Journal of Kidney

Atypical Haemolytic Uremic Syndrome with Acute Glomerulonephritis in a 15-Year-Old: A Case Report

Sneha Kenjale^* and Keta Vagha ^*Correspondence: Sneha Kenjale, Department of Paediatric, Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Sawangi (Meghe), Maharashtra, India, Tel: +919655351987, Email:

Author info »

Introduction

Haemolytic uremic syndrome (HUS) is a group of disorders that form second most common cause of acute kidney injury (AKI), after renal hypoperfusion in paediatric age group. It presents with triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal insufficiency [1].

Atypical HUS differs from classical HUS by absence of any preceding shiga toxin E.coli (STEC-HUS) or shigella infection and absence of any prodromal period [2]. It could be familial or sporadic and mostly has poor prognosis as around 50% cases progress to end stage renal disease [3]. Onset of disease in majority of cases is in childhood (less than or equal to 18 years of age in 60% cases) with equal female and male involvement [4]. The most common clinical feature is pallor and oliguria whereas other features like moderate to severe hypertension, oedema, proteinuria, haematuria and azotaemia are sometimes found [5]. In 20% cases, extra renal manifestations are reported, which include CNS involvement in form of altered consciousness, generalised tonic clonic seizures or focal seizures in 8% patients and gastrointestinal symptoms in 28% of cases [6]. In 10% cases cardiovascular system involvement like heart failure, cardiomyopathy and myocardial infarction can be seen. Rarely, pulmonary haemorrhage, rhabdomyolysis and gangrenous lesion of toes and fingers are seen [5]. Ocular manifestations in atypical HUS occur rarely but if present, indicates severity of disease. It includes symptoms like diplopia, ocular pain, scotoma and blurred vision [7].

Clinical presentation of atypical HUS characteristically lack episode of diarrhoea or dysentery due to STEC or shigella type1 and does not have any prodromal period. However, alongside symptoms of atypical HUS, pneumococcal infections like pneumonia, empyema and otitis media might be present [6].

In 1981, atypical HUS was found in two brothers who had deficiency of complement factor H (CFH) due to mutation in gene encoding for CFH. Thereafter since 1998, this gene mutation and CFH deficiency was found to be associated with atypical HUS [8]. Gene encoding for complement factor H (CFH), complement factor I, complement 3 and complement B are responsible for abnormal activation of alternate complement pathway [2].

Abnormal activation of this pathway causes endothelial damage in blood vessels and leads to activation of platelets and formation of microthrombus in arterioles and capillaries. Formation of thrombus leads to consumption of platelets and hence causing thrombocytopenia [9]. The red blood cells passing via these thrombosed blood vessels undergo breakage causing coombs test negative haemolytic anaemia.

This obliteration due to thrombosis in small arterioles involves kidneys, central nervous system, gastrointestinal system, lungs and heart. Kidneys, being the most commonly affected organ, undergo hypoxia and ischemic organ damage, hence causing acute kidney injury (AKI) [9].

Baseline investigations include: complete blood count (CBC) with TLC and DLC, peripheral blood smear examination, serum creatinine, serum urea, glomerular filtration rate, blood pressure monitoring, serum electrolyte, urine microscopy and culture [1]. Blood smear microscopy, culture and ASO (anti-streptolysin O) titres in serum provides clue to infections. Reticulocyte count, serum lactate dehydrogenase (LDH) and serum haptoglobin gives evidence of intravascular haemolysis suggestive of haemolytic anaemia [10]. Persistently lower levels of C3 levels is suggestive of atypical HUS (1), where in C4 levels in serum may or may not be normal. Autoimmune screening like anti-nuclear antibody (ANA), anti- dsDNA and APLA (anti-phospholipid antibody) is done to rule out connective tissue disorders causing secondary HUS. Genetic screening for atypical HUS include THBD (thrombomodulin), C3, CD46, CHFR5, CHFR1, CFH, CFB, CF1 and DGKE (diacylglycerol kinase epsilon) [11].

Closest differential to atypical HUS is secondary HUS and thrombotic thrombocytopenic purpura (TTP), hence it becomes essential to distinguish it from these two entities. ADAMTS13 activity is tested to differentiate atypical HUS from TTP. Less than 50% activity is suggestive of TTP and is abnormal [5].

To asses extra renal involvement, MRI is done to check CNS manifestations and ECG and echocardiography is done if CVS involvement is suspected. In case of ophthalmic symptoms, fundoscopy is done. Flame shaped haemorrhages on retina, optic disc oedema or papilledema and retinal vein or artery occlusion may be seen in few patients [7].

In management of atypical HUS, plasmapheresis or plasma exchange and infusion remains mainstay treatment. However, eculizumab is gold standard treatment of atypical HUS now and is replacing plasmapheresis. Eculizumab is a high affinity monoclonal anti- C5 antibody that helps to achieve disease remission by aborting abnormal alternate complement pathway. The drug is effective but is not available and affordable much in India [12]. Treatment of renal failure, haemodialysis, management of hypertension by betablockers and management of extra-renal manifestations are done simultaneously.

The case we are reporting here is a rare and varied presentation of atypical haemolytic uremic syndrome with acute glomerulonephritis and neurological involvement in a 15 year old boy.

Case Report

A 15 year old male child came with chief complaints of swelling over all four limbs and face since one week, hematemesis since four days and one episode of generalised tonic clonic seizures since morning. As narrated by mother of the child, child was apparently alright one week back when they noticed that the patient has developed swelling over his face and all four limbs. Following which, he was taken to local practitioner who advised complete blood count, kidney function tests including serum urea and creatinine. His haemoglobin at that point of time was found to be 5.9 gm/dl, total leucocyte count was 7200 per cumm and serum urea and creatinine was 148 and 2.4 respectively. Patient was immediately transfused with one unit of packed red cell. Patient developed multiple episodes of hematemesis since 4 days and later on developed hypertension with relative bradycardia. He was started on injection labetolol for hypertensive emergency and was referred to our hospital for further management.

Course in Hospital

Patient came to casualty when he was having an active episode of convulsion. He developed tightening of all four limbs associated with up rolling if eyes and clenching of teeth. The convulsive episode was aborted by injection midazolam and then patient was sifted to PICU.

On examining the patient, his pulse was 56 beats per minute with respiratory rate of 24 breaths per minute, blood pressure of 160/100 and Spo2 of 98%.

Patient was started on IV fluids, injection ceftriaxone, levera and tablet amlodipine and methylprednisolone.

Fundoscopy showed papilledema in left eye and MRI brain revealed oedematous and hyperintense gyri in bilateral parietofronto- occipital region suggestive of PRES syndrome (posterior reversible encephalopathy syndrome) and meningitis. EEG showed generalised epileptogenesis without active seizures. Ultrasonography of abdomen showed grade 1 renal parenchymal disease. Kidney function tests showed urea 126, creatinine 2.2 with continuous blood pressure readings to be on higher side and decreased urine output. Peripheral smear suggested schistocytes and repeated CBC and KFT were done henceforth.

Patient was advised and planned for plasmapheresis and renal biopsy but despite of clear explanation of patient’s condition, relatives denied biopsy and plasma therapy as it wasn’t affordable. With the help of medications and one unit of fresh frozen plasma, patient was stabilized. He was accepting feeds well orally, adequate urine out was established by means of Lasix, Blood pressure came to lie in normal range with haemoglobin of 10gm/dl and TLC of 47000 per cumm.

Repeat sonography of kidneys suggested grade 3 renal parenchymal disease and then patient was started on omnacortil for 15 days with gradual tapering. With repeated CBC, LFT, KFT and urine analysis patient was made vitally and hemodynamically stable and was discharged as relatives weren’t ready for further treatment.

Discussion

Atypical haemolytic uremic syndrome, a rare type of thrombotic microangiopathy, consisting of 5-10% cases of total HUS cases, forms one of the common causes of acute kidney injury in children.

It is labelled as atypical haemolytic uremic syndrome when triad of coombs negative haemolytic anaemia, thrombocytopenia and evidence of acute renal insufficiency exists. Our patient, a 15 year male child presented with haemoglobin of 5.6gm/dl with history swelling over face and all 4 limbs and deranged renal function tests, was diagnosed with atypical haemolytic uremic syndrome and acute glomerulonephritis. The blood peripheral smear showed schistocytes and serum urea and creatinine were elevated with moderate proteinuria and raised Lactate dehydrogenase (LDH). It was suggestive of renal involvement and intravascular haemolysis. Persistently low serum complement C3 levels without significant autoantibodies and negative urine and blood tests suggests atypical haemolytic uremic syndrome.

Another 15-year-old Srilankan girl reported with severe sepsis, pulmonary haemorrhage and high blood pressure of 180/100 and was diagnosed with atypical HS. Her blood picture had schistocytes, complete blood count showed thrombocytopenia, low C3 levels and LDH was raised similar to our case that led to diagnosis of disease. Complete remission was achieved after long treatment of 30 months with plasma exchange [9].

Variety of presentations are possible for atypical HUA and one of the common being generalised edema of all over or anasarca. Similar picture of significant anaemia and rapid weight gain of 3kgs due to gradually increasing oedema was reported in a 13 year old girl in Laos [2]. She was treated for presumptively diagnosed rapidly progressive glomerulonephritis secondary of post streptococcal glomerulonephritis as ASO titres were positive but she ultimately died due to rapid detoriation of renal function.

Whereas another report of 9 year old boy diagnosed with atypical HUS on investigations, was associated with Ebstein Barr virus infection but did not have usual symptom of oliguria, hypertension or oedema. He underwent dialysis and within twelve months remission was achieved and disease had god prognosis even with absence of common signs of atypical HUS [13].

Extra renal manifestations like generalised tonic clonic seizures with brain MRI finding suggestive of PRES syndrome was found in our case.

In a study carried out on 23 patients of atypical HUS, around 11 patients i.e. 48% of patients had convulsions and out of these 11, 6 of them had high blood pressure finding suggesting that seizure can occur in atypical HUS with or without hypertension [14].

Another study suggests that around 50% of patients with central nervous system manifestations or seizure were documented to have hypertension [7]. This was carried ut in 34 students, out of which 5 patients’ brain MRI scan showed PRES syndrome and another 13 patients had bilaterally symmetrical, hyperintense lesions in subcortical area. A similar finding was seen in case report of a 4 year old and 8 year old’s brain MRI [15, 16].

Apart from CNS involvement, significant ophthalmic findings were seen in our patient in form of papilledema and retinal haemorrhages, however no visual symptoms were present. Similar other cases like that of 11 year old girl with atypical HUS had recurrent ocular involvement in form of reduced visual acuity and fundoscopy showing optic disc oedema, retinal haemorrhages and central retinal vein occlusion. With repeated fresh frozen plasma (FFP) infusions, papilledema was subsided [17]. Other reported ophthalmic findings with atypical HUS are visual loss, bilateral central retinal artery and vein occlusion and vitreous haemorrhages [18]. Cases related to hemolytic anemia [19-21] and glomerulonephritis [22,23] were reviewed.

Various evidences state that atypical HUS has multisystem involvement and varied presentation with prognosis depending on severity of anaemia, thrombocytopenia and status of renal function.

Conclusion

Atypical haemolytic uremic syndrome, although has base of haemolytic anaemia, thrombocytopenia and renal insufficiency, may have varied presentation with different system involvement which may occur in different timelines. Focus of disease being on renal and haematological systems, it is also frequently reported with CNS, pulmonary and gastrointestinal findings. This is a type of thrombotic microangiopathy which has broad spectrum of clinical presentation and is a diagnosis of conclusion. Our patient with complaints of oedema, hypertension and seizures with ophthalmic involvement shows nature of disease and vast scope of extra renal manifestations in atypical HUS. Collecting the evidence of intravascular haemolysis, thrombocytopenia and renal injury in absence of any prior infection and prodromal phase helps in diagnosing disease. Autoantibodies, ASO titres, complement C3 levels and genetic screening may support the diagnosis. Prognosis of disease is as varied as its presentation i.e. prognosis may be good even in absence of typical signs and symptoms of atypical HUS or can prove to be fatal for the child. With appropriate treatment like FFP infusions, plasmapheresis, and management of extra renal manifestations and with newer modalities like eculizumab, outcome of treatment is better and remission can be achieved.

References

1. Kedsatha P, Cheong HI, Choi Y. Atypical Hemolytic Uremic Syndrome in a 13-year-old Lao Girl: A Case Report. Child Kidney Dis 2019;23:43-47.
2. Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol Berl Ger 2008;23(11):1957-1972.
3. Loirat C, Frémeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011;6(1):1-30.
4. Raina R, Krishnappa V, Blaha T, Kann T, Hein W, Burke L, et al. Atypical Hemolytic-Uremic Syndrome: An Update on Pathophysiology, Diagnosis, and Treatment. Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn 2019;23(1):4-21.
5. Zhang K, Lu Y, Harley KT, Tran MH. Atypical hemolytic uremic syndrome: a brief review. Hematol Rep 2017;9(2).
6. Formeck C, Swiatecka-Urban A. Extra-renal manifestations of atypical hemolytic uremic syndrome. Pediatr Nephrol 2019;34(8):1337-1348.
7. Franchini M. Atypical hemolytic uremic syndrome: from diagnosis to treatment. Clin Chem Lab Med CCLM 2015;53(11):1679-1688.
8. Basnayake BM, Wazil AW, Nanayakkara N, Samarakoon SM, Senavirathne EM, Thangarajah BU, et al. Atypical hemolytic uremic syndrome: a case report. J Med Case Rep 2020;14(1):1-5.
9. Nester CM, Thomas CP. Atypical hemolytic uremic syndrome: what is it, how is it diagnosed, and how is it treated?. Hematology 2010, the American Society of Hematology 2012;2012(1):617-625.
10. Mohammed SK, Mubarik A, Nadeem B, Khan K, Muddassir S. Atypical Hemolytic Uremic Syndrome: A Case Report. Cureus. 2019;11(5).
11. Yoshida Y, Kato H, Ikeda Y, Nangaku M. Pathogenesis of atypical hemolytic uremic syndrome. J Atheroscler Thromb 2019;26(2):99-110.
12. Fallahzadeh MA, Fallahzadeh MK, Derakhshan A, Shorafa E, Mojtahedi Y, Geramizadeh B, et al. A case of atypical hemolytic uremic syndrome. Ira J Kidn Dis 2014;8(4):341.
13. Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child 1997;76(6):518-21.
14. Koehl B, Boyer O, Biebuyck-Gougé N, Kossorotoff M, Frémeaux-Bacchi V, Boddaert N, et al. Neurological involvement in a child with atypical hemolytic uremic syndrome. Pediatr Nephrol Berl Ger 2010;25(12):2539-2542.
15. Chiodini BD, Davin JC, Corazza F, Khaldi K, Dahan K, Ismaili K, et al. Eculizumab in anti-factor h antibodies associated with atypical hemolytic uremic syndrome. Pediatrics 2014;133(6):e1764-8.
16. Zheng X, Gorovoy IR, Mao J, Jin J, Chen X, Cui QN. Recurrent ocular involvement in pediatric atypical hemolytic uremic syndrome. J Pediatr Ophthalmol Strabismus. 2014;51(6):e62-e65.
17. Greenwood GT. Case report of atypical hemolytic uremic syndrome with retinal arterial and venous occlusion treated with eculizumab. Int Med Case Rep J 2015;8:235.
18. Bhatia A, Bhagwat A, Acharya S, Bhawane A, Acharya N. Postpartum Haemolytic Uremic Syndrome (PHUS) with Posterior Reversible Encephalopathy Syndrome (PRES) Complicating Pregnancy: A Rare Case Report. J Clin Diag Res 2019;13(4).
19. Taksande A. The Neurodevelopmental Outcome of Severe Neonatal Haemolytic and Non-hemolytic Hyperbilirubinemia. J Pediat Res 2021;8(2):214.
20. Somani A, Gaidhane SA, Gaidhane PA, Khatib N, Acharya S. Posterior Reversible Encephalopathy Syndrome (PRES) in Haemolytic Anaemia--A Case Report. J Evo Med Dent Sci 2021;10(9):656-9.
21. Aradhey P, Bakre A, Kumar S, Acharya S. Clinical profile of Uremic polyneuropathy in Chronic Kidney Disease patients. Med Sci 2020;24(102):945-951.
22. Andhale A, Bhawane A, Acharya S, Shukla S, Annadatha A, Hulkoti V. Triple-positive” renal limited vasculitis presenting with rapidly progressive glomerulonephritis: A case report. J Acu Dis 2021;10(2):83.
23. Aradhey P, Bakre A, Kumar S, Acharya S. Clinical profile of Uremic polyneuropathy in Chronic Kidney Disease patients. Med Sci. 2020;24(102):945-951.