Vasopressin receptor mutations and nephrogenic diabetes insipidus

X-linked recessive nephrogenic diabetes insipidus is caused by mutations in the gene encoding the V2 vasopressin receptor (V2R), the mediator of the antidiuretic effect of arginine vasopressin (AVP) in mammalian kidneys. Upon binding to AVP, the receptor activates the G protein Gs, stimulating a phosphorylation cascade that promotes translocation of presynthesized water channels to the apical surface of the principal cells lining the last segments of the nephron. The presence of these channels allows the flow of water from the hypotonic lumen of the nephron into the hypertonic interstitium. More than 100 different mutations have been identified since the receptor gene was characterized--in most cases one per family, although some families bear two and three mutations in the same gene. The frequency of the de novo mutations identified suggests that the DNA at the end of the long arm of the X chromosome is very susceptible to alteration. The mutations are scattered within the coding region, not confined to a particular segment of the receptor protein, and in most cases confined to a single amino acid change that significantly reduces the number of receptors present on the plasma membrane. Some mutations do not affect protein synthesis but significantly reduce the coupling efficiency between the receptor and G protein. Analysis of the biochemical impact of the mutations has provided valuable information about the synthesis and regulation of the receptor.     

Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus.

A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for glucose. After recovery from hyperglycaemia, he remained polyuric despite normal blood glucose concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration.     

一个先天性肾性尿崩症家系的基因分析

Background As an X-linked recessive way, arginine vasopressin receptor 2 （AVPR2） gene mutation resulted in ahereditary disease - congenital nephrogenic diabetes insipidus （CNDI）. We found a suspect clinical CNDI pedigree. Inorder to identify the genetic etiology, we performed the genetic analysis.     

先天性肾性尿崩症的病因及临床特点

肾性尿崩症(nephrogenic diabetes insipidus,NDI)是一组少见的疾病,可以是遗传性的,也可以是获得性的。本研究对1980～2000年在北京协和医院内分泌科就诊的17例先天性NDI患者的病因及临床特点进行回顾性地总结分析。     

Idiopathic hypergammaglobulinaemia associated with nephrogenic diabetes insipidus and distal renal tubular acidosis.

Renal tubular dysfunction may be recognized in patients suffering from urinary light chain disease or non-myelomatous hypergammaglobulinaemia. We report a patient who has the combination of distal renal tubular acidosis and nephrogenic diabetes insipidus in association with hypergammaglobulinaemia due solely to increased IgG. We postulate that the abnormalities of distal nephron function resulted from cell-mediated immune damage.     

先天性肾性尿崩症患者精氨酸加压素受体2基因突变的检测分析

目的　探讨并检测先天性尿崩症患者精氨酸加压素受体 2 (AVPR2 )基因突变的临床意义。方法　对临床诊断为先天性尿崩症的 7例患者及 2 4名亲属的血液样本 ,提取基因组DNA ,通过PCR扩增AVPR2基因的 6个片断 ,用单链构象多肽性 (SSCP)进行基因突变的筛查 ,再对异常条带进行DNA测序证实基因的突变。结果　在 7例先天性尿崩症的患者中 ,发现 6例患者存在 5种类型共8个AVPR2的突变点 ,2例患者有AVPR2基因的双点突变 ,其余为单突变点 ,1例患者的母亲为AVPR2基因突变的携带者。其中 4个突变点国际尚未报道 ,它们分别是 :G 4 6 9 4 93del 2 4 ,G 5 4 1insT ,G 4 6 2delC和G 935T >C ,分别导致AVPR2受体蛋白A37 L4 4del(缺失突变 ) ,A6 1G 190X(插入移码突变 ,无义突变 ) ,P34R 36X(缺失移码突变和无义突变 ) ,C192R(错义突变 )。结论　发现了 4种新的AVPR2基因突变类型。采用PCR SSCP的方法可以对尿崩症的患者进行基因突变的粗筛 ,最后经过DNA测序可以做出基因突变的诊断。     

Hypernatraemia due to a reset osmostat for vasopressin release and thirst, complicated by nephrogenic diabetes insipidus

We describe a patient with chronic hypernatraemia (plasma sodium 148-155 mmol/l) and partial nephrogenic diabetes insipidus who had received prolonged lithium treatment. Despite stopping the drug for one year the abnormalities remained. Infusion of hypertonic saline (NaCl 855 mmol/l) allowed the characterization of osmoregulation of thirst and vasopressin secretion. Linear regression analysis of plasma vasopressin and osmolality defined the function, pAVP = 0.27 (pOsm - 301), and analysis of thirst measured by a visual analogue scale and plasma osmolality, the function, thirst = 0.16 (pOsm - 302) where pAVP and pOsm represent plasma arginine vasopressin and osmolality respectively. The slopes of the regression lines which describe the sensitivity of the osmoreceptors were within the normal range, but both abscissal intercepts, which define the thresholds for vasopressin release and thirst, were markedly elevated in comparison to normal (upper limit less than 290 mOsm/kg). Other investigations of electrolytes, anterior pituitary function and high definition computed tomographic scanning of hypothalamo-pituitary region were all normal. We conclude that this patient's chronic hypernatraemia was due to resetting of the osmostats for both vasopressin release and thirst, a rarely described mechanism to account for hypernatraemia. Although it is probable that the partial nephrogenic diabetes insipidus was related to prolonged lithium therapy, the cause of the reset osmostats remains unclear.     

Persistent nephrogenic diabetes insipidus, tubular proteinuria, aminoaciduria, and parathyroid hormone resistance following longterm lithium administration

We report a patient who developed persistent nephrogenic diabetes insipidus associated with renal tubular acidosis, renal resistance to parathyroid hormone, aminoaciduria and proximal tubule pattern proteinuria in the presence of a reduced glomerular filtration rate (19-24 ml/min). A review of the previous reports of persistent nephrogenic diabetes insipidus revealed that in all patients the glomerular filtration rate had been less than 60 ml/min at presentation. Chronic renal failure may therefore predispose to the development of persistent nephrogenic diabetes insipidus in patients receiving lithium.     

Rhabdomyolysis associated with cranial diabetes insipidus.

Rhabdomyolysis has been reported to be associated with hyperosmolality in diabetic ketoacidosis and non-ketotic hyperosmolal state. Whether the rhabdomyolysis was due to hyperosmolality per se or whether hyperglycaemia also played a role is not clear. We hereby report a case of cranial diabetes insipidus with hypernatraemia and hyperosmolality complicated by rhabdomyolysis. None of the known risk factors, such as coma, hypokalaemia, hypophosphataemia, diabetic ketoacidosis or non-ketotic hyperosmolality, were present in this patient. We believe that severe hyperosmolality per se is an important predisposing factor for non-traumatic rhabdomyolysis, and serum muscle enzymes should be closely monitored in the management of patients with diabetes insipidus.     

Cranial diabetes insipidus secondary to arrested hydrocephalus

An unusual case is described linking cranial diabetes insipidus with longstanding arrested hydrocephalus. The latter was demonstrated by computed tomographic (CT) and nuclear magnetic resonance (NMR) scans and cerebrospinal fluid pressure measurements. The increasing use of CT and NMR scans may result in this association of cranial diabetes and hydrocephalus being better defined.     

Vasopressin function in familial cranial diabetes insipidus.

A family suffering from cranial diabetes insipidus, that extends over 4 generations, is described. Inheritance of polyuria was autosomal dominant. Vasopressin function was studied in members of the last 2 generations, 4 of whom had polyuria. Osmoregulation of vasopressin secretion was assessed by infusion of hypertonic saline. Plasma vasopressin remained undetectable in one patient, while 2 others had very blunted vasopressin responses to osmotic stimulation. Three non-osmotic stimuli were applied. Controlled hypotension produced by trimetaphan infusion and insulin-induced hypoglycaemia did not increase plasma vasopressin but apomorphine-induced nausea caused a minimal rise in plasma vasopressin to 0.7 pg/ml. Polyuria and thirst resolved with antidiuretic therapy in all patients studied. Congenital absence of vasopressin as in Brattleboro rats is unlikely to account for diabetes insipidus in this disorder since small increases in vasopressin have been demonstrated in these patients. In view of previous post-mortem findings, familial cranial diabetes insipidus is most likely to be due to degeneration of vasopressin-synthesizing neurones.     

尿崩症159例临床分析

尿崩症(diabetes insipidus,DI)是由于下丘脑-神经垂体功能低下,抗利尿激素(antidiuretic hormone,AVP)分泌和释放不足,或者肾脏对AVP反应缺陷而引起的一组临床综合征,主要表现为多尿、烦渴、多饮、低比重尿和低渗透压尿。病变在下丘脑-神经垂体者称中枢性尿崩症(central diabetes insipidus,CDI),病变在。肾脏者称肾性尿崩症(nephrogenic diabetesins ipidus,NDI)。虽然DI的临床诊断不难且AVP的替代治疗也可达比较满意的疗效,但患者的预后与其病因密切相关,因此了解DI的病因诊断对于判断患者的治疗效果、生存质量及预后具有重要意义。笔者总结了1991年1月～2003年8月收治的159例DI患者,根据其临床表现、检查资料及其病因等作回顾性分析如下。