Version May 2024
INTRODUCTION — Thrombotic microangiopathy (TMA) is characterized by mechanical hemolytic anemia, thrombocytopenia, and kidney function impairment. There are multiple etiologies for TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
TMA may result in end-stage kidney disease (ESKD), requiring either dialytic therapy or transplantation. Among patients with ESKD due to TMA who undergo transplantation, the risk of recurrence depends upon the underlying etiology. Less commonly, patients who undergo kidney transplantation for other causes of ESKD may also develop TMA.
This topic reviews de novo and recurrent TMA in kidney transplant recipients. The causes, diagnosis, and treatment of TMA in nontransplant patients are discussed elsewhere:
●(See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
●(See "Drug-induced thrombotic microangiopathy (DITMA)".)
●(See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●(See "Complement-mediated hemolytic uremic syndrome in children".)
ETIOLOGY — Most cases of TMA in the nontransplant population, particularly among children, are secondary to infection with Shiga toxin-producing Escherichia coli serotypes or Streptococcus pneumoniae. Other causes include pregnancy, cancer, autoimmune diseases (eg, systemic lupus erythematosus), metabolic issues (eg, cobalamin C/vitamin B12 deficiency), and medications (eg, quinine, chemotherapeutic agents, and immunosuppressive drugs such as calcineurin inhibitors and mammalian [mechanistic] target of rapamycin [mTOR] inhibitors) (table 1). TMA may also be caused by abnormal regulation of the alternative pathway of complement activation secondary to either loss-of-function mutations in regulators (factor H, factor I, and membrane cofactor protein) or gain-of-function mutations in activators (C3 and factor B) of the alternative pathway. In addition, complement-mediated TMA can occur by acquired factors including development of autoantibodies to complement proteins (eg, autoantibodies to factor H). (See "Complement-mediated hemolytic uremic syndrome in children".)
TMA that occurs in the transplant recipient may be de novo or recurrent. Nearly all patients with recurrent TMA have a complement-mediated disease that produced both the pretransplant TMA and the recurrence after transplantation [1]. De novo TMA may be due to any of the etiologies that cause TMA in the general population or may be related to the transplantation. Causes of TMA that are more specific to transplant recipients include immunosuppressive drugs [2,3], ischemia reperfusion injury [4], viral infections, and antibody-mediated rejection (ABMR) [5-8].
●(See 'Epidemiology of de novo TMA' below.)
●(See "Drug-induced thrombotic microangiopathy (DITMA)".)
Transplant recipients who develop de novo TMA in association with any of these exposures may also have a genetic susceptibility to the disease [9,10]. This was shown in a study of 24 transplant recipients with de novo TMA, of whom seven (29 percent) had a mutation in one or more of the genes encoding the complement-regulatory proteins, factor H, and factor I [11].
EPIDEMIOLOGY
Epidemiology of de novo TMA — De novo TMA can affect 3 to 14 percent of kidney transplant recipients [3,12-15]. All of the causes of TMA that are present in the general population may affect the transplant recipient. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
The following causes are of particular importance to the transplant recipient [5,11,13,14,16-28]:
●Medications including calcineurin inhibitors (cyclosporine and tacrolimus), mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (sirolimus, everolimus), and valacyclovir (see "Drug-induced thrombotic microangiopathy (DITMA)")
●Infections including HIV, parvovirus B19, cytomegalovirus (CMV), coronavirus disease 2019 (COVID-19) [29], and others:
•(See "HIV-associated cytopenias", section on 'Other 'can't miss' diagnoses (TMAs, HLH, HHV8 disorders)'.)
•(See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
•(See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension".)
●Antibody-mediated rejection (ABMR) (see "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection")
Epidemiology of recurrent TMA — Among all patients who have TMA as a cause of end-stage kidney disease (ESKD) and receive a kidney transplant, the recurrence rate is between 25 and 50 percent [12,30-33]. However, among individual patients, the risk depends upon the underlying cause of TMA in the native kidney.
Adults who develop TMA and are transplanted are more likely to have recurrence compared with children with hemolytic uremic syndrome (HUS) who receive a transplant [31,34]. In a single-center study of 35 kidney transplant recipients whose ESKD was caused by TMA, recurrence occurred in 10 of 17 adult-onset cases (59 percent) versus 1 of 18 (6 percent) with childhood TMA [31]. This observation is likely due to the fact that the vast majority (90 percent) of cases of childhood-onset TMA are related to Shiga toxin-producing E. coli, which recurs in <1 percent of cases [10]. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Long-term outcome'.)
By contrast, many patients with complement-mediated TMA have recurrence after transplantation. Among such patients, the risk of recurrence depends upon the individual mutation [10]. Estimates of recurrence have been reported at 50 to 100 percent among patients with mutations involving circulating factors such as factor H or I and 15 to 20 percent among patients with mutations in the gene for the transmembrane protein, membrane cofactor protein (MCP, CD46) [10]. In addition, complement factor H (CFH) and complement factor I (CFI) mutations are more common than MCP mutations (table 2). A review of published outcomes after transplant (prior to the availability of the C5 inhibitor, eculizumab) in patients with non-Shiga toxin-associated TMA genotyped for CFH, CFI, and MCP mutations demonstrated an overall recurrence rate of 60 percent, with graft failure in 92 percent of those having recurrence [35]. (See "Complement-mediated hemolytic uremic syndrome in children".)
It is not entirely known why there is such disparity in the rate of recurrence among patients with different mutations. However, one of the main challenges in defining risk of recurrence is not knowing the functional consequences of the genetic variants. A potential explanation for the low recurrence rate of MCP-associated TMA is that MCP is a transmembrane protein and is potentially restored with the transplantation of a new kidney allograft. The potential mechanism was speculated to be endothelial microchimerism [36].
CLINICAL PRESENTATION — The clinical presentation of recurrent and de novo TMA is similar. Patients present with a microangiopathic hemolytic anemia with schistocytes on the blood smear (picture 1), thrombocytopenia, and acute kidney injury (AKI).
Typical laboratory abnormalities include an increased serum creatinine, evidence of mechanical hemolysis (increased reticulocyte percentage, reticulocytosis, and increased serum lactate dehydrogenase [LDH]), and a low platelet count. The urinalysis typically shows hematuria and only a small amount of proteinuria. Some patients may present with only an increased serum creatinine and abnormal urinalysis due to a kidney-limited lesion and without thrombocytopenia and hemolytic anemia [14,30].
Patients with recurrent TMA usually present within one year after transplantation and often within days to weeks [35,37]. In one study of 16 patients with recurrent disease, eight patients presented within one month of transplantation [37]. Patients with de novo TMA typically present within the first three months after transplantation [10].
DIAGNOSIS — The diagnosis of TMA should be suspected in any kidney transplant recipient who presents with an elevated serum creatinine after transplantation, especially if hemolytic anemia and thrombocytopenia are present. The general evaluation of kidney transplant patients who present with an increased serum creatinine is discussed separately. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
In transplant patients suspected of having TMA, a kidney allograft biopsy is not required to confirm the diagnosis of TMA, and the risk of bleeding may be prohibitive if thrombocytopenia is severe or if the patient is on a medication that increases bleeding risk. However, an allograft biopsy can be useful to elucidate the cause of TMA including antibody-mediated rejection (ABMR), viral infection (eg, cytomegalovirus [CMV]), and calcineurin inhibitor toxicity. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction", section on 'Causes of acute allograft dysfunction'.)
PREVENTION OF RECURRENT TMA
Evaluation for mutations — Prior to transplantation, we suggest that all patients with end-stage kidney disease (ESKD) due to hemolytic uremic syndrome (HUS), thrombocytopenic purpura (TTP), or other TMA be evaluated for genetic mutations that are associated with complement-mediated TMA, unless the disorder was clearly associated with a Shiga toxin-producing E. coli or other infection. Patients who reached ESKD due to pregnancy-associated TMA or another secondary TMA whose evolution was unusually aggressive should also be evaluated. Patients who have already been evaluated (eg, at the time of diagnosis) and found to have a mutation do not need to be retested. However, in patients who have been previously evaluated and not found to have a mutation, reevaluation for newly identified mutations and variants prior to transplant is reasonable, particularly if the initial evaluation was performed several years earlier. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Testing for STEC infection'.)
It is often difficult to accurately identify patients with TMA related to genetic mutations based upon clinical features alone. Some patients may be referred for transplant with a remote diagnosis of HUS or TTP, having started dialysis prior to the availability of complement inhibitors (eg, eculizumab). In addition, the transplant team may have limited information about the candidates' initial presentation and treatment. Identification of a genetic mutation clearly associated with complement-mediated TMA can confirm the diagnosis and reinforce the need for prophylactic complement inhibition after transplantation. Laboratories that offer complement genotyping for TMA can be found through the National Center for Biotechnology Information.
If genetic testing is not feasible, we base the need for prophylactic complement inhibition after transplantation on the patient's clinical presentation. We plan for prophylactic complement inhibition in patients with a well-documented clinical presentation consistent with complement-mediated TMA or with a known family history of complement-mediated TMA. In the absence of positive genetic testing or one of these scenarios, we do not plan for prophylactic complement inhibition but rather monitor the patient closely in the immediate posttransplant period for disease recurrence. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Clinical manifestations' and 'Prophylactic therapy with eculizumab' below.)
Selection of donor kidney — For several reasons, we avoid using a living-related donor kidney for patients with TMA attributed to a genetic mutation. Although genetic analysis may be performed in donors, some patients have more than one mutation, and approximately one-third of patients with TMA have complement mutations presently unidentified [9]. Thus, a negative mutational analysis of a potential living-related donor does not guarantee freedom from mutations associated with complement-mediated TMA. In addition, nephrectomy may trigger complement-mediated TMA in the genetically susceptible donor [38].
Living-related donors may be considered in patients with factor H-autoantibody complement-mediated TMA as well as those with TMA attributed to a nongenetic cause.
Prophylactic therapy with eculizumab — We initiate eculizumab (an antibody that targets the complement component C5) prior to transplantation in all patients with complement-mediated TMA due to a genetic deficiency or dysfunction of CFH or CFI [39-41]. We do not use eculizumab as prophylactic therapy in patients who had ESKD related to infection- or drug-associated TMA.
The optimal prophylactic regimen is not known. In patients with complement-mediated TMA related to a genetic mutation, we use the following approach:
●In patients who are receiving a living-unrelated donor kidney, we administer eculizumab at 900 mg intravenously 24 hours prior to transplantation and on days 7, 14, and 21 following transplantation, followed by 1200 mg every two weeks thereafter. Supplemental doses (900 mg or 1200 mg) may need to be administered in settings where complement activation is known to occur, such as following surgery or when there is infection.
●In patients who are receiving a deceased-donor kidney, we administer eculizumab at 900 mg intravenously on postoperative day 3 (after completion of antithymocyte globulin induction) and continue 900 mg weekly for three additional doses, followed by 1200 mg every two weeks thereafter.
The duration of eculizumab therapy after transplantation is unclear. It is possible that eculizumab could be discontinued with subsequent reinstitution among those who have disease recurrence [42,43]. However, no reliable marker of early disease recurrence is available. Until these data are available, we suggest continuing the drug indefinitely.
Some clinicians treat with eculizumab and plasmapheresis [39,44]. However, the added therapeutic benefit of plasmapheresis is unclear when using eculizumab. In addition, since eculizumab is removed with plasmapheresis, a supplemental dose must be given after each pheresis procedure. Given this, along with the costs and risks of the plasmapheresis procedure, we do not use plasmapheresis at our centers and use eculizumab alone.
Patients treated with eculizumab should receive prophylaxis against meningococcal infection, as discussed separately. (See 'Prophylaxis against meningococcal infection' below.)
Given the high cost of eculizumab therapy, some centers have tried to develop alternative transplant strategies that do not use prophylactic eculizumab. As an example, one case series from the Netherlands reported outcomes of 17 patients with complement-mediated TMA who underwent living-donor kidney transplantation without eculizumab prophylaxis [45]. All patients were at high or moderate risk for recurrent disease; 16 had pathogenic or likely pathogenic variants in factor H, C3, factor I, or membrane cofactor protein (MCP), and five had lost a previous transplant due to recurrent HUS. The transplant protocol consisted of induction therapy with basiliximab; triple-therapy maintenance immunosuppression with low-dose tacrolimus, mycophenolate mofetil targeted to a high area under the curve (AUC) level, and prednisone; strict blood pressure control (<130/80 mmHg); and early initiation of statins and angiotensin-converting enzyme inhibitors. At a median of 25 months, all patients had stable graft function (median serum creatinine 1.2 mg/dL [106 micromol/L]) without significant proteinuria; only one patient developed recurrent TMA, which responded to eculizumab treatment. These findings suggest that in patients with complement-mediated TMA, kidney transplant without prophylaxis may be feasible; however, additional longer-term studies are required to confirm the efficacy and safety of this approach.
Combined kidney-liver transplantation — In patients with ESKD due to TMA related to mutations of complement factors that are produced by the liver (eg, factor H), combined kidney-liver transplant has been used to correct the ESKD along with the underlying etiology of TMA [46-48]. However, dual-organ transplantation carries significant potential morbidity and mortality. Additionally, uncontrolled complement activation precipitated by the stress of surgery has led to widespread perioperative vascular thrombosis and graft loss as the liver allograft may not function initially to produce sufficient amounts of the complement protein. Success with combined kidney-liver transplant has improved with the use of intensive plasmapheresis in the pre- and perioperative time to restore levels of the complement protein [47,48]. Despite improvements in the results of simultaneous kidney-liver transplantation, this approach is not commonly used given the effectiveness of prophylactic complement inhibition. (See 'Prophylactic therapy with eculizumab' above.)
TREATMENT OF DE NOVO TMA — In all kidney transplant recipients with de novo TMA, we advocate inpatient admission for further evaluation and management, as discussed below.
Exclusion of potentially reversible causes — In patients who present with clinical features consistent with de novo TMA, we initially evaluate for and treat potentially reversible causes of TMA (see 'Etiology' above and 'Treatment with eculizumab' below):
●In all patients who have not already been evaluated for mutations that are associated with complement-mediated TMA, we perform genetic testing to evaluate for such mutations. If the patient is found to have a genetic mutation associated with TMA, we treat with eculizumab. (See 'Evaluation for mutations' above and 'Treatment with eculizumab' below.)
●In patients with a blood tacrolimus (or cyclosporine) concentration above the therapeutic range, we reduce the dose of the calcineurin inhibitor. We do not discontinue the calcineurin inhibitor unless the blood concentration is markedly elevated (ie, tacrolimus trough level >15 ng/mL or cyclosporine trough level >400 ng/mL or two-hour level >1500 ng/mL) [32,49]. Among patients who develop de novo TMA while on cyclosporine, switching to tacrolimus (or vice versa) is an alternative option once the acute episode of TMA resolves. If the patient is taking a mammalian (mechanistic) target of rapamycin (mTOR) inhibitor, we discontinue this agent. (See "Drug-induced thrombotic microangiopathy (DITMA)".)
●We exclude, by polymerase chain reaction (PCR), infections including cytomegalovirus (CMV), BK virus, parvovirus, and HIV. If testing for any of these infections is positive and eculizumab has not yet been initiated, we treat the infection before starting eculizumab. However, if the signs and symptoms of TMA persist or there is clinical deterioration despite treatment of an infectious agent, we initiate eculizumab and continue until the infection is controlled. Similarly, if testing for any of these infections is positive and eculizumab has already been started, we continue eculizumab until the infection has been treated and TMA has resolved [50].
•(See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy", section on 'Treatment'.)
•(See "Treatment and prevention of parvovirus B19 infection", section on 'Treatment'.)
•(See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
•(See 'Treatment with eculizumab' below.)
●Among patients who have diarrhea, we exclude infection with Shiga toxin-producing organisms (eg, E. coli serotypes O104:H4, O157:H7, O111; Shigella species) by stool studies. If stool testing for any of these organisms is positive, we administer eculizumab until diarrhea resolves and the patient's genetic status is known. In patients who have a genetic mutation associated with TMA, we continue eculizumab therapy as detailed below. In patients who do not have a genetic mutation, we discontinue eculizumab. (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment" and 'Treatment with eculizumab' below.)
●We perform ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) activity testing to exclude a diagnosis of thrombotic thrombocytopenic purpura (TTP). In patients who are found to have severe ADAMTS13 deficiency (activity <10 percent), we initiate treatment for TTP, as discussed separately. If the patient has already been started on eculizumab and genetic testing does not identify any mutations associated with TMA, we discontinue eculizumab. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing' and "Immune TTP: Initial treatment", section on 'Overview of treatment approach'.)
Treatment with eculizumab — In patients who are found to have a genetic mutation associated with TMA or have persistent symptoms and signs of TMA or progressive disease despite addressing potentially reversible causes (see 'Exclusion of potentially reversible causes' above), we treat with eculizumab. If eculizumab is not available, plasma exchange (1.5 volumes of fresh frozen plasma every 48 hours) can be performed [15]. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology".)
Dosing and duration of therapy — We administer eculizumab at 900 mg intravenously weekly for four doses, followed by 1200 mg every two weeks thereafter. The optimal duration of eculizumab treatment in patients with de novo TMA is unclear, and there is no evidence from randomized controlled trials to guide this decision. Our approach, which is based upon clinical experience at our centers, is as follows:
●In patients who are at moderate to high risk for disease recurrence, we continue eculizumab indefinitely. Such patients include those who are found to have a pathogenic mutation in any complement protein, except in membrane cofactor protein (MCP); those with a history of recurrence in a previous allograft or biopsy-proven TMA in the native kidney (even if no genetic variant is identified); and those who have a persistent factor H autoantibody [45]. For patients who have a genetic variant of uncertain significance, treatment duration is determined on a case-by-case basis based upon functional analysis of the variant (when available).
●In patients who are at low risk for disease recurrence (ie, those carrying an MCP mutation and patients who have been successfully treated for removal of factor H autoantibodies), we discontinue eculizumab after 6 to 12 months and monitor closely for disease recurrence.
There are limited data evaluating the discontinuation of eculizumab therapy in kidney transplant patients with TMA. In a case series that reported the safety of discontinuing eculizumab in 10 patients (including one kidney transplant recipient) in whom disease activity was monitored by means of home urine dipstick testing, three experienced relapse within six weeks of discontinuation [51]. All three patients who experienced relapse had pathogenic mutations in factor H but completely recovered after immediate reinitiation of treatment. Other studies in nontransplant patients have shown that eculizumab withdrawal can be considered on a case-by-case basis. These data are discussed separately. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Can anti-complement therapy be stopped?'.)
Monitoring during eculizumab therapy — Among patients treated with eculizumab, we monitor hemoglobin, platelet count, and lactate dehydrogenase (LDH) daily while patients are hospitalized and then at each subsequent clinic visit. To assess the effectiveness of complement blockade, we measure total hemolytic complement (CH50) prior to each dose of eculizumab for the first four doses; patients with complete suppression should have a CH50 of <10 percent. Measurement of CH50 can also confirm whether dose adjustment is indicated in patients not responding to the initial dose of eculizumab. In addition, trough serum eculizumab levels (if available) can be measured with a target level of >100 mcg/mL [52]. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Monitoring'.)
Prophylaxis against meningococcal infection — Treatment with eculizumab is associated with life-threatening and fatal meningococcal infections. Patients should receive meningococcal vaccination at least two weeks prior to initiation of eculizumab whenever possible. We ensure that patients listed for transplant with atypical hemolytic uremic syndrome (HUS) are vaccinated against meningococcus prior to transplant. We also administer daily antimicrobial prophylaxis for prevention of meningococcal infection in patients treated with eculizumab, despite vaccination, due to increased infection risk with immunosuppression. In addition, children should be vaccinated for S. pneumoniae and Haemophilus influenza type B (Hib) as they are at risk of developing serious infections due to these bacterial species.
●(See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)
●(See "Complement-mediated hemolytic uremic syndrome in children", section on 'Adverse effects'.)
Less commonly used therapies — Success has also been reported with intravenous immune globulin (IVIG), rituximab, and conversion to a calcineurin inhibitor-free maintenance regimen using belatacept [53-56].
TREATMENT OF RECURRENT TMA — In all patients with recurrent TMA, we advocate inpatient admission for further evaluation and management.
We treat all patients with recurrent TMA with eculizumab, 900 mg intravenously administered weekly for four weeks followed by 1200 mg every two weeks thereafter. The optimal duration of eculizumab treatment in patients with recurrent TMA is unclear, and there is no evidence from randomized controlled trials to guide this decision. Until these data are available, we suggest continuing the drug indefinitely.
The rationale for using eculizumab in patients with recurrent TMA is based upon observational data [57-62]:
●In two prospective series, 37 patients (15 of whom had recurrent TMA after transplantation) received eculizumab for a median of 64 and 62 weeks, respectively [60]. Eculizumab increased the platelet count and decreased lactate dehydrogenase (LDH) levels in most patients and improved kidney function in approximately one-half of patients; four of five patients were able to discontinue dialysis. Plasmapheresis was discontinued in nearly all patients who were treated with this therapy at baseline. Specific data for the 15 patients with recurrent TMA were not provided.
●In another series from the Netherlands that included 15 patients with recurrent TMA after kidney transplantation, seven patients had recurrence early after transplant (median 3 months) while eight presented late (median 46 months) after transplant [62]. Of note, in the Netherlands, kidney transplantation for complement-mediated TMA is usually performed without eculizumab prophylaxis, and the drug is given only in cases of posttransplant recurrence. All patients were considered at moderate to high risk for recurrence (ie, carried a genetic variant, had a diagnosis of TMA at the time of kidney transplantation, or had lost a previous kidney transplant to TMA recurrence). Treatment with eculizumab resulted in an initial improvement or stabilization of estimated glomerular filtration rate (eGFR) in 14 patients. However, at a median of 29 months, six patients had an eGFR <30 mL/min/1.73 m2, three of whom developed graft loss.
Nearly all patients who develop recurrent TMA are assumed to have a complement-mediated process. However, other potential precipitating factors for TMA should be excluded. Exclusion of these factors should not delay the initiation of eculizumab therapy. (See 'Exclusion of potentially reversible causes' above.)
Monitoring during eculizumab therapy in patients with recurrent TMA is similar to that in patients with de novo TMA who are treated with eculizumab. All patients treated with eculizumab should receive prophylaxis against meningococcal infection, as discussed separately:
●(See 'Monitoring during eculizumab therapy' above.)
●(See 'Prophylaxis against meningococcal infection' above.)
Plasma infusions and plasmapheresis similar to that used for the primary disease have been given, with some apparent success in selected patients [2,12,63,64]. In patients with recurrent TMA, plasmapheresis is generally reserved for patients who have TMA associated with factor H-autoantibodies or used as a temporizing measure in patients awaiting the availability of eculizumab therapy. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Plasma therapy'.)
PROGNOSIS — Overall graft outcomes are worse in patients with recurrent TMA [9]. In one study of kidney transplant recipients whose end-stage kidney disease (ESKD) was due to TMA, the one- and five-year allograft survival rates were lower for those who developed recurrent disease compared with those who did not (33 versus 57 percent at one year and 19 versus 57 percent at five years) [37]. However, these data were obtained prior to the availability of eculizumab.
RETRANSPLANTATION — Retransplantation is a potential option in selected patients with recurrent or de novo TMA after transplant. At our centers, we consider retransplantation in patients with graft loss due to complement-mediated TMA prior to the availability of eculizumab and in those with de novo TMA related to infection or medications. As discussed above (see 'Prophylactic therapy with eculizumab' above), prophylactic eculizumab is warranted in those with a genetic risk but may not be necessary for those with an infectious or medication-related cause of the TMA. However, these patients should be closely monitored posttransplant for TMA recurrence with the initiation of eculizumab if clinically indicated.
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: Kidney transplantation" and "Diagnosis of immune TTP" and "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)
SUMMARY AND RECOMMENDATIONS
●Etiology – Thrombotic microangiopathy (TMA) is characterized by mechanical hemolytic anemia, thrombocytopenia, and kidney function impairment that occasionally progresses to end-stage kidney disease (ESKD), requiring either dialysis or transplantation. Among patients with ESKD due to TMA who undergo transplantation, TMA commonly recurs, particularly among patients with TMA that is related to a genetic mutation. Less commonly, patients who undergo kidney transplantation for other causes of ESKD may develop de novo TMA due to immunosuppressive drugs, ischemia reperfusion injury, viral infections, and antibody-mediated rejection (ABMR). (See 'Etiology' above.)
●Clinical presentation and diagnosis – The clinical presentation of recurrent and de novo TMA is similar. Patients present with a microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Typical laboratory abnormalities include an increased serum creatinine, evidence of hemolysis, and a low platelet count. The urinalysis typically shows hematuria and only a small amount of proteinuria. Some patients may present with only an increased serum creatinine and abnormal urinalysis due to the kidney lesion associated with TMA and without thrombocytopenia and hemolytic anemia. Biopsy whenever possible may confirm the diagnosis as well as underlying etiologies. (See 'Clinical presentation' above and 'Diagnosis' above.)
●Prevention of recurrent TMA
•Prior to transplantation, all patients with ESKD due to TMA should be evaluated for genetic mutations that are associated with complement-mediated TMA, unless the disorder was caused by a Shiga toxin-producing Escherichia coli or other infection. (See 'Evaluation for mutations' above.)
•Among all patients with complement-mediated TMA, we advise using a living-unrelated donor kidney or a deceased-donor kidney rather than a living-related donor kidney. (See 'Selection of donor kidney' above.)
•For all patients with complement-mediated TMA due to genetic deficiency or dysfunction of complement factor H (CFH) or complement factor I (CFI), we suggest prophylactic treatment with eculizumab rather than plasmapheresis (Grade 2C). We do not use eculizumab as prophylactic therapy in patients who had ESKD related to infection- or drug-associated TMA. (See 'Prophylactic therapy with eculizumab' above.)
●Treatment of de novo TMA – Among all patients with de novo TMA, we evaluate for and treat all potentially reversible causes. Patients who have not already been evaluated for mutations that are associated with complement-mediated TMA should undergo genetic testing to evaluate for such mutations. In patients who are found to have a genetic mutation associated with TMA or have persistent symptoms and signs of TMA or progressive disease despite addressing potentially reversible causes, we treat with eculizumab. If eculizumab is not available, plasma exchange can be performed. (See 'Treatment of de novo TMA' above.)
●Treatment of recurrent TMA – For all patients who develop recurrent TMA, we suggest treating with eculizumab rather than plasmapheresis (Grade 2C). The optimal duration of eculizumab treatment in patients with recurrent TMA is unclear. In addition, other potential precipitating factors for TMA, such as medications and infections, should be excluded. (See 'Treatment of recurrent TMA' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mohamed H Sayegh, MD, and Christina Klein, MD, who contributed to earlier versions of this topic review.
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