The molecular knowledge of renal functioning now allows the precise classification of diabetes insipidus nephrogenic (DIN).Hereditary DINs are rare, but their identification has made it possible to understand the function of proteins essential to the reabsorption of the water like the receptors of type 2 to the vasopressin (AVPR2) and the aquaporin 2 (AQP2). The key carriers / channels in the establishment of the counter-current mechanism of the renal medullary also include the Na-K-2C1 transporter, the ROMK potassium channel, the chloride channel and its β subunit, bartlet. Hereditary nephrogenic diabetic insipid diabetes are therefore clinical equivalents of animal models of invalidation of these different genes (knock-outs). Early detection and prevention of episodes of dehydration are the therapeutic consequences of these new data.
DIN only includes states of resistance to the antidiuretic hormone.
DIN also includes pathological conditions characterized by the inability to establish a corticomedullary osmolar gradient associated or not with antidiuretic hormone resistance.
Mechanism of concentration of urine by counter-current:
The concentration of urine is not the result of active water transport. Such a system would consume too much energy.The urine is rather concentrated, at little metabolic cost, by a series of interactions between the Henle’s loops, the medullary interstitium, the medullary blood vessels or vasa recta and the collecting tubules. The counter-current mechanism owes its name to the particular anatomical arrangement of tubules and vascular elements. Indeed, in the kidney of mammals, the median part of the nephrons is folded over itself in the form of a hairpin, called the cove of Henle, named after the German anatomist who described it. The tubular fluids move from the cortex to the medullary papilla by borrowing the proximal tubules and then the descending Henle’s branches. Each handle of Henle then runs “counter-interstices” towards the cortex. The blood in the vasa recta also descends towards the papilla before proceeding to “counter-intersect” in the cortex. This particular arrangement of the tubular segments and the vasa recta makes it possible to establish a counter-current exchanger and a counter-current multiplier.
The production of a concentrated or diluted urine requires independent control of the reabsorption of water and sodium chloride. Under normal antidiuretic conditions, the osmolality of the renal medullary is close to 300 mOsm / kg at the corticomedullary junction, but is 1400 mOsm / kg at the tip of the papilla. Half of this medullary hypertonicity depends on NaCl, the other depends on the concentration of urea. In this scheme, it is assumed that vasopressin secretion is intact as well as its action at the main cells of the collecting tubule (see below).
The permeability and structural characteristics of the tubular and vascular elements responsible for the countercurrent mechanism are now described on a molecular scale. The presence and abundance of water channels, all members of the aquaporin family, determine the water permeability of the tubular and vascular structures involved in the countercurrent. The location, regulation, structure and function of aquaporins or water channels identified in mammals have been described in many recent reviews.
The aquaporin 1 is inserted into the membranes in the form of a homotetramer. Each monomer is composed of six helices inserted obliquely in the membrane. These propellers delimit the canal with water. Aquaporins 1, 2, 4, 5 and 10 are selective with water, while aquaporins 3, 7 and 9 are aquaglycero-porins since they transport glycerol and other particles.
Aquaporin 1 with ubiquitous distribution (AQP1) was the first aquaporin to be characterized. In the kidney, it is present both in the apical and basolateral membranes of the proximal tubular cells and in the thin descending branch of the cove of Henle. AQP1 is also expressed constitutively at the level of the endothelium of the descending vasa recta of the external medulla. AQP1 gives the membranes of the proximal renal tubules an exceptionally high permeability since a unidirectional flux of 3 billion molecules of water per second per aquaporin monomer is predicted. The selectivity of transport through AQP1 is also remarkable: water passes but the protons (H + ions) do not pass as a result:
– the electrostatic repulsion imposed by arginine 195, a cationic amino acid;
– the reorientation of the dipole of the water molecule: the oxygen atom temporarily forms hydrogen bonds with the amide groups of asparagine 192 and asparagine 76 which protrude in the pore. This reorientates the hydrogen atoms of the water molecule: they become perpendicular to the axis of the channel and can no longer form hydrogen bonds with the adjacent water molecules in the constricting baffle. Also the “proton conduction cable” is broken. The water passes but the protons do not pass. It is likely that this model applies to other members of the aquaporin family.
SELECTIVE REABSORPTION OF SODIUM IN THE HENLE ANSE ASCENDANTS: NKCC2, ROMK, CLCNK AND BARTTINE
The thin, wide ascending branches of Henle’s Loop are completely waterproof because they do not express any member of the aquaporin family.
The isotonic liquid (280 mOsm / kg) which penetrates the descending branch of the loop of Henle, which is extremely permeable to water (but impermeable to Na + and urea) is concentrated by subtraction of water. As a result, the tubular fluid entering the fine ascending limb of Henle’s Loop has a higher concentration of NaCl and a lower concentration of urea than the surrounding medullary interstitium. In the water-impermeable thin ascending branch, the efflux of NaCl exceeds the influx of urea, which results in a dilution of the tubular liquid. This dilution with progressive hypotonicity of the tubular fluid continues in the broad ascending limb of the loop of Henle characterized by a water impermeability and a powerful mechanism of sodium reabsorption responsible for 30% of the total reabsorption in NaCl of the nephron . This reabsorption depends on a low Na + intracellular concentration maintained by basolateral Na + -K + -ATPase (sodium pump). The entry of Na and K at the luminal level is carried out by the (scavenger) conveyor Na + , 2Cl – , K + (NKCC2). The K + which enters the cell is recycled into the light via the potassium channel ROMK. Recycling of K + has two major pathophysiological consequences:
The concentration of the luminal K + is restored and allows the continuation of NaCl transport inside the cell and then in the interstitium; in the absence of K + recycling, the amount of reabsorbed NaCl would be considerably less (see below, Bartter type II);
– K + recycling results in a transepithelial voltage with positivity within the lumen, a positivity that facilitates the paracellular transport of Na + , Ca ++ , Mg ++ , K + , NH 4 + . The chloride leaves
the cell by a channel (CLCNKB) whose function depends on a beta subunit called bartine.
Genetic and functional identification of the Na-K-2Cl cotransporter, ROMK and CLCNK channels, and bartine have been considerably facilitated by the genetic and molecular dismemberment of Bartter’s syndrome (OMIM601678), a hereditary disease characterized by NaCl loss, hypokalemic alkalosis and an inability to concentrate or dilute urine.Antenatal Bartter syndromes with hyperprostaglandinemia are all characterized by polyuric syndromes with natriuresis and are part of complex congenital DINs (see below).
ACTION OF VASOPRESSINE ON WATER REABSORPTION:
The antidiuretic hormone in humans is arginine vasopressin (AVP). In its presence, the collecting tubule becomes permeable to water.
The transcellular transport of water is facilitated by the osmotic pressure gradient between the concentrated medullary interstitium and the diluted tubular fluid. For the adult human kidney, the maximum osmolar concentration is 1200 mmol / kg; the osmolar excretion (urea, sulfates, phosphates, electrolytes) being close to 600 mmol / d, the kidney must therefore excrete a minimum of 0.5 l. The first step in the antidiuretic action of vasopressin is its binding to the V2 receptor inserted into the basolateral membrane of the main cells of the collecting tubule. The hormone receptor binding is responsible for the activation of adenylyl cyclase, a membrane enzyme whose activation allows the hydrolysis of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (AMP). The activation of adenylyl cyclase results from the interaction of the activated V2 receptor with a guanine nucleotide binding protein (G s ). The trimeric G proteins ( a , b , c ) have a molecular switch function (switch). In their conformation in combination with guanosine diphosphate (GDP), the α -subunit is associated with bc and the protein is at rest with respect to its interaction with the effector (adenylyl cyclase). The agonist-activated receptor V2 (AVP) acts catalytically to release the GDP from the α -subunit and allow the GTP to bind. The bound GTP induces an active conformation (on) of G s a .The G-protein GTPase cycle returns to the idle state when the GTP terminal phosphate is cleaved, GDP is reformed and the α -subunit returns to the quiescent (off) state. The intracellular increase of cyclic AMP leads to the phosphorylation of different effectors via protein kinase A (PKA) and to the fusion of endocytic vesicles containing the AQP2 water channels to the luminal membrane. AQP2 is the vasopressin-dependent water channel, expressed exclusively at the main cells of the collecting tubule. It is expressed diffuse in the cytoplasm under conditions of overhydration (aqueous diuresis). During dehydration or administration of 1-deamino-8-D-arginine-vasopressin (dDAVP), the localization of AQP2 is mainly apical, an observation that confirms the hypothesis of canals shuttle- (shuttle between a cytoplasmic compartment and an apical membrane compartment) proposed more than 20 years ago.
UREA TRANSPORTER AND INTRARENAL UREA RECYCLING:
Urea is synthesized by the liver and excreted by the kidney. Urea accounts for 40-50% of urinary osmolality, and its concentration in urine is remarkable (100 times the plasma urea concentration in humans and 250 times in rodents).Urea accumulates in the renal medulla, thus contributing to the mechanism of urinary concentration and to the conservation of water. There are two main families of urea transporters in mammals:
– renal tubular urea transporters (UTA);
Erythrocyte and vascular urea transporters (UTB).
Five isoforms of UTAs are identified, all derived, by alternative splicing, from a single gene. UT-A1 is expressed at the apical membranes of the terminal part of the collecting duct of the internal medullary. The expression of UT-A1 is increased by vasopressin. UT-A2 is expressed at the level of the thin descending branches of the short Henle coves.The recycling of urea comprises the following elements:
Urea is concentrated at the collecting tubule;
– diffuse urea from the terminal collecting tubule to the medullary interstitium;
Urea is taken up by ascending vasa recta;
– the urea is reintroduced into the fine descending branches of the cove of Henle and the descending vasa recta;
– the urea thus returns to the internal medullary.
DEFECTS OF EXPERIMENTAL URINARY CONCENTRATION BY GENERAL INVALIDATION:
It is now usual to determine the precise physiological function of a protein using gene invalidation models. For this purpose, gene constructs with loss of function of the following proteins: AQP1, AQP2, AQP3, AQP4, AQP3 and AQP4, CLCNK1, NKCC2, AVPR2, AGT, or UT-B were carried out in mice. The Aqp3 knockout mice,
Aqp4, Clcnk-1 and Agt have no recognized equivalents in human pathology, and humans without AQP1 have very little alteration in their urinary concentration. Mice with Aqp2-T126M mutations have an extremely severe clinical presentation that recalls the phenotypic characteristics of AQP2-T126M patients. Mice with invalidation of the NKCC2 gene also exhibit polyuric manifestations similar to those seen in patients with Bartter’s syndrome.
OSMOTIC STIMULATION AND NON-OSMOTIC STIMULATION OF VASOPRESSINE:
The osmotic regulation of AVP depends on osmoneceptor cells in the anterior part of the hypothalamus which perceive changes in extracellular osmolality, alter their volume and modify their nerve impulses directed to vasopressin-producing magnocellular cells of the supraoptic and paraventricular nuclei . The cell volume of osmoreceptors is modified by hypertonic saline solutions or by hypertonic mannitol. On the contrary, hypertonic urea is not restricted to the extracellular medium and penetrates rapidly into the cells: hypertonic urea does not modify either the volume of osmoreceptors or the secretion of AVP. Recent data on osmo- and tone detection and the description of membrane cation channels inactivated by stretching responsible for osmoreceptor have been recently reviewed. The osmeceptor cells are very sensitive to minimal changes in extracellular osmolality: in the case of dehydration, an increase as low as 1% of the osmolality stimulates the release of AVP. Conversely, following a water ingestion, a 1% decrease in osmolality suppresses the release of AVP.
AVP may be stimulated non-osmotically by significant changes ( > 10%) in blood volume or blood pressure.
Osmotic stimulation of AVP obtained by dehydration and / or fusion of hypertonic saline is used to determine the secretion capacity of vasopressin by the posterior pituitary. The direct secretory capacity test involves measuring plasma AVP at varying levels of dehydration and comparing them to normal values. The plasma concentrations of AVP obtained are then correlated to the urinary osmolality.
The indirect test of AVP’s secretory capacity is to measure the action of AVP on urinary osmolality rather than AVP itself.
To do this, plasma and urinary osmolalities are measured at regular intervals during dehydration.
The maximum urinary osmolality is then compared to the urinary osmolality obtained after injection of pitressin or dDAVP. In central diabetes insipidus (neurogenic), the secretion of vasopressin will be insufficient or abolished; on the contrary, normal or supranormal AVP secretion will be observed in nephrogenic diabetes insipidus.
Tests aimed at exploring the non-osmotic (baroreceptor-dependent) secretion of AVP are not used as diagnostic tests for central or nephrogenic diabetes insipidus because they provide little additional information and are technically difficult to perform.
Other cellular actions of vasopressin:
AVP binds to at least four distinct subtypes of receptors: the V1a, V1b, V2 and OT (oxytocin) receptors. These receptors are cloned and sequenced. They all belong to the very large family of receptors with seven membrane passages, the signaling of which is via a heterotrimeric G protein. The receptors V1a, V1b and OT interact selectively with the G proteins of the Gq11 family. These proteins activate distinct isoforms of phospholipase Cβ and lead to the hydrolysis of phosphatidyl-inositol-1,4,5 triphosphate and the formation of inositol-1,4,5 triphosphate (IP3). This small hydrosoluble and diffusible molecule is the intracellular messenger responsible for mobilization of calcium from the endoplasmic reticulum. Platelet aggregation, hepatic glycogenolysis and pressing effects of AVP are mediated by V1a receptors and increased intracellular calcium. The V1b receptors are expressed in the anterior pituitary.
These receptors are responsible for the secretion of adrenocorticotrophic hormone (ACTH) by the anterior pituitary.This secretion of ACTH is under the double control of corticotropin-releasing hormone (CRH) and AVP.
How to express quantitatively the excretion of water?
OSMOTIC AND NON-OSMOTIC POLYURIES:
Diabetes insipidus is characterized by the excretion of large amounts ( > 30 ml / kg / day) of hypo-osmolar urine ( <250 mmol / kg): this is a non-osmotic polyuria. On the contrary, diuresis is osmotic (excretion of solutes > 60 mmol / h) when the urine contains large quantities of exogenous osmotic substances (glycerol, mannitol, radiological contrast products) or endogenous (urea, glucose). Loop diuretics may also induce osmotic diuresis.
OSMOLAR CLEARANCE, FREE WATER CLAIRANCE AND BALANCE OF TONICITY:
Urinary flow can be divided into two compartments. The first compartment is isotonic; it is called osmolar clearance (C osm ): it is the volume necessary to excrete solutes at the same concentration as that of the plasma. The second compartment is called free water clearance (C H2O ): it is a theoretical volume of free water of solute; this volume, positive or negative, must be added to the isotonic portion of the urine (C Osm ) to create a hypo- or hypertonic urine (clearance of free water T C H2O ). The calculation of tonicity balance shows that hypernatremia is sometimes of iatrogenic origin and guides the treatment.
Clinical and biology of hereditary nephrogenic diabetes insipidus:
Ninety percent of patients with hereditary DIN are male with X-linked DIN (MIM 304800), related to mutations in the AVPR2 gene encoding vasopressin V2 receptor. This gene is located in Xq28.
In less than 10% of the families studied, hereditary nephrogenic diabetes insipidus has autosomal recessive or autosomal dominant inheritance (MIM 222000 and 125800). In these cases, the affected individuals carry mutations in the aquaporin-2 gene (AQP2). This gene located in the chromosomal region 12q13 codes the water channel AQP2 whose expression depends on vasopressin.
Bartter syndrome (MIM 601678) and cystinosis (MIM 219800) are also characterized by polyuric syndromes of variable intensity but sometimes very severe. In Bartter’s syndrome, the polyuric syndrome is impure because it is accompanied by a hereditary defect in sodium chloride reabsorption. In cystinosis, polyuria is part of a generalized tubular disorder of Fanconi type.
X-related HEREDITARY DIN:
DIN linked to X is a rare disease. We calculated a frequency of 8.8 per million inhabitants in the province of Quebec (Canada). However, some rural communities in Nova Scotia and New Brunswick in eastern Canada have a much higher frequency of this genetic disease. X-linked DIN is found in Caucasian, Afro-American, African, Iranian, Asian, etc. families. It seems that no ethnic group is spared.
CLINICAL CHARACTERISTICS AND DIFFERENTIAL DIAGNOSIS WITH CENTRAL (AUTOSOMIC) CENTRAL INSIPID DIABETES DOMINANT:
The “historical” clinical features of the disease are hypernatremia, hyperthermia, mental retardation and repeated episodes of dehydration. Early detection by genetic diagnosis from the first days of life should make it possible to relegate the characteristics mentioned above in the history of medicine and to retain, at the beginning of the 21st century, only the difficulty of hydrating and feeding these patients during the early years of their lives. For us, mental retardation, so abundantly described in the earlier literature, is a direct consequence of repeated episodes of dehydration unrecognized or treated too late. Thus, two historical characteristics suggesting an X-linked DIN diagnosis are hereditary and related mental retardation in affected boys. Thus the family described in 1892 by McIlraith and discussed by Reeves and Andreoli probably had a DIN bound to the X. Lacombe and Weil, on the other hand, described hereditary diabetes insipidus with autosomal dominant transmission and without mental retardation. The descendants of the family described by Weil have a dominant autosomal dominant diabetes insipidus (neurogenic).These patients retain a limited capacity to secrete vasopressin in the early years of life and thus suffer neither dehydration nor mental retardation. The ability of urinary concentration in response to exogenous vasopressin is entirely normal in patients with autosomal dominant central diabetes insipidus.
Polyuria and polydipsia were present very early and episodes of dehydration were observed as early as the third day of life.
The pregnancy of an affected child is never accompanied by a polyhydramnios. Polyhydramnios is exclusively observed during pregnancy which leads to the birth of children with Bartter’s syndrome. Children with X-linked DIN are irritable, cry almost constantly, and although dappled, frequently vomit milk given to them, unless the milk is preceded by the administration of water. Constipation, unexplained fever, inability to gain weight, lack of sweating, increased symptoms in warm weather are frequently observed. Severe episodes of dehydration can lead to death. The absorption of large amounts of water and the restriction of sodium and protein can lead to a low-calorie dwarfism. The “historical” evolution of affected children is well described by Mathieu and Loirat. In their experience, the initial evolution was dominated by the frequency of dehydration accidents; later the spontaneous adaptation of the drinks to the needs is excellent and the disease becomes compatible with a perfect physical health. We believe that severe dehydration can all be prevented by authoritarian detection and surveillance. Expansion of the urinary tree is secondary to polyuria. It is not specific to the disease, it can be observed regardless of the etiology of polyuria, for example in central diabetes insipids or in psychogenic polydipsies (or potomanias). Renal insufficiency may be the result of repeated episodes of dehydration with glomerular thrombosis.
CLINICAL DIAGNOSIS AND BIOCHEMISTRY:
It is important to emphasize the importance of a detailed family history and the construction of a specific family tree.Male children who died before the age of 1 year without a defined diagnosis with poor growth in the stomach and repeated vomiting may indicate the previous existence of the disease. The construction of the family tree is oriented to the transmission related to the X. In most cases (70% in our experience), a family history is found but several generations may have passed before the birth again of an affected boy.
Therefore, most cases represent ancestral mutations, but many sporadic cases may correspond to de novo mutations.
Genetic diagnosis and early recognition of DIN:
Ideally, in all families where the disease is well documented by the existence of a DIN boy, the mutation of the V2 receptor gene should be determined (see below) and all women at risk and of childbearing age should have their status dentified (transmitter or non-transmitter). If a female transmitter of the disease carries a male child, it is sufficient to obtain rapidly at the birth of the cord blood, to extract the deoxyribonucleic acid (DNA) and to perform a mutational analysis. The result of such a genetic study may take 2 to 4 days, and it will be sufficient to evaluate the symptoms and measure the urinary osmolality and serum sodium in the newborn at risk. If DIN is genetically assayed and the urinary osmolality is less than 100 mmol / kg, further testing is not necessary and careful hydration and treatment (hydrochlorothiazide, a low-salt diet) should start immediately.
Phenotypic diagnosis before the age of 1 year:
The polyuria is clear, equal to or greater than 500 ml / 24 hours, and reaches 1 to 21/24 hours in the infant, with normal density of less than 1005 and urinary osmolality between 50 and 100 mmol / kg. The U / P ratio Osm is always less than unity. These characteristics are quite different from normal urinary excretion. If chronic underhydration or dehydration has occurred, with serum sodium levels above 150 mEq / L and urinary osmolality below 300 mmol / kg, tubular resistance to vasopressin can be demonstrated by administering 1 μg of dDAVP ( 250 μl of a solution containing 4 μg / ml) by subcutaneous or slow intravenous route (in an infusion bag and 20 minutes). Urine is collected every 30 minutes over the next 120 minutes.
In the case of X-linked DIN, no increase in urinary osmolality was observed after dDAVP. During this dDAVP urine concentration test, water should not be restricted. The water restriction test is also unnecessary when plasma and urine biological data have been recorded in an acute dehydration event. Its sole purpose would be to make the differential diagnosis with psychogenic polydipsia, which is never accompanied by dehydration, or with central diabetes insipidus, exceptional at this age and responding immediately to the dDAVP.
Complete phenotypic diagnosis (child and adult) :
These tests are not essential for diagnosis or treatment, but it is useful to study at least one child or adult in each family. These tests and their interpretation allowed my team the strict phenotypic characterization of X-linked DINs. In all the families studied so far, phenotypic homogeneity goes hand in hand with genotypic homogeneity: we have always found mutations in these families in the V2 receptor gene.
Its aim is to demonstrate the renal tubular resistance to the endogenous secretion of vasopressin, secretion stimulated by dehydration. This test must always take place during the day under immediate medical supervision. It should never exceed 4 hours. Plasma sampling (Na, Osm, vasopressin) is performed every hour. Osmolality and urinary volume are measured every 30 minutes. The results of serum sodium should be immediately available after each blood sample to avoid any severe dehydration arbitrarily defined by serum sodium > 150 mEq / l. Thirst should be noted every hour using a visual scale.
For example, an 8-year-old boy (body weight 31 kg) with a clinical diagnosis of DIN, continues to excrete 300 ml / h diluted urine (U Osm = 85 mmol / kg) during a 4-hour dehydration test. He complained of intense thirst. Its maximum serum nematode was 155 mEq / L (P Osm = 310 mmol / kg). The patient received 1 μg of dDAVP subcutaneously and was allowed to drink water. Repeated measures of urinary osmolality will confirm resistance to the antidiuretic hormone.
It would have been dangerous and useless to continue dehydration in our experience.
Test at dDAVP:
Intravenous infusion of a pharmacological dose of dDAVP (0.3 μg / kg body weight up to a maximum of 24 μg) / its purpose is to demonstrate:
– urinary resistance to dDAVP;
– absence of haemodynamic and coagulant response to dDAVP – absence of stimulation of cyclic AMP by dDAVP.
This test takes place without dehydration. Plasma and urine samples are taken every 30 minutes. After a 60-minute control period, a slow infusion of dDAVP (0.3 μg / kg of body weight in 100 ml of physiological saline perfused in 20 minutes using a proportional pump) is performed and plasma samples and urine are performed every 30 minutes for 150 minutes after the start of the infusion. DDAVP should never be administered rapidly intravenously as it induces severe hypotension in normal individuals. In male patients with X-linked DIN, urinary osmolality and clearance of open water will remain unchanged; neither the blood pressure nor the von Willebrand factor will vary; cyclic plasma AMP will not be stimulated. These results indicate an abnormal functioning of the renal and extrarenal V2 receptors (extralenal V2 receptors are ill-defined but explain the stimulation of coagulation factors and hypotension observed after dDAVP administered at pharmacological dose). These data also indicate that the DIN bound to the X is a defect located upstream of the cyclic AMP. This hypothesis was confirmed by the discovery of mutations in the V2 receptor gene in families with DIN bound to X.
MOLECULAR GENETIC ANALYSIS: MUTATIONS OF THE V2 RECEIVER GENE, TRANSMETER DETECTION:
The cloning of the human vasopressin V2 receptor gene was published in 1992. This gene is called AVPR2 and is located at Xq28 (the most distal part of the long arm of chromosome X). The discovery of mutations in AVPR2, mutations that determine the X-linked DIN phenotype, confirmed the identification of this gene. This gene is small (about 2 kb), it contains three exons and two introns.
The sequence of the complementary DNA predicts a polypeptide of 371 amino acids (aa) with seven transmembrane domains, four extracellular domains and four intracellular domains. The structure of this receptor is characteristic of that of the G-protein-bound membrane receptors, a broad family comprising rhodopsin, adrenergic and muscarinic aand b receptors, thrombin receptors and the like. The genetic analysis of families with X-linked DIN is carried out by direct sequencing after polymerase chain reaction (PCR) amplification.
To date, more than 183 AVPR2 mutations have been identified in 239 families of different ancestral origins (see also the NDI Mutation Database at: http://www.medicine.mcgill.ca/nephros/).
Half of these mutations are missense mutations, that is, only one wild aa is replaced by another mutant aa. The rest of the mutations are distributed as follows: 27% are mutations with shift of the reading frame by deletion or insertion of one or more nucleotides, 11% are nonsense mutations, that is to say which generate a signal stop, 5% are large deletions, 4% are deletions or insertions in phase and 2% are splicing mutations. Mutations have been identified affecting each domain of the vasopressin V2 receptor. We have identified unique (“private”) mutations, recurrent mutations and probable mutagenesis mechanisms. Ten reoccurring mutations (D85N, V88M, R113W, Y128S, R137H, S167L, R181C, R202C, A294I, and S315R) were identified in 35 families of independent ancestral origins. In vitro expression of these AVPR2 mutations indicates that the majority of mutated receptors are retained in the endoplasmic reticulum: unable to enter the plasma membrane, they have lost their signaling function. This intracellular transport defect is a general mechanism shared by many hereditary diseases due to mutations in genes encoding membrane proteins. We have recently demonstrated that non-peptidic vasopressin receptor antagonists can “replicate” mutant AVPR2 receptors and increase urinary osmolality in patients with X-linked DIN carrying 162-64, R137H and W164S mutations.
DIABETES AUTOSOMIC NEPHROGENIC RECEPTACLES AND DOMINANTS SECONDARY TO MUTATIONS OF THE GENE AQP2:
DINs with father-son transmission, a defect located downstream of cyclic AMP and normal stimulation of coagulation factors by dDAVP in male subjects suggested the existence of another type of hereditary DIN. A patient with congenital DIN and normal stimulation of coagulation factors by dDAVP was found to have mutations (heterozygous compound R187C and S217P) on each allele of the AQP2 gene. To date, 32 AQP2 mutations have been identified in 40 families with autosomal dominant or autosomal recessive DIN. These mutations are distributed as follows: 65% false-sense mutations, 23% mutations with shift of the secondary reading frame to deletions or insertions of a small number of nucleotides, 8% nonsense mutations and 4% mutations. splicing mutations (for additional information.
Expression studies of mutant AQP2 proteins demonstrated intracellular retention and inability to achieve conformation consistent with intracellular maturation and insertion into endocytic vesicles, as in the in vitro expression of AVPR2 mutants.
The AQP2 mutations responsible for the autosomal recessive DIN are distributed throughout the AQP2 gene in its carboxylterminal part.
The family with autosomal dominant phenotype described by Ohzeki in 1984 was sequenced and identified as heterozygous for the carboxyl-terminal deletion 721delG.
The dominant phenotype of these specific mutations can be explained by the formation of heterotetramers with altered intracellular pathway.
POLYURIE, POLYDIPSIA AND DEHYDRATION IN PATIENTS WITH CYSTINOSE:
The polyuria can be minimal and only induce persistent enuresis, or, on the contrary, be severe and even contribute to death by dehydration in children with gastroenteritis.
POLYURIE AND TUBULOPATHIES WITH SALT AND POTASSIUM LOSSES:
Children with hypo- or isosthenuria, hypercalciuria and pregnancy leading to their birth have been characterized by polyhydramnios, have a loss of function of tubular carriers of the ascending branch of Henle ROMK loop (KCNJ1 gene) and NKCC2 ( gene SLC12A1). Patients with polyhydramnios, severe polyuria, hyponatremia, hypochloraemia, metabolic alkalosis and neurosensory deafness have a loss of bartlet function (BSND gene). Bartlet is the β-subunit of the chloride channel. It is expressed at the basolateral level of the ascending branch of the loop of Henle and in the inner ear. These new data confirm the importance of ROMK, NKCC2 and bartine proteins in transferring sufficient NaCl into the medullary interstitium and, in conjunction with the urea addition, generate a key hypertonic medium in the establishment and maintenance of against the current.
The recommendations and the theoretical calculations made by Mathieu and Loirat are still valid. These authors consider that the urinary osmolality of the affected patients is fixed, their urine flow is directly correlated with the osmotic load. The osmotic load can be calculated by the formula:
Q Osm = 2 ~ Na + K – mmol ! + 4 ~ prote’ines – g ! + phosphorus – mg ! 31
It is found that a desoded regime (1 mEq / kg / 24 h) with limited protein restriction (2 g / kg / 24 h) is important.
The theoretical water intake is:
Q Osm / U Osm + extracranial losses (U Osm being the urinary osmolality outside episodes of dehydration).
Abundant and continuous hydration and very careful monitoring of weight and temperature are required. Water should be offered every 2 to 3 hours, including at night!
The hospitalization of these children is sometimes indispensable as well as the installation of a gastric tube for nutrition and enteral hydration. Hydrochlorothiazide (1-2 mg / kg / day) and indomethacin (1.5-3.0 mg / kg) decreased water excretion by 30-50%.
The considerable amounts of water absorbed by these patients exaggerate physiological gastroesophageal reflux in children and many young patients vomit after absorption of large amounts of water. The use of H2 blockers, metoclopramide or domperidone improves these symptoms. The majority of adult patients do not take any treatment.
EARLY GENETIC DISEASES OF PATIENTS WITH DIABETES NEPHROGENIC INSIPID:
Early detection of AVPR2, AQP2 or Bartter syndrome (KCNJ1, SLC12A1, BSND) mutations in families already characterized by the presence of an affected child allows for early diagnosis and treatment and prevents severe episodes of dehydration (AVPR2, AQP2) or contraction of volume (KCNJ1, SLC12A1, BSND). We performed X-linked DIN diagnosis from chorionic villus samples (n = 4), cultured amniotic cells (n = 5), and cord blood (n = 17).
Twenty-three children were tested, 12 boys were affected, seven were unharmed and four were identified as non-transmitters. Affected boys are systematically treated, from the first week of life, with a diet low in salt with hydrochlorothiazide. However, these children require sustained attention during the first few years to avoid any episode of dehydration and to maintain an adequate growth curve.
Nephrogenic insipid diabetes acquired:
The secondary forms of DIN are rarely complete. Thus, the possibility of developing a weakly concentrated urine is preserved and the polyuria in adults is generally less than 6 to 8 l / 24 h.
The most common etiology is the chronic administration of lithium for psychiatric illness (mainly in manic-depressive psychoses). Under strict and repeated monitoring of lithiasis, a diet low in NaCl, which may or may not be associated with hydrochlorothiazide or amiloride, decreases the polyuria and reduces the dose of lithium carbonate necessary to maintain effective lithium mmol / l). Demeclocycline is useful in the treatment of syndromes of inappropriate secretion of antidiuretic hormone, not controlled by the usual maneuvers (treatment of the cause, restriction of water).
Polyuria, polydipsia and tubular resistance to arginine vasopressin are the characteristics of DIN. Mutations with loss of function of AVPR2 or AQP2 result in a classical pure DIN with exclusive water loss. Loss-to-function mutations of the Na, Cl, K (NKCC2), ROMK potassium channel or chloride channel β-subunit, bartine, induce a complex DIN with loss of salt, water, other electrolytes. Lithium remains the primary exogenous agent responsible for secondary DINs.DIN treatment is based on non-specific measures to reduce the amount of water present at the collecting channel and to avoid dehydration and volume contraction.