Search Results (28)

Lithium remains a cornerstone mood stabilizer for bipolar disorder, with strong evidence for relapse prevention and a unique association with reduced suicide risk. Its benefit is counterbalanced by renal adverse effects, ranging from impaired urinary concentrating capacity and nephrogenic diabetes insipidus (NDI) to chronic tubulointerstitial nephropathy with progressive loss of glomerular filtration rate in a minority of long-term users. Mechanistically, lithium enters collecting duct principal cells via the epithelial sodium channel, disrupts vasopressin-regulated water handling by downregulating aquaporin-2, and can drive chronic interstitial injury. Risk is amplified by episodes of lithium intoxication, dehydration, interacting medications that reduce renal lithium clearance, longer treatment duration, and comorbid kidney disease. This review integrates psychiatric and nephrologic perspectives on lithium’s indications, mechanisms, renal phenotypes, and prevention strategies, and proposes a practical shared-care pathway for patients with bipolar disorder who develop polyuria, NDI, acute kidney injury, or chronic kidney disease during lithium therapy, emphasizing monitoring, targeted treatment of polyuria, mitigation of toxicity, and structured shared decision-making when renal function declines. Full article

Background: Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal resistance to arginine vasopressin, most commonly caused by pathogenic variants in the AVPR2 gene. While X-linked NDI classically affects males, heterozygous females may exhibit variable clinical expression. Certain AVPR2 variants are associated with partial NDI and milder phenotypes. Methods: We conducted a retrospective family study of a multigenerational Greek pedigree with suspected hereditary NDI. Clinical, biochemical, and pedigree data were collected through chart review and family interviews. Genetic analysis was performed using whole-exome sequencing, and variant interpretation followed ACMG/AMP guidelines. Results: Fourteen individuals across four generations were evaluated. Molecular analysis identified a familial AVPR2 (NM_000054.7):c.964C>T (p.Pro322Ser) missense variant in three males and three females, with obligate carrier status inferred in two deceased females, segregating in an X-linked pattern. Hemizygous males exhibited a broad phenotypic spectrum, ranging from partial NDI with later onset to severe early-onset disease with urinary tract complications. Heterozygous females showed variable expression, from asymptomatic carriers to mildly symptomatic individuals. The variant co-segregated with disease and, based on ACMG criteria, it was classified as pathogenic. Conclusions: In our family, the AVPR2 c.964C>T (p.Pro322Ser) variant was associated with a remarkably broad clinical spectrum, ranging from asymptomatic heterozygous females to severe early-onset disease with urinary tract complications in affected males. These observations emphasize the need for early molecular diagnosis, systematic evaluation of female carriers, and long-term surveillance to prevent disease-related complications and optimize genetic counselling. Full article

Maintaining homeostasis in the body through water and sodium management is essential, and the central nervous system and kidneys play a key role in this process. However, knowledge of the diagnosis and treatment of these conditions in pediatric patients is still unsystematized. There are no up-to-date guidelines on managing children with sodium imbalance. Since sodium shifts are inextricably linked to water changes in the body, they should always be pondered together. Each of the sodium disorders should be considered in the context of changes in the vascular volume, whether it is hypo-, eu-, or hypervolemic. This review describes the most common sodium-water disorders encountered in pediatric clinics. It emphasizes conditions affecting the brain-kidney axis (syndrome of inappropriate antidiuresis, cerebral salt wasting syndrome, and central and nephrogenic diabetes insipidus). The article proposes diagnostic and therapeutic management based on scientific society publications, case series, and the authors’ clinical experience, and summarizes the available knowledge as of 2025 to improve the care of patients with hyponatremia or hypernatremia. A proper understanding of the physiology of sodium homeostasis is crucial for implementing appropriate treatment and reducing the risk of severe complications in young patients in the future. Full article

Nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by renal resistance to arginine vasopressin (AVP), resulting in the kidneys’ inability to concentrate urine. Approximately 90% of NDI cases follow an X-linked inheritance pattern and are associated with pathogenic variants in the AVPR2 gene, which encodes the vasopressin receptor type 2. The remaining 10% are attributed to mutations in the AQP2 gene, which encodes aquaporin-2, and may follow either autosomal dominant or recessive inheritance patterns. We present the case of a male infant, younger than nine months of age, who was clinically diagnosed with NDI at six months. The patient presented recurrent episodes of polydipsia, polyuria, dehydration, hypernatremia, and persistently low urine osmolality. Despite adjustments in pharmacologic treatment and strict monitoring of urinary output, the clinical response remained suboptimal. Given the lack of improvement and the radiological finding of an absent posterior pituitary (neurohypophysis), the possibility of coexistent central diabetes insipidus (CDI) was raised, prompting a therapeutic trial with desmopressin. Nevertheless, in the absence of clinical improvement, desmopressin was discontinued. The patient’s management was continued with hydrochlorothiazide, ibuprofen, and a high-calorie diet restricted in sodium and protein, resulting in progressive clinical stabilization. Whole-exome sequencing identified a novel homozygous missense variant in the AQP2 gene (c.398T > A; p.Val133Glu), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria: PM2 (absent from population databases), PP2 (missense variant in a gene with a low rate of benign missense variation), and PP3 (multiple lines of computational evidence supporting a deleterious effect)]. NDI is typically diagnosed during early infancy due to the early onset of symptoms and the potential for severe complications if left untreated. In this case, although initial clinical suspicion included concomitant CDI, the timely initiation of supportive management and the subsequent incorporation of molecular diagnostics facilitated a definitive diagnosis. The identification of a previously unreported homozygous variant in AQP2 contributed to diagnostic confirmation and therapeutic decision-making. The diagnosis and comprehensive management of NDI within the context of polyuria-polydipsia syndrome necessitates a multidisciplinary approach, integrating clinical evaluation with advanced molecular diagnostics. The novel AQP2 c.398T > A (p.Val133Glu) variant described herein was associated with early and severe clinical manifestations, underscoring the importance of genetic testing in atypical or treatment-refractory presentations of diabetes insipidus. Full article

Volatile anesthetics, while increasingly utilized in intensive care medicine, are associated with significant renal adverse effects. A critical safety concern—particularly with sevoflurane—involves its potential impact on renal function. Pathophysiologically, inorganic fluoride levels exceeding 50 µmol/L are recognized as a threshold for nephrogenic diabetes insipidus, a condition generally considered reversible. Additionally, the sevoflurane degradation product “compound A” has been implicated in direct renal tubular and glomerular toxicity. Specifically, exposure has been correlated with glomerular damage, evidenced by albuminuria, as well as injury to both proximal and distal tubules, indicated by elevated levels of α-glutathione-S-transferase. Postprandial glycosuria may also be observed. Unlike nephrogenic diabetes insipidus, the structural damage induced by compound A may result in irreversible renal impairment. Full article

Differentiating central diabetes insipidus (CDI), nephrogenic diabetes insipidus (NDI), and primary polydipsia (PP) in pediatric patients with polyuria–polydipsia syndrome (PPS) remains a clinical challenge. The water deprivation test (WDT) is the traditional gold standard; however, it is time-consuming, burdensome, and prone to equivocal results. Stimulated copeptin, a surrogate marker of vasopressin, has emerged as a promising diagnostic alternative. We conducted a prospective, observational, cross-sectional study involving 27 pediatric patients (ages 2–17) presenting with PPS. Each patient underwent a WDT with desmopressin and hypertonic saline infusion (3% NaCl) for stimulated copeptin testing. Diagnostic accuracy was assessed using clinical diagnoses as a reference. The WDT showed high accuracy with an area under the curve (AUC) of 0.97, and there was an increased optimal threshold of ≥14% urine osmolality after desmopressin acetate (1-deamino-8-D-arginine vasopressin, DDAVP) administration (sensitivity 88.9%, specificity 100%). Stimulated copeptin at a threshold of <6.5 pmol/L demonstrated 100% sensitivity and specificity (AUC = 1.00) for CDI versus PP. Basal copeptin ≥21.4 pmol/L accurately identified all NDI cases. The agreement between the WDT and copeptin was low (κ = 0.06, McNemar p = 0.021), suggesting that copeptin has greater specificity, particularly for borderline or partial CDI. These results support the use of stimulated copeptin as a first-line diagnostic tool in pediatric PPS, offering improved objectivity, tolerability, and diagnostic clarity compared with the WDT. Basal copeptin also demonstrated excellent performance in rapid noninvasive NDI identification. Full article

Background: Nephrogenic diabetes insipidus (NDI) is defined as the inability of the kidney to concentrate urine owing to the insensitivity of the distal nephron to the antidiuretic hormone, arginine vasopressin. NDI is a heterogeneous rare autosomal dominant or X-linked disease. Objective: We present a family with nephrogenic diabetes affecting three males in two generations. Methods: We report two boys with NDI: a 4-month-old infant who was treated for fever, vomiting, and failure to thrive, and his 10-year-old uncle (the mother’s brother), who was admitted concurrently for consuming 11 L of fluid per day. According to family history, the mother’s sibling passed away at the age of two from severe hypernatremic dehydration. Results: The infant’s clinical and laboratory evaluation revealed a 7.8 mL/kg/h urine output, hypernatremic hyperchloremic alkalosis, extremely low urine density (1002), and elevated copeptin level. In contrast, the uncle’s clinical and laboratory evaluation revealed marked polyuria, low urine density, and elevated copeptin, all of which were suggestive of diabetes insipidus. After starting hydrochlorothiazide treatment (2 mg/kg/body), the infant’s urine production reduced (2.85 mL/kg/h); however, severe hypokalemia and alkalosis followed. Spironolactone, an aldosterone antagonist, were added, with good therapeutic response. Hydrochlorothiazide was administered to the uncle, and his daily fluid intake decreased to 3–4 L. Given the family history, Sanger sequencing for the AVPR2 variant was performed on the boys and the infant’s mother. Analysis showed hemizygous likely pathogenic variant c.335G>A p. (Cys112Tyr) in the 2 boys and heterozygous (carrier) status of the mother. Within the same family, we observed phenotypic heterogeneity: one child died at the age of two, another lived well into ten years without therapy, and a four month-old baby could have had a poor outcome without specific treatment. Conclusions: NDI is a rare and possibly fatal genetic disorder with heterogeneous manifestations. In families with a history of NDI, molecular genetic testing is crucial for family planning. Full article

Pediatric patients with polyuria polydipsia syndrome (PPS) represent a diagnostic challenge for clinicians because of the technical difficulties in performing the gold standard water deprivation test (WDT). Copeptin, a stable biomarker representing the C-terminal portion of the polypeptide chain of the antidiuretic hormone, is a reliable diagnostic tool. To assess the diagnostic accuracy of baseline copeptin dosing, arginine/hypertonic saline copeptin stimulation tests, and WDT. This study aimed to establish the diagnostic utility of copeptin in pediatric patients by distinguishing between central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia. Comparative and non-comparative primary studies published between January 2018 and August 2024 focusing on children were searched and included in PubMed, Cochrane Library, Web of Science, ScienceDirect, Scopus, and Google Scholar. The QUADAS-2 tool was used to assess the risk of bias and applicability. Meta-analyses used fixed effects models because of low heterogeneity and the HSROC model. Eleven studies were included with an overall low bias and no significant applicability concerns. The mean pooled sensitivity = 0.98 (95% CI: 0.936–1.025), pooled specificity = 0.947 (95% CI: 0.920–0.973), and AUC = 0.972 (95% CI: 0.952–0.992), indicating excellent diagnostic accuracy. Stimulation methods for copeptin dosing represent an effective and less invasive diagnostic test for children with PPS, and future development of standard copeptin testing protocols is needed. Full article

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world’s population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD. Full article

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia. Full article

Sex hormones play an important role in the regulation of water homeostasis, and we have previously shown that tamoxifen (TAM), a selective estrogen receptor modulator (SERM), affects the regulation of aquaporin (AQP)-2. In this study, we investigated the effect of TAM on the expression and localization of AQP3 in collecting ducts using various animal, tissue, and cell models. The impact of TAM on AQP3 regulation was studied in rats subjected to 7 days of unilateral ureteral obstruction (UUO), with the rats fed a lithium-containing diet to induce nephrogenic diabetes insipidus (NDI), as well as in human precision-cut kidney slices (PCKS). Moreover, intracellular trafficking of AQP3 after TAM treatment was investigated in Madin-Darby Canine Kidney (MDCK) cells stably expressing AQP3. In all models, the expression of AQP3 was evaluated by Western blotting, immunohistochemistry and qPCR. TAM administration attenuated UUO-induced downregulation of AQP3 and affected the localization of AQP3 in both the UUO model and the lithium-induced NDI model. In parallel, TAM also affected the expression profile of other basolateral proteins, including AQP4 and Na/K-ATPase. In addition, TGF-β and TGF-β+TAM treatment affected the localization of AQP3 in stably transfected MDCK cells, and TAM partly attenuated the reduced AQP3 expression in TGF-β exposed human tissue slices. These findings suggest that TAM attenuates the downregulation of AQP3 in a UUO model and a lithium-induced NDI model and affects the intracellular localization in the collecting ducts. Full article

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. Full article

Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research. Full article

Knowledge of the impact of in utero exposure to lithium during the postnatal period is limited. Besides a possible teratogenic effect during the first trimester, exposure during the second and third trimesters might lead to neonatal effects. Uniform guidelines for postnatal management of these neonates are lacking. The aim was to retrospectively describe all neonates admitted to the University Hospitals Leuven after in utero exposure to lithium (January 2010 to April 2020), and to propose a postnatal care protocol. Descriptive statistics were performed. For continuous parameters with serial measurements, median population values were calculated. In total, 10 mother-neonate pairs were included. The median gestational age was 37 (interquartile range, IQR, 36–39) weeks. Neonatal plasma lithium concentration at birth was 0.65 (IQR 0.56–0.83) mmol/L with a median neonate/mother ratio of 1.02 (IQR 0.87–1.08). Three neonates needed respiratory support, 7/10 started full enteral (formula) feeding on day 1. The median length of neonatal stay was 8.5 (IQR 8–12) days. One neonate developed nephrogenic diabetes insipidus. This study reported in detail the postnatal characteristics and short-term neonatal outcomes. A postnatal care protocol was proposed, to enhance the quality of care for future neonates, and to guide parental counselling. Future prospective protocol evaluation is needed. Full article

Aquaporins (AQPs) are transmembrane channels essential for water, energy, and redox homeostasis, with proven involvement in a variety of pathophysiological conditions such as edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions. The 13 AQPs present in humans are widely distributed in all body districts, drawing cell lineage-specific expression patterns closely related to cell native functions. Compelling evidence indicates that AQPs are proteins with great potential as biomarkers and targets for therapeutic intervention. Aquaporin-9 (AQP9) is the most expressed in the liver, with implications in general metabolic and redox balance due to its aquaglyceroporin and peroxiporin activities, facilitating glycerol and hydrogen peroxide (H₂O₂) diffusion across membranes. AQP9 is also expressed in other tissues, and their altered expression is described in several human diseases, such as liver injury, inflammation, cancer, infertility, and immune disorders. The present review compiles the current knowledge of AQP9 implication in diseases and highlights its potential as a new biomarker for diagnosis and prognosis in clinical medicine. Full article