POS-001 A NOVEL CFHR5 COPY NUMBER VARIATION ASSOCIATED WITH POST-PARTUM ATYPICAL HUS SUPERIMPOSED TO HELLP SYNDROME

IntroductionPregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP. However, after an emergency delivery, the patient developed post-partum HUS with thrombocytopenia, hemolytic anemia, increased LDH and acute kidney injury.The patient received antihypertensives, fresh frozen plasma and packed red cell transfusions. From day 11 post-partum the patient also received antibiotics for sepsis by Klebsiella pneumoniae.Within day 18 post-partum blood pressure normalized and TMA resolved. However, NS persisted and renal biopsy (performed 13 days after delivery) disclosed a focal segmental glomerulosclerosis (FSGS) pattern with the collapsing variant.MethodsGenetic analyses included Next Generation Sequencing, to evaluate the presence of rare genetic variants in complement aHUS-associated genes (CFH, CD46, CFI, CFB, C3, THBD, and DGKE), and Multiplex Ligation-dependent probe amplification (MLPA), to investigate the copy number variations (CNVs) in the genomic region of CFH-CFHR1-5 genes. Proband serum (collected 14 days post-partum) was used to evaluate the FHR protein pattern by Western blot (WB) and to test C5b-9 deposition on human microvascular endothelial cells (HMEC-1), as marker of complement activation.ResultsAt the time of sample collection, platelet count and s-creatinine were normal, but anemia was still present, LDH was elevated, leucocytes were increased and proteinuria was still in nephrotic range. Complement profile showed normal C3 and C4 levels but elevated plasma sC5b-9 (615 ng/ml, nv <400). ADAMTS13 was normal.Proband serum caused higher than normal C5b-9 deposits on HMEC-1 (179%; nv <150%) indicating endothelial complement activation. Genetic results provided abnormal CNVs in the CFHR5 gene with deletion of coding regions from exon 4 to exon 9. WB analysis revealed a shorter than normal FHR5 protein (~20 kDa) consistent with the predicted product of the CFHR5 deleted gene.ConclusionsWe hypothesize that mutant FHR5 protein contributed to complement dysregulation predisposing to post-partum HUS. CFHR5 abnormalities were found in aHUS and also in other glomerulopathies (IgA nephropathy and C3 glomerulopathy). Cases with combined FSGS and HUS have been previously reported, but none in association with pregnancy. Functional studies are required to elucidate the pathogenic role of the FHR5 abnormality in the complex clinical picture here presented.No conflict of interest IntroductionPregnancy and postpartum are triggers for various forms of thrombotic microangiopathy (TMA), a lesion characterized by endothelial injury and thrombosis in the microcirculation of various organs. These forms include thrombotic thrombocytopenic purpura (TTP), caused by ADAMTS13 deficiency, and atypical hemolytic uremic syndrome (aHUS), most often associated with genetically determined dysregulation of complement system. HUS is the most common form of TMA in the post-partum period. The diagnosis of pregnancy-associated HUS can be difficult because preeclampsia and HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome may present with clinical and laboratory features of TMA that however commonly resolve spontaneously after delivery.Here, we report the biochemical and genetic characterization of a 22 years old primigravida of African origin who presented at 38 weeks of gestation with severe hypertension, nephrotic syndrome (NS) and elevated liver enzymes, consistent with a diagnosis of HELLP. However, after an emergency delivery, the patient developed post-partum HUS with thrombocytopenia, hemolytic anemia, increased LDH and acute kidney injury.The patient received antihypertensives, fresh frozen plasma and packed red cell transfusions. From day 11 post-partum the patient also received antibiotics for sepsis by Klebsiella pneumoniae.Within day 18 post-partum blood pressure normalized and TMA resolved. However, NS persisted and renal biopsy (performed 13 days after delivery) disclosed a focal segmental glomerulosclerosis (FSGS) pattern with the collapsing variant.