Daniel-G Bichet

• Université de Montréal

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder worldwide. The disease is characterized by renal cysts and progressive renal failure due to progressive enlargement of cysts and renal fibrosis. An estimated 45% to 70% of patients with ADPKD progress to end-stage renal disease by age 65 years. Although...

Purpose of review: In nephrogenic diabetes insipidus (NDI), the kidney is unable to concentrate urine despite elevated concentrations of the antidiuretic hormone arginine-vasopressin. In congenital NDI, polyuria and polydipsia are present from birth and should be immediately recognized to avoid severe episodes of dehydration. Unfortunately, NDI is...

Recent epidemiological studies have revealed novel relationships between low water intake or high vasopressin (AVP) and the risk of hyperglycemia and diabetes. AVP V1A and V1B receptors (R) are expressed in liver and pancreatic islets, respectively. The present study was designed to determine the impact of different levels of circulating AVP on glu...

Background: Fabry disease (FD) is characterized by the accumulation of sphingolipids in multiple organs, including the left atrium. It is uncertain if the left atrial (LA) reservoir, conduit, and contractile functions evaluated by speckle-tracking echocardiography are affected in Fabry cardiomyopathy and whether enzyme replacement therapy can impr...

Background: Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase (α-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable)...

Purpose: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity. Methods: A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migala...

Aquaporin-2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Mutations in the protein induce nephrogenic diabetes insipidus (NDI), which challenges the water balance by producing large urinary volumes. Although recessive AQP2 mutations are believed to generate non-functional and monomeric proteins, th...

β3-Adrenoreceptors and their importance to increase sodium reabsorption in the thick ascending loop of Henle and to increase water reabsorption in principal cells of the collecting duct are, for the first time, described here. This is an integrated brain response to dehydration perceived by osmosensitive cells in the hypothalamus and triggering thr...

Background Fabry’s disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. Methods The initial assay of mutant α-galactosidase forms that we...

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of central vasopressin release and perception of thirst is the key to diagnosis and management of these disorders. Mammals are osmoregulators; they have evolved mechanisms that maintain extracellular fluid osmolality near a s...

The renal proximal tubule reabsorbs 90% of the filtered glucose load through the Na(+)-coupled glucose transporter SGLT2, and specific inhibitors of SGLT2 are now available to patients with diabetes to increase urinary glucose excretion. Using expression cloning, we identified an accessory protein, 17 kDa membrane-associated protein (MAP17), that i...

Background Agalsidase β is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low α-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase β cleared glycolipid deposits from endothelial cells within 6...

Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90 percent...

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...

Le diabète insipide (DI), caractérisé par une polyurie hypotonique, est lié à un défaut de synthèse (DI central), une résistance à (DI néphrogénique) ou une destruction par vasopressinase placentaire de l’AVP (DI gestationnel). Nous rapportons le cas d’un homme de 36 ans adressé pour syndrome polyuro-polydipsique ayant débuté dans la petite enfance...

Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agals...

Healthy kidneys maintain fluid and electrolyte homoeostasis by adjusting urine volume and composition according to physiological needs. The final urine composition is determined in the last tubular segment: the collecting duct. Water permeability in the collecting duct is regulated by arginine vasopressin (AVP). Secretion of AVP from the neurohypop...

Trial design: This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial. Methods: Males aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major o...

Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decad...

High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. Obese Zucker rats and their lean coun...

Diabetes mellitus, widely known to the ancients for polyuria and glycosuria, budded off diabetes insipidus (DI) about 200 years ago, based on the glucose-free polyuria that characterized a subset of patients. In the late 19th century, clinicians identified the posterior pituitary as the site of pathology, and pharmacologists found multiple bioactiv...

Context: Vasopressin plays a central role in water homeostasis but it has also been recognized to be associated with adverse effects in several chronic diseases. Recently, copeptin has been increasingly used as a surrogate for vasopressin, as they are co-secreted, and copeptin is easier to measure. However, the relationship between plasma concentr...

Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that...

Hyponatremia, the most frequent electrolyte disorder, is caused predominantly by the syndrome of inappropriate antidiuresis (SIAD). A comprehensive characterization of SIAD subtypes, defined by type of osmotic dysregulation, is lacking, but may aid in predicting therapeutic success. Here, we analyzed serial measurements of serum osmolality and seru...

Background The Canadian Fabry disease Initiative (CFDI) tracks outcomes of subjects with Fabry disease treated enzyme replacement therapy (ERT) given to subjects who meet evidence-based treatment guidelines and cardiovascular risk factor modification. Methods We report 5 year follow up data on 362 subjects for a composite endpoint (death, neurolog...

The Na+/glucose cotransporter SGLT2, which accounts for over 90% of renal glucose reabsorption, has become a major pharmaceutical target for type 2 diabetes treatment. Unfortunately, functional studies on SGLT2 have been hindered due to its lack of activity when expressed heterologously. Using an expression cloning strategy to identify a required a...

Mutations in Aquaporin‐2 (AQP2) induce nephrogenic diabetes insipidus, a water reabsorption defect of the kidney. Using co‐immunoprecipitation and functional assays, we have recently shown that (at least) some mild recessive (rec) AQP2 mutants can adequately associate to its wild‐type (wt) counterpart to generate fully functional wt/rec heterotetra...

Mutations in Aquaporin‐2 (AQP2) induce nephrogenic diabetes insipidus (NDI), a water reabsorption defect of the kidney challenging water homeostasis. While the accepted NDI model claims that recessive (rec) mutations are misfolded and monomeric by nature, the partial activity (Pf= 15‐25% of wt‐AQP2) found with some mutations (D150E, V24A) challenge...

The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine-concentrating mechanism through the AVP/V2-type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongl...

Hyponatremia is the most frequent electrolyte disorder with the syndrome of inappropriate antidiuresis (SIAD) as its most common cause. However, comprehensive characterization of SIAD subtypes is still lacking, but may predict therapeutic success. Using hypertonic saline infusion, the osmoregulation in SIAD was studied in 50 patients with hyponatre...

Hyponatraemia, defined as a serum sodium concentration <135 mmol/L, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. Hyponatraemia is present in 15-20 % of emergency admissions to hospital and occurs in up to 20 % of critically ill patients. Symptomatology may vary from subtle to severe or even lif...

Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive disorder associated with germline mutations of the arginine vasopressin (AVP) receptor type 2 (AVPR2) gene. The researchers describe a novel mutation in the AVPR2 gene in a three-generational Turkish family with NDI. In the present report, a 22-year-old man is reported wit...

Mutations to PKD1 and PKD2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The absence of apparent PKD1/PKD2 linkage in five published European or North American families with ADPKD suggested a third locus, designated PKD3. Here we re-evaluated these families by updating clinical information, re-sampling where possible, an...

Nephrogenic diabetes insipidus (NDI) provides an excellent model for the benefits and insights that can be gained from studying rare diseases. The discovery of underlying genes identified key molecules involved in urinary concentration, including the type 2 vasopressin receptor AVPR2 and the water channel AQP2, which constitute obvious pharmacologi...

The study of human physiology is paramount to understand disease and develop rational and targeted treatments. Conversely, the study of human disease can teach us a lot about physiology. Investigations into primary inherited nephrogenic diabetes insipidus (NDI) have contributed enormously to our understanding of the mechanisms of urinary concentrat...

Background: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every ot...

(Named collaborator on this multi-centre study)

Background/aims: Owing to the precarious blood supply to the renal medulla and the high metabolic requirement of the medullary thick ascending limb of Henle's loop, this nephron segment should be especially vulnerable when its supply of O(2) declines. Methods: Rats were exposed to 8 or 21% O(2) at different time points up to 5 h, and samples wer...

A nephrogenic defect in urine concentration is well established in patients with polycystic kidney disease, but Ho et al. report a defect in the increase of plasma vasopressin in response to dehydration. On a cellular level, transient receptor potential channels responsible for osmoperception could interact with TRPPs encoded by the polycystic gene...

Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F...

Hyponatremia is a common electrolyte disorder associated with increased morbidity and mortality, particularly in the elderly. Lixivaptan, a new selective vasopressin V2-receptor antagonist, safely corrected serum sodium concentrations in phase II studies of patients with euvolemic hyponatremia. Here our multinational, double-blind, placebo-controll...

Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerabili...

Recent discoveries have shed new light on the understanding of water metabolism: (1.) in addition to hypothalamic osmoreceptor cells expressing a TRPV1 variant, there are peripheral TRPV4 receptors sensing tonicity in the portal vein and changing central vasopressin secretion and peripheral autonomic activity; (2.) the central osmoregulatory gain o...

A defect in urine-concentrating ability is discernable in patients with autosomal dominant polycystic kidney disease (ADPKD) before any decline in glomerular filtration rate, and is associated with elevated concentrations of vasopressin and copeptin. This defect is 'urea-selective' and accordingly, the urine-to-plasma ratio of urea concentration co...

It is clinically useful to distinguish between two types of hereditary nephrogenic diabetes insipidus (NDI): a ‘pure’ type characterized by loss of water only and a complex type characterized by loss of water and ions. Patients with congenital NDI bearing mutations in the vasopressin 2 receptor gene, AVPR2, or in the aquaporin-2 gene, AQP2, have a...

Background: Nephrogenic diabetes insipidus is rarely encountered in infants. The diagnosis is usually delayed due to lack of obvious signs in the initial stages of the disease and lack of awareness among primary physicians. Methods: The clinical diagnosis in this 70-day old boy was made using standard vasopressin testing. Mutation analysis was perf...

Most of the central diabetes insipidus cases seen in general practice are acquired but the rare cases of hereditary autosomal dominant or recessive neurohypophyseal diabetes insipidus have provided further cellular understanding of the mechanisms responsible for pre-hormone folding, maturation and release. Autosomal dominant central diabetes insipi...

Introduction L’hormone antidiurétique (ou vasopressine) est élevée dans le diabète. Or, l’administration de vasopressine chez l’homme sain augmente transitoirement la glycémie, probablement par la stimulation des récepteurs V1a hépatiques. Nous avons montré, chez 3615 sujets initialement normoglycémiques de la cohorte française D.E.S.I.R. (Données...

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disorder caused by activating mutations in arginine vasopressin receptor 2 (AVPR2), resulting in persistently concentrated urine. We report on a family affected by NSIAD with the known mutation R137C, an arginine to cysteine substitution at amino acid 137. The spectrum of sym...

To the editor: Desmopressin (dDAVP) is a synthetic analog of vasopressin that stimulates release of von Willebrand factor (VWF). This effect is attenuated in vitro by a type 2 vasopressin receptor (V2R) antagonist.[1][1] dDAVP is administered for prophylaxis and treatment of bleeding in von