INTRODUCTION — The occurrence of acute kidney injury (AKI) in adults associated with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia presents diagnostic and therapeutic challenges, as there are many diverse causes that cannot always be rapidly distinguished, and therapies vary widely, ranging from urgent anti-complement treatment to observation and supportive care.
Diagnosis and management are especially complex since the thrombotic microangiopathy (TMA) syndromes that primarily present with AKI, such as Shiga toxin-mediated (diarrheal) hemolytic uremic syndrome (ST-HUS) and complement-mediated TMA (CM-TMA) are less well-appreciated and less well-described in adults than thrombotic thrombocytopenic purpura (TTP), which is rarely associated with AKI.
This topic discusses our approach to the evaluation and management of ST-HUS and CM-TMA in adults.
Separate topic reviews present a general overview of TMA syndromes and our approach to their diagnoses, as well as HUS in children and HUS after kidney transplant and hematopoietic stem cell transplant:
●Overview of TMAs – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●HUS in children – (See "Overview of hemolytic uremic syndrome in children".)
●CM-TMA in children – (See "Complement-mediated hemolytic uremic syndrome in children".)
●ST-HUS in children – (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)
●HUS after kidney transplant – (See "Thrombotic microangiopathy after kidney transplantation".)
●TMA after hematopoietic stem cell transplant – (See "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy'.)
CONCEPTUAL FRAMEWORK — TMA describes a group of syndromes with multiple etiologies, both hereditary and acquired, that have a characteristic microvascular pathology causing microangiopathic hemolytic anemia (MAHA) and thrombocytopenia . The terminology for the various TMA syndromes has evolved as their underlying disease mechanisms have become clearer. (See 'Preferred terminology' below.)
Evolution of disease understanding — Originally, the TMA syndromes associated with AKI were recognized mostly in children. By far the most common etiology in children is an enteric infection by Shiga toxin-producing bacteria (Shigella dysenteriae and some strains of Escherichia coli, such as E. coli O157:H7). The clinical presentation characteristically begins with several days of severe abdominal pain and diarrhea, which becomes overtly bloody. As the diarrhea is decreasing, up to 15 percent of children develop AKI . This disorder is hemolytic uremic syndrome (HUS), sometimes described as Shiga toxin-mediated HUS (ST-HUS). Even in outbreaks, the diagnosis of ST-HUS is not always confirmed by documentation of Shiga toxin or Shiga toxin-producing organisms.
After the initial description of HUS, some children were described as having HUS without diarrhea. Often these children had persistent or recurrent disease. Some had a family history of HUS. These children were initially described as having "atypical" HUS, to distinguish them from "typical" HUS with a diarrhea prodrome caused by enteric infection. This distinction was initially appropriate for pediatric practice when there were no therapeutic implications in the era before complement-directed therapies became available.
Following the discovery that dysregulation of the alternative pathway of complement contributed to the etiology of "atypical" HUS, anti-complement therapy was developed. When complement dysregulation is associated with AKI, intervening with anti-complement therapy improves renal outcomes . The availability of anti-complement treatment and the lack of specificity of the diagnostic criteria for many of the TMA syndromes have rapidly expanded the consideration of this diagnosis, particularly in adults . Now nearly one-half of patients diagnosed with complement-mediated TMA (CM-TMA) are adults. The availability of anti-complement therapy and its potential therapeutic benefit when AKI is present makes it essential to distinguish CM-TMA from other causes of TMA and AKI. The diagnosis of CM-TMA is difficult to substantiate when turnaround time is slow for complete genetic studies. (See 'Terminal complement blockade' below.)
Thrombotic thrombocytopenic purpura (TTP) is a TMA that primarily causes microvascular symptoms in organ systems other than the kidney (eg, central nervous system). Immune TTP is caused by an autoantibody and is effectively treated with therapeutic plasma exchange (TPE) and therapies to reduce autoantibody production. In the era before TPE was used as effective therapy, TTP was characterized by a pentad that included MAHA, thrombocytopenia, fever, neurologic symptoms, and AKI; however, the AKI component of the pentad is rarely seen in the era of TPE because patients recover before AKI can develop. As an example, a 2017 review of kidney function in 78 consecutive patients in the Oklahoma TTP Registry found that only eight (10 percent) had KDIGO (Kidney Disease: Improving Global Outcomes) stage 3 AKI, and only three (4 percent) required dialysis . Presenting findings in TTP are discussed separately. (See "Diagnosis of immune TTP".)
Preferred terminology — We prefer the following terminology, which takes into account the etiology of TMA and therefore facilitates earlier recognition of directed therapy in affected individuals :
●ST-HUS – We reserve the name HUS for the disease caused by Shiga toxin (ST-HUS).
The term ST-HUS implies that recovery will occur spontaneously. Renal replacement therapy is frequently required in the acute phase and chronic kidney disease may occur. Recurrence of ST-HUS is rare. Supportive care involves hydration, treatment of pancreatitis-related manifestations (such as hyperglycemia), and transfusion for severe anemia. (See 'Causes of ST-HUS' below.)
●Complement-mediated TMA – Complement-mediated TMA (CM-TMA) is the preferred term (rather than atypical HUS) for the TMAs associated with inherited pathogenic variants in complement genes or acquired autoantibodies against complement factor H (CFH). In contrast with autoantibodies against CFH, autoantibodies against other complement components are not considered pathogenic for CM-TMA.
The term CM-TMA implies that anti-complement therapy is appropriate for treatment, especially if kidney function is rapidly deteriorating. Additional supportive care may involve hydration, dialysis, or transfusions for severe anemia. (See 'Causes of CM-TMA' below.)
Certain terms based on older nomenclature continue to be used, and these may inadvertently propagate ambiguities in understanding disease physiology and management.
CAUSES OF ST-HUS AND CM-TMA IN ADULTS
Causes of ST-HUS — Shiga toxin (ST or STX, also called verotoxin or verocytotoxin [VT]) is a two-subunit bacterial toxin that belongs to a family of proteins originally identified from Shigella dysenteriae type 1 . ST binds to a glycolipid receptor (globotriaosylceramide [Gb3]) that is expressed on kidney cells and other cell types [6,7]. There are several related Shiga-like toxins . ST can be produced by a number of organisms and may be transferred between bacteria by a bacteriophage .
●E. coli – The most common cause of ST-induced hemolytic uremic syndrome (ST-HUS) in industrialized societies is ST-producing E. coli (STEC). The most frequently isolated strain is E. coli O157:H7, although other serotypes of E. coli such as O104:H4 can also produce high levels of one or more Shiga toxins [2,5,10,11]. A list of selected outbreaks and their investigations is maintained by the Centers for Disease Control and Prevention (CDC) on their website (cdc.gov/ecoli/outbreaks) .
Important outbreaks include the following, listed in chronological order:
•An outbreak of E. coli O157:H7 infection from hamburgers at a fast-food chain in Seattle (United States) in 1993 focused national attention on ST-HUS . There were 501 cases of E. coli O157:H7 infection; 45 developed HUS; three died.
•An outbreak of E. coli O157:H7 infection in Walkerton, Ontario (Canada) in 2000 was eventually traced to the municipal water supply; 1346 cases of diarrheal illness were reported . Of these, 65 individuals were admitted to the hospital, 27 developed HUS, and six died. The median age of affected individuals was 29 years (range, <1 to 97 years).
•The strain responsible for the large outbreak in 2011 in Germany, causing ST-HUS in 845 patients with 54 deaths, was O104:H4 [15,16]. The O104:H4 strain was also responsible for a large outbreak in France the same year . These outbreaks in Germany and France were caused by contaminated sprouts. Since children rarely eat sprouts, most affected patients were adults.
•A 2016 outbreak of E. coli strain O121 was reported in the United States in association with ingestion of contaminated raw flour; there were 56 cases of infection and one case of HUS .
STEC is typically acquired by eating contaminated foods or beverages such as undercooked ground beef, unpasteurized juice or cider, raw milk, or raw produce (eg, lettuce, spinach, sprouts) [19-22]. Other sources include ingestion of contaminated water, contact with farm animals (eg, cattle), or person-to-person contact [19,22,23]. Although outbreaks are highly visible, most cases of STEC infections are sporadic (not due to outbreaks) .
●Other bacteria and viruses – Cases of TMA with AKI have been described with other bacterial organisms (salmonella, campylobacter) as well as viruses [30-32].
Causes of CM-TMA — Complement-mediated TMA (CM-TMA) may be caused by inherited pathogenic variants (disease-causing mutations) in complement gene variants or by autoantibodies directed against complement factor H (CFH) .
Role of complement system — The complement system plays a central role in host innate immunity. It participates in antibody-mediated immunity, promotes phagocytosis (via opsonization), directly lyses foreign cells via the membrane attack complex, and may recruit other immune mediators (eg, via cytokines) to a site of injury or infection. (See "Overview of hemostasis", section on 'Blood coagulation as part of the host defense system' and "Overview and clinical assessment of the complement system", section on 'Functions of the complement system' and "Complement pathways".)
In order to achieve immune surveillance, the alternative pathway of complement is constitutively active and inducible (ie, it has features that allow rapid amplification of necessary functions). This reactivity necessitates precise regulation in order to limit inadvertent injury to self-tissues. This concept is comparable with the continuous low-level activation of the coagulation system and the requirement for inhibitors (eg, proteins C and S) to prevent excessive thrombin generation. (See "Regulators and receptors of the complement system" and "The endothelium: A primer", section on 'Complement-mediated endothelial cell injury'.)
The complement regulatory proteins include CFH, complement factor I (CFI), membrane cofactor protein (MCP, also called CD46), and others. These prevent excessive and/or inappropriate activation of complement on host cells, as discussed separately. (See "Regulators and receptors of the complement system", section on 'Complement regulation'.)
In adults with CM-TMA, gene variants appear to be more common than autoantibodies (see 'Pathogenic sequence variants in complement genes' below). This was suggested by a series of individuals with TMA and AKI in a French database that included 125 adults . Autoantibodies were only seen in four (3 percent) compared with pathogenic variants in complement genes in 73 (58 percent). Pregnancy was the triggering factor in 18 of 93 females (19 percent) in this cohort.
Pathogenic sequence variants in complement genes — Pathogenic sequence variants in a number of complement genes have been described, including CFH, CFI, MCP/CD46, C3, and CFB . Additional details of these variants, the mechanisms by which they may promote TMA, and possible genotype-phenotype correlations are presented separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Genetic variants' and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Complement-mediated TMA pathogenesis'.)
Hereditary CM-TMA related to a variant in a complement gene may present at any age. In a series from a French database, disease variants in CFI and CFH appeared to present at an older age than variants in MCP, but numbers may have been too small to draw firm conclusions about genotype-phenotype correlations . Clinical features in this series such as the incidence of end-stage kidney disease and mortality were not different from disease caused by different genotypes. In data from Johns Hopkins, the median age of presentation in adults with TMA and AKI was 46 years, and the majority were female [35,36].
Sequence variants of uncertain significance in complement genes — Genetic testing may identify variants that have not been documented to be pathogenic. These are often referred to as variants of uncertain significance (VUS). The designation may apply to either a benign or pathogenic variant, if more data were available; therefore, they cannot be assumed to be pathogenic or to be the cause of CM-TMA. The gene variants must be considered to be a potential risk. Consultation with the genetic testing laboratory or a genetics professional may provide additional understanding of the risk for causing kidney disease. The perception of the pathogenic importance may be influenced by a personal or family history of a similar kidney disease.
Autoantibodies against CFH — Autoantibodies directed against complement factor H (CFH) are reported in approximately 8 to 10 percent of CM-TMA patients and may be more common in some countries [37,38]. While it was initially believed that these antibodies only occurred in children, it is clear that they may also be seen in adults. As an example, in a series of 45 patients who presented with CM-TMA who had autoantibodies against CFH, seven (15 percent) were adults .
Most individuals with an anti-CFH autoantibody appear to have a homozygous deletion of CFHR1 and/or CFHR3 genes, suggesting that these deletions have a pathogenic role in the development of the anti-factor H autoantibodies. These autoantibodies interfere with the binding of CFH to the C3 convertase and are associated with defective CFH-dependent cell protection. (See "Regulators and receptors of the complement system", section on 'Control of amplification'.)
Other disorders that present with MAHA and thrombocytopenia — A number of other conditions can present with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia; some of these are considered primary TMAs and some are not.
●Primary TMAs – Other primary TMAs include thrombotic thrombocytopenic purpura (TTP), drug-induced TMA (DITMA), metabolism-mediated TMA, and coagulation-mediated TMA . These disorders and our approach to distinguishing among them are summarized separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Evaluation for primary TMA syndromes'.)
●Other disorders – Other disorders causing MAHA, thrombocytopenia, and AKI, such as severe hypertension, autoimmune disorders such as systemic lupus erythematosus, catastrophic antiphospholipid syndrome (CAPS), disseminated intravascular coagulation (DIC), scleroderma renal crisis, hematopoietic stem cell and organ transplantation, and sepsis may resemble HUS and CM-TMA and require distinct, urgent treatments. These disorders should be labeled as complications of the underlying condition, with the implication that therapy should focus on that underlying disorder. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Exclude systemic disorders associated with MAHA and thrombocytopenia'.)
●Pregnancy-associated conditions – In pregnancy or postpartum, the occurrence of MAHA, thrombocytopenia, and AKI is a critical complication requiring urgent treatment. The key distinction is between conditions specifically associated with the pregnancy (placental abruption with DIC; preeclampsia with severe features; hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome) versus the TMA syndromes described above. Sometimes pregnancy is the triggering factor for a first episode of CM-TMA. Additionally, pregnancy complications such as placental abruption can cause hemorrhage, hypotension, and DIC, which may mimic a TMA syndrome. These pregnancy-specific terms imply that delivery is central to stopping the disease process. In contrast, the course of CM-TMA is not affected by delivery. (See "Thrombocytopenia in pregnancy", section on 'Management decisions'.)
EPIDEMIOLOGY — The prevalence of specific TMA syndromes with AKI is challenging to define in adults, both because disease definitions are evolving, the diagnosis is not always certain, and the diagnosis may not be considered, especially in adults.
Adults can present with any of the TMA syndromes associated with AKI, including an initial presentation of a genetic disorder. Unlike in children, where these syndromes are better described, the relative frequency of the different syndromes in adults in unknown .
Clues from the history — The following information from the history may help to establish the diagnosis:
●Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS) and complement-mediated TMA (CM-TMA) can present at any age. This is true for acquired forms as well as inherited forms. Initial presentations for CM-TMA are frequently associated with a trigger such as pregnancy, surgery, infections, and other inflammatory conditions. This explains the later onset and incomplete penetrance of germline pathogenic variants in complement genes. (See "Thrombocytopenia in pregnancy", section on 'Thrombotic microangiopathy (TMA)'.)
●Exposure to improperly prepared foods, inadequately cooked meats, or farm animals, all of which may be sources for ST-HUS. Additional information about the extent of exposure that can lead to infection is presented separately. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Transmission'.)
●Recent diarrheal illness with bloody stool or other infection could imply ST-HUS or other infectious cause of TMA. While diarrhea can be an indication of an ST-producing gastrointestinal infection, it can also be a manifestation of bowel ischemia secondary to another cause, and the pathologic features of bowel ischemia and enterohemorrhagic E. coli infection may be similar . The key distinguishing factors are the timing of AKI related to the occurrence of diarrhea. Typically, in ST-HUS, the diarrheal illness precedes the development of AKI by several days . (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Clinical features'.)
●Family history of TMA, kidney failure, or unexplained kidney failure or death during pregnancy may be suggestive of an inherited CM-TMA. In the Johns Hopkins complement-associated disease registry, 21 of 31 individuals had a trigger for acute illness with CM-TMA, including infection, autoimmune disease flare, pregnancy, surgery, or cancer/chemotherapy .
●The extent of oral intake is important because dehydration may increase the serum creatinine by causing acute tubular necrosis (ATN), making it appear that the patient has kidney involvement by TMA when in fact they have a pre-renal cause of AKI. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)
●If the patient has a history of an autoimmune disorder such as systemic lupus erythematosus (SLE) or scleroderma, this raises the possibility that symptoms may be due to a complication such as antiphospholipid syndrome (APS) or scleroderma renal crisis, respectively. (See "Hematologic manifestations of systemic lupus erythematosus" and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)
A more extensive discussion of the distinguishing features among various TMAs is presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Key distinguishing features among the primary TMA syndromes'.)
Initial laboratory testing — Most individuals with AKI, microangiopathic hemolytic anemia (MAHA), and thrombocytopenia will have already had a complete blood count (CBC), a review of the peripheral blood smear, serum chemistries including blood urea nitrogen (BUN) and creatinine, a lactate dehydrogenase (LDH), and a urinalysis with microscopic review. It is appropriate to obtain these tests if the results are not available and to request assistance from the hematologist and/or nephrologist in interpreting the microscopy findings.
Two algorithms have been developed to identify thrombotic thrombocytopenic purpura (TTP) based on the patient's history and initial laboratory testing.
●The PLASMIC score has seven items, two from the patient's history and five from initial laboratory data . Meeting six or all seven of these criteria predicts a 62 to 82 percent chance of having ADAMTS13 activity ≤10 percent, consistent with a diagnosis of TTP. The reliability of the PLASMIC score is lower in patients over 60 years old .
●A French score requires only the platelet count and serum creatinine concentration . Fulfilling both criteria (platelet count <30,000/microL and serum creatinine <2.25 mg/dL) predicts a 94 percent chance of having ADAMTS13 activity <10 percent, consistent with a diagnosis of TTP.
Features on the blood smear consistent with a TMA include schistocytes (picture 1) and reduced platelets; the white blood cell (WBC) count and appearance of WBCs on the blood smear are typically normal unless there is a concurrent infection. A diarrheal illness, ST-HUS, or other infectious process may be associated with mild leukocytosis.
There are no features on urinalysis that will definitively point toward a TMA as the cause of the AKI. The classic presentation of "muddy brown" casts suggests acute tubular necrosis (ATN) and is evidence against TMA. However, other causes of AKI may be identified based on specific findings such as red blood cell (RBC) casts, which are typical of glomerulonephritis. These findings should be confirmed by the nephrologist.
Additional testing in selected individuals — Most individuals will benefit from additional testing based on their presenting findings, as discussed in the following sections.
Experimental assays that may assist with distinguishing among the TMAs have been proposed (eg, modified HAM test) . However, these have not been validated in clinical practice.
ADAMTS13 activity — In the majority of cases, TTP will be a consideration, even though AKI is not characteristic of TTP. Thus, ADAMTS13 activity testing will be sent. Ideally, the sample should be sent before plasma infusion or plasma exchange therapy, as donor plasma contains ADAMTS13 and may confound the results. This subject is discussed in more detail separately. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)
Cultures — Testing for infection with blood cultures (and other body fluids if there are symptoms attributable to those sites or fluid collections) is generally appropriate, especially for fever or a change in clinical status, as most of these patients will have a central venous catheter for plasma exchange or hemodialysis, and sepsis is an ongoing concern.
Tests for Shiga toxin-producing organisms — Individuals with diarrhea should have stool testing for Shiga toxin-producing organisms and/or the Shiga toxin itself. This may include one or more of the following tests:
●Stool culture – Stool culture for specific organisms may include E. coli O157:H7 or O104:H4, Shigella species, or others, depending on geographic location and whether an organism has been identified in a known outbreak. Specimens should be sent to the laboratory as soon as possible; if they must be held before processing, they should be refrigerated . Culture for E. coli O157:H7 requires special agar. Microbiology laboratories typically use this special agar whenever the stool specimen is overtly bloody. (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Microbiologic diagnosis' and "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Testing for STEC infection'.)
●Shiga toxin – A Shiga toxin protein assay may be performed on a stool specimen. The sensitivity of this test is assay dependent.
●DNA testing – DNA testing for Shiga toxin genes may be done using polymerase chain reaction (PCR) to amplify Shiga toxin genes (STX1 and STX2). This testing can be performed on stool or on plate colonies. The advantage of these tests is that they are rapid and can distinguish which toxin is being produced. This testing may be used by public health laboratories.
The Centers for Disease Control and Prevention (CDC) in the United States advises combined testing using both stool culture and Shiga toxin assay, with the rationale that early treatment may decrease the risk of other complications, and early identification of outbreaks may be helpful in controlling exposures . The major reason for adding other forms of testing besides stool culture is that stool culture is not always reliable. Some Shiga toxin-producing bacteria may not be identified (eg, non-O157 E. coli), and in other cases, stool shedding of live bacteria may have ceased by the time testing is performed. Some laboratories will do reflex stool cultures if immunoassays are positive.
Public health laboratories may also use other methods to identify the causative organism in an outbreak such as pulsed-field gel electrophoresis (PFGE) of bacterial DNA.
Positive results from stool testing for Shiga toxin-producing organisms are considered reportable to most public health boards. Local guidelines for reporting should be followed.
Complement testing — Complement testing (for pathogenic variants in complement genes and for autoantibodies directed against complement factor H [CFH]) is appropriate in adults for whom CM-TMA remains on the differential diagnosis. This includes those with MAHA, thrombocytopenia, and AKI who do not have an alternative explanation for the findings (no known drug exposure associated with drug-induced TMA, no systemic lupus erythematosus [SLE] or scleroderma, no ADAMTS13 deficiency or Shiga toxin in stool). Results of this testing may be delayed for days to weeks, and anti-complement therapy should not be delayed while awaiting the results (algorithm 1). (See 'Terminal complement blockade' below.)
Testing is important because it confirms the diagnosis, facilitates testing of other family members (for CM-TMA and as possible kidney transplant donors), and may impact the duration of anti-complement therapy, as illustrated in the figure (algorithm 1). (See 'Can anti-complement therapy be stopped?' below.)
Complement testing includes testing for autoantibodies to CFH and genetic testing. This testing is becoming more widely available. Examples of academic centers in the United States that perform this testing include the University of Iowa, Cincinnati Children's Hospital, Washington University, Mayo Clinic, and the Versiti Blood Center of Wisconsin. Most institutions will have a preferred referral laboratory for complement gene testing.
In contrast with testing for antibodies to CFH and complement gene variants, testing serum complement biomarkers (such as the levels of CH50, C5b-9 [soluble membrane attack complex], C3, and C4 in the serum) have no diagnostic role in CM-TMA, because they have very low sensitivity and specificity. As an example, C3 levels may be low in only 35 percent of individuals at presentation . A low C3 level is most likely to be seen in certain mutations such as variants in CFH, CFB, and C3 .
Our approach to the evaluation and management of suspected CM-TMA is illustrated in the figure (algorithm 1).
Anti-CFH — Antibody testing for autoantibodies to complement proteins should include testing for antibodies to complement factor H (CFH). The presence of an autoantibody has important implications for treatment (eg, use of therapy to target B cells in addition to complement blockade, greater likelihood of successful discontinuation of anti-complement therapy); some of the centers above may include other antibodies as part of routine testing. (See 'Can anti-complement therapy be stopped?' below.)
Genetic testing (complement genes) — Complement gene testing may help determine the cause of the TMA, provide information on recurrence risk (in the native kidney or after kidney transplant), and assist with genetic testing and counseling of first-degree relatives. Genetic testing may thus inform long-term treatment plans, including patient surveillance, and preparation for kidney transplant should renal recovery not occur. As an example, if an individual has a pathogenic variant in a complement gene, any sibling being considered as a potential kidney donor should be evaluated for the presence of a familial variant.
Genetic testing should include evaluation of the following genes:
●CFH – Encodes complement factor H
●CFI – Encodes complement factor I
●MCP – Encodes membrane cofactor protein; also referred to as CD46
●CFB – Encodes complement factor B
●C3 – Encodes complement component 3
●CFHR region – Encodes several CFH-related proteins (see "Complement-mediated hemolytic uremic syndrome in children", section on 'Genetic variants')
For CFHR, sequencing alone may fail to identify duplications and deletions in the highly homologous region, and a genetic testing report is not complete without multiple ligation dependent probe amplification (MLPA). While uncommon, these variants are significant. (See "Genomic disorders: An overview", section on 'Copy number variations'.)
Involvement of a genetic counselor is appropriate in some cases to confirm a diagnosis of CM-TMA, to assist with genetic testing plans, and/or to prepare a patient for kidney transplant.
A number of limitations apply to complement genetic testing:
●Up to 50 percent of patients with a clinical diagnosis of CM-TMA (without an alternative explanation for their TMA) may not have a pathogenic sequence variant in one of the complement genes.
●The results of genetic testing may not be available during the acute presentation and before a treatment decision must be made.
●The majority of DNA variants that are identified in patients with suspected CM-TMA lack data about pathogenicity, which creates diagnostic uncertainty. Determining the significance of the variants that may be identified requires specialty consideration in order to limit the impact of confounding from otherwise incidental findings. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
●The cost of testing may be high and therefore may not be approved by third-party payers during the acute hospital stay.
Kidney biopsy — Biopsy of the kidney may be performed in the evaluation of unexplained AKI. It may confirm the presence of a TMA syndrome, but it does not help to identify a specific type of TMA (ie, there are no pathologic features that definitively point to a specific TMA).
Thus, kidney biopsy does not inform treatment decisions for specific TMAs, and we do not use biopsy to evaluate patients with AKI, MAHA, and thrombocytopenia unless there is a specific management decision that would be influenced by the results.
Examples of situations in which kidney biopsy may be helpful include the following:
●To identify the extent of ischemic injury sustained as a result of a renal TMA in order to facilitate an understanding of the degree of irreversible kidney injury.
●To facilitate decision-making regarding the next steps in therapeutic management for a patient whose kidney function does not recover in response to a specific therapy (ie, such as in the setting where no extra-renal symptoms have been present in a patient being treated with anti-complement therapy).
Renal-limited TMA is the term used when characteristic thrombi and histologic changes are noted on kidney biopsy (obtained to evaluate kidney dysfunction) when none of the usual systemic findings of TMA such as MAHA and thrombocytopenia are present. The management of TMA limited to the kidney requires a thorough evaluation for potential causes, as described above (see 'Causes of ST-HUS and CM-TMA in adults' above), as well as other thrombotic entities such as antiphospholipid syndrome (APS) and drug-induced TMA (DITMA). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Initial evaluation (all patients)'.)
The risk of bleeding with kidney biopsy is 1 to 2 percent, which is higher than biopsy of other sites. Thrombocytopenia may further increase this risk. Local practice will determine the platelet threshold at which a kidney biopsy may be relatively safe. We generally use a platelet count threshold of ≥50,000/microL for kidney biopsy. If the platelet count is below this threshold, platelet transfusions may be required. (See "Platelet transfusion: Indications, ordering, and associated risks" and "The kidney biopsy", section on 'Bleeding'.)
Overview of management and supportive measures — Appropriate management depends on the underlying cause of the TMA, which is not always known. Results of testing for the specific causes listed above may take days to weeks; a longer interval is common for genetic testing. (See 'Causes of ST-HUS and CM-TMA in adults' above.)
Initial interventions may be required before the diagnosis is established. The following general supportive measures are appropriate, depending on the patient's clinical status.
●Hydration – Hydration is used to maintain euvolemic status and improve electrolyte balance. Excessive hydration should be avoided, especially if urinary output is low. For individuals undergoing plasma exchange, volume status can be adjusted during the procedure.
●Antibiotics and antidiarrheals – For individuals with suspected Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS), antibiotics are used only for extra-renal, extra-Shiga toxin-induced sequelae (ie, pneumonia). Antidiarrheal agents are unlikely to be needed because the diarrhea is likely to have resolved by the time the TMA develops. (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Antibiotics'.)
●Avoidance of NSAIDS – We avoid the use of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), as patients with ST-HUS or complement-mediated TMA (CM-TMA) may be at increased risk of bleeding due to thrombocytopenia and AKI may be further exacerbated. (See "NSAIDs: Acute kidney injury" and "Nonselective NSAIDs: Overview of adverse effects".)
●RBC transfusions – Transfusion of red blood cells (RBCs) is appropriate for severe anemia (eg, hemoglobin <7 g/dL). Some individuals with a higher hemoglobin level (range, 7 to 10 g/dL) may also benefit from transfusion if they have severe symptoms or signs of end-organ damage (eg, acute coronary syndromes). (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)
●Platelet transfusions – Transfusion of platelets is appropriate when a patient with a platelet count of <50,000/microL requires an invasive procedure or has clinically important bleeding.
There is no role for routine platelet transfusion in TMAs without bleeding or anticipated bleeding. However, platelets should never be withheld from a patient with clinically important bleeding and thrombocytopenia or who requires an increased platelet count in anticipation of a surgical procedure. (See "Platelet transfusion: Indications, ordering, and associated risks".)
●Dialysis – Dialysis is performed for standard indications including fluid overload unresponsive to diuretics, hyperkalemia refractory to medical therapy, or metabolic acidosis and uremia. (See "Overview of the management of acute kidney injury (AKI) in adults" and "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)
●Therapeutic plasma exchange (TPE) – TPE is appropriate if immune thrombotic thrombocytopenic purpura (TTP) is suspected, if anti-complement therapy is not available, and as the initial approach to complement factor H (CFH) autoantibody-driven disease. If CM-TMA is suspected, anti-complement therapy is appropriate (see 'Terminal complement blockade' below), and because anti-complement therapy is required daily during TPE, we generally do not combine TPE with anti-complement therapy. We also do not use TPE for those with a high likelihood of ST-HUS or drug-induced TMA (DITMA), or for individuals with stable or improving kidney function; the effectiveness of TPE for TMA syndromes other than TTP is uncertain. When TPE is used due to a concern for possible TTP, it is generally continued until the results of ADAMTS13 activity testing become available.
There are no randomized controlled trials of TPE for individuals with CM-TMA, and it remains the common treatment of CM-TMA in some countries where patients do not have access to terminal complement blockade therapies. In an observational study involving 273 consecutive patients with presumed CM-TMA, over one-half (55 to 80 percent) had improvement with plasma exchange, but it is not clear what percent would have improved without plasma exchange . In those with improvement, hematologic response was more likely than renal response.
Terminal complement blockade
Indications for terminal complement blockade — Anti-complement therapy (terminal complement blockade) targets the underlying complement-mediated vascular lesion in CM-TMA.
●Recommendation – For individuals with a history suggestive of CM-TMA, we recommend anti-complement therapy, as illustrated in the figure (algorithm 1). Anti-complement therapy may also be appropriate in a patient with TMA without overt kidney injury when the underlying diagnosis is unclear (when CM-TMA is among the possible diagnoses).
A limited course of terminal complement blockade may be considered for TMA limited to the kidney if TTP has been excluded, an extensive review for other causes is inconclusive, and kidney injury is severe. (See 'Kidney biopsy' above.)
Examples of features that are strongly suggestive of CM-TMA include the following:
•TMA in an individual with a known family or personal history of CM-TMA
•Presentation of TMA with significant AKI during pregnancy or postpartum
•TMA with progressive deterioration in kidney function
•TMA with AKI in which there is no abdominal pain and overtly bloody diarrhea (ie, in which there is no evidence of ST-HUS)
•TMA with AKI in which there is no history of exposure to one of the drugs (table 1) associated with a DITMA
Features that suggest that CM-TMA is not the diagnosis include TMA lacking prominent renal findings, TMA in which kidney function is improving spontaneously (without intervention), TMA with severe ADAMTS13 deficiency (activity <10 percent), and/or TMA associated with a drug known to cause DITMA.
●Choice of therapy – If anti-complement therapy is indicated, we use either eculizumab or ravulizumab; both are monoclonal antibodies directed against the C-5 complement component approved for treating CM-TMA.
These antibodies block formation of the membrane attack complex (MAC) that is thought to mediate the microangiopathic changes and kidney injury in CM-TMA. (See "The endothelium: A primer", section on 'Complement-mediated endothelial cell injury'.)
●Supporting evidence – Supporting evidence includes observational studies; there are no randomized trials evaluating the efficacy of anti-complement therapy in CM-TMA. The basis for our recommendation is that patients with CM-TMA who were treated with terminal complement blockade appear to have an improved prognosis over historical controls, with a considerably lower rate of progression to end-stage kidney disease (ESKD) than would be expected based on the natural history of the disease. This includes improvements in kidney function, platelet count, and hemolysis in individuals with CM-TMA who were treated with eculizumab or ravulizumab, in some cases dramatic enough to allow discontinuation of hemodialysis [3,49-52].
Additional information about the natural history of untreated disease and results of studies in children are described separately. (See "Complement-mediated hemolytic uremic syndrome in children".)
•A series of five women with TMA and AKI described therapy involving eculizumab . Most of these had their initial episode of TMA before becoming pregnant, continued eculizumab during pregnancy (in some cases with additional doses or an increased dose), and delivered healthy babies, although several had pregnancy complications such as preeclampsia.
•Eight individuals treated with ravulizumab in a larger safety and efficacy trial had developed CM-TMA triggered by pregnancy and were treated with ravulizumab postpartum with improvements in kidney function and no additional pregnancy-related safety concerns .
•The largest body of evidence for eculizumab use during pregnancy comes from individuals treated with eculizumab for paroxysmal nocturnal hemoglobinuria (PNH). A report of the use of eculizumab in 61 PNH women during 71 pregnancies suggested that eculizumab use was associated with a high rate of fetal survival and a low rate of maternal complications . Some pregnant individuals have required increased dosing as they get closer to term. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Pregnancy'.)
Administration and dosing — Once the decision to use anti-complement therapy has been made, it should be instituted without delay (algorithm 1). Delays in starting anti-complement therapy have been associated with inferior outcomes related to preserving kidney function [36,55].
The choice between eculizumab and ravulizumab is individualized. These agents have not been compared directly but are expected to have similar safety and efficacy profiles, with the major difference being duration of action (longer with ravulizumab) and dosing interval (less frequent with ravulizumab). If the intended use is longer than 8 to 12 weeks, ravulizumab may be preferable.
●Eculizumab – Standard adult dosing for eculizumab is 900 mg intravenously once per week for four weeks, followed by a dose of 1200 mg one week later, followed by a "maintenance" dose of 1200 mg once every two weeks .
●Ravulizumab – Standard adult dosing for ravulizumab is 2700 mg intravenous loading dose (3000 mg if weight ≥100 kg) followed by a maintenance dose of 3300 mg (3600 mg if weight ≥100 kg), given every eight weeks, starting two weeks after the loading dose . Lower doses are used for individuals weighing <60 kg.
Individuals treated with eculizumab or ravulizumab should be vaccinated against encapsulated organisms . As the majority of patients in the United States who experienced a meningococcal infection while being treated with eculizumab had received at least one vaccination, the Advisory Committee on Immunization Practices (ACIP) also encourages clinicians to consider anti-meningococcal prophylaxis for the duration of eculizumab or ravulizumab treatment. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
Therapeutic plasma exchange (TPE) removes monoclonal antibodies (eculizumab, ravulizumab) from the circulation, risking reactivation of the terminal complement pathway. If one of these monoclonal antibodies is given to a patient being treated with TPE, an additional dose must be given immediately following TPE (eg, eculizumab: 600 mg). Whether this fully reinstates complement blockade has not been confirmed.
Pediatric dosing is discussed separately. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'.)
Can anti-complement therapy be stopped? — The appropriate duration of treatment with anti-complement therapy is unknown. Studies suggest that anti-complement therapy may be discontinued in carefully selected patients following disease remission, with the decision stratified based on the degree of risk for relapse once the therapy has been stopped (algorithm 1).
We discuss discontinuation with all individuals once their kidney function has normalized or stabilized. We are most likely to discontinue therapy in patients who do not have a pathogenic sequence variant in CFH, CFI, CFB, MCP, or C3. Patients with a pathogenic sequence variant in CFH, CFI, CFB, MCP, or C3 have the highest risk of relapse. For patients with a variant of uncertain significance (VUS) in one of these genes, we are most likely to continue therapy in those with a personal or family history of similar kidney disease. Patients with an autoantibody to CFH or those with negative testing have the lowest risk of relapse (algorithm 1).
●Outcomes after discontinuation, stratified by genetic testing – A prospective, single-arm study published in 2021 evaluated outcomes after eculizumab discontinuation in 55 individuals (19 children and 36 adults) with CM-TMA who had received eculizumab for at least six months and were in clinical remission . Notably, patients enrolled in this study were all considered to be candidates for stopping eculizumab; individuals with more severe kidney injury may not have been included. All had undergone genotyping for variants in complement genes, and approximately one-half had a variant, most commonly affecting MCP, CFH, or CFI.
•Of the 28 patients with pathogenic variants who stopped treatment with eculizumab, 13 subsequently relapsed and eculizumab was resumed. Eleven patients regained their baseline kidney function; two patients worsened, one progressing to ESKD.
•The likelihood of relapse was highest in those with mutations in MCP (six patients) and CFH (three patients).
•None of the patients who tested negative for pathogenic variants had a relapse (one patient who had been misdiagnosed as CM-TMA was discovered to have undiagnosed hereditary TTP, documented by biallelic variants in ADAMTS13).
•The only other variable associated with increased risk of relapse was female sex; age did not affect relapses.
These data suggest that discontinuing anti-complement therapy after clinical remission is feasible and safe in individuals who do not have a disease-causing variant in a complement gene. For patients in whom a pathogenic variant has been identified, discontinuing complement blockade treatment may be considered, particularly if there is no past history of similar kidney disease in the patient or their family, although this approach is likely to be associated with additional risk for recurrence of TMA.
●Outcomes after discontinuation, unselected – A prospective series of 31 adults enrolled in the Johns Hopkins complement-associated diseases registry who had native kidneys and been treated with eculizumab, with normalization of their platelet count, kidney function, and lactate dehydrogenase and were adherent to follow up, were offered the possibility of discontinuing therapy . There were 25 patients who discontinued eculizumab, 18 discontinued with physician direction; two had a subsequent relapse; an additional seven patients discontinued eculizumab because of nonadherence; three had a relapse. Four of the five patients who had a relapse were successfully retreated with clinical remission; the fifth died due to recurrent TMA and hypertensive emergency in the setting of nonadherence to eculizumab and antihypertensive therapy. There were no relapses in the six individuals who lacked a complement gene variant. The relapse rate was 40 percent in those with CFH or MCP variants, but numbers were too small to reach statistical significance.
●Outcomes before complement inhibitor therapy was available – In a 2013 French database series of 214 individuals (58 percent adults) with TMA and AKI who were treated in the pre-anti-complement therapy era, the relapse rate was approximately 40 percent . Of the 23 adults who had a relapse, 19 (82 percent) occurred within the first year.
These data support the practice of monitoring most closely during the first year and/or during episodes of infection or other acute inflammatory illness and considering the possibility of discontinuing therapy in carefully selected cases (algorithm 1). Decisions regarding the duration of anti-complement therapy are individualized and must take into account the specific gene variant, clinical features, patient's values and preferences regarding the costs and burdens of treatment, risk of relapse, and ability to identify a relapse if it occurs. Drug discontinuation is predicted to produce significant cost savings ($13 million USD in one study and $26 million Euros in another) [36,58].
Immunosuppressive therapy for individuals with antibodies to CFH — In individuals with autoantibodies to complement factor H (CFH), some experts use immunosuppressive therapy with cyclophosphamide or rituximab. The optimal approach has not been tested in a controlled trial. We tend to follow the approach used in one of the largest studies of patients with CFH autoantibodies . Plasma exchange is used initially to acutely decrease the autoantibody titer, and this is followed by either cyclophosphamide or rituximab. Once the titer has been decreased below 1000, mycophenolate mofetil is used for maintenance therapy. We then follow the antibody titer approximately every six months to ensure that it has remained below a risk for relapse threshold.
Indications for referral — Nephrology and hematology consultations are appropriate for any patient with suspected ST-HUS or CM-TMA, especially those for whom therapeutic plasma exchange (TPE), dialysis, and/or anti-complement therapy is being considered.
If laboratory testing or other clinical features suggest ST-HUS, it is important to report this information to local regulatory bodies (eg, State Department of Health) so that other affected individuals may be notified and a potential outbreak may be tracked. (See 'Causes of ST-HUS' above.)
Special populations with AKI and TMA
Pregnancy or postpartum — Pregnancy (including the postpartum period) is a major precipitating factor for CM-TMA. However, the development of TMA during pregnancy is not evidence in favor of CM-TMA over other primary TMAs, which are also commonly triggered by pregnancy (eg, hereditary thrombotic thrombocytopenic purpura [hTTP]), or pregnancy-related conditions such as preeclampsia with severe features and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Our approach to distinguishing among possible causes of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and AKI during pregnancy is presented separately. (See "Thrombocytopenia in pregnancy", section on 'Determining the likely cause(s)'.)
For women with a high likelihood of CM-TMA presenting during pregnancy, we administer eculizumab or ravulizumab. Evidence for safety and efficacy is presented above. (See 'Indications for terminal complement blockade' above and 'Administration and dosing' above.)
Delivery does not treat CM-TMA, and CM-TMA is not a reason to alter obstetric management, other than treating the pregnancy as high risk.
For individuals with known CM-TMA who wish to become pregnant, with appropriate patient counseling, we continue therapy during the pregnancy and breastfeeding, with dosing as described above. We do not consider CM-TMA to be a contraindication to pregnancy.
Kidney transplant recipients — When TMA presents in the kidney transplant setting, several of the potential causes of TMA must be considered including DITMA, recurrent CM-TMA, or others. Evaluation and management is discussed in detail separately . (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction" and "Thrombotic microangiopathy after kidney transplantation" and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Immunosuppressive agents'.)
Children — Management of ST-HUS and CM-TMA in children is discussed separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Complement-mediated hemolytic uremic syndrome in children".)
Therapies under investigation — Other therapies are under investigation, including additional therapies for terminal complement blockade (a C5a receptor blocking agent), alternative pathway blockade agents and a lectin pathway inhibitor. Their safety and efficacy in CM-TMA require further study.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Thrombotic microangiopathy (TMA) describes syndromes characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. We prefer terminology that takes into account the etiology. We use "hemolytic uremic syndrome" (HUS) to refer to disease caused by Shiga toxin (sometimes referred to as ST-HUS) and "complement-mediated TMA" (CM-TMA) for TMA with disrupted regulation of the complement system. (See 'Conceptual framework' above.)
●Causes of TMA with AKI – The most common cause of ST-HUS in industrialized societies is ST-producing Escherichia coli (STEC). Shigella species may be more common in rural Asia and India. CM-TMA in adults may be caused by heritable complement gene mutations or autoantibodies to complement factor H (CFH). (See 'Causes of ST-HUS' above and 'Causes of CM-TMA' above.)
●Evaluation – Clues from the history include exposures to sources of ST-producing organisms, bloody diarrhea, or positive family history of kidney disease with an autoimmune disorder. Initial laboratory testing includes a complete blood count (CBC), review of the peripheral blood smear, creatinine, lactate dehydrogenase (LDH), and urinalysis with microscopic review. ADAMTS13 testing may be appropriate to exclude thrombotic thrombocytopenic purpura (TTP). Hematologists and/or nephrologists are important for guiding evaluation and management. (See 'Clues from the history' above and 'Initial laboratory testing' above and 'Indications for referral' above.)
●Additional testing for diarrheal illnesses – Stool culture for specific organisms may include E. coli O157:H7 or O104:H4, Shigella species, or others, depending on geographic location and whether there is a known outbreak. Tests for Shiga toxin and DNA testing for specific organisms are also available. The Centers for Disease Control and Prevention (CDC) advises combined testing using stool culture and Shiga toxin assay. Positive results from stool testing for Shiga toxin-producing organisms is reportable to most public health boards. (See 'Tests for Shiga toxin-producing organisms' above.)
●Additional testing for complement disorders – Complement gene testing and testing for CFH autoantibodies is appropriate for individuals with possible CM-TMA. Genetic testing should include the following genes: CFH, CFI, MCP, CFB, C3, and the CFH-CFHR gene region. (See 'Complement testing' above.)
●Management – General supportive measures while awaiting test results may include hydration, antibiotics, antidiarrheal agents, transfusions, and/or dialysis. We avoid aspirin and nonsteroidal antiinflammatory drugs (NSAIDs). Therapeutic plasma exchange (TPE) is reserved for individuals with possible TTP, as the initial approach to CFH autoantibody-driven disease, or when CM-TMA is considered and terminal complement blockade is not available. (See 'Overview of management and supportive measures' above.)
●Anti-complement therapy – Decision-making is illustrated in the figure (algorithm 1).
•Indications – For individuals with a history suggestive of CM-TMA (known personal or family history of CM-TMA; TMA with significant AKI during pregnancy or postpartum; TMA with progressive deterioration in kidney function; lack of bloody diarrhea or abdominal pain; lack of drug known to cause TMA), we recommend anti-complement therapy (Grade 1B). Observational studies have reported improvements in kidney function, platelet count, and hemolysis, in some cases allowing discontinuation of hemodialysis.
Anti-complement therapy may also be appropriate when the diagnosis of TMA is unclear and kidney injury is severe. Involvement of the nephrology consultant is appropriate when anti-complement therapy is considered. (See 'Indications for terminal complement blockade' above.)
•Administration – Once the decision to use anti-complement therapy is made, it should be instituted without delay. (See 'Administration and dosing' above.)
-Standard adult dosing for eculizumab is 900 mg once weekly for four weeks followed by 1200 mg one week later, followed by a "maintenance" dose of 1200 mg once every two weeks.
-Dosing for ravulizumab is 2700 mg loading dose (3000 mg if weight ≥100 kg) followed by a maintenance dose of 3300 mg (3600 mg if weight ≥100 kg), given every eight weeks, starting two weeks after the loading dose. Lower doses are used for individuals <60 kg.
Vaccination against encapsulated organisms and anti-meningococcal prophylaxis is appropriate during therapy. Combining anti-complement therapy with plasma exchange is not advised. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
-For individuals who do not have a pathogenic variant in a complement gene, we suggest discontinuing anti-complement therapy after remission (Grade 2C).
-For those who have a pathogenic variant in a complement gene, the risk of discontinuation is higher, and the decision is individualized. Some individuals may reasonably continue therapy pending additional data.
●Pregnancy and postpartum – Pregnancy (including the postpartum period) is a major precipitating factor for CM-TMA and other primary TMAs. Eculizumab can be administered during pregnancy and breastfeeding; data on adverse fetal and neonatal effects are limited. Delivery does not treat CM-TMA, and CM-TMA is not a reason to alter obstetric management (other than treating the pregnancy as high risk). For individuals with CM-TMA planning pregnancy, we continue eculizumab during pregnancy and breastfeeding, provide education about risks of exacerbation, monitor closely, and emphasize the need to report suspicious symptoms immediately. (See 'Pregnancy or postpartum' above and "Thrombocytopenia in pregnancy", section on 'Thrombotic microangiopathy (TMA)' and "Thrombocytopenia in pregnancy", section on 'Conditions not treated by delivery'.)
●Kidney transplant recipients and children – Management of TMA in kidney transplant recipients and CM-TMA and ST-HUS in children are discussed separately. (See "Thrombotic microangiopathy after kidney transplantation" and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Complement-mediated hemolytic uremic syndrome in children".)
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