Thrombotic microangiopathy after kidney transplantation: diagnosis and management strategies

The Role of Endothelial Cell Injury in Thrombotic Microangiopathy

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy

The prevalence and clinical outcomes of microangiopathic hemolytic anemia in patients with biopsy-proven renal thrombotic microangiopathy.

Successful Treatment of aHUS Recurrence and Arrest of Plasma Exchange Resistant TMA Post-Renal Transplantation with the Terminal Complement Inhibitor Eculizumab.

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 < 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 < 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.

Thrombotic microangiopathy (TMA) is a well-recognised complication following transplantation, often due to an underlying genetic predisposition, medications or rejection. The use of eculizumab in these settings has been previously described, but its role still remains to be clarified. A 45-year-old man, with a history of type 1 diabetes mellitus and subsequent end-stage kidney failure, presented for a simultaneous pancreas-kidney transplant. Immunologically, he was well matched with the donor, and he received standard induction immunosuppression including tacrolimus. His early transplant course was complicated by Haemophilus parainfluenzae paronychia and a Pseudomonas aeruginosa catheter-associated urinary tract infection. Within 1 week, he developed thrombotic microangiopathy with significant renal dysfunction and eventual dialysis dependence, without evidence of transplant rejection on biopsy. He was also noted to have antiphospholipid antibodies in moderate titres. The TMA did not resolve despite cessation of tacrolimus, and he was subsequently commenced on eculizumab. The patient achieved a partial remission from TMA, with ongoing biochemical evidence of haemolysis, although now with stable graft function, despite significant damage. His transplanted pancreas remained seemingly unaffected by TMA, and continues to function well. This case describes an unusual presentation of TMA post-transplantation and is the only described case of eculizumab use following pancreas-kidney transplant. It remains unclear in this case what the likely precipitant for TMA was, although it seems to be, at least in part, controlled by ongoing use of eculizumab, presumably by terminal complement inhibition.

Risk for atypical hemolytic uremic syndrome (aHUS) recurrence after renal transplantation is low with an isolated membrane cofactor protein mutation (MCP). We report the case of a 32-year-old woman with a MCP who underwent kidney transplantation with a good evolution at 12 months. At 15 and 35 months, 2 episodes of thrombotic microangiopathy (TMA), after a miscarriage and a preeclampsia, were misinterpreted as triggered by tacrolimus. After each episode however serum creatinine returned to baseline. Five years after transplantation, she had a self-limited rhinosinusitis followed 3 weeks later by an oliguric renal failure. Her complement profile was normal. Graft biopsy showed C3 glomerulonephritis with no “humps” on electron microscopy. No significant renal function improvement followed methylprednisolone pulsing. A second biopsy showed severe acute TMA lesions with C3 glomerular deposits. Despite weekly eculizumab for 1 month, dialysis was resumed. A new workup identified the “at-risk” complement factor H haplotype. Thus, aHUS recurrence should be ruled out in aHUS patients considered at low recurrence risk when a TMA is found in graft biopsy. Prompt eculizumab therapy should be considered to avoid graft loss as aHUS recurrence can first present as a C3 glomerulonephritis.

Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy. De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.

Eculizumab for the Treatment of De Novo Thrombotic Microangiopathy Post Simultaneous Pancreas-Kidney Transplantation—A Case Report

Patient: Female, 64-year-oldFinal Diagnosis: Bevacizumab-associated thrombotic microangiopathySymptoms: Microangiopathic hemolytic anemia and acute kidney injuryClinical Procedure: —Specialty: NephrologyObjective:Rare diseaseBackground:Bevacizumab is an approved targeted therapy for metastatic cancer treatment. It can have adverse effects on multiple organs. Despite its low incidence, thrombotic microangiopathy (TMA) is the most severe complication. TMA has been associated with complement dysregulation, and treatment with eculizumab can be effective, despite the paucity of literature on eculizumab therapy for bevacizumab-associated TMA. To date, 10 cases have been reported, with less than half of them including a kidney biopsy. We present a new case of bevacizumab-associated TMA successfully treated with eculizumab, along with kidney biopsy records and an overview of mechanisms underlying TMA development in bevacizumab-treated patients.Case Report:A female patient diagnosed with metastatic breast cancer who was treated with bevacizumab in conjunction with chemotherapy was admitted to the hospital for acute kidney injury requiring hemodialysis, microangiopathic hemolytic anemia, and thrombocytopenia. TMA was diagnosed and was later confirmed by a kidney biopsy. Primary causes for TMA, such as ADAMTS13 deficiency and shiga toxin associated hemolytic-uremic syndrome, were ruled out, and the patient’s condition was ultimately found to be triggered by exposure to bevacizumab. After discontinuing bevacizumab and receiving 4 weekly doses of eculizumab, kidney function and hematological parameters improved.Conclusions:Bevacizumab-associated TMA can be reversed or attenuated in some patients with the use of eculizumab (inhibiting complement system overactivation), possibly reducing time to recovery, with fewer long-term sequelae. This additional case encourages future clinical trials to evaluate the safety and efficacy of eculizumab in cases of TMA associated with bevacizumab.

Атипичный гемолитикоуремический синдром (аГУС) ультраредкое (орфанное) заболевание прогрессирующего течения, представляющее собой системную тромботическую микроангиопатию (ТМА) вследствие хронической неконтролируемой активации альтернативного пути комплемента. В настоящее время установлено, что генетические аномалии комплемента, которые раньше рассматривали как основную причину заболевания, являются лишь фактором, предрасполагающим к возникновению ТМА. Классическую триаду клинических проявлений аГУС составляют тромбоцитопения, микроангиопатическая гемолитическая анемия и острое повреждение почек. У большинства пациентов независимо от возраста отмечается артериальная гипертензия, основными причинами которой являются гиперренинемия вследствие ишемии ткани почек, обусловленной ТМА, и перегрузка объемом при наличии олиго/анурии. Атипичный ГУС представляет собой системную ТМА, при которой могут поражаться не только почки, но и другие жизненно важные органы головной мозг, сердце, легкие, пищеварительный тракт, глаза и др. Диагноз аГУС это диагноз исключения. Он устанавливается на основании характерной клинической картины после исключения других форм ТМА, как первичных, так и вторичных. Для исключения тромботической тромбоцитопенической пурпуры (ТТП) всем больным с ТМА необходимо определение активности ADAMTS13: снижение ее до 10 и менее является диагностическим маркером ТТП. У пациентов с аГУС и другими ТМА активность ADAMTS13 может быть снижена, однако всегда превышает 10. Инновационным подходом к лечению аГУС, используемым в клинической практике в течение последнего десятилетия, стало применение экулизумаба препарата группы комплеменингибирующих антител, который является препаратом патогенетической терапии аГУС. Экулизумаб является средством первой линии для лечения детей с установленным диагнозом аГУС, при семейном характере заболевания, наличии экстраренальных проявлений. Совершенствование методов диагностики и внедрение новых подходов к лечению позволяет быстрее заподозрить и купировать проявления аГУС, добиться стойкой ремиссии и улучшить прогноз. Atypical hemolytic uremic syndrome (aHUS) is an ultra rare (orphan) progressive disease that is a systemic thrombotic microangiopathy (TMA) due to chronic uncontrolled activation of the alternative complement pathway. It is currently established that complement genetic abnormalities that were previously considered the main cause of the disease, are only a factor predisposing to TMA occurrence. The classic triad of aHUS clinical manifestations is thrombocytopenia, microangiopathic hemolytic anemia andacute kidney damage. Most patients, regardless of age, have arterial hypertension the main reasons of hypertension are hyperreninemia (due to kidney tissue ischemia because of TMA) and volume overload in the presence of oligo/anuria. Atypical HUS is a systemic TMA that affected not only the kidneys, but also other vital organs brain, heart, lungs, digestive tract, eyes, etc. The diagnosis of aHUS is a diagnosis of exclusion that is established on the basis of specifi c clinical picture after exclusion of other forms of TMA, both primary and secondary. To exclude thrombotic thrombocytopenic purpura (TTP), all patients with TMA need to determine ADAMTS13 activity: its reducing to 10 or less is a diagnostic marker of TTP. In patients with aHUS and other TMA, ADAMTS13 activity may be reduced, but always exceeds 10. The innovative pathogenetic approach to aHUS treatment over the last decade became the application of eculizumab that is a drug from complementinhibitory antibodies group. Eculizumab is a fi rstline treatment for children with proven aHUS diagnosis, with familial disease, with extrarenal manifestations. Progress in diagnostic methods and new treatment approaches allows us to quickly suspect and stop the manifestations of aHUS, achieve stable remission and improve the prognosis.

Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

Thrombotic microangiopathy (TMA) is a challenging and serious complication of kidney transplantation that significantly affects graft and patient survival, occurring in 0.8%-15% of transplant recipients. TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to endothelial damage and microthrombi formation in small vessels. However, clinical features can range from a renal-limited form, diagnosed only on a kidney biopsy, to full-blown systemic manifestations, which include neurologic, gastrointestinal, and cardiovascular injury. TMA can arise because of genetic or acquired defects such as in complement-mediated TMA or can occur in the context of other conditions like infections, autoimmune diseases, or immunosuppressive drugs, where complement activation may also play a role. Recurrent TMA after kidney transplant is almost always complement-mediated, although complement overactivation may also play a role in de novo post-transplant TMAs associated with ischemia-reperfusion injury, immunosuppressive drugs, antibody-mediated rejection, viral infections, and relapse of autoimmune diseases, such as antiphospholipid antibody syndrome. Differentiating between a complement-mediated process and one triggered by other factors is often challenging but critical to minimize allograft damage because the former is nonresponsive to supportive therapy, needs long-term anticomplement therapy, and has a high risk of recurrence. Given the central role of complement and effect of genetic defects on the risk of recurrence in many forms of post-transplant TMA, genetic testing for complement disorders is key for proper diagnosis and management. Given that complement activation may also play a role in a subset of TMAs associated with other conditions, prompt recognition and timely initiation of anticomplement therapy is equally important. In addition, TMA associated with noncomplement genes, often part of a broader syndromic process with distinct clinical features, has also been described. Early identification and treatment are essential to prevent graft failure and other severe complications. This review explores the pathophysiologic mechanisms underlying various post-transplant TMAs.

Severe COVID-19 infection and thrombotic microangiopathy: success does not come easily.

Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab. This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group). Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group. The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries.