Journal of Clinical Pediatrics and Neonatal Care

A Case of Atypical Hemolytic Uremic Syndrome Preceded by Intussusception

*Myra Chiang
Department Of Pediatric Nephrology, West Virginia University, Charleston Division, United States

*Corresponding Author:
Myra Chiang
Department Of Pediatric Nephrology, West Virginia University, Charleston Division, United States
Email:mlchiang@hsc.wvu.edu

Published on: 2019-12-02

Abstract

Hemolytic uremic syndrome (HUS) is defined as a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). It is one of the main causes of AKI in children. In the past, HUS was classified as either diarrhea associated HUS (D plus) or non-diarrhea associated HUS (D minus). However, ongoing research has provided a better understanding of the different underlying causes of HUS, many of which may present with some diarrhea and management and prognosis are different. HUS is best classified as either inherited or acquired based on pathophysiologic considerations [1].

Keywords

Hemolytic Uremic Syndrome; Intussusception

Introduction

Hemolytic uremic syndrome (HUS) is defined as a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). It is one of the main causes of AKI in children. In the past, HUS was classified as either diarrhea associated HUS (D plus) or non-diarrhea associated HUS (D minus). However, ongoing research has provided a better understanding of the different underlying causes of HUS, many of which may present with some diarrhea and management and prognosis are different. HUS is best classified as either inherited or acquired based on pathophysiologic considerations [1].

Hereditary causes of HUS:

• Complement gene mutations

• Diacylglycerol kinase epsilon mutations

• Inborn errors of cobalamin C metabolism

Acquired causes of HUS:

• Infection: Shiga toxin producing E coli (STEC), Streptococcus pneumoniae, Human immunodeficiency virus

• Autoantibodies to complement factors

• Drug toxicity

• Pregnancy

• Autoimmune disorders such as systemic lupus erythematosus

Compared to STEC HUS, Complement-mediated HUS (also called atypical HUS) is rare, with reported incidence of 7 per 1 million children in Europe [2], 1-2 per million in the United States [3], but we believe this is an underestimation.

Case Report

This is a case of a 2-year-old male who presented with bloody diarrhea to an outlying hospital and CT of the abdomen was suggestive of intussusception. He was transferred to our facility for possible need for surgical intervention. Lab evaluation on admission demonstrated a normal hemoglobin of 13.2, hematocrit of 39.1, platelet count of 354,000, BUN of 11, creatinine of 0.2. Intussusception was partially reduced on barium enema which was followed by laparoscopic inspection that revealed further spontaneous reduction of the intussusception. The patient did well post operatively and was about to be discharged two days later but was found to be pale and oliguric. Repeat blood test demonstrated a drop in hemoglobin to 9.3, hematocrit to 27, and platelet count to 37,000. Blood chemistry revealed hyponatremia with serum sodium of 129, potassium of 6.9, CO2 of 20, BUN of 118, creatinine of 4.5. HUS was suspected which was supported by the findings of schistocytes on peripheral smear, elevated LDH and low haptoglobin. PT/PTT and D dimer were normal. GI panel was negative for E coli 0157:H7 PCR. C3, C4 complement levels and ADAMTS13 activity were normal. The patient had emergent hemodialysis and tolerated it well. He developed hypertension and remained oliguric and continued to require intermittent hemodialysis for three weeks. This was followed by improvement of his urine output, resolution of his symptoms and lab abnormalities. His atypical HUS Genetic Susceptibilty Panel came back abnormal with low CD46 Lymph ratio of 0.49 (normal 0.85-1.18), low CD46 PMN Ratio of 0.55 (normal 0.73-1.31). CD46/Membrane Cofactor Protein (MCP) was significantly below the reference range. Further testing confirmed CD46/MCP gene mutation. Family history was negative for any kidney disease. Decision was made not to treat with eculizumab. He remained well with normal renal function and no recurrence of HUS. His family then moved out of state and he was lost to follow up.

Discussion:

Intestinal intussusception preceding or presenting with HUS concurrently, although rare, has been reported in the literature [4, 5, 6, 7, 8, 9]. Intussusception has also been reported in E coli 0157:H7 infections without HUS [10]. Almost all of the case reports of intussusception were attributed to STEC HUS even in those whose stool studies came back negative. It is postulated that the hemorrhage, necrosis, mucosal ulceration of the colonic wall serves as the leading point for the intussusception in STEC HUS. To our knowledge, this is the first case report of intussusception unmasking or triggering a HUS due to an abnormality in one of the complement regulatory proteins. CD46/MCP is widely expressed at a fairly consistent level across many cell lineages of healthy individuals and functions to protect cells from autologous complement mediated lysis[11]. CD 46 protects cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. CD46 defects can result in either decreased expression or decreased cofactor function [12]. The majority of mutations detected in 50-60% of aHUS involve loss of function mutation in the complement regulatory proteins (CFH, CFI, MCP) [13, 14, 15, 16], or a gain of function mutation in an effector gene complement factor B (CFB) or complement 3 (C3). Sellier-Leclerc Al et al reported that patients with CFH mutations had the worst prognosis with 60% progressing to end-stage renal disease (ESRD) or death in less than 1 year, compared to patients with MCP mutations that have good prognosis, with a relapsing course but none reaching ESRD at 1 year [17]. Caprioli et al studied mutations in complementary regulatory proteins that predisposed to non-Shiga toxin associated HUS [18]. Out of 156 patients with non-Shiga toxin HUS, he found 14, 11 and 5 were associated with MCP, CFH, and CFI mutations respectively and mutations with MCP had a better outcome in kidney transplantation and a better prognosis than CFH mutations and non-mutated patients [18, 19]. Patients with mutations in CFH and CFI had a worse outcome due to disease recurrence [18, 19]. The role of CD 46, formerly known as membrane cofactor protein (MCP) in aHUS follows an incomplete penetrance, with some mutations causing a reduced MCP expression, while a smaller proportion resulted in only a functional defect [11].

Eculizumab was approved for treatment of aHUS in 2011. It is a humanized monoclonal IgG2/4 that binds C5, preventing its conversion to C5a and C5b. Prevention of this step effectively blocks the formation of the terminal complement pathway and the membrane attack complex (MAC) which predisposes patients to meningococcal infections[12]. Maintenance treatment with eculizumab is expensive, with an estimated annual drug cost of $350,000 to $645,000 [2]. There are no clear current guidelines about the discontinuation of eculizumab therapy but long term therapy is warranted in aHUS genotypes that are associated with higher risk of relapse and progression to ESRD (CFH, CFB, C3, and CFI mutations). Since patients with MCP mutations tend to have a milder disease and may have spontaneous complete or partial remission as in our case, it is less clear if they need lifelong treatment with eculizumab. One strategy that has been suggested was to provide patients with home urine dipsticks and have them monitor their urine for blood (hemoglobinuria) on a regular basis especially during acute illnesses. The appearance of hemoglobinuria should trigger immediate clinic visit for assessment of aHUS recurrence[12].

In conclusion, we report a case of intussusception that triggered the diagnosis of aHUS due to MCP mutation. We recommend evaluation for complement gene mutations in patients presenting with intussusception and HUS, especially if STEC comes back negative as management and prognosis varies depending on the underlying pathology.

References:

1. Aigner C, Schmidt A, Gaggl M, et al. An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy. Clinical Kidney Journal 2019; 12(3):333-337.

2. Zhang K, Lu Y, Harley KT, et al. Atypical Hemolytic Uremic Syndrome: A Brief Review. Hematol Rep 2017; 9(2):7053.

3. Laurence J. Atypical hemolytic uremic syndrome (aHUS): making the diagnosis. Clin Adv Hematol Oncol 2012; 10(10 Suppl 17):1-12.

4. Fukushima H, Hashizume T, Morita Y, et al. Clinical experiences in Sakai City Hospital during the massive outbreak of enterohemorrhagic Escherichia coli O157 infections in Sakai City, 1996. Pediatr Int 1999; 41(2):213-7.

5. Hashimoto R, Yamamoto Y and Tanuma T. An Unusual Cause of Intussusception. J Gastrointestin Liver Dis 2015; 24(4):412.

6. Hagiwara S, Tobayama H and Kagimoto S. Successful colonoscopic approach in a child with intussusception associated with enterohemorrhagic Escherichia coli O157 infection. Pediatr Rep 2012 6; 4(4):e33.

7. Rahman RC, Cobeñas CJ, Drut R, et al. Hemorrhagic colitis in postdiarrheal hemolytic uremic syndrome: retrospective analysis of 54 children. Pediatr Nephrol 2012; 27(2):229-233.

8. KO EY, Kim JY, Lee HJ, et al. A case of hemolytic uremic syndrome preceded by intussusception. Korean J Pediatr 2011; 54(4):176-178.

9. Lamont PM and Davidson AI. Haemolytic-uraemic syndrome presenting as an acute abdomen. Postgrad Med J 1987; 63(743):807-809.

10. Cha PI, Gurland B and Forrester JD. First Reported Case of Intussusception Caused by Escherichia coli O157:H7 in an Adult: Literature Review and Case Report. Surg Infect (Larchmt) 2019; 20(1):95-99.

11. Fremeaux-Bacchi V, Moulton EA, Kavanagh D, et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2006; 17(7):2017-2025.

12. Afshar-Kharghan V. Atypical hemolytic uremic syndrome. Hematology Am Soc Hematol Educ Program 2016; 2016(1):217-225.

13. Noris M and Remuzzi G. Genetic abnormalities of complement regulators in hemolytic uremic syndrome: how do they affect patient management?. Nat Clin Pract Nephrol 2005; 1(1):2-3.

14. Józsi M, Licht C, Strobel S, et al. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 2008; 111(3):1512- 1514.

15. Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010; 5(10):1844-1859.

16. Noris M and Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361(17):1676-1687.

17. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 2007; 18(8):2392-2400.

18. Caprioli J, Noris M, Brioschi S, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006; 108(4):1267-1279.

19. Noris M and Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16(4):1035-50.