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

Covid-19 Associated Secondary Sclerosing Cholangitis - a Case Series of 4 Patients

Introduction: COVID-19 associated secondary sclerosing cholangitis (SSC) is a recently described cholestatic liver disease that seems to be a variant of SSC in critically ill patients (SSC-CIP). About 30 cases were described in the literature so far. In this disease, the direct cytophatic effect on cholangiocytes, the cytokine storm and hypercoagulability state add up to the mechanisms identified for SSC-CIP, such as ischemic cholangiopathy caused by invasive mechanical ventilation and hemodynamic instability, bile toxicity, biliary infection and drug-induced liver injury. Aims & Methods: We present a case series of 4 patients who developed SSC complicating the course of severe COVID-19. These cases are illustrated by detailed iconography. Result(s): Clinical cases of 63 and 64-years-old female patients and 56 and 78-years-old male patients are described. None of the individuals had a previously known liver disease. However, we documented previous hepatitis B virus (HBV) infection in one patient and chronic HBeAg negative HBV infection, with low DNA level, in another one. All patients had long stays in the intensive care unit (ICU) with invasive mechanical ventilation (high positive end-expiratory pressure [PEEP], periods of prone positioning, difficult ventilator weaning), need for vasopressors and multiple other drugs, including various antibiotics and high dose steroid therapy. Initially, a significant raise in aminotransferases (aspartate aminotransferase 13-17x upper limit of normal [ULN] and alanine aminotransferase 20-34x ULN) was observed, with subsequent improvement, followed by marked cholestasis (alkaline phosphatase 17-23x ULN and gamma-glutamyl transpeptidase 40-99x ULN) and jaundice (total bilirubin 3-7x ULN), in spite of clinical improvement. Magnetic resonance cholangiopancreatography (MRCP) showed similar aspects in different patients - prominence, thickening or irregularity of intra-hepatic biliary ducts (all patients), strictures and cystic dilations with a typical beaded appearance (three patients) and liver abcesses (two patients). In one patient, endoscopic retrograde cholangiopancreatography (ERCP) was performed, confirming rarefaction and focal dilations of intrahepatic ducts and a biliary cast was extracted. The liver biopsy performed in three patients revealed significant edema and mixed inflammatory infiltrate of portal spaces, ductulitis, proliferation of the bile duct epithelia, intra-hepatic cholestasis and inflammatory aspects of a small-medium size vessel. All patients were started on ursodeoxycholic acid. None of them reached normalization of liver enzymes and at least one patient progressed to liver cirrhosis (follow-up time of 4-15 months). Two patients were referred to a liver transplant center. Conclusion(s): COVID-19 associated SSC is a rare late complication of severe SARS-CoV-2 infection. These patients exhibit a spectrum of similar laboratory, cholangiographic and histological features. The prognosis is dismal with rapid progression to advanced chronic liver disease. Since effective medical treatment is lacking, early referral for liver transplantation should be considered.