GENETICS IN ENDOCRINOLOGY Pathophysiology, diagnosis and treatment of familial nephrogenic diabetes insipidus.

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.

A novel AVPR2 missense mutation in an Asian family with inherited nephrogenic diabetes insipidus: A case report.

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.

Double Trouble - Severe Hypernatremia Secondary to Central Diabetes Insipidus Complicated by Hypercalcemic Nephrogenic Diabetes Insipidus: A Case Report.

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.

RNA editing with CRISPR-Cas13.

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.

Diabetes insipidus--diagnosis and management.

Central diabetes insipidus (CDI) is the end result of a number of conditions that affect the hypothalamic-neurohypophyseal system. The known causes include germinoma/craniopharyngioma, Langerhans cell histiocytosis (LCH), local inflammatory, autoimmune or vascular diseases, trauma resulting from surgery or an accident, sarcoidosis, metastases and midline cerebral and cranial malformations. In rare cases, the underlying cause can be genetic defects in vasopressin synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits. The diagnosis of the underlying condition is challenging and raises several concerns for patients and parents as it requires long-term follow-up. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress to more sophisticated tools. Specifically, MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a clear marker of neurohypophyseal functional integrity, together with the careful analysis of pituitary stalk shape and size, have provided the most striking findings contributing to the diagnosis and understanding of some forms of 'idiopathic' CDI. MRI STIR (short-inversion-time inversion recovery sequencing) is a promising technology for the early identification of LCH-dependent CDI.

Interstitial nephritis and nephrogenic diabetes insipidus in a patient treated with pemetrexed.

We present a case of interstitial nephritis and nephrogenic diabetes insipidus (NDI) in a patient treated with pemetrexed (500 mg/m(2)) for non-small cell lung cancer. Renal impairment and diabetes insipidus appeared after the first treatment cycle while he totally received four cycles of chemotherapy. There was not any significant myelosuppression and the patient was on regular supplementation with folic acid and vitamin B(12). He was not on any other medications and he did not receive any nephrotoxic agents. Kidney biopsy showed acute tubular necrosis together with interstitial inflammatory infiltrate of mononuclear cells and interstitial fibrosis occupying 25% of the cortex. There was not any improvement of renal function after a 2-week trial of oral prednisone. In the present case report, we review the literature for pemetrexed-induced renal toxicity and the possible mechanisms involved.

Novel treatment for lithium-induced nephrogenic diabetes insipidus rat model using the Sendai-virus vector carrying aquaporin 2 gene.

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/DeltaF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.

Causes of reversible nephrogenic diabetes insipidus: a systematic review.

BACKGROUND: In nephrogenic diabetes insipidus (NDI), the kidney is unable to produce concentrated urine because of the insensitivity of the distal nephron to antidiuretic hormone (arginine vasopressin). In settings in which fluid intake cannot be maintained, this may result in severe dehydration and electrolyte imbalances. The risk for conversion of reversible to irreversible NDI seems to be a potential complication. This review summarizes the reversible causes of acquired NDI to facilitate earlier recognition and more effective treatment by clinicians. METHODS: Two reviewers independently searched MEDLINE, Experta Medica (EMBASE), and ISI bibliographic databases. Human studies that described NDI caused by drugs, substances, or metabolic disturbances were included. To evaluate the causal role of the risk factor, data were abstracted according to Koch's postulates. RESULTS: One hundred fifty-five studies published between 1957 and March 2004 described 30 risk factors. Of 155 studies, 58 studies provided a "definite" diagnosis of NDI; 83 studies, a "probable" diagnosis; and 14 studies, a "possible" diagnosis. Nine factors were considered "definite" causes of NDI; 15 factors, "probable" causes; and 6 factors, "possible" causes. The most reported risk factors were lithium (84 studies), antibiotics (16 studies), antifungals (11 studies), antineoplastic agents (9 studies), antivirals (8 studies), and metabolic disturbances (8 studies). Duration of NDI reversal, as well as conversion to irreversible symptoms, seemed to depend on the duration of exposure. CONCLUSION: Most risk factors for reversible NDI were medications, and their identification and removal resulted in resolution of the condition. Long-term treatment with lithium seemed to result in irreversible NDI.

Polyuria associated with high-dose methotrexate in two patients with acute lymphoblastic leukaemia.

Although methotrexate has an established safety profile in clinical practice, severe morbidity can still occur on rare occasions. We report two patients with leukemia treated with high dose methotrexate. Both patients developed profound polyuria that required aggressive fluid resuscitations during the treatments. Renal toxicity is a known complication of methotrexate, but polyuria associated with its use has not been reported before. Polyuria started shortly after the initiation of the medicine in both patients. The polyuria resolved as the drug level in blood became undetectable. The episodes of polyuria were transient and recurred every time when the patients received methotrexate. The clinical pictures were not compatible with classical drug induced nephrogenic diabetes insipidus. It is possible that the drug interferes with adenosine metabolism, which in turn alters the tubular ability of solute and fluid reabsorption.

Síndrome poliúrico / Poliuric syndrome

Se sospecha Síndrome Poliúrico (SP) cuando el volumen urinario excede en 2 a 3 veces lo esperado para la edad o cuando a raíz de una deshidratación o restricción hídrica no se produce concentración urinaria adecuada. El volumen y la osmolaridad de los líquidos orgánicos se regulan con gran precisión gracias a la actividad de la hormona antidiurética (HAD), producida en el eje hipotálamo hipofisiario, que maneja la permeabilidad del agua de los túbulos distales y colectores renales. El SP se clasifica en dos grandes grupos: 1) con niveles plasmáticos bajos de HAD (diabetes insípida central DIC o neurogénica y polidipsia primaria) y 2) con niveles plasmáticos normales de HAD (diuresis osmótica y diabetes insípida nefrogénica DIN). El diagnóstico diferencial se hace con la prueba de deprivación acuosa y el tratamiento consiste en reemplazo hormonal con HAD en DIC y en la DIN reducción del aporte calórico proteico con la ingesta libre de agua, más diuréticos tiazídicos y antiinflamatorios. En el presente artículo se hace una revisión actualizada del SP.

Nephrogenic diabetes insipidus in a dog with intestinal leiomyosarcoma.

Nephrogenic diabetes insipidus was diagnosed in a dog with an intestinal leiomyosarcoma. The diagnosis of nephrogenic diabetes insipidus was made on the basis of results of serum biochemical tests, urinalyses, and a water-deprivation test, along with a lack of response to exogenous administration of vasopressin following the water-deprivation test. The temporal association between resection of the intestinal mass and resolution of clinical signs of diabetes insipidus (i.e., polyuria and polydipsia) and between recurrence of clinical signs and detection of metastatic disease suggests that there may have been a causal relationship, and nephrogenic diabetes insipidus may have developed as a paraneoplastic syndrome in this dog.

A novel mutation in the vasopressin V2 receptor gene in a woman with congenital nephrogenic diabetes insipidus.

A 56-year-old Japanese woman with congenital nephrogenic diabetes insipidus (CNDI) is reported. She was diagnosed with CNDI accompanied by advanced gastric cancer. After total gastrectomy, approximately 500 ml fluid per hour was necessary to prevent dehydration. Urinary volume was decreased by administration of hydrochlorothiazide. We detected a novel mutation in the vasopressin V2 receptor gene of her chromosomal DNA. A substitution from G to A was found at the 631 nucleotide position, altering codon 12 from glycine (GGG) to glutamic acid (GAG) in the first extracellular domain. This missense mutation appeared to be the cause of her resistance to arginine vasopressin.