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

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.

Sars-Cov-2 Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria: An Italian Multicenter Survey

SARS-CoV-2 infection and vaccination have raised concerns in paroxysmal nocturnal hemoglobinuria (PNH). In fact, PNH patients carry an increased infectious risk secondary to complement inhibition treatment or associated bone marrow failure (BMF), and may therefore benefit from preventive strategies such as vaccinations. On the contrary, vaccines can be numbered among inflammatory complement amplifiers (e.g., infections, traumas, surgery), potentially triggering a disease exacerbation. In PNH patients on complement inhibitors, this phenomenon has been defined pharmacodynamic breakthrough hemolysis (BTH). Based on isolated reports of BTH following SARS-CoV-2 vaccines, we conducted a survey among 5 Italian reference centers to evaluate complications and BTH occurrence in PNH patients who completed the SARS-CoV-2 vaccination schedule from January, 2 2021 until the time of writing. Adverse events, hematologic and hemolytic parameters were recorded within 7-10 days before and after each dose of vaccine. A total of 67 patients (females/males 43/24, median age 47.6 years, range 21-90.5) were eligible for the analysis. According to the International PNH Interest Group classification, 45 patients suffered from hemolytic PNH, 20 from PNH in the context of BMF syndromes (aplastic anemia or myelodysplastic syndrome), and 2 from subclinical PNH. Fifty-five subjects (82%) were on regular complement inhibition therapy, i.e., eculizumab (N=35), ravulizumab (N=13), subcutaneous anti-C5 (N=3), anti-factor B (N=2) and ravulizumab + anti-factor D combination (N=2). Vaccines (Comirnaty/Pfizer-BioNTech N=53, mRNA-1273/Moderna N=12, and ChAdOx1 nCov-19/AstraZeneca N=2) were complessively well-tolerated, with 3 non-hematologic adverse events after the first dose (2 fever and 1 exercise-induced tachycardia, grade 1 according to CTCAE v5.0) and 2 after the second one (fever, accompanied by vomit in one patient, grade 1). During the observation period, 3 BTH and 1 hemolytic exacerbation were recorded (5.9% of patients), as detailed in Table 1. The most severe episode occurred in a young woman (Patient 3) on subcutaneous ravulizumab who experienced a hemoglobin (Hb) drop >2 g/dL, marked clinical signs of intravascular hemolysis and lactate dehydrogenase (LDH) increase >1.5 x upper limit of normal (ULN) from baseline, which is considered a clinical BTH according to the criteria proposed by the Severe Aplastic Anemia Working Party of the European group for Bone Marrow Transplantation. The patient required hospitalization for additional treatment with recombinant erythropoietin and anti-thombotic/bacterial prophylaxis. The second more severe BTH was registered in a male patient (Patient 1) on oral anti-factor B who experienced a Hb drop >2 g/dL without an overt hemolytic flare, and required hospitalization for intravenous antibiotic therapy (concomitant urinary tract infection). The remaining two patients experienced a subclinical BTH (Patient 2) and a hemolytic flare (Patient 4, not on complement inhibition). On the whole, a median delta variation from usual values of Hb and LDH of -25% (range -26+3%) and +80% (+18+105%) were observed, respectively. Of note, 3 episodes occurred after the second dose of vaccine, generally within 24-48 hours. Anti-complement drugs were not modified/discontinued in any of the 3 patients on regular treatment. Patients not experiencing BTH (94.1%) showed stable hematologic parameters after the first dose (Hb/LDH median delta variations from baseline -1%/+1%, range -14+12%/-32+40%) and the second dose of vaccine (Hb/LDH median delta variations from baseline +1%/0%, range -18+47%/-76+41%). Of note, 4 patients with a previous SARS-CoV-2 infection completed the vaccination without any complication/PNH exacerbation. In conclusion, this survey shows that BTH/hemolytic flares following SARS-CoV-2 vaccines are observed in about 6% of PNH patients, may be clinically relevant but manageable, and should not discourage vaccination. BTH has been registered mostly few days after the second dose of vaccine, suggesting a “booster⠝ effect favoring a higher inflammatory response. Watchful clinical and laboratory monitoring is advised, in order to promptly recognize severe hemolytic flares in both treated and naïve patients. [Formula presented] Disclosures: Fattizzo: Novartis: Speakers Bureau;Kira: Speakers Bureau;Alexion: Speakers Bureau;Annexon: Consultancy;Momenta: Honoraria, Speakers Bureau;Apellis: Speakers Bureau;Amgen: Honoraria, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sica: Jazz Pharma: Consultancy;Alexion: Consultancy. Barcellini: Novartis: Other: Invited speaker, Research Funding;Agios: Membership on an entity's Board of Directors or advisory committees;Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Other: Invited speaker, Research Funding;Bioverativ: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees.

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway.

The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.