Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Abstract

Thrombotic microangiopathy (TMA) is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys. This review is specifically focused on post-transplant TMA (PT-TMA) involving kidney transplant recipients. Its reported prevalence in the latter population varies from 0.8% to 14% with adverse impacts on both graft and patient survival. It has many causes and associations, and the list of etiologic agents and associations is growing constantly. The pathogenesis is equally varied and a variety of patho genetic pathways lead to the development of microvascular injury as the final common pathway. PT-TMA is categorized in many ways in order to facilitate its management. Ironically, more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case. Pathologically, the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature. Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists. The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase. Management of the condition is also challenging and still largely empirical. It varies from simple maneuvers, such as plasmapheresis, drug withdrawal or modification, or dose reduction, to lifelong complement blockade, which is very expensive. A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective. This review aims to increase the awareness of relevant stakeholders regarding this important, potentially treatable but under-recognized cause of kidney allograft dysfunction.

Keywords: Anemia; Kidney allograft failure; Microvascular injury; Thrombocytopenia; Thrombotic microangiopathy.

Figure 1

Common causes of thrombotic microangiopathies.

Figure 2

Glomerular lesions in thrombotic microangiopathies. A: High-power view showing a glomerulus containing fibrin thrombi in dilated capillaries at 9 to 12’O clock position (H&E, × 400); B: The same glomerulus on trichrome staining showing fibrin thrombi staining red with this stain (Masson’s Trichrome, × 400); C: Medium-power view showing one ischemic glomerulus and an arteriole exhibiting mucinous intimal thickening (H&E, × 200); D: Medium-power view showing completely infarcted glomerulus and an adjacent infarcted arteriole containing intraluminal fibrin thrombus. (H&E, × 200).

Figure 3

Vascular lesions in thrombotic microangiopathies. A: Medium-power view showing a glomerulus with an arteriole containing fibrin thrombi in acute phase of thrombotic microangiopathies (TMAs) (H&E, × 200); B: High-power view showing an arteriole with endothelial swelling and complete occlusion of the lumen. An adjacent small artery shows marked mucinous thickening of the intima with narrowing of the lumen (H&E, × 400); C: High-power view showing a small artery with fibrinoid necrosis of the vessel wall and intimal proliferation (H&E, × 400); D: Medium-power view showing fibrointimal thickening of an interlobular size artery in chronic phase of TMA. Mild tubular atrophy is seen in the background (Silver stain, × 200).

Figure 4

An algorithmic approach to diagnosis, classification and treatment of posttransplant thrombotic microangiopathy. ADAMTS13: A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13; AMR: Antibody-mediated rejection; IMS: Immunosuppression; LDH: Lactate dehydrogenase; MCP: Membrane cofactor protein; PT-TMA: Posttransplant thrombotic microangiopathy; SPEP: Serum protein electrophoresis; TMA: Thrombotic microangiopathy; UPEP: Urine protein electrophoresis; VUS: Variant of unknown significance.

Figure 5

Summary of the main etiologic agents and types of posttransplant thrombotic microangiopathy and their treatment and preventive strategies. CFB: Complement factor B; CFH: Complement factor H; CNI: Calcineurin inhibitor; IVIG: Intravenous immunoglobulin; mTOR: Mammalian target of rapamycin; TTP: Thrombotic thrombocytopenic purpura.