Abstract
Background: Our center previously reported a high lifetime prevalence of (HTN), chronic kidney disease (CKD), and major adverse cardiac events (MACE) in a cohort of patients with atypical hemolytic uremic syndrome, also called complement - mediated thrombotic microangiopathy (C-TMA). However, this cohort included patients with history of renal failure and renal transplant prior to being treated for CM-TMA. Recent studies have shown significant improvement in renal outcomes with prompt therapy with eculizumab (PMID: 26995002). In this study, we report the long-term renal and extra-renal outcomes of patients without baseline CKD who are diagnosed with C-TMA in the post-C5 inhibitor era.
Methods: Adult patients diagnosed with C-TMA between January 1, 2016 – December 31, 2024, who did not have a diagnosis of CKD at presentation, and were followed for >= 3 months after diagnosis were identified. The C-TMA diagnosis was based on laboratory and clinical parameters (with platelet count < 150 x 109/L, microangiopathic hemolytic anemia with schistocytes on peripheral blood smear), the absence of another evident cause of TMA, and ADAMTS13 activity > 20%. Patients were excluded if they better met “secondary” TMA syndrome (except for C-TMA occurring during pregnancy or postpartum). Patients were followed until death or last clinical contact. The prevalence and severity of HTN and CKD were recorded at the end of follow up. The prevalence of these outcomes was compared by mutation status using Chi-squared Test.
Results: Twenty-one adult patients met inclusion/exclusion criteria. The median age was 39 (IQR: 26-48) years, and 89.9% were female. Five patients had C-TMA in the setting of pregnancy or post-partum. Most patients were white (11, 52.4%) or black (7, 33%). None had baseline CKD and 4 (19.1%) had a preexisting diagnosis of HTN at time of index hospitalization for TMA. Genetic testing was available in 18/21 patients; of these, four patients had pathogenic mutations (two with heterozygous CD46 / membrane cofactor protein (MCP) mutations and two with heterozygous complement factor H (CFH) mutations), two had CFH autoantibodies, six had variants of uncertain pathogenicity, and six had negative testing. Most patients 18 /21 (85.7%) received eculizumab and 12/21 (57.1%) received plasma exchange (PEX) prior to switching to eculizumab therapy. Three patients experienced rapid recovery from TMA with supportive care alone and received neither PEX nor Eculizumab. Median length of hospitalization was 11 days (IQR 9 – 19). At last follow up, 20/21 (95.2%) patients were alive. One patient died during index hospitalization due to ST elevation myocardial infarction attributed to TMA and one patient was lost to follow up shortly after index hospitalization. For the remaining 19 patients, median follow up was 49.4 months (IQR: 22.3 – 75.3) Of patients who started Eculizumab 14/18 (77.8%) received a time-limited course of treatment, and 4/18 (22.2%) remained on indefinite therapy at last follow up. Median time on Eculizumab was 4.6 months (IQR: 2.9 – 13.1) At most recent follow up 8/19 (42.1%) of patients had CKD. Of the eight patients with CKD, five (62.5%) were early stage (stage 1 – 3), one (12.5%) was stage 4, and two required long-term renal replacement therapy (25%). At last follow up, 12/19 (63.2%) carried a diagnosis of chronic HTN and an additional 3/19 (15.8%) had documented hypertensive-range blood pressure (SBP >130 or DBP >80) despite no formal diagnosis. Only 5/19 patients (26.3%) were HTN-free at last follow up. Of the patients with HTN, the majority 6/11 (54.5%) were prescribed 3 or more anti-hypertensive medications at last follow up. The rates of HTN and CKD at last follow up were not significantly different between patients with and without pathogenic mutations.
Conclusion: In this contemporary cohort of patients with C-TMA without baseline CKD, 15.8% patients had CKD 4 or 5 at long-term follow up. Despite the lower rates of advanced CKD compared to cohorts in the pre-C5 inhibitor era, there was a high rate of HTN, including resistant HTN. While the follow up was too short to detect long-term cardiovascular outcomes, the high rates of HTN and CKD indicate a need to evaluate larger cohorts and longer follow up to examine rates of cardiovascular disease. Larger, well-phenotyped cohorts are also needed to elucidate the effect of complement factor mutations and duration of anti-complement therapy on outcomes.
