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Over the last three decades, advancements in the diagnosis, treatment, and supportive care of patients with cancer have significantly improved their overall survival. However, these advancements have also led to a higher rate of cancer-related complications. Acute kidney injury (AKI) and chronic kidney disease (CKD) are highly prevalent in patients with cancer, and they are associated with an increased risk of all-cause mortality. This bidirectional interplay between cancer and kidney, termed “the kidney–cancer connection” has become a very active area of research. This review aims to provide an overview of some of the most common causes of AKI in patients with cancer. Cancer therapy-associated AKI is beyond the scope of this review and will be discussed separately.

Atypical hemolytic uremic syndrome (aHUS) is a rare and complex disease resulting from abnormal alternative complement activation with a wide range of clinical presentations. Extra-renal manifestations of aHUS can involve many organ systems, including the peripheral and central nervous, gastrointestinal, cardiovascular, integumentary, pulmonary, as well as the eye. While some of these extra-renal manifestations occur in the acute phase of aHUS, some can also occur as long-term sequelae of unopposed complement activation. Extra-renal symptoms are observed in approximately 20% of patients with aHUS, with the incidence of specific organ system complications ranging from a few case reports to 50% of described patients. Careful monitoring for extra-renal involvement is critical in patients with aHUS, as prompt evaluation and management may decrease the risk of high morbidity and mortality associated with aHUS. [ABSTRACT FROM AUTHOR]

Background: Human immunodeficiency virus (HIV) infection increases the risk of thrombotic microangiopathy (TMA), but TMA in the setting of HIV infection is not well characterized. The experience with TMA in the setting of HIV infection at the University of Maryland Medical Center was reviewed. Study design and methods: Patients undergoing therapeutic plasma exchange (TPE) for TMA from January 1, 2000 through December 31, 2012 were reviewed. Those with known HIV‐positive and ‐negative status were compared. Results: Among 102 patients with known HIV status, 28 (27%) were HIV‐positive, including 3 with previously undiagnosed HIV. HIV‐positive patients had a median viral load of 89 500 copies/mL (range, 0‐>750 000 copies/mL) and a median CD4 count of 58 cells/µL (range, 2‐410 cells/µL). Compared to HIV‐negative patients, HIV‐positive patients more frequently presented with concurrent infections (60.7% vs. 23.7%; P = .0007), had a trend toward lower median platelet counts (3000/µL vs. 15 000/µL; P = .07) and more frequently had platelet counts less than 10 000/mcL (P = .02). Nevertheless, number of TPE procedures required for remission, remission rate, mortality, and relapse incidence were similar in HIV‐positive and HIV‐negative patients. Conclusions: The incidence described herein of HIV infection among TMA patients is the highest reported outside of South Africa. More severe thrombocytopenia in HIV‐positive patients may reflect TMA in the setting of preexisting HIV‐associated thrombocytopenia. HIV should be considered in patients with TMA, and TMA should be considered in HIV‐positive patients with severe thrombocytopenia. [ABSTRACT FROM AUTHOR]

HIV complicates the diagnostic and therapeutic approaches to idiopathic thrombotic thrombocytopenic purpura (TTP), prompting debate in the literature regarding the benefit of plasma exchange versus simple plasma infusion. Herein we present a case of HIV-TTP, initially treated conservatively with plasma infusion but because of progressive neurologic decline, required urgent plasma exchange for resolution of hematologic derangements and neurologic sequelae. Based on the available literature, there appears to be a spectrum of HIV-associated TTP disorders. Patients with advanced HIV disease and opportunistic infections who present with thrombotic microangiopathy tend to respond to simple plasma infusion, while patients with less progressive HIV disease tend to behave like those with idiopathic TTP, requiring plasma exchange rather than simple plasma infusion. This article illustrates that in patients with HIV-TTP who do not respond to plasma infusion, early escalation to plasma exchange may help avoid life-threatening complications such as seizures and even death. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA). It has an unfavorable outcome with death rates as high as 25% during the acute phase and up to 50% of cases progressing to end-stage renal failure. Uncontrolled complement activation through the alternative pathway is thought to be the main underlying pathopysiology of aHUS and corresponds to all the deleterious findings of the disease. Thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-associated HUS are the 2 other important TMA diseases. Although differentiating HUS from TTP is relatively easy in children with a preceding diarrheal illness or invasive S. pneumoniae, differentiating aHUS from TTP or other microangiopathic disorders can present a major diagnostic challenge in adults. ADAMTS13 analysis is currently the most informative diagnostic test for differentiating TTP, congenital TTP, and aHUS. Today empiric plasma therapy still is recommended by expert opinion to be used as early as possible in any patient with symptoms of aHUS. The overall treatment goal remains restoration of a physiological balance between activation and control of the alternative complement pathway. So it is a reasonable approach to block the terminal complement complex with eculizumab in order to prevent further organ injury and increase the likelihood organ recovery. Persistence of hemolysis or lack of improvement of renal function after 3-5 daily plasmaphereses have to be regarded as the major criteria for uncontrolled TMA even if platelet count has normalized and as an indication to switch the treatment to eculizumab. Eculizumab has changed the future perspectives of patients with aHUS and both the FDA and the EMA have approved it as life-long treatment. However, there are still some unresolved issues about the follow-up such as the optimal duration of eculizumab treatment and whether it can be stopped or how to stop the therapy.

Background The PLASMIC score was recently described as a convenient tool for predicting ADAMTS13 activity ≤10% in patients with possible thrombotic thrombocytopenic purpura (TTP), while awaiting the results of this send-out test. The purpose of this study was to validate the PLASMIC score at our University Medical Center. Methods Apheresis records were reviewed from 2008 to 2017 to identify patients who received plasma exchange (PLEX) for suspected TTP. The ADAMTS13 activity and PLASMIC scoring criteria were recorded, and the PLASMIC score was calculated. Results Of the 41 patients identified, 20 met inclusion criteria, of which 7 patients had ADAMTS13 activity ≤10%. Intermediate and high PLASMIC scores had 100% sensitivity, 46.2% specificity, 50% positive predictive value (PPV), and 100% negative predictive value (NPV). Conclusion These results are consistent with the original validation study of the PLASMIC score, supporting the efficacy of the PLASMIC score and validating its use at our institution. [ABSTRACT FROM AUTHOR]

Interferon (IFN) has been associated with development of thrombotic microangiopathy including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). We reviewed literature from the earliest reported association in 1993, to July 2016 and found 68 cases. Analysis of this data shows: (1) Mean age at diagnosis was 47 years (95% CI, 44–50). (2) Majority of cases were seen where IFN was used for the treatment of chronic myelogenous leukemia (CML), multiple sclerosis (MS), chronic hepatitis C virus infection (HCV) and one case each for hairy cell leukemia (HCL) and Sezary syndrome. (3) There were no cases reported for polycythemia vera (PV) or lymphoma. (4) Sex distribution was nearly equivalent with the exception in patients with multiple sclerosis where there was female predominance (12 of 16 with reported data). (5) For pooled analysis, the average duration of treatment with IFN before TMA was diagnosed was 40.4 months. (6) Comparative analysis showed that patients with MS required the highest cumulative dose exposure before developing TMA (MS 68.6 months, CML 35.5 months, HCV 30.4 months). (7) Cases of confirmed TTP (where A disintegrin and Metalloprotease with thrombospondin type 1 motif 13: ADAMTS 13 level was measured) showed presence of an inhibitor. (8) In all cases of confirmed TTP, moderate to severe thrombocytopenia was a striking clinical feature at presentation while this was not a consistent finding in all other cases of TMA. (9) Outcome analysis revealed complete remission in 27 (40%), persistent chronic kidney disease (CKD) in 28 (42%) and fatality in 12 patients (18%). (10) Treatment with corticosteroids, plasma exchange and rituximab resulted in durable responses. [ABSTRACT FROM AUTHOR]

Background: Atypical hemolytic uremic syndrome is a rare disorder which is known to cause acute thrombotic microangiopathy during pregnancy with poor maternal and fetal outcomes. Atypical hemolytic uremic syndrome is caused mostly by dysregulation of alternative complement pathway secondary to genetic mutations. Most of the cases reported have been in the post-partum period. We report a rare case of a patient who presents with thrombotic microangiopathy in the first trimester of her eleventh pregnancy and was successfully treated with eculizumab. Case presentation: A 30-year-old woman presented at 10 weeks of gestation with hypertension, hemolytic anemia, thrombocytopenia, and acute kidney injury, consistent with thrombotic microangiopathy. She was managed initially with daily plasmapheresis. However, her kidney function did not recover, requiring hemodialysis. ADAMTS13 activity was later found to be within normal limit, hence diagnosis of atypical hemolytic uremic syndrome was strongly considered at that time and she was immediately treated with anti-C5 humanized monoclonal antibody (eculizumab). The patient responded well (resolution of thrombotic microangiopathy and recovery of renal function) to eculizumab, with continued remission after discharge and successfully delivered a healthy baby at term without any peripartum complications. Conclusion: Early recognition of atypical hemolytic uremic syndrome is often difficult as several other conditions also manifest as thrombotic microangiopathy during pregnancy, causing delay in initiating appropriate treatment. Our case suggests that treatment of atypical hemolytic uremic syndrome in early trimester of pregnancy with eculizumab results in good outcome to mother and fetus. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies., (Copyright © 2023. Published by Elsevier Inc.)

From producing individual blood components for transfusion to the removal of pathogenic substances, apheresis is a cornerstone of modern medical therapies. The use of therapeutic plasma exchange (TPE), in which plasma and its soluble constituents are removed from the body in exchange for a replacement fluid, can be organ- and life-saving in many diseases. Given the notable similarities between TPE and hemodialysis, the nephrologist is often responsible for managing TPE. As such, one must be familiar with the technologies, approach to therapy, indications for use, and complications. TPE uses centrifugation or membrane separation technologies, with the latter able to be performed with certain hemodialysis machines familiar to the nephrologist. Furthermore, primary kidney diseases such as anti-glomerular basement membrane disease are frequently associated with autoantibodies, potentially making them ideal candidates for TPE. Nevertheless, the use of TPE in many kidney diseases is controversial because of the lack of supporting evidence. This review discusses TPE from the perspective of a nephrologist responsible for prescribing and managing TPE, as well as nephrologists engaged in the care of patients undergoing the procedure., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Pregnancy-associated renal cortical necrosis is a critical illness with a poor prognosis. We aimed to describe the clinical and magnetic resonance imaging (MRI) characteristics of a case series of patients with acute kidney injury in the setting of pregnancy-associated renal cortical necrosis., Study Design: Case series., Setting & Participants: Seventeen patients from a single center diagnosed by nonenhanced functional MRI and/or kidney pathology., Results: All patients presented with postpartum acute kidney injury stage 3. Of the 17 patients, 15 (88%) had pregnancy-associated atypical hemolytic uremic syndrome, 11 (65%) had postpartum hemorrhage, 7 (41%) had preeclampsia/hemolysis elevated liver enzymes low platelet count syndrome, and 4 (24%) had disseminated intravascular coagulation. On T2-weighted MRI, the diffuse phenotype showed outer cortex swelling in the early phase, with a dark signal rim involving the inner cortex and Bertin column, which became more apparent over time along with cortical thinning, substantially decreasing T2 signal intensity. The focal phenotype showed focally distributed hypointense signals in the cortex. After 8-101 (median: 60) months of follow-up, 4 individuals had estimated glomerular filtration rates ≥60 mL/min/1.73 m 2 , 6 had estimated glomerular filtration rates of 15-60 mL/min/1.73 m 2 , and 7 had kidney failure requiring kidney replacement therapy. The diffuse phenotype was present in all of the individuals who remained kidney replacement therapy dependent., Limitations: Retrospective study; small sample size., Conclusions: Different forms of pregnancy-associated thrombotic microangiopathy were the major causative diseases in our pregnancy-associated renal cortical necrosis case series. Nonenhanced functional MRI may provide valuable data for establishing diagnosis and kidney prognosis., (© 2023 The Authors.)

Résumé Les Escherichia.coli producteurs de Shiga-toxines ou E. coli enterohémorragiques (EHEC) sont responsables d’infections variées allant de la diarrhée aqueuse à la colite hémorragique pouvant évoluer vers un syndrome hémolytique et urémique chez l’enfant, principalement l’enfant de moins de 3 ans, ou une micro-angiopathie thrombotique chez l’adulte. La virulence de ces E. coli est associée à la présence de toxines appelées Shigatoxines. Les bovins constituent un important réservoir pour ces bactéries et l’homme se contamine par ingestion d’aliments contaminés. Les EHEC sont considérés, comme des pathogènes émergents en santé publique, à l’origine de nombreuses épidémies de par le monde, consécutives principalement à la consommation d’aliments contaminés. L’utilisation des antibiotiques est controversée pour le traitement de ces infections. La prévention de ces pathologies graves passe par des règles simples d’hygiène et de prévention alimentaire. Le diagnostic des EHEC repose sur l’isolement et la mise en évidence de leurs gènes de virulence Summary Enterohemorrhagic Escherichia coli (EHEC) are responsible for gastrointestinal diseases such as diarrhea or bloody diarrhea and can lead to hemolytic uremic syndrome (HUS) in children or thrombotic microangiopathy (TMA) in adults. HUS is the leading cause of acute renal failure in young children The most common EHEC serotype associated with human disease is O157:H7. Five major EHEC serotypes have been identified until now in Europe (O157:H7, O26:H11, O103:H2, O111:H8 and O145:H28), but a large number of other EHEC serotypes are also known like EHEC O104:H4 that recently caused two HUS outbreaks in Germany and France. The reservoir of EHEC is mainly the intestinal tract of ruminants: Transmission of EHEC to humans occurs through consumption of contaminated food or water and through direct contact from person to person or from infected animals (cattle in particular). The diagnosis of the EHEC infections relies on isolation of EHEC in stool samples or detection of genes encoding for Shigatoxins. [ABSTRACT FROM AUTHOR]

Objectives: Pathologists specializing in transfusion medicine, apheresis medicine, and/or coagulation are often consulted by clinicians to reach a diagnosis for patients with thrombotic microangiopathy (TMA), so that disease-specific, often life-saving therapy can be initiated as promptly as possible.Methods: This article describes how to proceed when treating a patient with TMA. The differential diagnosis is broad and potentially very challenging. Thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and typical hemolytic uremic syndrome (HUS) are three such TMAs that require timely diagnosis and treatment.Results: TTP is treated with daily therapeutic plasma exchange (TPE) and commonly with adjunctive immunosuppressive therapy, while aHUS may initially be managed with TPE but is best controlled with eculizumab once a presumptive diagnosis is made. TPE has no proven role in typical HUS, which is most commonly treated with supportive measures only.Conclusions: Prompt and accurate diagnosis of TMA subtypes optimizes treatment and improves patient outcomes. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathies (TMAs) represent a complex interaction of endothelial and podocyte biology, nephron physiology, complement genetics, and oncologic therapies with host immunology. The complexity of various factors, such as molecular causes, genetic expressions, and immune system mimicking, along with incomplete penetrance, make it difficult to find a straightforward solution. As a result, there may be variations in diagnosis, study, and treatment approaches, and achieving a consensus can be challenging. Here, we review the molecular biology, pharmacology, immunology, molecular genetics, and pathology of the various TMA syndromes in the setting of cancer. Controversies in etiology, nomenclature, and points requiring further clinical, translational, and bench research are discussed. Complement-mediated TMAs, chemotherapy drug–mediated TMAs, TMAs in monoclonal gammopathy, and other TMAs central to onconephrology practice are reviewed in detail. In addition, established and emerging therapies within the US Food and Drug Administration pipeline subsequently are discussed. Finally, a comprehensive review of critical areas of onconephrology clinical practice is presented as practical value to the clinical practitioner and seeds of investigation to be sown among the community of atypical hemolytic uremic syndrome researchers. [ABSTRACT FROM AUTHOR]

Hemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy of the glomerular microcirculation and other vascular beds. Its defining clinical phenotype is acute kidney injury, microangiopathic anemia, and thrombocytopenia. There are many etiologies of HUS including infection by Shiga toxin (Stx)-producing bacterial strains, medications, viral infections, malignancy, and mutations of genes coding for proteins involved in the alternative pathway of complement. In the aggregate, although HUS is a rare disease, it is one of the most common causes of acute kidney injury in previously healthy children and accounts for a sizable number of pediatric and adult patients who progress to end stage kidney disease. There has been great progress over the past 20 years in understanding the pathophysiology of HUS and its related disorders. There has been intense focus on vascular injury in HUS as the major mechanism of disease and target for effective therapies for this acute illness. In all forms of HUS, there is evidence of both systemic and intra-glomerular inflammation and perturbations in the immune system. Renewed investigation into these aspects of HUS may prove helpful in developing new interventions that can attenuate glomerular and tubular injury and improve clinical outcomes in patients with HUS

Objective: CblC deficiency, the most common cobalamin metabolic abnormality, is caused by pathogenic variants in the MMACHC gene. The renal complications of this disease have been described only in a small number of cases. This study aimed to better delineate renal phenotype and genetic characteristics in Chinese children with cblC defect., Methods: Children with cblC deficiency who manifested as kidney damage were enrolled. Clinical, renal pathological, and genetic data were reviewed in detail., Results: Seven cases were enrolled. Ages at disease onset ranged from 9 months to 5 years. All patients presented with hematuria and proteinuria, and 2/7 cases presented with nephrotic syndrome. Renal dysfunction was observed in 4/7 cases. Renal biopsy was performed in 5/7 cases, and all of them had renal thrombotic microangiopathy. Macrocytic anemia was detected in all seven patients. Six out of seven cases had hypertension, and 2/7 cases presented with pulmonary hypertension. Two of them had a mild intellectual disability, and one suffered from epilepsy. Increased urine methylmalonic acid and plasma homocysteine were detected in seven cases, while two patients had normal levels of urine methylmalonic acid at the initial evaluation. After diagnosis, all seven cases were treated with hydroxocobalamin IM. Six cases were followed-up for 3-8 years. After treatments, anemia was the first to be recovered, followed by proteinuria. Renal function recovered after 1 year in two cases, whereas patient 2 progressed to stage 2 chronic kidney disease 13 years after onset. While a case presented with end-stage kidney disease because of late diagnosis, one case died 3 months after disease onset due to giving up treatment. Three MMACHC pathogenic variants c.80A > G (8/14), c.609G > A (4/14), and c.658_660delAAG (2/14) were detected in all seven children., Conclusion: MMACHC variant c.80A > G may be associated with prominent renal complications in Chinese cblC patients. Macrocytic anemia and hyperhomocysteinemia are useful clues for patients with hematuria and proteinuria caused by cblC defect. The most frequent renal pathological manifestation is thrombotic microangiopathy. Early diagnosis and treatment resulted in improving renal and hematological signs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Liu, Xiao, Yao, Wang, Zhang, Zhong, Yang, Ding and Wang.)

High-risk transplantation-associated thrombotic microangiopathy (TMA) can present with multisystem involvement and is associated with a poor outcome after hematopoietic stem cell transplantation (HSCT), with < 20% 1-year survival. TMA may involve the intestinal vasculature and can present with bleeding and ischemic colitis. There are no established pathologic criteria for the diagnosis of intestinal TMA (iTMA). The goal of our study was to identify histologic features of iTMA and describe associated clinical features. We evaluated endoscopic samples from 50 consecutive HSCT patients for 8 histopathologic signs of iTMA and compared findings in 3 clinical groups based on the presence or absence of systemic high-risk TMA (hrTMA) and the presence or absence of clinically staged intestinal graft-versus-host disease (iGVHD): TMA/iGVHD, no TMA/iGVHD, and no TMA/no iGVHD. Thirty percent of the study subjects had a clinical diagnosis of systemic hrTMA. On histology, loss of glands, intraluminal schistocytes, intraluminal fibrin, intraluminal microthrombi, endothelial cell separation, and total denudation of mucosa were significantly more common in the hrTMA group ( P < .05). Intravascular thrombi were seen exclusively in patients with hrTMA. Mucosal hemorrhages and endothelial cell swelling were more common in hrTMA patients but this difference did not reach statistical significance. Patients with hrTMA were more likely to experience significant abdominal pain and gastrointestinal bleeding requiring multiple blood transfusions ( P < .05). Our study shows that HSCT patients with systemic hrTMA can have significant bowel vascular injury that can be identified using defined histologic criteria. Recognition of these histologic signs in post-transplantation patients with significant gastrointestinal symptoms may guide clinical decisions. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplant–related thrombotic microangiopathy (HSCT-TMA) is a severe complication whose pathophysiology is unknown. We describe 6 patients in which the disease was associated with complement regulatory gene abnormalities received from their respective donors. It is suggested that mutated and transplanted monocyte-derived cells are responsible for production of abnormal proteins, complement dysregulation, and, ultimately, for the disease. This observation might have important drawbacks as far as HSCT-TMA pathophysiology and treatment are concerned. [ABSTRACT FROM AUTHOR]

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA). It has an unfavorable outcome with death rates as high as 25% during the acute phase and up to 50% of cases progressing to end-stage renal failure. Uncontrolled complement activation through the alternative pathway is thought to be the main underlying pathopysiology of aHUS and corresponds to all the deleterious findings of the disease. Thrombotic thrombocytopenic purpura (TTP) and Shiga toxin-associated HUS are the 2 other important TMA diseases. Although differentiating HUS from TTP is relatively easy in children with a preceding diarrheal illness or invasive S. pneumoniae, differentiating aHUS from TTP or other microangiopathic disorders can present a major diagnostic challenge in adults. ADAMTS13 analysis is currently the most informative diagnostic test for differentiating TTP, congenital TTP, and aHUS. Today empiric plasma therapy still is recommended by expert opinion to be used as early as possible in any patient with symptoms of aHUS. The overall treatment goal remains restoration of a physiological balance between activation and control of the alternative complement pathway. So it is a reasonable approach to block the terminal complement complex with eculizumab in order to prevent further organ injury and increase the likelihood organ recovery. Persistence of hemolysis or lack of improvement of renal function after 3-5 daily plasmaphereses have to be regarded as the major criteria for uncontrolled TMA even if platelet count has normalized and as an indication to switch the treatment to eculizumab. Eculizumab has changed the future perspectives of patients with aHUS and both the FDA and the EMA have approved it as life-long treatment. However, there are still some unresolved issues about the follow-up such as the optimal duration of eculizumab treatment and whether it can be stopped or how to stop the therapy. [ABSTRACT FROM AUTHOR]

Rationale & Objective: Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation., Study Design: Case series., Setting & Participants: We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients., Findings: Monoclonal gammopathy-associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested., Limitations: Retrospective study without comparison group; limited number of patients, limited available blood samples., Conclusions: Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Calcineurin inhibitors such as cyclosporin A (CsA) and FK506 have been used in solid organ and hematopoietic stem cell transplantations to suppress immune function. However, these immunosuppresants are associated with severe endothelial dysfunction. We investigated whether CsA and FK506 induce endothelial dysfunction using a three-dimensional culture blood vessel model, in which human umbilical vein endothelial cells form and maintain capillary-like tube and lumen structures. We found that FK506, but not CsA, induced breakdown of the tube structures and endothelial cell death. FK506 inhibited calcineurin activity, but FK506-induced tube breakdown and cell death was not suppressed by RNA interference targeting calcineurin Aα. FK506 also induced caspase activation, but caspase inhibition by zVAD(OMe)-fmk failed to suppress FK506-induced tube breakdown and cell death. FK506 induced attenuation of Akt and extracellular-regulated kinase 1/2 (ERK1/2). Furthermore, Akt inhibition by LY294002 or ERK1/2 inhibition by PD98059 induced tube breakdown and cell death. Present results suggest that FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway. [Copyright &y& Elsevier]

Abstract: The complement system contains a great deal of biological “energy”. This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced “typical” HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase ε (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity. [Copyright &y& Elsevier]

Both atypical haemolytic uraemic syndrome (aHUS) and the HELLP syndrome (haemolytic anaemia, elevated liver enzymes, and low platelets) are thrombotic microangiopathies characterized by microvascular endothelial activation, cell injury and thrombosis. aHUS is a disease of complement dysregulation, specifically a gain of function of the alternative pathway, due to mutations in complement regulatory proteins and activating components. Recently, the same complement mutation identified in multiple patients with aHUS was found in a patient with the HELLP syndrome. The pathogeneses of both diseases are reviewed focusing on the role of the complement system and how its dysfunction could result in a thrombotic microangiopathy in the kidney in the case of aHUS and in the liver in the case of the HELLP syndrome. [ABSTRACT FROM AUTHOR]

Thrombotic microangiopathy (TMA) is a clinicopathological syndrome characterized by thrombosis formation in the microvasculature of various organs. Included in the broad category of TMA are the hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Typical HUS is caused by Escherichia coli O157:H7, which produces the Shiga-like toxins; Stx-1 and Stx-2. In addition to damaging endothelial cells via the inhibition of protein synthesis, Shiga-like toxins also activate endothelial cells to produce inflammatory mediators, amplifying the prothrombogenic state. Although most patients with typical HUS recover renal functions, recent analysis has shown that typical HUS is not a benign disease in the long term. Genetic abnormalities of complement regulatory proteins predispose patients to atypical HUS. Mutations in factor H, membrane cofactor protein, and factor I are known to be associated with atypical HUS. Atypical HUS forms have a poor outcome and show recurrent and progressive courses. Autoimmune IgG inhibitors of a disintegrin and metalloprotease, with thrombospodin-1-like domains (ADAMTS) 13 and mutations of the ADAMTS13 gene lead to the development of TTP. Without treatment, TTP is associated with a very high mortality rate. As it is for atypical HUS, plasma exchange is currently the most feasible treatment for TTP. Etiological diagnosis at the bedside and the development of disease-specific therapeutic modalities will enable us to optimize the management of patients with TMA and improve their prognosis in the future. [ABSTRACT FROM AUTHOR]

A 68-year-old woman with systemic sclerosis developed acute respiratory failure due to diffuse alveolar hemorrhage and normotensive scleroderma renal crisis (SRC) shortly after the initiation of corticosteroid therapy. Treatment with angiotensin-converting enzyme inhibitor and plasmapheresis had failed in this patient. Autopsy showed diffuse alveolar damage and thrombotic micro-angiopathy. The sequence of events in this patient clarifies the pathologic process of normotensive SRC, and suggests a causative role of corticosteroid therapy and normotensive SRC. [ABSTRACT FROM AUTHOR]