• atypical hemolytic uremic syndrome
• eculizumab
• kidney transplant
• thrombotic microangiopathy

• Eculizumab
• refractory posttransplant TMA
• thrombotic microangiopathy

• CFHR3/CFHR1 deletion
• Hemolytic uremic syndrome
• copy number variation
• next-generation sequencing

• Alternative complement pathway
• Complement activation
• DEAP-HUS
• Hemolytic uremic syndrome

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.

• atypical hemolytic uremic syndrome
• complement system activation
• eculizumab
• kidney transplantation
• thrombotic microangiopathy

• Complement
• complement dysregulation
• endothelial injury
• kidney transplantation
• microRNA
• thrombotic microangiopathy

• Biopsy
• Humans
• Kidney
• Kidney Transplantation/adverse effects
• MicroRNAs/genetics
• Thrombotic Microangiopathies/genetics

• Thrombotic microangiopathy
• belatacept
• eculizumab
• kidney transplant
• polycystic kidney disease

• Atypical hemolytic uremic syndrome
• Eculizumab (monoclonal antibody to C5)
• Genetic variants
• Kidney transplantation
• Transplant evaluation

For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy (a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases. Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.

• Complement-related diseases
• Kidney transplantation
• De novo
• Recurrent diseases

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.

• Kidney transplantation
• De novo thrombotic microangiopathy
• Thrombotic microangiopathy
• Recurrent thrombotic microangiopathy
• Atypical hemolytic uremic syndrome

• Atypical haemolytic uraemic syndrome
• Belatacept
• Eculizumab
• Kidney transplantation
• Microangiopatías trombóticas
• Síndrome hemolítico urémico atípico
• Thrombotic microangiopathies
• Trasplante de riñón

• Abatacept/therapeutic use
• Adult
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antilymphocyte Serum/therapeutic use
• Atypical Hemolytic Uremic Syndrome/genetics
• Atypical Hemolytic Uremic Syndrome/immunology
• Atypical Hemolytic Uremic Syndrome/surgery
• Complement Factor H/genetics
• Drug Therapy, Combination
• Female
• Humans
• Immunosuppressive Agents/therapeutic use
• Kidney Transplantation
• Mutation
• Treatment Outcome

• Belatacept
• Complement
• Eculizumab
• Hemolytic uremic syndrome
• Kidney transplantation
• Thrombotic microangiopathy

• Humans
• Kidney Failure, Chronic/surgery
• Kidney Transplantation/adverse effects
• Primary Graft Dysfunction/etiology
• Thrombotic Microangiopathies/complications

Atypical haemolytic uraemic syndrome (aHUS) may clinically present as acute renal graft failure resulting from excessive activation of the complement cascade. While mutations of complement-encoding genes predispose for aHUS, it is generally thought to require an additional insult (e.g. drugs) to trigger and manifest the full-blown clinical syndrome. Calcineurin inhibitors (CNIs) used for immunosuppression act as potential triggers, especially in the post-transplantation setting. Therefore, CNI-free immunosuppressive regimens may be beneficial. We report on a 58-year-old woman who developed aHUS with acute graft failure within 20 days after renal transplantation. Genetic investigation revealed a homozygous deletion of the CFH-related 1 (CFHR1) and CFHR3 genes in addition to the presence of autoantibodies against complement factor H (CFH). The patient was treated with plasmapheresis and administration of the complement component 5 (C5) antibody eculizumab, and her immunosuppressive regimen was switched from CNI (tacrolimus) to the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor belatacept. Renal graft function recovered and stabilized over an 18-month follow-up period. We describe the successful management of post-transplant aHUS using a CNI-free immunosuppressive regimen based on eculizumab and belatacept. Ideally, adequate molecular diagnostics, performed prior to transplantation, can identify relevant genetic risk factors for graft failure and help to select patients for individualized immunosuppressive regimens.

• atypical haemolytic uraemic syndrome
• recurrence
• renal transplantation