Review

Authors: Fouad T Chebib, Ronald D Perrone, Arlene B Chapman...

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

Topics: Algorithms; Antidiuretic Hormone Receptor Antagonists; Clinical Protocols; Dehydration; Disease Progression; Diuresis; Female; Glomerular Filtration Rate; Humans; Liver; Magnetic Resonance Imaging; Male; Patient Selection; Polycystic Kidney, Autosomal Dominant; Time Factors; Tolvaptan; Treatment Outcome

PubMed: 30228150
DOI: 10.1681/ASN.2018060590

Authors: Paul Grant, John Ayuk, Pierre-Marc Bouloux...

BACKGROUND

Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists.

DESIGN

A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review.

RESULTS

We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety.

CONCLUSION

The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care.

Topics: Algorithms; Anti-Bacterial Agents; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Demeclocycline; Fluid Therapy; Hospitalization; Humans; Hyponatremia; Inappropriate ADH Syndrome; Practice Guidelines as Topic; Tolvaptan; Water-Electrolyte Imbalance

PubMed: 25995119
DOI: 10.1111/eci.12465

Review

Authors: Sara S Jdiaa, Reem A Mustafa, Alan S L Yu...

Autosomal-dominant polycystic kidney disease (ADPKD) is a chronic systemic disease that affects all races and ethnicities. It is the fourth leading cause of end-stage kidney disease, and it has a heterogenous phenotype ranging from mild to severe disease. Identifying patients with ADPKD who are at risk of rapid progression can guide therapeutic decisions. Several tools to predict disease severity are available, based on features such as total kidney volume assessed with magnetic resonance imaging, PKD genotype, estimated glomerular filtration rate (eGFR) trajectory, and the occurrence of hypertension and urologic complications early in life. During the past decade, more evidence has emerged regarding optimal ADPKD management. The HALT PKD (Halt Progression of Polycystic Kidney Disease) trial supported intensive blood pressure control in patients younger than 50 years of age with preserved kidney function. A healthy lifestyle, including maintaining a healthy weight, salt restriction, and smoking cessation, is likely to be beneficial. Tolvaptan, the only disease-modifying agent for patients with ADPKD at risk of rapid progression, is gaining wider use, but is still limited by its side effects. This is an exciting time for the ADPKD community because multiple promising interventions are in the pipeline and being investigated.

Topics: Humans; Polycystic Kidney, Autosomal Dominant; Disease Progression; Tolvaptan; Antidiuretic Hormone Receptor Antagonists

PubMed: 39424253
DOI: 10.1053/j.ajkd.2024.08.008

Randomized Controlled Trial

Authors: Vicente E Torres, Arlene B Chapman, Olivier Devuyst...

BACKGROUND

In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.

METHODS

We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly.

RESULTS

The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected.

CONCLUSIONS

Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Bilirubin; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Tolvaptan; Young Adult

PubMed: 29105594
DOI: 10.1056/NEJMoa1710030

Randomized Controlled Trial

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.

Authors: Roman-Ulrich Müller, A Lianne Messchendorp, Henrik Birn...

Approval 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.

Topics: Antidiuretic Hormone Receptor Antagonists; Female; Humans; Kidney; Male; Patient Selection; Polycystic Kidney, Autosomal Dominant; Tolvaptan

PubMed: 35134221
DOI: 10.1093/ndt/gfab312

Authors: Joseph G Verbalis, Stephen R Goldsmith, Arthur Greenberg...

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.

Topics: Antidiuretic Hormone Receptor Antagonists; Humans; Hyponatremia; Vasopressins

PubMed: 17981159
DOI: 10.1016/j.amjmed.2007.09.001

Randomized Controlled Trial

Authors: Djalila Mekahli, Lisa M Guay-Woodford, Melissa A Cadnapaphornchai...

BACKGROUND

Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD.

METHODS

This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc.

RESULTS

Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable.

CONCLUSIONS

Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.

CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER

Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.

Topics: Adult; Humans; Adolescent; Child; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Antidiuretic Hormone Receptor Antagonists; Quality of Life; Benzazepines; Kidney

PubMed: 36719158
DOI: 10.2215/CJN.0000000000000022

Review

Authors: R Lemmens-Gruber, M Kamyar

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Binding Sites; Cardiovascular Diseases; Clinical Trials as Topic; Hormone Antagonists; Humans; Indoles; Pyrroles; Pyrrolidines; Tolvaptan; Vasopressins; Water-Electrolyte Imbalance

PubMed: 16794787
DOI: 10.1007/s00018-006-6054-2

Review

Authors: Biruh T Workeneh, Kenar D Jhaveri, Helbert Rondon-Berrios...

Hyponatremia is a common electrolyte disorder observed in a wide variety of malignancies and is associated with substantial morbidity and mortality. Newer cancer therapies have improved patient outcomes while contributing to new cases of hyponatremia. Patients should be monitored closely for the development of vasopressin- and non-vasopressin-mediated hyponatremia. Acute and symptomatic forms of hyponatremia require urgent intervention, and recent findings support the correction of chronic "asymptomatic" hyponatremia. Optimizing hyponatremia may reduce medical costs, and improve cancer survival likelihood and quality of life. In this article, we review the epidemiology, pathophysiology, etiology, diagnosis, and treatment of hyponatremia in the cancer patient.

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Humans; Hyponatremia; Inappropriate ADH Syndrome; Neoplasms; Quality of Life; Tolvaptan

PubMed: 32497528
DOI: 10.1016/j.kint.2020.05.015

Comparative Study Randomized Controlled Trial

Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial.

Authors: Vicente E Torres, Arlene B Chapman, Olivier Devuyst...

BACKGROUND

In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.

METHODS

TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.

RESULTS

Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). Adjusting for baseline covariates improved the TKV treatment difference at Month 24 in TEMPO 4:4 from -1.70% to - 4.15% between the groups (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4.

CONCLUSIONS

The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Female; Glomerular Filtration Rate; Humans; Male; Polycystic Kidney, Autosomal Dominant; Prognosis; Time-to-Treatment; Tolvaptan

PubMed: 28379536
DOI: 10.1093/ndt/gfx043