ABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is characterized by genetic and acquired abnormalities of the complement system leading to alternative pathway (AP) overactivation and by glomerular endothelial damage, thrombosis, and mechanical hemolysis. Mutations per se are not sufficient to induce aHUS, and nonspecific primary triggers are required for disease manifestation. We investigated whether hemolysis-derived heme contributes to aHUS pathogenesis. We confirmed that heme activates complement AP in normal human serum, releasing C3a, C5a, and sC5b9. We demonstrated that heme-exposed endothelial cells also activate the AP, resulting in cell-bound C3 and C5b9. This was exacerbated in aHUS by genetic abnormalities associated with AP overactivation. Heme interacted with C3 close to the thioester bond, induced homophilic C3 complexes, and promoted formation of an overactive C3/C5 convertase. Heme induced decreased membrane cofactor protein (MCP) and decay-accelerating factor (DAF) expression on endothelial cells, giving Factor H (FH) a major role in complement regulation. Finally, heme promoted a rapid exocytosis of Weibel-Palade bodies, with membrane expression of P-selectin known to bind C3b and trigger the AP, and the release of the prothrombotic von Willebrand factor. These results strongly suggest that hemolysis-derived heme represents a common secondary hit amplifying endothelial damage and thrombosis in aHUS.
Subject(s)
Complement Activation/immunology , Heme/immunology , Hemolytic-Uremic Syndrome/immunology , Atypical Hemolytic Uremic Syndrome , Cell Line , Cell Membrane/immunology , Cell Membrane/metabolism , Complement C3/chemistry , Complement C3/genetics , Complement C3/immunology , Complement C3/metabolism , Complement C3-C5 Convertases/metabolism , Complement C3b/immunology , Complement C3b/metabolism , Complement Pathway, Alternative/immunology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Heme/chemistry , Heme/metabolism , Hemolytic-Uremic Syndrome/metabolism , Humans , Mutation , P-Selectin/metabolism , Protein Binding/immunologyABSTRACT
The diabetes and renal phenotype of patients with maturity-onset diabetes of the young (MODY) on a transplantation waiting list is not known; neither is their outcome after pancreas (PT) and/or kidney transplantation (KT). Between 2002 and 2009, we screened 50 of 150 patients referred for kidney and pancreas transplantation to the Kremlin-Bicêtre center for HNF1B and HNF1A mutations if one or more of the following criteria was present (i) an atypical history of diabetes (ii) diabetes with at least one affected parent or two affected relatives, (iii) an absence of auto-antibodies at diagnosis (iv) a persistent secretion of fasting C peptide (v) a personal or a family history of renal cysts or dysplasia. Their phenotype and their outcome were analyzed. Four HNF1A (MODY3) and eight HNF1B mutations [renal cysts and diabetes (RCAD)] were identified. All MODY3 patients had diabetic nephropathy, but only 50% of RCAD patients. Four patients underwent a kidney and pancreas transplantation and two a kidney transplant alone. After 4.1 ± 1.1 years of follow-up, 83% of patients still have a functioning kidney and 75% a functioning pancreas. PT can be proposed with good results for MODY3 and RCAD patients.
Subject(s)
Central Nervous System Diseases/surgery , Diabetes Mellitus, Type 2/surgery , Islets of Langerhans Transplantation , Kidney Diseases, Cystic/surgery , Kidney Transplantation , Adult , Central Nervous System Diseases/genetics , Cohort Studies , Dental Enamel/abnormalities , Dental Enamel/surgery , Diabetes Mellitus, Type 2/genetics , Female , Follow-Up Studies , Graft Survival , Hepatocyte Nuclear Factor 1-alpha/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Humans , Islets of Langerhans Transplantation/physiology , Kidney Diseases, Cystic/genetics , Kidney Transplantation/physiology , Male , Middle Aged , Mutation , Survival AnalysisABSTRACT
A patient is admitted in hospital to explore a nephrotic proteinuria associated with milky urine. This is explained by a chyluria (presence of lymphatic fluid in the urines), which is due to a pyelolymphatic fistula probably linked to a lymphatic filariasis. Usually, the diagnosis of chyluria can be confirmed by the presence of urinary chylomicrons. The presence of an urinary-lymphatic fistula can be proved by different techniques (cystoscopy, retrograde pyelography, uroscanner, lymphoscintigraphy). The main cause of chyluria is parasitic infections (filarial infection, echinococcus, cysticercosis), but other causes can be found, such as granulomatosis, neoplasia, lymphatic malformations, or sequela of surgery or traumatism. Chyluria is one of the causes of post-nephronic nephrotic proteinuria. Depending on the impact of the chyluria for the patient, there will either be no treatment, or a treatment by sclerotherapy or surgery.
