Search Results (46)

Background: Tolvaptan, a vasopressin V2 receptor antagonist, is the only approved disease-modifying therapy for Autosomal Dominant Polycystic Kidney Disease (ADPKD), yet real-world data on its long-term effectiveness remain limited. Methods: In this single-center retrospective study, we evaluated 30 patients with ADPKD who received tolvaptan therapy for at least three years between 2019 and 2024. All patients met standard inclusion criteria and underwent serial magnetic resonance imaging to assess total kidney volume (TKV), along with longitudinal monitoring of renal function using estimated glomerular filtration rate (eGFR). Results: At the end of follow-up, the median annual TKV growth rate was 4.27% (IQR: 1.39–7.98), which did not differ significantly from the predicted without treatment growth rate of 5.3% (95% CI: −2.75 to 0.69, p = 0.194). Although the impact on TKV was limited, tolvaptan notably slowed the decline in kidney function, with a median eGFR of 65 mL/min/1.73 m² at follow-up, compared to a predicted value of 60.8 mL/min/1.73 m² (95% CI: −14.60 to −6.18, p < 0.001), reflecting a 33.9% relative benefit. In 80% of patients, renal function after three years was better than predicted. Conclusions: These findings suggest that tolvaptan provides significant functional benefit in ADPKD patients in routine clinical practice, even in the absence of marked suppression in TKV growth and support its continued use in carefully selected individuals. Full article

Background: Hyponatremia, defined as a serum sodium concentration below 135 mmol/L, is a common and serious electrolyte disturbance in patients with traumatic brain injury (TBI), and may be treated with vaptans—vasopressin receptor antagonists that promote water excretion. This study evaluates the safety and efficacy of tolvaptan, a vaptan, in correcting hyponatremia in TBI patients compared to a non-trauma cohort. Methods: We conducted a single-center retrospective analysis of 126 adult patients in the intensive care unit who received tolvaptan. The study included 73 TBI patients and 53 non-trauma patients with chronic medical conditions. Serum sodium levels were assessed 48 h after tolvaptan administration and compared between the two groups. Results: At baseline, the mean sodium level was higher in the TBI group compared to the non-trauma group (128.3 ± 4 mmol/L vs. 125.3 ± 5 mmol/L, p = 0.003). Both groups showed a significant increase in sodium levels after 48 h of tolvaptan therapy, and while the post-treatment sodium level was higher in the TBI group, the absolute change was not significantly different between the two groups (132.3 ± 5 mmol/L vs. 130.9 ± 7 mmol/L, p = 0.18). Sodium normalization (135–145 mmol/L) occurred in 48% of TBI patients versus 30% of non-trauma patients (p = 0.045), though this difference was not statistically significant after adjusting for baseline sodium levels. No cases of osmotic demyelination syndrome were observed. Conclusions: Our preliminary analysis suggests that tolvaptan effectively increases sodium levels in both TBI and non-trauma patients with hyponatremia. Further research is needed to fully characterize this response and determine the optimal use of tolvaptan for managing hyponatremia in the TBI population. Full article

Objective: The objective of this study was to compare the effectiveness of urea and tolvaptan in the treatment of plasma sodium levels in patients with hypotonic hyponatremia. Methods: This was an observational, longitudinal, and retrospective study including all adult patients who received treatment with urea or tolvaptan for hypotonic hyponatremia from 1 April 2014 to 31 October 2023 at the Department of Internal Medicine, Virgen del Rocío University Hospital, Seville, Spain. Results: Forty-seven (55.3%) patients received urea and 38 (44.7%) tolvaptan. The drugs were prescribed for the treatment of syndrome of inappropriate antidiuresis (SIAD) in 59 (69.4%) patients. The mean blood sodium level at the start of treatment was 123.5 ± 6.2 mEq/L. Overall, 61.7% and 63.2% of patients treated with urea and tolvaptan, respectively, achieved a normal blood sodium level (p = 0.89), although the time to have their sodium levels corrected differed between both groups: 41.7 ± 76 days with urea and 21 ± 23.9 days with tolvaptan (p = 0.038). The following were significant in the multivariate study: Initial sodium value (p = 0.037), absolute sodium improvement (p = 0.041), and percentage sodium improvement (p = 0.033). Among patients with SIAD, 69.5% achieved a normal sodium level; this figure was 45.5% for patients with heart failure. Three patients reported side adverse events in the urea group and none in the tolvaptan group. Conclusions: Our data, reflecting real-world practice and follow-up of patients with hypotonic hyponatremia, suggest that both urea and tolvaptan are safe, well-tolerated, and have a similar effectiveness in correcting blood sodium levels in patients with hypotonic hyponatremia, overall and secondary to SIAD, though treatment with tolvaptan achieved this goal earlier than urea. Full article

Background/Objectives: Although tolvaptan efficacy in ADPKD has been demonstrated in randomized clinical trials, there is no definitive method for assessing its efficacy in the individual patient in the clinical setting. In this exploratory feasibility study, we report a method to quantify the change in total kidney volume (TKV) growth rate to retrospectively evaluate tolvaptan efficacy for individual patients. Treatment-related changes in estimated glomerular filtration rate (eGFR) are also assessed. Methods: MRI scans covering at least 1 year prior to and during treatment with tolvaptan were performed, with deep learning facilitated kidney segmentation and fitting multiple imaging timepoints to exponential growth in 32 ADPKD patients. Clustering analysis differentiated tolvaptan treatment “responders” and “non-responders” based upon the magnitude of change in TKV growth rate. Differences in rate of eGFR decline, urine osmolality, and other parameters were compared between responders and non-responders. Results: Eighteen (56%) tolvaptan responders (mean age 42 ± 8 years) were identified by k-means clustering, with an absolute reduction in annual TKV growth rate of >2% (mean = −5.1% ± 2.5% per year). Thirteen (44%) non-responders were identified, with <1% absolute reduction in annual TKV growth rate (mean = +2.4% ± 2.7% per year) during tolvaptan treatment. Compared to non-responders, tolvaptan responders had significantly higher mean TKV growth rates prior to tolvaptan treatment (7.1% ± 3.6% per year vs. 3.7% ± 2.4% per year; p = 0.003) and higher median pretreatment spot urine osmolality (Uosm, 393 mOsm/kg vs. 194 mOsm/kg, p = 0.03), confirmed by multivariate analysis. Mean annual rate of eGFR decline was less in responders than in non-responders (−0.25 ± 0.04, CI: [−0.27, −0.23] mL/min/1.73 m² per year vs. −0.40 ± 0.06, CI: [−0.43, −0.37] mL/min/1.73 m² per year, p = 0.036). Conclusions: In this feasibility study designed to assess predictors of tolvaptan treatment efficacy in individual patients with ADPKD, we found that high pretreatment levels of annual TKV growth rate and higher pretreatment spot urine osmolality were associated with a responder phenotype. Full article

With the approval of tolvaptan as the first specific medicine for the treatment of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD), biomarker discovery has gained renewed interest as it is widely recognized that these will be crucial in clinical decision-making, serving as either prognostic or predictive tools. Since the marketing authorization was first issued in 2015 for ADPKD, tolvaptan has remained the sole pharmacological compound specifically targeting the disease. For ADPKD patients it is an invaluable medicine for retarding disease progression. Although the field of overall biomarker discovery and validation has been detailed in several publications, the role of inflammation remains largely overlooked in ADPKD. The current work aims to provide the reader with an updated review of inflammation biomarkers research in ADPKD, highlighting the role of urinary MCP-1 (monocyte chemoattractant protein-1) as the most promising tool. Full article

Background: Even in current guideline-directed medical therapy, including recently introduced vasopressin type 2 receptor antagonist tolvaptan, congestion has not been resolved in patients with heart failure. Kampo medicine goreisan has been receiving considerable attention as an additional therapy for patients who are refractory to conventional diuretics therapy, including tolvaptan. However, the impact of goreisan on urine electrolytes remains uncertain. Methods: Patients with congestive heart failure who received goreisan as an add-on therapy to tolvaptan-incorporated medical therapy were prospectively included. The changes in urine parameters during the first 24 h were assessed as a primary concern. Baseline factors associated with an increase in urine sodium excretion were investigated. Results: A total of 21 patients were included. The median age was 81 (77, 86), and 13 (62%) were men. Twenty-four hours after the initiation of goreisan, urine osmolality decreased significantly, urine sodium level remained unchanged, urine potassium and glucose levels decreased significantly, urine urea nitrogen level tended to decrease, and urine volume tended to increase. The fractional excretion of sodium tended to increase. Baseline plasma B-type natriuretic peptide level had a positive correlation with a change in fractional excretion of sodium from baseline to day 1 (r = 0.52, p = 0.015). Conclusions: Goreisan may increase urine volume via aquaretic and natriuretic effects in patients with congestive heart failure receiving tolvaptan-incorporated medical therapy. Goreisan may have the ability to “modulate” fluid balance depending on congestion status. Full article

Autosomal dominant polycystic kidney disease (ADPKD) is the predominant hereditary factor leading to end-stage renal disease (ESRD) worldwide, affecting individuals across all races with a prevalence of 1 in 400 to 1 in 1000. The disease presents significant challenges in management, particularly with limited options for slowing cyst progression, as well as the use of tolvaptan being restricted to high-risk patients due to potential liver injury. However, determining high-risk status typically requires magnetic resonance imaging (MRI) to calculate total kidney volume (TKV), a time-consuming process demanding specialized expertise. Motivated by these challenges, this study proposes alternative methods for high-risk categorization that do not rely on TKV data. Utilizing historical patient data, we aim to predict rapid kidney enlargement in ADPKD patients to support clinical decision-making. We applied seven machine learning algorithms—Random Forest, Logistic Regression, Support Vector Machine (SVM), Light Gradient Boosting Machine (LightGBM), Gradient Boosting Tree, XGBoost, and Deep Neural Network (DNN)—to data from the Polycystic Kidney Disease Outcomes Consortium (PKDOC) database. The XGBoost model, combined with the Synthetic Minority Oversampling Technique (SMOTE), yielded the best performance. We also leveraged explainable artificial intelligence (XAI) techniques, specifically Local Interpretable Model-Agnostic Explanations (LIME) and Shapley Additive Explanations (SHAP), to visualize and clarify the model’s predictions. Furthermore, we generated text summaries to enhance interpretability. To evaluate the effectiveness of our approach, we proposed new metrics to assess explainability and conducted a survey with 27 doctors to compare models with and without XAI techniques. The results indicated that incorporating XAI and textual summaries significantly improved expert explainability and increased confidence in the model’s ability to support treatment decisions for ADPKD patients. Full article

Polycystic kidney disease (PKD) is a rare but significant renal condition with major implications for global acute and chronic patient care. Oxidative stress and reactive oxygen species (ROS) can significantly alter its pathophysiology, clinical outcomes, and treatment, contributing to negative outcomes, including hypertension, chronic kidney disease, and kidney failure. Inflammation from ROS and existing cysts propagate the generation and accumulation of ROS, exacerbating kidney injury, pro-fibrotic signaling cascades, and interstitial fibrosis. Early identification and prevention of oxidative stress and ROS can contribute to reduced cystic kidney disease progression and improved longitudinal patient outcomes. Increased research regarding biomarkers, the pathophysiology of oxidative stress, and novel therapeutic interventions alongside the creation of comprehensive guidelines establishing methods of assessment, monitoring, and intervention for oxidative stress in cystic kidney disease patients is imperative to standardize clinical practice and improve patient outcomes. The integration of artificial intelligence (AI), genetic editing, and genome sequencing could further improve the early detection and management of cystic kidney disease and mitigate adverse patient outcomes. In this review, we aim to comprehensively assess the multifactorial role of ROS in cystic kidney disease, analyzing its pathophysiology, clinical outcomes, treatment interventions, clinical trials, animal models, and future directions for patient care. Full article

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by the development and enlargement of multiple kidney cysts, leading to progressive kidney function decline. To date, Tolvaptan, the only approved treatment for this condition, is able to slow down the loss of annual kidney function without stopping the progression of the disease. Furthermore, this therapy is approved only for patients with rapid disease progression and its compliance is problematic because of the drug’s impact on quality of life. The recent literature suggests that cystic cells are subject to several metabolic dysregulations, particularly in the glucose pathway, and mitochondrial abnormalities, leading to decreased oxidative phosphorylation and impaired fatty acid oxidation. This finding paved the way for new lines of research targeting potential therapeutic interventions for ADPKD. In particular, this review highlights the latest studies on the use of ketosis, through ketogenic dietary interventions (daily calorie restriction, intermittent fasting, time-restricted feeding, ketogenic diets, and exogenous ketosis), as a potential strategy for patients with ADPKD, and the possible involvement of microbiota in the ketogenic interventions’ effect. Full article

We have previously demonstrated that the vasopressin type 2 receptor (AVPR2) antagonist tolvaptan reduces cell proliferation and invasion and triggers apoptosis in different human cancer cell lines. To study this effect in vivo, a xenograft model of small cell lung cancer was developed in Fox1^nu/nu nude mice through the subcutaneous inoculation of H69 cells, which express AVPR2. One group of mice (n = 5) was treated with tolvaptan for 60 days, whereas one group (n = 5) served as the control. A reduced growth was observed in the tolvaptan group in which the mean tumor volume was significantly smaller on day 60 compared to the control group. In the latter group, a significantly lower survival was observed. The analysis of excised tumors revealed that tolvaptan effectively inhibited the cAMP/PKA and PI3K/AKT signaling pathways. The expression of the proliferative marker proliferating cell nuclear antigen (PCNA) was significantly lower in tumors excised from tolvaptan-treated mice, whereas the expression levels of the apoptotic marker caspase-3 were higher than those in control animals. Furthermore, tumor vascularization was significantly lower in the tolvaptan group. Overall, these findings suggest that tolvaptan counteracts tumor progression in vivo and, if confirmed, might indicate a possible role of this molecule as an adjuvant in anticancer strategies. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent hereditary disorder that affects the kidneys, characterized by the development of an excessive number of fluid-filled cysts of varying sizes in both kidneys. Along with the progression of ADPKD, these enlarged cysts displace normal kidney tissue, often accompanied by interstitial fibrosis and inflammation, and significantly impair renal function, leading to end-stage renal disease. Currently, the precise mechanisms underlying ADPKD remain elusive, and a definitive cure has yet to be discovered. This review delineates the epidemiology, pathological features, and clinical diagnostics of ADPKD or ADPKD-like disease across human populations, as well as companion animals and other domesticated species. A light has been shed on pivotal genes and biological pathways essential for preventing and managing ADPKD, which underscores the importance of cross-species research in addressing this complex condition. Treatment options are currently limited to Tolvaptan, dialysis, or surgical excision of large cysts. However, comparative studies of ADPKD across different species hold promise for unveiling novel insights and therapeutic strategies to combat this disease. Full article

Abdominal imaging of autosomal dominant polycystic kidney disease (ADPKD) has historically focused on detecting complications such as cyst rupture, cyst infection, obstructing renal calculi, and pyelonephritis; discriminating complex cysts from renal cell carcinoma; and identifying sources of abdominal pain. Many imaging features of ADPKD are incompletely evaluated or not deemed to be clinically significant, and because of this, treatment options are limited. However, total kidney volume (TKV) measurement has become important for assessing the risk of disease progression (i.e., Mayo Imaging Classification) and predicting tolvaptan treatment’s efficacy. Deep learning for segmenting the kidneys has improved these measurements’ speed, accuracy, and reproducibility. Deep learning models can also segment other organs and tissues, extracting additional biomarkers to characterize the extent to which extrarenal manifestations complicate ADPKD. In this concept paper, we demonstrate how deep learning may be applied to measure the TKV and how it can be extended to measure additional features of this disease. Full article

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (−3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy. Full article

Tolvaptan, an oral vasopressin V2 receptor antagonist, reduces renal volume expansion and loss of renal function in patients with autosomal dominant polycystic kidney disease (ADPKD). Data for predictive factors indicating patients more likely to benefit from long-term tolvaptan are lacking. Data were retrospectively collected from 55 patients on tolvaptan for 6 years. Changes in renal function, progression of renal dysfunction (estimated glomerular filtration rate [eGFR], 1-year change in eGFR [ΔeGFR/year]), and renal volume (total kidney volume [TKV], percentage 1-year change in TKV [ΔTKV%/year]) were evaluated at 3-years pre-tolvaptan, at baseline, and at 6 years. In 76.4% of patients, ΔeGFR/year improved at 6 years. The average 6-year ΔeGFR/year (range) minus baseline ΔeGFR/year: 3.024 (−8.77–20.58 mL/min/1.73 m²). The increase in TKV was reduced for the first 3 years. A higher BMI was associated with less of an improvement in ΔeGFR (p = 0.027), and family history was associated with more of an improvement in ΔeGFR (p = 0.044). Hypernatremia was generally mild; 3 patients had moderate-to-severe hyponatremia due to prolonged, excessive water intake in response to water diuresis—a side effect of tolvaptan. Family history of ADPKD and baseline BMI were contributing factors for ΔeGFR/year improvement on tolvaptan. Hyponatremia should be monitored with long-term tolvaptan administration. Full article