Dengue is the most prevalent arthropod-transmitted infection worldwide. Its clinical presentation ranges from subclinical illness to multi-organ failure. Acute kidney injury (AKI) is one of its complications, having a number of different pathogeneses. The patient herein described presented with thrombotic microangiopathy (TMA) and rhabdomyolysis, a combination never previously reported in the literature. He was diagnosed with dengue at a primary care hospital, after which he was referred to us with fever and oliguria. His blood workup and kidney biopsy revealed a picture of combined TMA and rhabdomyolysis-induced AKI. He developed sepsis after his first session of plasmapheresis, that had to be discontinued and he was further managed with dialysis and supportive care. The patient showed remarkable recovery, regaining kidney function after one month.

Lupus nephritis (LN) is one of the most common organ-specific manifestations of systemic lupus erythematosus (SLE). Various clinical signs of LN develop in at least 50% of patients with SLE. In addition to LN, the spectrum of renal lesions associated with SLE also includes vascular pathology. One of the variants of renal microvascular injury is thrombotic microangiopathy (TMA), the mechanisms of which are diverse. The review focuses on the main forms of TMA, including antiphospholipid syndrome and nephropathy associated with antiphospholipid syndrome, TMA caused by complement system regulation disorders and deficiency of ADAMTS13. In most cases, these forms of TMA are combined with LN. However, they may also exist as a single form of kidney damage. This article discusses the TMA pathogenesis, the impact on kidney prognosis, and treatment options.
Волчаночный нефрит (ВН) является одним из наиболее частых среди органных проявлений системной красной волчанки (СКВ). Его различные клинические признаки развиваются не менее чем у 50% больных СКВ. Помимо ВН в спектр ассоциированных с СКВ вариантов поражения почек входит и сосудистая патология. Одним из вариантов поражения микроциркуляторного русла почек является тромботическая микроангиопатия (ТМА), механизмы развития которой разнообразны. Обзор посвящен основным формам ТМА, включая антифосфолипидный синдром и нефропатию, ассоциированную с антифосфолипидным синдромом, ТМА, обусловленную нарушениями регуляции системы комплемента и дефицитом ADAMTS13. В большинстве случаев эти формы ТМА сочетаются с ВН, однако могут существовать и как единственные варианты поражения почек. Обсуждаются вопросы патогенеза, влияние ТМА на почечный прогноз и подходы к лечению.

BACKGROUND: The spectrum of diseases characterized by the development of renal thrombotic microangiopathy (TMA) encompasses the malignant hypertension (MHT). TMA in MHT has conventionally been regarded as a variation of secondary TMA, the treatment of which is restricted to the stabilization of blood pressure levels, a measure that frequently fails to prevent the rapid progression to end-stage renal disease in patients. Nevertheless, there exists a rationale to suggest that, in certain instances, endothelial damage in MHT might be rooted in the dysregulation of the complement system (CS), thereby presenting potential opportunities for the implementation of complement-blocking therapy.
OBJECTIVE: To study clinical manifestations and genetic profile of CS in patients with morphologically confirmed renal TMA combined with severe AH.
METHODS: 28 patients with morphologically verified renal TMA and severe AH were enrolled to the study. Patients with signs of microangiopathic hemolysis and thrombocytopenia were not included in the study due to possible compliance with the criteria for atypical hemolytic uremic syndrome (aHUS). The prevalence of rare genetic defects (GD) of the CS was assessed by molecular genetic analysis (search for mutations in the clinically significant part of the human genome - exome) by next-generation sequencing technology (NGS).
RESULTS: GD of CS were detected in a quarter of patients. Rare genetic variants classified as \"likely pathogenic\" including defects in CFI, C3, CD46, CFHR4, CFHR5 genes were detected in five cases. Two patients were found to have chromosomal deletions containing CFH-related proteins genes (CFHR1, CFHR3).
CONCLUSIONS: Rare variants of CS genes linked to aHUS were found in 25% of patients with renal TMA, the genesis of which was originally thought to be secondary and attributed to MHT, with partial or complete absence of hematological manifestations of microangiopathic pathology. The key to confirming TMA associated with MHT, particularly in the absence of microangiopathic hemolysis and thrombocytopenia, elucidating its nature, and potentially effective complement-blocking therapy in patients with GD of CS, appears to be a genetic study of CS combined with a morphological study of a renal biopsy.
Обоснование. Круг заболеваний, характеризующихся развитием почечной тромботической микроангиопатии (ТМА), включает в себя злокачественную артериальную гипертонию (ЗАГ). ТМА при ЗАГ традиционно рассматривается как вариант вторичной ТМА, симптоматическая терапия которой сводится лишь к стабилизации уровня артериального давления, что нередко не позволяет избежать быстрого развития у пациентов терминальной стадии почечной недостаточности. Однако есть основания предполагать, что в ряде случаев в основе эндотелиального повреждения при ЗАГ лежит дисрегуляция системы комплемента (СК), что открывает перспективы для применения комплемент-блокирующей терапии. Цель. Изучить клинические проявления и генетический профиль СК у пациентов с морфологически подтвержденной почечной ТМА, сочетающейся с тяжелыми формами АГ. Материалы и методы. В исследование включены 28 пациентов с морфологически верифицированной почечной ТМА и тяжелыми формами АГ. Больных, имевших признаки микроангиопатической гемолитической анемии и тромбоцитопении, не включали ввиду возможного соответствия критериям атипичного гемолитико-уремического синдрома. Общеклинические данные и распространенность редких генетических дефектов (ГД) СК оценивали путем проведения молекулярно-генетического анализа (поиска мутаций в клинически значимой части генома человека – экзоме) методом высокопроизводительного секвенирования (NGS). Результаты. ГД СК выявлены у 1/4 больных. В 5 случаях обнаружены редкие генетические варианты, классифицированные как «вероятно патогенные», включавшие дефекты генов CFI, C3, CD46, CFHR4, CFHR5. У 2 пациентов выявлены хромосомные делеции, содержащие гены релейт-факторов CFH (CFHR1, CFHR3). Заключение. У 25% больных с почечной ТМА, генез которой первоначально расценен как вторичный и атрибутирован к ЗАГ, при частичном или полном отсутствии гематологических проявлений микроангиопатической патологии обнаружены редкие варианты генов СК, ассоциированные с атипичным гемолитико-уремическим синдромом. Генетическое исследование СК в сочетании с морфологическим исследованием почечного биоптата являются, по-видимому, ключевыми инструментами для верификации ТМА, ассоциированной с ЗАГ, особенно в отсутствие микроангиопатической гемолитической анемии и тромбоцитопении, уточнения ее природы и применения потенциально эффективной комплемент-блокирующей терапии у пациентов с ГД СК.

UNASSIGNED: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS.
UNASSIGNED: This analysis reports 2-year data from 2 phase 3, single-arm studies.
UNASSIGNED: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219).
UNASSIGNED: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight.
UNASSIGNED: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart.
UNASSIGNED: All analyses used descriptive statistics. No formal statistical comparisons were performed.
UNASSIGNED: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m2) and pediatric patients (82.5 mL/min/1.73 m2). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years.
UNASSIGNED: Limitations were the small sample of pediatric switch patients and limited availability of genetic data.
UNASSIGNED: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS.
This research tested a drug called ravulizumab for the treatment of atypical hemolytic uremic syndrome (aHUS). aHUS is a rare disease that causes clots in tiny blood vessels. This can damage the kidneys and other organs. We analyzed data from 2 clinical trials in which children and adults with aHUS received ravulizumab through a tube placed in a vein (intravenous line). They received ravulizumab every 4-8 weeks depending on their weight. We found that treating patients for 2 years with ravulizumab was associated with improved blood health, kidney function, and quality of life and was well tolerated. These results support ravulizumab as a long-term treatment for people with aHUS.

Paraneoplastic glomerular disease (PGD) develops from tumor cell products, leading to renal dysfunction. Unlike direct tumor effects, PGD illustrates the complex association between cancer and diverse clinical presentations and outcomes. Initially detected in a Hodgkin\'s disease patient, current research has defined diagnostic criteria based on PGD symptoms and cancer progression. PGDs, although rare (found in <1% of adult cancer patients with overt renal manifestations), are crucial, as they can signal cancer onset and frequently resist standard glomerulonephritis treatments. The emerging field of onconephrology studies this relationship between kidney disorders and cancers. The exact cause of many PGD cases remains unknown. This review examines PGDs, their clinicopathological features, related cancers, and mechanisms, emphasizing the need for early diagnosis and tailored treatment for kidney disease and linked cancer.

Gene therapy has brought tremendous hope for patients with severe life-threatening monogenic diseases. Although studies have shown the efficacy of gene therapy, serious adverse events have also emerged, including thrombotic microangiopathy (TMA) following viral vector-based gene therapy. In this review, we briefly summarize the concept of gene therapy, and the immune response triggered by viral vectors. We also discuss the incidence, presentation, and potential underlying mechanisms, including complement activation, of gene therapy-associated TMA. Further studies are needed to better define the pathogenesis of this severe complication of gene therapy, and the optimal measures to prevent it.

UNASSIGNED: Atypical hemolytic uremic syndrome (aHUS) poses a significant health challenge due to its rarity and severity within the spectrum of thrombotic microangiopathy. Despite efforts to optimize and personalize health care for patients with aHUS, understanding the individual experiences, needs, and desires of patients with aHUS and their relatives remains limited.
UNASSIGNED: Here, we present a nationwide, exploratory, qualitative interview study with a direct content analysis approach. In-depth interviews and a 6-week evaluation were audio-recorded and conducted using a semistructured topic guide, based on the Institute for Positive Health (IPH) model.
UNASSIGNED: Analysis of 10 interviews involving 6 patients with aHUS and 13 relatives revealed the prevalence of long-term disease symptoms in adult patients, notably fatigue, which significantly impacted daily functioning. Moreover, the resilience demonstrated by patients and their relatives was noteworthy; however, the acute phase of aHUS and the unpredictable nature of disease recurrence could profoundly affect mental well-being. The emotional toll of aHUS is pervasive, with feelings of fear, guilt, and trauma persisting across disease phases in both patients and relatives. Challenges in medical care, including delays in diagnosis and the need for personalized and uniform protocols, were highlighted. Support was deemed crucial, indicating the necessity for enhancements in the accessibility to comprehensible disease information and psychological counseling. Finally, complexities surrounding genetic testing and carriership were discussed.
UNASSIGNED: This study underscores the profound, enduring, and multifaced impact of aHUS. The insights gleaned from the experiences and needs of patients with aHUS and their relatives could lay the foundation for development and implementation of more personalized innovations in aHUS health care.

Thrombotic microangiopathy (TMA) is an anatomopathological lesion mediated by endothelial dysfunction and characterized by the creation of microthrombi in small vessels. In patients with cancer, it may be due to toxicity secondary to chemotherapy, tumor embolization, or hematopoietic progenitor transplantation. Cancer-associated TMA is an underestimated entity that generally appears in the final stages of the disease, although it may also be the initial manifestation of an underlying cancer. Support treatment is necessary in all cases and, depending on the cause, different targeted therapies may be used. The prognosis is very poor. In this article we present a comprehensive review of the existing literature on the physiological mechanisms of cancer-associated TMA. Afterwards, five clinical cases will be presented of patients who developed TMA and were diagnosed in our Department in 2023. We present a discussion of the different causes that triggered the condition, the possible reasons behind the underestimation of this pathology, and the measures that may be adopted.

Thrombotic microangiopathy (TMA) in association with RNA exosome encoding mutations has only recently been recognized. Here, we present an infant (female) with an EXOSC5 mutation (c.230_232del p.Glu77del) associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA. At the age of four months, she presented with signs of septic illness, after which she developed TMA. A stool culture showed rotavirus as a potential trigger. The patient received eculizumab once, alongside supportive treatment, while awaiting diagnostic analysis of TMA, including genetic complement analysis, all of which were negative. Eculizumab was withdrawn and the patient\'s TMA recovered quickly. A review of the literature identified an additional four patients (age < 1 year) who developed TMA after a viral trigger in the presence of mutations in EXOSC3. The recurrence of TMA in one of these patients with an EXOSC3 mutation while on eculizumab treatment underscores the apparent lack of responsiveness to C5 inhibition. In conclusion, mutations in genes influencing the RNA exosome, like EXOSC3 and EXOSC5, characterized by neurodevelopment and neurodegenerative disorders could potentially lead to TMA in the absence of complement dysregulation. Hence, these patients were likely non-responsive to eculizumab.

UNASSIGNED: Thrombotic thrombocytopenic purpura (TTP) is a rare but debilitating thrombotic microangiopathy that results from severe deficiency of the enzyme ADAMTS13. The disorder was first described in the early 20th century, but the pathophysiology of the disease has only been elucidated in the past three decades. In this narrative review, we will summarize the milestone moments in the history of TTP research and discovery.
UNASSIGNED: We searched literature using PubMed from 1924 to 2023 using the following free text searches: \"thrombotic thrombocytopenic purpura\", \"Moschcowitz disease\", and \"thrombotic microangiopathy\". We found 6,917 peer-reviewed articles and sorted through these for relevant literature pertinent to the review. A total of 46 articles were included for review and the remainder were excluded.
UNASSIGNED: The history of TTP research was reviewed, with a sampling of major events in the evolution of the understanding of the pathophysiology and treatment of the disease discussed here. There remains much to be learned about the nature of the disease in order to develop more specific and less harmful treatments.
UNASSIGNED: An overview of the major discoveries that have led to our current understanding of TTP reveals the results of collaboration of multiple groups of physicians and scientists through the past century, with additional breakthroughs likely to occur in the future because of that same collaborative spirit.