Hemolytic uremic syndrome is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. It predominantly affects children and is the most common cause for acute renal failure in the pediatric population.1 The more common form (eg, typical, classic, or D+ hemolytic uremic syndrome), is often triggered by Escherichia coli 0157:H7 and affects 2 or 3 of every 100,000 children.1 Its pathogenesis is described by the thickening of arterioles and capillary walls and endothelial swelling and detachment.1 Multiple sequelae occur following hemolytic uremic syndrome, including gastrointestinal complications, severe hypertension, and central nervous system involvement.1 Although less common, ocular involvement has been described in typical and atypical hemolytic uremic syndrome, with most cases presenting with retinal ischemia, hemorrhages, and neovascularization in typical hemolytic uremic syndrome.2–6 We report the progression of retinal fibrosis as a rare complication of typical hemolytic uremic syndrome in a 2-year-old boy.
A 35-month-old boy presented to hospital with acute onset of diarrhea, fever, and lethargy. He was diagnosed as having typical hemolytic uremic syndrome and stayed in the hospital for 3 months. He deteriorated rapidly and had multiple complications, including acute pancreatitis, type 1 diabetes mellitis, severe hypertension, pancolitis, and multiple gut perforations requiring multiple laparotomies. He received hemodialysis and peritoneal dialysis for end-stage renal failure secondary to hemolytic uremic syndrome, followed by a renal transplant 2 years following initial presentation.
The patient was referred to a pediatric ophthalmologist with a diagnosis of suspected strabismus 1 year prior to his hemolytic uremic syndrome event. He was examined and found to have hypermetropic anisometropia, but otherwise had a normal ocular examination, including healthy discs. He was prescribed glasses. His corrected visual acuity was measured using Allen pictures singles matching and recorded as 20/25 in the right eye and 20/30 in the left eye. Eleven months following his acute event (age 46 months), his corrected visual acuity was 20/20 in the right eye and 20/25 in the left eye. Serial fundus photographs of both eyes were taken using the Topcon50 IX Fundus Camera (Topcon Medical Systems, Paramus, NJ). Fundus examination of the right eye was within normal limits (Figure 1A). Fundus examination of the left eye showed a central area of retinal traction and fibrosis in the posterior pole and the disc and the macula in the center, which is associated with a significant vascular tortuosity (Figure 1B).
Fundus photography of (A) the right eye at 46 months within normal limits and (B) the left eye at 46 months showing the central area of the retinal traction and fibrosis in the posterior pole with vascular tortuosity.
The retinal surgeon recommended no active treatment because the patient's visual acuity was 20/25 in the affected left eye. Close monitoring was performed every 2 months initially. The retinal changes were thought to be related to his previous event of hemolytic uremic syndrome. During the following months, there was a progression of fibrosis, vascular tortuosity (Figure 2), and gradual deterioration of visual acuity in his left eye, documented as 20/50 and 20/70 at 48 and 50 months of age, respectively.
Fundus photography of the left eye at 48 months showing further progression of fibrosis and vascular tortuosity.
He was lost to follow-up for 20 months due to multiple hospital admissions, including renal transplant surgery. When reexamined, his corrected visual acuity measured 20/20 in the right eye and his visual acuity in the left eye had deteriorated to 2/200. Dilated fundus examination of the left eye showed an extensive area of preretinal fibrosis with significant glial tissue involving the disc and macula with total loss of any macular structure features. Retinal pigmentation was noted at the edge of the lesion nasally, superiorly, and inferiorly (Figure 3). Fundus examination of his right eye was within normal limits.
Fundus photography of the left eye at 67 months showing end-stage significant preretinal fibrosis with retinal pigmentation at the edge of the lesion.
Surgery was not offered at this stage in view of the extensive fibrosis along the posterior pole with poor prognosis for recovering vision in the left eye. Cycloplegic refraction was prescribed for the right eye (+2.25 diopters) and the patient was encouraged to wear glasses for both correction of the refractive error and ocular protection. The fundus appearance of the left eye remained stable on all subsequent visits over the following 6 years, as documented by serial fundus photography. Throughout his follow-up visits, there was no evidence of rubeosis iridis and his intraocular pressure remained within the normal range.
We describe the 7-year follow-up of a patient who developed progressive vision loss due to retinal fibrosis as a rare sequela of hemolytic uremic syndrome. In children, 90% of hemolytic uremic syndrome cases are typical hemolytic uremic syndrome associated with Shiga-toxigenic stereotypes of Escherichia coli.1 The pathophysiology of typical hemolytic uremic syndrome involves the binding of Shiga toxin to Gb3Cer receptors on the surface of the glomerular endothelium, leading to thrombogenic changes.7 The release of cytokines and chemokines has been suggested as a possible mechanism in platelet activation causing thrombosis.7 Furthermore, Shiga toxin directly activates the alternative complement pathway and binds to factor H, a complement cascade inhibitor.7 The resulting endothelial cell injury and changes in the coagulation pathway result in end-organ damage.
Reports on ocular involvement associated with hemolytic uremic syndrome in children are rare. Thrombotic microangiopathy of the retinal vessels associated with increased platelet consumption has been suggested as a mechanism of ocular injury.4 To our knowledge, there have been only six published case reports examining eight children with retinal findings secondary to typical hemolytic uremic syndrome.2–6,8 The most common ocular findings reported include retinal ischemia, hemorrhages, neovascularization, and subretinal fibrosis.2–6 Although bilateral ocular involvement is more common in systemic disease and all previously reported cases mention bilateral involvement, this is the first reported case of unilateral retinal findings suspected to be secondary to typical hemolytic uremic syndrome to our knowledge. Our case report demonstrates the progression of retinal findings with serial photographs. Oral fluorescein angiography would have been a useful, additional modality to investigate retinal pathology, but the age of the patient and his overall condition prevented us from pursuing this investigation.
It is currently unclear how to best treat children with ocular sequele secondary to hemolytic uremic syndrome. Eculizumab, a C5 complement inhibitor, has been shown to be a promising treatment for atypical hemolytic uremic syndrome and its ocular complications.9 Although no cases have examined the role of eculizumab on ocular complications in typical hemolytic uremic syndrome, improvement in neurological outcome and normalization of markers of disease status have been demonstrated following early eculizumab infusion.8,10 We propose that all children who develop hemolytic uremic syndrome should receive an early ocular consultation and regular ophthalmic follow-up. Initial ocular presentation could be helpful to guide treatment options (eg, anti-vascular endothelial growth factor therapy for neovascularization). Early ocular examinations would help to document the natural history of this condition and guide treatment options to reduce ocular morbidity in children presenting with hemolytic uremic syndrome.
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- Sandhu H, Vavvas D. Bilateral tractional retinal detachment in a patient with hemolytic uremic syndrome. J AAPOS. 2015;19:484–486. doi:10.1016/j.jaapos.2015.05.017 [CrossRef]
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- Sturm V, Menke MN, Landau K, Laube GF, Neuhaus TJ. Ocular involvement in paediatric haemolytic uraemic syndrome. Acta Ophthalmol. 2010;88:804–807. doi:10.1111/j.1755-3768.2009.01552.x [CrossRef]
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- Zoja C, Buelli S, Morigi M. Shiga toxin-associated hemolytic uremic syndrome: pathophysiology of endothelial dysfunction. Pediatr Nephrol. 2010;25:2231–2240. doi:10.1007/s00467-010-1522-1 [CrossRef]
- Krott R, Querfeld U, Bartz-Schmidt UK, Hammers H, Hammers W, Heimann K. Progressive subretinal fibrosis in a child following hemolytic uremic syndrome. Retina. 1999;19:77–79. doi:10.1097/00006982-199901000-00014 [CrossRef]
- David R, Hochberg-Klein S, Amer R. Resolution of ocular involvement with systemic eculizumab therapy in atypical hemolytic uremic syndrome. Eye (Lond). 2013;27:997–998. doi:10.1038/eye.2013.111 [CrossRef]
- Lapeyraque AL, Malina M, Fremeaux-Bacchi V, et al. Eculizumab in severe Shiga-toxin-associated hemolytic uremic syndrome. N Engl J Med. 2011;364:2561–2563. doi:10.1056/NEJMc1100859 [CrossRef]