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Year : 2018  |  Volume : 1  |  Issue : 1  |  Page : 33-37

Complete renal recovery following delayed therapy with eculizumab in atypical hemolytic uremic syndrome

1 Department of Pediatric Nephrology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
2 Department of Pathology and Laboratory Medicine, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia

Date of Web Publication28-Jun-2018

Correspondence Address:
Saeed M Alzabli
Children Specialized Hospital, King Fahad Medical City, Riyadh
Kingdom of Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_4_18

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Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening illness characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Plasma therapy, previously considered the primary treatment for this condition, is associated with death and permanent kidney injury in over 50% of patients. Eculizumab, a monoclonal antibody that blocks C5, is far more effective and is the current treatment of choice, but it is not widely available. An 18-month-old boy presented with AKI, anemia, and normal platelet count. While managed initially as proliferative antineutrophil cytoplasmic antibody-associated glomerulonephritis, a diagnosis of partial HUS was suggested by low levels of complement C3, complement factor I (CFI) and complement Factor B (CFB), and histological changes suggesting microangiopathy without thrombi. Later, next-generation sequencing indicated homozygous pathogenic mutations in CFI and heterozygous variations in C3 and CFB. Corticosteroid pulses and plasmapheresis were ineffective in resolving the need for dialysis, and hypertension was refractory to polytherapy. Therapy with eculizumab, initiated only after 5 months on dialysis, was associated with rapid increase in urine output, control of hypertension, and slow but complete renal recovery. Dialysis was discontinued after 5 months of eculizumab therapy, and renal function has been within normal range after 33 months of initiating therapy with eculizumab. Our case emphasizes that a diagnosis of aHUS should be considered in the appropriate clinical setting even in the absence of thrombocytopenia. Kidney biopsy and genetic testing are useful in confirming the diagnosis. Therapy with eculizumab in patients with severe AKI may be associated with complete renal recovery even if therapy is delayed by several months.

Keywords: Acute kidney injury, complement blockade, partial hemolytic uremic syndrome, thrombotic microangiopathy

How to cite this article:
Alzabli SM, Al Anazi A, Ur Rahman MA, Rahim KA. Complete renal recovery following delayed therapy with eculizumab in atypical hemolytic uremic syndrome. Asian J Pediatr Nephrol 2018;1:33-7

How to cite this URL:
Alzabli SM, Al Anazi A, Ur Rahman MA, Rahim KA. Complete renal recovery following delayed therapy with eculizumab in atypical hemolytic uremic syndrome. Asian J Pediatr Nephrol [serial online] 2018 [cited 2022 Jul 7];1:33-7. Available from: https://www.ajpn-online.org/text.asp?2018/1/1/33/235478

  Introduction Top

Thrombotic microangiopathy (TMA) is a term that was coined in 1952 to describe postmortem findings of disseminated thrombosis of small blood vessels.[1] The pathological process of microvascular occlusion, thrombocytopenia, and microangiopathic hemolytic anemia [2] presents with primary and secondary diseases such as atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura.[3] aHUS is a rare, progressive, and often life-threatening disease that presents at any age with the triad of HUS, namely hemolysis, thrombocytopenia, and renal dysfunction. About 60% of cases are caused by uncontrolled activation of the alternate complement pathway,[4] leading to the formation of membrane attack complex that causes endothelial cell injury and systemic TMA. Apart from HUS, extrarenal features may follow neurological, cardiovascular, pulmonary, or gastrointestinal organ injury.[4],[5],[6],[7] Presentation of aHUS with microangiopathic hemolytic anemia and acute kidney injury (AKI) without thrombocytopenia, termed partial HUS, is uncommon. Kidney biopsy and/or genetic testing for the underlying defects in complement pathway enables the correct diagnosis.[8] Lack of awareness of this association may cause confusion in diagnosis that delays specific therapy and reduces survival.

The outcome for patients with aHUS has changed considerably following the use of eculizumab, a humanized monoclonal antibody that binds to and blocks the cleavage of complement C5 to C5a and C5b, thus inhibiting the formation of the terminal complement complex, C5b-9.[7] Before the availability of eculizumab, more than half of the patients with aHUS would die, become dialysis dependent, or develop permanent kidney damage within a year of diagnosis.[5] Early initiation of therapy with eculizumab is associated with significant and sustained renal recovery in patients with aHUS.[9] However, it is unclear whether kidney function can be salvaged if therapy is delayed. We present here the case of a young child in whom the diagnosis of partial aHUS was considered late after presentation with severe AKI, and in whom complete and sustained renal recovery was observed despite several months of delay in therapy with eculizumab.

  Case Report Top

An 18-month-old boy presented with vomiting, decreased urine output, respiratory distress and generalized edema, preceded by upper respiratory tract infection. The baby was born of nonconsanguineous marriage by vaginal delivery at term and had required valvuloplasty to correct pulmonary stenosis. For the current illness, he was admitted to the intensive care unit at a hospital for 18 days, during which he underwent mechanical ventilation for cardiorespiratory failure for 2 days and required amlodipine, captopril and intermittent intravenous (IV) hydralazine for hypertension. Blood investigations had shown urea of 35.2 mmol/L, creatinine of 192 μmol/L, alanine aminotransferase of 379 U/l and albumin of 19 g/L, while urine had 2 + proteinuria by dipstick.

Upon transfer to our center, blood pressure was 125/75 mm Hg (>99th percentile) and urine output was 0.4 ml/kg/hr. Investigations revealed blood urea of 28.5 mmol/L, creatinine of 136 μmol/L, bicarbonate of 15.5 mmol/L, sodium of 138 mmol/L, potassium of 5.9 mmol/L, lactate dehydrogenase of 472 U/L, hemoglobin of 10.5 g/dL, and platelet count of 813 × 109/L. The corrected reticulocyte percentage was 4.6% and there were a few schistocytes on peripheral blood film. Urinalysis showed 36 red blood cells per high-power field, with proteinuria (spot urine protein-to-creatinine ratio of 0.2 g/mmol and 24-h urine protein of 0.7 g/day). He received bicarbonate and sodium polystyrene to correct electrolyte disturbances. Furosemide administration improved the urine output to 1.4 ml/kg/hr. Hypertension was managed with amlodipine, intermittent IV hydralazine and, later, oral minoxidil. Complement levels, available later, showed low C3 (0.6 g/L) and normal C4 (0.25 g/L); antinuclear antibody was negative. Kidney biopsy was unsuccessful as the renal poles were poorly visualized on ultrasound. At discharge, the urine output was normal, blood pressure was controlled on minoxidil and amlodipine, and serum creatinine was 66 μmol/L; kidney biopsy was planned during follow up.

The boy returned after 5 days with edema, oliguria, hematuria, and hypertension. Blood investigations revealed creatinine of 77 μmol/L, hemoglobin of 9 g/dL, and platelets of 450 × 109/L. Antineutrophil cytoplasmic antibody (ANCA) was negative for antimyeloperoxidase antibody (5.2 IU/mL), but antiproteinase 3 was 60.5 IU/mL (normal range: 0–20 IU/mL); there were no anti-glomerular basement membrane antibodies and activity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) was normal (>100%). Kidney biopsy suggested proliferative glomerulonephritis with occlusion of most arterioles without obvious thrombosis, suggesting microangiopathy; and tubular atrophy and fibrosis in 15%–20% of cortex [Figure 1]. Considering the histopathological findings of proliferative glomerulonephritis, three IV pulses of methylprednisolone were administered. However, there was no response and the child developed massive pericardial effusion requiring pericardiocentesis. Dialytic support included continuous renal replacement therapy, followed by intermittent hemodialysis, and, finally, automated peritoneal dialysis. In view of ANCA positivity and worsening renal function, plasmapheresis was administered for 5 sessions daily and 5 sessions on alternate days, along with two IV doses of rituximab. ANCA became undetectable and blood pressure was controlled; however, dialysis dependence persisted.
Figure 1: Findings on kidney biopsy. (a) Hypercellular glomeruli with endocapillary proliferation (hematoxylin and eosin). (b) A cellular crescent (periodic acid–Schiff). (c) Subintimal mucoid change within artery wall (hematoxylin and eosin) and (d) Subendothelial widening on electron microscopy

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Complement factor assays showed normal level of complement factor H and low levels of factors I (19.6 mg/L; range: 29.3–58.5 mg/L) and B (146.2 mg/L; range: 191–382 mg/L). Results of next-generation gene sequencing, available later, showed a homozygous variant in complement C3, factor I, c.1246A>C (p. Ile416 Leu), that is rare (minor allele frequency 0.001), reported to be associated with aHUS, and pathogenic;[6],[9] a heterozygous variant in C3, c.3326T>G (p. Leu1109Arg), that is novel, predicted by in silico models to be pathogenic (located in functional domain; has a high Combined Annotation Dependent Depletion score of 23), but it is classified as a variant of unknown significance; and a heterozygous variant in CFB, c.1697A>C (p. Glu566Alaor E541A), that is rare (minor allele frequency 0.01), previously reported in association with aHUS, but it is likely to be benign or have a partial phenotype rather than being functionally relevant.[10],[11],[12]

While therapy with eculizumab was planned, the drug could not be procured immediately. Kidney biopsy, repeated to assess the chronicity of renal injury prior to starting eculizumab, was consistent with chronic TMA associated with tubular atrophy and interstitial fibrosis involving 20–25% of the cortex. Immunofluorescence showed focal and segmental staining with IgG (2+) and C3 (2+). The first dose of eculizumab was given to the patient after 5 months of dialysis, two weeks after a dose of tetravalent meningococcal conjugate vaccine. The urine output increased within 2 weeks and renal function began to improve [Figure 2]. Maintenance therapy with eculizumab was continued with doses given every 2 weeks. Five months after initiating eculizumab, peritoneal dialysis could be discontinued. At the last follow-up, 33 months after initiating therapy with eculizumab, serum creatinine was 40 μmol/L with estimated glomerular filtration rate (eGFR) of 105 mL/min/1.73 m 2; there was no proteinuria and hypertension was well controlled with lisinopril alone. Kidneys appeared normal on ultrasound and echocardiography showed normal ventricular systolic function.
Figure 2: Serum creatinine (μmol/L) in relation to therapies, including eculizumab

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  Discussion Top

aHUS is a rare disease that usually follows chronic uncontrolled activation of complement pathway.[7] Incomplete forms, lacking thrombocytopenia (15%), anemia (6%) or renal dysfunction (17%), are reported.[4],[12] aHUS without thrombocytopenia, termed partial HUS, is not uncommon in children and may be associated with an unfavorable renal outcome.[8] Thrombocytopenia was lacking in 40–44% of patients in two case series of HUS or TTP, one with a high proportion of secondary TMA [13] and another reporting biopsy-proven TMA.[14] Similarly, prospective cohorts from Marseilles (n = 43) and France (n = 107) reported partial HUS in 12–18% of episodes in 13–14% of patients during follow up.[8],[10] Similarly, our patient had normal platelet count throughout his illness, despite biopsy evidence of TMA, indicating partial HUS.

Therapy in our patient was considerably delayed because of lack of thrombocytopenia, serologic and histologic suggestion of ANCA-associated vasculitis, and the inability to procure eculizumab promptly. Appropriate diagnosis was enabled by histology, complement assays and next-generation genetic sequencing. This report underscores the utility of histology in identifying TMA and specific genetic testing in detecting pathogenic variations in genes encoding complement regulatory proteins.[6],[9],[10],[11],[12] Two of the three variants detected by genetic workup in our patient were likely pathogenic and contributed to the severe phenotype.[6],[9],[10],[11],[12]

Normalization of platelet count is not a reliable marker of improvement in aHUS. As indicated in our patient, TMA may persist despite resolution of hematological activity; improvement of vascular lesions is indicated by improved renal function, hypertension, or other organ functions.[15] The Marseille database and the French cohort reported similar renal outcome for patients with normal platelet counts and those presenting with thrombocytopenia.[8],[10] On the contrary, the renal outcome for patients with normal platelet count was reported to be worse than that in the thrombocytopenic group in a retrospective single-center study and was attributed to delayed diagnosis.[14] Despite delayed diagnosis, our patient, who was dialysis dependent, showed complete renal recovery following therapy with eculizumab.

By blocking the cleavage of C5 to C5a and C5b, eculizumab prevents the formation of pro-inflammatory C5a and the membrane attack complex C5b-9, thus ablating complement activation that causes the endothelial lesions characteristic of TMA. Eculizumab was approved for treating aHUS by the European Medicines Agency and the United States Food and Drug Administration in 2011.[16] International guidelines recommend treating children and adults diagnosed with aHUS with eculizumab within 24 hr of presentation.[4] If the diagnosis is delayed awaiting results of investigations, and in cases lacking significant improvement in renal and hematological parameters, therapy with eculizumab should be initiated after five plasma exchanges.[4],[17] Response to eculizumab was linked to time to therapy in a series of dialysis-dependent patients, in which four patients treated after 6–26 days of dialysis showed significant improvement in renal function, while two patients treated with eculizumab after 119 and 1128 days of onset had continuous requirement of dialysis.[18] In four prospective clinical studies, the mean change in eGFR from baseline to 1 year was significantly higher for patients treated with eculizumab within a week of presentation versus those treated later.[7],[19]

In contrast, some reports indicate encouraging outcomes despite delay in the use of eculizumab. Initiation of eculizumab after 6 months of dialysis significantly improved cardiac function in an 18-month-old child with aHUS and enabled eGFR to increase to 70 mL/min/1.73 m 2.[20] A 7-month-old girl with aHUS and CFH mutation could go off dialysis following delayed eculizumab therapy; however, renal recovery was incomplete and eGFR was 42 mL/min/1.73 m 2 at 18 months of age.[21] Following eculizumab therapy on day 55 of diagnosis in a 4-month-old child with idiopathic aHUS, peritoneal dialysis could be discontinued and hypertension was controlled.[22] Dialysis could be discontinued despite 5-month delay in therapy in our patient, the longest reported duration of dialysis preceding therapy with eculizumab. Further, unlike previous reports, renal recovery in our patient was complete and not partial.

  Conclusion Top

Thrombocytopenia is not essential at the presentation of aHUS and the diagnosis should be ascertained by renal biopsy and/or genetic studies. Normal platelet count is not always associated with unfavorable renal outcome. Every effort should be made to procure eculizumab because therapy, even if considerably delayed, may enable cessation of dialysis, with renal recovery, improved quality of life and enhanced patient survival.

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Conflicts of interest

There are no conflicts of interest.

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.


The authors would like to thank Academic and Training Affairs in King Fahad Medical City.

  References Top

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  [Figure 1], [Figure 2]


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