Gastrointestinal pathogens in anti-FH antibody positive and negative Hemolytic Uremic Syndrome

Togarsimalemath, Shambhuprasad Kotresh; Si-Mohammed, Ali; Puraswani, Mamta; Gupta, Akshat; Vabret, Astrid; Liguori, Sandrine; Mariani‐Kurkdjian, Patricia; Bagga, Arvind; Dragon-Durey, Marie-Agnès

doi:10.1038/s41390-018-0009-9

Cited by 13 publications

(14 citation statements)

References 41 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Of relevance to understand the immunologic basis of anti-FHs, are data that the large majority of patients with anti-FHs of our cohort had prodromal infectious illnesses, most commonly upper respiratory tract and gastrointestinal infections, and developed the disease between 4 and 12 years of age, which corresponds to the peak of incidence of common infections. These findings, together with published reports showing a high prevalence of respiratory tract infections (19, 66), and gastrointestinal pathogens in aHUS patients with anti-FHs (67), would support a “two-hit” model according to which the autoimmunity toward FH could develop as a result of an infection in subjects with genetic predisposing background (28). Bhattacharjee et al (26) identified an anti-FH autoantibody epitope cluster within SCR20, which includes amino acids used by microbes to bind FH and evade the immune system (68–70).…”

Section: Discussionsupporting

confidence: 65%

“…Anti-FHs aHUS is an ultra-rare disease with a prevalence of about 1/1,000,000 people in Europe and the USA (1, 28) which does not fit with the ~5% prevalence of FHR1 deficiency in European Caucasian populations (29), and with bacterial infections that commonly occur during school-age (67). From these observations we infer that multiple genetic and/or environmental risk factors are required for the disease to manifest, as reported for other autoimmune disorders (71).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS

et al. 2019

View full text Add to dashboard Cite

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3 , and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined “supercontrols,” as a reference group. “Supercontrols” are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6–9.9] years) and 83% lacked FHR1 ( n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion ( n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions ( n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon ( n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency (“supercontrols”). Rare likely pathogenetic variants in CFH, THBD , and C3 were found in 24% of cases ( n = 6) compared to 2.1% of the “supercontrols” ( P -value = 0.005). We also found that the CFH H3 and the CD46 GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS

et al. 2019

View full text Add to dashboard Cite

show abstract

“…While a gastrointestinal prodrome is reported by others (1, 25), the chief preceding illness in the present patients was low-grade fever (55%) or a respiratory tract infection. A previous study from this center, using multiplex polymerase chain reaction on stool specimens, showed multiple gastrointestinal pathogens in 35 patients predominantly in patients with anti-FH antibodies (26).…”

Section: Discussionmentioning

confidence: 90%

Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database

et al. 2019

Self Cite

View full text Add to dashboard Cite

Background: Atypical hemolytic uremic syndrome (aHUS), an important cause of acute kidney injury (AKI), is characterized by dysregulation of the alternative complement pathway. Autoantibodies to factor H (FH), a chief regulator of this pathway, account for a distinct subgroup. While high anti-FH titers predict relapse, they do not correlate well with disease activity and their functional characterization is required. Methods: Of 781 patients <18-year-old of aHUS in the nationwide database from 2007 to 2018, 436 (55.8%) had anti-FH antibodies. Clinical features and outcome of patients managed in the last 6-year ( n = 317) were compared to before ( n = 119). In plasma samples of 44 patients, levels of serial circulating FH immune complexes (CIC), free FH, soluble terminal complement complex (sC5b-9), sheep red blood cell (SRBC) lysis and epitope specificity ( n = 8) were examined. Functional renal reserve, ambulatory hypertension, left ventricular hypertrophy (LVH), and proteinuria were evaluated in a subset. Results: Patients presented with markedly elevated anti-FH titers (10,633.2 ± 998.5 AU/ml). Management varied by center, comprising plasma exchange (PEX; 77.5%) and immunosuppression (73.9%). Patients managed in the last 6-year showed better renal survival at mean 28.5 ± 27.3 months (log rank P = 0.022). Mean anti-FH titers stayed 700–1,164 AU/ml during prolonged follow-up, correlating with CIC. Patients with relapse had lower free-FH during remission [Generalized estimating equations (GEE), P = 0.001]; anti-FH levels ≥1,330 AU/ml and free FH ≤440 mg/l predicted relapse (hazards ratio, HR 6.3; P = 0.018). Epitope specificity was similar during onset, remission and relapse. Antibody titer ≥8,000 AU/ml (HR 2.23; P = 0.024), time to PEX ≥14 days (HR 2.09; P = 0.071) and PEX for <14 days (HR 2.60; P = 0.017) predicted adverse renal outcomes. Combined PEX and immunosuppression improved long-term outcomes (HR 0.37; P = 0.026); maintenance therapy reduced risk of relapses (HR 0.11; P < 0.001). At 4.4±2.5 year, median renal reserve was 15.9%; severe ambulatory, masked and pre-hypertension were found in 38, 30, and 18%, respectively. Proteinuria and LVH occurred in 58 and 28% patients, respectively. Conclusion: Prompt recognition and therapy with PEX and immunosuppression, is associated with satisfactory outcomes. Free-FH predicts early relapses in patients with high anti-FH titers. A significant proportion of impaired functional reserve, ambulatory hypertension, proteinuria and LVH highlight the need for vigilant long-term follow-up.

show abstract

“…Cases of norovirus induced HUS are still rare in pediatric population but have been documented in 2 older children, a 9 year-old female and a 7-year-old male respectively. The latter had a concomitant Clostridium detected in the stool specimen [11, 12].…”

Section: Discussionmentioning

confidence: 99%

Norovirus: a novel etiologic agent in hemolytic uremic syndrome in an infant

et al. 2019

View full text Add to dashboard Cite

Background Hemolytic uremic syndrome is a rare thrombotic microangiopathy usually seen in infants and children below the age of 5 years. It usually follows a bout of bloody diarrhea caused by Shiga toxin producing E coli and is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. We report the first case of hemolytic uremic syndrome in an infant following Norovirus gastroenteritis. Case presentation A nine-month-old male infant, was admitted with an 8-day history of watery, non-bloody diarrhea, vomiting and decreased oral intake. Physical exam revealed normal blood pressure, pallor and generalized edema. Laboratory findings were significant for microangiopathic hemolytic anemia, thrombocytopenia and azotemia. Stool studies with Multiplex Qualitative reverse transcriptase PCR were positive for Norovirus GI/G II. His clinical course was unusually severe, complicated by oligoanuria and worsening uremia requiring peritoneal dialysis but with eventual complete recovery. Conclusions To our knowledge this is the first case of Norovirus associated HUS in an infant. Given the ubiquity of this virus as a major cause of diarrhea, together with the increased availability of Multiplex Qualitative PCR in reference laboratories, it is quite possible that we shall be seeing more such cases in the future.

show abstract

Gastrointestinal pathogens in anti-FH antibody positive and negative Hemolytic Uremic Syndrome

Abstract: This study reveals a higher prevalence of GI pathogens in anti-FH positive than in negative patients. No single pathogen was implicated exclusively in one form of HUS. These pathogens may play a role in the disease initiation by inducing complement activation or an autoimmune response.

Cited by 13 publications

References 41 publications

Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS

Rare Functional Variants in Complement Genes and Anti-FH Autoantibodies-Associated aHUS

Clinical and Immunological Profile of Anti-factor H Antibody Associated Atypical Hemolytic Uremic Syndrome: A Nationwide Database

Norovirus: a novel etiologic agent in hemolytic uremic syndrome in an infant

Contact Info

Product

Resources

About