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In a trial involving patients with later-stage ADPKD, the V 2 -receptor antagonist tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period, which may slow the onset of end-stage kidney disease.

The authors investigated whether tolvaptan, an orally active vasopressin V 2 -receptor antagonist that promotes electrolyte-free water loss, might improve hyponatremia. Serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia and mild or marked hyponatremia improved with therapy at day 4 and day 30. Tolvaptan holds promise for treating patients with hyponatremic states. Serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia and mild or marked hyponatremia improved with tolvaptan therapy. Tolvaptan holds promise for treating patients with hyponatremic states. Hyponatremia, the most common electrolyte derangement occurring in hospitalized patients, 1 , 2 is usually classified as hypovolemic, euvolemic, or hypervolemic. The secretion of arginine vasopressin appears to be of central importance in the decline of serum sodium concentrations in all these conditions. 1 , 2 Hyponatremia is reported to be associated with increased morbidity and mortality among patients with heart, liver, or neurologic disease. 3 – 8 Even mild chronic hyponatremia has been associated with subtle neurologic defects, manifested as impairments in balance and attention that can increase the incidence of falls. 9 These deficits may be reversed with the correction of the hyponatremia. Tolvaptan, a . . .

In this trial, patients with autosomal dominant polycystic kidney disease were randomly assigned to tolvaptan, a vasopressin V 2 -receptor antagonist, or placebo. Over 3 years, the increase in total kidney volume in the tolvaptan group was half that in the placebo group. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and the fourth leading cause of end-stage kidney disease in adults worldwide. 1 , 2 It results in the progressive development of kidney cysts, kidney pain, hypertension, and, ultimately, kidney failure. Effective treatment for ADPKD has been lacking. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its second messenger adenosine-3′,5′-cyclic monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V 2 -receptor blockade all reduce the . . .

Autonomous cortisol secretion (ACS) from an adrenal adenoma can increase the risk for comorbidities and mortality. The dexamethasone suppression test (DST) is the standard method to diagnose ACS. A multi-site, retrospective cohort of adults with diagnosed adrenal tumors was used to understand patient characteristics associated with DST completion and ACS. Time to DST completion was defined using the lab value and result date; follow-up time was from the adrenal adenoma diagnosis to the time of completion or censoring. ACS was defined by a DST > 1.8 µg/dL (50 nmol/L). The Cox proportional hazards regression model assessed associations between DST completion and patient characteristics. In patients completing a DST, a logistic regression model evaluated relationships between elevated ACS and covariates. We included 24,259 adults, with a mean age of 63.1 years, 48.1% obese, and 28.7% with a Charlson comorbidity index ≥ 4. Approximately 7% (n = 1768) completed a DST with a completion rate of 2.36 (95% CI 2.35, 2.37) per 100 person-years. Fully adjusted models reported that male sex and an increased Charlson comorbidity index were associated with a lower likelihood of DST completion. Current or former smoking status and an increased Charlson comorbidity index had higher odds of a DST > 1.8 μg/dL. In conclusion, clinical policies are needed to improve DST completion and the management of adrenal adenomas.

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. Hyponatremia resulting from para‐neoplastic Syndrome of Inappropriate Antidiuretic Hormone is common in many types of cancer and correlates with poor outcomes. In this subanalysis of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT) clinical trials, once‐daily oral tolvaptan safely restored serum sodium levels in cancer patients with SIADH, thereby reducing the need for fluid restriction and electrolyte infusions.

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.

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.

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 60ml/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: <30ml/min per 1.73m2. Measurements were performed before, after 3 weeks of tolvaptan (up titration to 90/30mg/day, split dose), and 3 weeks after the last dose of tolvaptan. With tolvaptan, a minor, reversible decrease in GFR (125I-iothalamate clearance) was found that reached significance in groups A and B: –7.8 (interquartile range –13.7 to –1.3) and –4.3 (–9.7 to –0.9) ml/min per 1.73m2, respectively, but not in group C (GFR decrease –0.7 (–1.1 to 1.5) ml/min/1.73m2). The percentage change in GFR, ERPF (131I-hippuran clearance), and filtration fraction with tolvaptan did not differ between the three study groups. No differences between the three study groups were found in other main efficacy variables, besides smaller increases in urine volume in group C during tolvaptan treatment. Tolvaptan was well tolerated, with only two patients withdrawing. Thus, doses of tolvaptan typically used in patients with ADPKD do not produce a difference in renal hemodynamic profile in chronic kidney disease stages 1 through 4, but minor GFR drops may be observed in individual patients.

Tolvaptan and related V2-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V2-driven adenosine cyclic 3′,5′-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

Adrenal incidentalomas (AIs) may secrete excess cortisol, representing an elevated endogenous exposure to glucocorticoids, which could decrease bone mineral density and increase fracture risk. However, measurement of cortisol excess is not routinely done in patients with AI; thus, those with hormonally active AI at increased risk for fracture are under-identified. We sought to examine the association between excess cortisol levels and the incidence of fragility fracture in people with AI. This retrospective cohort study, conducted within two Kaiser Permanente regions (Southern California and Georgia), comprised women and men aged ≥50 yr with identified AI in the study period January 1, 2015-August 31, 2022. Patients’ cortisol excess status was categorized by the type of test conducted (if any) and the test result. Fractures and relevant covariates were ascertained via International Classification of Diseases (ICD)-9/10 codes. Hazard ratios (HR) were estimated using Cox proportional hazard models with mortality as a competing risk. Among the cohort of 14 886 patients with AI, 273 (1.8%) had autonomous cortisol secretion (ACS) confirmed by dexamethasone suppression test (DST) results >1.8 μg/dL (>50 nmol/L), and another 201 (1.4%), tested with urine free or random cortisol tests, had results suggestive of excess cortisol production. Most of the cohort (n = 9353, 62.8%) were untested around AI diagnosis or during follow-up. Compared to patients with normal DST results (and adjusted for age, sex, race/ethnicity, and several other clinical characteristics), the estimated HR of fracture risk for patients with ACS (HR 1.42, CI 0.86-2.32), evidence of cortisol excess (1.41, 0.85-2.32), and untested patients (1.28, 0.88-1.87) were suggestive of elevated risk. However, none of the elevated hazard rates were statistically significant at the 95% significance level. The apparent elevated risk in the untested patients suggests that many untested patients may have hormonally active AI that puts them at risk for fracture from secondary osteoporosis. Lay Summary Adrenal incidentalomas (AIs) are small tumors found during workups for other conditions. Some AI could secrete excess cortisol, which could lead to osteoporosis and fractures. Among our patients with AI who had laboratory testing for cortisol, fractures were more common for patients with excess cortisol production compared to patients with normal levels; however, this finding was not statistically significant. Patients who were not tested for cortisol had more fractures than the group with testing who had normal cortisol levels. This suggests that the untested group may have included people with excess cortisol production. We conclude that more people with AI should be assessed for cortisol excess because they may be at risk of having fractures.