Atypical hemolytic uremic Syndrome Triggered by malignancy and drug exposure: A systematic review and meta-analysis

Abstract

Abstract Background Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy driven by complement dysregulation. Malignancy and drugs are known triggers but remain underreported and poorly characterized. This study aims to explore the malignancy and drugs induced aHUS.  Methods Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, Google Scholar, and ClinicalTrials.gov, and 44 original studies reporting aHUS secondary to malignancy or drug exposure were included. Pooled proportions with 95% confidence intervals were calculated using the DerSimonian–Laird estimator and analyzed with the 'meta’ package in R (version 4.16-2). Demographic, clinical, genetic, and treatment-related data were extracted and analyzed descriptively. Results A total of 168 patients from 44 studies were included. The median age was 45 years (1–86); and 68% were female. Tacrolimus was the most reported drug trigger (n=6)followed by gemcitabine (n=5), vincristine (n=5), bevacizumab (n=3), carfilzomib (n=3), 6-mercaptopurine (n=2), methotrexate (n=2), and mitomycin (n=2). Aflibercept, bactrim, bleomycin, capecitabine, cisplatin, cyclophosphamide, cytarabine, dasatinib, deferasirox, dinutuximab, estarylla, ketoprofen, L-asparaginase, modakafusp alfa, PEG-asparaginase, sunitinib, synthetic psychoactive drugs, tamoxifen, and topotecan were reported as potential triggers for aHUS in one patient each. B cell acute lymphocytic leukemia (B-ALL) (n = 10), followed by multiple myeloma (n = 2) and Hodgkin's lymphoma (n = 1) were the most common triggering hematologic malignancies whileneuroblastoma (n = 4), ovarian cancer (n = 3), breast cancer (n = 3), and cholangiocarcinoma (n = 2) were the most common solid malignancies. Fibrolamellar hepatocellular carcinoma, pancreatic cancer, lung cancer, urothelial cancer, prostate cancer, metastatic mullerian adenocarcinoma, large granular lymphocytic leukemia, and renal cell carcinoma were reported in one patient each. All patients were presented with anemia and thrombocytopenia. The pooled rates for patients who had acute kidney injury (AKI) and who required hemodialysis were 100% (95% CI, 0.993-1.00, p = 1.00, I2 = 0%) and 76% (95% CI, 0.642-0.868, p < 0.01, I2 = 55%), respectively. The pooled rates for low ADAMTS13 activity and low complement levels were 37% (95% CI, 0.181-0.589, p = 0.06, I2 = 32%) and 47% (95% CI, 0.266-0.682, p = 0.12, I2 = 28%), respectively. The pooled rate of treatment with eculizumab was 74% (95% CI, 0.629-0.842, p < 0.01, I2 = 72%), and the pooled rate of renal recovery was 65% (95% CI, 0.525-0.761, p < 0.01, I2 = 55%).  Conclusion Tacrolimus, B-ALL, and neuroblastoma are frequently reported aHUS triggers, along with a plethora of chemotherapeutic drugs and malignancies. AKI and hematological abnormalities in these patients should prompt an emergent work-up and treatment. Current evidence is primarily derived from case reports, so prospective trials are necessary to establish the incidence, associations, triggers, and outcomes to devise preventive strategies.