Vascular endothelial growth factor (VEGF) inhibitors are used for the treatment of various malignancies. Many cases reported DITMA as a result of bevacizumab use, a humanized monoclonal antibody directed against VEGF (46–49). Ramucirumab, anti-VEGF receptor 2 monoclonal antibody, and cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), are also implicated in causing renal-limited TMA (51, 52). Drug-induced TMA has been reported in children with acute lymphoblastic leukemia (34, 35) and adults with solid tumors (36, 37), receiving multiagent chemotherapy. Jodele et al. described 13 patients developing TMA after high-dose chemotherapy and autologous stem cell transplantation for neuroblastoma (12 patients receiving carboplatin/etoposide/melphalan and one cyclophosphamide/thiotepa) (38).
Antiplatelet Therapy
The recent trend of rapid increase in the approval of new drugs brings challenges to the management of TMA. In fact, introducing new targeted therapies may lead to nephrotoxicity by unexpected mechanisms. ADAMTS13 activity could help clinicians to decide if the initial treatment should be plasmapheresis or complement inhibition 83.
Mutations in complement proteins and anti-H factor autoantibodies should be investigated in selected patients 107. GVHD is an epithelial cell disease mostly affecting the gastrointestinal tract, skin and liver, that has been identified as a major risk factor for HSCT-TMA 8,94, 95, 96, 97. Kidney disease could be a complication of monoclonal gammopathy, including cast nephropathy, glomerular diseases and electrolyte disorders. It is essential to distinguish proteasome inhibitors (PIs) kidney toxicity from complications of gammopathies 78.
Mechanisms
Despite the varied pathophysiology the presence of endothelial damage leading to microvascular ischemia is the hallmark of TMA 1,4, 5, 6, 7, 8. We searched 12 databases to identify English-language reports of patient data that described TTP, HUS, or TMA attributed to a drug or other substance (supplemental Table 1, see supplemental Data available at the Blood Web site). Articles were selected for review if their title or abstract suggested that they reported individual patient or group data on patients with a diagnosis of TTP, HUS, or TMA and a suspected drug etiology. All articles were reviewed independently by 2 or 3 of the authors (Z.L.A.-N., J.A.R., J.N.G.).
Role Of Calcineurin Inhibitors
- Routine blood examinations were collected prior to each narsoplimab dose and then twice weekly.
- Table 1 presents the levels of evidence supporting a causal association with TMA for the 78 reported drugs.
- All responding patients were free from platelet and red-blood-cell transfusions at the end of the treatment.
- Creatinine later improved (1.4 mg/dl at 2 months and 1.0 mg/dl at 6 months).
In children, TTP is rare, and PE has a more side effects, therefore, complement inhibitors are first line.47 PE remains the only treatment in countries where access to complement inhibitors is restricted due to cost. There are other drugs that have been used in refractory cases, such as vincristine, bortezomib and azathioprine, and splenectomy has also been used. The mechanism is direct endothelial injury with release of von Willebrand factor multimers, which overwhelm ADAMTS13 capacity and activate coagulation-complement crosstalk. Preeclampsia results from abnormal placentation with production of anti-angiogenic (i.e., anti-VEGF) factors triggering complement activation. This typically occurs later in the pregnancy; helpful diagnostic tests are abnormal uterine doppler and elevated sFlt-1/PlGF ratios (the latter are not yet available in the United States). Failure of TMA to resolve upon delivery is suggestive of other etiologies.
Other Monoclonal Antibodies
Ravulizumab was engineered from eculizumab and targets the same epitope in C5. A histidine switch was performed in the complementarity‐determining regions of eculizumab to preserve binding to C5 in serum but to allow dissociation of C5 from ravulizumab in the acidified endosome. Additionally amino acid alterations to the Fc region of eculizumab resulted in increased efficiency of neonatal Fc receptor‐mediated recycling. This resulted in ravulizumab having an increased half‐life of ~52 days compared to ~11 days with eculizumab and therefore, up to an 8‐week dosing interval with ravulizumab versus 2 weekly with eculizumab.
Study Design
Viralkumar Amrutiya is a second-year nephrology fellow at Virginia Commonwealth University, Richmond, VA. He is a graduate of Hebei Medical University, Shijiazhuang, Hebei, China, and completed his residency and chief year at Hackensack Meridian Health – Palisades Medical Center in North Bergen, NJ. He has special clinical interest in management of CKD and transplant nephrology. He would like to work towards minimizing disparities and bringing equality in kidney care. The TMAs are substituted amphetamines, however, their action does not resemble that of the unsubstituted compound amphetamine, which is a stimulant and not a psychedelic.
Immediately after HSCT there is a high risk of AKI, with risk factors attributable to the procedure and the drugs administrated. Serum creatinine levels will probably not provide a reliable estimation of GFR, because these patients may display large fluctuations in nutritional status, weight and muscle mass 91,97. Immunotherapy is an emerging strategy to treat solid and hematologic malignancies, improving overall survival. Immune checkpoint inhibitors (CPIs) are part of this class of drugs, consisting of monoclonal antibodies that target inhibitory receptors expressed on T cells 85. Some authors reported favourable results using eculizumab in carfilzomib-induced TMA.
Management Of Chemotherapy-Associated TMA
The evolving landscape of TA-TMA management requires collaborative efforts to use standardized diagnostic criteria, prognostic markers, and therapeutic approaches for this severe post-HSCT complication. There is common agreement on avoiding toxic serum concentration of calcineurin inhibitors (CNIs) 8 and tapering their dosage as soon as the laboratory evidence of endothelial damage becomes available. Much less agreement on CNI withdrawal exists when a formal diagnosis of TA-TMA is posed because of the risk of inducing or exacerbating acute GvHD, a known trigger of endothelial damage and TA-TMA 9,10,11. Recently, evidence of a central role of complement has emerged, with involvement of both classic and alternative pathways (Fig. 1) 100, 101, 102, 103, 104, 105, 106, 107, 108, 109. In fact, some of the described risk factors also have the ability to activate complement pathways, including high doses of CNI/mTORI, viral infections and GVHD 102,110.
What Are The Causes And Symptoms Of Thrombotic Microangiopathy?
In a healthy kidney, VEGF is produced by podocytes and regulates the integrity and function of the actin skeleton of endothelial cells. This makes glomerular endothelium particularly susceptible to VEGF inhibition, leading to loss of the fenestrated endothelium, microvascular injury and, eventually, TMA 63,64. Type 1 and type 2 DiTMA cancer drugs; VEGF – vascular endothelial growth factor. Plasmapheresis plays a central role in TTP and remains an invaluable asset in other forms of TMA, at least in particular situations.
Monoclonal Antibodies
Besides, the majority includes both solid and hematologic tumours, with a broad incidence rate for the latter – 8% to 50% of TiTMA 34,139,141,142. The most common hematologic tumours behind TiTMA are Hodgkin lymphoma, aggressive Non-Hodgkin lymphomas, acute leukaemia and multiple myeloma 34,141,144. Pulmonary TMA is a rare condition, but more common in TiTMA patients, being characterized by intimal proliferation of the pulmonary arterioles with presence of tumor emboli 141,142.
Close monitoring of renal function and hematological parameters after eculizumab withdrawal is mandatory; however, there are no evidence-based data about the reliability of a specific parameter and the optimal frequency of testing 33. These include the retrospective design, the limited number of patients treated, and their highly heterogeneous clinical presentation including the presence of both pediatric and adult cases. However, given the difficulties or the impossibility in promoting prospective control trials, real-world data are of paramount importance to understand the clinical potential of innovative treatment proposals in such a rare and often fatal disease.
