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REVIEW
De Novo and Recurrent Thrombotic Microangiopathy After Renal Transplantation: Current Concepts in Management

Abstract

Thrombotic microangiopathy is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome can greatly depend on the underlying etiology and on the timing of therapeutic interventions. Thrombotic microangiopathy syndrome may occur with no previous history of thrombotic microangiopathy (that is, de novo thrombotic microangiopathy), mostly due to medica­tions or infections. More frequently, it may recur after kidney transplant in patients with end-stage renal failure due to atypical hemolytic uremic syndrome. However, for patients with Shiga-toxin-induced hemolytic uremic syndrome, particularly pediatric patients, there is a favorable prognosis. A fundamental tool for management of this disease is genetic screening for abnormal mutations; this can recognize the suggested approach of therapy and may determine the outcome of the disease to a large extent. Although patients with complement factor
H and I mutations have worse prognosis, other patients with membrane cofactor protein mutations, for example, have a more favorable prognosis. Accordingly, the plan of therapy can be tailored with a better chance of cure. Unfortunately, the successful use of the biological agent eculizumab, an anti-C5 agent, in some of these syndromes is largely impeded by its high cost, which is linked to its use as a life-long therapy. However, newly suggested therapeutic options may ameliorate this drawback.


Key words : De novo thrombotic microangiopathy, Hemolytic uremic syndrome, Recurrent thrombotic microangiopathy, Renal allograft

Introduction

The evolution of thrombotic microangiopathy (TMA) after renal transplant, either de novo or as recurrent disease, is a well-documented complication that not only affects allograft function but also adversely influences patient and allograft longevity.1 Man­agement of this serious disease, which encompasses hemolytic uremic syndrome (HUS), depends largely on the underlying etiology. With the form of TMA recognized as Shiga toxin-associated HUS (classic HUS), there is a favorable prognosis; however, for TMA recognized as complement-mediated HUS (atypical HUS [aHUS]), there is usually a worse outcome that requires a more sophisticated therapeutic approach.1

The association between cyclosporine and TMA was first described in 1981.2 Thrombotic micro­angiopathy has also been linked to the commonly used calcineurin inhibitor (CNI) tacrolimus, with a previously estimated incidence of approximately 3% to 14% or as much as 25%.2,3

Atypical HUS is a systemic disease involving the kidney and recurs in up to 100% of kidney transplants, with poor allograft outcome. Pathogenesis can be attributed to the dysregulation of the alternative complement pathway that triggers uncontrolled cleavage of terminal complement protein C5 with excessive C5b-9 complex production.4 This cascade results in endothelial injury, increased expression of adhesion molecules that is consequently followed by fibrin-rich microthrombi with an end-organ ischemia, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA).4-6 In this review, we will review recent concepts in the management of different types of TMA.

Definition of Thrombotic Microangiopathy

Thrombotic microangiopathy refers to a histo­pathologic entity that includes vessel wall thickening (arterioles and capillaries), intraluminal thrombi, and vessel luminal occlusion. The resultant platelet and red blood cell (RBC) consumption at the level of the microvasculature of vital organs, including the kidney, leads to thrombocytopenia and MAHA. Two clinical situations with overlapping features have been recognized: thrombotic thrombocytopenic purpura (TTP) and HUS. Neurological features are essential for TTP diagnosis but not for HUS.7,8

Hemolytic Uremic Syndrome

De novo and recurrent forms
Kidney transplant recipients (KTRs) can develop HUS either de novo or as a recurrent disease. De novo HUS includes TMA that occurs in native kidneys and transplant-related causes. Medications such as CNIs, viral infection, ischemia-reperfusion injury, and antibody-mediated rejection (AMR)9-11 are among transplant-related causes. De novo HUS secondary to genetic mutations in complement-regulatory proteins may also develop, but this is less frequent.12

Recurrent HUS is almost always as a result of dysregulation of complement secondary to genetic mutations in complement proteins regulating the alternative pathway. These occurrences are usually called “complement-mediated” HUS or aHUS.

Prevalence
Approximately 3% to 14% of KTRs develop de novo HUS.2,13 Factors encountered in KTRs that can lead to de novo HUS include AMR, infections (eg, cytomegalovirus, HIV, and parvovirus B19), and medications (eg, CNI, mechanistic target of rapamycin [mTOR] inhibitors, and valacyclovir). Switching patients on cyclosporine immunosup­pression to tacrolimus can reverse cyclosporine-induced HUS in more than 80% of patients. However, evidence clarifying this response is limited.

Childhood-onset HUS, which is related to the Shiga toxin-producing Escherichia coli (E. coli) in more than 90% of patients, has a recurrence rate of less than 1% in KTRs.14 Recurrence is uncommon in infection-related HUS. In contrast, many patients with complement-mediated HUS (aHUS) develop recurrent disease after transplant, with a reported rate of recurrence in patients on dialysis secondary to HUS ranging between 25% and 50%.15,16 For patients with complement-mediated HUS, recurrence depends to a large extent on the type of genetic mutations,14 with estimated rate of recurrence of 50% to 100% in patients having mutations involving complement factor H (CFH) and complement factor I (CFI) but only 15% to 20% in patients with mutations involving membrane cofactor protein (MCP).14 A reason for the low recurrence incidence of MCP-associated HUS is that MCP is highly expressed on the kidney and thus is rapidly restored after transplant of a new graft.16

Other reported factors that contribute to HUS recurrence may include CNI use, living related donor kidney transplant, and short duration between HUS onset and start of dialysis.

Clinical presentation
Both de novo and recurrent HUS have a similar presentation (MAHA, thrombocytopenia, and acute kidney injury). Low platelet count, increased serum creatinine level, and evidence of hemolysis (reticulocytosis and schistocytes on peripheral smear and increased lactate dehydrogenase) have also been observed. Hematuria/proteinuria syndrome can also be present. Nevertheless, this presentation is not universal, as some patients may present with only graft dysfunction with abnormal urine analysis.2 With regard to timing of presentation, de novo HUS typically presents within the first 3 months posttransplant,14 whereas recurrent HUS usually presents within days to weeks.17

Diagnosis
For any KTR who presents with allograft dysfunction, the possibility of HUS should be raised, particularly if hemolytic anemia is present and lowered platelet count. However, final diagnosis is ultimately documented via a tissue diagnosis.

Pathology
Typical histopathologic findings include glomerular and arteriolar thrombosis, intracapillary engorgement with RBCs and RBC fragments, basement membrane detachment, and endothelial swelling with glomerular ischemia. With healing of the arteriolar walls, an onion-skin hypertrophy supervenes (Figure 1 and Figure 2).5

Two pathological entities in tissue biopsy can
be observed in allograft biopsy: (1) cyclosporine nephrotoxicity, showing proximal tubular vacuo­lations with obliterative arteriopathy; and (2) acute AMR, showing intraluminal thrombi, circulating donor-sensitive antibody, and C4d staining of peritubular capillaries. A differential diagnosis of AMR from HUS is difficult, as both conditions share in allograft dysfunction and resistance to antirejection therapy. However, the presence of predominant endarteritis with global involvement of the whole vascular tree of the graft is characteristic of an acute AMR.5

In about 30% of cases, TMA is strictly confined to allograft tissues, with no associated manifestations of hemolysis or drop in platelet count. Therefore, tissue diagnosis is necessary. For any young KTR who presents with severe hypertension associated with decline in allograft function, the possibility of TMA should be raised.2

Pathogenesis
An endothelial cell injury associated with imbalance between thrombotic and antithrombotic factors at the level of microvasculature has been postulated to be the culprit mechanism. Risk of TMA appears to be highest during the first 3 months posttransplant, with female and elderly patients seeming to be more vulnerable.3

Classic Hemolytic Uremic Syndrome

Internalization of the Shiga toxin occurs in the endothelial cells, which is followed by activation through cytokine release and endothelial damage, resulting in a cascade of endothelial disruption and platelet clustering, and thrombosis could develop. The latter is the hallmark of TMA.18

Calcineurin Inhibitor-Related Hemolytic Uremic Syndrome

Through potent vasoconstriction, endothelial toxicity, and prothrombotic and antifibrinolytic factors,16,19 CNI can induce HUS. Cyclosporine and tacrolimus can upregulate the production of the vasoconstrictors elements (eg, endothelin 1 and angiotensin II), which can result in evolution of a procoagulation state that triggers platelet aggregation and thrombosis.16

Two different types of TMA have been described by Schwimmer and associates in their retrospective study: systemic TMA (62%) and localized TMA (38%) without systemic extension.2 Graft loss was more often observed with the systemic form (more aggressive and disseminated disease) compared with the localized type.2

Antibody-Mediated Rejection and Hemolytic Uremic Syndrome

Satoskar and colleagues19 first suggested AMR as an etiology of TMA. The investigators found 55% of their biopsies were C4d positive. Another study found 88% of biopsies had C4d deposits.20 Both C4d staining of peritubular capillaries and DSA were found to be 2 fundamental links between TMA and AMR.5,21

Genetic Predisposition for Hemolytic Uremic Syndrome

When there is no clear evidence of any HUS manifestations before transplant, a de novo HUS diagnosis is proposed. However, Broeders and col­leagues have described a case of silent polymorphism of factor “H” that presents as de novo HUS after transplant.22 Thus, a genetic predisposition to aHUS may be hidden until clinically triggered via an inciting factor (“second hit”) such as transplant surgery or an associated infection.23

Risk Factors of De Novo Hemolytic Uremic Syndrome

The reported incidence of de novo HUS due to high doses of cyclosporine is 4% to 15% with 43% graft survival.8,24 About 1% of KTRs who receive tacrolimus can also develop de novo HUS. For CNI-related TMA, the following mechanisms have been postulated: potent vasoconstriction, endothelial toxicity, and prothrombotic and antifibri­nolytic activity.

Other risk factors for de novo HUS after transplant include the following: use of mTOR inhibitor, with rapamycin reported to be associated with de novo TMA25; the use of donors after cardiac death5; prolonged warm ischemia time, where resultant endothelial injury in the graft may increase the antigenic presentation, which can induce acute rejection and TMA5; infections (eg, viral infection, including cytomegalovirus infection)5; de novo carcinoma, AMR, scleroderma, and antiphospholipid syndrome5; and genetic mutations, with mutations in CFH, CFI, and CFH/CFI combination contri­buting to an incidence of 29% of patients with de novo TMA.

Donor-sensitive antibodies may be included in HUS evolution through an alternative mechanism of platelet activation that results in HUS with decline in allograft function due to associated AMR. Both TMA and HUS may be linked to AMR under an umbrella of genetic as well as acquired risk factors, with the resultant development of this serious variant of allog­raft rejection.21 Factor V Leiden may also be a factor among a constellation of genetic defects that share in TMA evolution, especially with CNI exposition.26

Role of Complement Abnormalities in Recurrence of Atypical Hemolytic Uremic Syndrome

Outcomes of aHUS are largely dependent on the type of complement aberrations.19,27-29 Worse outcomes occur in KTRs with CFH mutations; presence of CFH mutation is usually complicated by a high rate of recurrence (76%) and a high incidence of graft loss (86%) compared with that shown in patients without CFH mutations.17 Worse outcomes are also shown with CFI mutations, with rate of recurrence increased to 92% in KTRs with CFI mutations; graft loss occurs in almost 85% of recurrent cases. Moreover, patients with C3 and complement factor B mutations also have a high rate of recurrence.5

Better outcomes have been shown in patients with “anti-CFH autoantibodies”5 and in patients with MCP mutations; MCP is a membrane-associated regulator that controls complement activity. Recurrence of aHUS is rare as allograft endothelial cells express normal MCP.5 Patients with thrombomodulin mutations also have a low risk of recurrence, as thrombomodulin is a transmembrane protein that resembles MCP.24

For patients with combined mutations, it is difficult to interpret outcomes because of the rarity of cases. However, heterozygous mutations in CFI/MCP and CFH/CFI rarely result in recurrence after renal transplant, whereas, recurrences have been reported in patients with other combinations of CFH/CFI mutations and combinations with 3 mutations in MCP/CFH/CFI.29,30

Prognosis of Hemolytic Uremic Syndrome

Prognosis of de novo is usually better than that of recurrent HUS.4 Patients with HUS have a favorable prognosis if the lesions are confined to the glomeruli (localized form).31 In KTRs with end-stage renal disease (ESRD) due to HUS, 1- and 5-year survival rates have been shown to be lower in those with HUS recurrence versus in those without recurrence (33% vs 57% at 1 year and 19% vs 57% at 5 years).31 Table 1 summarizes the fundamental differences between de novo and recurrent HUS.

Prevention of Hemolytic Uremic Syndrome Recurrence

Prevention of HUS recurrence should adhere to the following approaches. First, a living related donor kidney should be avoided for patients who develop ESRD due to complement-mediated HUS because of the documented high rate of recurrence,14,32 because nephrectomy can trigger HUS in susceptible subjects,27 and because negative genetic testing does not guarantee the absence of mutations, as some patients may have more than 1 mutation.8 Second, genetic screening for mutations is advised. Before transplant, all patients on dialysis due to HUS and candidates for renal transplant should be screened for genetic mutations, as a sole dependence on clinical features alone can be misleading.16 Third, with regard to prophylactic interventions for complement-mediated HUS due to genetic mutations, KTRs who receive deceased donor kidneys should start antithymocyte globulin induction followed by 900 mg eculizumab at day 3 posttransplant, then 900 mg weekly for 3 weeks, then 1200 mg every 2 weeks thereafter.16 Fourth, a combination of plasma exchange with immunosup­pression with corticosteroids and/or rituximab has been shown to be a successful strategy in those with anti-CFH autoantibodies to lower the antibody titer and to prevent HUS recurrence.33,34

Treatment of Thrombotic Microangiopathy

As stated earlier, TMA encompasses TTP, Shiga toxin-associated HUS (classic HUS), and aHUS. Although TTP responds well to plasmapheresis (plasma exchange; PE) and Shiga toxin-associated HUS can be managed by supportive measures, aHUS, on the other hand, is a life-threatening event necessitating more aggressive therapeutic interventions.7

Atypical HUS usually presents with throm­bocytopenia, hemolysis, and kidney failure. Prognosis is ultimately poor due to unlimited complement activity leading to TMA. Although 50% of untreated patients progress to ESRD, 10% of patients can have progression in the earlier phase of disease. Kidney transplant is a robust therapeutic option. Unfortunately, with high rate of recurrence, graft loss is a real threat35 and use of PE therapy has shown an extremely limited response, with patients ultimately returning to dialysis.36 Eculizumab (a complement 5 blocker) has recently shown increasing popularity due to rapid resumption of allograft function.37 Moreover, kidney transplant can be successfully performed under an umbrella of eculizumab prophylaxis.38 However, this biological agent has a high cost, which can be of concern when applying a “lifelong prophylactic strategy”39,40 with the agent; other options are discussed below.

Treatment of de novo hemolytic uremic syndrome
For treatment of de novo HUS, CNI/mTOR inhibitor withdrawal or dose reduction to a lower trough level is advised, depending on the suspected etiology. With the consideration that these agents are also common causes of HUS, their withdrawal or reduction can induce resolution of de novo HUS.16 Switching to tacrolimus is another therapeutic option for patients who are receiving cyclosporine.

If the disease progresses despite withdrawal of CNI/mTOR inhibitor, PE (1.5 volume fresh frozen plasma every 48 h) is recommended. The beneficial effects of PE may be attributed to the removal of platelet-aggregating factors like thromboxane A2 with simultaneous replenishment of missing factors.13 For patients refractory to PE, eculizumab at 900 mg intravenous weekly for 4 weeks, followed by 1200 mg every 2 weeks, is advised.

Genetic screening for mutations (eg, CFH and CFI) associated with complement-mediated HUS should be performed. When there are negative results for culprit mutations, eculizumab should be held and the patient should be monitored closely for other triggering factors (eg, cytomegalovirus and E. coli infections). For patients with positive screening results, eculizumab should be continued indefinitely (other options are described below).16

Vaccinations for life-threatening infections (eg, Neisseria meningitis, Streptococcus pneumoniae, and Haemophilus influenzae type B) should be performed for patients on eculizumab therapy.16

Therapeutic options in addition or instead of eculizumab are belatacept and rituximab.41-44 Belatacept was successfully combined with eculizum­ab as an alternative to CNI to reverse de novo aHUS in a patient with a heterozygous deletion in the CFH-related protein (CFHR)3-CFHR1 gene.7 In that case presentation from Dedhia and colleagues,7 the patient showed a successful response to eculizumab plus belatacept, a CD80-binding fusion protein, for maintenance immunosuppression as an alternative to the CNI agent tacrolimus.

Treatment of recurrent atypical hemolytic uremic syndrome
The significant role of a complement-mediated pro­cess as a culprit mechanism of HUS recurrence is now universally accepted. However, all other precipitating factors should be excluded before considering eculizumab therapy. First, CNI and mTOR inhibitors should be withdrawn or at least reduced to a lower trough level, with continuation of steroids and antimetabolites.16 Second, cytomegalovirus, BK virus, parvovirus, and HIV infections should be excluded through polymerase chain reaction tests. Third, for patients with diarrhea, E. coli serotype O104:H4 (responsible for E. coli outbreak-associated HUS) should be excluded through stool examination.16 Fourth, patients who missed genetic screening for mutations in complement-associated aHUS should commence with genetic testing.16

Depending on the currently available data,37,45-48 eculizumab therapy has had a clear beneficial impact on aHUS recurrence. Many patients can be withdrawn from dialysis, with elevation of the platelet count and normalization of the lactate dehydrogenase level. Therefore, all patients with recurrent aHUS should receive eculizumab therapy at 900 mg intravenously weekly for 4 weeks followed by 1200 mg every 2 weeks; a target trough level of eculizumab >100 ?g/mL is recommended.49 The duration is indefinite for patients with recurrent aHUS, as no randomized controlled trials have been performed for other options (see below). For patients under eculizumab treatment, daily hemoglobin level, platelet count, and lactate dehydrogenase measure­ments should be made for hospitalized patients, with regular measurements in the outpatient clinic. Response of eculizumab should be measured by total hemolytic complement (CH50) level before each dose for the first 4 doses; a reasonable response of complete suppression is usually expected at a level below 10%.49

Patients who are resistant to eculizumab should receive PE or plasma infusion (1.5 volume) every 48 hours; a booster dose of eculizumab is advised prior to each plasma infusion (300 mg) or after each PE session (600 mg). Meningococcal vaccination before eculi­zumab therapy is advised to guard against life-threatening infections, with at least 2 weeks of prophylactic broad-spectrum antibiotics thereafter.16

In view of the high cost of eculizumab therapy, a recent discussion of experts in the last “EDTA 2017” confe­rence described other cost-effective options. Alterna­tive options included bortezomib and eculizumab only “upon recurrence.” Depletion of plasma cells with the proteasome inhibitor bortezomib has been proposed as a new therapeutic option for management of recurrent aHUS.5 Eculizumab upon recurrence was recently described by Brand and colleagues in KTRs with aHUS without the need for eculizumab prophylaxis.50 A 2.6-year follow-up in KTRs who avoided risk factors that can trigger aHUS recurrence (eg, surgery and viral infection) showed a decline in recurrence rate of up to 10%. Moreover, a reasonable cost-effective rate was achieved with an eculizumab upon recurrence strategy, which depended primarily on monitoring the risk of recurrence through observation of trigger factors. Monitoring of early markers (eg, thrombomodulin and soluble C5b-9, both shown to promising early markers of disease recurrence6) in urine was also performed by the investigators.50

Both an “eculizumab induction” strategy and a “lifelong maintenance therapy” strategy could result in an overtreatment burden, which will not only have a negative effect on the cost-effective balance but also will exaggerate untoward effects burden. No evidence is currently available that curative eculizumab is less effective than a prophylactic strategy. Therefore, the policy of “therapy upon recurrence” is preferable for a better cost-effective balance. Furthermore, the need to explore early markers of disease recurrence appears to be urgently warranted. The promising markers thrombomodulin and soluble C5b-9 in urine6 can be used to not only predict HUS recurrence but can also help to evaluate eculizumab response and draw the best therapeutic plan. Fulfillment of these parameters in large cohorts of randomized studies can help achieve the best cost-effective strategy.50

Brand and associates50 used the decision analytical approach (Markov modeling) to evaluate 5 strategies: (1) dialysis therapy only, (2) kidney transplant without eculizumab, (3) eculizumab upon recurrence (kidney transplant plus 3 months of eculizumab therapy in case of HUS recurrence), (4) eculizumab induction (kidney transplant plus 12 months of eculizumab prophylaxis and retreatment after HUS recurrence), and (5) lifelong eculizumab treatment (kidney transplant plus lifelong eculizumab prophylaxis). The investigators demonstrated that eculizumab therapy resulted in a substantial benefit in quality-adjusted life years. The novel suggested strategy of “eculizumab upon recurrence” was shown to be more efficacious with regard to gain in quality-adjusted life years compared with both eculizumab induction and lifelong eculizumab prophylaxis. The latter 2 treatment options can also result in a higher cost-effective balance. Finally, living donor kidney transplant for patients with aHUS appeared to be more feasible with no need for eculizumab prophylaxis as long as monitoring of trigger factors of recurrence was continued with utmost priority.50

Conclusions

The pathogenesis of TMA and its risk factors remain important topics of interest among the transplant community. The proper preparation of KTRs, particularly regarding genetic mutation abnormalities related to the evolution of aHUS (complement-mediated HUS), is a fundamental step before commencing with kidney transplant. This is particularly crucial in patients with ESRD due to HUS disease. A careful evaluation of KTRs can result in detection of a simple and avoidable etiology for HUS (eg, medications, switching of which can result in a complete disease reversal and avoidance of unnecessary costly medications). Therapeutic agents are under robust investigation to reduce cost and to improve the cost-effective balance (eg, through the therapy upon recurrence strategy). However, more efforts are needed to simplify these complicated therapeutic strategies of this serious disease and to guarantee better patient and graft outcomes.


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DOI : 10.6002/ect.2021.0069


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From the 1Nephrology Department, Jaber El Ahmed Military Hospital, Safat, Kuwait; the 2Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool, United Kingdom; and the 3College of Medicine, Ain Shams University, EMP, 15028, Cairo, Egypt
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Fedaei Abbas, Jaber El Ahmed Military Hospital, Nephrology department, PO Box 454, Safat 13005
Phone: +965 97529091
E-mail: Fedaeyabbas2009@gmail.com, edaeyabbas2008@yahoo.com