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Introduction A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults. Methods TRACTION-2 is a phase 2a, double-blind, placebo-controlled, multiple−ascending dose study of GFB-887 in patients with focal segmental glomerulosclerosis (FSGS), treatment-resistant minimal change disease (TR-MCD), or diabetic nephropathy (DN) (NCT04387448). Adult patients on stable renin−angiotensin system blockade and/or immunosuppression with persistent proteinuria will be randomized and dosed in 3 ascending dose levels to GFB-887 or placebo for 12 weeks. Cohorts may be expanded or biomarker-enriched depending upon results of an adaptive interim analysis. Results The primary objective is to evaluate the effect of increasing doses of GFB-887 on proteinuria. Safety and tolerability, quality of life, pharmacokinetic/pharmacodynamic profiles, and the potential association of urinary Rac1 with efficacy will also be evaluated. The projected sample size has 80% power to detect a treatment difference in proteinuria of 54% (FSGS/TR-MCD) or 44% (DN) compared to placebo. Conclusion TRACTION-2 will explore whether targeted blockade of the TRPC5-Rac1 pathway with GFB-887 is an efficacious and safe treatment strategy for patients with FSGS, TR-MCD, and DN and the potential value of urinary Rac1 as a predictive biomarker of treatment response., Graphical abstract

Background HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of autonomous cortisol secretion (ACS) and Cushing's syndrome, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition. Single and multiple SPI-62 doses decreased urinary cortisol metabolites indicating a similar decrease of hepatocellular cortisol in this important target tissue. After a corresponding transient decrease, circulating cortisol homeostasis was restored rapidly by ACTH increase which also resulted in a moderate adrenal androgen increase. SPI-62's effects on ACTH and androgens did not result in adverse effects. Urinary free cortisol was not affected. The ACSPIRE trial will assess SPI-62 safety and efficacy in patients with dysregulated cortisol production due to ACS or adrenal Cushing's syndrome (aCs) for the first time. Methods In this randomized, placebo-controlled, multinational, Phase 2 clinical trial, adult patients with ACS or aCs with otherwise benign adrenal adenomas, persistently elevated morning cortisol after verifiably adequate dexamethasone suppression, and at least two morbidities associated with hypercortisolism [A) insulin-resistance/type-2 diabetes mellitus, B) dyslipidemia, C) hypertension, or D) osteopenia] will be randomized to receive SPI-62 or placebo for 12 weeks. Subjects must have declined, delayed, or been deemed ineligible for adrenalectomy and not recently taken approved or experimental medical therapies for cortisol excess. Medical conditions or treatments likely to interfere with study assessments or subject safety are also excluded. Efficacy at 12-weeks is assessed by reduction of cortisol-associated morbidities of hyperglycemia and dyslipidemia while also examining, adiposity, hepatic steatosis, hypertension, inflammatory cytokines, osteopenia, muscle strength, cognition, sleep, and mood. Safety is assessed by adverse events, vital signs, ECGs, clinical laboratory analyses. Pharmacology is assessed by effects on HPA/HPG axis biomarkers and suppression of the urinary ratio of hepatic 5- and 3-steroid reductase metabolites of cortisol and cortisone (tetrahydrocortisol + allotetrahydrocortisol)/tetrahydrocortisone). Assessments include timed up-and-go and hand-grip strength tests, dual-energy x-ray absorptiometry, oral glucose tolerance test, continuous glucose monitoring, and 24-hour ambulatory blood pressure monitoring. Results This trial is ongoing; results are pending. Discussion This Phase 2 explores SPI-62 safety, HSD-1 inhibition, effects on HPA/HPG axes, and clinical effects in patients with ACS and aCs. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Background HSD-1, an intracellular enzyme, converts cortisone to cortisol in tissues where cortisol excess is associated with morbidity including liver, adipose, bone, brain, muscle, skin, and eye. SPI-62 is a potent and specific HSD-1 inhibitor in development for treatment of Cushing's syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In Phase 1 clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition. SPI-62 decreased urinary cortisol metabolites indicating a similar decrease of hepatocellular cortisol in this important target tissue. After a corresponding transient decrease, circulating cortisol homeostasis was restored by ACTH increase which also resulted in a moderate adrenal androgen increase. SPI-62's effects on androgens did not result in adverse effects. Urinary free cortisol was unaffected. The RESCUE trial will assess SPI-62 safety and efficacy in patients with a dysregulated HPA axis, ie., ACTH-dependent Cushing's syndrome. Methods In this randomized, placebo-controlled, crossover, multinational, Phase 2 clinical trial, adult patients (N=26) with ACTH-dependent Cushing's syndrome with active and consistently elevated urinary free cortisol (UFC) will be randomized to receive SPI-62 and placebo for 12 weeks each. A diagnosis of an inadequately treated pituitary adenoma (Cushing's disease) or ectopic ACTH or CRH producing tumor based on established criteria is required. Evidence of Cushing's associated morbidities including at least 2 of A) insulin-resistance/type-2 diabetes mellitus, B) dyslipidemia, C) hypertension, or D) osteopenia is required. Subjects must not have had recent Cushing's surgical, radiation other approved or experimental medical therapies for cortisol excess. Medical conditions or treatments likely to interfere with study assessments or subject safety are also excluded. The primary outcome is pharmacological suppression of the urinary ratio of hepatic 5- and 3-steroid reductase metabolites of cortisol and cortisone (tetrahydrocortisol+allotetrahydrocortisol)/tetrahydrocortisone). Safety is assessed by adverse events, vital signs, ECG, and clinical laboratory analyses including effects on HPA/HPG axis biomarkers. Efficacy is assessed by reduction of Cushing's features and morbidities of hyperglycemia, dyslipidemia, adiposity, hepatic steatosis, hypertension, glaucoma, osteopenia, muscle strength, cognition, sleep, and mood. Assessments include tumor-imaging by MRI, ocular tonometry, timed up-and-go and hand-grip strength tests, dual-energy x-ray absorptiometry, oral glucose tolerance, continuous glucose monitoring, and ambulatory blood pressure monitoring. Results This trial is ongoing; results are pending. Discussion This Phase 2 explores SPI-62 safety, HSD-1 inhibition, effects on HPA/HPG axes, and clinical effects in patients with ACTH-dependent Cushing's syndrome. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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.

BACKGROUND AND OBJECTIVES: In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up. RESULTS: Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m(2) per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m(2) per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m(2) per year; P

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.

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.

In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient-reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split-dose regimen: a single ascending-dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split-dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8-week open-label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm ) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to 50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30-mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.

Introduction Tolvaptan, a treatment for autosomal dominant polycystic kidney disease (ADPKD), inhibits vasopressin V2 receptor signaling, which causes aquaretic adverse events (AAEs). The short-term efficacy and tolerability of a once-daily, modified-release (MR) formulation was assessed relative to the twice-daily, immediate-release (IR) formulation. Methods This Phase 2 multicenter, randomized (1:1:1:1), placebo-controlled, double-blind, placebo-masked, parallel-group study (NCT01451827) compared tolvaptan MR 50 mg once daily or tolvaptan MR 80 mg once daily with tolvaptan IR 60/30 mg daily split dose and placebo over 8 weeks in 177 subjects. The primary endpoint was percent change from baseline in total kidney volume (TKV) at week 3. Other endpoints included tolerability, assessed by adverse events and quality of life (QOL) measures. Results Mean percentage decreases in TKV at week 3 were observed for the pooled group of all (MR+IR) tolvaptan-treated subjects (−2.07%), tolvaptan MR 80 mg (−2.55%), and tolvaptan MR 50 mg (−2.46%) versus placebo (0.09%; P < 0.02 for each comparison with placebo), whereas the decrease with tolvaptan IR 60/30 mg (−1.17%; P = 0.24) did not reach significance. All tolvaptan regimens were associated with AAEs, but scores on ADPKD-specific and generic patient-reported outcome assessments showed little impact based on dosage on overall health-related QOL versus placebo. Conclusion Tolvaptan MR and tolvaptan IR demonstrated similar short-term efficacy, tolerability, and safety, with low impact on multiple measures of QOL. Conclusions regarding long-term efficacy are limited by the short duration of follow-up., Graphical abstract

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 m(2) 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 m(2) 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.

BACKGROUND: The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable. METHODS: Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). RESULTS: Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. CONCLUSIONS: In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.

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

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.

Background: A recent study showed that tolvaptan, a vasopressin V-2 receptor antagonist, decreased total kidney volume (TKV) growth and estimated glomerular filtration rate (GFR) loss in autosomal dominant polycystic kidney disease (ADPKD) with creatinine clearance >= 60 mL/min. The aim of our study was to determine whether the renal hemodynamic effects and pharmacodynamic efficacy of tolvaptan in ADPKD are dependent on GFR.Study Design: Clinical trial with comparisons before and after treatment.Setting & Participants: Patients with ADPKD with a wide range of measured GFRs (mGFRs; 18-148 mL/min) in a hospital setting.Intervention: Participants were studied at baseline and after 3 weeks of treatment with tolvaptan given in increasing dosages, if tolerated (doses of 60, 90, and 120 mg/d in weeks 1, 2, and 3, respectively).Outcomes: Change in markers for aquaresis (free-water clearance, urine and plasma osmolality, 24-hour urine volume, and plasma copeptin) and kidney injury (TKV and kidney injury biomarkers).Measurements: GFR was measured by 125 I-iothalamate clearance; TKV, by magnetic resonance imaging; biomarker excretion, by enzyme-linked immunosorbent assay; and osmolality, by freezing point depression.Results: In 27 participants (52% men; aged 46 +/- 10 years; mGFR, 69 +/- 39 mL/min; TKV, 2.15 [IQR, 1.10-2.77] L), treatment with tolvaptan led to an increase in urine volume and free-water clearance and a decrease in urine osmolality, TKV, and kidney injury marker excretion. Changes in urine volume and osmolality with treatment were less in participants with lower baseline mGFRs (both P Limitations: Limited sample size, no control group.Conclusions: In patients with ADPKD with decreased kidney function, response to tolvaptan is lower for TKV, urinary volume, and osmolality, but larger for fractional free-water clearance. This latter finding suggests that patients with ADPKD with lower GFRs might benefit from long-term treatment with tolvaptan, as has been observed for patients with preserved GFRs. (C) 2015 by the National Kidney Foundation, Inc.

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 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 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.

Background: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by multitudes of expanding renal cysts associated with mononuclear interstitial infiltrates. Monocyte chemotactic protein-1 is produced in the kidneys and excreted in the urine (uMCP1) of these patients in increased amounts. In the TEMPO 3:4 trial, tolvaptan slowed the rate of increase in total kidney volume (TKV) and the rate of decline in estimated glomerular filtration rate (eGFR). In a sub-analysis, we determined whether tolvaptan administration for up to 3 years changed the urinary excretion of MCP-1 referenced to creatinine in 869 treated subjects compared with 438 placebo subjects.Methods: Treatment group differences of uMCP1 at 0.75, 12, 24 and 36 months were evaluated by ANCOVA with factor of treatment and covariate baseline.Results: At baseline, mean uMCP1 was 429 +/- 224 pg/mg in the tolvaptan and 434 +/- 233 pg/mg in the placebo groups, similar to 4-fold greater than normal. Log uMCP1 associated positively with log TKV (r = 0.2645, P Conclusion: Tolvaptan, administered for 3 years to patients with ADPKD, caused a sustained reduction in the urinary excretion of MCP-1 relative to placebo.

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.

The Leydig tumor cell line, MA-10, expresses the luteinizing hormone receptor, a G protein-coupled receptor that, when activated with luteinizing hormone or chorionic gonadotropin (CG), stimulates cAMP production and subsequent steroidogenesis, notably progesterone. These cells also respond to epidermal growth factor (EGF) and phorbol esters with increased steroid biosynthesis. In order to probe the intracellular pathways along with heterologous receptor down-regulation and cellular desensitization, cells were preincubated with EGF or phorbol esters and then challenged with CG, EGF, dibutryl-cyclic AMP, and a phorbol ester. Relative receptor numbers, steroid biosynthesis, and expression of the early response genes, JUNB and c-FOS, were measured. It was found that in all cases but one receptor down-regulation and decreased progesterone production were closely coupled under the conditions used; the exception involved preincubation of the cells with EGF followed by addition of CG where the CG-mediated stimulation of steroidogenesis was considerably lower than the level of receptor down-regulation. In a number of instances JUNB and c-FOS expression paralleled the decreases in receptor number and progesterone production, while in some cases these early response genes were affected little if at all by the changes in receptor number. This finding may indicate that even low levels of activated signaling kinases, e.g. protein kinase A, protein kinase C, or receptor tyrosine kinase, may suffice to yield good expression of JUNB and c-FOS, or it may suggest alternative pathways for regulating expression of these two early response genes., Highlights • Leydig tumor cells respond to hCG, cAMP, EGF, and phorbol esters with increased steroidogenesis. • These same agents increase expression of the early response genes JUNB and c-FOS. • Down-regulation of EGF receptors reduced hCG receptors and steroidogenesis. • Desensitization of the PKC pathway reduced hCG receptors and steroidogenesis. • Often expression of JUNB and c-FOS paralleled receptor loss, but not always.

Introduction Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease. Methods A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively. Results The statistical association between predicted TKV at the time of a 30% decline of eGFR and that at the time of end-stage renal disease were both highly significant (P < 0.0001). The drug development tool was applied to demonstrate the utility of trial enrichment according to prespecified baseline TKV, age, and eGFR as enrollment criteria in hypothetical clinical trials. Patients with larger TKV (≥1000 ml) displayed steeper slopes of hazard, which translated into a higher risk of a 30% decline of eGFR within each baseline age (< or ≥40 years) or baseline eGFR (< or ≥50 ml/min per 1.73 m2) subgroups. Discussion These results suggest that, when eGFR is preserved, patients with larger TKV are more likely to progress to a 30% decline of eGFR within the course of a clinical trial, whereas eGFR and age displayed limited predictive value of disease progression in early disease. Pharmaceutical sponsors and academic investigators are encouraged to prospectively employ the above drug development tool to optimize trial designs in patients with autosomal dominant polycystic kidney disease.

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 +/- 22 mL/min/1.73 m(2); 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 0.05). 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. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

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.

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 m 2 , P

In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2‐receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient‐reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split‐dose regimen: a single ascending‐dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split‐dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8‐week open‐label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg). Urine osmolality (Uosm) was chosen as the biomarker of V2 receptor inhibition. Two tolvaptan doses per day were necessary to suppress Uosm to 50% of subjects. Therefore, this regimen was selected as the starting regimen for the TEMPO 3:4 trial. The 90/30‐mg regimen suppressed Uosm in 85% of subjects tested; however, only 28/46 subjects agreed to uptitrate to 90/30 mg due to tolerability. Higher concentrations of tolvaptan were less well tolerated, resulting in adverse events of pollakiuria, thirst, polyuria, nocturia, and a higher number of times out of bed to urinate. Subjects who agreed to uptitrate to 90/30 mg had lower eGFR than those who did not uptitrate.

Introduction Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. TKV is a promising imaging biomarker for tracking and predicting the natural history of autosomal dominant polycystic kidney disease. The prognostic value of TKV was evaluated, in combination with age and eGFR, for the outcomes of 30% decline in eGFR and progression to ESRD. Observational data including 2355 patients with TKV measurements were available. Methods Multivariable Cox models were developed to assess the prognostic value of age, TKV, height-adjusted TKV, eGFR, sex, race, and genotype for the probability of a 30% decline in eGFR or ESRD. Results TKV was the most important prognostic term for 30% decline in eGFR in autosomal dominant polycystic kidney disease patients with and without preserved baseline eGFR. For a 40-year-old subject with preserved eGFR (70 ml/min per 1.73 m 2 ), the adjusted hazard ratios for a 30% decline in eGFR were 1.86 (95% CI, 1.65–2.10) for a 2-fold larger TKV (600 vs. 1200 ml) and 2.68 (95% CI, 2.22–3.24) for a 3-fold larger TKV (600 vs. 1800 ml), respectively. Hazard ratios for progression to ESRD for 2- and 3-fold larger TKV were 1.72 (95% CI, 1.49–1.99) and 2.36 (95% CI, 1.88–2.97), respectively. Discussion The capability to predict 30% decline in eGFR is a novel aspect of this study. TKV was formally qualified, both by FDA and EMA, as a prognostic enrichment biomarker for selecting patients at high risk for a progressive decline in renal function for inclusion in interventional clinical trials.

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 PCONCLUSIONS: This post hoc analysis suggests clinically similar beneficial effects of tolvaptan in ADPKD across CKD stages 1-3.

Summary Background and objectives Autosomal dominant polycystic kidney disease (ADPKD), a frequent cause of end-stage renal disease, has no cure. V2-specific vasopressin receptor antagonists delay disease progression in animal models. Design, setting, participants, and measurements This is a prospectively designed analysis of annual total kidney volume (TKV) and thrice annual estimated GFR (eGFR) measurements, from two 3-year studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR. Prespecified end points were group differences in log-TKV (primary) and eGFR (secondary) slopes for month 36 completers, using linear mixed model (LMM) analysis. Sensitivity analyses of primary and secondary end points included LMM using all subject data and mixed model repeated measures (MMRM) of change from baseline at each year. Pearson correlation tested the association between log-TKV and eGFR changes. Results Fifty-one subjects (81%) completed 3 years of tolvaptan therapy; all experienced adverse events (AEs), with AEs accounting for six of 12 withdrawals. Baseline TKV (controls 1422, tolvaptan 1635 ml) and eGFR (both 62 ml/min per 1.73 m 2 ) were similar. Control TKV increased 5.8% versus 1.7%/yr for tolvaptan (P 0.001, estimated ratio of geometric mean 0.96 [95% confidence interval 0.95 to 0.97]). Corresponding annualized eGFR declined: 2.1 versus 0.71 ml/min per 1.73 m 2 /yr (P 0.01, LMM group difference 1.1 ml/min per 1.73 m 2 /yr [95% confidence interval 0.24 to 1.9]). Sensitivity analyses including withdrawn subjects were similar, whereas MMRM analyses were significant at each year for TKV and nonsignificant for eGFR. Increasing TKV correlated with decreasing eGFR (r 0.21, P 0.01). Conclusion ADPKD cyst growth progresses more slowly with tolvaptan than in historical controls, but AEs are common. Clin J Am Soc Nephrol 6: 2499–2507, 2011. doi: 10.2215/CJN.03530411

ObjectiveTolvaptan, an oral antagonist of the vasopressin V2receptor, has been found to improve hyponatremia in patients with mixed etiologies. This study analyzed a subgroup of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) to evaluate the efficacy and safety of tolvaptan in this group.Design and patientsHyponatremic patients in the SALT-1 and SALT-2 studies with a diagnosis of SIADH were identified based on clinical diagnosis by individual study investigators. Subjects were randomized to receive oral placebo (n=52) or tolvaptan 15 mg daily, with further titration to 30 and 60 mg daily, if necessary, based on the response of serum [Na+] (n=58).ResultsIn patients with SIADH, improvement in serum [Na+] was significantly greater (P+] declined to values similar to placebo. A significant positive treatment effect favoring tolvaptan on the physical component, and a near-significant trend on the mental component, was found using the SF-12 Health Survey. Tolvaptan was associated with a significantly reduced incidence of fluid restriction.ConclusionsResults for the SIADH subgroup were analogous to those of the combined SALT population regarding efficacy and safety but demonstrated a greater improvement in the physical component of the SF-12 Health Survey than in the full mixed etiology SALT patient group.

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (≤30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.

Hyponatremia (serum sodium [Na+] concentration136 mmol/L) is a prevalent and potentially life-threatening medical comorbidity for schizophrenic patients. No definitive pharmacological treatments have been established. Tolvaptan (OPC-41061), an oral non-peptide V2-receptor antagonist, was recently shown to correct hyponatremia in a diverse population of 448 hyponatremic patients. Efficacy in a sub-set of 19 schizophrenic patients with idiopathic hyponatremia included in that sample is specifically examined.Nineteen subjects were randomly assigned to receive placebo (n = 12) or tolvaptan (n = 7) once daily for 30 days. Dosage adjustment was based on serum Na+ changes, initially 15 mg, titratable to 30 or 60 mg. The average daily area under the curve (AUC) changes in serum Na+ from baseline to Day 4 and Day 30 were co-primary end points.Increases in serum Na+ concentrations were significantly greater with tolvaptan than placebo at Day 4 (p = .0055) and at Day 30 (p.0001). Two subjects receiving tolvaptan (28.6%) became dehydrated and experienced hypotension, and five subjects receiving placebo (41.7%) experienced symptoms associated with dilutional hyponatremia.These results suggest that tolvaptan effectively normalizes idiopathic hyponatremia in schizophrenic patients. Clinicians are advised to carefully monitor fluid status especially at the beginning of treatment to prevent dehydration.

This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia.Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study.57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration120-135 mEq/L) at 16 sites.Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance.Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations.Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03).There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating.Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.

Objective OPC-28326 is a selective α-adrenergic antagonist with preferential binding to the α2C-adrenergic receptor (α2C-AR) subtype. This study observed the effect of OPC-28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma. Methods The study was designed as a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of OPC-28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature. Results Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC-28326 40-mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P = 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P = 0.01]). These recovery times tended to be shorter in the 10 mg OPC-28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P = 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P = 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC-28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug-related were reported more frequently with 40 mg OPC-28326 than with 10 mg OPC-28326 or with placebo, but none were serious or sustained. Conclusion OPC-28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC-28326 suggests that selective α2C-AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.

It has been previously shown that cilostazol (Pletal), a drug for relief of symptoms of intermittent claudication, potently inhibits cyclic nucleotide phosphodiesterase type 3 (PDE3) and moderately inhibits adenosine uptake. It elevates extracellular adenosine concentration, by inhibiting adenosine uptake, and combines with PDE3 inhibition to augment inhibition of platelet aggregation and vasodilation while attenuating positive chronotropic and inotropic effects on the heart. In the present study, we tested the hypothesis that cilostazol combined with a more potent adenosine uptake inhibitor, dipyridamole, synergistically inhibited platelet aggregation in human blood. In the presence of exogenous adenosine (1 microM), the combination of cilostazol and dipyridamole synergistically increased intra-platelet cAMP. Furthermore, cilostazol inhibited platelet aggregation in a washed platelet assay concentration-dependently with IC50s of 0.17 +/- 0.04 microM (P < 0.05 versus plus adenosine alone of 0.38 +/- 0.05 microM), 0.11 +/- 0.06 microM (P < 0.05), and 0.01 +/- 0.01 microM (P < 0.005) when combined with 1, 3, or 10 microM dipyridamole, respectively (n = 5). In whole blood, cilostazol (0.3 to 3 microM) and dipyridamole (1 or 3 microM) synergistically inhibited collagen- and ADP-induced platelet aggregation in vitro. Furthermore, the synergism was confirmed in an open-label, sequential study in healthy human subjects using ex vivo whole-blood collagen-induced platelet aggregation. Four hours after oral co-administration of cilostazol (100 mg) and dipyridamole (200 mg), platelet aggregation was inhibited by 45 +/- 17%, while no significant inhibition was observed from subjects treated with either drug alone. The combination may provide a potential treatment of arterial thrombotic disorders.

Data standards provide a structure for consistent understanding and exchange of data and enable the integration of data across studies for integrated analysis. There is no data standard applicable to kidney disease. We describe the process for development of the first-ever Clinical Data Interchange Standards Consortium (CDISC) data standard for autosomal dominant polycystic kidney disease (ADPKD) by the Polycystic Kidney Disease Outcomes Consortium (PKDOC). Definition of common data elements and creation of ADPKD-specific data standards from case report forms used in long-term ADPKD registries, an observational cohort (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease [CRISP] 1 and 2), and a randomized clinical trial (Halt Progression of Polycystic Kidney Disease [HALT-PKD]) are described in detail. This data standard underwent extensive review, including a global public comment period, and is now available online as the first PKD-specific data standard (www.cdisc.org/therapeutic). Submission of clinical trial data that use standard data structures and terminology will be required for new electronic submissions to the US Food and Drug Administration for all disease areas by the end of 2016. This data standard will allow for the mapping and pooling of available data into a common data set in addition to providing a foundation for future studies, data sharing, and long-term registries in ADPKD. This data set will also be used to support the regulatory qualification of total kidney volume as a prognostic biomarker for use in clinical trials. The availability of consensus data standards for ADPKD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among completed clinical trials, thereby improving our understanding of disease progression and treatment.

Vasopressin V2-receptor antagonists may delay disease progression in ADPKD. Trials with V2-receptor antagonists have been performed predominantly in patients with an estimated creatinine clearance of 60 ml/min or more. Here we determined renal hemodynamic effects of the V2-receptor antagonist tolvaptan in 27 patients with ADPKD at various stages of chronic kidney disease: group A: >60, group B: 30-60, and group C

In vivo, fibroblast growth factor-2 (FGF-2) inhibits longitudinal bone growth. Similarly, activating FGF receptor 3 mutations impair growth in achondroplasia and thanatophoric dysplasia. To investigate the underlying mechanisms, we chose a fetal rat metatarsal organ culture system that would maintain growth plate histological architecture. Addition of FGF-2 to the serum-free medium inhibited longitudinal growth. We next assessed each major component of longitudinal growth: proliferation, cellular hypertrophy, and cartilage matrix synthesis. Surprisingly, FGF-2 stimulated proliferation, as assessed by [3H]thymidine incorporation. However, autoradiographic studies demonstrated that this increased proliferation occurred only in the perichondrium, whereas decreased labeling was seen in the proliferative and epiphyseal chondrocytes. FGF-2 also caused a marked decrease in the number of hypertrophic chondrocytes. To assess cartilage matrix synthesis, we measured 35SO4 incorporation into newly synthesized glycosaminoglycans. Low concentrations (10 ng/ml) of FGF-2 stimulated cartilage matrix production, but high concentrations (1000 ng/ml) inhibited matrix production. We conclude that FGF-2 inhibits longitudinal bone growth by three mechanisms: decreased growth plate chondrocyte proliferation, decreased cellular hypertrophy, and, at high concentrations, decreased cartilage matrix production. These effects may explain the impaired growth seen in patients with achondroplasia and related skeletal dysplasias.