Vasopressin V2 Receptor Antagonist Tolvaptan Research Articles

#1636 Treatment of Tolvaptan related polyuria with bendroflumethiazide for ADPKD: Does it really work?

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease worldwide and accounts for 10% of patients on renal replacement therapy. Currently, the arginine vasopressin (AVP) V2 receptor antagonist Tolvaptan is the only available treatment for ADPKD which slows cyst formation and thus the progression of kidney disease by inducing AVP resistance. However, its aquaretic side effects can be debilitating and is the most common reason for medication discontinuation. Thiazides such as bendroflumethiazide are natriuresis-promoting diuretics through their action on the sodium-chloride channel in the distal convoluted tubule that are widely used to treat polyuria in inherited AVP deficiency or resistance. However, there is limited information about their effect in patients treated with Tolvaptan. The aim of this observational study is to review the impact on patients’ quality of life by using a low dose bendroflumethiazide with Tolvaptan in patients with ADPKD who are suffering from Tolvaptan induced aquaretic side effects. Method Details of all patients with ADPKD who are on Tolvaptan with or without bendroflumethiazide who are currently attending the polycystic kidney disease (PKD) clinic at Royal Free London NHS Foundation Trust were obtained, and their medications reviewed. Patients who have previously been or were currently on bendroflumethiazide to enable them to continue Tolvaptan therapy were identified. Information about the impact of bendroflumethiazide on their quality of life and their aquaretic side effects were obtained via phone call. If they discontinued bendroflumethiazide, the reason for this was explored. In addition, eGFR, sodium, potassium, and calcium at the time of bendroflumethiazide initiation as well as at three, six, nine and twelve months post bendroflumethiazide initiation were obtained. Results Out of 136 patients receiving Tolvaptan for treatment of ADPKD at our centre, eight (5.8%) were prescribed bendroflumethiazide for treatment of their aquaretic side effects from Tolvaptan. Two of these eight patients (25%) stopped bendroflumethiazide due to adverse reactions. The remaining six patients (75%) remained on the medication, and all reported significant subjective improvement in their symptoms of polyuria, nocturia and in their overall quality of life. Two of the six patients (33.3%) that remained on bendroflumethiazide had also subsequently increased their Tolvaptan dose. No electrolyte disturbances were noted after initiation of bendroflumethiazide. Conclusion Using bendroflumethiazide appears to improve the quality of life through reduction of polyuria and nocturia in patients suffering from Tolvaptan-induced aquaretic side effects with some patients subsequently able to increase their Tolvaptan dose by taking bendroflumethiazide which might result in augmented therapeutic benefit of Tolvaptan. Further placebo-controlled randomised studies with longitudinal will be needed to determine the true benefit-disbenefit balance of thiazide therapy in patients taking tolvaptan, especially to determine whether there is a negative effect on efficacy of tolvaptan on the underlying ADPKD. However, based on our small observational study, the number of patients needed to determine whether bendroflumethiazide improves the tolerability and medication adherence in patients who are debilitated by the aquaretic side effects of Tolvaptan would be small.

Antiproliferative role of the vasopressin V2 receptor antagonist tolvaptan in a murine xenograft model of small cell lung cancer

Antiproliferative role of the vasopressin V2 receptor antagonist tolvaptan in a murine xenograft model of small cell lung cancer

Additional renoprotective effect of the SGLT2 inhibitor dapagliflozin in a patient with ADPKD receiving tolvaptan treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney disease (ESKD). Vasopressin plays a pivotal role in ADPKD progression; therefore, the selective vasopressin V2 receptor antagonist tolvaptan is used as a key drug in the management of ADPKD. On the other hand, sodium-glucose cotransporter-2 inhibitors (SGLT2i), which may possibly stimulate vasopressin secretion due to the diuretic effect of the drug, have been shown to have both renal and cardioprotective effects in various populations, including those with non-diabetic chronic kidney disease. However, the effect of SGLT2i in patients with ADPKD have not been fully elucidated. Herein, we report the case of a patient with ADPKD on tolvaptan who was administered the SGLT2i dapagliflozin. The patient was a Japanese woman diagnosed with ADPKD at age 30. Despite the treatment with tolvaptan, eGFR was gradually declined from 79.8 to 50ml/min/1.73m2 in almost 5years and 10mg of dapagliflozin was initiated in the hope of renoprotective effects. Although a small increase in vasopressin levels was observed, eGFR decline rate was moderated after dapagliflozin initiation. This case suggested an additional renoprotective effect of dapagliflozin in patient with ADPKD receiving tolvaptan. Although there is no evidence about the renal protective effect of SGLT2i in patients with ADPKD, we hereby report a case successfully treated with dapagliflozin for approximately 2 years. Further research, including clinical trials, is needed to evaluate whether SGLT2i are effective in patients with ADPKD.

Research progress of arginine vasopressin V2 receptor antagonist tolvaptan in the treatment of cirrhotic ascites

Research progress of arginine vasopressin V2 receptor antagonist tolvaptan in the treatment of cirrhotic ascites

Effect of vasopressin V2-receptor antagonist tolvaptan on syndrome of inappropriate antidiuresis (SIAD) after transsphenoidal pituitary surgery: recovery of measured osmolality

BackgroundDelayed hyponatremia after pituitary surgery can be treated with the V2-receptor antagonist, oral tolvaptan. We investigated the pharmacological effect of oral tolvaptan against SIAD in patients with hyponatremia after pituitary surgery. MethodsThirty-nine patients with pituitary adenoma treated by endoscopic transsphenoidal surgery developed SIAD according to the major guidelines, and 7 patients (17.9%) were treated with tolvaptan. Tolvaptan was administrated orally half a tablet (3.75 mg) once in the first two cases, and half a tablet twice in the other five cases. Serum osmolality, urinary osmolality, urinary sodium concentration, urinary volume, and serum sodium and potassium concentration were evaluated before administration, and after the last oral administration of tolvaptan. Serum osmolality and urine osmolality were physically measured. ResultsSerum sodium concentration was significantly increased from 132.1 ± 4.0 to 143.0 ± 2.9 mmol/L (mean ± standard deviation, n = 7, P < 0.001). Serum osmolality was significantly increased from 266.3 ± 7.7 to 289.6 ± 6.7 mOsm/kg (n = 7, P < 0.001). Urine osmolality was significantly reduced from 607.1 ± 240.4 to 262.7 ± 115.6 mOsm/kg (n = 7, P = 0.01). Urinary sodium concentration was significantly decreased from 121.3 ± 48.4 to 36.9 ± 35.0 mOsm/kg (n = 7, P = 0.001). Urine output (24-hour including the first administration) was significantly increased from 1384.2 ± 550.7 to 3291.3 ± 1710.9 mL/day (n = 6, P = 0.026). ConclusionsOral tolvaptan administration corrects SIAD after pituitary surgery. Hyponatremia after pituitary surgery was confirmed to be due to SIAD.

Pathophysiology of Drug-Induced Hyponatremia

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.

Outcomes from the Northeast England cohort of autosomal dominant polycystic kidney disease (ADPKD) patients on tolvaptan.

Autosomal dominant polycystic kidney disease (ADPKD) is a cause of end-stage kidney disease (ESKD). The vasopressin V2-receptor antagonist tolvaptan has been shown within randomized clinical trials to slow down decline of kidney function in patients with ADPKD at risk of rapid progression. We performed a retrospective review of a Northeast England cohort of adult ADPKD patients who had been established on tolvaptan therapy to determine its efficacy in a real-world clinic setting. Other inclusion criteria involved a pre-treatment decline in greater than 2.5 ml/min/1.73m2/year based on readings for a 3 year period, and ability to tolerate and maintain tolvaptan treatment for at least 12 months. We calculated based on eGFR slopes, predicted time to reach ESKD with and without tolvaptan therapy. The cohort of patients included 21 from the Northeast of England. The mean rate of eGFR decline prior to treatment was -6.02 ml/min/1.73m2/year for the cohort. Following tolvaptan treatment, the average decline in eGFR was reduced to -2.47 ml/min/1.73m2/year, gaining a mean 8 years and 4 months delay to reach ESKD. The majority of patients (n=19) received and tolerated full dose tolvaptan (90 mg/30 mg). The real-life use of tolvaptan gave a dramatic improvement in eGFR slopes, much more than previously reported in clinical studies. These effects may be in part due to careful patient identification, selection and inclusion of patients who were able to tolerate tolvaptan therapy, excellent compliance with medication and a "tolvaptan clinic" effect where great personal care was given to these patients.

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

The Role of Vasopressin V2 Receptor in Drug-Induced Hyponatremia.

Hyponatremia is frequently encountered in clinical practice and usually induced by renal water retention. Many medications are considered to be among the various causes of hyponatremia, because they either stimulate the release of arginine vasopressin (AVP) or potentiate its action in the kidney. Antidepressants, anticonvulsants, antipsychotics, diuretics, and cytotoxic agents are the major causes of drug-induced hyponatremia. However, studies addressing the potential of these drugs to increase AVP release from the posterior pituitary gland or enhance urine concentration through intrarenal mechanisms are lacking. We previously showed that in the absence of AVP, sertraline, carbamazepine, haloperidol, and cyclophosphamide each increased vasopressin V2 receptor (V2R) mRNA and aquaporin-2 (AQP2) protein and mRNA expression in primary cultured inner medullary collecting duct cells. The upregulation of AQP2 was blocked by the V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors. These findings led us to conclude that the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the main mechanism of drug-induced hyponatremia. Previous studies have also shown that the V2R has a role in chlorpropamide-induced hyponatremia. Several other agents, including metformin and statins, have been found to induce antidiuresis and AQP2 upregulation through various V2R-independent pathways in animal experiments but are not associated with hyponatremia despite being frequently used clinically. In brief, drug-induced hyponatremia can be largely explained by AQP2 upregulation from V2R-cAMP-PKA signaling in the absence of AVP stimulation. This paper reviews the central and nephrogenic mechanisms of drug-induced hyponatremia and discusses the importance of the canonical pathway of AQP2 upregulation in drug-induced NSIAD.

Raynaud's phenomenon triggered by the vasopressin V2 receptor antagonist tolvaptan in a patient with autosomal dominant polycystic kidney disease and Sjögren's syndrome.

Raynaud's phenomenon triggered by the vasopressin V2 receptor antagonist tolvaptan in a patient with autosomal dominant polycystic kidney disease and Sjögren's syndrome.

An update on the use of tolvaptan for autosomal dominant polycystic kidney disease: consensus statement on behalf of the ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and Polycystic Kidney Disease International.

ABSTRACTApproval of the vasopressin V2 receptor antagonist tolvaptan—based on the landmark TEMPO 3:4 trial—marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use.

Рекомендації щодо застосування толваптану при аутосомно-домінантному полікістозі нирок: затвердження позицій від імені Робочої групи зі спадкових захворювань нирок ERA-EDTA і European Renal Best Practice

Нещодавно Європейське агентство лікарських засобів схвалило використання толваптану — антагоніста рецепторів вазопресину V2 для сповільнення прогресування розвитку кіст і ниркової недостатності при аутосомно-домінантному полікістозі нирок (АДПН) у дорослих пацієнтів із хронічною хворобою нирок 1–3-ї стадії на початку терапії за наявності доказів швидкого прогресування захворювання. У цьому документі від імені Робочої групи зі спадкових захворювань нирок ERA-EDTA і European Renal Best Practice ми прагнемо забезпечити керівництво для прийняття рішення про те, яких пацієнтів з АДПН слід лікувати толваптаном.Наявні затверджені позиції включають ряд рекомендацій, у результаті чого з’являється ієрархічний алгоритм рішення, що включає послідовність оцінки факторів ризику в порядку зниження за ознакою надійності. Переглянувши в першу чергу найбільш вірогідні маркери, ми прагнемо виявити пацієнтів з АДПН, у яких документально підтверджено швидке прогресування захворювання, або тих, що мають такий ризик. Ми вважаємо, що ця процедура пропонує кращі можливості для відбору пацієнтів, які перш за все матимуть перевагу від використання толваптану, таким чином покращуючи співвідношення користі до ризику і економічної ефективності цього лікування. Важливо підкреслити, що рішення щодо початку лікування вимагає розгляду багатьох факторів, окрім прийнятності, таких як: протипоказання, можливі ускладнення, а також мотивація пацієнта й фактори способу життя. Тому необхідне спільне прийняття рішення разом з пацієнтом.

The effect of trichlormethiazide in autosomal dominant polycystic kidney disease patients receiving tolvaptan: a randomized crossover controlled trial

The vasopressin V2 receptor antagonist tolvaptan delays the progression of autosomal dominant polycystic kidney disease (ADPKD). However, some patients discontinue tolvaptan because of severe adverse aquaretic events. This open-label, randomized, controlled, counterbalanced, crossover trial investigated the effects of trichlormethiazide, a thiazide diuretic, in patients with ADPKD receiving tolvaptan (n = 10) who randomly received antihypertensive therapy with or without trichlormethiazide for 12 weeks. The primary and secondary outcomes included amount and osmolarity of 24-h urine and health-related quality-of-life (HRQOL) parameters assessed by the Kidney Disease Quality of Life-Short Form questionnaire, renal function slope, and plasma/urinary biomarkers associated with disease progression. There was a significant reduction in urine volume (3348 ± 584 vs. 4255 ± 739 mL; P < 0.001) and a significant increase in urinary osmolarity (182.5 ± 38.1 vs. 141.5 ± 38.1 mOsm; P = 0.001) in patients treated with trichlormethiazide. Moreover, trichlormethiazide improved the following HRQOL subscales: effects of kidney disease, sleep, emotional role functioning, social functioning, and role/social component summary. No significant differences were noted in renal function slope or plasma/urinary biomarkers between patients treated with and without trichlormethiazide. In patients with ADPKD treated with tolvaptan, trichlormethiazide may improve tolvaptan tolerability and HRQOL parameters.

Effect of oral tolvaptan for 1 year in patients with functional mitral regurgitation.

The effect of the oral selective vasopressin V2-receptor antagonist tolvaptan for chronic phase therapy on patients with FMR remains unclear. We aimed to determine the efficacy of oral tolvaptan in patients with significant functional mitral regurgitation (FMR) to reduce the mortality and rehospitalization due to worsening heart failure (HF). We enrolled 219 patients (mean age 76 ± 9years, 59.4% men) who were admitted at our hospital due to congestive HF during different two 1-year periods. The patients were divided into 2 groups: those who had significant FMR (MR ≥ grade 2 [n = 76]) and those who did not (MR < grade 2 [n = 143]) at discharge. The patients were further divided into a study group that received tolvaptan during follow-up and a control group that did not receive tolvaptan. We used an inverse probability of treatment weighting method with the primary end point defined as overall all-cause mortality and rehospitalization due to worsening HF within 1year. Of the 76 patients with significant FMR at discharge, 2 of 20 (10%) who were administered tolvaptan died and 8 (40%) were readmitted to a hospital. Of the 56 patients who did not receive tolvaptan, 2 (3.5%) died and 18 (27.5%) required rehospitalization. After multiple adjustments, there were no significant differences for overall survival and rehospitalization between the groups (log-rank p = 0.700 and 0.510, respectively). Our results suggest that oral tolvaptan administration in addition to conventional diuretics had less impact on outcomes in patients with significant FMR.

Tolvaptan or transplant: why wait?

The vasopressin V2-receptor antagonist tolvaptan has been approved in multiple countries to slow kidney function decline in patients at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The efficacy, side effects, and risks associated with tolvaptan are described in detail in the accompanying article.2 A question that has arisen in our clinical practice is whether the potential benefit of tolvaptan in delaying the progression of ADPKD outweighs the daily impact of increased aquaresis and the risk of hepatotoxicity.

Differences in pharmacological property between combined therapy of the vasopressin V2-receptor antagonist tolvaptan plus furosemide and monotherapy of furosemide in patients with hospitalized heart failure

BackgroundTolvaptan has been shown to improve congestion in heart failure patients. The purpose of this study was to evaluate the pharmacology and clinical efficacy of combined tolvaptan and furosemide therapy. MethodsThis study included 40 patients with systemic volume overload who were hospitalized for heart failure. Patients who showed no improvement in the condition after receiving 20 mg intravenous furosemide were included and were randomly selected to receive tolvaptan as an add-on to furosemide or to receive an increased dose of furosemide. We evaluated the bioelectrical impedance analyzer parameters, the parameters of the inferior vena cava using echocardiography, vital signs, body weight, urine output, and laboratory data for 5 days. ResultsIn the changes from baseline between intracellular water volume (ICW) and extracellular water volume (ECW) after additional use of tolvaptan or furosemide from Day 1 to Day 5, there were no significant differences observed between ICW and ECW over 5 days in the tolvaptan + furosemide group, although differences were found in the furosemide group from Day 2 onward. Changes in the respiratory collapse of inferior vena cava increased significantly, and systolic blood pressure decreased significantly only in the furosemide group. ConclusionsThe present study clearly demonstrates that combined therapy with tolvaptan and furosemide removed excess ICW and ECW to an equal extent, while furosemide alone primarily removed ECW, including intravascular water.

Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation

ObjectiveTo perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. Materials and MethodsWe enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. ResultsTwo females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively went from baseline of −312, −82, −353, and −628 mg/L to 97, 111, 75, and −3 mg/L on high dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9, and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued treatment or reduced dose. ConclusionDilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.

SO001BOTH HYDROCHLOROTHIAZIDE AND METFORMIN AMELIORATE AQUARETIC SIDE-EFFECTS IN ADPKD PATIENTS THAT ARE TREATED WITH TOLVAPTAN

Abstract Background and Aims The vasopressin V2 receptor antagonist tolvaptan is the first drug that was proven to ameliorate kidney function decline in ADPKD. Blockade of the vasopressin V2 receptor, however, also results in nephrogenic diabetes insipidus (NDI), with an associated polyuria of on average 6 to 8 L/24h, limiting its clinical use. Hydrochlorothiazide (HCT) is an established treatment in NDI of other origins, but is unclear whether it is also efficacious in tolvaptan-caused NDI. Importantly, the combination of HCT and tolvaptan could cause electrolyte disturbances, and HCT treatment could theoretically increase vasopressin, which might accelerate ADPKD disease progression. Recently, metformin has been shown to ameliorate aquaresis in an animal model of NDI, but has never been investigated for this indication in humans. We aimed to investigate efficacy and safety of hydrochlorothiazide and metformin treatment to ameliorate the aquaretic side-effects of tolvaptan. Method This is an investigator driven, double-blind, randomized, controlled cross-over trial. ADPKD patients (Ravine criteria) were eligible for inclusion if they were 18-55 years of age, had an eGFR ≥ 30 mL/min/1.73m2 and were treated with a stable dose of tolvaptan. Patients were treated for three 2 week-periods with hydrochlorothiazide (HCT) 25 mg (12.5 mg in the first week), metformin 2000 mg (1000 mg in the first week) or placebo (half dose in the first week), in random order. Primary outcome was change in 24-hour urine volume (average of 2 collections) compared to baseline. Key secondary outcomes were measured GFR (mGFR), plasma copeptin (the stable precursor of vasopressin), quality of life and electrolytes. Results All 13 patients that were included were able to complete every treatment period in the trial. Their mean age was 45±8 years, 54% was female and mGFR was 55±11 mL/min/1.73m2 (Table). 85% of participants used the maximum tolvaptan dose (90/30 mg). At baseline urine volume was 6.9±1.4 L/24h. On HCT treatment urine volume decreased with -25±13% (p&amp;lt;0.001) and on metformin with -22±10% (p&amp;lt;0.001). Metformin treatment induced no change in mGFR and copeptin compared to baseline. During HCT treatment however, both mGFR and copeptin were lower (p=0.002 and p=0.001, respectively). There were no adverse events that required dose reductions. Quality of life was found to be equal on metformin and borderline better (p=0.06) on HCT treatment when compared to tolvaptan only. Plasma sodium was similar during all three treatment periods. Plasma potassium was significantly lower during HCT treatment (p=0.01), but in only three cases mild hypokalemia was noted (plasma potassium 3.0-3.5 mmol/L). Conclusion This is the first study to show that metformin can ameliorate aquaresis in NDI, and that HCT improves tolvaptan-caused NDI. Both treatments were well tolerated and safe during short-term use. The fact that copeptin is not increased by metformin, and even decreased by HCT suggests that these treatments will not negatively impact renoprotection by tolvaptan. These data provide an evidence base to test metformin and especially HCT in a real life setting to improve aquaresis and tolerability in patients with tolvaptan induced NDI. BaselineHCTPlaceboMetforminAbsolute urine volume (L/24h)6.95.1**6.35.4**Change in urine volume (%)0-25**-8-22**Creatinine excretion (mmol/24h)15.815.416.115.7Osmolar excretion (mOsm/24h)104410201013947*mGFR (mL/min/1.73m2)5551**5554SBP (mmHg)125117**122120Plasma copeptin (pmol/L)2520**2628Plasma sodium (mmol/L)141139141140Plasma potassium (mmol/L)3.83.6*3.94.0Plasma urea (mmol/L)7.08.6**6.97.2QoL ImprovedN/A7 (58%)2 (17%)1 (8%)Results in n=13 ADPKD patients on highest tolerated tolvaptan dose*P&amp;lt;0.05 compared to placebo ** p&amp;lt;0.01 compared to placeboFigure:

The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease

BackgroundSodium–glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic action. We recently reported that the SGLT2 inhibitor dapagliflozin ameliorates extracellular volume expansion with a mild increase in urine volume. However, the impact of the pretreatment extracellular volume status on the body fluid response to SGLT2 inhibitors remains unclear.MethodsThirty-six diabetic kidney disease (DKD) patients were treated with dapagliflozin. The body fluid volume, including intracellular water (ICW), extracellular water (ECW) and total body water (TBW), were measured on baseline and day 7 using a bioimpedance analysis (BIA) device. The ECW/TBW and ECW were used as markers of the extracellular volume status. For a comparison, the extracellular volume status responses to loop diuretic furosemide (n = 16) and vasopressin V2 receptor antagonist tolvaptan (n = 13) were analyzed.ResultsThe body weight, brain natriuretic peptide and body fluid parameters measured by a BIA (ICW, ECW, TBW, and ECW/TBW) were significantly decreased for 1 week after dapagliflozin administration. The change in the ECW/TBW in the high-ECW/TBW group (over the median value of 0.413) was significantly higher than in the low-ECW/TBW group (− 2.1 ± 0.4 vs. − 0.5 ± 0.4%, p = 0.006). Only with dapagliflozin treatment (not furosemide or tolvaptan treatment) was the baseline ECW/TBW significantly correlated with the changes in the ECW/TBW (r = − 0.590, p < 0.001) and ECW (r = − 0.374, p = 0.025).ConclusionsThe pretreatment extracellular volume status predicts the body fluid response to the SGLT2 inhibitor dapagliflozin in DKD patients. The diminished extracellular fluid reduction effect of dapagliflozin in patients without severe extracellular fluid retention may contribute to maintaining a suitable body fluid status.

Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling

PurposeAutosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V2 receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury.MethodsIn prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathematical model of drug-induced liver injury. In the current study, we evaluated lixivaptan, another proposed ADPKD treatment and vasopressin V2 receptor antagonist, using DILIsym®. Simulations were conducted that assessed the potential for lixivaptan and its three main metabolites to cause hepatotoxicity due to three injury mechanisms: bile acid accumulation, mitochondrial dysfunction, and oxidative stress generation. Results of these simulations were compared to previously published DILIsym results for tolvaptan.ResultsNo ALT elevations were predicted to occur at the proposed clinical dose for lixivaptan, in contrast to previously published simulation results for tolvaptan. As such, lixivaptan was predicted to have a markedly lower risk of hepatotoxicity compared to tolvaptan with respect to the hepatotoxicity mechanisms represented in DILIsym.ConclusionsThese results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity.