Eculizumab is a monoclonal drug that inhibits C5-factor, thus not permitting the formation of the Complement Membrane Attack Complex, avoiding, the facto, cell lysis and death. Criteria and levels of evidence for an association of a single drug with TMA were defined using criteria by Al-Nouri et al. (2015), previously adapted from drug-induced thrombocytopenia (George et al., 1998). The criteria differ whether the etiopathogenic mechanism is immune or toxic. The presence of TMA can be daunting due to its rarity, high morbidity, and mortality; the need for specialized diagnostic testing; and the urgency for therapeutic intervention. However, a structured approach to this clinical presentation can help clinicians move rapidly toward a correct diagnosis and optimal treatment. Hematopoietic stem cell transplantation (HSCT) is no stranger to TMA, with an occurrence rate of 3%-39%.
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Patients often can recall the exact time, place, and circumstances of their initial symptoms, and these symptoms typically occur within several hours of quinine exposure. Quinine exposure may be from tablets, typically used for the common symptom of leg cramps, or from common beverages, such as tonic water, Schweppes Bitter Lemon, and Dubonnet aperitif. These clinical characteristics of quinine-induced TMA are assumed to be similar for other drugs (or foods or beverages) that may cause immune-mediated TMA.
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Blood pressure control is essential and renin-angiotensin system blockers are preferred, since VEGF inhibition induces renin secretion through tissue ischemia 64,67. Some case reports described the successful use of eculizumab, even while still administrating VEGFi 57,68. 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. MMC is an antibiotic that works as a cell-cycle specific alkylating agent, still used in bladder cancer 17.
Chemotherapy offers curative treatment for early stage cancer and palliation for late-stage cancer but may have off-target effects including kidney toxicity. One such adverse effect is TMA which constitutes microangiopathic hemolytic anemia (MAHA), thrombocytopenia, intravascular thrombosis, and ischemia-induced end-organ damage. This disease, now known as thrombotic thrombocytopenic purpura (TTP), is one of the most extensively studied subtypes of TMA. Primary TMAs mainly include hereditary or acquired forms of TTP and primary atypical hemolytic uremic syndrome (aHUS). Their pathogeneses are well-understood, and their respective diagnosis and treatment are well-developed.
Drugs Reported To Have A Definite Causal Association With TMA In 177 Individual Patient Reports
This is described for example for interferon (Kavanagh et al., 2016), oxaliplatin and gemcitabine (Al-Nouri et al., 2015; Saleem et al., 2018). Second, the toxic group comprises different drugs, having heterogeneous biological targets, such as signal transducer, transcription factor or receptors. Moreover, these targets have different distributions above tissues and organs. In fact, as described above, anti-VEGF and TK inhibitors have tropism for endothelial-podocyte complexes.
- For 2 drugs, gemcitabine and oxaliplatin, most reports were consistent with a toxic mechanism but each of these drugs also had reports consistent with an immune-mediated mechanism.
- All articles were reviewed independently by 2 or 3 of the authors (Z.L.A.-N., J.A.R., J.N.G.).
- When the target is complement factor H, the paraprotein overactivates the alternative complement pathway, leading to C3 glomerulopathy or aHUS 147, 148, 149.
- In the setting of COVID‐19 induced complement‐mediated aHUS, C5 inhibition would be the treatment of choice.
- There is no evidence on plasmapheresis for treatment of monoclonal gammopathy in this setting.
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There are other drugs that have been used in refractory cases, such as vincristine, bortezomib and azathioprine, and splenectomy has also been used. The 43 evaluable articles reporting group data described 46 patient groups with TMA attributed to 12 drugs, including 3 drugs which were not described in the reports of individual patients. One of the 12 drugs, cyclosporine, accounted for 20 of the 46 patient groups (43%).
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Two additional patients had evidence supporting a probable association of the suspected drug with their episode of TMA (one attributed to quinine, the other to trimethoprim-sulfamethoxazole). Samples from patients in the Oklahoma Registry are not included in these data. Moreover, according to consensus opinion (Palma et al., 2021), regardless of whether a toxic or immune-mediated form, a trial of TPE is recommended in all patients with a suspected diagnosis of severe DITMA, in addition to suspected-causative drug suspension.
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The poor understanding of the underlying etiopathogenetic mechanisms of DITMA and the absence of clinical trials on this topic are reflected in treatment guidelines not supported by strong scientific evidence. Kidney biopsy is not a requisite when distinct hematologic features of MAHA are in plain view, as histopathology is unlikely to supply the exact cause of TMA. Moreover, thrombocytopenia and anemia can sometimes make the biopsy a risky game. In classic cases, successful empiric treatment itself would clinch the diagnosis. On the other hand, it’s been observed that arterial wall changes are more specific for malignant hypertension (HTN) or scleroderma renal crisis, whereas glomerular changes are more specific for CM-TMA.
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In the column describing the number of drugs, each drug is listed only once according to its highest level of evidence. The analysis of all 387 articles is described, with their citation, in supplemental Table 3. If patients present atypical clinical features of TMA or fail to respond to treatments for idiopathic TMA, some authors recommend searching for systemic malignancy, after excluding other secondary causes 14,141,143,144. Despite the arising number of available drugs in recent years, post-HSCT kidney dysfunction remains a significant complication 138. A retrospective study showed that patients who recover from HSCT-TMA preserve only 40% of initial kidney function 99.
5 Drug Induced TMA
The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels.
The authors represent individuals active in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. All are clinicians involved in treating pediatric or adult patients presenting with TMA. Most are also involved in clinical and/or basic science research in this area, and all are involved in lecturing on related topics at the University, national or international level. Others (e.g., vincristine, adriamycin, and 5-fluorouracil 5-FU) have also been implicated in fewer case reports almost always in the setting of concomitant or recent exposure with the abovementioned agents or antiangiogenic therapy. MAHA, microangiopathic hemolytic anemia; LDH, lactate dehydrogenase; ADAMTS13, a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13. The mortality rate of cancer-related TMA is high due to its association with disseminated malignancies or withdrawal of chemotherapy.
- Glomeruli were globally sclerotic except one with a fibrocellular crescent.
- Additionally, complications of acute infection have been described including macro thrombosis and AKI.
- Failure to recognize a drug as the cause of TMA, especially immune-mediated TMA, may have critical consequences if the patient is reexposed to the drug.
- Interpretation of which treatment provides benefit is difficult in many cases where multimodal treatments are used.
Review of the blood film and early bone marrow biopsy may accelerate the diagnosis of the underlying malignancy 7,14. A kidney biopsy would give precious diagnostic and prognostic information. However, it is not always feasible, mainly because of high bleeding risk 122. In rare cases, tubular reticular inclusions can be found, suggesting a high level of interferon activity, even in the absence of viral infection. Immunofluorescence is generally negative for immune complexes, although there may be unspecific fibrin deposition 8.
However, in all reports of bleomycin and TMA, there is a concurrent drug that could trigger TMA by itself 42,43,46. There is no evidence to define whether TMA is caused by a synergic mechanism. At least one case report reported successfully on the use of eculizumab 57. Kwa et al. 56 reported 3 patients with a biopsy-proven kidney TMA following years of PLD administration and high cumulative doses (880 to 1445 mg/m2).
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A 63-year-old woman with 2 years of stage IIIB serous ovarian carcinoma presented to nephrology clinic for evaluation of AKI. Cancer treatment included debulking surgery followed by adjuvant carboplatin/paclitaxel and then paclitaxel/bevacizumab. Six months before presentation, disease progression prompted treatment change to bevacizumab/gemcitabine, although one month ago, bevacizumab was discontinued due to new-onset difficult-to-control hypertension. Serum creatinine had increased from 0.8 mg/dl (3 months prior) to 2.2 mg/dl with new proteinuria of 8.6 g/g creatinine. Laboratory results revealed decreasing hemoglobin (8.4 g/dl from 12 g/dl) and platelet count (144×1000/µl). Lactate dehydrogenase (705 U/L), reticulocyte count (3.11%), and fibrinogen (492 mg/dl) were elevated.
