Disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP) should be ruled out in patients with suspected HUS. Infections that mimic/trigger HUS, e.g., malaria, leptospirosis, dengue, rickettsia and H1N1 infection should be excluded, if clinically suspected.

DIC is characterized by prolonged prothrombin time or activated partial thromboplastin time, low fibrinogen, elevated D-dimer and soluble fibrin monomers. TTP is rare in childhood; persistent thrombocytopenia (<30,000/µL) and mild/no AKI is suggestive. Blood samples should be stored and later processed for ADAMTS13 activity, if etiology of microangiopathic anemia is unclear.

ISPN guidelines endorse the etiology-based classification of HUS (Fig.1) [3]. Epidemiology of HUS in India differs from that in developed countries. Worldwide, the chief cause of HUS is gastrointestinal infection with Shiga toxin producing E. coli (STEC-HUS), which is seen in 80% patients. In India, infection with S. dysenteriae has declined significantly and prevalence of patients with STEC-HUS is also low. STEC-HUS is suspected if occurring within 2 weeks of bloody diarrhea – infection is diagnosed by stool culture and demonstration of virulence genes, fecal Shiga toxin or IgM antibodies to serogroup specific lipopoly-saccharide.

ADAMTS13, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; CD46, membrane co-factor protein; DIC, disseminated intravascular coagulation; LDH, lactate dehydrogenase; *See Box I for evaluating patients with HUS, including storing and processing of samples; **Also consider atypical HUS if positive non-synchronous family history or recurrent disease. Reprinted by permission from Springer Nature: Pediatric Nephrology (Bagga A, Khandelwal P, Mishra K, Thergaonkar R, Vasudevan A, Sharma J, et al. Hemolytic uremic syndrome in a developing country: Consensus guidelines. Pediatr Nephrol. 2019;34:1465-82.).

Fig. 1 Approach to patients with hemolytic uremic syndrome (HUS).

Cobalamin deficiency accounts for ~6-8% patients with HUS. Feeding difficulties, seizures, abnormal muscle tone, developmental delay and megaloblastic anemia are common; one-third lack extra-renal features. High blood levels of total homocysteine (>100 µM/L) followed by genetic screening is confirmatory [4]. Samples may be stored and processed later (Box I). Specific therapy includes parenteral hydroxycobalamin, oral betaine and folate [4]. Secondary causes of HUS include systemic lupus, malignant hypertension and antiphospholipid antibody syndrome.

In a significant proportion of patients, HUS is associated with uncontrolled activation of the alternate complement pathway, termed atypical HUS (aHUS). A diagnosis of aHUS is made when infection, cobalamin-associated and secondary forms of HUS are excluded (Fig. 1). These patients need detailed evaluation to determine the underlying cause. However, access to microbiological and complement assays is limited in India. Given the implications of accurate diagnosis, physicians taking care of these patients must be aware regarding appropriate screening. Units lacking facilities for assays must store samples for later analyses.

Screen for anti-FH Antibodies

Unlike European cohorts, anti-FH antibody-associated illness accounts for ~50% pediatric atypical HUS (aHUS) in India, chiefly affecting children aged between 5 and 15 years. Given therapeutic implications of this diagnosis, experts recommend prompt screening for anti-FH antibodies prior to instituting plasma exchange (PEX) therapy. ELISA test is available at multiple centers, with turn-around of 7-14 days [5]. Commercial ELISA kits may show false positive results and underestimate antibody titers, limiting their role on follow-up; a positive threshold for these kits is also not defined [6].

Pathogenic variants in genes encoding proteins of complement and coagulation pathways: CFH, CFI, CFB, C3, CD46, THBD and DGKE are associated with aHUS in 30-40% cases. Patients without anti-FH antibodies require sequencing of these and other genes by next-generation sequencing (NGS) and CFHR1-5 copy number variations by multiplex ligation-dependent probe amplification (MLPA). These studies are useful for guiding management, prognosis, risk of relapses and allograft recurrence, and allow genetic counseling. NGS allows rapid, simultaneous sequencing of multiple genes; declining costs have made studies more accessible. Patients with anti-FH antibody-associated HUS do not require genetic screening, except if: (i) onset before 4 years of age, (ii) relapsing course, (iii) family history of HUS, (iv) illness that is refractory to PEX, and (v) prior to kidney transplantation.

Atypical HUS: Across the developed world, complement blockade with eculizumab, the C5 monoclonal antibody, is the standard of care for patients with aHUS. However, eculizumab is expensive and not available in India and developing countries. In absence of anti-complement therapies, intensive PEX is less than ideal, but the only alternative. For our country, timely institution of PEX (60-75 mL/kg; fresh frozen plasma as exchange fluid) is most appropriate for patients with suspected aHUS.

Given limited diagnostic capabilities and lack of access to eculizumab, international guidelines on aHUS are not likely to be implemented in developing countries in the near future. The present guidelines provide a systematic and algorithmic approach to management of patients with HUS, tailored to the distinct epidemiology and available repertoire of investigations and therapy. The guidelines underscore the importance of appropriate supportive care, and need for regular and prolonged follow-up. Capacity building for diagnosis and therapy of HUS and other complement related disorders is also required.

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4. Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A, Benoist JF, et al. Guidelines for Diagnosis and Management of the Cobalamin-related Remethylation Disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR Deficiency. J Inherit Metab Dis. 2017;40:21-48.

5. Sinha A, Gulati A, Saini S, Blanc C, Gupta A, Gurjar BS, et al. Prompt plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H autoantibody-associated hemolytic uremic syndrome in children. Kidney Int. 2014;85:1151-60.

6. Watson R, Lindner S, Bordereau P, Hunze EM, Tak F, Ngo S, et al. Standardisation of the factor H autoantibody assay. Immunobiology. 2014;219:9-16.

7. Khandelwal P, Thomas CC, Rathi BS, Hari P, Tiwari AN, Sinha A, et al. Membrane-filtration based plasma exchanges for atypical hemolytic uremic syndrome: Audit of efficacy and safety. J Clin Apher. 2019;34:555-62.

8. Puraswani M, Khandelwal P, Saini H, Saini S, Gurjar BS, Sinha A, et al. Clinical and immunological profile of anti-factor H antibody associated atypical hemolytic uremic syndrome: A nationwide database. Front Immunol. 2019;10:1282.