Functional analysis of VUSs can assist in defining the significance of the variant and helping to re-classify them as pathogenic or benign. Complement-mediated TMA (CM-TMA) results from dysregulation of the complement system, mainly the alternative pathway, which then leads to inappropriate activation of the terminal pathway. In Primary TMA, alternative pathway dysregulation can be genetic (due to mutations in complement proteins), acquired (due to autoantibodies against complement proteins), or idiopathic. The alternative pathway was an MVP in NephMadness 2019 for the Complement Region. To refresh our memory, let’s play a game of “Alternative Basketball” (Figure 2).
Platinum-based Drugs
However, less than 50% of the genetically identified variants have a known functional consequence. Computational prediction algorithms are used to predict the potential impact of these “variants of uncertain clinical significance” (VUS) on the mature protein. The presence of such variants is particularly vexing for clinical management.
- Haemolytic uraemic syndrome (HUS) is a triad of thrombocytopenia, MAHA, and acute renal failure.
- Narsoplimab has been recently investigated in a phase 2 study for the treatment of different patterns of microangiopathy and was converted into a pivotal trial for TA-TMA only upon request to the U.S.
- Moore et al. 79 reported a patient with a syndrome similar to TTP with autoantibodies directed to ADAMTS13.
- One published report of gemcitabine-mediated TMA described the clinical features of an acute, immune-mediated mechanism;(22) the other 5 patients had the clinical features of a chronic, dose-dependent toxic mechanism.
- If none of these infections is present, there is a suspicion of an atypical hemolytic uremic syndrome (aHUS), also referred to as complement-mediated HUS (cmHUS) (7).
MCM, AG, AA, FL, MCF, BR, and GR contributed to screening potentially eligible adult patients, treating them with the drug, and monitoring them. FV, MV, SB, AB, AB are responsible for screening eligible pediatric patients for treatment, administering therapy, and monitoring. PT contributed to histological diagnosis, providing photographs of biopsies, and their description. CP is responsible for statistical analyses and contributed to data extraction. Throughout treatment with narsoplimab no safety signals of concern were observed. This safety profile is particularly significant for HSCT recipients, a population prone to severe infections, especially while undergoing immunosuppressive therapy such as CNIs.
Malignant Hypertension
As with aTTP, patients with cTTP (Upshaw–Schulman syndrome) require plasmapheresis—possibly followed by long-term treatment with repetitive plasma infusions—if they sustain organ damage. Asymptomatic patients with no signs of hemolysis and normal platelet counts may undergo watchful waiting without plasma infusions (15). Immunosuppressive therapy is not useful in cTTP, as there are no autoantibodies to be targeted. The establishment of a nationwide registry in Germany with an attached biobank might help reveal yet unknown genetic predispositions.
TMA investigation will only be pursued if a complete anamnesis and physical examination allows for a high grade of suspicion. This is an important aspect due to the fact that TMA is the presentation of many different diseases, with a wide differential diagnosis that demands a multidisciplinary approach 4. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Recent research developments have revolutionized the understanding of the disease processes and lead to the development targeted therapeutics for TMAs. These therapies have markedly improved morbidity and mortality from disease. We are the EMCrit Project, a team of independent medical bloggers and podcasters joined together by our common love of cutting-edge care, iconoclastic ramblings, and FOAM.
Role Of Calcineurin Inhibitors
Patients typically present with hemolysis after exposure to an infection or drug, sometimes accompanied by thrombocytopenia and ATN. Finding G6PD deficiency by measuring G6PD activity in red blood cells once TMA is in remission can spare a patient with TMA the risk and cost of long-term complement blockade. In STEC-HUS, Shiga toxin translocates from the gut, combines with glycolipid Gb3 in the circulation, enters endothelial cells via GB3 receptor, and creates havoc disrupting protein synthesis and egging on tissue factor and von Willebrand factor release. In a fascinating move, Shiga toxin can also bind to Factor H on endothelial surfaces, thus bringing complement into the game.
Fresh Frozen Plasma Infusion While Waiting For Plasma Exchange
A diagnostic and therapeutic algorithm, as well as a classification of thrombotic microangiopathies, are shown in Figure 1, Table 1, eTable 2, and eTable 3, and the relevant differential diagnoses, in eTable 1. The establishment of a nationwide disease registry in Germany with a biobank would now be desirable. HELLP is a more severe form of the disease spectrum, which can lead to a glomerular endotheliosis. There is known endothelial dysfunction thought to be due to greater circulating levels of the soluble form of the vascular endothelial growth factor receptor (sFlt‐1), syncytiotrophoblast‐derived antiangiogenic factors and soluble endoglin. During the last decade, laboratory criteria have been added to support the causal relationship between a drug and TMA (2).
Cancer-associated Thrombotic Microangiopathies
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. Therefore, a biopsy should be considered when the clinical picture is ambiguous, there is no response to definitive therapy, the degree of reversibility of kidney injury is unclear, or a second pathology is suspected. For this study we included all patients enrolled through 2014 with their first episode of clinically suspected acquired TTP (475 patients) and also all patients in whom TMA was first identified by a kidney biopsy (12 patients). Not included in this study were the 12 patients who were enrolled at the time of a recurrent episode of TTP.
Immunosuppressive Therapy
We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy.
Treatment Schedule
Cetuximab and trastuzumab have been implicated in DiTMA in case reports. Additional cases are essential to attribute TMA to these drugs 86, 87. Gemcitabine-induced TMA clinically presents as a predominantly kidney-limited disease, with AKI in almost every patient, frequently requiring haemodialysis.
However, metastatic disease is more common in cancer-related TMA, whereas in chemotherapy-induced TMA, little or no active malignancy is detectable 10. While discontinuation of the offending drug and supportive care are the primary treatment options in drug-induced TMA, in some cases this intervention is unable to limit the already dysregulated complement activity and requires therapeutic complement inhibition. The term thrombotic microangiopathy describes an etiologically very heterogeneous group of diseases (table 1), which in the presence of endothelial damage can lead to thrombosis of small and micro vessels, both arterial and venous. Microangiopathy can lead to secondary consumption of platelets and mechanical hemolysis. Thrombotic microangiopathy is defined by the triad of Coombs-negative hemolytic anemia with evidence of schistocytes in the blood, thrombocytopenia (microangiopathic hemolytic anemia), and ischemic end-organ damage. Depending on the vascular systems involved, renal failure, neurological symptoms, cardiac complications, respiratory failure, visual disturbances, pancreatitis, intestinal ischemia, and (less commonly) skin changes may occur (1, 2).
During 47 months of follow-up, renal function continued to improve (eGFR 68 mL/min), and no relapse of TMA has occurred (Figure 1A) (Table 2). In contrast, HUS most often occurs when your body is exposed to a certain type of toxin (Figure 4). Generally this infection must be serious enough to cause bloody diarrhea. The toxin makes its way into the blood stream and then damages endothelial cells in the kidney. This triggers platelets to clot and red blood cells to burst as described above. MC, GG, and AR are responsible for designing the review protocol, writing the protocol and report, conducting the search, extracting, and analyzing data, interpreting results, updating reference lists, and creating tables and figures.
