From Doc Wire News, By Victoria Socha
Tolvaptan, a vasopressin V2 receptor antagonist (V2RA), is the first treatment shown to slow the rate of kidney function decline in patients with ADPKD; it is approved for clinical use in Japan, Canada, the European Union, and the United States. Results of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3:4 trial that included patients with earlier stage ADPKD, demonstrated that the rate of kidney function decline was decreased by 26% with use of tolvaptan, compared with placebo. The later REPRISE trial showed that in patients with later-stage disease, tolvaptan slowed kidney function decline by 35% compared with placebo.
Common side effects experienced by more than half of the patients in the treated groups included polyuria, and resulting thirst, nocturia, and polydipsia. Polyuria amounts to urine output of 6.0 L per day, affecting daily life, and was the primary reason for dose reduction and drug discontinuation in the TEMPO 3:4 trial.
Bart J. Kramers, MD, and colleagues recently conducted an assessment of determinants of polyuria in patients with ADPKD using V2RAs such that the determinants could be used to assist in the development of strategies to limit urine volume and increase tolerability. The researchers conducted an analysis of a study that included patients with ADPKD with chronic kidney disease stages 1 to 4 who received 120 mg of tolvaptan daily. Participants collected 24-hour urine in three separate portions (during the day, evening, and night). Results of the analysis were reported in the American Journal of Kidney Diseases [2019;73(3):354-362].
The researchers conducted analyses at baseline, after 3 weeks of V2RA treatment (tolvaptan, 90/30 mg, in the last week), and after a 3-week washout period.
The analysis included 27 individuals with a mean age of 46 years and a wide range of kidney function. Mean measured glomerular filtration rate (mGFR) was 61 mL/min/1.73 m2 (range, 18-148 mL/min/1.73 m2). Median total kidney volume was 2147 mL. In the final week of treatment, tolvaptan 90/30 mg was tolerated by 26 of the 27 patients; one patient received 60/30 mg.
During the 3-week treatment period, the median increase in 24-hour urine volume was 128%, from urine volume of 2584 mL at baseline to 5930 mL during treatment with V2RA. During the three urine collection periods, median increases over baseline were 106% during the day, 177% during the evening, and 87% during the night. There was a strong association between higher baseline mGFR and a higher percentage and absolute increase in 24-hour urine volume during the treatment period. During the treatment period, urine volume per hour was higher during the evening (333 mL/h) compared with the day (236 mL/h; P=.001) and night (205 mL/h; P<.001). At baseline, free-water clearance was –491 mL/24 hours; during the treatment period, it increased to 2991 mL/24 hours; following the washout period, free-water clearance returned to baseline values, at a mean of –616 mL/24 hours. There were no changes in osmolar water clearance between the study periods. There was a small but statistically significant increase in plasma sodium and plasma osmolality.
Following initiation of V2RA treatment, median 24-hour urine osmolality decreased by 60%, to 139 mOsm/kg (P<.001). There was no association between baseline mGFR and urine osmolality during the V2RA treatment period. Urine osmolality during the day and evening were similar (146 and 136 mOsm/kg, respectively; however, urine osmolality was significantly higher during the night (154 mOsm/kg; P=.001 and P<.001 vs day and evening, respectively).
There were no independent associations observed between 24-hour urine volume and mGFR, total kidney volume, or V2RA concentration
The authors cited some limitations to the findings, including the small sample size, the lack of a standardized diet, and the observational design of the analysis, limiting the ability to allow firm conclusions regarding causality.
In conclusion, the researchers said, “To date, V2Ra tolvaptan is the only treatment that has been proven to slow disease progression in ADPKD. Polyuria and related side effects, such as thirst, are the most common reasons for treatment discontinuation. We found that due to the maximally dilute urine induced by use of V2RAs, osmolar excretion becomes the major determinant of urine volume. Our data suggest that limiting osmolar intake could reduce urine volume and make treatment with V2RAs more tolerable. Furthermore, patients could be informed that they may be able to change the timing of the highest urine output by adjusting their meal schedule and the amounts of osmoles ingested, allowing them to have more control over the aquaretic side effects of tolvaptan.”
Takeaway Points
- Treatment with the vasopressin V2 receptor tolvaptan for patients with ADPKD is associated with polyuria in more than half the patients, affecting daily life and resulting in discontinuation of the drug.
- In results of a recent study of patients treated with tolvaptan, osmolar excretion was the major determinant of urine volume as a consequence of the inability to concentrate urine.
- The results suggest that restriction of osmolar intake may reduce polyuria related to tolvaptan, improving its tolerability.
Polycystic kidney disease (PKD) is a leading cause of kidney failure, and one of the most prominent rare hereditary diseases in New Zealand, as well as globally. The autosomal dominant form of this disease (ADPKD) has a country dependant prevalence rate of between one in 400 and one in 1000, and a 50% inheritance rate of the causal polycystin gene mutation in the offspring of an affected individual.
The polycystin proteins act as a cell signalling complex in many cell types including the cilia of kidney tubule cells. Polycystin-1 makes contact with the extracellular matrix while polycystin-2 promotes the flow of calcium into the cell to regulate a cellular response during environmental change. A malfunction in the polycystin complex caused by genetic mutation results in the dysregulation of cellular processes due to a change in cyclic-AMP mediated activity and release of the cells from the highly moderated cell cycle, leading to uncontrolled proliferation and cyst formation.
Once the kidney cells become cystic they lose the ability to exchange material with surrounding capillaries which ultimately reduces the kidney’s ability to filter the blood. Tolvaptan treatment is the only current means of slowing the process of cyst formation, by targeting the vasopressin pathway and inhibiting the conversion of ATP to cyclic AMP, thus reducing fluid uptake into the cells.
Alongside Tolvaptan, a number of other drug targets have proven promising in PKD models, yet these therapies often fail to proceed past clinical trials due to drug toxicity and off target side effects which cause the continuation of treatment to be intolerable for patients.
Therefore, investigation of a long-term solution for cyst reduction to treat PKD is imperative. This project investigated the efficacy of novel compounds to reduce cyst growth by targeting pathways modified in ADPKD, as well as the use of a kidney specific peptide as a compound chaperone.
Ultimately this study aimed to identify the impact of novel compounds on cyst growth, compound associated pathway alterations, and kidney specific peptide uptake. The novel compounds (SAHA, EG1, Gymnodimine and Portimine) were optimised for treatment of the ADPKD cyst growth cell line models MDCK and LLC-PK1. These cell lines were used to measure the effect compound treatment had on cystic area and changes in the activity of the compound’s target. The actions of the compounds were determined via HDAC activity assay, western blotting or Annexin V flow cytometry assays.
Uptake of the G3-C12 peptide into cells of the kidney tubules was achieved through flow cytometry detection of a fluorescently labelled peptide in vitro, as well as immunofluorescent staining of kidney derived cells and peptide injected mouse kidneys. Treating the cyst growth assays with EG1 and Portimine caused significant decreases in cystic growth. The EG1 treated cultures had 2 to 7-fold less area growth than the controls, and the Portimine treated cultures had 2 to 9-fold less area growth than the controls.
Gymnodimine treatment produced a significant reduction in the LLC-PK1 spheroid growth area, with these cultures having 22-fold less area growth than the controls. Additionally, the therapeutic compound SAHA caused the MDCK spheroids to have reduced cystic area growth but was unable to reach statistical significance, yet when attached to the peptide there was a significant 2 to 3-fold decrease in the cyst growth area of the MDCK cultures.
The cyst growth assays suggested that novel therapeutic compound treatment of EG1 and Portimine consistently had the greatest impact on cyst growth area change in vitro, however the attachment of the kidney specific peptide to SAHA also enabled this compound to slow cystic growth. Additionally, kidney targeted peptide uptake in vivo and in vitro identified peptide accumulation within the proximal tubular cells of mice kidneys, and in vitro human ADPKD cells.
From PKD Foundation
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