Introduction
Polyuria, a condition characterized by the production of an abnormally high volume of urine (more than 3 liters per day in adults), is a critical symptom that may signal a variety of underlying disorders. These include DI, PP, and various renal pathologies. The causes of polyuria are diverse and multifactorial, involving a complex interplay of genetic, epigenetic, environmental, and behavioral factors. These factors collectively disrupt the body's ability to maintain proper water balance, resulting in excessive urine production. Polyuria can arise from one or more of the following: abnormal secretion or action of antidiuretic hormone (ADH), impaired renal water reabsorption, or excessive fluid intake. This introduction explores the intricate mechanisms underlying polyuria, with a focus on its genetic, epigenetic, and environmental etiologies, as well as current diagnostic and therapeutic approaches.
Among the most well-studied causes of polyuria is DI, a condition that occurs when the kidneys are unable to concentrate urine. DI is primarily divided into two major forms. Central Diabetes Insipidus (CDI), caused by a deficiency in the production or secretion of ADH (also known as vasopressin). Nephrogenic Diabetes Insipidus (NDI) – caused by the kidneys' inability to respond to ADH.
Genetic mutations play a pivotal role in both forms of DI. In central DI, mutations in the AVP gene, which encodes the precursor of ADH, are a major cause. These mutations lead to a gradual decline in ADH production, resulting in the hallmark symptoms of polyuria and polydipsia (excessive thirst) (Mortensen et al., 2020). On the other hand, NDI is often associated with mutations in the vasopressin 2 receptor (V2R) and aquaporin 2 (AQP2) genes. V2R mutations impair the kidneys’ ability to respond to ADH, while AQP2 mutations disrupt water reabsorption in the kidney's renal collecting ducts, further exacerbating water loss through urine [11, p. 746-753].
Diagnosing polyuria and identifying its underlying cause requires a comprehensive approach that integrates laboratory tests, imaging techniques, and clinical assessments. Given the complexity of the condition, accurate diagnosis is critical to ensure appropriate treatment. Copeptin, a peptide derived from the same precursor as ADH, has emerged as a valuable diagnostic marker. Unlike ADH, copeptin is stable and can be easily measured in serum. Copeptin levels, especially after stimulation (e.g., hypertonic saline infusion), are highly effective in differentiating between central DI and other causes of polyuria, offering a more accurate alternative to the traditional water deprivation test (WDT) [10, p. 141-157; 12, p. 565] (Newell-Price et al., 2024; Martino et al., 2023). The WDT, combined with desmopressin (DAVP) administration, is a classic diagnostic tool for evaluating the ADH-renal axis. However, its use is often limited due to its low diagnostic accuracy and the requirement for strict patient compliance [10, p. 141-157]. Measuring urine and blood osmolality allows clinicians to distinguish between solute diuresis and water diuresis. Blood osmolality and sodium levels are also assessed to evaluate water-electrolyte balance and differentiate between DI and PP [13, p. 301-308]. When central DI is suspected, magnetic resonance imaging (MRI) of the hypothalamic-pituitary region is often performed to detect structural abnormalities that could affect ADH production [17, p. 2382-2383]. In critically ill patients, computed tomography (CT) scans may be used to rule out intracranial pathologies that contribute to polyuria [17, p. 2382-2383]. A thorough clinical history, including medication use and pre-existing conditions, is essential for identifying potential causes of polyuria [14, p. 62-70]. A common diagnostic tool measures urine output over a full day and helps distinguish between different types of polyuria [6]. Evaluating the function of endocrine organs (e.g., the thyroid and adrenal glands) and conducting routine renal function tests are critical in diagnosing systemic causes of polyuria [14, p. 62-70]. Beyond genetic mutations, epigenetic mechanisms have emerged as significant contributors to the regulation of genes involved in fluid balance. Epigenetic modifications–such as DNA methylation, histone modifications, and microRNA (miRNA) regulation–can alter gene expression without changing the underlying DNA sequence. These epigenetic changes can influence physiological processes that regulate fluid homeostasis, thus contributing to polyuria and related conditions.
For example, DNA methylation influences the renin-angiotensin-aldosterone system (RAAS), a key regulator of blood pressure and fluid balance. Hypomethylation of specific CEBP-binding sites has been associated with increased angiotensinogen gene expression, which can promote fluid retention and contribute to polyuria [16, p. 8099]. Similarly, histone acetylation and methylation regulate chromatin structure and gene accessibility, playing crucial roles in the transcription of genes involved in renal function and water reabsorption [9]. miRNAs further modulate gene expression by interfering with mRNA stability and translation. Several miRNAs have been implicated in regulating the RAAS pathway, thereby influencing blood pressure and fluid balance [16, p. 8099]. While research on miRNAs in the context of polyuria is still in its infancy, these non-coding RNAs hold promise as both biomarkers and therapeutic targets for conditions involving disordered fluid homeostasis. Genetic and epigenetic factors are crucial in understanding polyuria's pathophysiology, environmental and behavioural influences also play a significant role. PP for example, is largely driven by excessive water intake, which overwhelms the kidneys' ability to excrete water efficiently. PP is often observed in individuals with PD such as schizophrenia, where patients may exhibit compulsive drinking behaviors that lead to hyponatremia [3, p. 719].
Medications, such as lithium, are another important environmental factor contributing to polyuria. Long-term lithium use, commonly prescribed for bipolar disorder, is associated with nephrogenic DI, underscoring the complex interaction between drug-induced environmental factors and genetic susceptibility [5, p. 250-254].
Broader Perspectives: Gene-Environment Interactions
The broader view of polyuria underscores the importance of understanding the gene-environment interaction. While environmental factors such as diet, medications, and fluid intake are well-known contributors to polyuria, their effects are often modulated by an individual's genetic background. For example, prolonged use of certain medications, such as lithium, can induce epigenetic changes that exacerbate polyuria [5, p. 250-254].
Moreover, stress and chronic disease states (e.g., heart failure, neurodegenerative disorders) can lead to epigenetic dysregulation, further complicating fluid balance and increasing the risk of polyuria [4]. This highlights the need for a comprehensive approach to polyuria, incorporating genetic, epigenetic, and environmental factors to provide more accurate diagnoses and tailored treatments.
In summary, polyuria is a multifactorial condition with a wide range of underlying causes, including genetic mutations, epigenetic modifications, and environmental influences. Understanding the complex interplay of these factors is essential for developing accurate diagnostic tools and effective treatment strategies. Advances in genetic testing, epigenetic therapies, and behavioral interventions offer new opportunities for managing polyuria in a more personalized and precise manner.
This article is a comprehensive review of the current literature on the genetic factors associated with polyuria. Relevant articles were identified through searches of PubMed, Embase, and Cochrane databases using keywords such as "diabetes insipidus," "primary polydipsia," "polyuria," "genetics," "mutations," and "prognosis." The selected articles were critically analyzed to synthesize the current understanding of the genetic and non-genetic contributors to polyuria, as well as the diagnostic approaches and prognostic factors.
The exploration of genetic factors contributing to polyuria has a long history, with early studies focusing on the physiological mechanisms that regulate water balance in the body. The term "polyuria" was first introduced in the 19th century to describe a condition characterized by excessive urine output. One of the earliest distinctions made was between diabetes mellitus (DM) and DI, two conditions that share common symptoms of increased urine production but have distinct pathophysiological mechanisms. While DM is associated with glucose metabolism, diabetes insipidus was later identified as a disorder of water regulation, related to a deficiency in ADH or the kidneys' inability to respond to ADH.
In the 20th century, significant progress was made in understanding the hormonal and genetic causes of polyuria. The discovery of ADH (also known as vasopressin) and its role in maintaining water homeostasis was a turning point. Researchers identified the vasopressin receptors and aquaporins in the kidneys, which play a fundamental role in water reabsorption. By the 1990s, key mutations in genes such as AVP (which encodes vasopressin) and AQP2 (which encodes aquaporins) were identified, marking a major advancement in genetic research related to polyuria.
Today, polyuria is understood as a symptom associated with a variety of conditions, including central and nephrogenic diabetes insipidus DI, PP, and other rare genetic syndromes. Modern theories propose three main components that contribute to polyuria:
- Impaired ADH secretion: Central diabetes insipidus is caused by a deficiency in vasopressin secretion from the hypothalamus, leading to an inability to retain water in the body.
- Impaired renal response to ADH: Nephrogenic diabetes insipidus is caused by the kidneys' inability to respond to circulating ADH, which is often due to mutations in the AVPR2 and AQP2 genes. These mutations affect vasopressin receptors and aquaporins, respectively, leading to excessive water loss through urine.
- PP: Unlike DI, PP is characterized by excessive intake of fluids, which overwhelms the kidneys' ability to excrete water efficiently. PP is often associated with psychiatric disorders, such as schizophrenia, and may have a genetic predisposition [7, p. 165].
Heeren et al. [8, p. 260] conducted studies on the neural correlates of social anxiety and exclusion, discovering that individuals with social anxiety demonstrate heightened sensitivity to social rejection. While this study focuses on social exclusion, its findings about stress-induced physiological responses may be relevant to conditions like primary polydipsia, where psychological factors influence water intake.
Strawn & Levine [15, p. 100024] explored biomarkers in anxiety disorders and their response to treatment. Their work has implications for understanding the physiological processes, including water balance, that are disrupted by anxiety and stress, factors often linked to polyuria in psychiatric contexts.
Bixo et al. [1] investigated the effects of neuroactive steroids on GABA-A receptors in women suffering from premenstrual dysphoric disorder (PMDD). Their research opened new avenues in understanding hormonal influences on fluid retention and possible polyuria during hormonal fluctuations.
Chen et al. [2, p. 571-582] studied the role of GABA-A receptor subtypes selective for anxiety, highlighting potential targets for treating polyuria in patients with underlying neurological or psychiatric disorders.
The understanding of polyuria has evolved significantly, especially concerning its genetic and neurobiological mechanisms. Conditions such as diabetes insipidus and primary polydipsia are now better understood through the lens of genetic mutations in key genes such as AVP, AVPR2, and AQP2, which regulate vasopressin signaling and water reabsorption. Recent advancements in genetic research have paved the way for improved diagnostic methods and treatment strategies for managing polyuria, particularly in cases linked to hereditary factors or psychiatric conditions.
Polyuria, characterized by excessive urine production, is a condition with various underlying causes, including DI and PP. A significant body of empirical research has been conducted to understand the genetic and physiological mechanisms that contribute to these conditions, with a focus on both hereditary and acquired factors.
One of the most intensely studied causes of polyuria is diabetes insipidus, which can be divided into two primary forms: CDI and NDI. Central DI is usually caused by a deficiency in ADH due to mutations in the AVP gene. This gene encodes the precursor of ADH, and mutations can lead to a gradual reduction in ADH production, resulting in polyuria and polydipsia [11, p. 746-753]. On the other hand, NDI is caused by mutations in the V2R gene or the AQP2 gene. V2R mutations impair the kidney’s response to ADH, while AQP2 mutations affect water reabsorption in the renal collecting ducts [11, p. 746-753]. These studies highlight the critical role of ADH signaling and water channel function in maintaining water homeostasis.
Another significant area of research has explored PP, a condition often associated with excessive water intake, commonly found in individuals with PD such as schizophrenia. While the pathophysiology of PP is less understood than DI, researchers suggest that PD may disrupt the normal regulation of thirst, leading to excessive fluid consumption. Some studies have proposed potential genetic predispositions for PP, though these remain less well-defined. Environmental and behavioral influences, such as compulsive water intake, are more commonly cited as primary factors [3, p. 719].
Recent studies have also explored the epigenetic regulation of genes involved in fluid balance. For example, DNA methylation and histone modifications have been found to influence the expression of genes in the RAAS, a key system in regulating blood pressure and fluid balance [16, p. 8099]. Epigenetic modifications such as these may also play a role in hereditary forms of polyuria, further complicating the genetic landscape of the disorder.
The empirical studies highlight the complexity of polyuria, especially when considering its genetic underpinnings. Mutations in the AVP, V2R, and AQP2 genes are well-established as primary causes of diabetes insipidus, significantly impairing the body's ability to concentrate urine. In patients with central DI, the lack of ADH production due to AVP mutations leads to an inability to retain water, resulting in excessive urine production. Similarly, in nephrogenic DI, the V2R and AQP2 mutations directly impair the kidney’s ability to respond to ADH, causing a failure in water reabsorption [11, p. 746-753].
In contrast, primary polydipsia appears to be driven more by behavioral and environmental factors, particularly in psychiatric populations. Although some studies suggest a genetic component, such as the Cx37 gene influencing water regulation, the evidence remains inconclusive. This highlights a significant gap in the literature, as most research has concentrated on DI rather than PP. Further studies are needed to fully understand the genetic and epigenetic contributions to PP, particularly in populations with psychiatric comorbidities.
Another key finding from recent research is the role of epigenetics in regulating genes involved in water balance. For instance, research has shown that DNA methylation at key promoter regions can influence the activity of genes related to fluid retention, such as those in the RAAS pathway [16, p. 8099]. These findings suggest that, aside from genetic mutations, epigenetic modifications could also contribute to the development of polyuria by altering the expression of genes involved in fluid homeostasis. This highlights the potential for future therapeutic approaches that target epigenetic mechanisms to manage polyuria.
The empirical evidence on polyuria, particularly DI and PP, underscores the multifactorial nature of the condition, with contributions from both genetic mutations and epigenetic modifications. Most studies have focused on the genetic mutations that lead to DI, particularly in the AVP, V2R, and AQP2 genes. These mutations impair the body’s ability to produce or respond to ADH, thereby disrupting water balance and causing polyuria.
The findings suggest that genetic testing could be highly beneficial for diagnosing hereditary forms of DI. By identifying mutations in the AVP, V2R, or AQP2 genes, clinicians could more accurately diagnose DI and tailor treatments to enhance water retention. For example, desmopressin (a synthetic ADH analogue) is commonly used to manage central DI, and understanding the genetic basis of the disorder could help optimize this treatment.
In the case of primary polydipsia, the research points to a more complex interplay between behavioral and environmental factors. While some genetic predispositions have been suggested, such as potential mutations in the Cx37 gene, the evidence is not as robust as that for DI. PP is more frequently seen in individuals with psychiatric conditions, such as schizophrenia, where compulsive water consumption plays a significant role. Here, the challenge lies in managing the behavioral aspects of the disorder, often requiring psychiatric interventions alongside fluid restriction.
The exploration of epigenetic modifications opens new avenues for understanding polyuria. The reversible nature of these modifications, such as DNA methylation and histone acetylation, offers potential therapeutic targets. For instance, histone deacetylase inhibitors (HDACi) have shown promise in modulating renal function and fluid balance [9]. However, the application of epigenetic therapies in clinical settings remains in its early stages, with challenges related to ensuring specificity and minimizing off-target effects.
One of the major gaps in the current literature is the lack of comprehensive studies on the gene-environment interactions that may contribute to polyuria. While mutations in key genes like AVP, V2R, and AQP2 are well understood, the role of environmental factors, such as medication use (e.g., lithium-induced NDI) and behavioral influences (e.g., excessive water intake in PP), requires further exploration. Understanding these interactions could lead to more personalized treatment approaches, particularly in cases where genetic predisposition and environmental triggers converge.
The genetic factors underlying polyuria, particularly in the context of DI and PP, are well-documented for conditions like central and nephrogenic diabetes insipidus. Mutations in the AVP, V2R, and AQP2 genes play a central role in the pathogenesis of DI, impairing the body's ability to regulate water balance. However, the genetic underpinnings of primary polydipsia remain less clear, with behavioral and environmental factors playing a more prominent role.
The findings also emphasize the importance of epigenetic mechanisms, such as DNA methylation and histone modifications, in regulating genes involved in fluid balance. These epigenetic factors offer potential therapeutic targets for managing polyuria, particularly in conditions where gene expression is dysregulated.
Future research should focus on exploring the gene-environment interactions that contribute to polyuria, as well as further investigating the epigenetic modifications that may influence the condition. By integrating genetic, epigenetic, and environmental insights, healthcare providers can develop more effective diagnostic and therapeutic strategies for managing polyuria and improving patient outcomes.
Research on polyuria, particularly focusing on DI and PP, has highlighted significant genetic, epigenetic, and environmental factors contributing to these conditions. Genetic mutations in key genes, such as AVP, V2R, and AQP2, are central to the pathophysiology of diabetes insipidus, impairing the body’s ability to produce or respond to ADH, leading to excessive urine output [11, p. 746-753]. In contrast, primary polydipsia is more behaviorally driven, often linked to PD like schizophrenia, and its genetic basis remains less well-defined [3, p. 719].
Recent studies have also underscored the role of epigenetic mechanisms, such as DNA methylation and histone modifications, in regulating fluid balance, suggesting that gene expression can be modulated without direct genetic mutations [16, p. 8099]. These findings open new avenues for understanding complex gene-environment interactions and the multifactorial nature of polyuria.
While significant progress has been made in understanding the genetic basis of diabetes insipidus, future research should address several important gaps. More research is needed to explore the potential genetic predispositions for PP, particularly in psychiatric populations. Investigating genes linked to thirst regulation and compulsive behaviors could provide deeper insights into the etiology of PP. Understanding how environmental factors, such as water intake behavior and medication use (e.g., lithium-induced nephrogenic DI), interact with genetic predispositions will be critical for developing personalized treatment approaches.
Further research should explore the therapeutic potential of targeting epigenetic modifications to manage polyuria. Preclinical studies on histone deacetylase inhibitors (HDACi) and other epigenetic agents offer promising, but still experimental, avenues for therapy [9].
Future studies should employ longitudinal designs and larger sample sizes to better understand the long-term outcomes of DI and PP, and how genetic and epigenetic factors evolve over time.
The findings from current research offer several practical applications, especially in the clinical management of polyuria. Routine genetic screening for AVP, V2R, and AQP2 mutations could significantly enhance the diagnostic accuracy for patients suspected of having diabetes insipidus. This would enable early intervention and personalized treatment, such as the use of desmopressin in patients with central DI [11, p. 746-753]. Given the behavioral etiology of primary polydipsia, integrating cognitive-behavioral therapy (CBT) and psychiatric care could help manage excessive water intake in patients with psychiatric disorders. Fluid intake monitoring and behavioral modifications may also help reduce the risk of complications like water intoxication. In cases where epigenetic dysregulation is contributing to polyuria, targeted epigenetic therapies may offer a novel treatment strategy. Although still in its early stages, future development of these therapies could provide a more nuanced approach to managing conditions like nephrogenic DI that are resistant to conventional treatments [16, p. 8099].
In conclusion, while much has been learned about the genetic and epigenetic underpinnings of polyuria, ongoing research is essential to fully unravel the complexities of conditions like DI and PP. By integrating genetic insights with behavioral and environmental factors, healthcare providers can offer more precise and effective treatments, improving patient outcomes in the management of polyuria.
