Kidney Limited Complement-Mediated Thrombotic Microangiopathy- a Challenging Case

Introduction: Complement-mediated thrombotic microangiopathy (CM-TMA) is a rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and organ injury. The absence of hemolysis and thrombocytopenia is rare. We present a case of kidney limited CM-TMA successfully treated with eculizumab. Method(s): A 36 year-old man with poorly controlled hypertension, obesity, CKD (baseline creatinine (sCr) 2,6mg/dL, albuminuria 150mg/g), hyperlipidemia, obstructive sleep apnea, hyperuricemia, SARS-CoV-2 infection 3 months earlier, and family history of CKD of unknown etiology (father started kidney replacement therapy (KRT) at young age) presented to the ER with high blood pressure and right hemiplegy. Head CT scan showed left thalamo-capsular hemorrhage. Oftalmologic exam was normal. Laboratory findings were: hemoglobin (Hb) 12.5g/dL, elevated white cell count (17.900/uL), platelet count 214.000/uL, sCr 4.3mg/dL, lactate dehydrogenase (LDH) 303U/L. Urine dipstick revealed protein+ and Hb++. Chest X-ray showed signs of pneumonia. The patient was admitted in ICU and mechanically ventilated. After 3 weeks, renal function recovered to its baseline (sCr 1.5mg/dL, no proteinuria) without KRT, and the patient was transferred to the medical ward. Several infectious complications prolonged hospital stay. After 3 months, a new mild SARS-CoV-2 infection was detected. At this time: Hb 9.9g/dL, platelets 220.000/uL, sCr 2.2mg/dL. Six days later the patient showed Hb 9.5 g/dL, without reticulocytosis, platelets 195.000/uL, sCr 6.3mg/dL, LDH 348U/L, normal haptoglobin, no schizocytes on blood smear. After 3 days, the patient was anuric and sCr increased to 10mg/dL, prompting KRT. Kidney ultrasound showed no abnormalities. Autoimmunity study was negative, normal C3/C4, no monoclonal gammopathy, and negative viral serologies. Kidney biopsy (KB) was performed as the etiology of AKI remained unclear. Light microscopy revealed thickned glomerular capillary walls with subendothelial expansion forming double contouring, arteriolar intimal expansion and fibrin thrombi occluding the vascular lumina. Scarse C3 deposition was observed in capillary walls. Since the morphological features were consistent with TMA, secondary causes were excluded and primary causes also investigated: ADAMTS13 activity, complement factor B and I were within normal range, slight decrease of factor H with normal anti factor H antibody. The molecular studies of complement genes were performed by NGS-based gene panel revealing a rare heterozygous missense mutation on gene CFB, c.1189G>A (p.Asp397Asn), described as a genetic risk factor of CM-TMA in the presence of a trigger. Result(s): Treatment with eculizumab was started and the patient showed signs of kidney recovery allowing KRT suspension 1 month later (sCr 5.53mg/dL). Of note, the patient never presented MAHA or thrombocytopenia. After 5 months, renal function improved to sCr 3.9mg/dL. Conclusion(s): We report a case of CM-TMA with isolated kidney injury without laboratory hallmarks of TMA. Patients usually require a secondary trigger for the disease to manifest, and in this case SARS-CoV-2 infection may have been the causative agent. A mutation in gene CFB may have predisposed the patient to the outcome. KB was crucial for diagnosis and prompted the treatment with eculizumab with partial recovery without the need for chronic KRT. No conflict of interestCopyright © 2023

POS-011 PRIMARY ATYPICAL HEMOLYTIC-UREMIC SYNDROME ASSOCIATED WITH COVID-19: A BRIEF REVIEW

Introduction: Since the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in December 2019, coronavirus disease 2019 (COVID-19) has spread tremendously. We now know that infected individuals can experience a wide range of systemic complications, including thrombotic microangiopathy (TMA). Among the total of 45 published cases of COVID-19-associated TMA, there were 4 cases of primary atypical hemolytic-uremic syndrome (aHUS). COVID-19 likely represents a second hit of primary aHUS that manifests in genetically predisposed individuals. Methods: We reviewed the global literature reported from the first mention of COVID-19 in 2019 to February 2022, including individual case reports and case series of adult patients with COVID-19-associated TMAs. Electronic searches were conducted in the PubMed database using keywords and their combinations: »thrombotic microangiopathy, COVID-19, thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome«. Results: Among the total of 45 published cases of COVID-19-associated TMA, there were 18 cases reported as acquired thrombotic thrombocytopenic purpura (TTP) and 19 cases presented as mixed forms of TMA associated with multifactorial triggers (without proven abnormalities of ADAMTS13 activity or proven inhibitors of ADAMTS13 or proven Shiga toxin). The remaining 8 cases were complement-mediated TMAs: • 2 cases of hereditary aHUS (patient 1 and 2);• 1 case of probable hereditary aHUS, where the patient had a heterozygous variant with unknown significance in complement factor I and was heterozygous for the complement factor H H3 haplotype reported as a risk factor of aHUS (patient 3);• 1 case of aHUS with significantly elevated factor H autoantibodies in the absence of genetic testing (patient 4);• 4 cases with decreased complement levels in the absence of genetic testing. We focused on the 4 patients with primary aHUS. Among those, there were 2 females and 2 males with an average age of 28.75 +/- 6.18 years. Although in all cases nasopharyngeal swab was positive for SARS-CoV-2 infection by a polymerase chain reaction-based test, none of the patients had any respiratory symptoms. Patients 2 and 3 underwent renal biopsies, which confirmed the diagnosis of TMA. Patients 2, 3, and 4 required treatment with hemodialysis (HD). Patient 3 did not receive any specific treatment due to delayed diagnosis and lack of availability of eculizumab, while patients 2 and 4 underwent therapeutic plasma exchange and received steroids and eculizumab (patient 2 received only the initial dose of eculizumab because further doses were not granted). Patients 2 and 3 remained HD-dependent, while the renal function of patient 4 partially recovered. Patient 1, who did not need HD, was treated with eculizumab and had partial recovery of renal function. Conclusions: In conclusion, different types of TMA may occur during the course of COVID-19, including aHUS. COVID-19 likely represents a second hit of primary aHUS that manifests in genetically predisposed individuals (e.g., those with an underlying complement risk factor). Early identification of COVID-19-associated primary aHUS is needed in order to promptly start treatment with eculizumab. No conflict of interest

2nd Toronto Complement Conference

The proceedings contain 17 papers. The topics discussed include: a helix-swapped C3d dimer mediated by immune evasion protein Sbi hints at a novel s. aureus complement modulation strategy;the role of factor H in macrophages;an antibody targeting complement factor H causes anti-tumor immunity through B-cell activation;C5aR2 deficiency ameliorates inflammation in antibody transfer experimental epidermolysis Bullosa Acquisita and suggests regulating action on the decisive C5a receptor 1;clinical and biomarker characteristics of patients with C3G enrolled in two phase 2 studies investigating the factor D inhibitor Danicopan;perceiver-based machine learning diagnosis of TMA in renal biopsies;and recurrence of atypical hemolytic uremic syndrome After COVID-19 vaccination.

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection.

BACKGROUND: The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger. METHODS: We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi. RESULTS: We report 5 patients, 4-13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25-85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m2; one patient was dialysis-dependent. CONCLUSION: Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. A higher resolution version of the Graphical abstract is available as Supplementary information.

Case Report: Severe Complement-Mediated Thrombotic Microangiopathy in IgG4-Related Disease Secondary to Anti-Factor H IgG4 Autoantibodies.

Objective: To first describe and estimate the potential pathogenic role of Ig4 autoantibodies in complement-mediated thrombotic microangiopathy (TMA) in a patient with IgG4-related disease (IgG4-RD). Methods: This study is a case report presenting a retrospective review of the patient's medical chart. Plasma complement C3 and C4 levels, immunoglobulin isotypes and subclasses were determined by nephelometry, the complement pathways' activity (CH50, AP50, MBL) using WIESLAB® Complement System assays. Human complement factor H levels, anti-complement factor H auto-antibodies were analyzed by ELISA, using HRP-labeled secondary antibodies specific for human IgG, IgG4, and IgA, respectively. Genetic analyses were performed by exome sequencing of 14 gens implicated in complement disorders, as well as multiplex ligation-dependent probe amplification looking specifically for CFH, CFHR1-2-3, and 5. Results: Our brief report presents the first case of IgG4-RD with complement-mediated TMA originating from both pathogenic CFHR 1 and CFHR 4 genes deletions, and inhibitory anti-complement factor H autoantibodies of the IgG4 subclass. Remission was achieved with plasmaphereses, corticosteroids, and cyclophosphamide. Following remission, the patient was diagnosed with lymphocytic meningitis and SARS-CoV-2 pneumonia with an uneventful recovery. Conclusion: IgG4-RD can be associated with pathogenic IgG4 autoantibodies. Genetic predisposition such as CFHR1 and CFHR4 gene deletions enhance the susceptibility to the formation of inhibitory anti-Factor H IgG4 antibodies.