key: cord-1023315-krxj4t4g authors: Palma, Lilian Monteiro P.; Sridharan, Meera; Sethi, Sanjeev title: Complement in secondary thrombotic microangiopathy date: 2020-10-21 journal: Kidney Int Rep DOI: 10.1016/j.ekir.2020.10.009 sha: 8820df9820ee111941bca53b490764baa0ec7ee1 doc_id: 1023315 cord_uid: krxj4t4g Thrombotic microangiopathy (TMA) is a condition characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with varying degrees of organ damage in the setting of normal International Normalized Ratio (INR) and activated Partial Thromboplastin Time (aPTT). Complement has been implicated in the etiology of TMA, which are classified as Primary TMA - when genetic and acquired defects in complement proteins are the primary drivers of TMA (complement-mediated TMA or atypical hemolytic uremic syndrome, aHUS) or Secondary TMA, when complement activation occurs in the context of other disease processes, such as infection, malignant hypertension, autoimmune disease, malignancy, transplantation, pregnancy and drugs. It is important to recognize that this classification is not absolute as genetic variants in complement genes have been identified in patients with secondary TMA, and distinguishing complement/genetic-mediated TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. In this review, we focus on data supporting the involvement of complement in aHUS and in secondary forms of TMA associated with malignant hypertension, drugs, autoimmune diseases, pregnancy and infections. In aHUS, genetic variants in complement genes are found in up to 60% of patients, whereas in the secondary forms the finding of genetic defects is variable, ranging from almost 60% in TMA associated with malignant hypertension to less than 10% in drug-induced TMA. Based on these findings, a new approach to management of TMA is proposed. Thrombotic microangiopathy (TMA) is an overarching term used to describe any condition characterized by non-immune thrombocytopenia and microangiopathic hemolytic anemia (MAHA)(1) with varying degrees of organ damage in the setting of normal Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) (2) . Thrombocytopenia due to peripheral consumption should also be ruled out. Although microthrombi in tissue specimensmainly kidney biopsies -is the hallmark of TMA (Figure 1 ), TMA is often inferred from the observation of thrombocytopenia and MAHA in the appropriate clinical setting. Determining the underlying etiology can be a major challenge but is important for directed therapy. One of the most useful classifications is that originally proposed by Nester and George (3) , which was subsequently modified by others grouping TMA into primary (genetic and acquired) and secondary causes(4, 5) ( Figure 2 ). Primary genetic causes of TMA include: 1) deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type-1 repeats, 13th member), which is seen in congenital thrombotic thrombocytopenic purpura (TTP) (6) ; 2) complement-mediated HUS, also known as atypical hemolytic uremic syndrome (aHUS), which is driven by abnormalities in complement genes; 3) and a few rare diseases such as cobalamin C (cblC) deficiency, which is most commonly due to mutations in the MMACHC (methylmalonic aciduria cblC type with homocystinuria) gene, mutations of DGKE (diacylglycerol epsilon), and mutations in the INF2 (inverted formin 2) gene. Primary acquired causes of TMA include: 1) TTP secondary to autoantibodies to ADAMTS13 (acquired TTP); 2) complement-mediated HUS secondary mainly to autoantibodies to factor H (FH). Secondary TMA signifies a TMA occurring in the context of another disease process, such as infection, malignant hypertension, autoimmune disease, malignancy, transplantation, pregnancy and drugs. It is important to recognize that this classification is not absolute as genetic variants in complement genes have been identified in patients with secondary TMA associated with pregnancy, transplantation, infections, systemic and glomerular diseases and J o u r n a l P r e -p r o o f malignant hypertension, suggesting an overlap between primary and secondary TMA and illustrating the importance of genetic background in disease susceptibility. Regardless of etiology, TMA is frequently associated with increased mortality or endorgan damage (7) (8) (9) (10) (11) . While TTP (12) , STEC-HUS (13) (14) (15) and Streptococcus pneumoniaeassociated HUS (16) have well established diagnostic tests and treatment guidelines, distinguishing aHUS and other genetic types of TMA from secondary causes of TMA can be challenging and lead to potentially harmful delays in treatment. Cavero et al.(17) have demonstrated that patients with secondary TMA respond to eculizumab as a temporary approach to complement blockade (18) . In this article, we will focus on data supporting the involvement of alternative complement pathway in secondary forms of TMA associated with malignant hypertension, drug exposure, autoimmune diseases, pregnancy, IgA Nephropathy and infections. For an in-depth overview of specific analysis of complement pathways, we recommend the manuscripts from Skattum et al (19) and Angioi et al (20) . Thrombotic Microangiopathy -aHUS is a disease characterized by dysregulation of the alternative pathway of complement on cell surfaces. Uncontrolled activity of the terminal complement pathway leads to the generation of massive amount of Membrane Attack Complex (MAC) with consequent damage to endothelial cells and the generation of fibrin thrombi in the microvasculature (21) , culminating in platelet adhesion, mechanical intravascular destruction of erythrocytes and tissue ischemia. There is no diagnostic test that conclusively confirms aHUS and the diagnosis is considered to be one of exclusion. Genetics: Although genetic data is useful in diagnosis of aHUS, the absence of detectable mutations in complement proteins does not rule out aHUS as genetic abnormalities are only J o u r n a l P r e -p r o o f identified in about half of patients (7, 8, (22) (23) (24) (25) (26) (27) . Genetic data can be broadly divided into inactivating mutations in genes that encode complement regulating proteins such as CFH, CFI and MCP or a gain-of-function mutations in genes that encode complement activating proteins such as C3 and CFB (Figure 3 ). The penetrance of aHUS in families is very complicated and has been estimated to be 50% (7) . In light of incomplete penetrance, the current hypothesis is that the development of aHUS requires 'two hits' (combination of genetic background and a trigger). Approximately 50% of cases are triggered by infections (8, 28) . Pregnancy is another frequent trigger for women and most will present in the post-partum period(29) (see below). CFH mutations can result in either aHUS or C3G. In aHUS the mutations tend to be missense mutations involving the C-terminus of CFH with normal CFH regulatory activity in plasma (but limited capacity to protect cells at tissue level) whereas in C3G the mutations tend to be at the N-terminus of CFH with decreased complement regulating activities of CFH in the plasma (fluid phase dysregulation) (30) . Medical Genetics and Genomics (ACMG) guidelines (31) . Accurate classification is paramount to clinical care and remains one of the main challenges today. As such, testing is best done in laboratories with specialized expertise in complement genetics. Acquired: Factor H autoantibodies (FHAA) are also associated with aHUS, typically in children who are homozygous deleted for the CFHR1 gene, a member of the CFH gene family. The frequency of this deletion allele varies across the globe from a high of over 50% in Nigeria to very rare in South America and Japan. How deletion of CFHR1 leads to development of FHAA is complicated and may involve slight differences in structural conformation of FHR1 and FH as well as an individual's susceptibility to the development of autoantibodies in general (32, 33) . Complement Evaluation: Complement pathway assessment can be a useful tool to aide in diagnosis of aHUS, however, similar to genetic analysis normal results do not exclude a diagnosis of aHUS. Standard complement evaluation comprises quantitative and qualitative analyses. Reduction in complement proteins are not invariably seen with aHUS, however determining serum proteins levels can assist in the interpretation of genetic and functional data(34). In aHUS patients, there is preferential activation of the alternative complement J o u r n a l P r e -p r o o f pathway and the expected serum complement profile consists of low serum C3 and normal C4, which reflects the preferential activation of the alternative complement pathway even though C3 levels are reduced in only 30% of patients. Low C3 with normal or decreased FB concentration, associated with normal C4, suggests alternative pathway-mediated complement activation. The concentrations of FH, FD and FI can clarify the mechanism of C3 consumption. It is common that abnormal results may not all be found simultaneously, and in about 60% of aHUS patients, all complement protein levels are normal. This has given rise to an extensive debate on which tests are the most sensitive and specific for aHUS (35) (36) (37) (38) . Finally, complement activation and C5b-9 (MAC) deposition on endothelial cell surface can also be determined in the laboratory by incubating serum/plasma using endothelial cell culture (HMEC-1) (39, 40) . Complement serology may be useful, when available, for monitoring of C5 blockade in patients receiving complement directed therapy. One of the challenges in TMA classification is whether patients with secondary causes also have a significant component of TMA from complement activation and whether these patients will benefit from anti-complement therapy. Here we discuss the available data on the role of complement in various secondary causes of TMA. Patients with hypertensive emergency -defined as out of range elevation in blood pressure associated with failure of at least three organs(41) -may present with features of microangiopathic hemolytic anemia (MAHA) (42, 43) . Scleroderma Renal Crisis should be ruled out (see below). In a study of 97 patients with malignant hypertension, one-third had MAHA of which 56% needed dialysis (as opposed to only 3% in the group without MAHA) and only 40% where able to stop dialysis after blood pressure control suggesting additional mechanisms of injury(44). Indeed, it has recently been shown that complement abnormalities are present in a J o u r n a l P r e -p r o o f significant number of patients who develop TMA in the setting of malignant hypertension. In recent studies, variants in genes encoding regulatory proteins of the alternative complement pathway were identified in 6 of 9 patients (45, 46) . In another series of 26 patients with malignant hypertension and TMA (43) , 35% of the patients had variants in complement genes. In addition, soluble and glomerular deposits of C5b-9 have been identified in the patients with malignant hypertension who develop TMA (47) . Thus, patients who had massive tissue deposition of C5b-9 more often progressed to end-stage renal disease (72% vs. 38%) than patients with minor deposition, irrespective of complement genetic status; the patients with significant complement activation also had more glomerular thrombi. In this same cohort, complement inhibition with eculizumab prevented end stage renal disease in five out of six patients with massive ex vivo complement activation after blood pressure lowering failed. In another cohort of patients with aHUS, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome, preeclampsia and malignant hypertension, a modified endothelial cell assay for deposition of C5b-9 (using activated plasma instead of serum) was used to detect complement activation. Ex vivo C5b-9 deposition was increased in the active phase of patients with aHUS, as well as in 100% of patients with HELLP and 90% of patients with preeclampsia. In the subgroup of patients with malignant hypertension, C5b-9 deposition was similar to control levels, and there was partial TMA response after blood pressure control alone (40) . Given the severity of renal disease presenting with TMA in the setting of malignant hypertension, early detection of complement involvement may help identify a subset of patients that would benefit from complement inhibition especially when blood pressure lowering does not improve TMA (48) . Eculizumab (Soliris, Alexion Pharma.) has been used for a variable length in patients developing TMA in the setting of malignant hypertension (49, 50) with good response even when initiated 5.5 months after initial TMA presentation (10) .The length of administration of complement blockers may be guided by TMA response and presence of a positive genetic test for complement genes ( Figure 4 ). In summary, based on data available approximately one-third of patients with malignant hypertension may present with TMA, of which complement abnormalities are found in 35-65%. These patients have worse outcome compared to patients without complement defects and J o u r n a l P r e -p r o o f usually TMA does not subside with blood pressure control. Complement abnormalities should be suspected in patients with TMA in the setting of malignant hypertension. Thrombotic microangiopathy may be mediated by drugs and medicinal plants (51) . DITMA has two primary underlying mechanisms: 1) dose-related idiosyncrasies that is immune- DITMA is suspected when there is a sudden onset of severe systemic symptoms, usually acute kidney injury with anuria, within days (usually < 21 days in antibody-mediated TMA) or hours after exposure to the drug (in cases of direct toxicity), although some cases may occur long after drug exposure. There may be a history of malaise after previous exposure. Another diagnostic criterion is resolution or improvement of TMA when the suspected drug is stopped or dose reduced, although some degree of kidney injury may persist (55) . The detection of antibody-dependent reaction to the drug supports the clinical diagnosis; however, a negative test does not exclude drug-induced TMA(53). Management of DITMA predominantly involves withholding the causative medication, however, often that alone is not enough to lead to clinical recovery and in patients with escalating renal injury other therapies such as plasma exchange and eculizumab sometimes needs to be considered. As noted above, gemcitabine J o u r n a l P r e -p r o o f may have direct endothelial toxicity, with release of large amounts of von Willebrand factor multimers and concomitant activation of the coagulation cascade (56) , however a few case reports of the benefit of steroids, plasma exchange and rituximab (57, 58) in gemcitabinerelated TMA also supports the role of an immune mediated mechanism. Further highlighting the complexity of DITMA are case reports of gemcitabine-related TMA resolution with short term eculizumab after no response to plasma exchange, raising the possibility of complement involvement in the pathogenesis of this entity in adults (59) (60) (61) (62) and children (63) . In a large registry study (64) Anti-phospholipid syndrome (APS) can occur in isolation (primary) or associated with other autoimmune diseases such as SLE (secondary). Catastrophic antiphospholipid syndrome (CAPS), defined as intravascular thrombosis in patients with persistent antiphospholipid antibodies affecting three or more systems simultaneously or within one week (72) , occurs in less than 1% of patients with APS and has a high mortality rate (approximately 30%) despite treatment with steroids, anticoagulation, plasma exchange, intravenous immunoglobulin and rituximab. Renal involvement is commonly found in CAPS and a frequent finding is TMA(73). Regardless of whether TMA is noted in APS, a role for complement activation on endothelial cells in the hypercoagulability status of patients with antiphospholipid antibodies (74) has been identified and eculizumab has been used to treat refractory cases of CAPS. A systematic review on the use of eculizumab in six patients with CAPS found improvement or stabilization in all cases (75) . Elevated soluble C5b-9 and other complement products upstream of C5 were found in a patient with CAPS who was treated with eculizumab with good response to complement inhibition in hours (76) . In scleroderma, the presence of kidney injury, thrombocytopenia and microangiopathic hemolytic anemia, with or without malignant hypertension, is known as Scleroderma Renal Crisis (SRC) (77) and occurs in less than 5% of patients with Systemic Sclerosis (2.4% in a cohort of 637 patients). Steroid use is one risk factor (78) and viral infections, such as influenza B, may precipitate SRC (79) . Differentiating SRC from other causes of TMA may be difficult, with poor kidney and patient outcomes(80) despite standard treatment (plasma exchange, angiotensin converting enzyme inhibitors) (81) , even in normotensive patients (66) . The pathophysiology is still not completely unraveled and comprises Major Histocompatibility Complex class I haplotypes, B and T cells, antibodies to angiotensin 2 receptor 1 and RNA polymerase III(77), which may have a role in endothelial cell activation, overexpression of endothelin-1 and complement activation as seen with C4d deposition in peritubular capillaries (82) and C3b staining in kidney biopsies of patients with SRC (83) . Recurrence rate after kidney transplantation is low (<2%) and there may be a role for mTOR inhibitors (78) . Good response to eculizumab in resistant cases even with negative complement genetic findings reinforce the role of complement activation in SRC (84) (85) (86) . In summary, the presence of underlying genetic variants in complement genes seems rare in patients with systemic diseases and TMA. Some patients, though, demonstrate a good response to eculizumab that suggests secondary complement involvement. The differential diagnosis of TMA in pregnancy includes cases of eclampsia, preeclampsia and HELLP syndrome, which can show an overlap of signs and symptoms. aHUS should be suspected when despite delivery, TMA fails to improve and extends beyond 72 hours, which would be the expected time for recovery in cases of eclampsia, preeclampsia and HELLP syndrome (87) . In 2010, Fakhouri et al (29) . found that among 100 women with aHUS, 21 cases were associated with pregnancy (P-aHUS) -and 79% of the cases occurred in the postpartum period. In this series, genetic defects in alternative complement pathway were detected in 18/21 patients. Without specific treatment, the prognosis in these cases was quite reserved since 76% of patients progressed to End Stage Kidney Disease. The authors also observed a higher risk of having TMA in a second pregnancy. In another cohort of 29 patients with secondary TMA treated with eculizumab(17), two patients presented P-aHUS with good response to eculizumab despite absence of detectable pathogenic variants. Complement mediated disorders in pregnancy were elegantly reviewed in a recent paper (88) and reinforces that TMA associated with pregnancy, especially in the post-partum period, is highly associated with genetic complement abnormalities and most patients benefit from eculizumab. IgA Nephropathy is the most common primary glomerulonephritis worldwide. In a Similarly, no mutations in CFH were identified in another large series of IgA nephropathy (90) . Taken together, genetic variants of complement genes do not appear to play a role in TMA in the setting of IgAN. TMA in the context of infectious diseases have been extensively (91, 92) In summary, genetic variants in complement proteins can be present in TMA associated with infections. The type and incidence of genetic variants depends on the infection. The role of complement inhibitors in TMA-associated with infections is unclear. Monoclonal gammopathy has been shown to be associated with C3G, a disease associated with abnormalities of the complement pathway (128) . Recently, monoclonal gammopathy was also shown to be associated with TMA. Complement evaluation has not yet been evaluated in patients in this group (129) . In conclusion, the severity and extent of genetic complement abnormalities in secondary TMA is variable. 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