Change In Total Kidney Volume Research Articles

A Case of Good Efficacy of Tolvaptan in a Patient with Markedly Enlarged Polycystic Kidney

A 61-year-old patient with autosomal dominant polycystic kidney disease (Irazabal class 1E) in whom renal function had decreased and kidney size had increased over the past 3 years (change in serum creatinine, 1.3 mg/dL to 1.5 mg/dL; change in total kidney volume, 5632 cm3 to 7301 cm3) was treated with tolvaptan 60 mg/day. After 8 years of tolvaptan treatment, serum creatinine remained at 1.51 mg/dL, and total kidney volume was at 6812 cm3. Adequate salt intake and good weight control may have resulted in good outcomes, even in patients with treatment-resistant giant cystic kidney disease.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial

Aims/hypothesisThe apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium–glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV).MethodsThis was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the ‘semaglutide’ group), or the combination of semaglutide and empagliflozin (referred to as the ‘combination-therapy’ group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico–medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI.ResultsBoth semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: −0.20×10−3 mm2/s [95% CI −0.30, −0.10], p<0.001; empagliflozin: −0.15×10−3 mm2/s [95% CI −0.26, −0.04], p=0.01). No significant change was observed in the combination-therapy group (−0.05×10−3 mm2/s [95%CI −0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of −0.13×10−3 mm2/s (95% CI −0.22, −0.04; p=0.01). Compared with placebo, TKV decreased by −3% (95% CI −5%, −0.3%; p=0.04), −3% (95% CI −5%, −0.4%; p=0.02) and −5% (95% CI −8%, −2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c.Conclusions/interpretationIn a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38Graphical

Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease

Background and objectivesEvidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. Material and methodsA single-center observational study (2016–2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. ResultsA total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (−3.52ml/min/1.73m2 [−4.98%] vs −3.98ml/min/1.73m2 [−8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. ConclusionsThis study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

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

Rationale & ObjectiveBody-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 DesignA retrospective cohort study. Setting & Participants1053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and high risk of rapid disease progression. PredictorEstimates of visceral adiposity extracted from coronal plane MRIs using deep learning. OutcomeAnnual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. Analytical ApproachMultinomial logistic regression and linear mixed models. ResultsIn fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of ≥7% vs. <5% (OR: 4.78 [3.03, 7.47]). The association was stronger in females than males (interaction p<0.01). In linear mixed models with an outcome of % change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (three-way interaction of treatment*time*visceral adiposity p=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual % change in TKV for individuals with a normal BMI (De-Long’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 females (fully adjusted OR 1.06 [1.01, 1.11] per 10 unit increase in visceral adiposity) but not males (0.98 [0.95, 1.02]). LimitationsRetrospective; rapid progressors; computational demand of deep learning. ConclusionsVisceral 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.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AimsThe aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. MethodsOne hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OutcomesThe primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. ConclusionThis study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing.Registration: This study is registered on Clinicaltrials.gov # NCT03273413

Comparing Effects of Tolvaptan and Instruction to Increase Water Consumption in ADPKD: Post Hoc Analysis of TEMPO 3:4.

In addition to decreasing water excretion and increasing urinary concentration, the antidiuretic hormone vasopressin plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). It has been hypothesized that by suppressing vasopressin release, drinking large amounts of water might exert therapeutic effects in ADPKD similar to those of tolvaptan, an antagonist of the vasopressin type 2 receptor, but evidence is lacking. We analyzed data from tolvaptan clinical trials to evaluate relationships among water intake, urine osmolality (Uosm), and change in total kidney volume (TKV). Analysis of the TEMPO 3:4 clinical trial in which participants were randomized to tolvaptan or placebo and instructed to drink large amounts of water. The relationship between change in spot Uosm from baseline to Week 3 and change in TKV to Month 12 was assessed using linear regression modeling. Two short-term tolvaptan trials were analyzed to explore relationships between intermittent Uosm sampling and 24-hour Uosm suppression. With both tolvaptan and placebo (i.e., mandated high water intake alone), Uosm reduction at Week 3 was associated with reduction in TKV growth at Month 12. However, for the same decrease in spot Uosm, the corresponding reduction in TKV growth was greater for tolvaptan (for example, a -250 mOsm/kg reduction in Uosm at Week 3 was associated with a -1% change in TKV at Month 12 for tolvaptan versus +4.5% for placebo). In short-term trials, similar reductions in spot or trough Uosm values were achievable with tolvaptan and high water intake, but cumulative 24-hour suppression was greater with tolvaptan. This analysis supports a relationship between effects on Uosm and inhibition of disease progression by tolvaptan and high water intake alone. The findings further suggest that 24-hour Uosm measurement is superior to spot Uosm for assessing suppression of vasopressin activity by tolvaptan.

Changes in Kidney and Liver Volumes in Patients With Autosomal Dominant Polycystic Kidney Disease Before and After Dialysis Initiation

ObjectiveTo examine the changes in total kidney volume (TKV) and total liver volume (TLV) before and after dialysis initiation in patients with autosomal dominant polycystic kidney disease. Patients and MethodsThis was a retrospective, single-center cohort study to investigate the changes in TKV and TLV before and after dialysis initiation, along with influencing factors, using linear mixed models. We enrolled 95 patients with autosomal dominant polycystic kidney disease (85 receiving hemodialysis [HD] and 10 receiving peritoneal dialysis [PD]) who began receiving dialysis at Toranomon Hospital from January 1, 2008, to December 31, 2020. ResultsThe least squares mean TKV ratio (TKV at each time point/TKV at dialysis initiation) was 63.8% (95% confidence interval [CI], 54.7%-72.9%) at 6 years before dialysis initiation and 95.5% (95% CI, 82.9%-108.2%) at 6 years after dialysis initiation (P<.001). A multivariate linear mixed model analysis revealed that dialysis style (HD or PD) had the strongest effect on changes in TKV (P=.002). The least squares mean TLV ratio was 98.2% (95% CI, 88.4%-108.0%) at 6 years before dialysis initiation and 95.7% (95% CI, 85.2%-106.2%) at 6 years after dialysis initiation (P=.01). Although PD did not have significant effects on changes in TLV (P=.27), the changes in TLV were greater in patients on PD than in those on HD. ConclusionThe TKV increased until dialysis initiation and generally decreased after dialysis initiation. The TLV continued to increase even after dialysis initiation, however, changes in the TLV significantly decreased after dialysis initiation. The increases in TKV and TLV were greater in patients on PD than in those on HD.

PS-C26-10: THE PROPKD SCORE IS ASSOCIATED WITH THE PROGRESSION OF RENAL INVOLVEMENT IN PATIENTS WITH POLYCYSTIC KIDNEY DISEASE TREATED WITH TOLVAPTAN

Background: The PROPKD score has been proposed to evaluate the risk of the progression to end stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD), based on gender (male: 1point), hypertension under 35 years old (2 points), urological event under 35 years old (2 points), and gene mutation (PKD1 truncating mutation: 4 points, PKD1 non-truncating mutation: 2 points, PKD2: 0 point). Although tolvaptan has benefits for renal involvement, whether PROPKD score could predict future renal involvement in patients with ADPKD treated with tolvaptan is unknown. Thus, we explored the effects of tolvaptan on the annual changes in total kidney volume (%TKV) and estimated glomerular filtration rate (%eGFR) according to the PROPKD score in these patients. Methods: 32 ADPKD patients treated tolvaptan for at least a year were retrospectively analyzed (the mean observation period: 3.6 years). We examined the decline in renal function, %TKV by computed tomography, and gene mutation. The association between %eGFR and %TKV change before and after tolvaptan treatment, annual TKV change (%TKV) and PROPKD score was analyzed. Results: We identified gene mutations in ADPKD patients: PKD1 truncating mutation (n = 15), PKD1 non-truncating mutation (n = 5), PKD2 mutation (n = 6), and mutation not found (n = 6). Mean %TKV and eGFR were 1843 ± 986 ml and 54.7 ± 21.0 ml/min/1.73 m2, respectively. The mean PROPKD score was 3.3 ± 2.4 points and showed a significant negative correlation with %eGFR before and after tolvaptan treatment (p = 0.044/0.016), and no significant correlation with %TKV before and after tolvaptan treatment. Conclusion: The higher PROPKD score, the faster the decrease in %eGFR during tolvaptan therapy, suggesting that the PROPKD score may be useful as a predictor of the risk of progression to renal failure after tolvaptan introduction.

Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. Enrollment included 236 and 242 patients in stages 1 and 2, respectively. In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. The short follow-up period after the end of treatment and limited generalizability of the findings. In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. This study was funded by Sanofi. Registered at ClinicalTrials.gov with study number NCT03523728.

RESET-PKD: a pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease.

Ketogenic dietary interventions (KDI) have been shown to be effective in animal models of polycystic kidney disease (PKD), but data from clinical trials are lacking. Ten autosomal dominant PKD (ADPKD) patients with rapid disease progression were enrolled at visit V1 and initially maintained a carbohydrate-rich diet. At V2, patients entered one of the two KDI arms: a 3-day water fast (WF) or a 14-day ketogenic diet (KD). At V3, they resumed their normal diet for 3-6 weeks until V4. At each visit, magnetic resonance imaging kidney and liver volumetry was performed. Ketone bodies were evaluated to assess metabolic efficacy and questionnaires were used to determine feasibility. All participants [KD n=5, WF n=5; age 39.8±11.6 years; estimated glomerular filtration rate 82±23.5mL/min/1.73 m2; total kidney volume (TKV) 2224 ± 1156mL] were classified as Mayo Class 1C-1E. Acetone levels in breath and beta-hydroxybutyrate (BHB) blood levels increased in both study arms (V1 to V2 average acetone: 2.7±1.2p.p.m., V2 to V3: 22.8±11.9p.p.m., P=.0006; V1 to V2 average BHB: 0.22±0.08mmol/L, V2 to V3: 1.88±0.93mmol/L, P=.0008). Nine of 10 patients reached a ketogenic state and 9/10 evaluated KDIs as feasible. TKV did not change during this trial. However, we found a significant impact on total liver volume (ΔTLV V2 to V3: -7.7%, P=.01), mediated by changes in its non-cystic fraction. RESET-PKD demonstrates that short-term KDIs potently induce ketogenesis and are feasible for ADPKD patients in daily life. While TLV quickly changed upon the onset of ketogenesis, changes in TKV may require longer-term interventions.

Clinical Utility and Tolerability of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Autosomal dominant polycystic kidney disease, also known as ADPKD, is the most common hereditary kidney disease, affecting different age groups. ADPKD can eventually lead to end-stage renal disease. The etiology of ADPKD is genetic, resulting in the formation of cysts containing fluids on the kidneys. Patients with ADPKD present a range of symptoms following a decline in kidney function. Pain, stones, proteinuria and osteoporosis are few of the many symptoms, resulting from decreased kidney function. Tolvaptan, a selective V2 receptor antagonist, is the etiological treatment used for ADPKD. In this paper, we conducted a systematic review of the literature between 2011 and 2021 to gather data regarding the tolerability and efficacy of tolvaptan use in ADPKD. A total of 22 trials were reviewed. Tolvaptan efficacy in the trials was measured using changes in eGFR or changes in total kidney volume. Results showed that tolvaptan use in ADPKD was associated with a slower decline in kidney function and a decrease in total kidney volume. Side effects of this drug include polyuria, nocturia and polydipsia along with hepatotoxicity. The two biggest trials, TEMPO and REPRISE, change in eGFR from pre-treatment baseline to post-treatment was 1.3 mL/min/1.73 for REPRISE and 1 mL/min/1.73 for TEMPO 3:4. A mean decrease of 49% in total kidney volume from baseline to post-treatment was found in the TEMPO 3:4 study.

The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD

Rationale & ObjectiveVenglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials.Study DesignSTAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies.Setting & ParticipantsTarget enrollment in stages 1 and 2 was 240 and 320 patients, respectively.InterventionsStage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data.OutcomesPrimary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2).LimitationsIf stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects.ConclusionsModeling allows the design and powering of a 2-stage combined study to assess venglustat’s impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration.FundingThis study was funded by Sanofi.Trial registrationSTAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.

Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. Prospective randomized controlled double-blind clinical trial. 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. Short study duration. We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. Government and philanthropic grants (NIDDK and the Zell Foundation). Registered at ClinicalTrials.gov with study number NCT02903511.

Urinary Aquaporin 2 as a Potential Indicator Predicting Tolvaptan Response in Patients With ADPKD

IntroductionTolvaptan is used to treat autosomal dominant polycystic kidney disease (ADPKD) because it inhibits binding of the antidiuretic hormone vasopressin to the vasopressin V2 receptor (V2R), which suppresses the insertion of preformed water channel aquaporin 2 (AQP2) molecules in the luminal membrane of the collecting duct cells.MethodsThis single-center, prospective observational cohort study investigated whether decreased AQP2 elimination in urine affects the renal prognosis of patients who received tolvaptan. We selected 92 patients with ADPKD who were administered tolvaptan in our hospital. We evaluated correlations between changes in urinary AQP2 (U-AQP2) and clinical parameters and the annual change in total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) as renal prognostic factors using univariable and multivariable multiple regression analyses.ResultsThe observation period was 2.4 ± 1.5 years. U-AQP2 per milligram of urinary creatinine (U-AQP2/Cr) decreased from 67.8 ± 50.6 to 20.7 ± 15.1 fmol/mg urinary creatinine after 1 month of tolvaptan treatment. This initial change in U-AQP2/Cr was correlated with high baseline U-AQP2/Cr, low baseline eGFR, and a large initial change in eGFR (baseline to 1 month). The initial change in U-AQP2/Cr (baseline to 1 month) was strongly correlated with the annual change in TKV and eGFR in multivariable analysis.ConclusionInitial decrease in U-AQP2/Cr in the first month of treatment reflects the pharmacologic effect of tolvaptan and could be an indicator of renal prognosis during tolvaptan treatment.

Safety and efficacy of Tolvaptan in real-world patients with autosomal dominant polycystic kidney disease- interim results of SLOW-PKD surveillance

BackgroundTolvaptan is a vasopressin type 2 receptor antagonist and has been used to treat autosomal dominant polycystic kidney disease (ADPKD) since 2014. There has been limited real-world data on the safety and efficacy of tolvaptan.MethodsThis post-marketing surveillance was conducted to evaluate the long-term safety and the efficacy of tolvaptan in Japanese patients with ADPKD in real-world clinical settings. The baseline characteristics of 1630 patients treated with tolvaptan are reported. Safety analysis comprises evaluation of adverse drug reactions (ADRs). The efficacy evaluation includes percent change in total kidney volume (TKV) and change in estimated glomerular filtration rate (eGFR) before and after tolvaptan treatment.ResultsMean age was 49.7 ± 11.2 years and 843 (51.7%) patients were male. Baseline TKV was 2158 ± 1346 mL and eGFR was 44.4 ± 21.7 mL/min/1.73 m2. The majority of CKD patients were stage G3b (27.0%) and G4 (30.1%). Frequently reported ADRs were hepatic function abnormal (8.3%), thirst (8.2%), and hyperuricaemia (6.9%). The frequency of ALT elevation (> 30 and > 90 IU/L) was slightly high (32.9 and 8.3%) to previous studies. After tolvaptan treatment, the annual rate of percentage change in TKV reduced from 11.68%/year to 2.73%/year (P < 0.0001). Similar results were also obtained for the effect on change in eGFR from − 3.31 to − 2.28 mL/min/1.73 m2/year after initiation of tolvaptan treatment (P = 0.0403).ConclusionThere were no major problems with safety of tolvaptan treatment and comparable efficacy for TKV and eGFR was observed in relation to the previous pivotal two randomized control trials in this post-marketing surveillance.

Overweight and Obesity and Progression of ADPKD.

On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity. A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 m2) who were at high risk of rapid progression were categorized by body mass index (BMI; calculated using nonkidney weight) as normal weight (18.5-24.9 kg/m2; n=670), overweight (25.0-29.9 kg/m2; n=429), or obese (≥30 kg/m2; n=213). Linear and multinomial logistic regression models were used to determine the association of baseline overweight and obesity with change in total kidney volume (TKV) over the 3-year study period. In fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus <5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of -0.95 [95% CI, -2.32 to 0.40] ml/min per 1.73 m2 per year per five-unit higher BMI). The three-way interaction (treatment×time×BMI group) was not statistically significant in linear mixed models with an outcome of TKV (log-transformed estimated coefficient comparing the treatment effect for overweight versus normal weight: 0.56% [95% CI, -0.70% to 1.84%] per year; P=0.38; obese versus normal weight: 0.07% [95% CI, -1.47% to 1.63%] per year; P=0.93) or eGFR (estimated coefficient comparing overweight versus normal weight: -0.07 [95% CI, -0.95 to 0.82] ml/min per 1.73 m2 per year; P=0.88; obese versus normal weight: 0.22 [95% CI, -0.93 to 1.36] ml/min per 1.73 m2 per year; P=0.71). Overweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization. Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948.

FC 130RANDOMIZED, PLACEBO-CONTROLLED, PHASE 3B TRIAL OF TOLVAPTAN IN THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): 1-YEAR DATA

Abstract Background and Aims Tolvaptan (TOL) is a vasopressin V2 receptor antagonist that inhibits total kidney volume (TKV) growth and kidney function decline in adults with rapidly progressing ADPKD. The therapeutic potential of TOL in pediatric patients at risk of early disease progression has not been previously reported. We conducted a clinical trial of TOL in children and adolescents with early manifesting ADPKD to evaluate pharmacodynamic properties and preliminary efficacy and safety information in this age group. Method This was a Phase 3b, 2-part trial (EudraCT: 2016-000187-42; ClinicalTrials.gov: NCT02964273). Phase A (reported here) was a 1-year, randomized, double-blind, placebo (PBO)-controlled, multicenter trial; Phase B is an ongoing, 2-year, open-label extension. Subjects had to be diagnosed with ADPKD (presence of renal cysts with family history and/or genetic diagnosis), with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and body weight ≥20 kg. The target population was aged 12-17 years; subjects aged 4-11 years were also allowed to enter if eligibility criteria were met. Starting and maintenance TOL/PBO doses were based on body weight. The co-primary endpoints were changes from baseline in spot urine osmolality (Uosm) and specific gravity at Week 1; additional endpoints were the 12-month changes in TKV and eGFR. Safety and tolerability were monitored. In this exploratory trial, outcomes were summarized descriptively, with no statistical comparisons planned between groups. Results Of 91 subjects enrolled (66 aged 12–17 years and 25 aged &amp;lt;12 years), 48 were randomized to TOL and 43 to PBO. Among enrolled subjects, there was a history of hypertension in 23.1%, proteinuria 15.4%, kidney pain 12.1%, and hepatic cysts 6.6%. Mean changes (±SD) from baseline in spot Uosm and specific gravity at Week 1 were greater with TOL vs PBO: -386 (284) vs -93 (332) mOsm/kg and -0.009 (0.007) vs -0.002 (0.008), respectively. In subjects aged 12–17 years (1 subject with tuberous sclerosis and ADPKD excluded as an outlier), the mean % TKV change (±SD) from baseline to Month 12 was 4.6% (9.1) for TOL and 7.7% (9.3) for PBO (Figure 1). Mean change (±SD) in eGFR from Day 7 to Month 12 in subjects ages 12–17 years was 0.4 (10.3) mL/min/1.73 m2 for TOL and -3.5 (10.9) mL/min/1.73 m2 for PBO (Figure 2). The most frequent treatment-emergent adverse events during Phase A were (TOL vs PBO): polyuria (25.0% vs 2.3%), blood creatinine increased (18.8% vs 4.7%), pollakiuria (18.8% vs 0.0%), cough (14.6% vs 11.6%), nocturia (14.6% vs 4. 7%), thirst (14.6% vs 2.3%), abdominal pain (12.5% vs 7.0%), constipation (10.4% vs 2.3%), and orthostatic hypotension (10.4% vs 0.0%). Potentially clinically significant increases in creatinine (&amp;gt;1.5 x baseline) occurred in 4 TOL subjects and no PBO subject. No subject had elevated transaminases or drug-induced liver injury. Serious adverse events were reported in 1 TOL subject (viral pericarditis) and 6 PBO, none considered related to treatment. One subject discontinued due to pollakiuria (TOL) and 1 due to dizziness (PBO). Conclusion TOL demonstrated activity indicative of effective V2 receptor antagonism in children and adolescents with ADPKD. In addition, our trial yielded preliminary results suggestive of efficacy in slowing TKV growth and eGFR decline with acceptable tolerability, warranting further investigation in pediatric patients with ADPKD. The 2-year, Phase B extension to this trial is ongoing. Sponsored by OPDC, Inc.

POS-494 An Open label randomized controlled study to evaluate the role of Metformin to retard the progression of ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the inherited renal cystic diseases, contributes to 7- 10% of ESRD patients requiring dialysis. Currently the treatment for ADPKD lacks an effective therapy to retard the progression of the disease. AMPK (AMP activated protein kinase) activation may decrease cell proliferation in cyst wall and fluid secretion in cyst; thereby retarding kidney growth and disease progression. Metformin , a common oral hypoglycemic agent, activates AMPK. Though animal studies show promising result, human studies are few. Current study was planned with hypothesis that patients receiving metformin may have less increase in total kidney volume (TKV) at the end of 1 year follow up than the patients receiving placebo. 70 ADPKD patients, with eGFR > 45ml/min were randomly assigned to either metformin or placebo arm in 1: 1 block. Diabetics, pregnant, breastfeeding females, patients suffering from liver disease were excluded. BP target was fixed at 130/80 and ACEI/ARB were used as 1st line antihypertensive. Primary outcome was percent change in TKV as measured by MRI with planimetry method. Secondary outcomes were percentage change in eGFR and proteinuria from baseline. difference in flank pain episodes requiring analgesic intake, numbers of minor and major adverse events. All the patients were subjected to a detailed clinical and laboratory evaluation at baseline, along with TKV estimation by MRI . In the metformin group patients were given Tab. Metformin 1000 mg/day in two divided doses to start with and increased to 1 gram twice daily. Patients in the placebo arm were given placebo tablets in BD dose. Patients were followed up at 3 monthly intervals. Physical examination and biochemical evaluation (serum creatinine, eGFR by MDRD formula, and 24 hour urine protein test) were performed at each visit. Repeat MRI were obtained at the end of 12 months. Any adverse effects reported during the study period were noted. Results: Total 60 patients (30 patients in each group) was available for final analysis demographic and biochemical parameters like serum creatinine, eGFR and proteinuria were not different among the two groups at baseline with similar BP control in both arms. Mean TKV, as measured by MRI, at baseline, was 588.33 cc vs 563.71 cc in metformin vs control arm. At MO12 increase of TKV by 0.11% (intervention arm) and 1.01%(control arm) were observed , p value (0.001).When analysed among two age groups (< 45 and >45 years) percent change of TKV in metformin arm becomes even more significantly better (p value 0.00026) in the younger age group. Intervention arm shows better proteinuria control ( M0,169.10 and M12: 141.10mg/day, 15.79% decrease and placebo arm M0:186.62 and M12 182.05 mg/day, 2.89% decrease, p value 0.00004), less eGFR decline though not significant. Pain episodes in metformin vs control arm were 72 vs 63, dyspepsia being the commonest side effect in metformin arm. Conclusion: Treatment with metformin significantly slows the rate of growth of kidney

A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD.MethodsThis Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function.ResultsEighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio.ConclusionsIn this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Genetic identification of inherited cystic kidney diseases for implementing precision medicine: a study protocol for a 3-year prospective multicenter cohort study

BackgroundInherited cystic kidney disease is a spectrum of disorders in which clusters of renal cysts develop as the result of genetic mutation. The exact methods and pipelines for defining genetic mutations of inherited cystic kidney disease are not clear at this point. This 3-year, prospective, multicenter, cohort study was designed to set up a cohort of Korean patients with inherited cystic kidney disease, establish a customized genetic analysis pipeline for each disease subtype, and identify modifying genes associated with the severity of the disease phenotype.Methods/designFrom May 2020 to May 2022, we aim to recruit 800 patients and their family members to identify pathogenic mutations. Patients with more than 3 renal cysts in both kidneys are eligible to be enrolled. Cases of simple renal cysts and acquired cystic kidney disease that involve cyst formation as the result of renal failure will be excluded from this study. Demographic, laboratory, and imaging data as well as family pedigree will be collected at baseline. Renal function and changes in total kidney volume will be monitored during the follow-up period. Genetic identification of each case of inherited cystic kidney disease will be performed using a targeted gene panel of cystogenesis-related genes, whole exome sequencing (WES) and/or family segregation studies. Genotype-phenotype correlation analysis will be performed to elucidate the genetic effect on the severity of the disease phenotype.DiscussionThis is the first nationwide cohort study on patients with inherited cystic kidney disease in Korea. We will build a multicenter cohort to describe the clinical characteristics of Korean patients with inherited cystic kidney disease, elucidate the genotype of each disease, and demonstrate the genetic effects on the severity of the disease phenotype.Trial registrationThis cohort study was retrospectively registered at the Clinical Research Information Service (KCT0005580) operated by the Korean Center for Disease Control and Prevention on November 5th, 2020.