Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-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 m2 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 m2 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 m2 (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m2 (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 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 .).

Plasma copeptin levels predict disease progression and tolvaptan efficacy in autosomal dominant polycystic kidney disease.

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.

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.

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.

Can we further enrich autosomal dominant polycystic kidney disease clinical trials for rapidly progressive patients? Application of the PROPKD score in the TEMPO trial.

Background: The PROPKD score has been proposed to stratify the risk of progression to end-stage renal disease in autosomal dominant polycystic kidney disease (ADPKD) subjects. We aimed to assess its prognostic value in a genotyped subgroup of subjects from the Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (TEMPO3/4) trial. Methods: In the post hoc analysis, PKD1 and PKD2 were screened in 770 subjects and the PROPKD score was calculated in mutation-positive subjects (male: 1 point; hypertension <35 years: 2 points; first urologic event <35 years: 2 points; nontruncating PKD1 mutation: 2 points; truncating PKD1 mutation: 4 points). Subjects were classified into low-risk (LR; 0-3 points), intermediate-risk (IR; 4-6 points) and high-risk (HR; 7-9 points) groups. Results: The PROPKD score was calculated in 749 subjects (LR = 132, IR = 344 and HR = 273); age was inversely related to risk (LR = 43.6 years, IR = 39.5 years, HR = 36.2 years; P < 0.001). Subjects from the HR group had significantly higher height-adjusted total kidney volume (TKV) and rates of TKV growth. While baseline renal function was similar across all risk groups, the rate of estimated glomerular filtration rate (eGFR) decline significantly increased from LR to HR in the placebo group. Tolvaptan treatment effectiveness to reduce TKV growth was similar in all three risk categories. While tolvaptan significantly slowed eGFR decline in the IR (tolvaptan = -2.34 versus placebo = -3.33 mL/min/1.73 m2/year; P = 0.008) and HR groups (tolvaptan = -2.74 versus placebo = -3.94 mL/min/1.73 m2/year; P = 0.002), there was no difference in the LR group (tolvaptan = -2.35 versus placebo = -2.50 mL/min/1.73 m2/year; P = 0.72). Excluding the LR subjects from the analysis improved the apparent treatment effect of tolvaptan on eGFR decline. Conclusion: This study confirms the prognostic value of the PROPKD score and suggests that it could reduce costs and enhance endpoint sensitivity by enriching future study populations for rapidly progressing ADPKD subjects.

Urine Osmolality, Response to Tolvaptan, and Outcome in Autosomal Dominant Polycystic Kidney Disease: Results from the TEMPO 3:4 Trial.

The vasopressin-cAMP-osmolality axis is abnormal in autosomal dominant polycystic kidney disease (ADPKD). In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 Trial, a 3-year randomized, placebo-controlled trial in adults, the vasopressin V2 receptor antagonist tolvaptan slowed ADPKD progression in patients with preserved GFR. Here, we investigated the determinants of baseline urine osmolality (Uosm) and its value as a severity marker of ADPKD, the factors influencing the response to tolvaptan, and whether change in Uosm associated with key trial end points. At baseline, lower Uosm independently associated with female sex, presence of hypertension, lower eGFR, higher total kidney volume (TKV), and higher age. Tolvaptan consistently reduced Uosm by 200-300 mOsm/kg over 36 months. The Uosm response to tolvaptan depended on baseline eGFR and Uosm. Subjects with greater change in Uosm experienced a significant reduction in clinical progression events. Among subjects receiving tolvaptan, those with a greater suppression of Uosm had slower renal function decline. Assessment at follow-up, off medication, revealed a significant decrease in Uosm in both placebo and treated groups. Tolvaptan significantly increased plasma osmolality, which returned to baseline at follow-up. In conclusion, baseline Uosm in ADPKD reflects age, renal function, and TKV, and baseline Uosm, eGFR, and TKV influence the effect of tolvaptan on Uosm. The greatest renal benefit occurred in subjects achieving greater suppression of Uosm, that is, those with better eGFR at baseline. These results support the link between vasopressin V2 receptor signaling and ADPKD progression.

Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial.

BACKGROUND: Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain. STUDY DESIGN: Secondary analysis from a randomized controlled trial. SETTING & PARTICIPANTS: Patients with ADPKD with preserved kidney function. INTERVENTION: Tolvaptan or placebo. OUTCOMES: Kidney pain events defined by objective medical interventions. MEASUREMENTS: Kidney pain events were recorded and independently adjudicated. Incidence of a first kidney pain event was assessed overall and categorized into 5 subgroups according to severity. RESULTS: Of 1,445 participating patients (48.4% women; mean age, 39±7 [SD] years; mean estimated glomerular filtration rate, 81±22mL/min/1.73m2; median total kidney volume, 1,692 [IQR, 750-7,555] mL), 50.9% reported a history of kidney pain at baseline. History of urinary tract infections, kidney stones, or hematuria (all P<0.001) and female sex (P<0.001) were significantly associated with history of kidney pain. Tolvaptan use resulted in a significantly lower incidence of kidney pain events when compared to placebo: 10.1% versus 16.8% (P<0.001), with a risk reduction of 36% (HR, 0.64; 95% CI, 0.48-0.86). The reduction in pain event incidence by tolvaptan was found in all groups irrespective of pain severity and was independent of predisposing factors (P for interaction > 0.05). The effect of tolvaptan was explained at least in part by a decrease in incidence of urinary tract infections, kidney stones, and hematuria when compared to placebo. LIMITATIONS: Trial has specific inclusion criteria for total kidney volume and kidney function. CONCLUSIONS: Tolvaptan decreased the incidence of kidney pain events independent of patient characteristics predisposing for kidney pain and possibly in part due to reductions in ADPKD-related complications.

Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function. METHODS: Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks. RESULTS: Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests. CONCLUSION: Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.

Prevalence of autosomal dominant polycystic kidney disease in the European Union.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, but estimates of its prevalence vary by >10-fold. The objective of this study was to examine the public health impact of ADPKD in the European Union (EU) by estimating minimum prevalence (point prevalence of known cases) and screening prevalence (minimum prevalence plus cases expected after population-based screening). METHODS: A review of the epidemiology literature from January 1980 to February 2015 identified population-based studies that met criteria for methodological quality. These examined large German and British populations, providing direct estimates of minimum prevalence and screening prevalence. In a second approach, patients from the 2012 European Renal Association‒European Dialysis and Transplant Association (ERA-EDTA) Registry and literature-based inflation factors that adjust for disease severity and screening yield were used to estimate prevalence across 19 EU countries (N = 407 million). RESULTS: Population-based studies yielded minimum prevalences of 2.41 and 3.89/10 000, respectively, and corresponding estimates of screening prevalences of 3.3 and 4.6/10 000. A close correspondence existed between estimates in countries where both direct and registry-derived methods were compared, which supports the validity of the registry-based approach. Using the registry-derived method, the minimum prevalence was 3.29/10 000 (95% confidence interval 3.27-3.30), and if ADPKD screening was implemented in all countries, the expected prevalence was 3.96/10 000 (3.94-3.98). CONCLUSIONS: ERA-EDTA-based prevalence estimates and application of a uniform definition of prevalence to population-based studies consistently indicate that the ADPKD point prevalence is <5/10 000, the threshold for rare disease in the EU.

Performance of an Artificial Multi-observer Deep Neural Network for Fully Automated Segmentation of Polycystic Kidneys.

Deep learning techniques are being rapidly applied to medical imaging tasks-from organ and lesion segmentation to tissue and tumor classification. These techniques are becoming the leading algorithmic approaches to solve inherently difficult image processing tasks. Currently, the most critical requirement for successful implementation lies in the need for relatively large datasets that can be used for training the deep learning networks. Based on our initial studies of MR imaging examinations of the kidneys of patients affected by polycystic kidney disease (PKD), we have generated a unique database of imaging data and corresponding reference standard segmentations of polycystic kidneys. In the study of PKD, segmentation of the kidneys is needed in order to measure total kidney volume (TKV). Automated methods to segment the kidneys and measure TKV are needed to increase measurement throughput and alleviate the inherent variability of human-derived measurements. We hypothesize that deep learning techniques can be leveraged to perform fast, accurate, reproducible, and fully automated segmentation of polycystic kidneys. Here, we describe a fully automated approach for segmenting PKD kidneys within MR images that simulates a multi-observer approach in order to create an accurate and robust method for the task of segmentation and computation of TKV for PKD patients. A total of 2000 cases were used for training and validation, and 400 cases were used for testing. The multi-observer ensemble method had mean ± SD percent volume difference of 0.68 ± 2.2% compared with the reference standard segmentations. The complete framework performs fully automated segmentation at a level comparable with interobserver variability and could be considered as a replacement for the task of segmentation of PKD kidneys by a human.

A small molecule inhibitor of endoplasmic reticulum oxidation 1 (ERO1) with selectively reversible thiol reactivity.

Endoplasmic reticulum oxidation 1 (ERO1) is a conserved eukaryotic flavin adenine nucleotide-containing enzyme that promotes disulfide bond formation by accepting electrons from reduced protein disulfide isomerase (PDI) and passing them on to molecular oxygen. Although disulfide bond formation is an essential process, recent experiments suggest a surprisingly broad tolerance to genetic manipulations that attenuate the rate of disulfide bond formation and that a hyperoxidizing ER may place stressed cells at a disadvantage. In this study, we report on the development of a high throughput in vitro assay for mammalian ERO1alpha activity and its application to identify small molecule inhibitors. The inhibitor EN460 (IC(50), 1.9 mum) interacts selectively with the reduced, active form of ERO1alpha and prevents its reoxidation. Despite rapid and promiscuous reactivity with thiolates, EN460 exhibits selectivity for ERO1. This selectivity is explained by the rapid reversibility of the reaction of EN460 with unstructured thiols, in contrast to the formation of a stable bond with ERO1alpha followed by displacement of bound flavin adenine dinucleotide from the active site of the enzyme. Modest concentrations of EN460 and a functionally related inhibitor, QM295, promote signaling in the unfolded protein response and precondition cells against severe ER stress. Together, these observations point to the feasibility of targeting the enzymatic activity of ERO1alpha with small molecule inhibitors.

Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress.

It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk(-/-) mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk(+/+) and Perk(-/-) MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.

Standardizing total kidney volume measurements for clinical trials of autosomal dominant polycystic kidney disease.

BACKGROUND: The ability of unstandardized methods to track kidney growth in clinical trials for autosomal dominant polycystic kidney disease (ADPKD) has not been critically evaluated. METHODS: The Tolvaptan Efficacy and Safety Management of ADPKD and its Outcomes (TEMPO) 3:4 study involved baseline and annual magnetic resonance follow-up imaging yearly for 3 years. Total kidney volume (TKV) measurements were performed on these four time points in addition to the baseline imaging in TEMPO 4:4, initially by Perceptive Informatics (Waltham, MA, USA) using planimetry (original dataset) and for this study by the Mayo Translational PKD Center using semiautomated and complementary automated methods (sequential dataset). In the original dataset, the same reader was assigned to all scans of individual patients in TEMPO 3:4, but readers were reassigned in TEMPO 4:4. Two placebo-treated cohorts were included. In the first (n = 158), intervals between the end of TEMPO 3:4 and the start of TEMPO 4:4 scan visits ranged from 12 to 403 days; in the second (n = 95), the same scan (measured twice) visit was used for both. RESULTS: Growth rates in TEMPO 3:4 were similar in the original and sequential datasets (5.5 and 5.9%/year). Growth rates during the TEMPO 3:4 to TEMPO 4:4 interval were higher in the original (13.7%/year) but were not different in the sequential dataset (4.0%/year). Comparing volumes from the same images, TKVs showed a bias of 2.2% [95% confidence interval (CI) -5.2-9.7] in the original and -0.16% (95% CI -1.91-1.58) in the sequential dataset. CONCLUSIONS: Despite using the same software, TKV and growth rate changes were present, likely due to reader differences in the transition from TEMPO 3:4 to TEMPO 4:4 in the original but not in the sequential dataset. Robust, standardized methods are essential in ADPKD trials to minimize errors in serial TKV measurements.

Activating transcription factor 4 is translationally regulated by hypoxic stress.

Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2alpha at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2alpha was able to attenuate the phosphorylation of eIF2alpha and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2alpha-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.

Tolvaptan use in cancer patients with hyponatremia due to the syndrome of inappropriate antidiuretic hormone: a post hoc analysis of the SALT-1 and SALT-2 trials.

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P < 0.0001) at day 4, and 6.9 versus 1.0 mEq/L (P < 0.0001) at day 30; the observed treatment effects were similar to those in the overall SIADH population (i.e., with and without cancer) at both time points. Serum sodium normalization was observed in 6/12 and 0/13 subjects at day 4 and 7/8 and 2/6 subjects at day 30 in the tolvaptan and placebo groups, respectively (P < 0.05 for both). Common treatment-emergent AEs for tolvaptan were consistent with previously reported results. In this post hoc study of the SALT trial population, oral tolvaptan was an effective and safe therapy for the treatment of hyponatremia in subjects with SIADH and cancer.

Tolerability of Aquaretic-Related Symptoms Following Tolvaptan for Autosomal Dominant Polycystic Kidney Disease: Results From TEMPO 3:4.

INTRODUCTION: In the randomized placebo-controlled Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes (TEMPO) 3:4 trial, tolvaptan slowed kidney growth and renal function decline in subjects with autosomal dominant polycystic kidney disease (ADPKD). Consistent with its primary pharmacologic activity, tolvaptan use was commonly associated with aquaretic adverse events (AAEs) attributable to excess free water clearance. METHODS: A post hoc analysis of tolvaptan-related discontinuations from the pivotal randomized controlled trial TEMPO 3:4 and its open-label extension TEMPO 4:4. RESULTS: In total, 750 of 961 tolvaptan-treated subjects (78%) in TEMPO 3:4 reported at least one AAE. Of these 750 subjects, 72 (10%) discontinued because of an AAE (aquaretic-discontinued group) and 573 (76%) continued (aquaretic-continued group). The aquaretic-discontinued subjects were younger, had better baseline renal function, and had higher fasting urine osmolality than aquaretic-continued subjects. Of the 750 subjects reporting an AAE, 105 (14%) discontinued for another reason (non-aquaretic-discontinued group). Compared to non-aquaretic-discontinued subjects, aquaretic-discontinued subjects were more commonly male, had better baseline renal function, and discontinued the study drug faster. After 3 years of therapy, 75% of tolvaptan subjects indicated that they could tolerate their current dose for the rest of their lives, compared to 85% of placebo subjects. These findings were corroborated by results in the open-label extension trial TEMPO 4:4. DISCUSSION: In this study, AAEs were common but well tolerated in ADPKD patients on tolvaptan. ADPKD patients in earlier stages of disease progression may be more sensitive to aquaretic symptoms, which may help in guiding tolvaptan dosing and titration decisions in the future.

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial.

BACKGROUND: and objectives The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study demonstrated a significant beneficial effect of the vasopressin V2 receptor antagonist tolvaptan on rates of kidney growth and eGFR decline in autosomal dominant polycystic kidney disease (ADPKD). This post hoc analysis was performed to reassess the primary and secondary efficacy endpoints by CKD stage at baseline. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients with ADPKD (age 18-50 years), with total kidney volume (TKV) ≥750 ml and estimated creatinine clearance ≥60 ml/min, were randomly assigned 2:1 to split-dose tolvaptan (45/15, 60/30, or 90/30 mg daily as tolerated) or placebo. The primary endpoint was annualized rate of TKV change. Secondary endpoints included a composite endpoint of time to multiple composite ADPKD-related events (worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney function decline. RESULTS: Tolvaptan reduced annualized TKV growth by 1.99%, 3.12%, and 2.61% per year (all P<0.001; subgroup-treatment interaction, P=0.17) and eGFR decline by 0.40 in CKD1 (P=0.23), 1.13 in CKD2 (P<0.001) and 1.66 ml/min per 1.73 m(2) per year in CKD3 (P<0.001) with a trend for a positive subgroup-treatment interaction (P=0.07) across CKD1, CKD2 and CKD3. ADPKD-related events were less frequent in tolvaptan recipients than in placebo recipients among those with CKD1 (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.70-0.98; P=0.03) and those with CKD 3 (HR, 0.71; 95% CI, 0.57-0.89; P=0.003), but not among those with CKD2 (HR, 1.02; 95% CI, 0.85-1.21; P=0.86). Aquaresis-related adverse events (more frequent in the tolvaptan group) and ADPKD-related adverse events (more frequent in the placebo group) were not associated with CKD stage. Hypernatremia events in tolvaptan-treated patients with CKD3 and plasma aminotransferase elevations in tolvaptan-treated patients across CKD stages 1-3 occurred more frequently than in placebo recipients. CONCLUSIONS: This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.

Prognostic Enrichment Design in Clinical Trials for Autosomal Dominant Polycystic Kidney Disease: The TEMPO 3:4 Clinical Trial.

INTRODUCTION: Patients with slowly progressive autosomal dominant polycystic kidney disease (ADPKD) are unlikely to experience outcomes during randomized controlled trials (RCTs). An image classification of ADPKD into typical (diffuse cyst distribution) class 1A to E (by age- and height-adjusted total kidney volume [TKV]) and atypical (asymmetric cyst distribution) class 2 was proposed for prognostic enrichment design, recommending inclusion of only classes 1C to 1E in RCTs. METHODS: A post hoc exploratory analysis was conducted of the TEMPO 3:4 Trial, a prospective, randomized, double-blinded, controlled clinical trial in adult subjects with ADPKD, an estimated creatinine clearance >60 ml/min and total kidney volume >750 ml. RESULTS: Due to the entry criteria, the study population of TEMPO 3:4 was enriched for classes 1C-E (89.5 % of 1436 patients with baseline magnetic resonance images) compared to unselected populations (e.g., 60.5% of 590 Mayo Clinic patients). The effects of tolvaptan on TKV and eGFR slopes were greater in classes 1C to E than in 1B. In TEMPO 3:4, tolvaptan reduced TKV and eGFR slopes from 5.51% to 2.80% per year and from -3.70 to -2.78 ml/min/1.73 m2 per year, and lowered the risk for a composite endpoint of clinical progression events (hazard ratio = 0.87). Restricting enrollment to classes 1C to E would have reduced TKV and eGFR slopes from 5.78% to 2.91% per year and from -3.93 to -2.82 ml/min/1.73 m2 per year, and the risk of the composite endpoint (hazard ratio = 0.84, P = 0.003), with 10.5% fewer patients. DISCUSSION: Prognostic enrichment strategies such as the entry criteria used for TEMPO 3:4 or preferably the proposed image classification should be used in RCTs for ADPKD to increase power and to reduce cost.

Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database.

INTRODUCTION: Subjects with autosomal dominant polycystic kidney disease (ADPKD) who were taking tolvaptan experienced aminotransferase elevations more frequently than those on placebo in the TEMPO 3:4 (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) clinical trial. METHODS: An independent, blinded, expert Hepatic Adjudication Committee re-examined data from TEMPO 3:4 and its open-label extension TEMPO 4:4, as well as from long-term (>14 months) non-ADPKD tolvaptan trials, using the 5-point Drug-Induced Liver Injury Network classification. RESULTS: In TEMPO 3:4, 1445 subjects were randomized 2:1 (tolvaptan vs. placebo) and 1441 had post-baseline assessments of hepatic injury. Sixteen patients on tolvaptan and one on placebo had significant aminotransferase elevations judged to be at least probably related to study drug. No association with dose or systemic exposure was found. Two of 957 subjects taking tolvaptan (0.2 %) and zero of 484 taking placebo met the definition of a Hy's Law case. One additional Hy's Law case was identified in a TEMPO 4:4 subject who had received placebo in the lead study. The onset of a hepatocellular injury occurred between 3 and 18 months after starting tolvaptan, with gradual resolution over the subsequent 1-4 months. None of the events were associated with liver failure or chronic liver injury/dysfunction. No imbalance in hepatic events was observed between tolvaptan and placebo in lower-dose clinical trials of patients with hyponatremia, heart failure, or cirrhosis. CONCLUSIONS: Although hepatocellular injury following long-term tolvaptan treatment in ADPKD subjects was infrequent and reversible, the potential for serious irreversible injury exists. Regular monitoring of transaminase levels is warranted in this patient population.

Internal ribosome entry site-mediated translation of Apaf-1, but not XIAP, is regulated during UV-induced cell death.

Components of the cellular translation machinery are targets of caspase-mediated cleavage during apoptosis that correlates with the inhibition of protein synthesis, which accompanies apoptosis. Paradoxically, protein synthesis is required for apoptosis to occur in many experimental settings. Previous studies showed that two proteins that regulate apoptosis by controlling caspase activity, XIAP and Apaf-1, are translated by a unique, cap-independent mechanism mediated by an internal ribosome entry site (IRES) that is used preferentially under conditions in which normal cap-dependent translation is repressed. We investigated the regulation of XIAP and Apaf-1 following UVC irradiation. We show that UVC irradiation leads to the inhibition of translation and cell death. Furthermore, IRES-mediated translation of Apaf-1, but not XIAP, is enhanced by UVC irradiation, and this increase in Apaf-1 translation correlated with cell death. The enhanced Apaf-1 IRES-mediated translation is caspase-independent but is negatively modulated by the eIF2alpha kinase protein kinase RNA-like endoplasmic reticulum kinase. These data suggest that progression of UV-induced apoptosis requires IRES-mediated translation of Apaf-1 to ensure continuous levels of Apaf-1 despite an overall suppression of protein synthesis.