Recurrent Thrombotic Microangiopathy Research Articles

Recurrent Atypical Hemolytic Uremic Syndrome: A Masquerade of Antibody-Mediated Rejection?

Abstract Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy (TMA) resulting from uncontrolled activation of the alternate complement pathway. It is necessary to distinguish a recurrent aHUS posttransplant from de novo aHUS, as the former is usually associated with complement abnormalities and has a poorer prognosis. Furthermore, COVID-19 is believed to unmask underlying complement defects triggering a relapse of aHUS. In this report, we present one such unique histologic presentation of recurrent TMA following a COVID-19 infection, which was not just a diagnostic challenge but could easily have been misdiagnosed as an antibody-mediated rejection.

Thrombotic microangiopathy after kidney transplantion

Background and objectives: Thrombotic microangiopathy after kidney transplantation is rare but serious complication. The purpose of this study is to describe the cases of thrombotic microangiopathy after kidney transplantation. Patients and Methods: This retrospective study used the reports of all kidney transplant biopsies that were done in Kurdistan region from January 2017 to April 2022. The biopsy reports with diagnosis of Thrombotic microangiopathy were extracted from this total number and the patients, and pathological data included in the reports were recorded. Results: The total number of 1635 graft biopsies, of which 82 (5.01%) were found to have Thrombotic microangiopathy features. The mean age of studied patients with Thrombotic microangiopathy was (38.2 years) and male to female ratio as 2.3:1. We found 67.1% of cases of Thrombotic microangiopathy were associated with calcineurin inhibitor toxicity, 35.4% with rejection, 15.9% were recurrent thrombotic microangiopathy, and 40.2% were associated with other miscellaneous causes. Conclusions: Thrombotic microangiopathy after kidney transplantation is rare but debilitating complication. The cause is multifactorial in most cases in the light of coexistence of multiple risk factors in the kidney transplant recipients. Further studies are required to disentangle these overlapping risk factors. And allow for better prevention and treatment of this condition.

Genetic Landscape of Thrombotic Microangiopathies with Focus on Plasminogen Mutation Variants

Background: Complement-mediated thrombotic microangiopathy (CM-TMA) or atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a triad of thrombocytopenia, hemolytic anemia, and kidney injury, presumably caused by dysregulation of the complement system. Around 50-60% of all the patients carry a genetic mutation that predisposes them to CM-TMA and influences primarily their risk of recurrence if therapy is stopped. While most of these mutations are in the complement pathway, other genes beyond the complement system have also been recognized. Plasminogen (PLG) gene encodes for plasminogen and plays a role in the coagulation pathway. Bu et al screened 36 patients with clinical diagnosis of aHUS and found 4 patients with variants in the PLG gene ( Bu et al. J Am Soc Nephrol 2014). However, phenotypic correlation with PLG gene mutations and comparisons to other CM-TMAs have not been reported. Aims: 1) To summarize the genetic variants identified in individuals with CM-TMA from a single center cohort and compare the clinical characteristics of individuals with complement mutation versus coagulation pathway mutation 2) Describe the unique phenotypic features of patients with PLG mutations. Methods: This was a single center retrospective study of patients referred or presenting to the Ohio State University for evaluation for an initial clinical diagnosis of CM-TMA that had TMA gene panel testing performed from 2011 until February 2023. Patients were excluded if the diagnosis of CM-TMA was inconclusive or information regarding their initial presentation or treatment were not available. For individuals who met the criteria, data were collected regarding demographics, clinical features at their first presentation, management, renal outcomes, genetic test findings and disease recurrence. Results: We initially identified 121 individuals who met the study criteria. Final analysis included 105 individuals. Median age at diagnosis was 42 years. Two-thirds of the cohort was female. About half of the patients had no identifiable mutation (n=59, 58.6%). Of those with an identifiable mutation (n=46), 66% (n=30) had a complement mutation and 21% (n=9) had a coagulation pathway mutation. When comparing the presentation at diagnosis, individuals with a coagulation pathway mutation had a comparable degree acute kidney injury (AKI) as reflected by elevated creatinine at presentation, but less thrombocytopenia and hemolysis compared to patients with complement pathway mutations (Table 1). Within the coagulation pathway gene variants cohort, there were initially 6 individuals with PLG mutation and 4 with THBD mutation. We excluded one individual with PLG mutation from this cohort since he also had MCP mutation, and his clinical course was well explained by the presence of MCP mutation. The 5 patients with PLG mutation were females (Table 2). Compared to THBD and complement gene variants, patients with PLG mutation had less AKI, thrombocytopenia, and hemolysis at presentation. These individuals demonstrated quicker recovery of renal function within a few weeks to a month, even in the absence of complement blockade therapy, and most were independent of hemodialysis by 3 months after diagnosis. 2 of the 5 (40%) had recurrent TMA and one of had recurrent TMA episodes despite being on long-term complement blockade therapy which was started after a future relapse. These recurrent events resolved completely with supportive therapy that included plasmapheresis. Three patients are on long-term anticoagulation therapy. None have had any aHUS recurrences while on anticoagulation. None of the patients with PLG mutations developed postpartum presentations despite multiple pregnancies in this limited cohort. Conclusions: Our cohort of CM-TMA subjects shows that patients with PLG mutation associated TMAs have a distinct clinical presentation and possible a lack of response to complement blockade therapy compared with complement gene variants in this cohort. Larger multicenter studies are needed to further validate our findings. Given the role of plasminogen in the coagulation pathway, studies are indicated to explore the role of anticoagulation to prevent recurrence in this subset of patients. Additionally, functional studies of these disease specific PLG variants are vital to identify the pathogenic mechanisms for what might be a distinct form of TMA from CM-TMA.

TMA in Kidney Transplantation.

Thrombotic microangiopathy (TMA) is a rare and devastating complication of kidney transplantation, which often leads to graft failure. Posttransplant TMA (PT-TMA) may occur either de novo or as a recurrence of the disease. De novo TMA can be triggered by immunosuppressant drugs, antibody-mediated rejection, viral infections, and ischemia/reperfusion injury in patients with no evidence of the disease before transplantation. Recurrent TMA may occur in the kidney grafts of patients with a history of atypical hemolytic uremic syndrome (aHUS) in the native kidneys. Studies have shown that some patients with aHUS carry genetic abnormalities that affect genes that code for complement regulators (CFH, MCP, CFI) and components (C3 and CFB), whereas in 10% of patients (mostly children), anti-FH autoantibodies have been reported. The incidence of aHUS recurrence is determined by the underlying genetic or acquired complement abnormality. Although treatment of the causative agents is usually the first line of treatment for de novo PT-TMA, this approach might be insufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve kidney function. Targeted complement inhibition is an effective treatment for recurrent TMA and may be effective in de novo PT-TMA as well, but it is necessary to establish which patients can benefit from different therapeutic options and when and how these can be applied.

342.3: Outcome Analysis of Patients With Genetic Mutations of Complement Regulatory Proteins in Relation to Incidence of Post Renal Transplant Thrombotic Microangiopathy

Introduction: Thrombotic Microangiopathy is an occlusive disorder of microvasculature characterized by thrombocytopenia, systemic or intrarenal platelet aggregation, thrombus formation and hemolytic anemia caused by fragmentation of erythrocytes due to the disturbed microvasculature. TMA developing after renal transplantation can be categorized into either De novo TMA, developing for the first time without any evidence of the disease before the transplant or recurrent TMA where native kidneys have failed due to TMA and recur after kidney transplantation. The contribution of complement regulatory gene (CRG) mutation to post-transplant Thrombotic Microangiopathy (TMA) in Indian kidney transplant recipients (KTR) is unknown. This is a study to determine the association of CRG on post-transplant TMA and graft failure. Methods: A Single Centre, Prospective Observational Cohort Study was undertaken in renal transplant recipients. All live and Deceased donor renal allograft recipients who underwent transplantation from 1st December 2019 onwards till 31st December 2020 were recruited and were followed up for 1 year beyond the last enrolment. Genetic testing was performed with MLPA and Clinical exome sequencing. Results: 78 KTRs with a mean age of 37.09 ± 13.23 years were enrolled. The Native cause of kidney disease in 55 (70.5%) patients was undetermined and 23 (29.5%) had established cause of chronic kidney disease. 58 (74.4%) were males and 20 (25.6%) were females. CRG mutation was seen in 48/78 (61.5%) KTRs. The allele frequency of the CRG mutation was seen in 48/78 (61.53%) of which duplication of CFHR gene was predominantly seen in 40/78 (51.2%) patients. CRG mutation in this cohort was seen more in the younger age group patients. There was no gender predominance for patients with CRG mutation. None of the patients had a mutation for CFH, CFI, CFB, C3, THBD, DGKE genes. One patient had a mutation for the PLG gene. The incidence of post-transplant TMA was seen in 4/78 (5.12%) patients. Mutation related to aHUS was seen in 2 patients. There was no significant difference in serum creatinine levels of patients with or without CRG mutation at the end of 1 year. Conclusion: The prevalence of CRG mutation in our KTR cohort was high and is associated with post-transplant TMA in 50% of patients with de novo TMA. The graft outcome at the end of 1 year was similar in patients with mutation and those without mutation. This study suggests that the presence of CRG mutation should not preclude renal transplantation in patients with ESRD.

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

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 medica tions or infections. More frequently, it may recur after kidney transplant in patients with endstage renal failure due to atypical hemolytic uremic syndrome. However, for patients with Shiga-toxininduced 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.

De Novo and recurrent thrombotic microangiopathy (TMA) after renal transplantation: current concepts in management

Thrombotic microangiopathy (TMA) is a well-recognized complication of kidney transplantation that leads frequently to allograft failure. This serious outcome depends greatly on the underlying etiology as well as the timing of therapeutic interventions. TMA syndromes may occur with no previous history of TMA, i.e., de novo TMA, mostly due to medications or infection, or more frequently recurs after kidney transplantation i.e., recurrent TMA in patients with ESRF due to the atypical hemolytic uremic syndrome (aHUS). On the other hand, patients with shiga-toxin induced HUS (classic HUS), particularly in childhood has a favorable prognosis. One of the fundamental tools of management of this disease is the genetic screening for abnormal mutations, determination of which will recognize the tools of therapy and consequently outcome of the disease to a large extent. While patients with CFH and CFI mutations have a worse prognosis, other patients with MCP mutations-for example- have a more favorable prognosis. Accordingly, plan of therapy can be thoroughly drawn 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 linked to its use as a life-long therapy. However, a new therapeutic option has been recently admitted ameliorating this drawback and improve the cost-effectiveness balance.

Functional and Genetic Landscape of Complement Dysregulation Along the Spectrum of Thrombotic Microangiopathy and its Potential Implications on Clinical Outcomes

IntroductionThe syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment.MethodsWe studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA.ResultsMassive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (n/N = 11/11) and in 59% of patients with TMA and coexisting conditions (n/N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [n/N = 20/44] vs. 0% [n/N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [n/N = 12/14] vs. 31% [n/N = 5/16] of untreated patients; P < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA.ConclusionsEx vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications.

Eculizumab discontinuation in atypical haemolytic uraemic syndrome: TMA recurrence risk and renal outcomes.

BackgroundEculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited.MethodsPatients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function.ResultsWe analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation.ConclusionsEculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

Thrombotic microangiopathy after kidney transplantation: causes, clinical specifics and outcomes

Background: Thrombotic microangiopathy (TMA) is a clinical and morphological phenomenon characterized by specific microvascular injury, microangiopathic hemolytic anemia, and damage of various target organs. TMA after kidney transplantation (post-renal transplant TMA) is a serious complication affecting the recipient and graft survival.Aim: To analyze the timing, causes, specifics of the clinical course and outcomes of TMA in renal transplant recipients.Materials and methods: This one-center study was based on a comprehensive examination and follow-up of 697 patients who had undergone 728 kidney transplantations (KT) from deceased donors in 2003–2019. Post-transplant TMA of the renal graft was confirmed morphologically in all cases.Results: We identified 32 episodes of post-transplant TMA in 32 patients; thus, the incidence of TMA was 4.4%. All cases developed after KT de novo; no recurrent TMA was observed. TMA was systemic in 37.5% and locally renal in 62.5% of the patients. The median time to the development of post-transplant TMA was 0.55 (range, 0.1 to 51.6) months. The patients with TMA did not differ from those without by gender, age, body mass index, underlying disorders, type and duration of dialysis before KT, protocols of immunosuppressive therapy, incidence of surgical, urological, infectious, cardiovascular and oncological complications. The patients with TMA were significantly more likely to have graft rejection (25.0% vs 11.2%, p = 0.035) and a never-functioning transplant (28.1% vs 4.9%, p &lt; 0.001). The presence of TMA negatively affected the transplantation outcomes. The cumulative 1-year graft survival in the patients without and with TMA was 91% and 44%, respectively, whereas their 5-year survival rates were 68% and 25% (p &lt; 0.001). The leading causes of TMA were: donor pathology (31.2%), antibody-mediated rejection (28.1%), and cyclosporine/tacrolimus nephrotoxicity (21.9%); the proportion of other causes was 18.8%. A combination of TMA etiological factors was identified in 68.7% of the recipients. The recipients with of calcineurin inhibitors nephrotoxicity had a more favorable prognosis compared to those with other causes of TMA.Conclusion: Post-renal transplant TMA is an infrequent but serious complication that worsens the graft survival and often is life-threatening for recipients. In most cases, TMA develops in the early post-operative period; however, it can occur any time thereafter. To improve the outcome of TMA, early diagnosis is necessary based on clinical suspicion and a prompt biopsy of the renal graft with suspected TMA. Treatment should be started quickly with consideration of the cause of the complication.

P1810INFECTION TRIGGERS AS A COMPLEMENT-ACTIVATING STATE IN ATYPICAL HEMOLYTIC-UREMIC SYNDROME IN CHILDREN

Abstract Background and Aims Atypical hemolytic-uremic syndrome (aHUS) is a rare life-threatening disease, which is based on the dysregulation of the complement system. Different complement-activating factors is known for aHUS, including infections, vaccination, concomitant diseases, pregnancy, surgical interventions, transplantation, etc. In 24% of cases, a connection with diarrheal prodrome is revealed, in 18% - with acute respiratory infections. The diagnosis of aHUS is established if other forms of thrombotic microangiopathy (TMA) are rejected: HUS associated with Stx-producing strains of E. Coli and Shigella dysenteriae (STEC / Stx - HUS), TTP. We analyze the etiology of trigger events in children with aHUS. Method An analysis of 165 case histories of children with aHUS was carried out for the period from 2000 to 2019. Of these, 70 are boys and 95 are girls. The average age was 4.83 ± 3.84 years (from 2.5 months to 17.8 years). The diagnosis of aHUS was established on the basis of microangiopathic hemolysis, thrombocytopenia, organ dysfunction and recurrent TMA activity. 66 patients were genetically screened, among which mutations in genes encoding complement proteins were detected in 23 (34.9%) children. Results The prodromal period of patients with aHUS was characterized by fever (53.9%), weakness (42.4%), decreased appetite (27.3%), catarrhal symptoms (20.6%), nausea (17.6%), and vomiting ( 63%), abdominal syndrome (26.7%), diarrhea (38.8%), hemocolitis (12.1%). Among the trigger events, acute intestinal infections accounted for 44.2% of cases, acute viral infections - 26.0% (with catarrhal syndrome - 20.6%, intestinal - 5.4%), herpetic infection (CMV, VEB, HSV 1 type) was found in 3% of cases. In 10.3% of children, the TMA symptom complex developed after vaccination with mainly live attenuated vaccines, in 4.2% against other rare conditions (trauma, taking an unknown drug, tonsillitis, etc.). In 12.1% of cases, the disease manifested itself without a complement-activating state. E.coli was confirmed in 16 observations (EHEC - 12, EagEC - 2, EPEC - 2), shigellosis (Shigella Flexner 6) was detected in 1 case. The nature of viral diarrhea was identified in 8 patients: rotovirus RNA - 4, adenovirus DNA - 2, norovirus RNA - 2, type 5 Coxsackie RNA - 1. In the case of TMA after E.coli and shigella, the initial diagnosis was STEC / STx - HUS, which was subsequently transformed into aHUS due to the recurrent TMA activity with persistent dialysis-dependent AKI, and the addition of extrarenal symptoms not associated with volume overload. Conclusion Infectious diseases are the most common complement-activating condition for the implementation of aHUS in children. Among them, in most cases, diarrheal prodrome is associated with acute intestinal infections, which differs from population data (44.2% vs 24%). With the development of TMA in children with escherichiosis/shigellosis, repeated episodes of hemolysis, platelet consumption, the appearance of extrarenal symptoms with normalization of hematological parameters, the detection of pathogenic mutations in complement genes and the positive effect of complement blocking therapy (eculizumab) confirms the diagnosis of aHUS in this category of patients. To exclude or confirm aHUS in these cases, monitoring of clinical and laboratory data is necessary.

Акушерский атипичный гемолитико- уремический синдром: виновата беременность или ее осложнения?

Atypical hemolytic-uremic syndrome (aHUS) is one of the most severe forms of thrombotic microangiopathy (TMA) that might develop during pregnancy and after childbirth. It is conditioned by a severe, progressive course of disease, unfavourable prognosis and difficult differential diagnosis between this and other forms of TMA – first of all, with classical obstetric complications: preeclampsia (PE) and HELLP syndrome. It is considered that pregnancy-associated aHUS (P-aHUS) is triggered by pregnancy itself. But an analysis of publications dealing with pregnancy-associated aHUS and our own experience accumulated by the present time indicate that the overwhelming majority of P-aHUS cases develop not during pregnancy, but after delivery, and almost always an acute TMA episode is preceded by various complications of pregnancy (PE, bleeding, placental abruption, antenatal intrauterine fetal death), infections, operative interventions, etc. As is known, they all might be regarded as a complement-activating conditions (CACs). The objective. To study the effects of obstetric complications, mainly preeclampsia, on the development, course and prognosis of pregnancy-associated aHUS. Patients and methods. From 2011 to 2019, 69 patients aged 16–44 years were examined, in whom aHUS developed during pregnancy or directly after childbirth. Most women (47 of 69, 68%) were secondiparas without any bad obstetric history. In 62 (90%) of 69 patients disease developed during the postpartum period at terms from several hours to 8 days after childbirth. Results. All patients had a full symptom complex of TMA: microangiopathic hemolytic anaemia (lower haemoglobin levels 62.3 ± 15.0 g/l, higher lactate dehydrogenase levels 2683.7 ± 2143.1 U/l, schisocytosis, a decrease in haptoglobin), thrombocytopenia (50.0 ± 32.8 thous. per μl), involvement of the kidneys (higher creatinine levels 509.0 ± 349.8 μmol/l, oligoanuria) and other organs (liver, heart, central nervous system, lungs). Severe multiple organ failure was observed in 91.3% of patients. In all cases, the development of aHUS was preceded by additional CACs, the most common of which were caesarean section (73.5%), bleeding (69.5%) and PE (69.5%), although the number of CACs did not have a significant effect on the severity and outcome of aHUS. Neither were found significant differences in the clinical and laboratory manifestations in patients with the presence/absence of caesarean section, PE or bleeding (each taken separately). 40 (58%) of 69 patients received a complement-blocking therapy with Eculizumab. In patients receiving Eculizumab, compared to the patients who received only fresh frozen plasma therapy (29 women), complete recovery of renal function was noted in 26 (65%) vs 10 (34.5%) women, 5 (12.5%) vs 5 (17.5%) remained dialysis-dependent, 5 (12.5%) vs 11 (38%) died. Nineteen (47.5%) of 40 patients received only a full course of induction therapy or only 1–2 infusions of Eculizumab, in three more patients the drug was discontinued after 4–24 months. None of the women had a recurrence of TMA after discontinuation of Eculizumab. Conclusion. In all women with P-aHUS pregnancy was combined with additional CACs, as a rule, their number was &gt;3. In 69.5% of cases, the disease was preceded by PE, which, in its turn, is considered as a specific obstetric variant of TMA. Considering interrelationships between PE and P-aHUS, we can suppose that glomerular capillary endotheliosis, characteristic for PE and conditioned by an imbalance between PlGF- and sFlt1-factors of angiogenesis/antiangiogenesis, promotes additional activation of the complement, creating preconditions for fast generalisation of endothelial lesions in patients with genetic defects in the complement system, which gives every reason to discuss the possibility of transformation of PE into aHUS. In this connection, all patients with PE, especially with severe one, should be referred to a group of risk for possible postpartum generalisation of the microangiopathic syndrome. It would be appropriate to regard P-aHUS as a heterogeneous group that includes both «classical» aHUS, and «secondary» HUS, not associated with constitutional ysregulation of the complement system. Early beginning of Eculizumab therapy permits not only to save the life of a patient with aHUS, but also to fully recover their health. In case of development of «secondary» aHUS, a course of Eculizumab might be reduced to 1–2 infusions. Key words: pregnancy-associated atypical haemolytic-uraemic syndrome, pregnancy, thrombotic microangiopathy, Eculizumab

Outcomes after Treatment with Upfront Cyclophosphamide or Rituximab for Initial Acquired Thrombotic Thrombocytopenic Purpura

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening emergency caused by auto-antibodies against ADAMTS13. Current standard therapy utilizes plasma exchange (PLEX) and corticosteroids. Although this induces remission, disease relapse remains a common problem. Since more than 90% of aTTP is caused by an antibody to ADAMTS13, additional immunosuppressive therapy with rituximab (RTX) given upfront has been shown to lower relapse rates. An alternative therapy, Cyclophosphamide (CTX) has been used in relapsed disease, but data on its use in upfront management is limited to case reports only. Our study aims to compare outcomes at our institution between upfront CTX, RTX, and standard therapy alone. Our secondary objective is to identify initial presenting features that are predictive of higher relapse risk. Methods: In a retrospective cohort study, we identified all patients at our institution with a diagnosis code of TTP (ICD 9, 10: 446.6, M31.1) between 2009 and 2019. We only included patients with a confirmed diagnosis of aTTP, defined as having an ADAMTS13 level &lt;10%, and either a positive ADAMTS13 inhibitor or antibody. We excluded patients with follow-up of less than 30 days, or thrombotic microangiopathy (TMA) due to other causes. Relapse was defined as recurrence of TMA in addition to an ADAMTS13 level &lt;10%, or "laboratory relapse" evidenced as an acute drop of ADATMS13 level with a positive inhibitor with/without TMA. Time to first relapse was measured from the onset of remission, defined as the time of normalization of both platelets and lactate dehydrogenase (LDH) for at least 48 hours, until the time of relapse. The cumulative incidence of relapse (CIR) was estimated using Kaplan-Meier method, and its difference among treatment groups was examined by log-rank test. The effect of continuous and categorical covariates on relapse rate was estimated by univariate Cox model. The association of categorical variables was examined using chi-square test and the difference of continuous measurements among groups was tested using T-test or ANOVA. Results: A total of 42 patients with a diagnosis of aTTP were identified in our cohort. The average age at diagnosis was 43.7 years. All patients received standard therapy with PLEX and steroids upon initial diagnosis. The prophylaxis group (n=29) received additional upfront therapy with either RTX (n=22) or CTX (n=6), and the control group (n=12) was treated with PLEX and steroids alone. There were no significant differences in the baseline characteristics between both groups. The median time to first relapse was 34.9 months in the control group, and 108.3 months in the prophylaxis group. Treatment with standard therapy alone was associated with a multi-variate hazard risk of 6.38 (95% CI: 1.1-37.7, p&lt;0.05) for time to initial relapse. CIR at 2, 4, and 8 years was higher in the control group (41.7%, 53.3%, and 68.8%) as compared to the prophylaxis group (31.3%, 43.8%, and 43.8%, respectively). No difference was noted in CIR with CTX versus RTX, which was 40% at 4 years with CTX compared to 47% with RTX, p = 0.97 (Figure 1). Similarly, no statistically significant difference was noted in the time to first remission between CTX and RTX treatment (18 days in with CTX versus 14.9 days with RTX, p=0.583). Inhibitor titer at diagnosis correlated inversely with duration of remission (HR: 1.29, 95% CI: 1.03-1.61, p&lt;0.05). Initial presenting platelet count, peak LDH value or co-existing autoimmune disease were not predictive of the duration of remission. Conclusion: Our study is the first to examine outcomes in a subset of patients treated with upfront CTX therapy for initial aTTP, and suggests similar time to first remission and 4-year CIR as compared to RTX. Our institutional experience suggests that CTX may be considered as an alternative therapy in patients intolerant to RTX. However, given the small group of patients treated with CTX, larger, prospective studies are warranted to confirm this observation. Consistent with currently published literature, PLEX and steroid therapy alone was associated with a significantly shorter duration of remission compared to additional immunosuppressive therapy. Furthermore, higher inhibitor titers were predictive of a shorter duration of remission, suggesting a role for aggressive upfront immunosuppressive treatment in these patients. Disclosures No relevant conflicts of interest to declare.

Outcomes of Kidney Transplant Patients with Atypical Hemolytic Uremic Syndrome Treated with Eculizumab: A Systematic Review and Meta-Analysis.

Background: Kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) is frequently complicated by recurrence, resulting in thrombotic microangiopathy in the renal allograft and graft loss. We aimed to assess the use of eculizumab in the prevention and treatment of aHUS recurrence after kidney transplantation. Methods: Databases (MEDLINE, EMBASE and Cochrane Database) were searched through February 2019. Studies that reported outcomes of adult kidney transplant recipients with aHUS treated with eculizumab were included. Estimated incidence rates from the individual studies were extracted and combined using random-effects, generic inverse variance method of DerSimonian and Laird. Protocol for this systematic review has been registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018089438). Results: Eighteen studies (13 cohort studies and five case series) consisting of 380 adult kidney transplant patients with aHUS who received eculizumab for prevention and treatment of post-transplant aHUS recurrence were included in the analysis. Among patients who received prophylactic eculizumab, the pooled estimated incidence rates of recurrent thrombotic microangiopathy (TMA) after transplantation and allograft loss due to TMA were 6.3% (95%CI: 2.8–13.4%, I2 = 0%) and 5.5% (95%CI: 2.9–10.0%, I2 = 0%), respectively. Among those who received eculizumab for treatment of post-transplant aHUS recurrence, the pooled estimated rates of allograft loss due to TMA was 22.5% (95%CI: 13.6–34.8%, I2 = 6%). When the meta-analysis was restricted to only cohort studies with data on genetic mutations associated with aHUS, the pooled estimated incidence of allograft loss due to TMA was 22.6% (95%CI: 13.2–36.0%, I2 = 10%). We found no significant publication bias assessed by the funnel plots and Egger’s regression asymmetry test (p > 0.05 for all analyses). Conclusions: This study summarizes the outcomes observed with use of eculizumab for prevention and treatment of aHUS recurrence in kidney transplantation. Our results suggest a possible role for anti-C5 antibody therapy in the prevention and management of recurrent aHUS.

Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease.

Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.

C5b9 Formation on Endothelial Cells Reflects Complement Defects among Patients with Renal Thrombotic Microangiopathy and Severe Hypertension

Background Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control.Methods We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific ex vivo serum-based microvascular endothelial cell assay.Results Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient.Conclusions These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.

Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study examined the epidemiological characteristics of pediatric patients with TMA classified according to etiology. The survey evaluated 258 Japanese pediatric patients diagnosed with TMA between 2012 and 2015. The primary diseases responsible for TMA were categorized as TTP (15 cases), Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) (166 cases), atypical HUS (aHUS) (40 cases), and secondary TMA (27 cases). The remaining 10 cases were unable to be classified to one of the four categories of the primary disease. Renal replacement therapy was required in the acute phase in 103 patients with TMA, including 65 with STEC-HUS, 22 with aHUS, two with TTP, 10 with secondary TMA, and four unclassified cases. The last observational findings were normal renal function in 95 patients and chronic kidney disease (CKD) stage 1 in 62. For 31 patients, chronic renal insufficiency (CKD stage 2-5) persisted, including four patients with end-stage kidney disease (CKD stage 5). Seventeen patients suffered recurrence of TMA, and eight patients died. This study clarified differences in the relative proportions of primary diseases between patients from Japan and North America and Europe. The difference may be attributable to the lower estimated incidence of STEC-HUS in Japan.

De novo thrombotic microangiopathy after kidney transplantation.

Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS. Here, we review the etio-pathogenesis, diagnosis and treatment options for de novo post-transplant TMA. It is usually in the setting of calcineurin inhibitor use, mammalian target of rapamycin inhibitor use, or antibody mediated rejection; recently genetic mutations in complement regulatory genes for Factor H and Factor I similar to those described in aHUS have been reported in up to a third of these patients. Systemic signs of TMA are frequently absent, and a renal allograft biopsy is often needed to establish the diagnosis. Although withdrawal of the offending agents is usually the first line of treatment and resolution of laboratory abnormalities has been documented with this approach in several case reports and case series, available retrospective data demonstrate lack of benefit in long-term graft outcomes. Co-stimulation blockage with belatacept provides an effective alternate immunosuppressive strategy for these patients. Anti-complement therapy with eculizumab is effective in some cases; further work is required to define which patients with TMA (with and without concomitant antibody-mediated rejection) would benefit from receiving this treatment, and what biomarkers can be used to identify them.

Living Donor Kidney Transplantation in Atypical Hemolytic Uremic Syndrome: A Case Series

The development of complement inhibitors has greatly improved the outcome of patients with atypical hemolytic uremic syndrome (aHUS), making kidney transplantation a more feasible option. Although prophylactic eculizumab therapy may prevent recurrent disease after transplantation, its necessity for all transplant recipients is debated. A case series. Patients with aHUS who underwent living donor kidney transplantation after 2011 at 2 university centers, prospectively followed up with a protocol of eculizumab therapy limited to only recipients with documented posttransplantation recurrent thrombotic microangiopathy. In addition, the protocol emphasized lower target level tacrolimus and aggressive treatment of high blood pressure. Recurrence of aHUS, kidney function, acute kidney injury. We describe 12 female and 5 male patients with a mean age of 47 years. 5 patients had lost a previous transplant due to aHUS recurrence. 16 patients carried a pathogenic or likely pathogenic variant in genes encoding complement factor H, C3, or membrane cofactor protein, giving a high risk for aHUS recurrence. Median follow-up after transplantation was 25 (range, 7-68) months. One patient had aHUS recurrence 68 days after transplantation, which was successfully treated with eculizumab. 3 patients were treated for rejection and 2 patients developed BK nephropathy. At the end of follow-up, median serum creatinine concentration was 106 (range, 67-175) μmol/L and proteinuria was negligible. Small series and short duration of follow-up. Living donor kidney transplantation in aHUS without prophylactic eculizumab treatment appears feasible.

Recurrent Thrombotic Microangiopathy in a Renal Allograft: A Clinical Conundrum

Recurrent Thrombotic Microangiopathy in a Renal Allograft: A Clinical Conundrum