New Insights into TMA in Kidney Transplantation

Thrombotic microangiopathy (TMA) is a clinicopathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, occurring due to endothelial damage and microthrombi formation in small vessels (1, 2). It can affect up to 15% of transplanted patients and is associated with significant morbidity and mortality (3).

TMA is primary when a genetic or acquired defect is identified (as in atypical hemolytic uremic syndrome [aHUS] and thrombotic thrombocytopenic purpura) or secondary when occurring in the context of another disease process, such as infection, autoimmune disease, malignancy, or drugs (4) (Table 1). This classification is not absolute because genetic defects have been identified in secondary TMA (6). Kidney transplantation poses a challenging setting due to multiple potential triggers for TMA development (Table 1). Posttransplant TMA can be recurrent or de novo. Recurrent TMA is almost always complement mediated, whereas de novo TMA may be complement mediated or secondary to triggers. De novo TMA is reported in 1%−15% of patients, although the true frequency is unknown, and the implication of a dysregulated complement system may be underestimated (7). We have identified patients carrying a complement genetic variant who did not manifest TMA in the native kidneys but developed posttransplant disease in the setting of multiple triggers (unpublished results). Therefore, all patients presenting with “de novo TMA” should undergo genetic testing for complement disorders. Differentiating between a primary complement-mediated process and one triggered by secondary factors is critical to minimize allograft damage since the former is non-responsive to supportive therapy and has a high risk of recurrence.

Table 1

Causes of thrombotic microangiopathy (TMA)

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Clinical features of TMA range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations (8). TMA commonly occurs in the first 3 months but can appear at any time in the posttransplant course. An update on the most common TMAs associated with kidney transplantation is presented below.

Complement-mediated TMA (aHUS) stems from a dysregulated complement system due to genetic variants in complement proteins or due to acquired defects (such as factor H autoantibodies), which predispose patients to endothelial damage. However, less than 50% of the identified variants have a known functional consequence and are therefore classified as variants of uncertain significance (VUSs). The presence of VUSs is vexing for clinical management. Laboratories that specialize in functional analysis of genetic variants can assist in defining the significance of the variant. Eculizumab should be initiated early to offer the best chance of renal recovery, and duration depends on the underlying genetic abnormality (Figure 1).

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Guidelines for duration of eculizumab in kidney transplantation

Citation: Kidney News 14, 8

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Drug-induced TMA can occur after calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor use and is commonly direct toxicity mediated due to arteriolar vasoconstriction and endothelial injury (10). The endothelial injury results in release of von Willebrand factor multimers overwhelming the capacity of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), thereby causing platelet aggregation and complement activation (due to the complement-coagulation crosstalk). Management involves supportive care and withholding the causative medication. Case reports have shown resolution of TMA when the CNI was switched (for example, from tacrolimus to cyclosporine) (11, 12). It is my speculation that patients who responded to the drug change developed TMA from a combination of triggers in the early posttransplant phase but did not manifest disease when a CNI was introduced later in the course (in the absence of triggers). Some centers would consider switching to belatacept if CNI-induced TMA is suspected. ADAMTS13 assay and genetic testing should be undertaken in cases that do not respond to conventional treatment. As a gentle reminder, all clinicians should ask for other agents in the medications list that can also cause TMA, such as quinine.

Antibody-mediated rejection (AMR)-associated TMA has the highest risk for premature graft loss compared with other TMAs (13, 14). Concomitant rejection is believed to be the main driver for kidney failure with an aberrant humoral alloimmune response being the most important risk factor (because donor-specific antibodies can bind to human leukocyte antigens on the endothelium and activate complement). C4d staining and presence of donor-specific antibodies help to distinguish AMR-associated TMA from other causes. Transplant glomerulopathy may represent a chronic smoldering form of TMA (the pathology pattern of injury is membranoproliferative glomerulonephritis).

Infection-associated TMA can occur due to direct endothelial injury (because of virus tropism), platelet activation and generation of thrombin, development of ADAMTS13 inhibitors, and complement activation. Cytomegalovirus (CMV) is most frequently associated with TMA after transplantation and typically responds to anti-viral treatment. TMA can also occur after COVID-19 due to the combined effects of complement activation, dysregulated neutrophilia, endothelial injury, and hypercoagulability induced by coronaviruses (15). Supportive management and treatment of the underlying infection should be the initial focus. Testing for complement genetic variants should be conducted when the clinical picture is unusually severe.

A high degree of suspicion is needed for prompt recognition and treatment of TMAs. A thorough systematic approach can help make the correct diagnosis and facilitate individualized treatment decisions for patients (Figure 2).

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Approach to diagnosis of posttransplant TMA

Citation: Kidney News 14, 8

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