Atypical Hemolytic Uremic Syndrome After Kidney Transplantation: Lessons Learned From the Good, the Bad, and the Ugly. A Case Series With Literature Review

Fayek, Sameh; Allam, Sridhar R.; Martinez, Eryberto; Pan, Gilbert; Dao, Ann; Rofaiel, George

doi:10.1016/j.transproceed.2019.10.015

Cited by 8 publications

(8 citation statements)

References 30 publications

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“… 3 Postinfectious TMA relapse on a kidney allograft with initial stabilization of renal function after eculizumab reinitiation subsequently developed overlapping acute tubular necrosis due to a second insult leading to progressive renal function loss over 6 months and, ultimately, allograft loss 29 and posttransplant recurrence of TMA in patient with CFI NOS variant with no response to 3 months of eculizumab retrial and subsequent allograft loss. 47 CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease. …”

Section: Resultsmentioning

confidence: 99%

“… 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 The 40 remaining publications were reviewed extensively. 3 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 14 , 15 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 Individual cases were excluded due to lack of eculizumab discontinuation, subsequent evidence of Shiga toxin-producing Escherichia coli , lack of information on eculizumab dosing, no complement genetic testing, case duplication, and eculizumab discontinuation in the setting of lack of a hematologic response.…”

Section: Methodsmentioning

confidence: 99%

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Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

Acosta‐Medina

Moyer

et al. 2023

Blood Advances

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Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation is limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before January 1st, 2021 were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred and eighty patients from 40 publications were included. Median age was 28 years-old and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n=59) and MCP/CD46 (n=38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant, while the remaining had variants of uncertain significance. Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. Variants of uncertain significance (p<0.001) and likely pathogenic/pathogenic variants (p<0.001) were associated with increased relapse. Presence of a renal allograft (p=0.009); decreasing age (p=0.029); and detection of variants in CFH (p<0.001), MCP/CD46 (p<0.001) or C3 (p<0.001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

Acosta‐Medina

Moyer

et al. 2023

Blood Advances

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“…Previous reports from the pre-eculizumab era documented a strong association between CFH genetic abnormalities and the risk of relapses after kidney transplant, almost invariably leading to graft loss ( 2 ). In recent studies the use of prophylactic eculizumab was independently associated with a reduced risk of recurrence and with longer graft survival ( 47 , 48 ). Consistent with this, here we observed overall unfavorable outcomes in 8 out of 9 grafts without prophylactic eculizumab, while 3 grafts transplanted under eculizumab prophylaxis have maintained normal function.…”

Section: Discussionmentioning

confidence: 99%

CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome

et al. 2023

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IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare disease that manifests with microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, and is associated with dysregulation of the alternative complement pathway. The chromosomal region including CFH and CFHR1-5 is rich in repeated sequences, favoring genomic rearrangements that have been reported in several patients with aHUS. However, there are limited data on the prevalence of uncommon CFH-CFHR genomic rearrangements in aHUS and their impact on disease onset and outcomes.MethodsIn this study, we report the results of CFH-CFHR Copy Number Variation (CNV) analysis and the characterization of resulting structural variants (SVs) in a large cohort of patients, including 258 patients with primary aHUS and 92 with secondary forms.ResultsWe found uncommon SVs in 8% of patients with primary aHUS: 70% carried rearrangements involving CFH alone or CFH and CFHR (group A; n=14), while 30% exhibited rearrangements including only CFHRs (group B; n=6). In group A, 6 patients presented CFH::CFHR1 hybrid genes, 7 patients carried duplications in the CFH-CFHR region that resulted either in the substitution of the last CFHR1 exon(s) with those of CFH (CFHR1::CFH reverse hybrid gene) or in an internal CFH duplication. In group A, the large majority of aHUS acute episodes not treated with eculizumab (12/13) resulted in chronic ESRD; in contrast, anti-complement therapy induced remission in 4/4 acute episodes. aHUS relapse occurred in 6/7 grafts without eculizumab prophylaxis and in 0/3 grafts with eculizumab prophylaxis. In group B, 5 subjects had the CFHR31-5::CFHR410 hybrid gene and one had 4 copies of CFHR1 and CFHR4. Compared with group A, patients in group B exhibited a higher prevalence of additional complement abnormalities and earlier disease onset. However, 4/6 patients in this group underwent complete remission without eculizumab treatment. In secondary forms we identified uncommon SVs in 2 out of 92 patients: the CFHR31-5::CFHR410 hybrid and a new internal duplication of CFH.DiscussionIn conclusion, these data highlight that uncommon CFH-CFHR SVs are frequent in primary aHUS and quite rare in secondary forms. Notably, genomic rearrangements involving the CFH are associated with a poor prognosis but carriers respond to anti-complement therapy.

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“…В исследованиях, проведенных A. Edefonti и соавт. [36][37][38] еще в 1985 г., было выявлено, что при высокой концентрации серотонина в плазме крови и нормальном уровне тромбоцитов может сохраняться клиническая картина гемолитико-уремического синдрома и происходить прогрессирование поражения почек до их хронической болезни. Нормальные уровни тромбоцитарного серотонина в период ремиссии гемолитико-уремического синдрома могут служить признаками благоприятного исхода заболевания, поэтому необходимы дополнительные исследования для оценки прогностической ценности низких уровней тромбоцитарного серотонина у детей с поражением почек.…”

Section: обзоры литературыunclassified

Clinical and diagnostic significance of endothelial dysfunction and serotonin levels in children with hemolytic-uremic syndrome

Макарова

Нигматуллина

Davlieva

et al. 2021

Ross. vestn. perinatol. pediatr.

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Hemolytic-uremic syndrome is a serious problem in pediatrics and pediatric nephrology. Hemolytic-uremic syndrome is one of the leading causes of acute kidney injury with potential transformation into terminal chronic kidney disease. Currently, the endothelial dysfunction is strongly associated with changes in the serotonergic system in the pathogenesis of hemolytic-uremic syndrome. There are few studies that have revealed an increase in the blood plasma serotonin concentration in children with hemolytic-uremic syndrome, but its role in the pathogenesis of chronic kidney disease has been insufficiently studied. The progressive course of hemolytic-uremic syndrome, up to the terminal stage of renal failure, requires the search for markers of renal tissue damage as prognostically significant factors for the development of nephrosclerosis, which is of particular importance for optimizing the management of such children.

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Atypical Hemolytic Uremic Syndrome After Kidney Transplantation: Lessons Learned From the Good, the Bad, and the Ugly. A Case Series With Literature Review

Cited by 8 publications

References 30 publications

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

CFH and CFHR structural variants in atypical Hemolytic Uremic Syndrome: Prevalence, genomic characterization and impact on outcome

Clinical and diagnostic significance of endothelial dysfunction and serotonin levels in children with hemolytic-uremic syndrome

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