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
758 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:
758 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:
2026-07-08 | Clean intermittent catheterization reverses hydronephrosis in a child with congenital nephrogenic diabetes insipidus: a case report.
Congenital nephrogenic diabetes insipidus (CNDI) is most frequently caused by mutations in the AVPR2 gene. Patients exhibit persistent polyuria due to renal insensitivity to antidiuretic hormone. Chronic high urine output predisposes to bladder dysfunction and upper urinary-tract dilatation, notably hydronephrosis. Although pharmacotherapy can partially reduce urine volume, its capacity to reverse established hydronephrosis is limited. Clean intermittent catheterization (CIC), a mainstay in managing neurogenic bladder, warrants investigation regarding its utility in CNDI-associated hydronephrosis. A 9-year-old Chinese boy presented with lifelong polydipsia and polyuria, with a peak 24-h urine output of approximately 7100 mL. Renal ultrasonography demonstrated bilateral moderate hydronephrosis. Whole-exome sequencing identified a hemizygous nonsense mutation, AVPR2 c.968G>A (p.Trp323*); his mother was a heterozygous carrier of the same variant. After one month of standard therapy with hydrochlorothiazide and indomethacin, his daily urine volume decreased to approximately 3400 mL/d, but the hydronephrosis showed no improvement. A subsequent video urodynamic study revealed decreased bladder sensation, reduced compliance, and diminished detrusor contractility. In addition to the continued pharmacological regimen, clean intermittent catheterization (performed three times daily at home) was introduced. Follow-up ultrasonography one month later showed significant improvement in the bilateral hydronephrosis. For pediatric CNDI patients with persistent incomplete bladder emptying and hydronephrosis despite pharmacotherapy, short-term clean intermittent catheterization can break the vicious cycle of "chronic urinary retention-elevated bladder pressure-upper urinary tract dilatation," representing a safe, effective, and readily implementable adjuvant intervention.
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.
2026-06-05 | 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.
2026-07-08 | Clean intermittent catheterization reverses hydronephrosis in a child with congenital nephrogenic diabetes insipidus: a case report.
Congenital nephrogenic diabetes insipidus (CNDI) is most frequently caused by mutations in the AVPR2 gene. Patients exhibit persistent polyuria due to renal insensitivity to antidiuretic hormone. Chronic high urine output predisposes to bladder dysfunction and upper urinary-tract dilatation, notably hydronephrosis. Although pharmacotherapy can partially reduce urine volume, its capacity to reverse established hydronephrosis is limited. Clean intermittent catheterization (CIC), a mainstay in managing neurogenic bladder, warrants investigation regarding its utility in CNDI-associated hydronephrosis. A 9-year-old Chinese boy presented with lifelong polydipsia and polyuria, with a peak 24-h urine output of approximately 7100 mL. Renal ultrasonography demonstrated bilateral moderate hydronephrosis. Whole-exome sequencing identified a hemizygous nonsense mutation, AVPR2 c.968G>A (p.Trp323*); his mother was a heterozygous carrier of the same variant. After one month of standard therapy with hydrochlorothiazide and indomethacin, his daily urine volume decreased to approximately 3400 mL/d, but the hydronephrosis showed no improvement. A subsequent video urodynamic study revealed decreased bladder sensation, reduced compliance, and diminished detrusor contractility. In addition to the continued pharmacological regimen, clean intermittent catheterization (performed three times daily at home) was introduced. Follow-up ultrasonography one month later showed significant improvement in the bilateral hydronephrosis. For pediatric CNDI patients with persistent incomplete bladder emptying and hydronephrosis despite pharmacotherapy, short-term clean intermittent catheterization can break the vicious cycle of "chronic urinary retention-elevated bladder pressure-upper urinary tract dilatation," representing a safe, effective, and readily implementable adjuvant intervention.
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.
2026-06-05 | 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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