Thrombotic Microangiopathy and the Kidney

Etiology

TMAs have commonly been classified into TTP/ADAMTS13 deficiency TMA (congenital or acquired), primary TMA (occurring due to dysregulation of the complement system due to genetic or acquired abnormalities), and secondary TMA (occurring secondary to various triggers or associated diseases). [6] With primary TMAs, approximately 50% to 70% of patients have mutations in complement genes or regulatory proteins. [6] [7] [8] These mutations have incomplete penetrance and often require a “second hit” or environmental trigger to cause TMA. [7]

In contrast to primary TMA, genetic abnormalities in complement or regulatory proteins are typically less common in those with secondary TMA. Consequently, after the environmental trigger or underlying disease process is controlled, secondary TMAs often resolve and have a much lower risk of recurrence. Thus, the additive benefits of anticomplement therapy in secondary TMAs are contentious and should be considered on a case-by-case basis. [6] [8]

More recently, a working group of international multispecialty TMA experts supported by the National Kidney Foundation (NKF) proposed a new etiology-based classification for TMA. Specifically, the expert panel recommended discarding the term “atypical" HUS since it is nonspecific and does not reflect the underlying pathophysiology. Below is the proposed etiology-based classification for TMA from the NKF Working Group. [4]

Known Etiology

Thrombotic thrombocytopenic purpura (ADAMTS13 deficiency)

• Hereditary
  • Mutation in ADAMTS13 gene
• Acquired
  • Autoantibodies to ADAMTS13
• Please see StatPearls' companion review, " Thrombotic Thrombocytopenic Purpura," for further information.

Complement-mediated TMA

• Genetic TMA
• Acquired factor H autoantibody-associated TMA
• Nongenetic CM-TMA

Genetic non-CM-TMA

• Examples include diacylglycerol kinase epsilon-TMA, TSEN-TMA, interferon-TMA, EXOSC3-TMA.

• MMACHC gene mutations increase the risk of cobalamin deficiency-associated TMA.

Metabolic-associated TMA

• Cobalamin deficiency: This deficiency can present in childhood and adulthood (as noted above, the risk is increased with mutations in the MMACHC gene).

Predisposing Conditions

These forms may need additional diagnostic tests such as genetic predispositions, complement dysregulation, metabolic disease, or other testing to further define their etiology. Overlap with categories above from "Known Etiology" also exists. For example, infection-associated TMA often causes abnormal complement activation, and many patients who develop TMA after a hematopoietic stem cell transplant have a genetic predisposition to abnormal complement regulation. [7]

• Transplant-associated TMA
  • Hematopoietic stem cell transplant: TMA occurs in up to 40% of allogeneic stem cell transplants. [9]  This condition occurs due to an underlying genetic predisposition (hit 1), use of a conditioning regimen that includes chemotherapeutic agents and total body irradiation (hit 2). Associated conditions (eg, use of calcineurin inhibitors [CNIs] /mammalian target of rapamycin [mTOR], infections) can further activate the complement system .
  • Solid organ transplant: TMA after solid organ transplant can be multifactorial due to drugs (particularly CNI or mTOR use), infections, or antibody-mediated rejection. TMA has been reported to occur in up to 14% of patients after a kidney transplant, about 4% after a liver transplant, and 2.3% after a lung transplant. Complement gene mutations increase the risk of developing TMA. TMA commonly occurs in the first 3 months after transplant but can appear at any time in the posttransplant course. Posttransplant TMA can be recurrent or de novo. Recurrent TMA is almost always complement-mediated (due to underlying genetic mutations), while de novo TMA may be complement-mediated or secondary to the associated conditions or triggers mentioned above. Complement activation may also play a role in de novo TMAs. [10]

• Pregnancy-associated TMA
  • Preeclampsia. Please see StatPearls' companion reviews, " Thrombocytopenia in Pregnancy" and " Preeclampsia." Pregnancy and the postpartum period are considered a high-risk time for TMA development. Pregnancy-associated TMAs include TTP, HELLP (hemolysis, elevated liver enzymes, and low platelet count), atypical hemolytic uremic syndrome (aHUS)/CM-TMA, and TMA associated with antiphospholipid syndrome.
  • Pregnancy, particularly the postpartum period, is considered one of the major triggers for CM-TMA as the levels of many complement proteins (which increase during pregnancy) decrease during the postpartum period. Complement activation can also occur due to an imbalance in the production between anti-angiogenic (soluble Feline McDonough sarcomas, like tyrosine kinase-1) and pro-angiogenic factors (vascular endothelial growth factor [VEGF] and placental growth factor). [11] [12]
  • HELLP syndrome is a serious pregnancy complication. Please see StatPearls' companion reference, " HELLP Syndrome."
  • Triggering of catastrophic antiphospholipid syndrome, aHUS, or TTP can also occur during pregnancy. Please see StatPearls' companion reference, " Antiphospholipid Syndrome."

• Hypertension-associated TMA
  • Hypertension is speculated to cause TMA due to the mechanical shear stress on the endothelium. Although hypertension could be the cause in some patients, investigating for other etiologies is strongly recommended, as complement abnormalities have been identified in 35% to 65% of patients who develop TMA in the setting of malignant hypertension. TMA features will persist in these patients despite blood pressure control beyond 48 to 72 hours. Therefore, identifying these patients is important from both therapeutic and prognostic standpoints because they can benefit from complement inhibition. [13]

• Drug-induced TMA 

  • This may be immune-mediated or direct toxicity-mediated. Immune-mediated TMA occurs due to the production of antibodies against the drug (or its metabolite). This condition is often associated with sudden onset of severe symptoms within hours or days after drug exposure. These antibodies can interact with platelets or circulating factors and cause endothelial injury. Direct toxicity-mediated TMA occurs due to cumulative effect dose and can occur at any time after being on the medication. [6] [14]

  • Mechanisms include direct endothelial damage and interruption of various pathways, such as VEGF, mTOR pathway, or deregulation of transcription factors (eg, nuclear factor-kappa B). TMA after an mTOR or calcineurin inhibitor (eg, drugs specifically relevant to transplant) use can also occur due to arteriolar vasoconstriction and endothelial injury, which can result in Von Willebrand factor multimer release, thereby causing platelet aggregation and complement activation (due to the complement-coagulation crosstalk). [15]

  • Common drugs that are associated with TMA include the following:

    • Chemotherapeutic agents: tyrosine kinase inhibitors, vascular endothelial growth factor (VEGF) inhibitors, immune checkpoint inhibitors  [14]
    • Immunosuppressive agents: calcineurin inhibitors, interferon-β, sirolimus
    • Antibiotics: penicillin, ciprofloxacin, levofloxacin, metronidazole, nitrofurantoin  [6]
    • Illicit drugs: cocaine, ecstasy

• Vasculitis/autoimmune disease associated TMA
  • Autoimmune diseases commonly associated with TMA include systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and scleroderma. TMA has also been reported to be associated with immunoglobulin A nephropathy, antineutrophil cytoplasmic antibodies-associated vasculitis, membranous nephropathy, and focal segmental glomerulosclerosis.
  • The pathophysiology of TMA in these diseases is multifactorial. Deficiency of early complement components (such as C1q, C2, or C4) in SLE can promote the generation of autoantibodies that can form immune complexes and trigger complement activation. Neutrophil extracellular traps (NETs) have also been implicated to play a role in TMA pathogenesis in these conditions since NETs incorporate complement components such as C3 cleavage products, properdin, and factor B, which can together form a C3 convertase leading to excessive complement activation. Genetic defects in the complement pathway genes have also been identified in a subset of these patients. [16] [17]

• Cancer-associated TMA
  • TMA in patients with cancer can be due to chemotherapy or due to the direct effect of the tumor. [18] [19]
  • Cancers associated with TMA typically include the following:
    • Solid organ malignancy: breast, lungs, stomach, prostate, and ovaries
    • Hematologic: monoclonal gammopathies and lymphoproliferative disorders (leukemia, lymphoma) 
  • Possible mechanisms involve abnormal angiogenesis in the marrow that can lead to endothelial injury of the marrow vasculature by direct invasion. Additionally, microvascular tumor emboli, procoagulants produced by tumor cells, and impaired fibrinolysis have also been implicated. TMA associated with hematologic malignancies is speculated to be either due to monoclonal immunoglobulins causing direct endothelial injury, functioning like anti-complement antibodies, or inhibiting ADAMTS13.

• Infection-associated TMA
  • TMA can be associated with a wide range of infections, including the following: Shiga toxin-producing Escherichia coli, pneumococcal, influenza, human immunodeficiency virus, COVID, dengue virus, or cytomegalovirus infection.
  • Shiga toxin binds to endothelial cells and releases tissue factor and von Willebrand factor, thereby creating a prothrombogenic environment.
  • Pneumococcal and influenza infections are known to cause the production of neuraminidase, which cleaves sialic residues from red cells and platelets and decreases factor H binding, leading to endothelial damage and impaired complement regulation. [20]
  • Other mechanisms of infectious disease-associated TMA can include the activation of platelets, generation of thrombin, or development of ADAMTS13 inhibitors. [21] [22]

Epidemiology

CM-TMA is a rare disease. Annual incidence rates are variable due to imprecise nomenclature affecting cohort inclusion or exclusion criteria and difficulty of diagnosis but typically range from 0.2 to 2 cases per million depending on age and geographic region.[4][23][24] Furthermore, the etiology of the disease varies based on age. CM-TMA has more diverse etiologies in adults, as noted in the preceding section. Among children, there is no gender discrepancy, while in adults, a female preponderance is present, particularly in the child-bearing years.[25][26][27] Extra-renal manifestations are common and occur in 20% of cases.[28]

Pathophysiology

The underlying pathophysiology of TMA involves endothelial injury causing microthrombi formation and platelet consumption. These microthrombi can mechanically damage erythrocytes to form schistocytes, in addition to causing ischemic end-organ damage. TTP has a genetic (homozygous or heterozygous gene variants) or acquired (inhibitory autoantibodies) deficiency of ADAMTS13. Under normal circumstances, endothelial cells release von Willebrand factor (vWF), folded ultra-large multimers, from Weibel-Palade bodies. With blood flow, shear stress unfolds vWF and exposes cleavage sites for ADAMTS13 to snip into smaller multimers. With reduced ADAMTS13 activity, the Von Willebrand factor unfolds and adheres to circulating platelets to form thrombi, further increasing shear stress, platelet aggregation, and microthrombi formation, eventually leading to ischemic tissue damage.

In CM-TMA, there are genetic (complement gene mutations) or acquired factors (autoantibodies) that cause dysregulation of the complement system's alternative pathway, leading to endothelial injury. Other pathophysiological mechanisms include direct toxicity or immune-mediated injury in drug-induced TMA, platelet activation, thrombin generation, complement evasion, and direct endothelial invasion in infection-associated TMA. Metabolic causes of TMA have also been described, along with varied underlying pathophysiological mechanisms.[6][8]

Histopathology

Biopsies are often not performed with severe thrombocytopenia; biopsies may be skewed towards those without hemolytic uremic syndrome or TTP.[3] The kidney-related histopathologic features reflect endothelial injury occurring in the glomeruli or arterioles. In the acute phase, the glomerular capillary wall thickens from endothelial cell swelling, subendothelial accumulation of acellular material, and mesangiolysis. Microthrombi may be present in glomerular capillaries, although their absence does not exclude the diagnosis. Generally, there is no mesangial or endocapillary hypercellularity. If arterioles are involved, they may have fibrinoid necrosis (especially in afferent arterioles), and arterial/arteriolar intimal swelling may be present.[3] 

With chronicity, there is duplication or “double contouring” of the glioblastoma from new subendothelial basement membrane formation. This appears as a membranoproliferative pattern without immune deposits and requires further examination by immunofluorescence and electron microscopy. Additionally, an “onion-skinning” appearance of interlobular and arcuate arterioles may form from myointimal hyperplasia.[12] Immunofluorescence will be negative for immunoglobulin or complement staining. Electron microscopy may show subendothelial electron-lucent material corresponding to the "double contours" seen in light microscopy; electron-dense deposits should not be seen.[3] 

History and Physical

TMA can be a very challenging diagnosis and consequently often goes unrecognized. Although the typical presentation involves non-immune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, less severe and incomplete presentations have been described. In addition, renal-limited forms of TMA exist that are only identified on a kidney biopsy and lack hematologic manifestations. Often, the earliest manifestation of disease may be new-onset or worsening of previously controlled hypertension. Hence, comprehensive history taking and a physical exam are essential to properly diagnosing this condition. 

Triggering Factors

A patient should be asked about these potential triggering factors:

• Recent illnesses or infections
• Newly prescribed medications or illicit substance use
• Newly diagnosed or exacerbation of previously well-controlled hypertension
• Exacerbations of chronic illnesses (particularly autoimmune disorders, ie, lupus or antiphospholipid syndrome)
• History of malignancy
• Prior history or family history of TMA
• Unusual food consumption or exposure to potential food poisoning

History

Immediate history may include fevers, chills, nausea, vomiting, diarrhea, palpitations, abdominal pain, bleeding from the gums, bruising, swelling of the extremities, discolored or decreased urine, and confusion.

Physical

Physical findings also depend on the etiology but may involve the following organ systems. 

• Systemic findings: lethargy, fevers, confusion
• Dermatologic: (most common finding) petechiae, purpura, bruises, pallor (from anemia), jaundice (from hemolysis)
• Neurologic: focal deficits, seizures (in severe cases)
• Renal: hypertension, hematuria, oliguria
• Cardiovascular: tachycardia, edema
• Gastrointestinal: vomiting, diarrhea, blood in the stool (especially with Shiga toxin-related hemolytic uremic syndrome)

Evaluation

TTP is a medical emergency requiring urgent intervention. Therefore, a predictive scoring system like PLASMIC or the French TMA scoring system can be used to assess its likelihood while ADAMTS13 activity levels are pending. One suggestion is to treat anyone with a PLASMIC score greater than 5 empirically for TTP.[29][30][31] Please see StatPearls' companion reference, "Thrombotic Thrombocytopenic Purpura," PLASMIC score section, for details on this scoring system.

 Laboratory evaluation

• Complete blood count for anemia, thrombocytopenia (<150K or >25%-50% decrease from baseline), and reticulocytosis
• Hemolysis markers: lactate dehydrogenase, low haptoglobin, high indirect bilirubin
• Peripheral smear 1% or higher schistocytes
  • Less than 1% of schistocytes can be present in chronic kidney disease, liver disease, and prosthetic valves.
• Coagulation profile to rule out disseminated intravascular coagulation
• Coombs test to rule out immune hemolytic anemia
• ADAMTS13 level/activity
• Antiphospholipid antibody testing
• Vitamin B12 and homocysteine levels
• If indicated, testing for autoimmune diseases (eg, antinuclear antibody for lupus)
• Urinalysis for proteinuria and hematuria
• Stool studies (for STEC-HUS, and viral serologies)
• Complement investigations
  • Genetic testing for complement variants (confirms a diagnosis of TMA and provides prognostic information regarding the risk of progression to end-stage renal disease, risk of relapse in the native kidney, or recurrence after a kidney transplant)
  • Testing for acquired factors (commonly factor H autoantibody)
  • Serum antigenic level of complement proteins (C3, C4, factor H, factor I, factor B, properdin) and cell surface expression of membrane cofactor protein (membrane cofactor protein, cluster of differentiation 46 using flow cytometry)
  • Complement functional assays: 50% hemolytic complement (classical), alternative pathway method (alternative), hemolytic assays, recombinant production of the variant followed by in vitro functional assays

Kidney Biopsy

If clinical suspicion remains high and laboratory evaluation is equivocal, a kidney biopsy can be considered (if thrombocytopenia is not a limiting factor). Results from a French retrospective study reported a 45% incidence of renal-limited TMA.[32]

Treatment / Management

Management of TMA is variable depending on the etiology of the TMA or any potential genetic involvement.[6] Management of TTP, particularly immune-mediated, typically involves therapeutic plasma exchange (TPE) and immunosuppression with corticosteroids with or without rituximab.[6][7][13][33] Additionally, caplacizumab can be considered; this medication is an immunoglobulin preventing the vWF-platelet glycoprotein Ib interaction and consequent microvascular thrombosis.[34][35](B3)

Congenital or hereditary forms of TTP are managed with plasma infusions to replenish ADAMTS13 levels.[7][12][13][33] In severe cases, plasma exchange may be considered to remove vWF multimers.[12] Additionally, case reports and results from a recent phase 3 study suggest a potential role for recombinant ADAMTS13 in management.[12][36] (B3)

Addressing the underlying conditions or precipitating factors is an essential first step in TMAs associated with other etiologies.[6] If the TMA persists or has a severe presentation, anti-complement therapy with eculizumab or the longer-acting eculizumab (both are C5 complement stabilizers) can be considered.[6][37] See Table. Different TMA Syndromes and Suggested Treatment Options, which highlights the different management options for different TMA syndromes.(B3)

Table. Different TMA Syndromes and Suggested Treatment Options

Differential Diagnosis

Early identification and treatment of thrombotic microangiopathies is essential. However, TMA is a heterogeneous disorder with diagnosis primarily dependent on nonspecific markers of endothelial injury. Thus, many disorders can mimic TMAs and must be differentiated to ensure appropriate and timely treatment. These disorders and specific investigations to differentiate them from TMA are summarized in Table. Differential Diagnosis of TMA below.

 Table. Differential Diagnosis of TMA

Prognosis

TMA was previously associated with very high rates of morbidity and mortality. However, the introduction of anti-complement therapy, therapeutic plasmapheresis (TPE), and immunosuppressive therapies have led to significant decreases in these rates. While TTP was once a nearly fatal diagnosis, it still has a mortality rate of up to 20% with TPE and maximal treatment, leaving room for improvement.[34][39][35][39]

Similarly, CM-TMA was reported to have a 25% mortality, 50% risk of progression to end-stage renal disease (ESRD), and a 60% to 90% risk of recurrence with subsequent allograft loss in the absence of timely treatment.[39][40] With anti-complement therapy, comparable improvements have been observed in reducing morbidity and mortality. Results from a United Kingdom cohort study reported that eculizumab therapy had improved 5-year ESRD-free survival in patients with complement gene mutations or factor H autoantibodies from 40% to 85%.[4][41]

With anti-complement therapy, hematologic response typically occurs within 1 week and kidney recovery within 30 days (but can occur up to 6-12 months after treatment).[4][40][41] However, age at presentation, early disease recognition and initiation of eculizumab, presence of complement gene mutations, and severity of kidney injury are among key predictors of treatment response. Despite anti-complement therapy, 30% of patients may develop advanced chronic kidney disease (stage 3-5), and 20% may be left with permanent kidney injury.[4][39]

Complications

If left untreated, TMA can lead to widespread organ damage, including thrombotic complications, kidney fibrosis, kidney failure, and ESRD requiring dialysis with poor outcomes. Anticomplement therapy carries the risk of infections and is costly, posing a significant physical and psychological burden on patients and their families. Even after kidney transplantation, some forms of TMA can recur, worsening outcomes.