Daniel-G Bichet

• Université de Montréal

Congenital nephrogenic diabetes insipidus (NDI; also known as arginine vasopressin resistance) is a rare inherited disorder of water homeostasis, caused by insensitivity of the distal nephron to arginine vasopressin. Consequently, the kidney loses its ability to concentrate urine, which leads to polyuria, polydipsia and the risk of hypertonic dehyd...

Fabry disease is a progressive, X‐linked lysosomal disorder caused by reduced or absent α‐galactosidase A activity due to GLA variants. The effects of migalastat were examined in a cohort of 125 Fabry patients with migalastat‐amenable GLA variants in the followME Pathfinders registry (EUPAS20599), an ongoing, prospective, patient‐focused registry e...

Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disea...

Genetic variations in the genes encoding G protein-coupled receptors (GPCRs) can disrupt receptor structure and function, which can result in human genetic diseases. Disease-causing mutations have been reported in at least 55 GPCRs for more than 66 monogenic diseases in humans. The spectrum of pathogenic and likely pathogenic variants includes loss...

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme replacement therapy (ERT) to migalastat. Methods: Sixteen Gb 3 isoforms and eight lyso-Gb 3 analogues were analyzed in plasma and urine by LC–MS/MS at baseline and at three different time points in naive participants and participants swi...

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment...

Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [94]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2...

OBJECTIVES: The objective of this review was to depict the physiological and clinical rationale for the use of vasopressin in hemodynamic support of organ donors. After summarizing the physiological, pharmacological concepts and preclinical findings, regarding vasopressin’s pathophysiological impacts, we will present the available clinical data....

Diabetes insipidus refers to the inability of the kidneys to concentrate the urine by water extraction in the collecting duct. This can be due to a deficiency in the mediating hormone (central diabetes insipidus), variably called antidiuretic hormone (ADH) or arginine vasopressin (AVP), or an impaired ability of the kidneys to respond to the hormon...

Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired α-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should be routinely monito...

Introduction: The course of autosomal dominant polycystic kidney disease (ADPKD) varies greatly among affected individuals, necessitating natural history studies to characterize the determinants and effects of disease progression. Therefore, we conducted an observational, longitudinal study (OVERTURE; NCT01430494) of patients with ADPKD. Methods:...

Background Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incide...

Under normal circumstances, about 90% of the 180 L/day glomerular filtrate is constitutively reabsorbed in the proximal tubule and descending limb of Henle’s loop. According to the needs, the remaining 10% of the fluid is reabsorbed in the collecting duct by a tightly regulated process under control of arginine vasopressin (AVP). After binding of A...

Genetic testing is transforming kidney care, arguably with similar impact as the adoption of kidney biopsies in the 1950s. It is incumbent on nephrologists to teach the genetics of kidney disease and the accessibility of genetic testing. Proper usage of genetic testing can avoid “diagnostic odysseys” with multiple nonspecific investigations, some o...

Introduction: The group of Yuki Oka, working at Caltech, recently discovered unique populations of neurons in the mouse brain that separately drive osmotic thirst and hypovolemic thirst [ 1 ]. After eating salty chips, the concentration of salts and minerals in blood becomes elevated which induces a state called osmotic thirst. On the other hand,...

Purpose: To determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. Methods: 13 members from 3 generations of the kindred with familial diabetes insipidus were studied. Water intake, urine volume, urine osmolality, plasma osmolality and pla...

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of vasopressin (AVP), perception of thirst, AVP receptors, and aquaporin water channels is key to the diagnosis and management of these disorders. Mammals are osmoregulators: they have evolved mechanisms that maintain extrace...

https://www.asn-online.org/education/kidneyweek/2021/program-abstract.aspx?controlId=3605480

Peritoneal dialysis in adults involves diffusion and osmosis through a peritoneal membrane, measuring 1 m², that is highly vascularized (flow rate, 100 to 150 ml per minute) and has a total available capillary surface area of approximately 2 m².¹ For decades, glucose has been used as the prototypical crystalloid osmotic agent to drive water removal...

[This corrects the article DOI: 10.1016/j.ymgmr.2021.100786.].

The adverse effects of vasopressin (AVP) in diverse forms of chronic kidney disease have been well described. They depend on the antidiuretic action of AVP mediated by V2 receptors (V2R). Treatment with tolvaptan, a selective V2R antagonist, is now largely used for the treatment of patients with ADPKD. Another way to reduce the adverse effects of A...

Background and objective: Fabry disease, an X-linked lysosomal storage disorder characterized by absent or reduced alpha-galactosidase activity, is a lifelong disease that impairs patients' quality of life. Patients with Fabry disease have a considerably shortened lifespan, with mortality being mainly due to renal failure, cardiovascular disease,...

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry diseas...

Aquaporin‐2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Disease‐causing AQP2 mutations induce nephrogenic diabetes insipidus (NDI), a condition that challenges the bodily water balance by producing large urinary volumes. In this study, we characterize three new AQP2 mutations identified in our la...

Modified encore presentation of a poster presented at WORLD 2021

Background Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational...

Background Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. Methods Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. Results Data were collected on 315 patients (22 countries, male 84%, adults...

[This corrects the article DOI: 10.1093/ckj/sfy027.][This corrects the article DOI: 10.1093/ckj/sfy027.].

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Objectives Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may no...

Purpose: To assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods: A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (N...

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation...

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal cli...

Encore presentation.

Background Fabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus pheno...

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but ge...

Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as recommended by NC-IUPHAR [92]) are activated by the endogenous cyclic nonapeptides vasopressin and oxytocin. These peptides are derived from precursors which also produce neurophysins (neurophysin I for oxytocin; neurophysin II for vasopressin). Vasopressin and oxytocin differ at only 2...

Vasopressin is known to contribute to disease progression in autosomal dominant polycystic disease (ADPKD) by its influence on cyclic adenosine monophosphate that directly promotes cyst growth. In addition, vasopressin probably contributes to progression by inducing glomerular hyperfiltration as shown in other forms of chronic kidney diseases. The...

The four hyperpolarization-activated cylic-nucleotide gated (HCN) channel isoforms and their auxiliary subunit KCNE2 are important in the regulation of peripheral and central neuronal firing and the heartbeat. Disruption of their normal function has been implicated in cardiac arrhythmias, peripheral pain, and epilepsy. However, molecular details of...

Background: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta re...

Background: Podocytes are highly differentiated visceral cells, and several related specific proteins, such as podocalyxin and podocin are potential tools for the evaluation of podocyturia. However, precise quantitation of podocyturia-related proteins is complex and often unreliable. Method: A reversed-phase ultra-performance liquid chromatograp...

Recent experiments using optogenetic tools facilitate the identification and functional analysis of thirst neurons and vasopressin-producing neurons. Four major advances provide a detailed anatomy and physiology of thirst, taste for water, and arginine-vasopressin (AVP) release: ( a) Thirst and AVP release are regulated by the classical homeostatic...

Purpose: Outcomes in patients with Fabry disease receiving migalastat during the phase 3 FACETS trial (NCT00925301) were evaluated by phenotype. Methods: Data were evaluated in two subgroups of patients with migalastat-amenable GLA variants: "classic phenotype" (n = 14; males with residual peripheral blood mononuclear cell α-galactosidase A <3%...

Background: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. Methods: We evaluated minimal clinically important differences (MCID) in diarrhea based on the correspondi...

Introduction Évaluer les effets au long cours du migalastat sur la morphologie et la fonction cardiaque (évaluées par lecture centralisée des échocardiographies) chez des patients atteints de la maladie de Fabry, porteurs de mutations sensibles du gène GLA selon le Migalastat Amenability Assay, et recrutés dans deux essais randomisés de Phase 3 : F...

Purpose The purpose of this article is to update the previously published consensus recommendations from March 2017 discussing the optimal management of adult patients with autosomal dominant polycystic kidney disease (ADPKD). This document focuses on recent developments in genetic testing, renal imaging, assessment of risk regarding disease progre...

Background Fabry disease (FD) is a lysosomal storage disorder caused by an enzymatic deficiency. Conduction abnormalities and bradyarrhythmias are common and can occur prior to the onset of left ventricular (LV) hypertrophy. We aimed to describe the clinical, electrocardiographic and echocardiographic, including left atrial (LA) function, determina...

Recent experiments using optogenetic tools allow the identification and functional analysis of thirst neurons and vasopressin producing neurons. Two major advances provide a detailed anatomy of taste for water and arginine-vasopressin (AVP) release: (1) thirst and AVP release are regulated not only by the classical homeostatic, intero-sensory plasm...

Background Inherited nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by impaired urinary concentrating ability. Little clinical data on long-term outcome exists. Method This was a single-centre retrospective medical record review of patients with a diagnosis of NDI followed between 1985 and 2017. We collected available data o...

Background Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs. An independent international initiative compared clinical and biochemical outcomes of the two enzymes. Methods In this multicentre retrospe...

Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, and galabiosylceramide (Ga2) isoforms/analogs may accumulate in biological fluids and different organs. The aims of t...

Water is the major constituent of the body. It represents the unique solvant of various molecules (electrolytes) of our body. Although sodium is largely extracellular and potassium is intracellular, body fluids can be considered as being in a single “tub” containing sodium, potassium and water, because osmotic gradients are quickly abolished by wat...

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of vasopressin, perception of thirst, vasopressin receptors, and aquaporin water channels is key to the diagnosis and management of these disorders. Mammals are osmoregulators: they have evolved mechanisms that maintain extra...

Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER-associated degradation (ERAD) is responsible for the clearance of misfolded pro-argi...

Introduction Le migalastat est un chaperon pharmacologique par voie orale qui se fixe sur certaines formes mutantes et instables de l’α GAL A, sensibles au migalastat afin de restaurer leur transfert vers le lysosome et leur activité enzymatique. Patients et méthodes Des analyses en sous-groupe ont évalué le bénéfice du migalastat sur 24 mois, dan...

Introduction Le migalastat est un chaperon pharmacologique par voie orale qui se fixe sur certaines formes mutantes et instables de l’α GAL A, sensibles au migalastat afin de restaurer leur transfert vers le lysosome et leur activité enzymatique. Patients et méthodes Une analyse rétrospective à partir de données de l’étude de phase III FACETS vers...

Vasopressin ( AVP ) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in bloo...

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the man...

The transcription factor hepatocyte nuclear factor-1β (HNF-1β) is essential for normal kidney development and function. Inactivation of HNF-1β in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1β specifically in renal collecting ducts (CDs). CD-specific HNF-1β mutant mice...