RESUMEN
Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.
Asunto(s)
Arginina Vasopresina , Desamino Arginina Vasopresina , Oxitocina , Poliuria , Humanos , Oxitocina/uso terapéutico , Oxitocina/sangre , Oxitocina/deficiencia , Arginina Vasopresina/sangre , Arginina Vasopresina/deficiencia , Poliuria/diagnóstico , Desamino Arginina Vasopresina/uso terapéutico , Polidipsia/diagnóstico , Diagnóstico Diferencial , Glicopéptidos/sangre , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/terapia , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/tratamiento farmacológico , Diabetes Insípida Neurogénica/terapiaRESUMEN
Diabetes insipidus (DI) is a disorder characterised by the excretion of large amounts of hypotonic urine, with a prevalence of 1 per 25,000 population. Central DI (CDI), better now referred to as arginine vasopressin (AVP)-deficiency, is the most common form of DI resulting from deficiency of the hormone AVP from the pituitary. The less common nephrogenic DI (NDI) or AVP-resistance develops secondary to AVP resistance in the kidneys. The majority of causes of DI are acquired, with CDI developing when more than 80% of AVP-secreting neurons are damaged. Inherited/familial CDI causes account for approximately 1% of cases. Although the pathogenesis of NDI is unclear, more than 280 disease-causing mutations affecting the AVP2 protein or AVP V2 receptor, as well as in aquaporin 2 (AQP2), have been described. Although the cAMP/protein kinase A pathway remains the major regulatory pathway of AVP/AQP2 action, in vitro data have also revealed additional cAMP independent pathways of NDI pathogenesis. Diagnosing partial forms of DI, and distinguishing them from primary polydipsia, can be challenging, previously necessitating the use of the water deprivation test. However, measurements of circulating copeptin levels, especially after stimulation, are increasingly replacing the classical tests in clinical practice because of their ease of use and high sensitivity and specificity. The treatment of CDI relies on desmopressin administration, whereas NDI requires the management of any underlying diseases, removal of offending drugs and, in some cases, administration of diuretics. A better understanding of the pathophysiology of DI has led to novel evolving therapeutic agents that are under clinical trial.
Asunto(s)
Diabetes Insípida Nefrogénica , Diabetes Insípida Neurogénica , Diabetes Insípida , Diabetes Mellitus , Humanos , Acuaporina 2/genética , Diabetes Insípida/diagnóstico , Diabetes Insípida/tratamiento farmacológico , Diabetes Insípida/genética , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/tratamiento farmacológico , Diabetes Insípida Neurogénica/genética , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/terapia , Receptores de Vasopresinas/genéticaRESUMEN
BACKGROUND: Intensive care management of diabetic ketoacidosis (DKA) is targeted to reverse ketoacidosis, replace the fluid deficit, and correct electrolyte imbalances. Adequate restoration of circulation and treatment of shock is key. Pediatric treatment guidelines of DKA have become standard but complexities arise in children with co-morbidities. Congenital nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by impaired kidney concentrating ability and treatment is challenging. NDI and DKA together have only been previously reported in one patient. CASE DIAGNOSIS/TREATMENT: We present the case of a 12-year-old male with NDI and new onset DKA with hyperosmolality. He presented in hypovolemic shock with altered mental status. Rehydration was challenging and isotonic fluid resuscitation resulted in increased urine output and worsening hyperosmolar state. Use of hypotonic fluid and insulin infusion led to lowering of serum osmolality faster than desired and increased the risk for cerebral edema. Despite the rapid decline in serum osmolality his mental status improved so we allowed him to drink free water mixed with potassium phosphorous every hour to match his urinary output (1:1 replacement) and continued 0.45% sodium chloride based on his fluid deficit and replacement rate with improvement in his clinical status. CONCLUSIONS: This case illustrates the challenges in managing hypovolemic shock, hyperosmolality, and extreme electrolyte derangements driven by NDI and DKA, as both disease processes drive excessive urine output, electrolyte and acid-base imbalances, and rapid fluctuation in osmolality.
Asunto(s)
Diabetes Insípida Nefrogénica , Diabetes Mellitus , Cetoacidosis Diabética , Desequilibrio Hidroelectrolítico , Niño , Diabetes Insípida Nefrogénica/complicaciones , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/terapia , Cetoacidosis Diabética/tratamiento farmacológico , Cetoacidosis Diabética/terapia , Electrólitos , Fluidoterapia , Humanos , Insulina , Masculino , Cloruro de SodioRESUMEN
Nephrogenic diabetes insipidus (NDI) is characterized by the inability to concentrate urine that results in polyuria and polydipsia, despite having normal or elevated plasma concentrations of arginine vasopressin (AVP). In this study, we review the clinical aspects and diagnosis of NDI, the various etiologies, current treatment options and potential future developments. NDI has different clinical manifestations and approaches according to the etiology. Hereditary forms of NDI are mainly caused by mutations in the genes that encode key proteins in the AVP signaling pathway, while acquired causes are normally associated with specific drug exposure, especially lithium, and hydroelectrolytic disorders. Clinical manifestations of the disease vary according to the degree of dehydration and hyperosmolality, being worse when renal water losses cannot be properly compensated by fluid intake. Regarding the diagnosis of NDI, it is important to consider the symptoms of the patient and the diagnostic tests, including the water deprivation test and the baseline plasma copeptin measurement, a stable surrogate biomarker of AVP release. Without proper treatment, patients may developcomplications leading to high morbidity and mortality, such as severe dehydration and hypernatremia. In that sense, the treatment of NDI consists in decreasing the urine output, while allowing appropriate fluid balance, normonatremia, and ensuring an acceptable quality of life. Therefore, therapeutic options include nonpharmacological interventions, including sufficient water intake and a low-sodium diet, and pharmacological treatment. The main medications used for NDI are thiazide diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and amiloride, used isolated or in combination.
Asunto(s)
Diabetes Insípida Nefrogénica , Diabetes Insípida , Diabetes Mellitus , Arginina Vasopresina/genética , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/etiología , Diabetes Insípida Nefrogénica/terapia , Humanos , Mutación , Poliuria/diagnóstico , Calidad de VidaRESUMEN
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 clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.
Asunto(s)
Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/fisiopatología , Deshidratación/prevención & control , Diabetes Insípida Nefrogénica/terapia , Femenino , Tamización de Portadores Genéticos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pruebas Genéticas , Humanos , Hipernatremia , Recién Nacido , Glomérulos Renales/fisiopatología , Masculino , Mutación , Neurofisinas/sangre , Neurofisinas/fisiología , Concentración Osmolar , Embarazo , Diagnóstico Prenatal , Precursores de Proteínas/sangre , Precursores de Proteínas/fisiología , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/fisiología , Vasopresinas/sangre , Vasopresinas/fisiologíaRESUMEN
In the pregnant patient, hypotonic polyuria in the setting of elevated serum osmolality and polydipsia should narrow the differential to causes related to diabetes insipidus (DI). Gestational DI, also called transient DI of pregnancy, is a distinct entity, unique from central DI or nephrogenic DI which may both become exacerbated during pregnancy. These three different processes relate to vasopressin, where increased metabolism, decreased production or altered renal sensitivity to this neuropeptide should be considered. Gestational DI involves progressively rising levels of placental vasopressinase throughout pregnancy, resulting in decreased endogenous vasopressin and resulting hypotonic polyuria worsening through the pregnancy. Gestational DI should be distinguished from central and nephrogenic DI that may be seen during pregnancy through use of clinical history, urine and serum osmolality measurements, response to desmopressin and potentially, the newer, emerging copeptin measurement. This review focuses on a brief overview of osmoregulatory and vasopressin physiology in pregnancy and how this relates to the clinical presentation, pathophysiology, diagnosis and management of gestational DI, with comparisons to the other forms of DI during pregnancy. Differentiating the subtypes of DI during pregnancy is critical in order to provide optimal management of DI in pregnancy and avoid dehydration and hypernatremia in this vulnerable population.
Asunto(s)
Diabetes Insípida/diagnóstico , Diabetes Insípida/terapia , Deshidratación/complicaciones , Deshidratación/diagnóstico , Deshidratación/fisiopatología , Deshidratación/prevención & control , Diabetes Insípida/etiología , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/etiología , Diabetes Insípida Nefrogénica/terapia , Diabetes Insípida Neurogénica/diagnóstico , Diabetes Insípida Neurogénica/terapia , Diagnóstico Diferencial , Femenino , Humanos , Hipernatremia/diagnóstico , Hipernatremia/etiología , Hipernatremia/terapia , Neurofisinas/fisiología , Neurofisinas/uso terapéutico , Osmorregulación/fisiología , Polidipsia/sangre , Polidipsia/diagnóstico , Polidipsia/terapia , Poliuria/sangre , Poliuria/diagnóstico , Poliuria/terapia , Embarazo , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/terapia , Precursores de Proteínas/fisiología , Precursores de Proteínas/uso terapéutico , Vasopresinas/fisiología , Vasopresinas/uso terapéutico , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
Patients affected by nephrogenic diabetes insipidus (NDI) can present with hypernatremic dehydration, and first-line rehydration schemes are completely different from those largely applied in usual conditions determining a mild to severe hypovolemic dehydration/shock. In reporting the case of a patient affected by NDI and presenting with severe dehydration triggered by acute pharyngotonsillitis and vomiting, we want to underline the difficulties in managing this condition. Restoring the free-water plasma amount in patients affected by NDI may not be easy, but some key points can help in the first line management of these patients: (1) hypernatremic dehydration should always be suspected; (2) even in presence of severe dehydration, skin turgor may be normal and therefore the skinfold recoll should not be considered in the dehydration assessment; (3) decreased thirst is an important red flag for dehydration; (4) if an incontinent patient with NDI appears to be dehydrated, it is important to place the urethral catheter to accurately measure urine output and to be guided in parenteral fluid administration; (5) if the intravenous route is necessary, the more appropriate fluid replenishment is 5% dextrose in water with an infusion rate that should slightly exceed the urine output; (6) the 0.9% NaCl solution (10 mL/kg) should only be used to restore the volemia in a shocked NDI patient; and (7) it could be useful to stop indomethacin administration until complete restoration of hydration status to avoid a possible worsening of a potential prerenal acute renal failure.
Asunto(s)
Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/terapia , Fluidoterapia , Diagnóstico Diferencial , Humanos , Lactante , MasculinoRESUMEN
Body fluid homeostasis is essential for normal life. In the maintenance of water balance, the most important factor and regulated process is the excretory function of the kidneys. The kidneys are capable to compensate not only the daily fluctuations of water intake but also the consequences of fluid loss (respiration, perspiration, sweating, hemorrhage). The final volume and osmolality of the excreted urine is set in the collecting duct via hormonal regulation. The hormone of water conservation is the vasopressin (AVP), and a large volume of urine is produced and excreted in the absence of AVP secretion or if AVP is ineffective in the kidneys. The aquaporin-2 water channel (AQP2) is expressed in the principal cells, and it plays an essential role in the reabsorption of water in the collecting ducts via type 2 vasopressin receptor (V2R)-mediated mechanism. If neural or hormonal regulation fails to operate the normal function of AVP-V2R-AQP2 system, it can result in various diseases such as diabetes insipidus (DI) or nephrogenic syndrome of inappropriate diuresis (NSIAD). The DI is characterized by excessive production of hyposmotic urine ("insipidus" means tasteless) due to the inability of the kidneys to concentrate urine. In this chapter, we focus and discuss the pathophysiology of nephrogenic DI (NDI) and the potential therapeutic interventions in the light of the current experimental data.
Asunto(s)
Diabetes Insípida Nefrogénica/fisiopatología , Acuaporina 2/metabolismo , Diabetes Insípida Nefrogénica/terapia , Humanos , Receptores de Vasopresinas/metabolismo , Equilibrio HidroelectrolíticoRESUMEN
RATIONALE: X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disease, and is characterized by renal resistance to arginine vasopressin (AVP). Its diagnosis can be clinically challenging. The application of molecular genetic analysis can provide a rapid and definitive diagnosis. PATIENT CONCERNS: A 75-year-old woman presented with recurrent nausea and vomiting was admitted to the Department of Gastroenterology. The patient had a strong family history of polydipsia and polyuria. Sequencing analysis of the antidiuretic hormone arginine vasopressin receptor 2 (AVPR2) revealed the novel missense mutation p. Trp164Cys (c.492G>G/C) in exon 2. There was a heterozygous mutation in the patient's sister and niece, while there was a mutation in her sons, brother and nephews. The locus is located on the X chromosome Xq28, and its mutation can lead to X linked recessive NDI. The p. Trp164Cys mutation of AVPR2 gene has not been reported in literature before. The mutation was predicted to be probably damaging by several prediction methods, including SIFT and PolyPhen-2. There was no significant abnormal variation in other detection regions of the gene. And there was also no abnormal variation in AVP and AQP2 genes in this family. DIAGNOSIS: X-linked NDI was diagnosed according to the patient's family history and DNA sequencing analysis. INTERVENTIONS AND OUTCOMES: After treated with desmopressin, antiemetic drugs and massive infusion glucose transfusion, the patient's urine volume decreased and electrolyte disturbance was corrected, and the symptoms of nausea and vomiting gradually disappeared. LESSONS: The patients with suspected congenital NDI should undergo genetic sequencing analysis of AVPR2, AVP and AQP2 genes. A definitive diagnosis can benefit patient and avoid unnecessary investigations.
Asunto(s)
Diabetes Insípida Nefrogénica/genética , Mutación Missense , Receptores de Vasopresinas/genética , Anciano , Pueblo Asiatico/genética , Diabetes Insípida Nefrogénica/fisiopatología , Diabetes Insípida Nefrogénica/terapia , Familia , Femenino , Humanos , FenotipoRESUMEN
Nephrogenic diabetes insipidus (NDI) results from the inability of the late distal tubules and collecting ducts to respond to vasopressin. The lack of ability to concentrate urine results in polyuria and polydipsia. Primary and acquired forms of NDI exist in children. Congenital NDI is a result of mutation in AVPR2 or AQP2 genes. Secondary NDI is associated with electrolyte abnormalities, obstructive uropathy, or certain medications. Management of NDI can be difficult with only symptomatic treatment available, using low-solute diet, diuretics, and prostaglandin inhibitors.
Asunto(s)
Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/terapia , Niño , Diabetes Insípida Nefrogénica/etiología , Diagnóstico Diferencial , Dieta Hiposódica , Diuréticos/uso terapéutico , Humanos , Chaperonas Moleculares/uso terapéutico , Antagonistas de Prostaglandina/uso terapéuticoRESUMEN
BACKGROUND Patients with malignancies often have electrolyte abnormalities. We present a case of a patient with central diabetes insipidus secondary to metastatic pituitary invasion complicated by hypercalcemic nephrogenic diabetes insipidus. CASE REPORT We present a case of 40-year-old female with a history of stage IV breast cancer with skeletal and leptomeningeal metastasis, who was admitted with polyuria, polydipsia, and recent onset of confusion. The patient was found to have profound hypernatremia and severe hypercalcemia with normal parathyroid and vitamin D serum levels. Urine studies showed low urine osmolality and high urine output, despite the higher serum osmolality. The patient received 5% dextrose for rehydration, 1 dose of intravenous (IV) pamidronate, 1 dose of IV desmopressin, and 4 days of subcutaneous calcitonin 200 international units Q12H. Initially, her urine output in the hospital was in the range of 350-400 milliliters/hour, which responded well to 1 dose of 1-desamino-8d-arginine vasopressin (DDAVP). In the subsequent days, her confusion resolved with normalization of serum sodium and calcium, but she died because of the extensive malignancy. CONCLUSIONS Our case emphasizes the importance of identification of causes and complications of electrolyte abnormalities associated with metastatic cancers. These electrolyte abnormalities can be primary or paraneoplastic and should be actively pursued and treated in such cases.
Asunto(s)
Neoplasias de la Mama/patología , Diabetes Insípida Nefrogénica/etiología , Diabetes Insípida Neurogénica/etiología , Hipercalcemia/etiología , Hipernatremia/etiología , Neoplasias Hipofisarias/secundario , Adulto , Diabetes Insípida Nefrogénica/terapia , Diabetes Insípida Neurogénica/terapia , Femenino , Humanos , Hipercalcemia/terapia , Hipernatremia/terapia , Neoplasias Hipofisarias/complicacionesRESUMEN
Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.
Asunto(s)
Acuaporina 2/genética , Arginina Vasopresina/genética , Diabetes Insípida Nefrogénica/genética , Receptores de Vasopresinas/genética , Diabetes Insípida Nefrogénica/fisiopatología , Diabetes Insípida Nefrogénica/terapia , Exocitosis/genética , Humanos , MutaciónRESUMEN
Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided ribonuclease Cas13. We profiled type VI systems in order to engineer a Cas13 ortholog capable of robust knockdown and demonstrated RNA editing by using catalytically inactive Cas13 (dCas13) to direct adenosine-to-inosine deaminase activity by ADAR2 (adenosine deaminase acting on RNA type 2) to transcripts in mammalian cells. This system, referred to as RNA Editing for Programmable A to I Replacement (REPAIR), which has no strict sequence constraints, can be used to edit full-length transcripts containing pathogenic mutations. We further engineered this system to create a high-specificity variant and minimized the system to facilitate viral delivery. REPAIR presents a promising RNA-editing platform with broad applicability for research, therapeutics, and biotechnology.
Asunto(s)
Proteínas Bacterianas/metabolismo , Sistemas CRISPR-Cas , Endonucleasas/metabolismo , Técnicas de Silenciamiento del Gen , Edición de ARN , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Proteínas Bacterianas/clasificación , Proteínas Bacterianas/genética , Biotecnología , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/terapia , Endonucleasas/clasificación , Endonucleasas/genética , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética , Células HEK293 , Humanos , Mutagénesis , Ingeniería de Proteínas/métodos , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
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 still often recognized late after a 'diagnostic odyssey' involving false leads and dangerous treatments.Once diagnosed, appropriate treatment can be started. Moreover, laboratory studies have identified promising new compounds, which may help achieve urinary concentration independent of vasopressin. RECENT FINDINGS: MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome.We distinguish two types of hereditary NDI: a 'pure' type with loss of water only and a complex type with loss of water and ions. Mutations in the AVPR2 or AQP2 genes, encoding the vasopressin V2 receptor and the water channel Aquaporin2, respectively, lead to a 'pure' NDI with loss of water but normal conservation of ions. Mutations in genes that encode membrane proteins involved in sodium chloride reabsorption in the thick ascending limb of Henle's loop lead to Bartter syndrome, a complex polyuric-polydipsic disorder often presenting with polyhydramnios. A new variant of this was recently identified: seven families were described with transient antenatal Bartter's syndrome, polyhydramnios and MAGED2 mutations.Multiple compounds have been identified experimentally that may stimulate urinary concentration independently of the vasopressin V2 receptor. These compounds may provide new treatments for patients with X-linked NDI. SUMMARY: A plea for early consideration of the diagnosis of NDI, confirmation by phenotypic and/or genetic testing and appropriate adjustment of treatment in affected patients.
Asunto(s)
Deshidratación/prevención & control , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/terapia , Predisposición Genética a la Enfermedad , Receptores de Vasopresinas/genética , Terapia Combinada , Deshidratación/terapia , Diabetes Insípida Nefrogénica/congénito , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Mutación , Enfermedades Raras , Medición de RiesgoRESUMEN
A 4-year-old boy was referred to the nephrologist with daytime urinary incontinence and suspicion of an overactive bladder. At the age of 17 months he had been referred to the pediatric endocrinologist because of polyuria and polydipsia in order to exclude diabetes insipidus. Repeated water deprivation tests and a magnetic resonance imaging scan of the brain were normal. Diabetes insipidus was excluded, and primary polydipsia was thought to be most likely since diabetes mellitus also had been excluded. At the current presentation, he drank up to 3 L a day and quite often had wet diapers. He also seemed to pass stools infrequently and with difficulty. Curiously his grandmother had similar symptoms of polyuria and polydipsia since childhood and had been diagnosed with primary polydipsia. The physical examination of our pediatric patient was normal. In the differential diagnosis we included diabetes insipidus but also contemplated other possibilities, such as nephronophthisis, tubulopathies and hypercalciuria. Laboratory results including urinalysis and an ultrasound of the kidney did not show any abnormalities, making a tubulopathy or hypercalciuria unlikely. A desmopressin test by the intravenous route came back completely normal, pointing to another cause than diabetes insipidus. Genetic testing for the nephronophthisis came back negative but was positive for a missense mutation in the AVPR2 gene (p.Arg104Cys) associated with partial nephrogenic diabetes insipidus. He was started on daily desmopressin. Within 3 days the urinary incontinence resolved as did the polyuria and faecal incontinence. His grandmother was referred to the geneticist and eventually the adult nephrologist. This case highlights the importance of being thorough when confronted with a difficult diagnosis. It also emphasizes that a test result does not necessarily equate to the presence or absence of a condition since the test with 100 % sensitivity and specificity has yet to be discovered.
Asunto(s)
Incontinencia Urinaria/terapia , Preescolar , Diabetes Insípida/diagnóstico , Diabetes Insípida/genética , Diabetes Insípida/terapia , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/terapia , Diagnóstico Diferencial , Humanos , Masculino , Mutación Missense , Receptores de Vasopresinas/genética , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/genéticaRESUMEN
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 neurohypophysis is regulated by a complex signalling network that involves osmosensors, barosensors and volume sensors. AVP facilitates aquaporin (AQP)-mediated water reabsorption via activation of the vasopressin V2 receptor (AVPR2) in the collecting duct, thus enabling concentration of urine. In nephrogenic diabetes insipidus (NDI), inability of the kidneys to respond to AVP results in functional AQP deficiency. Consequently, affected patients have constant diuresis, resulting in large volumes of dilute urine. Primary forms of NDI result from mutations in the genes that encode the key proteins AVPR2 and AQP2, whereas secondary forms are associated with biochemical abnormalities, obstructive uropathy or the use of certain medications, particularly lithium. Treatment of the disease is informed by identification of the underlying cause. Here we review the clinical aspects and diagnosis of NDI, the various aetiologies, current treatment options and potential future developments.
Asunto(s)
Diabetes Insípida Nefrogénica , Diabetes Insípida Nefrogénica/congénito , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/fisiopatología , Diabetes Insípida Nefrogénica/terapia , Predicción , HumanosRESUMEN
Lithium still retains its critical position in the treatment of bipolar disorder by virtue of its ability to prevent suicidal tendencies. However, chronic use of lithium is often limited by the development of nephrogenic diabetes insipidus (NDI), a debilitating condition. Lithium-induced NDI is due to resistance of the kidney to arginine vasopressin (AVP), leading to polyuria, natriuresis and kaliuresis. Purinergic signalling mediated by extracellular nucleotides (ATP/UTP), acting via P2Y receptors, opposes the action of AVP on renal collecting duct (CD) by decreasing the cellular cAMP and thus AQP2 protein levels. Taking a cue from this phenomenon, we discovered the potential involvement of ATP/UTP-activated P2Y2 receptor in lithium-induced NDI in rats and showed that P2Y2 receptor knockout mice are significantly resistant to Li-induced polyuria, natriuresis and kaliuresis. Extension of these studies revealed that ADP-activated P2Y12 receptor is expressed in the kidney, and its irreversible blockade by the administration of clopidogrel bisulphate (Plavix(®)) ameliorates Li-induced NDI in rodents. Parallel in vitro studies showed that P2Y12 receptor blockade by the reversible antagonist PSB-0739 sensitizes CD to the action of AVP. Thus, our studies unravelled the potential beneficial effects of targeting P2Y2 or P2Y12 receptors to counter AVP resistance in lithium-induced NDI. If established in further studies, our findings may pave the way for the development of better and safer methods for the treatment of NDI by bringing a paradigm shift in the approach from the current therapies that predominantly counter the anti-AVP effects to those that enhance the sensitivity of the kidney to AVP action.
Asunto(s)
Acuaporinas/metabolismo , Arginina Vasopresina/antagonistas & inhibidores , Diabetes Insípida Nefrogénica/terapia , Litio/toxicidad , Receptores Purinérgicos P2Y2/metabolismo , Animales , Arginina Vasopresina/metabolismo , Diabetes Insípida Nefrogénica/inducido químicamente , Humanos , Natriuresis/fisiologíaAsunto(s)
Diabetes Insípida Nefrogénica/complicaciones , Fallo Renal Crónico/etiología , Adulto , Análisis Mutacional de ADN , Diabetes Insípida Nefrogénica/diagnóstico , Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/terapia , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Fallo Renal Crónico/diagnóstico , Masculino , Mutación , Fenotipo , Receptores de Vasopresinas/genética , Diálisis Renal , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Nephrogenic diabetes insipidus (NDI) is characterized by the kidney's inability to concentrate urine, which causes intense polyuria that may lead to urinary tract dilation. We report the morphological findings of the urinary tract in ten boys with NDI specifically addressing the presence and changes of urinary tract dilation during treatment. DIAGNOSIS/TREATMENT: Patients were diagnosed at a median age of 1.6 years (range, 0.16-6.33 years) and treated with a low osmotic diet, hydrochlorothiazide-amiloride and indomethacin, which decreased the diuresis from a median of 10.5 ml/kg/h to 4.4 ml/kg/h (p < 0.001). Three patients showed normal renal ultrasound before treatment until last control, while the remaining seven showed urinary tract dilation. In this second group, dilation was reduced with treatment in four patients and disappeared in the remaining three. Children without dilation or in whom the dilation disappeared were diagnosed and treated earlier than those with persistent dilation (median 1.66 versus 4.45 years, respectively). After a median of 10.4 (range, 2.3-20.3) years of follow-up, no patients showed urological complications. CONCLUSIONS: Medical treatment of the disease improved the dilation in all cases, preventing its potential complications. Regardless of the good outcome of our patients, periodic urologic follow-up is recommended in NDI patients.