recipients need careful evaluation and peritransplant management. Screening of recipients for mutations in relevant genes and for anti-FH antibodies is recommended.
| Comparison of Guidelines|| |
[Table 1] compares the guidelines proposed in the document under discussion, with those from other countries. The etiology of HUS is different in various parts of the world. The majority (90%) of patients in Japan have STEC-associated HUS. Most guidelines recommend that all patients with HUS should be screened with tests for STEC.,,, The Japanese and Australian guidelines recommend supportive care, adequate fluids, and consideration of PEX in patients with neurological symptoms.,
|Table 1: Comparison of guidelines from India with those published from developed countries,,,|
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Guidelines from most expert groups recommend genetic studies in all children with aHUS including those with anti-FH-associated disease. Guidelines from Australia and New Zealand are similar to ours, and recommend genetic testing should be done depending on clinical circumstances. Worldwide data emphasize that complement factor abnormalities are the chief cause of aHUS; prompt therapy with eculizumab is thus recommended.,,, Treatment with eculizumab has been shown to result in satisfactory response in a high proportion of cases, with reduction in mortality and morbidity. Patients treated with eculizumab do not require therapy with PEX, which might be associated with complications of vascular access and repeated plasma infusions. For anti-FH-related aHUS, PEX with immunosuppression is proposed as the primary modality in developing countries; other guidelines also suggest the use of this approach as an alternative to treatment with eculizumab.
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Conflicts of interest
There are no conflicts of interest.
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