A novel AVPR2 gene mutation in a Chinese pedigree with nephrogenic diabetes insipidus.

Nephrogenic diabetes insipidus (NDI) is a rare genetic disorder primarily associated with mutations in the arginine vasopressin receptor 2 (AVPR2) gene or the aquaporin 2 (AQP2) gene, resulting in impaired water reabsorption in the renal tubules. This report describes a case of a young male patient with NDI from China with a history of polydipsia and polyuria for over 15 years. Laboratory examinations of the proband indicated low urine-specific gravity and osmolality. Urologic ultrasound revealed severe bilateral hydronephrosis in both kidneys, bilateral dilatation of the ureters, roughness of the bladder wall, and the formation of muscle trabeculae. The diagnosis of diabetes insipidus was confirmed by water deprivation tests. The administration of posterior pituitary hormone did not alter urine-specific gravity, and osmolality remained at a low level (<300 mOsm/kg). Based on these findings, and the genetic tests of the proband and his parents were performed. A missense mutation (c.616 G>C) in exon 3 of the AVPR2 gene of the proband was found, caused by the substitution of amino acid valine to leucine at position 206 [p.Val206Leu], which was a hemizygous mutation and consistent with X-chromosome recessive inheritance. The administration of oral hydrochlorothiazide improves the symptoms of polydipsia and polyuria in the proband. This novel AVPR2 gene mutation may be the main cause of NDI in this family, which induces a functional defect in AVPR2, and leads to reduced tubular reabsorption of water.

The ß3-AR agonist BRL37344 ameliorates the main symptoms of X-linked nephrogenic diabetes insipidus in the mouse model of the disease.

X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the ß3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the ß3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the ß3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human ß3-AR agonists might represent an effective possible treatment strategy for X-NDI.

Genetic analysis of nephrogenic diabetes insipidus patients: A study on the Iranian population.

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.

Nephrogenic diabetes insipidus in a geriatric patient affected by SARS-CoV-2: complexity of a diagnosis, complexity of a virus.

Background: Coronavirus disease 2019 (COVID-19) has an important impact on the kidney through direct and indirect damage mechanisms. Most previous studies have highlighted lesions caused by this virus in the early segments of the nephron. However, due to the antigenic characteristics of the virus, with almost ubiquitous receptors, and the molecular release it triggers, the distal segments of the nephron could also be affected. Methods: A 71 year-old-man with respiratory failure while suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia presented with typical symptoms of diabetes insipidus after ~20 days of hospitalization. The water deprivation test led to the diagnosis of nephrogenic diabetes insipidus. The aetiological study was complex, in particular because of the patient's previous lithium therapy. Results: The sequence of pathognomonic events typical of diabetes insipidus associated with anamnestic, clinical and laboratory evidence strongly supported the diagnosis of nephrogenic diabetes insipidus due to SARS-CoV-2 rather than other aetiologies. Conclusions: The collecting duct could represent a target for SARS-CoV-2 infection, directly or indirectly, as a result of lesions of upstream portions of the nephron, which would cascade into the distal segment. Other molecules, besides angiotensin 2 converting enzyme, might be involved in facilitating the viral aggression. The complexity of the geriatric patient shows the importance of a comprehensive approach that integrates careful monitoring of clinical signs and symptoms and laboratory and instrumental tests. This is especially important in the context of SARS-CoV-2 infection and in the management of its unexpected complications.

Targeted long-read sequencing identified a causal structural variant in X-linked nephrogenic diabetes insipidus.

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.

First report on female monozygotic twins discordant for congenital nephrogenic diabetes insipidus.

Ninety percent of congenital nephrogenic diabetes insipidus (NDI) are X-linked inherited and are caused by mutations in the vasopressin type 2 receptor gene (AVPR2). Most affected individuals are males. Only sporadic female cases have been reported. Here, we first reported a female monozygotic twin with discordant phenotypes for NDI carrying a missense variant c.845T>C (p.Leu282Pro) in exon 4 of AVPR2. Intracellular cAMP concentrations in COS7 cells transfected with AVPR2-L282P were significantly decreased by about 60% compared with those in wild-type AVPR2 plasmid transfected cells, suggesting this variation was pathogenic. The X-inactivation pattern was investigated in peripheral leukocytes and urine sediments in both the unaffected and affected pair. Results showed that the affected pair had a skewed X chromosome inactivation (XCI) pattern in urine sediments and a random XCI pattern in leukocytes, while the unaffected pair showed a random XCI pattern both in leukocytes and urine sediments. This was the first report of monozygotic twins who developed different phenotypes of NDI. Our study suggested that the development of NDI symptoms is more closely associated with the XCI pattern in urine sediments compared with the XCI pattern in peripheral leukocytes. Analysis of XCI in peripheral leukocytes may not be enough to explore possible mechanisms.

Ifosfamide-induced nephrotoxicity in oncological patients.

INTRODUCTION: Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of various neoplasms. Its main adverse effects include renal damage. AREAS COVERED: A comprehensive review was conducted, including 100 articles from the Scielo, Scopus, and EMBASE databases. Ifosfamide-induced nephrotoxicity is attributed to its toxic metabolites, such as acrolein and chloroacetaldehyde, which cause mitochondrial damage and oxidative stress in renal tubular cells. Literature review found a 29-year average age with no gender predominance and a mortality of 13%. Currently, no fully effective strategy exists for preventing ifosfamide-induced nephrotoxicity; however, hydration, forced diuresis, and other interventions are employed to limit renal damage. Long-term renal function monitoring is essential for patients treated with ifosfamide. EXPERT OPINION: Ifosfamide remains essential in neoplasm treatment, but nephrotoxicity, often compounded by coadministered drugs, poses diagnostic challenges. Preventive strategies are lacking, necessitating further research. Identifying timely risk factors can mitigate renal damage, and a multidisciplinary approach manages established nephrotoxicity. Emerging therapies may reduce ifosfamide induced nephrotoxicity.

Ifosfamide is a type of chemotherapy used to treat different types of cancers. However, one of its main side effects is kidney damage. Researchers reviewed 100 articles from medical databases to understand how ifosfamide affects the kidneys. The kidney damage is caused by harmful substances produced when ifosfamide is broken down in the body. These substances can harm the cells in the kidneys. Studies have shown that 13% of the patients treated with ifosfamide can die. Currently, there is no perfect way to prevent kidney damage from ifosfamide, but doctors try to protect the kidneys by giving patients plenty of fluids and using other treatments, so it's important for patients who receive ifosfamide to have their kidney function checked regularly. Although ifosfamide is effective against cancer, its potential kidney side effects should be carefully considered by doctors when deciding on the best treatment for each patient.

Urine concentration impairment in sickle cell anemia: genuine nephrogenic diabetes insipidus or osmotic diuresis?

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.

Three Pediatric Patients with Congenital Nephrogenic Diabetes Insipidus due to AVPR2 Nonsense Mutations and Different Clinical Manifestations: A Case Report.

Congenital nephrogenic diabetes insipidus (CNDI), a rare hereditary disorder, is characterized by the inability of the kidneys to concentrate urine in response to the antidiuretic hormone arginine vasopressin (AVP); as a result, large volumes of unconcentrated urine are excreted. In addition to the clinical manifestations of CNDI, such as dehydration and electrolyte disturbances (hypernatremia and hyperchloremia), developmental delay can result without prompt treatment. In approximately 90% of cases, CNDI is an X-linked disease caused by mutations in the arginine vasopressin receptor 2 (AVPR2) gene. In approximately 9% of cases, CNDI is an autosomal recessive disease caused by mutations in the water channel protein aquaporin 2 (AQP2), and 1% of cases are autosomal dominant. We report a case of CNDI caused by a novel AVPR2 nonsense mutation, c.520C>T (p.Q174X), and cases of siblings in another family who had a different AVPR2 nonsense mutation, c.852G>A (p.W284X). Both cases responded well to treatment with hydrochlorothiazide and spironolactone. If CNDI is suspected, especially in carriers and neonates, aggressive genetic testing and early treatment may alleviate growth disorders and prevent irreversible central nervous system disorders and developmental delay.

Lithium-induced Nephrogenic Diabetes Insipidus with Efficacy of Desmopressin in Combination with Thiazide Diuretics and Non-steroidal Anti-inflammatory Drugs: A Case Report with a Review of the Literature.

Nephrogenic diabetes insipidus (NDI) is characterized by excessive urination and an inability to concentrate urine. Lithium is the most common cause of acquired NDI. Treatment typically involves thiazide diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs). However, the efficacy of desmopressin in NDI remains unclear. We herein report a case of lithium-induced NDI in a 71-year-old woman with lithium-induced NDI. Thiazide diuretics and NSAIDs reduced the urine output by approximately 40% compared to pretreatment, while the addition of desmopressin reduced it by approximately 70%. This case suggests that desmopressin can be a viable treatment option for lithium-induced NDI.

[Lithium-induced nephrogenic diabetes insipidus during acute intoxication: a case report]. / Diabète insipide néphrogénique induit par le lithium au cours d'une intoxication aiguë: à propos d'un cas.

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.

Bioinformatics-guided disproportionality analysis of sevoflurane-induced nephrogenic diabetes insipidus using the FDA Adverse Event Reporting System database.

AIMS: Sevoflurane is an ether-based inhalational anaesthetic that induces and maintains general anaesthesia. Our study aimed to detect sevoflurane-induced nephrogenic diabetes insipidus using data mining algorithms (DMAs) and molecular docking. The FAERS database was analysed using OpenVigil 2.1 for disproportionality analysis. METHODS: We analysed FAERS data from 2004 to 2022 to determine the incidence of nephrogenic diabetes insipidus associated with sevoflurane. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) with 95% confidence intervals were calculated. We also used molecular docking with AutoDock Vina to examine sevoflurane's binding affinity to relevant receptors. RESULTS: A total of 554 nephrogenic diabetes insipidus cases were reported in FAERS, of which 2.5% (14 cases) were associated with sevoflurane. Positive signals were observed for sevoflurane with ROR of 76.012 (95% CI: 44.67-129.35) and PRR of 75.72 (χ2 : 934.688). Of the 14 cases, 50% required hospitalization, 14% resulted in death, and the remaining cases were categorized as other outcomes. Molecular docking analysis showed that sevoflurane exhibited high binding affinity towards AQP2 (4NEF) and AVPR2 (6U1N) with docking scores of -4.9 and -5.3, respectively. CONCLUSIONS: Sevoflurane use is significantly associated with the incidence of nephrogenic diabetes insipidus. Healthcare professionals should be cautious when using this medication and report any adverse events to regulatory agencies. Further research is needed to validate these findings and identify risk factors while performing statistical adjustments to prevent false-positives. Clinical monitoring is crucial to validate potential adverse effects of sevoflurane.

Lithium-Induced Arginine Vasopressin Resistance (AVP-R): A Case of Chronic Exposure to Lithium.

Lithium salts (lithium) is a psychotropic drug widely used as a pharmacological option in managing bipolar disorder. Regular monitoring of serum levels is necessary due to the narrow therapeutic range of lithium. Typically, the diagnosis of lithium intoxication is based on the presence of elevated plasma levels. Nevertheless, poisoning can ensue from either acute ingestion or chronic use, even in patients with normal plasma levels. The utilization of lithium has been decreasing due to its potential for multiorgan toxicity. Lithium accumulation in renal distal tubular cells is a prevalent cause of acquired arginine vasopressin resistance (AVP-R), previously known as nephrogenic diabetes insipidus (DI). Some patients might also experience neurologic persistent symptoms after plasma level normalization, a condition known as the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). We present a case report of acquired AVP-R following prolonged lithium use. This case report aims to increase awareness, particularly among those who may be unfamiliar with the use of lithium and its associated adverse reactions. In addition, it seeks to highlight the dissociation between clinical manifestations and lithium plasma levels, emphasizing the need for careful evaluation in patients receiving lithium treatment.

A Case of Hypernatremia With Dementia.

The authors report a case of hypernatremia in a patient with a history of dementia. This case highlights the challenges and scope of taking care of such patients. It also highlights the hardships in diagnosing and caring for patients with inadequate documentation of past diagnoses and treatments.

V2 vasopressin receptor mutations: future personalized therapy based on individual molecular biology.

The diluting and concentrating function of the kidney plays a crucial role in regulating the water homeostasis of the body. This function is regulated by the antidiuretic hormone, arginine vasopressin through the type 2 vasopressin receptor (V2R), allowing the body to adapt to periods of water load or water restriction. Loss-of-function mutations of the V2R cause X-linked nephrogenic diabetes insipidus (XNDI), which is characterized by polyuria, polydipsia, and hyposthenuria. Gain-of-function mutations of the V2R lead to nephrogenic syndrome of inappropriate antidiuresis disease (NSIAD), which results in hyponatremia. Various mechanisms may be responsible for the impaired receptor functions, and this review provides an overview of recent findings about the potential therapeutic interventions in the light of the current experimental data.

Metabolic reprogramming of renal epithelial cells contributes to lithium-induced nephrogenic diabetes insipidus.

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.

Early onset of nephrogenic diabetes insipidus due to fabry disease in a child with GLA N215S mutation: Case report and literature review.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder. Renal involvement in FD is characterized by proteinuria and progressive renal decline. Reports on FD with nephrogenic diabetes insipidus as the initial manifestation are rare. In this paper, we report a pediatric case with an N215S variant. Results: A boy with an onset of polydipsia and polyuria at approximately 4 years of age was diagnosed with nephrogenic diabetes insipidus. Whole-exome sequencing showed a GLA N215S variation with no secondary cause of diabetes insipidus. No family history of polydipsia or polyuria was reported; however, the patient's maternal grandmother and her two younger brothers had hypertrophic cardiomyopathy. Both brothers required surgery due to severe cardiac involvement, and the youngest brother died of heart disease at the age of 50 years. The patient's polydipsia and polyuria worsened over the next 7 years. Serum sodium was normal, but the patient required high-dose potassium chloride to maintain normal serum potassium levels. His physical and intellectual development was normal, with no common complications of nephrogenic diabetes insipidus, such as anemia, malnutrition, vomiting, high fever, or convulsions. Dried blood spot testing showed α-galactosidase A (α-gal A) activity of 0.6 µmol/L/h and a Lyso-GL-3 level of 7.01 ng/ml. The patient developed mild proteinuria and mild myocardial hypertrophy. Renal biopsy showed myeloid bodies and zebra bodies. After more than 1 year of ERT, his urine specific gravity increased to 1.005-1.008, which was a new sign reflecting the efficacy of ERT, although urine output was maintained at 3-5 ml/kg/hour. We will continue to monitor the patient's renal tubular function and urine output. Conclusions: Nephrogenic diabetes insipidus may be the initial manifestation in children with FD and/or N215S variation. In FD, the same mutation in a family may present a completely different phenotype.

'Aquaporin-omics': mechanisms of aquaporin-2 loss in polyuric disorders.

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.

Autophagy and regulation of aquaporins in the kidneys.

Aquaporins (AQPs) are water channel proteins that facilitate the transport of water molecules across cell membranes. To date, seven AQPs have been found to be expressed in mammal kidneys. The cellular localization and regulation of the transport properties of AQPs in the kidney have been widely investigated. Autophagy is known as a highly conserved lysosomal pathway, which degrades cytoplasmic components. Through basal autophagy, kidney cells maintain their functions and structure. As a part of the adaptive responses of the kidney, autophagy may be altered in response to stress conditions. Recent studies revealed that autophagic degradation of AQP2 in the kidney collecting ducts leads to impaired urine concentration in animal models with polyuria. Therefore, the modulation of autophagy could be a therapeutic approach to treat water balance disorders. However, as autophagy is either protective or deleterious, it is crucial to establish an optimal condition and therapeutic window where autophagy induction or inhibition could yield beneficial effects. Further studies are needed to understand both the regulation of autophagy and the interaction between AQPs and autophagy in the kidneys in renal diseases, including nephrogenic diabetes insipidus.

Lithium poisoning and renal replacement therapy: pathophysiology and current clinical recommendations.

Lithium intoxication is still an undefined and underestimated disease, especially those cases requiring extracorporeal treatment. Lithium is a monovalent cation with small molecular mass of 7 Da that has been regularly and successfully used since 1950 in the treatment of mania and bipolar disorders. However, its careless assumption can lead to a wide spectrum of cardiovascular, central nervous system and kidney diseases in case of acute, acute on chronic and chronic intoxications. In fact, lithium serum range is strict between 0.6 and 1.3 mmol/L, with a mild lithium toxicity observed at the steady-state of 1.5-2.5 mEq/L, moderate toxicity when lithium reaches 2.5-3.5 mEq/L, and severe intoxication with observed serum levels > 3.5 mEq/L. Its favorable biochemical profile allows the complete filtration and partial reabsorption in the kidney due to the similarity to sodium and also the complete removal by renal replacement therapy, that should be considered in specific poisoning conditions. In this narrative and updated review we discussed a clinical case of lithium intoxication, the different pattern of diseases attributable to excessive lithium load and the current indications for extracorporeal treatment.