Complement Prospective Evaluation of Thrombotic Microangiopathy on Endothelium

NCT ID: NCT04745195

Last Updated: 2025-10-01

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 42 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-08-11
• Study Completion Date: 2026-12-31

Brief Summary

Thrombotic microangiopathy (TMA) is a severe and life-threatening condition, often affecting the kidneys and brain. It can occur on the background of various clinical conditions. Dysregulation of the alternative pathway of complement may be the etiological factor and this type of TMA is classified, according to the current nomenclature, as primary atypical hemolytic uremic syndrome (HUS). Half the patients with primary atypical HUS present with rare variants in complement genes, although coexisting conditions are often needed for the TMA to become manifest. In patients with secondary atypical HUS, certain coexisting conditions appear to drive the disease and treatment should target the underlying condition to remit the TMA.

Recently, the investigators demonstrated, by using a novel in-house developed functional endothelial cell-based test, that complement dysregulation and overactivation is the dominant cause of disease and its sequelae in a subset of patients with secondary atypical HUS, having impact on treatment and prognosis. The investigators did first prove this concept in patients presenting with TMA and hypertensive emergency. A prospective study is needed to further corroborate these findings along the spectrum of TMA. The investigators hypothesize that their functional endothelial cell-based test, the so-called "HMEC" test, can better categorizes the TMA into different groups with potential therapeutic and prognostic implications. Thus, paving the road to the ultimate goal of precision medicine.

Conditions

Thrombotic Microangiopathies; Hemolytic Uremic Syndrome, Atypical; Hemolytic-Uremic Syndrome

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Complement-mediated thrombotic microangiopathy

No interventions assigned to this group

Thrombotic microangiopathty with normal complement regulation

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Males or females at least 18 years of age;
• Have acute kidney injury, defined as estimated GFR <45 mL/min/1.73m2;
• Have documented TMA either on peripheral blood, defined as Coombs negative microangiopathic hemolytic anemia (hematocrit <30%, hemoglobin <6.5 mmol/L [<10 g/dL], lactate dehydrogenase >500 U/L, and either schistocytes on peripheral blood smear or undetectable haptoglobin), and platelets <150,000 per µL, or kidney biopsy;
• Have primary atypical HUS or a coexisting condition linked to complement dysregulation:

• Hypertensive emergency, defined as SBP/DBP of >180/120 mmHg and impending organ damage secondary to hypertension (at least one of the following: neurologic disease, hypertensive retinopathy grade III and/or IV, left ventricular hypertrophy); OR
• Pregnancy, including 12 weeks postpartum; OR
• Kidney donor recipient; OR
• Systemic auto-immune disease associated with TMA, including systemic sclerosis, systemic lupus erythematosus, anti-phospholipid syndrome;
• Have the ability to understand the requirements of the study, provide written informed consent, and comply with the study protocol procedures.

Exclusion Criteria

• Have secondary causes of hypertensive emergency, including renovascular hypertension, Cushing syndrome, aldosteronism, pheochromocytoma, thyroid disease;
• Have a nephropathy not related to thrombosis on kidney biopsy;
• Have ADAMTS13 deficiency, defined as ADAMTS13 activity <10%;
• Have a positive stool culture for Shiga toxin producing bacteria;
• Have positive serologic test for viral infections, including HIV and CMV;
• Have a history of malignant disease, excluding non-melanoma skin cancer;
• Have a history of bone marrow or solid organ transplantation, excluding kidney transplantation;
• Received at least one of the following agents: chemotherapeutics, sirolimus, anti-VEGF agents;
• Have a history of recent past exposure to illicit drug(s).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Maastricht University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Sjoerd Timmermans

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Pieter van Paassen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Maastricht University Medical Center

Locations

Maastricht University Medical Center

Maastricht, Limburg, Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Sjoerd A.M.E.G. Timmermans, MD, PhD

Role: CONTACT

sjoerd.timmermans@mumc.nl

+31(0)433871198

Daan P.C. van Doorn, MD

Role: CONTACT

daan.vandoorn@maastrichtuniversity.nl

+31(0)433871198

Facility Contacts

Sjoerd A.M.E.G. Timmermans, MD, PhD

Role: primary

sjoerd.timmermans@mumc.nl

+31(0)433871198

Daan P.C. van Doorn, MD

Role: backup

daan.vandoorn@maastrichtuniversity.nl

+31(0)433871198

Other Identifiers

23OK1056

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NL74928.068.20

Identifier Type: -

Identifier Source: org_study_id