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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 64-66

Atypical hemolytic uremic syndrome with large vessel involvement

1 Department of Pediatrics, Calcutta National Medical College and Hospital, Kolkata, West Bengal, India
2 Pediatric Intensive Care Unit, Institute of Child Health, Kolkata, West Bengal, India
3 Pediatric Intensive Care Unit, Institute of Child Health, Apollo Gleneagles Hospital, Kolkata, West Bengal, India
4 Pediatric Nephrology Unit, Institute of Child Health, Kolkata, West Bengal, India

Date of Submission01-Jun-2020
Date of Decision22-Jul-2020
Date of Acceptance10-Oct-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Alolika Nandi
C/o Dr. Siddhartha Nandi, Marikpara, Nawabganj, Ichapur, Barrackpur, North 24 Parganas, Kolkata - 743 144, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2589-9309.305899

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Hemolytic uremic syndrome (HUS) is a rare, life-threatening disorder caused by thrombotic microangiopathy. Atypical hemolytic uremic syndrome (aHUS) is usually secondary to genetic mutation or autoantibody against the alternate complement pathway that produces a dysregulated complement activation, endothelial cell damage, and thrombosis. Here, we report the case of a 7-year-old boy who presented to us with aphasia, hemiparesis, and frank acute kidney injury and hemolysis, due to anti-complement factor H (anti-CFH) antibody associated aHUS. Investigations revealed multiple stenoses in bilateral internal carotid arteries and right proximal cerebral artery, producing a progressive massive infarct, an unusual finding in aHUS.

Keywords: Anti-complement factor H antibody, artery stenosis

How to cite this article:
Nandi A, Giri PP, Saha A, Sinha R. Atypical hemolytic uremic syndrome with large vessel involvement. Asian J Pediatr Nephrol 2020;3:64-6

How to cite this URL:
Nandi A, Giri PP, Saha A, Sinha R. Atypical hemolytic uremic syndrome with large vessel involvement. Asian J Pediatr Nephrol [serial online] 2020 [cited 2021 Jun 20];3:64-6. Available from: https://www.ajpn-online.org/text.asp?2020/3/2/64/305899

  Introduction Top

Hemolytic uremic syndrome (HUS) is a life-threatening thrombotic microangiopathy (TMA) characterized by a triad of nonimmune, Coombs-negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI).[1] Majority of the cases of HUS cases follow infection with Shiga toxin-producing organisms, mainly Escherichia coli. Other forms of HUS are those associated with systemic diseases, known as secondary HUS, and with disorders of complement regulation, known as atypical hemolytic uremic syndrome (aHUS). In aHUS, abnormalities in the alternate pathway (AP), result in uncontrolled complement activation and subsequent tissue damage. About 40% patients with aHUS have mutation in genes encoding regulatory proteins of the AP, like factor H (FH), factor I, CD46, factor B, C3 or mutations in genes encoding proteins outside the complement pathway, such as, diacylglycerol kinase ε, and plasminogen etc.[2] Twenty percent of patients of aHUS show extrarenal manifestations, with central nervous system (CNS) involvement being the most frequent, more often than that found in Shiga-toxin-producing E. coli (STEC) HUS (3%–10%).[3] Large vessel involvement in the acute phase of aHUS has not been reported anecdotally. Here, we present one such case of anti-FH antibody associated aHUS with the features of pediatric stroke, involving the entire left cerebral hemisphere and a major part of right hemisphere as well, who finally succumbed due to cerebral hemorrhage.

  Case Report Top

A 7-year-old boy, born in a non-consanguinous marriage, with no prior history of diarrhea or respiratory symptoms, was admitted in a local hospital with complaints of acute onset non-bilious vomiting and, oliguria, followed by right-sided weakness and aphasia. His family history was unremarkable. Magnetic resonance imaging (MRI) of the brain revealed a large infarct in the left frontoparietal region. On day 2 of admission, he had facial puffiness and abdominal swelling along with elevated blood pressure (118/80 mm/Hg). Investigations revealed low hemoglobin (5.4 g/dl), raised serum urea (266 mg/dL), and creatinine (1.3 mg/dl), following which he was transferred to our institute. At our center, on examination, child had severe pallor, facial puffiness, ascites with hypertension (120/82 mm Hg, >95th percentile). However, there were no features of hypertensive crisis. Neurological examination revealed motor aphasia with right-sided hemiparesis. Blood investigations suggested acute hemolysis indicated by falling hemoglobin (5.4 g/dL to 4.9 g/dL); fragmented red blood cells, schistocytes, helmet cells, Burr cells in peripheral smear [Figure 1], hyperbilirubinemia (indirect bilirubin 2.4 mg/dL), raised lactate dehydrogenase (2154 U/L), negative direct Coomb's test, with thrombocytopenia (platelet 45,000/cmm), and AKI (creatinine 1.45 mg/dl). Complement was low C3 (58.3 mg/dl, normal-90-180) with a normal C4 (21.3 mg/dl, normal-10-40), normal anti-streptolysin O antibody and presence of anti-complement factor H (CFH) antibody (8244 arbitrary units [AU]/mL at 1:50 dilution; normal <150 AU/mL) confirming the diagnosis of aHUS secondary to FH antibody. Echocardiography was normal, and eye checkup did not reveal any changes suggestive of hypertensive crisis. Evaluation for coagulation abnormalities, including prothrombin time (12.5 sec), activated partial thromboplastin time (32 sec), antinuclear antibody (ANA titer <1:40), anti-neutrophil cytoplasmic antibody (ANCA), anti-cardiolipin antibody, and anti-phospholipid antibody were negative, excluding the possibilities of any vasculitis disorder. MRI brain showed extensive acute nonhemorrhagic infarcts in left cerebral hemisphere, bilateral basal ganglia and right frontal-parietal, and parasagittal regions with mass effect [Figure 2]a. Magnetic resonance angiogram (MRA) of cerebral arteries showed multiple stenotic lesions involving the cavernous part of right internal carotid artery and origins of both posterior cerebral arteries and left internal carotid artery [Figure 2]b. Standard measures were taken to lower intracranial tension and therapy with low molecular weight heparin was initiated. The child underwent seven sessions of plasma exchange and received three doses of pulse methylprednisolone from day 1 of admission. Hematological remission was not attained, and the child continued to needed hemodialysis. On day 10 of admission, he had repeated episodes of refractory seizures controlled with midazolam infusion. He was intubated and ventilated. A repeat MRI showed further worsening of the infarct with hemorrhagic transformation and transtentorial bulging of left temporal lobe [Figure 2]c and [Figure 2]d. Repeat PT, APTT was normal. The patient developed features of raised ICT, not responding to 3% NaCl and mannitol infusions. Decompressive craniotomy was planned, but the patient lost brainstem reflexes on day 14 of admission and succumbed.
Figure 1: Peripheral blood smear showing predominantly normocytic normochromic and, some hypochromic-microcytic red cells, anisopoikilocytosis, fair number of schistocytes, a few spherocytes, polychromatic cells, and occasional nucleated red blood cells

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Figure 2: (a) Magnetic resonance imaging of the brain shows extensive acute non-hemorrhagic infarcts in left cerebral hemispheres, bilateral basal ganglia and right fronto-parietal parasagittal regions with mass effect. (b) Magnetic resonance angiogram of cerebral arteries shows multiple stenotic lesions involving the cavernous part of right internal carotid artery, origins of posterior cerebral arteries and left internal carotid artery. (c) Magnetic resonance angiogram of neck vessels shows marked stenotic lesions in the left internal carotid artery. (d) Repeat magnetic resonance imaging revealed further worsening with hemorrhagic transformation

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  Discussion Top

The pathophysiology behind HUS is a thrombotic microangiopathy, caused by endothelial cell injury in STEC–HUS or complement dysregulation in aHUS.[4] Mutations in genes-encoding proteins that regulate the alternate pathway or autoantibodies inhibiting these regulatory proteins are identified in approximately 60%–70% of aHUS patients[5] with CFH mutations being the most common and affecting about 50% of Indian pediatric patients.[2] Anti-FH-associated aHUS is aggressive, with high frequency of extra-renal complications, as in our case, who presented with, oliguria, hemiparesis, and aphasia followed by seizures.[5] Neurological involvement is the most frequent (20%–50% cases) extrarenal complication in aHUS, and is consequence of the microangiopathic process.[6] Few cases with involvement of large vessel as an acute presentation, mostly in STEC HUS patients, have been reported.[7] Large vessel involvement in aHUS is reported mainly in chronic presentation unlike our index case.[8] Chronic continuous complement dysregulation contributing to vascular lesions has been proposed by some authors based on a positive correlation of C5b-9 deposits and the disease state, but a definite pathogenesis behind these vascular events in acute phase of aHUS is yet to be proved.[9] Investigations were done in our case to rule out, differentials such as Moyamoya Disease vasculitis or thrombophilic disorders. MRA was not consistent with these entities.[10] However, in our case, due to the lack of complete thrombophilic work up and histological evidence of TMA, HUS as a causal factor for the CNS involvement could not be definitely ascertained. HUS leading to large vessel disease appeared probable.

Eculizumab, a humanized monoclonal antibody against terminal complement components, has revolutionized the treatment of a HUS, especially in severe forms of the disease like in our case. Although currently the treatment of choice for aHUS, it is not used in our country because of non-availability.[11] Prompt plasmapheresis with immunosuppression is still the standard treatment option in anti-CFH associated HUS which was also followed in our case but with a poor outcome.[12] Limitations of the report include an inability to perform postmortem biopsy, as the patient's family denied permission. Complete thrombophilic evaluation for anti-beta 2 glycoprotein, homocysteine levels, proteins C and S, factor V Leiden mutations, genetic analysis of the MTHFR gene were not done. While gain of mutation in C3 and CFB has particularly been associated with “macrovascular” and neurological involvement in aHUS, we did not perform genetic analysis for concomitant variations and CFHR1 deletion. Overall, the cause of the large vessel stenoses noted in our patient with anti-CFH antibody associated aHUS remains unknown and the role of complement blockade in such cases in our country still needs to addressed.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Campistol JM, Arias M, Ariceta G, Blasco M, Espinosa M, Grinyó JM, et al. An update for atypical haemolytic uraemic syndrome: Diagnosis and treatment. A consensus document. Nefrologia 2013;33:27-45.  Back to cited text no. 1
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.  Back to cited text no. 2
Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 2010;21:2180-7.  Back to cited text no. 3
Nester CM. Multifaceted hemolytic uremic syndrome in pediatrics. Blood Purif 2013;35:86-92.  Back to cited text no. 4
Yoshida Y, Kato H, Ikeda Y, Nangaku M. Pathogenesis of atypical hemolytic uremic syndrome. J Atheroscler Thromb 2019;26:99-110.  Back to cited text no. 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.  Back to cited text no. 6
Trevathan E, Dooling EC. Large thrombotic strokes in hemolytic-uremic syndrome. J Pediatr 1987;111:863-6.  Back to cited text no. 7
Davin JC, Majoie C, Groothoff J, Gracchi V, Bouts A, Goodship TH, et al. Prevention of large-vessel stenoses in atypical hemolytic uremic syndrome associated with complement dysregulation. Pediatr Nephrol 2011;26:155-7.  Back to cited text no. 8
Vergouwen MD, Adriani KS, Roos YB, Groothoff JW, Majoie CB. Proximal cerebral artery stenosis in a patient with hemolytic uremic syndrome. Am J Neuroradiol 2008;29:e34.  Back to cited text no. 9
Fujimura M, Tominaga T. Diagnosis of Moyamoya disease: International standard and regional differences. Neurol Med Chir (Tokyo) 2015;55:189-93.  Back to cited text no. 10
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.  Back to cited text no. 11
Sethi SK, Rohatgi S, Dragon-Durey MA, Raghunathan V, Dhaliwal M, Rawat A, et al. Eculizumab for atypical hemolytic-uremic syndrome in India: First report from India and the challenges faced. Indian J Nephrol 2017;27:58-61.  Back to cited text no. 12
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