Visceral Adiposity and Progression of ADPKD: A Cohort Study of Patients From the TEMPO 3:4 Trial.

RATIONALE & OBJECTIVE: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR: Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME: Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH: Multinomial logistic regression and linear mixed models. RESULTS: In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS: Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY: We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.

Using Tolvaptan to Treat Hyponatremia: Results from a Post-authorization Pharmacovigilance Study.

INTRODUCTION: Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness. METHODS: This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians. RESULTS: A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1-1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred. CONCLUSION: In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01228682.

Hospitalized patients often experience abnormally low blood sodium levels (hyponatremia), which can cause significant symptoms and poses a serious health risk (Wald et al. in Arch Intern Med 170:294­302, 2010). Yet, increasing sodium levels too rapidly in these patients can unintentionally cause osmotic demyelination syndrome, resulting in long-term neurologic damage or death. Tolvaptan was approved in the European Union to treat one type of hyponatremia caused by a hormonal imbalance known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Tolvaptan effectively increased patient sodium levels in clinical trials, but real-world data are needed to understand tolvaptan treatment more fully in everyday clinical practice. We evaluated patterns of use, efficacy, and safety of tolvaptan in patients treated in hospitals and after discharge for hyponatremia due to SIADH. Tolvaptan was correctly used to treat only hyponatremia caused by SIADH in nearly all of the 252 patients studied. Patient sodium levels increased in the first week of tolvaptan treatment and then stabilized. Hyponatremia symptoms, such as confusion, nausea, tiredness, and dizziness, were present in 48.4% of patients before treatment and in 18.3% after starting tolvaptan. Consistent with earlier studies, some patients (24.6%) experienced excessively rapid correction of hyponatremia. However, no subsequent neurologic problems or deaths were attributed to the rapid correction, which suggests that medical providers were carefully monitoring and managing sodium levels to prevent serious consequences. Our study indicates that tolvaptan is being used safely and effectively to treat hyponatremia due to SIADH in a patient population with complex medical needs.

Hyponatremia in hospitalized patients: the potential role of tolvaptan.

Hyponatremia (typically defined as serum sodium level < 135 mEq/L) is a common electrolyte abnormality among hospitalized patients. Whether present at admission or acquired during hospitalization, hyponatremia is associated with higher mortality and longer hospital stays. Failure to adequately investigate and treat hyponatremia may also be associated with adverse outcomes. The presence and severity of clinical symptoms largely depend on the rate and extent of the decline in serum sodium; rapid or large decreases may cause serious neurologic complications. The approach to treatment depends on the presence and severity of symptoms, the timing of their onset, the underlying etiology, and the patient's volume status. Patients with euvolemic or hypervolemic hyponatremia usually have inappropriately elevated levels of arginine vasopressin, which stimulates water reabsorption even in the presence of low serum osmolality. Tolvaptan is an orally active, selective V2-receptor antagonist that blocks the effects of arginine vasopressin in the renal collecting duct to promote aquaresis without increasing sodium or potassium excretion; as a result, it increases serum sodium in a controlled manner. Tolvaptan offers a mechanism-based treatment option for patients with euvolemic or hypervolemic hyponatremia who have serum sodium levels < 125 mEq/L or persistent symptoms resistant to fluid restriction.