Dataset Information

Thrombotic microangiopathy after kidney transplantation: Analysis of the Brazilian Atypical Hemolytic Uremic Syndrome cohort

ABSTRACT:

Background

Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab.

Methods

This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group).

Results

Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients’ mean age was 30 years (24–40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01–0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00–0.28], p = 0.002 in the eculizumab Therapeutic Group.

Conclusion

The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries.

SUBMITTER: Nga H

PROVIDER: S-EPMC8575299 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:IntroductionRare cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), have been reported with interferon β products. We performed a cumulative review of TMA cases recorded in a Global Safety Database for patients with multiple sclerosis who received subcutaneous interferon β-1a treatment.MethodsSearch criteria were: all reported cases, serious and non-serious, from all sources (including non-health care professionals and clinical trial reports), regardless of event ranking and causality assessment by reporter or company. Data lock was May 3, 2014, with additional analysis of cases reported between August 1, 2014-November 30, 2014.ResultsNinety-one patient cases (76.9% female) with 105 events were retrieved. Time to onset varied from 2 months to 14 years, and in 31.9% of patients the event occurred within 2 years of treatment initiation. Seven patients had a fatal outcome (five were secondary to other causes and two reported insufficient information). Forty-four patients recovered, 32 patients had not recovered at the time of the report, and in eight cases outcome was either not reported or unknown. Treatment was discontinued in 84.6% (77/91) of patients. In 67% (61/91) of patients, the reporter suspected a causal association between treatment and TMA/TTP-HUS. Risk factors and/or confounding factors were present in 45.1% (41/91) of patients. Early prodromal syndrome or specific patterns were not detected, although 54.9% (50/91) of cases contained insufficient information. Overall reporting rate of TMA/TTP-HUS was estimated as 7.2 per 100,000 patient-years. Reporting rates for human serum album (HSA)-containing and HSA-free formulations were 5.72 and 7.68 per 100,000 patient-years, respectively.ConclusionNo new signal relating specifically to increased frequency of TMA/TTP-HUS with HSA-free subcutaneous interferon β-1a was detected and no additional risk mitigation measures are required regarding the different formulations. The benefit-risk balance of subcutaneous interferon β-1a remains positive, and routine pharmacovigilance monitoring is appropriate.FundingAres Trading SA, Aubonne, Switzerland, a subsidiary of Merck Serono SA.

Project description:The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.