RARE DISEASE
Arginine vasopressin resistance
Arginine vasopressin resistance
Arginine vasopressin resistance
Synonyms: Nephrogenic diabetes insipidus
Synonyms: Nephrogenic diabetes insipidus
Synonyms: Nephrogenic diabetes insipidus
Drug discovery
2
drugs
With orphan designations
Overview
Arginine Vasopressin Resistance (AVP-R) is a renal disorder characterized by impaired kidney response to vasopressin (AVP), leading to excessive dilute urine output (polyuria) and compensatory thirst. Causes include genetic mutations (AVPR2 or AQP2), lithium toxicity, chronic kidney disease, and electrolyte imbalances. Diagnosis involves urine osmolality, serum electrolytes, and water deprivation testing. Management focuses on hydration, sodium restriction, thiazide diuretics, and NSAIDs to reduce urine volume [1][2][5][6].
Burden
Acute risks: Severe dehydration, hypernatremia, seizures, and coma if untreated [5][8][12].
Chronic complications: Developmental delays in children, renal damage, and reduced quality of life due to frequent urination [6][8][12].
Healthcare utilization: Requires lifelong monitoring, electrolyte management, and specialized care for hereditary cases [5][8][13].
Therapies
Hydration: Adequate free water intake to prevent dehydration [2][6][11].
Pharmacotherapy: Thiazide diuretics (hydrochlorothiazide) + NSAIDs to reduce urine output; low-salt/protein diets [2][6][13].
Underlying cause management: Discontinuing lithium (if applicable), correcting electrolyte imbalances [2][6][13].
Categories: rare genetic diseases, rare renal diseases
Research Papers
762 drug discovery papers about Arginine vasopressin resistance, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
762 drug discovery papers about Arginine vasopressin resistance, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-08-02 | Arginine vasopressin as the primary vasopressor in high-risk patients undergoing major non-cardiac surgery: A propensity-matched hemodynamic analysis.
Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.
2026-07-06 | Proteomic profile of urinary extracellular vesicles from rats with lithium-induced nephrogenic diabetes insipidus.
Lithium (Li) salts have been widely used to treat bipolar disorder and unipolar depression for more than 50 years. However, up to 40% of people taking Li develop Nephrogenic Diabetes Insipidus (NDI). NDI is associated with cellular remodeling in the rodent kidney collecting duct and reduced aquaporin-2. Patients taking Li for more than 10-20 years are at risk of chronic kidney disease, which ultimately can lead to end-stage renal disease, hemodialysis, transplantation, or death. The purpose of this study was to investigate whether the rat urinary proteome can be used as an indicator of Li-induced changes in kidney. Extracellular vesicles were isolated from the urine of rats treated with Li for 2 or 4 weeks followed by LC-MS/MS analysis. The results showed a limited correlation between protein changes in urine and kidney. However, the urine contained markers of mitochondrial dysfunction. The cytoskeletal protein, Keratin 8, showed a tendency to be higher in the urine and was greatly increased in collecting duct principal cells in response to Li, suggesting a potential role in cellular remodeling. Canonical Histone H4 was increased in the urine, and was observed in the nuclei of collecting duct principal and intercalated cells following Li. Moreover, Histone H4 positive cells co-localized with the proliferation marker, PCNA. This correlates with the known increased proliferation in the collecting duct in response to Li. Thus, replication-dependent Histone H4 is a possible urinary marker for the Li induced cellular remodeling of the collecting duct.
2026-06-25 | Infant Nephrogenic Diabetes Insipidus: Challenges Leading to Delayed Management.
Nephrogenic diabetes insipidus (NDI) is a rare, potentially life-threatening renal tubular disorder characterized by a decreased ability to concentrate urine due to antidiuretic hormone (ADH) resistance, leading to significant free water loss. The congenital form, most often caused by X-linked mutations in the AVPR2 gene, typically presents in early infancy. Due to its rarity and nonspecific clinical features in young children, such as failure to thrive, vomiting, and excessive fluid intake, diagnostic delays are common, especially in centers with limited prior experience in managing NDI. We report a case of a 17-month-old male infant presenting with severe hypernatremia, dehydration, vomiting, and failure to thrive. Initial clinical findings, a partial response to desmopressin, and absent neurohypophysis signaling on MRI suggested central diabetes insipidus (CDI), leading to a delay in the correct diagnosis. However, persistent polyuria, despite escalating desmopressin doses, prompted reconsideration. Genetic testing confirmed a pathogenic AVPR2 mutation (c.541C > T, p. Arg181Cys), establishing the diagnosis of congenital NDI. Therapeutic management included thiazide diuretics, NSAIDs, and dietary sodium restriction, resulting in slow and gradual clinical stabilization. This case highlights several diagnostic challenges, such as misinterpreting partial desmopressin response and MRI results. It emphasizes the importance of systematic diagnostic algorithms for infants with polyuria and early genetic testing when clinical presentations lack clarity. We aim to share our clinical experience and the pitfalls encountered while managing a patient with NDI and contribute to earlier and more effective recognition and treatment of this rare condition, preventing the development of life-threatening complications.
2026-06-05 | Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity.
Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This drug accumulates intracellularly via sodium transport pathways, and its effects on complex cellular signaling mechanisms, including glycogen synthase kinase-3 β inhibition, form the basis of its therapeutic efficacy and toxicity. Increased intracellular levels disrupt cellular processes and trigger injury via mitochondrial dysfunction and oxidative stress. Lithium has a narrow therapeutic index and causes dose-dependent nephrotoxicity. A tubulointerstitial pattern of kidney injury is typical; however, lithium can rarely cause glomerular injury as well. An acute rise in serum lithium levels can result in severe volume depletion from lithium-induced natriuresis and aquaresis and cause AKI. Changes in kidney function and various drug interactions can acutely affect serum lithium levels further increasing the risk of toxicity. Arginine vasopressin resistance is the most common complication of chronic lithium use and can be an early manifestation. CKD occurs after a longer latency of over 10 years with a variable slope of GFR decline. Progression to ESKD is relatively low but is affected by the presence of other nephrotoxic risk factors. Epithelial sodium channel blockers such as amiloride can be helpful in mitigating lithium nephrotoxicity by reducing cellular accumulation. Hypercalcemia secondary to lithium-induced hyperparathyroidism is associated with a higher risk of nephrolithiasis and CKD progression. Kidney microcystic changes are common in lithium-induced CKD, and distal renal tubular acidosis can also be seen. Using the lowest effective lithium dose, close monitoring of kidney function and serum lithium levels and early diagnosis of lithium nephrotoxicity is critical in preventing irreversible kidney injury. The decision to discontinue lithium is challenging, and the benefits versus risks must be carefully weighed. This comprehensive review provides a pathogenetic basis and practical clinical framework for diagnosis and management of lithium nephrotoxicity.
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-08-02 | Arginine vasopressin as the primary vasopressor in high-risk patients undergoing major non-cardiac surgery: A propensity-matched hemodynamic analysis.
Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.
2026-07-06 | Proteomic profile of urinary extracellular vesicles from rats with lithium-induced nephrogenic diabetes insipidus.
Lithium (Li) salts have been widely used to treat bipolar disorder and unipolar depression for more than 50 years. However, up to 40% of people taking Li develop Nephrogenic Diabetes Insipidus (NDI). NDI is associated with cellular remodeling in the rodent kidney collecting duct and reduced aquaporin-2. Patients taking Li for more than 10-20 years are at risk of chronic kidney disease, which ultimately can lead to end-stage renal disease, hemodialysis, transplantation, or death. The purpose of this study was to investigate whether the rat urinary proteome can be used as an indicator of Li-induced changes in kidney. Extracellular vesicles were isolated from the urine of rats treated with Li for 2 or 4 weeks followed by LC-MS/MS analysis. The results showed a limited correlation between protein changes in urine and kidney. However, the urine contained markers of mitochondrial dysfunction. The cytoskeletal protein, Keratin 8, showed a tendency to be higher in the urine and was greatly increased in collecting duct principal cells in response to Li, suggesting a potential role in cellular remodeling. Canonical Histone H4 was increased in the urine, and was observed in the nuclei of collecting duct principal and intercalated cells following Li. Moreover, Histone H4 positive cells co-localized with the proliferation marker, PCNA. This correlates with the known increased proliferation in the collecting duct in response to Li. Thus, replication-dependent Histone H4 is a possible urinary marker for the Li induced cellular remodeling of the collecting duct.
2026-06-25 | Infant Nephrogenic Diabetes Insipidus: Challenges Leading to Delayed Management.
Nephrogenic diabetes insipidus (NDI) is a rare, potentially life-threatening renal tubular disorder characterized by a decreased ability to concentrate urine due to antidiuretic hormone (ADH) resistance, leading to significant free water loss. The congenital form, most often caused by X-linked mutations in the AVPR2 gene, typically presents in early infancy. Due to its rarity and nonspecific clinical features in young children, such as failure to thrive, vomiting, and excessive fluid intake, diagnostic delays are common, especially in centers with limited prior experience in managing NDI. We report a case of a 17-month-old male infant presenting with severe hypernatremia, dehydration, vomiting, and failure to thrive. Initial clinical findings, a partial response to desmopressin, and absent neurohypophysis signaling on MRI suggested central diabetes insipidus (CDI), leading to a delay in the correct diagnosis. However, persistent polyuria, despite escalating desmopressin doses, prompted reconsideration. Genetic testing confirmed a pathogenic AVPR2 mutation (c.541C > T, p. Arg181Cys), establishing the diagnosis of congenital NDI. Therapeutic management included thiazide diuretics, NSAIDs, and dietary sodium restriction, resulting in slow and gradual clinical stabilization. This case highlights several diagnostic challenges, such as misinterpreting partial desmopressin response and MRI results. It emphasizes the importance of systematic diagnostic algorithms for infants with polyuria and early genetic testing when clinical presentations lack clarity. We aim to share our clinical experience and the pitfalls encountered while managing a patient with NDI and contribute to earlier and more effective recognition and treatment of this rare condition, preventing the development of life-threatening complications.
2026-06-05 | Diagnosis and Management of Acute and Chronic Lithium-Associated Nephrotoxicity.
Lithium remains a mainstay of therapy for bipolar disease and refractory depression with future potential for expanded use on the basis of novel data demonstrating its immunomodulatory and neuroprotective effects. This drug accumulates intracellularly via sodium transport pathways, and its effects on complex cellular signaling mechanisms, including glycogen synthase kinase-3 β inhibition, form the basis of its therapeutic efficacy and toxicity. Increased intracellular levels disrupt cellular processes and trigger injury via mitochondrial dysfunction and oxidative stress. Lithium has a narrow therapeutic index and causes dose-dependent nephrotoxicity. A tubulointerstitial pattern of kidney injury is typical; however, lithium can rarely cause glomerular injury as well. An acute rise in serum lithium levels can result in severe volume depletion from lithium-induced natriuresis and aquaresis and cause AKI. Changes in kidney function and various drug interactions can acutely affect serum lithium levels further increasing the risk of toxicity. Arginine vasopressin resistance is the most common complication of chronic lithium use and can be an early manifestation. CKD occurs after a longer latency of over 10 years with a variable slope of GFR decline. Progression to ESKD is relatively low but is affected by the presence of other nephrotoxic risk factors. Epithelial sodium channel blockers such as amiloride can be helpful in mitigating lithium nephrotoxicity by reducing cellular accumulation. Hypercalcemia secondary to lithium-induced hyperparathyroidism is associated with a higher risk of nephrolithiasis and CKD progression. Kidney microcystic changes are common in lithium-induced CKD, and distal renal tubular acidosis can also be seen. Using the lowest effective lithium dose, close monitoring of kidney function and serum lithium levels and early diagnosis of lithium nephrotoxicity is critical in preventing irreversible kidney injury. The decision to discontinue lithium is challenging, and the benefits versus risks must be carefully weighed. This comprehensive review provides a pathogenetic basis and practical clinical framework for diagnosis and management of lithium nephrotoxicity.
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Drug Discovery Landscape
2 orphan drug designations for Arginine vasopressin resistance.
2 orphan drug designations for Arginine vasopressin resistance.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
1-[12-(1 Carboxycyclopropyl) dodecyl] cyclopropane-1-carboxylic acid | small molecules | FDA | 2022-12-07 | — | NephroDI Therapeutics, Inc. |
1,1¿-(1, 12- Dodecanediyl)bis[cyclopropanecarboxamide] | small molecules | FDA | 2022-02-03 | — | NephroDI Therapeutics, Inc. |
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