Search

A 9‐month‐old male presented with vomiting and dehydration with mild hypernatremia in the context of failure to thrive. He was later diagnosed with nephrogenic diabetes insipidus (NDI) during this hospitalisation and was also found to have eosinophilic esophagitis (EoE). He has since been growing well after EoE and NDI were properly managed. Molecular genetic testing revealed an unreported deletion in AQP2 which was deemed pathogenic and of autosomal dominant inheritance when correlated with his clinical findings and family history. This case report describes the clinical course of this patient in comparison to his family members and reviews current literature on autosomal dominant NDI caused by AQP2 mutations. [ABSTRACT FROM AUTHOR]

Background: Acute lymphoblastic leukemia is the most common pediatric malignancy, characterized by fever, anemia, hemorrhage, and symptoms brought on by blasts infiltrating organs. Case presentation: This is a case report of a 9-year-old Asian patient with acute lymphoblastic leukemia who presented with polyuria alone as a presenting feature without any other clinical manifestation; primary renal disease or inherited metabolic disease was highly suspected. However, the water deprivation test and water deprivation pressurization test suggested nephrogenic diabetes insipidus, and the renal biopsy displayed diffuse lymphocytic infiltration in the renal interstitium. Bone marrow aspiration was performed immediately, and a comprehensive diagnosis of B-lymphoblastic leukemia was finally made. Conclusions: Renal infiltration with leukemic blasts mostly remains asymptomatic, but our case suggests that it can present with nephrogenic diabetes insipidus. This case fully demonstrates that the presentation of extramedullary infiltration in acute lymphoblastic leukemia is varied. When the patient has renal diabetes insipidus as the first symptom, the possibility of hematological tumor infiltration should be considered when finding the cause, and timely bone marrow cytology should be performed. [ABSTRACT FROM AUTHOR]

Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin‐2 (AQP2) from collecting duct principal cells, explaining the associated polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium‐induced NDI, unilateral ureteral obstruction, endotoxin‐induced NDI) or proteomics (hypokalaemia‐associated NDI, hypercalcaemia‐associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress‐sensor proteins, namely death receptors and stress‐sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. Key points: Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin‐2 (AQP2) protein is a common feature.Investigations of acquired NDI using transcriptomics (RNA‐seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss.Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling.These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression. [ABSTRACT FROM AUTHOR]

Introduction: Nephrogenic diabetes insipidus (NDI) is a rare genetic disease that causes water imbalance. The kidneys play a crucial role in regulating body fluids by controlling water balance through urine excretion. This highlights their essential function in managing the body's water levels, but individuals with NDI may have excess urine production (polyuria), that leads to excessive thirst (polydipsia). Untreated affected individuals may exhibit poor feeding and failure to thrive. This disease is caused by mutations in the AVPR2 and the AQP2 genes which have the X‐linked and autosomal recessive/dominant inheritance, respectively. Both of these genes are expressed in the kidney. Methods: Twelve Iranian patients from 10 consanguineous families were studied in this project. DNA was extracted from the whole blood samples of the patients and their parents. All coding exons and exon‐intron boundaries of the AVPR2 and AQP2 genes were sequenced in the affected individuals, and the identified variants were investigated in the parents. All variants were analyzed according to the ACMG (American College of Medical Genetics and Genomics) guidelines. Results: In this study, 6 different mutations were identified in the patients, including 5 in the AQP2 gene (c.439G>A, c.538G>A, c.140C>T, c.450T>A, and the novel c.668T>C) and 1 in the AVPR2 gene (c.337C>T) in the present study. Discussion: As expected, all the detected mutations in this study were missense. According to the ACMG guideline, the identified mutations were categorized as pathogenic or likely pathogenic. Unlike previous studies which showed more than 90% of mutations were in the AVPR2 gene, and only less than 10% of the mutations were in the AQP2 gene, it was found that more than 90% of our identified mutations located in the AQP2 gene, and only one mutation was observed in the AVPR2 gene, which seems it may be a result of the high rate of consanguineous marriages in the Iranian population. We observed genotype‐phenotype correlation in some of our affected individuals, and some of the mutations were observed in unrelated families from same ethnicity which could be suggestive of a founder mutation. [ABSTRACT FROM AUTHOR]

The urine concentration impairment responsible for hyposthenuria in sickle cell nephropathy is currently thought to be a consequence of renal medulla lesions, which lead to nephrogenic diabetes insipidus. The objective of the present study was to investigate the mechanism of hyposthenuria in patients with sickle cell anemia. We performed an observational study of patients with homozygous SS sickle cell anemia and data available on the fasting plasma antidiuretic hormone (ADH) concentration. A total of 55 patients were analyzed. The fasting plasma ADH values ranged from 1.2 to 15.4 pg/mL, and 82% of the patients had elevated ADH values and low fasting urine osmolality (<505 mosmol/kgH2O). Plasma ADH was positively associated with plasma tonicity and natremia (P < 0.001). None of the patients experienced polyuria and fasting free water clearance was negative in all cases, thus, ruling out nephrogenic diabetes insipidus. The tertile groups did not differ with regard to fasting urine osmolality, plasma renin level, mGFR, or several hemolysis biomarkers. The negative fasting free water clearance in all cases and the strong association between 24-h osmolal clearance and 24-h diuresis favors the diagnosis of osmotic diuresis due to an impaired medullary gradient, rather than lesions to collecting tubule. NEW & NOTEWORTHY The urine concentration impairment in sickle cell anemia is an osmotic diuresis related to an impaired renal medullary gradient leading to an ADH plateau effect. The fasting plasma ADH was high in the context of a basic state of close-to-maximal urine concentration probably driven by short nephrons maintaining a cortex-outer medullary gradient (about 400 milliosmoles). The patients had a low daily osmoles intake without evidence of thirst dysregulation so no one experienced polyuria. [ABSTRACT FROM AUTHOR]

Background: X-linked nephrogenic diabetes insipidus (NDI) is a rare genetic renal disease caused by pathogenic variants in the AVPR2 gene. Single nucleotide variants and small insertions/deletions in AVPR2 are reliably detected by routine clinical sequencing. Nevertheless, structural variants involving AVPR2 are challenging to identify accurately by conventional genetic testing. Here, we report a novel deletion of AVPR2 in a Czech family identified for the first time by targeted long-read sequencing (T-LRS). Methods: A male proband with X-linked NDI underwent clinical sequencing of the AVPR2 gene that failed and thus indicated possible whole-gene deletion. Therefore, PCR mapping and subsequent targeted long-read sequencing (T-LRS) using a Pacific Biosciences sequencer were applied to search for the suspected deletion. To validate the deletion breakpoints and prove variant segregation in the family with X-linked NDI, Sanger sequencing of the deletion junction was performed. Quantitative real-time PCR was further carried out to confirm the carrier status of heterozygous females. Results: By T-LRS, a novel 7.5 kb deletion of AVPR2 causing X-linked NDI in the proband was precisely identified. Sanger sequencing of the deletion junction confirmed the variant breakpoints and detected the deletion in the probands´ mother, maternal aunt, and maternal cousin with X-linked NDI. The carrier status in heterozygous females was further validated by quantitative real-time PCR. Conclusions: Identifying the 7.5 kb deletion gave a precise molecular diagnosis for the proband, enabled genetic counselling and genetic testing for the family, and further expanded the spectrum of structural variants causing X-linked NDI. Our results also show that T-LRS has significant potential for accurately identifying putative structural variants. [ABSTRACT FROM AUTHOR]

Background Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. Methods Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. Results Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0–60) years and at last follow-up 14.0 (0.1–70) years. In adults, height was normal with a mean (standard deviation) score of −0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients. Conclusion This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems. [ABSTRACT FROM AUTHOR]

In case of dehydration, lithium can cause acute intoxication. This picture is mainly manifested by neurological disorders that can go as far as coma, digestive disorders, hydroelectrolytic disorders, and cardiovascular disorders. We report the case of a patient followed for bipolar disorder for 20 years and treated with lithium for 14 years and who presented an acute lithium intoxication resulting from a diabetes insipidus. Our objective is to underline the importance of good hydration and strict monitoring of lithium levels especially in situations favouring dehydration, notably the polyuria of diabetes insipidus. [ABSTRACT FROM AUTHOR]

We previously reported the novel finding that β3-AR is functionally expressed in the renal tubule and shares its cellular localization with the vasopressin receptor AVPR2, whose physiological stimulation triggers antidiuresis by increasing the plasma membrane expression of the water channel AQP2 and the NKCC2 symporter in renal cells. We also showed that pharmacologic stimulation of β3-AR is capable of triggering antidiuresis and correcting polyuria, in the knockout mice for the AVPR2 receptor, the animal model of human X-linked nephrogenic diabetes insipidus (XNDI), a rare genetic disease still missing a cure. Here, to demonstrate that the same response can be evoked in humans, we evaluated the effect of treatment with the β3-AR agonist mirabegron on AQP2 and NKCC2 trafficking, by evaluating their urinary excretion in a cohort of patients with overactive bladder syndrome, for the treatment of which the drug is already approved. Compared to baseline, treatment with mirabegron significantly increased AQP2 and NKCC2 excretion for the 12 weeks of treatment. This data is a step forward in corroborating the hypothesis that in patients with XNDI, treatment with mirabegron could bypass the inactivation of AVPR2, trigger antidiuresis and correct the dramatic polyuria which is the main hallmark of this disease. [ABSTRACT FROM AUTHOR]

Nephrogenic diabetes insipidus, decreased ability to concentrate urine, with production of large amounts of urine, is caused by the refractory response of renal tubules to the action of antidiuretic hormone. This rare disorder, known as X-linked nephrogenic diabetes insipidus, is caused by a mutation in the AVPR2 gene. Because it is hereditary, most patients are male. This report highlights a case of nephrogenic diabetes insipidus in a 3-year 5-month-old female; upon presentation to the hospital, her symptoms included frequent urination and consumption of a significant amount of water, which had begun 2 years ago. The results of blood tests showed increased levels of serum antidiuretic hormone, and sellar magnetic resonance imaging showed no abnormality. The results of the water restriction test and the desmopressin administration test confirmed the diagnosis of nephrogenic diabetes insipidus showing a partial response to desmopressin. The results of genetic testing indicated the presence of an AVPR2 mutation, a heterozygous missense mutation (p.Val88Met), suggesting inheritance of X-linked nephrogenic diabetes insipidus. This report describes a significant case of symptomatic X-linked nephrogenic diabetes insipidus in a female patient who showed a partial response to desmopressin. [ABSTRACT FROM AUTHOR]

We describe the unexpected challenges pediatricians may experience when children conceived with assisted reproduction are diagnosed with a rare genetic condition. A local case series triggered a dialogue between many stakeholders with varied expertise. Indeed, diagnosing a genetic disease in a child conceived by embryo, egg, or sperm donation is becoming more common now that genetic testing and in vitro fertilization (IVF) are readily accessible. However, how and whether to share that information with other stakeholders in the gamete donation process has not been fully explored, and the clinical responsibilities of the treating clinician remain ill-defined. This work centers on a patient with a confirmed diagnosis of X-linked nephrogenic diabetes insipidus. Ultimately, we found the same AVPR2 mutation in two children from two families conceived by egg donation. It led to multigenerational cascade diagnoses in the family of the shared, anonymous egg donor. First, we review current genetic testing practices in gamete donation and third-party reproduction. Then, we provide an overview of relevant genomic, ethical, legal, and psychosocial considerations for sharing relevant genomic information. Finally, and to maximize the best interests of genetic relatives, we discuss how a pediatrician can play a role in the early disclosure of relevant clinical information to all stakeholders in the gamete donation process, starting with the fertility clinic. While these clinical cases are cast in a Canadian context, we submit that its important lessons generally apply to medical systems of nearly all developed countries, broadly defined. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: In patients with relapsed or refractory lymphoma, high-dose chemoimmunotherapy with subsequent autologous hematopoietic cell transplantation (HCT) is a standard of care. Bendamustine, an alkylating agent, is used in the BeEAM (bendamustine, etoposide, cytarabine, melphalan) protocol for conditioning therapy before autologous HCT in patients with relapsed or refractory lymphoma who are eligible for transplant. There is no consensus regarding an optimal salvage regimen and the approach varies according to toxicity. Case report: We present a case of partial nephrogenic diabetes insipidus after receiving bendamustine, as part of the BeEAM protocol. Management and outcome: The patient was managed with parenteral fluid administration and intranasal desmopressin before the condition resolved on its own. Discussion: We summarize published reports of bendamustine-induced diabetes insipidus. [ABSTRACT FROM AUTHOR]

Nephrogenic diabetes insipidus (NDI) is rarely considered against more common differentials such as diabetes mellitus in patients presenting with polydipsia and polyuria. Hypokalemia and hypercalcemia are known to induce NDI, but not much is known about hypomagnesemia. Hypokalemia refractory to therapy should prompt consideration of hypomagnesemia. [ABSTRACT FROM AUTHOR]

Aquaporin‐2 (AQP2) is a homotetrameric water channel responsible for the final water reuptake in the kidney. Disease‐causing AQP2 mutations induce nephrogenic diabetes insipidus (NDI), a condition that challenges the bodily water balance by producing large urinary volumes. In this study, we characterize three new AQP2 mutations identified in our lab from NDI patients (A120D, A130V, T179N) along the previously reported A47V variant. Using Xenopus oocytes, we compared the key functional and biochemical features of these mutations against classical recessive (R187C) and dominant (R254Q) forms, and once again found clear functional recovery features (increased protein stability and function) for all mutations under study. This behaviour, attributed to heteromerization to wt‐AQP2, challenge the classical model to NDI which often depicts recessive mutations as ill‐structured proteins unable to oligomerize. Consequently, we propose a revised model to the cell pathophysiology of AQP2‐related NDI which accounts for the functional recovery of recessive AQP2 mutations. [ABSTRACT FROM AUTHOR]

Patients with nephrogenic diabetes insipidus should establish a support network system by contacting the government to ensure that water can be preferentially obtained in the event of a disaster and create and carry a medical alert card. [ABSTRACT FROM AUTHOR]

Objective: Lithium remains an important treatment for mood disorders but is associated with kidney disease. Nephrogenic diabetes insipidus (NDI) is associated with up to 3‐fold risk of incident chronic kidney disease among lithium users. There are limited randomized controlled trials (RCT) for treatments of lithium‐induced NDI, and existing therapies can be poorly tolerated. Therefore, novel treatments are needed for lithium‐induced NDI. Method: We conducted a 12‐week double‐blind pilot RCT to assess the feasibility and efficacy of 20 mg/d atorvastatin vs placebo in the treatment of NDI in chronic lithium users. Patients, recruited between September 2017 and October 2018, were aged 18 to 85, currently on a stable dose of lithium, and determined to have NDI. Results: Urinary osmolality (UOsm) at 12 weeks adjusted for baseline was not statistically different between groups (+39.6 mOsm/kg [95% CI, −35.3, 114.5] in atorvastatin compared to placebo groups). Secondary outcomes of fluid intake and aquaporin‐2 excretions at 12 weeks adjusted for baseline were −0.13 L [95% CI, −0.54, 0.28] and 98.68 [95% CI, −190.34, 387.70], respectively. A moderate effect size was observed for improvements in baseline UOsm by ≥100 mOsm/kg at 12 weeks in patients who received atorvastatin compared to placebo (38.45% (10/26) vs 22.58% (7/31); Cohen's d = 0.66). Conclusion: Among lithium users with NDI, atorvastatin 20 mg/d did not significantly improve urinary osmolality compared to placebo over a 12‐week period. Larger confirmatory trials with longer follow‐up periods may help to further assess the effects of statins on NDI, especially within patients with more severe NDI. [ABSTRACT FROM AUTHOR]

Background: Disorders of water and sodium balance can occur after brain injury. Prolonged polyuria resulting from central diabetes insipidus and cerebral salt wasting complicated by gradient washout and a type of secondary nephrogenic diabetes insipidus, however, has not been described previously, to the best of our knowledge. We report an unusual case of an infant with glioblastoma who, after tumor resection, was treated for concurrent central diabetes insipidus and cerebral salt wasting complicated by secondary nephrogenic diabetes insipidus.Case Presentation: A 5-month-old Hispanic girl was found to have a large, hemorrhagic, suprasellar glioblastoma causing obstructive hydrocephalus. Prior to mass resection, she developed central diabetes insipidus. Postoperatively, she continued to have central diabetes insipidus and concurrent cerebral salt wasting soon after. She was managed with a vasopressin infusion, sodium supplementation, fludrocortisone, and urine output replacements. Despite resolution of her other major medical issues, she remained in the pediatric intensive care unit for continual and aggressive management of water and sodium derangements. Starting on postoperative day 18, her polyuria began increasing dramatically and did not abate with increasing vasopressin. Nephrology was consulted. Her blood urea nitrogen was undetectable during this time, and it was thought that she may have developed a depletion of inner medullary urea and osmotic gradient: a "gradient washout." Supplemental dietary protein was added to her enteral nutrition, and her fluid intake was decreased. Within 4 days, her blood urea nitrogen increased, and her vasopressin and fluid replacement requirements significantly decreased. She was transitioned soon thereafter to subcutaneous desmopressin and transferred out of the pediatric intensive care unit.Conclusions: Gradient washout has not been widely reported in humans, although it has been observed in the mammalian kidneys after prolonged polyuria. Although not a problem with aquaporin protein expression or production, gradient washout causes a different type of secondary nephrogenic diabetes insipidus because the absence of a medullary gradient impairs water reabsorption. We report a case of an infant who developed complex water and sodium imbalances after brain injury. Prolonged polyuria resulting from both water and solute diuresis with low enteral protein intake was thought to cause a urea gradient washout and secondary nephrogenic diabetes insipidus. The restriction of fluid replacements and supplementation of enteral protein appeared adequate to restore the renal osmotic gradient and efficacy of vasopressin. [ABSTRACT FROM AUTHOR]

Nephrogenic diabetes insipidus (DI) is a rare disease in which the patient cannot concentrate urine despite appropriate or high secretion of antidiuretic hormone. Congenital nephrogenic DI is caused by the arginine vasopressin receptor 2 (AVPR2) or aquaporin 2 (AQP2) gene mutation; the AVPR2 genetic mutation accounts for 90% of the cases. National health screening for infants and children was launched in 2007 in order to prevent accidents and promote public health in infants and children in Korea. The program has been widely used as a primary clinical service in Korea. We treated an infant with faltering growth and delayed development detected by the National health screening program, and diagnosed the problem as nephrogenic DI caused by a rare missense mutation of c.490T>C on the AVPR2 gene. This case can be a good educational nephrogenic DI with a rare AVPR2 mutation, which was well screened and traced by the national health screening program for infants and children in Korea. [ABSTRACT FROM AUTHOR]

Lithium is widely used in psychiatry as the golden standard for more than 60 yr due to its effectiveness. However, its adverse effect has been limiting its long-term use in clinic. About 40% of patients taking lithium develop nephrogenic diabetes insipidus (NDI). Lithium can also induce proliferation of collecting duct cells, leading to microcyst formation in the kidney. Lithium was considered an autophagy inducer that might contribute to the therapeutic benefit of neuropsychiatric disorders. Thus, we hypothesized that autophagy may play a role in lithium-induced kidney nephrotoxicity. To address our hypothesis, we fed mice with a lithium-containing diet with chloroquine (CQ), an autophagy inhibitor, concurrently. Lithium-treated mice presented enhanced autophagy activity in the kidney cortex and medulla. CQ treatment significantly ameliorated lithium-induced polyuria, polydipsia, natriuresis, and kaliures is accompanied with attenuated downregulation of aquaporin-2 and Na+-K+-2Cl− cotransporter protein. The protective effect of CQ on aquaporin-2 protein abundance was confirmed in cultured cortical collecting duct cells. In addition, we found that lithium-induced proliferation of collecting duct cells was also suppressed by CQ as detected by proliferating cell nuclear antigen staining. Moreover, both phosphorylated mammalian target of rapamycin and β-catenin expression, which have been reported to be increased by lithium and associated with cell proliferation, were reduced by CQ. Taken together, our study demonstrated that CQ protected against lithium-induced NDI and collecting duct cell proliferation possibly through inhibiting autophagy. [ABSTRACT FROM AUTHOR]

The water channel aquaporin 2 (AQP2) is responsible for water reabsorption by kidney collecting duct cells. A substitution of amino acid leucine 137 to proline in AQP2 (AQP2-L137P) causes Nephrogenic Diabetes Insipidus (NDI). This study aimed to determine the cell biological consequences of this mutation on AQP2 function. Studies were performed in HEK293 and MDCK type I cells, transfected with wildtype (WT) AQP2 or an AQP2-L137P mutant. AQP2-L137P was predominantly detected as a high-mannose form of AQP2, whereas AQP2-WT was observed in both non-glycosylated and complex glycosylated forms. In contrast to AQP2-WT, the AQP2-L137P mutant did not accumulate on the apical plasma membrane following stimulation with forskolin. Ubiquitylation of AQP2-L137P was different from AQP2-WT, with predominance of non-distinct protein bands at various molecular weights. The AQP2-L137P mutant displayed reduced half-life compared to AQP2-WT. Treatment of cells with chloroquine increased abundance of AQP2-WT, but not AQP2-L137P. In contrast, treatment with MG132 increased abundance of AQP2-L137P but not AQP2-WT. Xenopus oocytes injected with AQP2-WT had increased osmotic water permeability when compared to AQP2-L137P, which correlated with lack of the mutant form in the plasma membrane. From the localization of the mutation and nature of the substitution it is likely that AQP2-L137P causes protein misfolding, which may be responsible for the observed functional defects. The data suggest that the L137P mutation results in altered AQP2 protein maturation, increased AQP2 degradation via the proteasomal pathway and limited plasma membrane expression. These combined mechanisms are likely responsible for the phenotype observed in this class of NDI patients. [ABSTRACT FROM AUTHOR]

Lithium is the first line therapy of bipolar mood disorder. Lithium-induced nephrogenic diabetes insipidus (Li-NDI) and lithium nephropathy (Li-NP, i.e., renal insufficiency) are prevalent side effects of lithium therapy, with significant morbidity. The objective of this systematic review is to provide an overview of preventive and management strategies for Li-NDI and Li-NP. For this, the PRISMA guideline for systematic reviews was used. Papers on the prevention and/or treatment of Li-NDI or Li-NP, and (influenceable) risk factors for development of Li-NDI or Li-NP were included. We found that the amount of evidence on prevention and treatment of Li-NDI and Li-NP is scarce. To prevent Li-NDI and Li-NP we advise to use a once-daily dosing schedule, target the lowest serum lithium level that is effective and prevent lithium intoxication. We emphasize the importance of monitoring for Li-NDI and Li-NP, as early diagnosis and treatment can prevent further progression and permanent damage. Collaboration between psychiatrist, nephrologist and patients themselves is essential. In patients with Li-NDI and/or Li-NP cessation of lithium therapy and/or switch to another mood stabilizer should be considered. In patients with Li-NDI, off label therapy with amiloride can be useful. [ABSTRACT FROM AUTHOR]

The kidney is the central organ involved in maintaining water and sodium balance. In human kidneys, nine aquaporins (AQPs), including AQP1– 8 and AQP11, have been found and are differentially expressed along the renal tubules and collecting ducts with distinct and critical roles in the regulation of body water homeostasis and urine concentration. Dysfunction and dysregulation of these AQPs result in various water balance disorders. This review summarizes current understanding of physiological and pathophysiological roles of AQPs in the kidney, with a focus on recent progress on AQP2 regulation by the nuclear receptor transcriptional factors. This review also provides an overview of AQPs as clinical biomarkers and therapeutic targets for renal diseases. [ABSTRACT FROM AUTHOR]

Context. Diabetes insipidus (DI) is rare in the neonatal period but of great importance due to increased renal risk and mental retardation despite treatment. Objective. This report describes the case of a patient with congenital nephrogenic diabetes insipidus (NDI). Detection of this pathology during the neonatal period, especially in premature newborns, is difficult because of the electrolyte variations that occur as a result of the immature kidney function. Subjects and methods. The subject was a preterm infant with very low birth weight (VLBW) and persistent hypernatremic hyperosmolarity that developed polyuria and polydipsia in the first weeks of life. Results. Taking into account blood and urine laboratory tests, vasopressin levels, as well as family history, the infant was diagnosed with congenital NDI. Early treatment allowed a good development, proving that the prevention of long-term complications is possible through multidisciplinary care and frequent monitoring. The particularity of this case was the presence of persistently elevated presepsin levels. This association prompted the investigation into underlying renal hypernatremia. Conclusions. NDI is a rare condition and the onset in the neonatal period is a sign of severity and hereditary causality. Early diagnosis, symptomatic treatment and multidisciplinary monitoring may decrease the risk of longterm complications. [ABSTRACT FROM AUTHOR]

Hypertonicity increases water permeability, independently of vasopressin, in the inner medullary collecting duct (IMCD) by increasing aquaporin-2 (AQP2) membrane accumulation. We investigated whether protein kinase C (PKC) and adenosine monophosphate kinase (AMPK) are involved in hypertonicity-regulated water permeability. Increasing perfusate osmolality from 150 to 290 mosmol/kgH2O and bath osmolality from 290 to 430 mosmol/kgH2O significantly stimulated osmotic water permeability. The PKC inhibitors chelerythrine (10 µ M) and rottlerin (50 µ M) significantly reversed the increase in osmotic water permeability stimulated by hypertonicity in perfused rat terminal IMCDs. Chelerythrine significantly increased phosphorylation of AQP2 at S261 but not at S256. Previous studies show that AMPK is stimulated by osmotic stress. We tested AMPK phosphorylation under hypertonic conditions. Hypertonicity significantly increased AMPK phosphorylation in inner medullary tissues. Blockade of AMPK with Compound C decreased hypertonicity-stimulated water permeability but did not alter phosphorylation of AQP2 at S256 and S261. AICAR, an AMPK stimulator, caused a transient increase in osmotic water permeability and increased phosphorylation of AQP2 at S256. When inner medullary tissue was treated with the PKC activator phorbol dibutyrate (PDBu), the AMPK activator metformin, or both, AQP2 phosphorylation at S261 was decreased with PDBu or metformin alone, but there was no additive effect on phosphorylation with PDBu and metformin together. In conclusion, hypertonicity regulates water reabsorption by activating PKC. Hypertonicity-stimulated water reabsorption by PKC may be related to the decrease in endocytosis of AQP2. AMPK activation promotes water reabsorption, but the mechanism remains to be determined. PKC and AMPK do not appear to act synergistically to regulate water reabsorption. [ABSTRACT FROM AUTHOR]

Lithium, mainstay treatment for bipolar disorder, frequently causes nephrogenic diabetes insipidus (NDI) and renal injury. However, the detailed mechanism remains unclear. Here we used the analysis of metabolomics and transcriptomics and metabolic intervention in a lithium-induced NDI model. Mice were treated with lithium chloride (40 mmol/kg chow) and rotenone (ROT, 100 ppm) in diet for 28 days. Transmission electron microscopy showed extensive mitochondrial structural abnormalities in whole nephron. ROT treatment markedly ameliorated lithium-induced NDI and mitochondrial structural abnormalities. Moreover, ROT attenuated the decrease of mitochondrial membrane potential in line with the upregulation of mitochondrial genes in kidney. Metabolomics and transcriptomics data demonstrated that lithium activated galactose metabolism, glycolysis, and amino sugar and nucleotide sugar metabolism. All these events were indicative of metabolic reprogramming in kidney cells. Importantly, ROT ameliorated metabolic reprogramming in NDI model. Based on transcriptomics analysis, we also found the activation of MAPK, mTOR and PI3K-Akt signaling pathways and impaired focal adhesion, ECM-receptor interaction and actin cytoskeleton in Li-NDI model were inhibited or attenuated by ROT treatment. Meanwhile, ROT administration inhibited the increase of Reactive Oxygen Species (ROS) in NDI kidneys along with enhanced SOD2 expression. Finally, we observed that ROT partially restored the reduced AQP2 and enhanced urinary sodium excretion along with the blockade of increased PGE2 output. Taken together, the current study demonstrates that mitochondrial abnormalities and metabolic reprogramming play a key role in lithium-induced NDI, as well as the dysregulated signaling pathways, thereby serving as a novel therapeutic target. • Lithium induced mitochondrial abnormalities in proximal and distal tubules. • Rotenone remarkably ameliorated lithium-induced NDI and renal mitochondrial abnormalities. • Metabolic reprogramming played an important role in the pathogenesis of lithium-induced NDI. [ABSTRACT FROM AUTHOR]

Background. Nephrogenic diabetes insipidus (NDI) is a disease characterized by a defective response to the antidiuretic hormone (ADH) of the renal collecting duct leading to a decline in the ability of the pro-urine concentration. Case presentation. A 23-year-old man presented with an over 20-year history of polyuria concomitant with hydronephrosis. The diagnosis of NDI was established by gene analysis as well as a water-deprivation and vasopressin test. All exons of arginine vasopressin V2 receptor (AVPR2) gene were amplified and sequenced. A novel hemizygous intragenic inframe deletion, cDNA 255th bp to 263th bp in exon 2 of AVPR2, was identified. These relevant translations from the 85th amino acid Asp to 88th amino acid Val were missed and replaced by amino acid Glu. After treating the patient with hydrochlorothiazide, his symptoms improved significantly. Conclusion. The genetic analysis revealed a novel X-linked intragenic inframe deletion, AVPR2 gene cDNA 255th bp to 263th bp, causing NDI. [ABSTRACT FROM AUTHOR]

Despite having been discovered in 1800, the contemporary history of lithium salts in psychiatry began only in 1949. Lithium has proved to be a very effective treatment for patients with affective disorders. It can prevent both suicide and relapse in patients with bipolar disorder and is also effective as adjunctive treatment in unipolar depression. In spite of its well-known efficacy though, lithium is being used in clinical practice less often nowadays. Two of the reasons for this phenomenon are its narrow therapeutic index and its nephrotoxicity. The toxic effects of lithium in renal function began to trouble scientists approximately 40 years ago. Today, it is well documented that lithium can cause, in decreasing order of frequency, nephrogenic diabetes insipidus, chronic kidney disease and nephrotic syndrome. Unfortunately, chronic kidney disease may eventually lead to renal dialysis even if lithium administration is stopped. The relation between lithium treatment and manifestation of renal tumors has not been proved yet. The molecular and pathophysiological mechanisms of lithium-induced toxic renal effects are partially elucidated. Their knowledge increases the pharmacovigilance of clinical psychiatrist so as to use clinical examination and laboratory tests to properly detect or prevent renal side-effects and treat them in co-operation with nephrologists. [ABSTRACT FROM AUTHOR]

Background/Aims: We recently showed that the β3-adrenoreceptor (β3AR) is expressed in mouse kidney collecting ducts (CD) cells along with the type-2 vasopressin receptor (AVPR2). Interestingly, a single injection of a β3AR selective agonist promotes a potent antidiuretic effect in mice. Before considering the feasibility of chronic β3AR agonism to induce antidiuresis in vivo, we aimed to evaluate in vitro the signaling and desensitization profiles of human β3AR. Methods: Human β3AR desensitization was compared with that of human AVPR2 in cultured renal cells. Video imaging and FRET experiments were performed to dissect β3AR signaling under acute and chronic stimulation. Plasma membrane localization of β3AR, AVPR2 and AQP2 after agonist stimulation was studied by confocal microscopy. Receptors degradation was evaluated by Western blotting. Results: In renal cells acute stimulation with the selective β3AR agonist mirabegron, induced a dose-dependent increase in cAMP. Interestingly, chronic exposure to mirabegron promoted a significant increase of intracellular cAMP up to 12 hours. In addition, a slow and slight agonist-induced internalization and a delayed downregulation of β3AR was observed under chronic stimulation. Furthermore, chronic exposure to mirabegron promoted apical expression of AQP2 also up to 12 hours. Conversely, long-term stimulation of AVPR2 with dDAVP showed short-lasting receptor signaling, rapid internalization and downregulation and apical AQP2 expression for no longer than 3 h. Conclusions: Overall, we conclude that β3AR is less prone than AVPR2 to agonist-induced desensitization in renal collecting duct epithelial cells, showing sustained cAMP production, preserved membrane localization and delayed degradation after 12 hours agonist exposure. These results may be important for the potential use of chronic pharmacological stimulation of β3AR to promote antidiuresis overcoming in vivo renal concentrating defects caused by inactivating mutations of the AVPR2. [ABSTRACT FROM AUTHOR]

Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by resistance of the kidney to the action of antidiuretic hormone (ADH), resulting in a decrease in the capacity of the kidney to concentrate the urine. NDI can be inherited or acquired due to, for example, chronic lithium therapy. Current treatment options are limited to attempts to lower urine output by a low-solute diet and the use of diuretics or anti-inflammatory drugs. These measures are only partially effective. Recent reports suggested that sildenafil, metformin, and simvastatin might improve ADH-independent urine concentration. If confirmed, this would provide interesting additional therapeutic options for patients with NDI. We, therefore, tested the effect of these drugs on ADH-independent urine concentrating capacity in healthy volunteers. We included 36 healthy volunteers who received sildenafil 20 mg thrice daily, metformin 500 mg thrice daily or simvastatin 40 mg once daily during 1 week. At baseline and at the end of treatment, a water loading test was performed. No significant increase in lowest urine osmolality was seen after the use of metformin or sildenafil (P = 0.66 and P = 0.09 respectively). Lowest urine osmolality increased modestly but significantly after the use of simvastatin (70 mOsm/kg to 85 mOsm/kg, P = 0.05). Our data suggest that only simvastatin has an effect on urine osmolality in healthy volunteers. Validation studies are needed and, most importantly, these drugs should be tested in patients with NDI. [ABSTRACT FROM AUTHOR]

Lithium, given to bipolar disorder patients, causes nephrogenic diabetes insipidus (Li-NDI), a urinary-concentrating defect. Li-NDI occurs due to downregulation of principal cell AQP2 expression, which coincides with principal cell proliferation. The metabolic effect of lithium on principal cells, however, is unknown and investigated here. In earlier studies, we showed that the carbonic anhydrase (CA) inhibitor acetazolamide attenuated Li-induced downregulation in mouse-collecting duct (mpkCCD) cells. Of the eight CAs present in mpkCCD cells, siRNA and drug treatments showed that downregulation of CA9 and to some extent CA12 attenuated Li-induced AQP2 downregulation. Moreover, lithium induced cell proliferation and increased the secretion of lactate. Lithium also increased urinary lactate levels in wild-type mice that developed Li-NDI but not in lithium-treated mice lacking ENaC, the principal cell entry site for lithium. Inhibition of aerobic glycolysis with 2-deoxyglucose (2DG) attenuated lithium-induced AQP2 downregulation in mpkCCD cells but did not attenuate Li-NDI in mice. Interestingly, NMR analysis demonstrated that lithium also increased the urinary succinate, fumarate, citrate, and NH4 + levels, which were, in contrast to lactate, not decreased by 2DG. Together, our data reveal that lithium induces aerobic glycolysis and glutaminolysis in principal cells and that inhibition of aerobic glycolysis, but not the glutaminolysis, does not attenuate Li-NDI. [ABSTRACT FROM AUTHOR]

The kidney plays a central role in the regulation of the body water balance. The process of targeting the water channel aquaporin-2 (AQP2) on the apical plasma membrane of the collecting duct (CD) principal cells is mainly regulated by the antidiuretic peptide hormone arginine vasopressin (AVP), which is responsible for the maintenance of water homeostasis. Recently, much attention has been focused on the local factors modulating renal water reabsorption by AQP2 in the collecting ducts, especially prostaglandin E2 (PGE2). PGE2 is a lipid mediator involved in a variety of physiological and pathophysiological processes in the kidney. The biological function of PGE2 is mainly mediated by four G-protein-coupled receptors, namely EP1-4, which couple to drive separate intracellular signaling pathways. Increasing evidence demonstrates that PGE2 is essential for renal water transport regulation via multiple mechanisms. Each EP receptor plays a unique role in regulating water reabsorption in renal collecting ducts. This brief review highlights the role of PGE2 in the regulation of water reabsorption and discusses the involvement of each EP receptor subtype in renal collecting duct. A better understanding of the role of PGE2 in renal water transport process may improve disease management strategies for water balance disorders, including nephrogenic diabetes insipidus. [ABSTRACT FROM AUTHOR]

Background: Despite lithium being a highly effective drug, it is commonly associated with inducing nephrogenic diabetes insipidus (NDI) in a high number of patients. In this case report we describe the successful use of amiloride as an effective means to manage and minimise NDI occurring in patients while they are on lithium therapy. Clinical details: The patient had been taking lithium for management of her bipolar disorder for approximately 5 years. While on this medication the patient suffered from acute kidney impairment, hypernatraemia, reduced urine osmolality, increased plasma osmolality, polyuria, polydipsia and severe dehydration. These clinical results were consistent with an adverse reaction known as NDI acquired from long-term lithium use and fluid restriction. Outcomes: Lithium was ceased on day two of admission. Intravenous fluid replacements were provided until the patient' s renal function and sodium levels returned to normal. Once the patient was symptomatically stable, lithium was reintroduced at initiating dosage levels concomitantly with amiloride with aims of reversing the concentrating defect and preventing this side effect from occurring again. The patient was discharged 15 days later. Conclusion: In most cases NDI is reversible with the cessation of lithium. However, a subset of the mental health population is resistant to other forms of therapy, leaving lithium as their only option to successfully manage their mood disorder. For patients who suffer from mental health disorders, the literature has found that amiloride can be an effective means to restore a patient' s impaired urine concentrating ability. [ABSTRACT FROM AUTHOR]

Roflumilast is a cyclic nucleotide phosphodiesterase inhibitor that is FDAapproved for treatment of chronic obstructive pulmonary disease. With a view toward possible use for treatment of patients with X-linked nephrogenic diabetes insipidus (NDI) due to hemizygous mutations in the V2 vasopressin receptor, this study sought to determine the effect of roflumilast on aquaporin-2 (AQP2) phosphorylation, AQP2 trafficking, and water permeability in the rat inner medullary collecting duct (IMCD). In the presence of the vasopressin analog dDAVP (0.1 nmol/L), both roflumilast and its active metabolite roflumilast N-oxide (RNO) significantly increased phosphorylation at S256, S264, and S269, and decreased phosphorylation at S261 (immunoblotting) in IMCD suspensions in a dose-dependent manner (3-3000 nmol/L). Another commonly used phosphodiesterase inhibitor, IBMX, affected phosphorylation only at the highest concentration in this range. However, neither roflumilast nor RNO had an effect on AQP2 phosphorylation in the absence of vasopressin. Furthermore, roflumilast alone did not increase AQP2 trafficking to the plasma membrane (immunofluorescence) or increase water permeability in freshly microdissected perfused IMCD segments. We conclude that roflumilast can be used to enhance vasopressin's action on AQP2 activity in the renal collecting duct, but has no detectable effect in the absence of vasopressin. These findings suggest that roflumilast may not have a beneficial effect in X-linked NDI, but could find useful application in acquired NDI. [ABSTRACT FROM AUTHOR]

Fundamental kidney physiology research can provide important insight into how the kidney works and suggest novel therapeutic opportunities to treat human diseases. This is especially true for nephrogenic diabetes insipidus (NDI). Over the past decade, studies elucidating the molecular physiology and signaling pathways regulating water transport have suggested novel therapeutic possibilities. In patients with congenital NDI due to mutations in the type 2 vasopressin receptor (V2R) or acquired NDI due to lithium (or other medications), there are no functional abnormalities in the aquaporin-2 (AQP2) water channel, or in another key inner medullary transport protein, the UT-A1 urea transporter. If it is possible to phosphorylate and/or increase the apical membrane accumulation of these proteins, independent of vasopressin or cAMP, one may be able to treat NDI. Sildenifil (through cGMP), erlotinib, and simvastatin each stimulate AQP2 insertion into the apical plasma membrane. Some recent human data suggest that sildenafil and simvastatin may improve urine concentrating ability. ONO-AE1-329 (ONO) stimulates the EP4 prostanoid receptor (EP4), which stimulates kinases that in turn phosphorylate AQP2 and UT-A1. Clopidogrel is a P2Y12-R antagonist that potentiates the effect of vasopressin and increases AQP2 abundance. Metformin stimulates AMPK to phosphorylate and activate AQP2 and UT-A1, and it increases urine concentrating ability in two rodent models of NDI. Since metformin, sildenafil, and simvastatin are commercially available and have excellent safety records, the potential for rapidly advancing them into clinical trials is high. [ABSTRACT FROM AUTHOR]

Objective: To describe a case of partial nephrogenic diabetes insipidus in a burned patient after prolonged delivery of low inspired concentrations of sevoflurane via an Anesthetic Conserving Device.Data Sources: Clinical observation.Study Selection: Case report.Data Extraction: Relevant clinical information.Data Synthesis: A 34-year-old man was admitted with burns covering 52% of his total body surface area. Mechanical ventilation was provided during sedation with continuous infusions of sufentanil and midazolam. Sedation became increasingly difficult, and in order to limit administration of IV agents, sevoflurane was added to the inspiratory gas flow. This was provided using an Anesthetic Conserving Device and continued for 8 days. The patient rapidly developed polyuria and hypernatremia with an inappropriate decrease in urinary osmolality. Administration of desmopressin resulted in only a modest effect on renal concentrating ability. After cessation of sevoflurane, all variables returned to normal within 5 days. The results of further investigations (cerebral computed tomographic scan, cerebral magnetic resonance imaging, and serum arginine vasopressin concentration) were compatible with a diagnosis of partial nephrogenic diabetes insipidus. The temporal sequence of clinical findings in relation to sevoflurane administration suggests that the sevoflurane was the probable underlying cause.Conclusions: Clinicians should be aware of the possibility of sevoflurane-induced diabetes insipidus not only during general anesthesia but also in the intensive care setting of sedation in critically ill patients. This is especially important in patients, such as those with severe burns, in whom preserved renal concentrating ability is important to ensure compensation for extrarenal fluid losses. [ABSTRACT FROM AUTHOR]

Diabetes insipidus is a clinical condition, characterized by polyuria and polydipsia, that results from either insufficient production or end organ resistance to antidiuretic hormone (ADH). Diabetes insipidus is of two types: central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI). Children with diabetes insipidus may present with polyuria, polydipsia, frequent dehydration, constipation, and failure to thrive. Acquired NDI may results from various drugs and conditions but NDI due to obstructive uropathy is very rare. There are very few case reports of NDI due to obstructive uropathy. We report a 2-year-old child who presented with diabetes insipidus as a consequence of obstructive uropathy. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial or harmful depending on the specific risk factors affecting the disease. In hypertension, the vascular relaxation response to acetylcholine is blunted, and that to direct NO donors is maintained. A reduction in the activity of eNOS is mainly responsible for the elevation of blood pressure, and an abnormal expression of iNOS is likely to be related to the progression of vascular dysfunction. While eNOS/nNOS-derived NO is protective against the development of atherosclerosis, iNOS-derived NO may be proatherogenic. eNOS-derived NO may prevent the progression of myocardial infarction. Myocardial ischemia/reperfusion injury is significantly enhanced in eNOS-deficient animals. An important component of heart failure is the loss of coronary vascular eNOS activity. A pressure-overload may cause severer left ventricular hypertrophy and dysfunction in eNOS null mice than in wild-type mice. iNOS-derived NO has detrimental effects on the myocardium. NO plays an important role in regulating the angiogenesis and slowing the interstitial fibrosis of the obstructed kidney. In unilateral ureteral obstruction, the expression of eNOS was decreased in the affected kidney. In triply n/i/eNOS null mice, nephrogenic diabetes insipidus developed along with reduced aquaporin-2 abundance. In chronic kidney disease model of subtotal-nephrectomized rats, treatment with NOS inhibitors decreased systemic NO production and induced left ventricular systolic dysfunction (renocardiac syndrome). [ABSTRACT FROM AUTHOR]

Background: Exposure to psychotropic agents, including lithium, antipsychotics and antidepressants, has been associated with nephrogenic diabetes insipidus (NDI). This is especially concerning in older adults already at risk of developing chronic kidney disease (CKD) and hypernatremia with advanced aging. This study investigates whether commonly performed random urinespecific gravity (USG) tests can predict adverse NDI outcomes (CKD and hypernatremia) in psychotropic-exposed older adults. Methods: This was a retrospective longitudinal study of 173 geriatric psychiatry patients (age ⩾65 years) exposed to psychotropic medications. Our main continuous outcome was 'decrease in estimated glomerular filtration rate (eGFR) >10 mL/ min/1.73m2' over 5-year follow-up. Hypernatremia and acute kidney injury (AKI) were secondary outcomes. Whether baseline USG <1.010 predicted outcomes was assessed in bivariate and multivariate analyses. Results: USG <1.010 predicted hypernatremia episodes (sodium concentration ⩾150 mmol/L-28.1 versus 12%, X2 = 4.7, P = 0.03). USG <1.010 [odds ratio 2.36 (95% confidence interval 0.93-6.0), P = 0.07], baseline eGFR and typical antipsychotic use independently predicted decrease in eGFR >10 mL/min/1.73m2. Patients with a single baseline sodium concentration of ⩾140 mmol/L and USG <1.010 have a 26.3% incidence of AKI and a 57.9% incidence of hypernatremia over the ensuing 5 years. Conclusions: In psychotropic-exposed older adults, there appears to be a clinically important association between lowUSG and developing both hypernatremia and CKD. USG may be a useful surrogate measure for NDI-related outcomes in large administrative database studies, where ideal measures such as 24-h urine volume may not be available. [ABSTRACT FROM AUTHOR]

In this study, the first molecular dynamics simulation of the human aquaporin 2 is performed and for a better understanding of the aquaporin 2 permeability performance, the characteristics of water transport in this protein channel and key biophysical parameters of AQP2 tetramer including osmotic and diffusive permeability constants and the pore radius are investigated. For this purpose, recently recovered high resolution X-ray crystal structure of` the human aquaporin 2 is used to perform twenty nanosecond molecular dynamics simulation of fully hydrated tetramer of this protein embedded in a lipid bilayer. The resulting water permeability characteristics of this protein channel showed that the water permeability of the human AQP2 is in a mean range in comparison with other human aquaporins family. Finally, the results reported in this research demonstrate that molecular dynamics simulation of human AQP2 provided useful insights into the mechanisms of water permeation and urine concentration in the human kidney. [ABSTRACT FROM AUTHOR]

Unlabelled: Molecular diagnosis is a useful diagnostic tool in primary nephrogenic diabetes insipidus (NDI), an inherited disease characterized by renal inability to concentrate urine. The AVPR2 and AQP2 genes were screened for mutations in a cohort of 25 patients with clinical diagnosis of NDI. Patients presented with dehydration, polyuria-polydipsia, failure to thrive (mean ± SD; Z-height -1.9 ± 2.1 and Z-weight -2.4 ± 1.7), severe hypernatremia (mean ± SD; Na 150 ± 10 mEq/L), increased plasma osmolality (mean ± SD; 311 ± 18 mOsm/Kg), but normal glomerular filtration rate. Genetic diagnosis revealed that 24 male patients were hemizygous for 17 different putative disease-causing mutations in the AVPR2 gene (each one in a different family). Of those, nine had not been previously reported, and eight were recurrent. Moreover, we found those same AVPR2 changes in 12 relatives who were heterozygous carriers. Further, in one female patient, AVPR2 gene study turned out to be negative and she was found to be homozygous for the novel AQP2 p.Ala86Val alteration.Conclusion: Genetic analysis presumably confirmed the diagnosis of nephrogenic diabetes insipidus in every patient of the studied cohort. We emphasize that we detected a high presence (50 %) of heterozygous females with clinical NDI symptoms.What Is Known: • In most cases (90 %), inherited nephrogenic diabetes insipidus (NDI) is an X-linked disease, caused by mutations in the AVPR2 gene. • In rare occasions (10 %), it is caused by mutations in the AQP2 gene. What is new: • In this study, we report 10 novel mutations associated with NDI. • We have detected a high presence (50 %) of heterozygous carriers with clinical NDI symptoms. [ABSTRACT FROM AUTHOR]

Lithium-associated hyperparathyroidism is the leading cause of hypercalcemia in lithium-treated patients. Lithium may lead to exacerbation of pre-existing primary hyperparathyroidism or cause an increased set-point of calcium for parathyroid hormone suppression, leading to parathyroid hyperplasia. Lithium may cause renal tubular concentration defects directly by the development of nephrogenic diabetes insipidus or indirectly by the effects of hypercalcemia. In this study, we present a female patient on long-term lithium treatment who was evaluated for hypercalcemia. Preoperative imaging studies indicated parathyroid adenoma and multinodular goiter. Parathyroidectomy and thyroidectomy were planned. During the postoperative course, prolonged intubation was necessary because of agitation and delirium. During this period, polyuria, severe dehydration, and hypernatremia developed, which responded to controlled hypotonic fluid infusions and was unresponsive to parenteral desmopressin. A diagnosis of nephrogenic diabetes insipidus was apparent. A parathyroid adenoma and multifocal papillary thyroid cancer were detected on histopathological examination. It was thought that nephrogenic diabetes insipidus was masked by hypercalcemia preoperatively. A patient on lithium treatment should be carefully followed up during or after surgery to prevent life-threatening complications of previously unrecognized nephrogenic diabetes insipidus, and the possibility of renal concentrating defects on long-term lithium use should be sought, particularly in patients with impaired consciousness. [ABSTRACT FROM AUTHOR]

Background: Inherited renal tubular dysgenesis (RTD) is caused by mutations in the genes encoding the components of the renin-angiotensin system (RAS). RTD is characterized by oligohydramnios, renal failure, neonatal hypocalvaria, and severe hypotension. The histological characteristics, underlying mechanism, and long-term prognosis remain poorly known. Case-diagnosis/treatment: We describe here a 4-year-old female with RTD. Endocrinologic analysis showed a discrepancy between low plasma renin activity and high active renin concentration, suggesting a loss of the renin substrate, angiotensinogen (AGT). Direct sequencing revealed a frameshift deletion at nucleotide 1,355 in exon 5 in the AGT gene. Although a histological hallmark is regarded to be the absence or poor development of the proximal tubule, the patient does have minimally impaired function of the proximal tubule. Glomerular cysts without glomerular tufts were noted in approximately half of the glomeruli. The urinary concentrating ability and sodium reabsorption and potassium excretion in the distal nephron were severely affected. Conclusions: The patient has an impaired function of the distal nephron despite minimally affected function of the proximal tubule, probably attributed to renal tubular dysgenesis and fetal hypoperfusion. The renal tubular maturity and the severity of ischemic injury may be key determinants of the clinical symptoms and pathological findings in RTD, in which the RAS plays an important role. [ABSTRACT FROM AUTHOR]

Objectives Polyuria increases the risk of dehydration and lithium toxicity in lithium-treated patients. Risk factors have been inconsistently described and the variance of this adverse effect remains poorly understood. This study aimed to establish independent risk factors for polyuria in a community, secondary-level lithium-treated sample of patients. Methods This was a cross-sectional study of the lithium-treated patients attending a general adult and an old age psychiatry service. Participants completed a 24-hour urine collection. Urine volume and the presence of polyuria were the outcomes of interest. The relationship between outcome and the participant's demographic and clinical characteristics was explored with univariable and multivariable analysis. Results A total of 122 participants were included in the analysis, with 38% being diagnosed with polyuria. Female gender and increased body weight independently predicted the presence of polyuria (standardized regression coefficient 1.01 and 0.94, respectively; p = 0.002 and p = 0.003, respectively). Female gender and increased body weight, lithium dose, and duration of lithium treatment independently predicted higher 24-hour urine volumes (standardized regression coefficients 0.693, p < 0.0005; 0.791, p < 0.0005; 0.276, p = 0.043; 0.181, p = 0.034, respectively). Of three different weight metrics, lean body weight was the most predictive. Conclusions Female gender and increased body weight explain part of the variance of this adverse effect. Both risk factors offer fresh insights into the pathophysiology of this potentially reversible and dangerous adverse effect of lithium treatment. Future research should focus on understanding the differences between the genders and between different body compositions in terms of lithium pharmacokinetics and pharmacodynamics. [ABSTRACT FROM AUTHOR]

The lysosome, an organelle central to macromolecule degradation and recycling, plays a pivotal role in normal cell processes, ranging from autophagy to redox regulation. Not surprisingly, lysosomes are an integral part of the renal epithelial molecular machinery that facilitates normal renal physiology. Two inherited diseases that manifest as kidney dysfunction are Fabry's disease and cystinosis, each of which is caused by a primary biochemical defect at the lysosome resulting from loss-of-function mutations in genes that encode lysosomal proteins. The functions of the lysosomes in the kidney and how lysosomal dysfunction might contribute to Fabry's disease and cystinosis are discussed. Unlike most other pediatric renal diseases, therapies are available for Fabry's disease and cystinosis, but require early diagnosis. Recent analysis of ceroid neuronal lipofuscinosis type 3 ( Cln3) null mice, a mouse model of lysosomal disease that is primarily associated with neurological deficits, revealed renal functional abnormalities. As current and future therapeutics increase the life-span of those suffering from diseases like neuronal ceroid lipofuscinosis, it remains a distinct possibility that many more lysosomal disorders that primarily manifest as infant and juvenile neurodegenerative diseases may also include renal disease phenotypes. [ABSTRACT FROM AUTHOR]

Tubular disorders form a significant proportion of pediatric kidney diseases and are an important differential diagnosis of failure to thrive (FTT) in children. Data regarding their outcome is scarce from India. We evaluated the clinical profile of these children and studied the outcome in terms of their growth and renal failure. This is a retrospective longitudinal study of all children with renal tubular disorders attending a tertiary care pediatric nephrology center from 2005 to 2010. Growth and renal outcomes were assessed by Z scores and estimated glomerular filtration rate at diagnosis and. The common disorders encountered were distal renal tubular acidosis (d‑RTA) (44%), Bartter‑like (Bartter’s and Gitelman) syndromes (22%) followed by hereditary Fanconi syndrome (cystinosis and idiopathic Fanconi syndrome) (13%) and few cases of nephrogenic diabetes insipidus, hypophosphatemic rickets and idiopathic hypercalciuria. Male: female ratio was 1.22. The median age at diagnosis was 1.5 (range 0.13-11) years. Growth failure was the presenting feature in 86% of children followed by polyuria (60%) and bone deformities (47%). In 60% of children with hereditary Fanconi syndrome, nephropathic cystinosis was diagnosed, all of whom progressed to stage III chronic kidney disease (CKD) within 3.41 ± 1.42 years. With appropriate therapy, catch‑up growth was noted in d‑RTA and Bartter syndrome. Renal tubular disorders usually present with FTT. d‑RTA is the most common etiology followed by Bartter‑like syndrome. Renal function is preserved in all these disorders except for nephropathic cystinosis, who ultimately progressed to CKD. With appropriate and inexpensive therapy, these children do grow well. [ABSTRACT FROM AUTHOR]

The anti-diuretic hormone arginine-vasopressin (AVP) is released from the pituitary and regulates water reabsorption in the principal cells of the kidney collecting duct. Binding of AVP to the arginine-vasopressin receptor type-2 in the basolateral membrane leads to translocation of aquaporin-2 water channels to the apical membrane of the principal cells of the collecting duct, inducing water permeability of the membrane. This results in water reabsorption in the collecting duct of the nephron following an osmotic gradient. Nephrogenic diabetes insipidus is caused by partial or complete renal resistance to the effects of AVP. Congenital nephrogenic diabetes insipidus is a disorder associated with mutations in either the AVPR2 or AQP2 gene, causing the inability of patients to concentrate their urine. Acquired nephrogenic diabetes insipidus can be caused by electrolyte imbalances (e.g., hypercalcemia, hypokalemia), renal/extra-renal diseases and drugs (e.g., lithium toxicity). This article reviews the causes, clinical manifestations, diagnosis and treatment of patients with nephrogenic diabetes insipidus. Based on more in-depth mechanistic understanding, new therapeutic strategies are current being explored. [ABSTRACT FROM AUTHOR]

We describe herein a case of hypokalemia due to proximal renal tubular acidosis (RTA) and Fanconi's syndrome (FS) and nephrogenic diabetes insipidus with DIC – a rare complication of Sjögren's syndrome (SS) and brucellosis. The interesting feature of this case was the presentation with severe hypokalemia, causing acute flaccid quadriparesis with cardiac arrest which is extremely rare. The patient was a 48-year-old woman who suffered cardiopulmonary arrest an hour after hospitalization. Analysis of a blood sample obtained before her cardiopulmonary arrest yielded surprising results: laboratory investigations showed profound hypokalemia (1.1 mEq/L) with renal K wasting, hyperchloremic metabolic acidosis with normal anion gap, hypophosphatemia with hypouricemia, glucosuria, and proteinuria. A diagnosis of RTA and FS were made. On the seventh day, she looked acutely ill, temperature 38.8 °C and pale, and her physical examination revealed purpuric skin lesions on both legs. The serum antibrucella titration agglutination test was found to be 1 of 160 positive with a nosocomial infection. The clinical and laboratory findings were consistent with disseminated intravascular coagulation (DIC). She was unable to concentrate her urine and so a diagnosis of nephrogenic diabetes insipidus (NDI) was reached. A thorough survey for the cause of FS, RTA and NDI revealed that she had xerophthalmia and xerostomia accompanied by high anti-Ro antibody, positive Schirmer test, confirming the diagnosis of SS. [ABSTRACT FROM AUTHOR]

One of the clinical alterations observed in chronic renal disease (CRD) is the impaired urine concentration, known as diabetes insipidus (DI). Tubulointerstitial fibrosis of the kidney is also a pathological finding observed in CRD and involves composition of extracellular matrix (ECM). However, an association between these two events has not been elucidated. In this study, we showed that the extracellular-to-intracellular scaffold protein integrin-linked kinase (ILK) regulates expression of tubular water channel aquaporin-2 (AQP2) and its apical membrane presence in the renal tubule. Basally, polyuria and decreased urine osmolality were present in ILK conditional-knockdown (cKD-ILK) adult mice compared with nondepleted ILK littermates. No changes were observed in arginine-vasopressin (AVP) blood levels, renal receptor (V2R), or AQP3 expression. However, tubular AQP2 was decreased in expression and apical membrane presence in cKD-ILK mice, where the canonical V2R/cAMP axis activation is still functional, but independent of the absence of ILK Thus, cKD-ILK constitutes a nephrogenic diabetes insipidus (NDI) model. AQP2 and ILK colocalize in cultured inner medullary collecting duct (mIMCD3) cells. Specific ILK siRNAs and collagen I (Col) decrease ILK and AQP2 levels and AQP2 presence on the membrane of tubular mIMCD3 cells, which impairs the capacity of the cells to transport water under hypotonic stress. The present work points to ILK as a therapeutic target in NDI. [ABSTRACT FROM AUTHOR]