Impact of Tolvaptan Combined with Low-Dose Dopamine in Heart Failure Patients with Acute Kidney Injury.

The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kg・minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.

Case report: Secondary failure to tolvaptan in a patient with SCLC and paraneoplastic SIADH.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequent in lung cancer patients. Here, we report a case with persistent hyponatremia, which suggested malignant SIADH and facilitated an early diagnosis of small cell lung cancer (SCLC). A combined radio-chemotherapy led to a partial remission and resolution of SIADH. An early relapse was indicated by reoccurring severe hyponatremia and increased copeptin levels, which were used as surrogate markers for the antidiuretic hormone (ADH). As palliative immunochemotherapy, together with fluid restriction and solute substitution, were unable to control hyponatremia, treatment with the ADH V2-receptor antagonist tolvaptan was initiated. Over time, the dose of tolvaptan needed to be increased, paralleled by a well-documented exponential increase of copeptin levels. In summary and conclusion, this is a rare case of a secondary failure to tolvaptan with unique documentary evidence of increasing copeptin levels. This observation supports the hypothesis that exceedingly high ADH levels may lead to competitive displacement of tolvaptan from the V2 receptor.

Clinical efficacy of tolvaptan in acute decompensated heart failure patients with severe aortic stenosis and atrial fibrillation: a sub-analysis from the LOHAS registry.

BACKGROUND: Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined. METHODS: Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4 days, comparing patients with AF (AF group) versus those with SR (SR group). RESULTS: There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9 years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm2, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7 mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2 kg [p < 0.01] and from 53.5 to 51.0 kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2 days of treatment with tolvaptan. CONCLUSIONS: Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.

Juxtaglomerular apparatus-mediated homeostatic mechanisms: therapeutic implication for chronic kidney disease.

INTRODUCTION: Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD). AREA COVERED: JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs. EXPERT OPINION: When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.

Long-Residence Time Peptide Antagonist for the Vasopressin V2 Receptor to Treat Autosomal Dominant Polycystic Kidney Disease.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.

A population pharmacokinetics model of balovaptan to support dose selection in adult and pediatric populations.

Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.

HYDROchlorothiazide versus placebo to PROTECT polycystic kidney disease patients and improve their quality of life: study protocol and rationale for the HYDRO-PROTECT randomized controlled trial.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) leads to progressive renal cyst formation and loss of kidney function in most patients. Vasopressin 2 receptor antagonists (V2RA) like tolvaptan are currently the only available renoprotective agents for rapidly progressive ADPKD. However, aquaretic side effects substantially limit their tolerability and therapeutic potential. In a preliminary clinical study, the addition of hydrochlorothiazide (HCT) to tolvaptan decreased 24-h urinary volume and appeared to increase renoprotective efficacy. The HYDRO-PROTECT study will investigate the long-term effect of co-treatment with HCT on tolvaptan efficacy (rate of kidney function decline) and tolerability (aquaresis and quality of life) in patients with ADPKD. METHODS: The HYDRO-PROTECT study is an investigator-initiated, multicenter, double-blind, placebo-controlled, randomized clinical trial. The study is powered to enroll 300 rapidly progressive patients with ADPKD aged ≥ 18 years, with an eGFR of > 25 mL/min/1.73 m2, and on stable treatment with the highest tolerated dose of tolvaptan in routine clinical care. Patients will be randomly assigned (1:1) to daily oral HCT 25 mg or matching placebo treatment for 156 weeks, in addition to standard care. OUTCOMES: The primary study outcome is the rate of kidney function decline (expressed as eGFR slope, in mL/min/1.73 m2 per year) in HCT versus placebo-treated patients, calculated by linear mixed model analysis using all available creatinine values from week 12 until the end of treatment. Secondary outcomes include changes in quality-of-life questionnaire scores (TIPS, ADPKD-UIS, EQ-5D-5L, SF-12) and changes in 24-h urine volume. CONCLUSION: The HYDRO-PROTECT study will demonstrate whether co-treatment with HCT can improve the renoprotective efficacy and tolerability of tolvaptan in patients with ADPKD.

Tolvaptan for Treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in a Child with Corpus Callosum Agenesis.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the common causes of euvolemic hyponatremia (serum Na+ < 135 mEq/L) in hospitalized children. It is characterized by increased serum ADH, leading to water retention via its action on V2 receptors in the distal renal tubules. Various conditions such as pain, the postoperative state, drugs, central nervous system infections, tumors, malformations, and pneumonia can predispose a person to SIADH. The conventional treatment of SIADH includes fluid restriction and salt supplementation. Occasionally, this may fail to control hyponatremia, mandating pharmacological therapy. V2-receptor antagonists are an FDA-approved therapy for adults with euvolemic and hypervolemic hyponatremia. However, there is limited experience with their use in the pediatric population. Here, the authors present a girl with corpus callosum agenesis with severe symptomatic hyponatremia due to SIADH who was successfully managed with the V2-receptor antagonist tolvaptan.

Real-life use of tolvaptan in ADPKD: a retrospective analysis of a large Canadian cohort.

Tolvaptan is the first disease-modifying drug proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers from the patient perspective to its use in real-life settings have not been systemically examined in a large cohort. This was a single-center, retrospective study of 523 existing or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario, between January 1, 2016 to December 31, 2018. All patients underwent clinical assessment including total kidney volume measurements and Mayo Clinic Imaging Class (MCIC). Those who were deemed to be at high risk were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Overall, 315/523 (60%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at their last follow-up. Among these high-risk patients, those not treated versus treated with tolvaptan were more likely to have a higher eGFR (82 ± 26 vs. 61 ± 27 ml/min/1.73 m2), CKD stages 1-2 (79% vs. 41%), and MCIC 1C (63% vs. 31%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥ 60 (12%), and pregnancy/family planning (6%). In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had early stages of CKD with well-preserved eGFR and as such, were prime targets for tolvaptan therapy to slow disease progression. Given that the most common reason for tolvaptan refusal was the concern for intolerability of the aquaretic side-effect, strategies to mitigate this may help to reduce this barrier to tolvaptan therapy.

Effects of recombinant human brain natriuretic peptide combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure.

This study examined the effects of recombinant human brain natriuretic peptide (rhBNP) combined with tolvaptan on cardiac and renal function and serum inflammatory factors in patients with severe heart failure (HF). This retrospective study included 90 patients with severe HF who were treated at our hospital between January 2019 and August 2021. Patients treated with tolvaptan tablets were assigned to the control group, and those treated with rhBNP combined with tolvaptan were assigned to the observation group. Efficacy, cardiac function, levels of inflammatory factors, renal function, 6 minutes walking test, Minnesota Living with Heart Failure Questionnaire score, and adverse reactions were assessed. The curative effect (97.78% vs 77.78%) and improvement in cardiac function were greater in the observation group than in the control group (P < .05). Decreased levels of inflammatory factors were seen in both groups after treatment, and the levels of tumor necrosis factor-α, interleukin-33, and intercellular adhesion factor-1 in the observation group were lower than those in the control group (P < .05). The 6 minutes walking test was higher and the Minnesota Living with Heart Failure Questionnaire score was lower in the observation group compared with the control group (P < .05). The incidence of adverse reactions such as dry mouth, nausea, polyuria, hypotension, and headache in the observation group was lower than that in the control group (P < .05). In conclusion, for patients with severe HF, rhBNP combined with tolvaptan can improve cardiac function, alleviate symptoms of dyspnea, protect renal function, and reduce serum inflammatory factor levels when compared with tolvaptan alone.

Desmopressin enhances random-pattern skin flap survival in rats: Possible role of vasopressin Type-1a and 2 receptors.

BACKGROUND: Many drugs have been explored for their role in improving skin flap survival. 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin) is a synthesized form of anti-diuretic hormone (ADH) and a selective agonist for vasopressin type-2 receptors (V2 receptors). Desmopressin has been shown to improve endothelial function, induce vasodilation, and reduce inflammation. We aimed to evaluate its efficacy in enhancing flap survival and assess the role of vasopressin receptors in this process. MATERIALS AND METHODS: We randomly assigned six male Wistar rats to each study group. Different doses of desmopressin were injected intraperitoneally to find the most effective amount (8 µg/rat). SR-49059, a selective V1a receptor antagonist, was given at 2µg/rat before providing the most effective dose of desmopressin (8µg/rat). Histopathological assessments, quantitative measurements of interleukin-1ß (IL-1ß), Tumor necrosis factor-alpha (TNF-α), and Nuclear Factor-κB (NF-κB), optical imaging, and measurement of the expression levels of V2 receptor in the rat skin tissue were performed. RESULTS: Desmopressin (8µg/rat) significantly reduced the mean percentage of necrotic area compared to the control group (19.35% vs 73.57%). Histopathological evaluations revealed a notable reduction in tissue inflammation, edema, and degeneration following administration of desmopressin (8). The expression of the V2 receptor was increased following desmopressin administration. It also led to a reduction in IL-1ß, TNF-α, and NF-κB levels. The protective effect of desmopressin on flap survival was reversed upon giving SR-49059. The optical imaging revealed enhanced blood flow in the desmopressin group compared to the control group. CONCLUSIONS: Desmopressin could be repurposed to improve flap survival. V1a and V2 receptors probably mediate this effect.

LRBA signalosomes activate vasopressin-induced AQP2 trafficking at recycling endosomes.

Aquaporin-2 (AQP2) water channels are proteins that are recycled between intracellular vesicles and the apical plasma membrane in renal collecting ducts. Lipopolysaccharide-responsive beige-like anchor protein (LRBA) is a protein kinase A (PKA) anchoring protein that creates compartmentalized PKA signalling responsible for AQP2 phosphorylation. In response to increased plasma osmolality, vasopressin/cyclic adenosine monophosphate (cAMP)/PKA signalling phosphorylates AQP2, promoting AQP2 trafficking into the apical plasma membrane and increasing water reabsorption from urine. However, the molecular mechanisms by which LRBA mediates vasopressin-induced AQP2 phosphorylation remain unknown. To investigate AQP2 intracellular localization and phosphorylation status in vivo, a density gradient ultracentrifugation technique was combined with an in situ proximity ligation assay, super-resolution structured illumination microscopy and immunoelectron microscopy. Most of the AQP2 was localized on the recycling endosome in the presence of tolvaptan, a vasopressin type 2 receptor (V2R) antagonist. Desmopressin, a V2R agonist, phosphorylated AQP2, translocating it from the recycling endosome to the apical plasma membrane. In contrast, LRBA was constitutively localized at the recycling endosome. Therefore, LRBA and AQP2 were well colocalized in the absence of vasopressin stimulation. The loss of LRBA/PKA signalling by Lrba knockout impaired vasopressin-induced AQP2 phosphorylation, resulting in AQP2 retention at the recycling endosome. Defective AQP2 trafficking caused low urinary concentrating ability in Lrba-/- mice. The LRBA-PKA complex created compartmentalized PKA signalling at the recycling endosome, which facilitated AQP2 phosphorylation in response to vasopressin. KEY POINTS: Membrane proteins are continuously internalized into the endosomal system via endocytosis, after which they are either recycled back to the plasma membrane or degraded at the lysosome. In T cells, lipopolysaccharide-responsive beige-like anchor protein (LRBA) binds directly to the cytotoxic T lymphocyte antigen 4 (CTLA-4), a checkpoint immune molecule, to prevent CTLA-4 lysosomal degradation and promote its vesicle recycling. LRBA has different physiological functions in renal collecting ducts. LRBA and aquaporin-2 (AQP2) water channels were colocalized on the recycling endosome in vivo in the absence of the anti-diuretic hormone vasopressin. LRBA promoted vasopressin-induced AQP2 trafficking, increasing water reabsorption from urine via AQP2. LRBA determined renal responsiveness to vasopressin at recycling endosomes. LRBA is a ubiquitously expressed anchor protein. LRBA signalosomes might regulate membrane trafficking of several constitutively recycled proteins at recycling endosomes.

Effects of door-to-tolvaptan time on short-term clinical outcome in patients with acute heart failure.

AIMS: We investigated the effects of door-to-tolvaptan (D2T) time on short-term urine volume and in-hospital clinical outcomes in patients with acute heart failure (AHF). METHODS AND RESULTS: Patients with AHF, treated with tolvaptan at two hospitals, were enrolled in this retrospective observational study. The D2T time was defined as the time elapsed from the arrival of a patient at a participating hospital to the first administration of tolvaptan. The group with the D2T time within 6 h was defined as the 'early group'. The primary outcome was 48-h urine volume. The secondary outcomes were in-hospital death, length of hospital stay, and worsening renal function (WRF) incidence. A restricted cubic spline model was used to evaluate the presence of a nonlinear association between the D2T time and 48-h urine volume and the odds ratio of WRF incidence. Our study included a total of 138 patients with AHF who were started on tolvaptan after hospitalization. The median D2T time was 5.3 h (interquartile range: 3.0-31.9 h). Seventy-four patients (53.6%) were classified to be in the early group. Baseline characteristics were similar in the two groups: mean age (85.4 ± 9.6 years vs. 84.5 ± 9.5 years; P = 0.59) and male sex (n = 22 [33.3%] vs. n = 29 [46%]; P = 0.16), except that patients in the early group had higher systolic blood pressure than those in the delayed group (138.2 ± 22.9 vs. 125.7 ± 21.7; P = 0.001). The initial tolvaptan dose in the delayed group was much lower than that in the early group (7.5 [7.5, 7.5] vs. 7.5 [5.6, 7.5] mg; P = 0.01). Total urine volume in 48 h did not differ in the early and delayed groups (4113 ± 1758 mL vs. 4201 ± 1893 mL; P = 0.80). The relationship between D2T time and total urine volume within 48 h increased slightly, with a peak at a D2T time of 15 h, and gradually decreased, thereafter. In-hospital death and the length of hospital stay did not differ significantly between the two groups (n = 1, 1.3% vs. n = 4, 6.3%; P = 0.18, and 5.0 [12.0, 30.0] vs. 22.0 [14.5, 30.0] days; P = 0.17, respectively). Notably, the restricted cubic spline model for the odds ratio of WRF incidence increased as the D2T time was delayed (P for effect<0.01). CONCLUSIONS: The shorter D2T time did not affect the short-term urine volume and in-hospital outcomes but reduced the risk of WRF incidence in patients with AHF.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

PURPOSE: Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. METHODS: The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). RESULTS: Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. CONCLUSIONS: Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Long-term low-dose tolvaptan efficacy and safety in SIADH.

PURPOSE: Tolvaptan, a selective vasopressin V2-receptor antagonist, is approved for the treatment of SIADH-related hyponatremia, but its use is limited. The starting dose is usually 15 mg/day, but recent clinical experience suggests a lower starting dose (<15 mg/day) to reduce the risk of sodium overcorrection. However, long-term low-dose efficacy and safety has not been explored, so far. Aim of our study is to characterize safety and efficacy of long-term SIADH treatment with low-dose Tolvaptan. METHODS: We retrospectively evaluated 11 patients receiving low-dose Tolvaptan (<15 mg/day) for chronic SIADH due to neurological, idiopathic and neoplastic causes. Plasma sodium levels were measured before and 1, 3, 5, 15 and 30 days after starting Tolvaptan and then at 3-month intervals. Anamnestic and clinical data were collected. RESULTS: Mean time spanned 27.3 ± 29.8 months (range 6 months-7 years). Mean plasma sodium levels were within normal range 1, 3 and 6 months after starting Tolvaptan as well as after 1, 2, 3, 5 and 7 years of therapy. Neither osmotic demyelination syndrome nor overcorrection were observed. Plasma sodium levels normalization was associated with beneficial clinical effects. Neurological patients obtained seizures disappearance, improvement in neurological picture and good recovery from rehabilitation. Neoplastic patients were able to start chemotherapy and improved their general condition. Patients did not show hypernatremia during long-term follow-up and reported mild thirst and pollakiuria. CONCLUSIONS: The present study shows that long-term low-dose Tolvaptan is safe and effective in SIADH treatment. No cases of overcorrection were documented and mild side effects were reported.

Syndrome of inappropriate secretion of anti-diuretic hormone due to hypothalamic hamartoma: use of tolvaptan.

OBJECTIVES: Hypothalamic hamartoma (HH) typically presents with gonadotrophin-dependent precocious puberty and/or seizures. Other endocrine disturbances are rare. We describe an infant with syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) and a HH. CASE PRESENTATION: A 6-week-old infant presented with seizures and life-threatening hyponatremia. A HH was identified on magnetic resonance imaging. Clinical examination and biochemistry were consistent with SIADH, and serum copeptin was high during hyponatremia, further supporting this diagnosis. Tolvaptan was effective in normalizing plasma sodium and enabling liberalization of fluids to ensure sufficient nutritional intake and weight gain and manage hunger. CONCLUSIONS: Hyponatremia due to SIADH is novel at presentation of a HH, and can be challenging to diagnose and manage. Successful management of hyponatremia in this case was achieved using tolvaptan.

Thirst intensity survey in ADPKD patients.

INTRODUCTION: With increased fluid intake and tolvaptan treatment, the growth rate of cysts can be theoretically decelerated in autosomal polycystic kidney disease. In this prospective study, it was planned to evaluate thirst sensation in these patients and the parameters affecting its intensity. METHODS: Forty-one ADPKD patients on tolvaptan and 40 ADPKD patients not on tolvaptan as the control group were evaluated for thirst distress sensation and intensity. The feeling of thirst and the discomfort caused by excessive fluid intake was assessed with Thirst Distress Scale-HF 12 questions (60/12). Thirst intensity was evaluated with a 100 mm visual scale. RESULTS: Of the whole group, 35.8% (29) were males, and 64.2% (52) were females. The mean age of the tolvaptan group was 39.17 ± 9.35 years and for the control group, it was 41.95 ± 12.29 years. There was a negative correlation between the thirst distress score of the patients and an increase in creatinine level after a year of tolvaptan treatment (r = - 0.335, p = 0.035). The patients not taking thiazide had higher thirst intensity scores (p = 0.004). There was no impact of tolvaptan dosage, total kidney volume, serum sodium, urinary osmolarity or eGFR on thirst distress and thirst intensity scores. DISCUSSION/CONCLUSION: Only thiazide co-treatment had a positive impact on thirst distress and intensity when given tolvaptan. Thirst Distress Scale for ADPKD patients can be used to classify patients before and during tolvaptan treatment.

Pharmacologic Management of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder and the fourth leading cause of end-stage kidney disease. ADPKD encompasses a wide range of morbidity in addition to chronic kidney disease and end-stage kidney disease, and its pathogenesis remains incompletely understood. Progress in the management of this condition includes the 2018 FDA approval of tolvaptan as the only mechanism-specific treatment available for individuals at risk of rapid progression. Assessing the risk of rapid progression is discussed at greater length in a separate article in this special issue. This section will address use and prescription of tolvaptan in more detail and address other therapies that may be considered in the treatment of patients with ADPKD.

Autosomal Dominant Polycystic Kidney Disease Therapies on the Horizon.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.

Drug repurposing in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease is characterized by progressive kidney cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor antagonist, is the only drug approved to treat patients with autosomal dominant polycystic kidney disease who have rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of autosomal dominant polycystic kidney disease is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition because of its cost-efficiency and time-efficiency and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat autosomal dominant polycystic kidney disease and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.