Complement Prospective Evaluation of Thrombotic Microangiopathy on Endothelium

Diagnostic and Risk Criteria for Complement Defects in Thrombotic Microangiopathy and Amplifying Conditions, Such as Severe Hypertension: The COMPETE Study.

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.

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).