A Diagnostic Challenge: Distinguishing Complement-Mediated and Hypertension-Induced Thrombotic Microangiopathy

Introduction: Thrombotic Microangiopathy (TMA) is a serious condition characterized by microangiopathic anemia, thrombocytopenia, and end organ damage. Prompt initiation of treatment for TMA is important in preventing irreversible damage, though tests can take multiple days to result and sometimes a clear diagnosis is not made. In particular, several articles have suggested links between malignant hypertension and genetic mutations in the complement pathway, making the distinction between the two very difficult. Case Description: A 39-year-old female presented with hypertensive emergency and was found to have acute kidney injury with creatinine of 12 mg/dl. Workup revealed hemolytic anemia, thrombocytopenia, proteinuria, and hematuria but broad serologic work-up was negative. She became oliguric and required dialysis shortly after admission. She had evidence of hypertensive damage including left ventricular hypertrophy and hypertensive retinopathy. The patient’s anemia, thrombocytopenia, and general symptoms improved with blood pressure control. Kidney biopsy was consistent with TMA with evidence of hypertensive damage including “onion skinning” and marked arteriosclerosis. Her renal function failed to improve despite adequate blood pressure management. Genetic testing revealed a heterozygous variant in C3AR1 gene, a variant of undetermined significant that has been associated with complement mediated TMA. She was started on eculizumab for potential complement mediated TMA. Discussion: The potential overlap in pathophysiology between complement mediated TMA and hypertension induced TMA is less recognized. Genetic abnormalities are not discovered in a significant proportion of cases of complement mediated TMA. Meanwhile, approximately 50% of cases of hypertension induced TMA reveal abnormalities in complement genes. Case reports have shown renal function improvement in cases of refractory hypertension induced TMA, even months after diagnosis, after eculizumab treatment. With the relatively efficacious treatment for complement mediated HUS with anti-complement therapy and the diagnostic ambiguity in these cases, the decision to initiate eculizumab therapy remains difficult. Fortunately, there is growing research into tests that may help identify patients that would benefit from eculizumab therapy.Fibrin Deposition and Luminal Occlusion