Thrombotic microangiopathy with kidney involvement in a patient with coronavirus disease 2019: A case report and literature review (preprint)

Background and aim: Millions of people worldwide have suffered from coronavirus disease 2019 (COVID-19). COVID-19 can lead to coagulopathy and thrombosis, presenting as pulmonary artery thromboembolism, deep vein thrombosis, and thrombotic microangiopathy (TMA), the latter being a rare finding in affected patients’ kidneys. Prior reports have rarely addressed the pathophysiology, clinical presentations, and therapeutic options in patients with COVID-19-associated TMA. Case presentation: We herein described a case of renal biopsy-proven TMA after COVID-19 in a 36-year-old woman. Initial examination revealed inflammation, acute kidney injury (AKI), anemia, and thrombocytopenia. She was diagnosed with hemolytic uremic syndrome, pulmonary infection, and COVID-19. After treatment, her condition stabilized but remained hemodialysis-dependent after discharge. One week later, she was re-hospitalized, and physical examination showed anemia and bilateral lower extremity edema. Abdominal ultrasound showed increased bilateral kidney echogenicity. Whole-exome sequencing detected an unknown variant of the C3 gene associated with hemolytic uremic syndrome susceptibility type 5/complement C3 deficiency. Kidney biopsy showed renal artery lesions, including small arteriole endothelial swelling, intimal thickening, mucinous degeneration, luminal occlusion, and small arterial wall necrosis. She received plasma exchange and steroids with significant renal function recovery. Conclusion: TMA likely contributed to AKI after COVID-19,thus supporting the notion that TMA plays an important role in the pathogenesis of COVID-19-related kidney injury. When diagnosing and treating COVID-19 patients with abnormal renal function, clinicians should incorporate kidney biopsy and genetic testing for the complement system, identify renal-limited and systemic TMA, and treat accordingly, which can improve patient outcomes.

Drug-induced thrombotic thrombocytopenic purpura: A systematic review and review of European and North American pharmacovigilance data.

Many medications have been reported to be associated with thrombotic thrombocytopenic purpura (TTP) through pharmacovigilance data and published case reports. Whilst there are existing data available regarding drug-induced thrombotic microangiopathy, there is no available synthesis of evidence to assess drug-induced TTP (DI-TTP). Despite this lack of evidence, patients with TTP are often advised against using many medications due to the theoretical risk of DI-TTP. This systematic review evaluated the evidence for an association of medications reported as potential triggers for TTP. Of 5098 records available 261 articles were assessed further for eligibility. Fifty-seven reports, totalling 90 patients, were included in the final analysis. There were no cases where the level of association was rated as definite or probable, demonstrating a lack of evidence of any drug causing DI-TTP. This paucity of evidence was also demonstrated in the pharmacovigilance data, where 613 drugs were reported as potential causes of TTP without assessment of the strength of association. This systematic review demonstrates the need for standardised reporting of potential drugs causing TTP. Many reports omit basic information and, therefore, hinder the chance of finding a causative link if one exists.

Renal Thrombotic Microangiopathy: A Review.

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.

AHUS mistaken for TTP associated with COVID-19: a case report (preprint)

Thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) are both thrombotic microangiopathies that share several clinical traits including microangiopathic hemolytic anemia, thrombocytopenia, and organic damage. There is inherent opportunity for misdiagnosis. As thrombocytopenia and thrombus are strongly related to COVID-19, it may be more difficult to tell an aHUS from a TTP when COVID-19 is present. Thus, we describe a patient presenting with severe COVID-19 who was misdiagnosed with TTP but in the end corrected to aHUS. We suggest that perform detection to ADAMTS-13 activity and complement gene mutation as soon as possible is necessary.

Renal Biopsy Diagnosis of Acute Tubular Injury After Pfizer-BioNTech COVID-19 Vaccination: A Case Report (preprint)

Recently, there have been reports of new cases of acute kidney injury (AKI) after coronavirus disease 2019 (COVID-19) vaccination. Podocytic damage, IgA nephropathy, vasculitis, tubulointerstitial damage, and thrombotic microangiopathy have been reported as the causes. However, there are no reports of acute tubular injury (ATI) as the sole cause of AKI. In this case, a 54-year-old man with type 2 diabetes visited a local physician. He was highly obese with a body mass index of 36 kg/m2. He was treated with metformin and insulin. Diabetic retinopathy, urinary protein, and occult blood were absent. He had received four COVID-19 vaccines; three were from Pfizer and one from Moderna. He was referred to our hospital 5 days after receiving the fourth dose of the Pfizer-BioNTech COVID-19 vaccine. He had stage 3 AKI. Urinary findings revealed the presence of new proteinuria and glomerular occult blood. Steroids were introduced on the day of admission for rapidly progressive glomerulonephritis. A renal biopsy was performed on the second day, with results obtained on the fifth day revealing no findings other than ATI. The patient was therefore deemed unamenable to steroids. After steroid discontinuation, renal function recovered spontaneously, and urinalysis abnormalities disappeared. In this case, ATI was the sole pathogenesis of COVID-19 vaccine-induced AKI, and treatment with immunosuppressive drugs was not necessary.

Atypical immunologic manifestations of COVID-19: A case report and a comprehensive review (preprint)

Introduction: COVID-19 usually presents with classic signs and symptoms, but it can involve multiple systems in atypical cases. SARS-CoV-2 has a complex interaction with the host immune system leading to atypical manifestations.  Case Presentation: In our case, a 32-year-old male patient presented with fatigue, sores on hands and feet, headache, productive cough with blood-tinged mucus, conjunctival hyperemia, purpuric rash on hands and feet, and splinter hemorrhages of fingernails for two weeks. The patient’s SARS-CoV-2 antigen and PCR test were positive. Chest x-ray showed mixed density perihilar opacities in both lungs. Computed tomography of the chest showed extensive airspace opacities in both lungs, suggesting COVID-19 multifocal, multilobar pneumonitis. A renal biopsy indicated limited thrombotic microangiopathy and tubulointerstitial nephritis, for which he was started on steroids, and his renal functions gradually improved. He tested positive for C-ANCA during an immune workup. He was discharged with a steroid taper for nephritis. Once the taper reached less than 10 mg/day, he developed acute scleritis and a new pulmonary cavitary lesion of 6 centimeters. The biopsy via bronchoscopy revealed acute inflammatory cells with hemosiderin-laden macrophages. He was restarted on systemic steroids for scleritis after failing topical steroids, which incidentally also reduced the size of the cavitary lesion, indicating an immune component.  Conclusions: Our case demonstrates the involvement of kidneys and vasculitis of the skin, sclera, and lungs by COVID-19. The patient’s symptoms were not explained by any diseases other than COVID-19. Atypical cases of COVID-19 disease with multifocal systemic symptoms involving the skin, sclera, lungs, and kidneys should be high on differentials. Early recognition and intervention may decrease hospital stays and morbidity.

Diagnosis and treatment of thrombotic microangiopathy.

Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic haemolytic anaemia and end organ damage. TMAs have varying underlying pathophysiology and can therefore present with an array of clinical presentations. Renal involvement is common as the kidney is particularly susceptible to the endothelial damage and microvascular occlusion. TMAs require rapid assessment, diagnosis, and commencement of appropriate treatment due to the high morbidity and mortality associated with them. Ground-breaking research into the pathogenesis of TMAs over the past 20 years has driven the successful development of targeted therapeutics revolutionizing patient outcomes. This review outlines the clinical presentations, pathogenesis, diagnostic tests and treatments for TMAs.

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: Literature Review.

Coronavirus disease 2019 (COVID-19) can lead to clinically significant multisystem disorders that also affect the kidney. According to recent data, renal injury in the form of thrombotic microangiopathy (TMA) in native kidneys ranks third in frequency. Our review of global literature revealed 46 cases of TMA in association with COVID-19. Among identified cases, 18 patients presented as thrombotic thrombocytopenic purpura (TTP) and 28 cases presented as atypical hemolytic uremic syndrome (aHUS). Altogether, seven patients with aHUS had previously proven pathogenic or likely pathogenic genetic complement abnormalities. TMA occurred at the time of viremia or even after viral clearance. Infection with COVID-19 resulted in almost no or only mild respiratory symptoms in the majority of patients, while digestive symptoms occurred in almost one-third of patients. Regarding the clinical presentation of COVID-19-associated TMA, the cases showed no major deviations from the known presentation. Patients with TTP were treated with plasma exchange (88.9%) or fresh frozen plasma (11.1%), corticosteroids (88.9%), rituximab (38.9%), and caplacizumab (11.1%). Furthermore, 53.6% of patients with aHUS underwent plasma exchange with or without steroid as initial therapy, and 57.1% of patients received a C5 complement inhibitor. Mortality in the studied cohort was 16.7% for patients with TTP and 10.7% for patients with aHUS. The exact role of COVID-19 in the setting of COVID-19-associated TMA remains unclear. COVID-19 likely represents a second hit of aHUS or TTP that manifests in genetically predisposed individuals. Early identification of the TMA subtype and appropriate prompt and specific treatment could lead to good outcomes comparable to survival and recovery statistics for TMA of all causes.

Renal Histopathological Changes in Coronavirus Disease 2019 Patients: A Systematic Review and Meta-analysis of Individual Patient Data.

The major targets of coronavirus disease 2019 (COVID-19) are the respiratory and immune systems. However, a significant proportion of hospitalized patients had kidney dysfunction. The histopathological surveys have principally focused on respiratory, hematopoietic, and immune systems, whereas histopathologic data of kidney injury are lacking. Our study aimed to summarize the renal histopathological findings in COVID-19 from the published case report and case series. We conducted a systematic searching of databases such as MEDLINE, EMBASE, and Cochrane Library for published reports of COVID-19 patients with renal histopathological changes from autopsy studies and from "for cause" indication biopsies. Included in our study are case reports and case series with extractable quantitative data on patient demographics such as age, sex, ethnicity, as well as data on renal function tests, their comorbidities, and biopsy to study the histopathological changes. Data were analyzed with Microsoft Excel. To evaluate the methodological quality, we chose the framework for appraisal, synthesis, and application of evidence suggested by Murad et al. Systematic searches of literature found 31 studies that fulfilled the eligibility criteria. These studies included a total of 139 cases, where individual case details including clinical and histopathological findings were available. The median age of the cases was 62 years with a male:female ratio of 2.5:1. Associated comorbidities were noted in 78.4% of cases. The majority of the cases had renal dysfunction with proteinuria which was documented in more than two-thirds of the cases. The histopathological findings observed the frequent tubular involvement manifested by acute tubular injury. Regarding glomerular pathology, collapsing glomerulopathy emerged as a distinct lesion in these patients and was noted among 46.8% of cases with glomerular lesions. A small subset of cases (4.3%) had thrombotic microangiopathy. Collapsing glomerulopathy emerged as a hallmark of glomerular changes among COVID-19 patients. Tubular damage is common and is linked to multiple factors including ischemia, sepsis among others. In the form of thrombotic microangiopathy seen in a subset of patients, vascular damage hints toward the hyper-coagulable state associated with the infection. The demonstration of viral particles in renal tissue remains debatable and requires further study.

Thrombotic microangiopathy in children.

The syndrome of thrombotic microangiopathy (TMA) is a clinical-pathological entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end organ involvement. It comprises a spectrum of underlying etiologies that may differ in children and adults. In children, apart from ruling out shigatoxin-associated hemolytic uremic syndrome (HUS) and other infection-associated TMA like Streptococcus pneumoniae-HUS, rare inherited causes including complement-associated HUS, cobalamin defects, and mutations in diacylglycerol kinase epsilon gene must be investigated. TMA should also be considered in the setting of solid organ or hematopoietic stem cell transplantation. In this review, acquired and inherited causes of TMA are described with a focus on particularities of the main causes of TMA in children. A pragmatic approach that may help the clinician tailor evaluation and management is provided. The described approach will allow for early initiation of treatment while waiting for the definitive diagnosis of the underlying TMA.

Atypical hemolytic uremic syndrome induced by SARS-CoV2 infection in infants with EXOSC3 mutation.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy mainly in the kidneys and mostly due to genetic disorders leading to uncontrolled activation of the complement system. Severe complications of SARS-CoV2 infection are linked to microvascular injury and complement activation is suspected to play a role in the pathogenesis of endothelial cell damage in severe COVID-19. METHODS: We present the first two cases of aHUS triggered by SARS-CoV-2 infection in two unrelated infants with the same mutation in the RNA exosome gene EXOSC3. This mutation is known to cause pontocerebellar hypoplasia type 1b, an autosomal-recessive neurodegenerative disease. So far, no kidney involvement in affected persons was reported. RESULTS: As eculizumab treatment was unsuccessful and complement-mediated disorders were ruled out, we suppose that the atypical HUS in our two patients is not due to complement-mediated thrombotic microangiopathy but rather due to a dysfunction of the RNA exosome. CONCLUSIONS: The RNA exosome is crucial for the precise processing and degradation of nuclear and cytoplasmatic RNA. We suspect that the SARS-CoV-2 infection led to changes in RNA that could not be offset by the defective RNA exosome in our two patients. The accumulation/wrong processing of the viral RNA must have led to the endothelial cell damage resulting in aHUS. This would be a new - "RNA-induced" - mechanism of aHUS.

Kidney Transplant Recipients and Omicron: Outcomes, effect of vaccines and the efficacy and safety of novel treatments (preprint)

We aimed to describe the outcomes of Omicron infection in kidney transplant recipients (KTR), compare the efficacy of the community therapeutic interventions and report the safety profile of molnupiravir. From 142 KTRs diagnosed with COVID-19 infection after Omicron had become the dominant variant in the UK, 116 (78.9%) cases were diagnosed in the community; 47 receiving sotrovimab, 21 molnupiravir and 48 no treatment. 10 (20.8%) non-treated patients were hospitalised following infection, which was significantly higher than the sotrovimab group (2.1%), p=0.0048, but not the molnupiravir treated group (14.3%), p=0.47. The only admission following sotrovimab occurred in a patient infected with BA.2. One patient from the molnupiravir and no-treatment groups required ICU support, and both subsequently died, with one other death in the no-treatment group. No patient receiving sotrovimab died. 6/116 (5.2%) patients required dialysis following their diagnosis; 2 (9.5%) patients receiving molnupiravir and 4 (8.3%) no-treatment. This requirement was significantly higher in the molnupiravir group compared with the sotrovimab treated patients, in whom no patient required dialysis, p=0.035. Both molnupiravir treated patients requiring dialysis had features of systemic thrombotic microangiopathy. Post-vaccination serostatus was available in 110 patients. Seropositive patients were less likely to require hospital admission compared with seronegative patients, 6 (7.0%) and 6 (25.0%) respectively, p=0.023. Seropositive patients were also less likely to require dialysis therapy, (p=0.016). In conclusion, sotrovimab treatment in the community was associated with superior patient and transplant outcomes; its clinical efficacy against the BA.2 variant requires a rapid review. The treatment benefit of molnupiravir was not evident, and wider safety reporting in transplant patients is needed.

[A hemolytic episode following COVID-19 in a case with atypical hemolytic uremic syndrome].

Atypical hemolytic uremic syndrome (aHUS) is a lethal disease resulting in systemic thrombotic microangiopathies due to complement dysregulation. Immune activation by viral infections, such as SARS-CoV-2, may trigger hemolytic attack. A 38-year-old man, who had been previously diagnosed with aHUS due to complement component 3 mutation, was proven to be positive for SARS-CoV-2 without respiratory symptoms. No specific intervention was given to the patient, and he developed hematuria and oliguria three days after diagnosis. The patient was subsequently referred to our hospital and treated with eculizumab (900 mg). Afterward, the hemolytic symptoms improved rapidly. To the best of our knowledge, there have been reports of at least ten cases of hemolysis triggered by COVID-19 in patients with aHUS, and a potential clinical benefit of eculizumab for hemolytic attack, as well as for COVID-19, has been suggested. Here, we report the findings of a case, which indicate the efficacy of eculizumab introduction at an early stage.

New-onset diabetic ketoacidosis with purpura fulminans in a child with COVID-19-related multisystem inflammatory syndrome.

BACKGROUND: Coronavirus disease 2019 (COVID 19) usually causes a mild illness among children. However, in a minority of children, it may be associated with the life-threatening multisystem inflammatory syndrome (MIS-C), or thrombotic microangiopathy, or sequelae like type-1 diabetes mellitus (T1DM). We describe a previously healthy, 12-year-old boy with new-onset T1DM with diabetic ketoacidosis (DKA) in the setting of MIS-C, with a course complicated by thrombotic microangiopathy. CASE PRESENTATION: The patient presented with four days history of fever, non-bilious vomiting, polyuria and polydipsia. On evaluation, he was noted to have diabetic ketoacidosis. Although Diabetic ketoacidosis with insulin and intravenous fluids, his hospital course was notable for shock requiring vasopressor, purpura fulminans with eschar formation, neurological manifestations (left hemiparesis due to right middle cerebral artery territory infarct, mononeuritis multiplex) and thrombotic microangiopathy. MIS-C-like illness secondary to COVID-19 was suspected due to diabetic ketoacidosis, thrombotic microangiopathy, elevated inflammatory markers, history of contact with COVID-19-infected individual and detectable COVID-19 IgG antibodies. He improved following management with methylprednisolone, intravenous immunoglobulin, low-molecular-weight heparin and aspirin, and was discharged on hospital day 48. CONCLUSION: MIS-C-like illness should be considered in children and adolescents presenting with complex multisystem involvement in this era of COVID 19. Management with immunomodulatory agents can be lifesaving.

Anticoagulation for Left Ventricular Thrombi Secondary to COVID -- Is Three Months Too Long? (preprint)

Length of anticoagulation for thrombotic events related to COVID-19 is unknown. We present a patient with COVID-19 complicated by a thrombotic anterior STEMI and multiple left ventricular (LV) thrombi that resolved after 8 weeks of anticoagulation. We suggest a shorter length of anticoagulation with COVID-19 related LV thrombus.

FDP Fluctuation in Severe COVID-19 is Associated With the Development of Thrombotic or Bleeding Complications and Systemic Coagulopathy (preprint)

Purpose: COVID-19 is sometimes associated with coagulation disorders. In such cases, patients developed elevated D‐dimer and fibrin degradation products (FDP) levels, both of which are associated with high risks of thromboembolic complications and poor prognosis. To date, time course changes of FDP values in COVID-19 patients has not been well evaluated. The aim of this study is to evaluate whether FDP fluctuation in COVID-19 patients are associated with systemic coagulopathy. Methods: We retrospectively analyzed the changes in coagulofibrinolytic markers including FDP in 42 COVID-19-ARDS patients. FDP elevation as the fluctuation was defined as follows: 1) FDP>10μg/mL for the first time after admission and 2) 10μg/mL or more elevation after the improvement of the first or subsequent FDP elevations. Results: FDP elevation was observed a total of 30 times in 21 patients (50%). Marked intravascular coagulofibrinolytic activation occurred at the same time as the FDP elevation (soluble fibrin: SF, 27.0 [14.9–80.0] μg/mL; thrombin-antithrombin complex: TAT, 7.5 [2.9–17.8] μg/L; plasmin-α 2 -plasmin inhibitor complex: PIC, 2.4 [1.4–4.2] μg/mL). FDP was elevated in all patients who met sepsis-induced coagulopathy (SIC) or disseminated intravascular coagulation (DIC) diagnosis criteria. Thrombotic or bleeding complications developed in 12 patients (28.6%) and were significantly correlated with FDP elevation ( OR [odds ratio] 4.50, 95% CI [confidence interval] 1.01–20.11, p = 0.049). However, there were no significant differences in coagulofibrinolytic activities between the patients with and without SIC or DIC. Conclusions: Coagulation activation which can lead to the development of systemic coagulopathy such as DIC occurred with FDP fluctuation in severe COVID-19 patients. However, there is a limit of the application of existing DIC and SIC diagnosis criteria to COVID-19.

CASE REPORT: Coronavirus with acute kidney injury (preprint)

Known case COVID-19 is with the appearance of acute kidney injury with no previous history. Pathology studies mainly showed histological findings are consistent with thrombotic microangiopathy. With a high prevalence of comorbidities such as acute kidney injury, patients could suffer from severe forms of COVID-19.