Implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial.
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SUBMITTER: Janssens P
PROVIDER: S-EPMC7062834 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
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Implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial.
Janssens Peter P Jouret François F Bammens Bert B Liebau Max C MC Schaefer Franz F Dandurand Ann A Perrone Ronald D RD Müller Roman-Ulrich RU Pao Christina S CS Mekahli Djalila D
Scientific reports 20200309 1
It is unknown whether early diagnosis of autosomal dominant polycystic kidney disease (ADPKD) can enable earlier management and improve outcomes. We conducted a post hoc analysis of data from the TEMPO 3:4 trial. Subjects were stratified by ADPKD diagnosis at age ≤18 (childhood diagnosis [CD]) or>18 (adulthood diagnosis [AD]). Groups were compared for baseline characteristics and total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline over 3 years. 294 CD and 114 ...[more]
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Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials.MethodsPatients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed.ResultsIn patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was - 3.480 in TEMPO 3:4 and - 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (- 4.287) to TEMPO-EXTJ (- 3.364), a difference of 0.923 (P = 0.0441).ConclusionThe TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.
| S-EPMC8357671 | biostudies-literature
Project description:The clinical use of conventional ultrasonography (US) in autosomal dominant polycystic kidney disease (ADPKD) is currently limited by reduced diagnostic sensitivity, especially in at-risk subjects younger than 30 years of age. In this single-center prospective study, we compared the diagnostic performance of MRI with that of high-resolution (HR) US in 126 subjects ages 16-40 years born with a 50% risk of ADPKD who underwent both these renal imaging studies and comprehensive PKD1 and PKD2 mutation screening. Concurrently, 45 healthy control subjects without a family history of ADPKD completed the same imaging protocol. We analyzed 110 at-risk subjects whose disease status was unequivocally defined by molecular testing and 45 unaffected healthy control subjects. Using a total of >10 cysts as a test criterion in subjects younger than 30 years of age, we found that MRI provided both a sensitivity and specificity of 100%. Comparison of our results from HR US with those from a previous study of conventional US using the test criterion of a total of three or more cysts found a higher diagnostic sensitivity (approximately 97% versus approximately 82%) with a slightly decreased specificity (approximately 98% versus 100%) in this study. Similar results were obtained in test subjects between the ages of 30 and 40 years old. These results suggest that MRI is highly sensitive and specific for diagnosis of ADPKD. HR US has the potential to rival the diagnostic performance of MRI but is both center- and operator-dependent.
| S-EPMC4341484 | biostudies-other
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and accounts for approximately 5% of ESRD population in the United States. The disorder is characterized by the focal and sporadic development of renal cysts, which increase in size and number with age. Mutations of PKD1 and PKD2 account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of ESRD. In general, renal ultrasonography is commonly used for the diagnosis of ADPKD, and age-dependent criteria have been defined for subjects at risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinic setting is unclear because their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage or gene-based direct sequencing are now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, subjects with a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living-related kidney donors. Here, we review the clinical utilities and limitations of both imaging- and molecular-based diagnostic tests and outline our approach for the evaluation of individuals suspected to have ADPKD.
| S-EPMC2841025 | biostudies-literature
Project description:BackgroundTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) who are at risk of rapid progression. Given that treatment requires commitment to long-term use, we evaluated the effects of tolvaptan discontinuation on the trajectory of ADPKD progression.MethodsThis was a post hoc analysis of pooled data from two clinical trials of tolvaptan (TEMPO 2:4 [NCT00413777] and TEMPO 3:4 [NCT00428948]), an extension trial (TEMPO 4:4 [NCT01214421]), and an observational study (OVERTURE [NCT01430494]) that enrolled patients from the other trials. Individual subject data were linked longitudinally across trials to construct analysis cohorts of subjects with a tolvaptan treatment duration > 180 days followed by an off-treatment observation period of > 180 days. For inclusion in Cohort 1, subjects were required have ≥ 2 outcome assessments during the tolvaptan treatment period and ≥ 2 assessments during the follow-up period. For Cohort 2, subjects were required to have ≥ 1 assessment during the tolvaptan treatment period and ≥ 1 assessment during the follow-up period. Outcomes were rates of change in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). Piecewise-mixed models compared changes in eGFR or TKV in the on-treatment and post-treatment periods.ResultsIn the Cohort 1 eGFR population (n = 20), the annual rate of eGFR change (in mL/min/1.73 m2) was -3.18 on treatment and -4.33 post-treatment, a difference that was not significant (P = 0.16), whereas in Cohort 2 (n = 82), the difference between on treatment (-1.89) and post-treatment (-4.94) was significant (P < 0.001). In the Cohort 1 TKV population (n = 11), TKV increased annually by 5.18% on treatment and 11.69% post-treatment (P = 0.06). In Cohort 2 (n = 88), the annual TKV growth rates were 5.15% on treatment and 8.16% post-treatment (P = 0.001).ConclusionsAlthough limited by small sample sizes, these analyses showed directionally consistent acceleration in measures of ADPKD progression following the discontinuation of tolvaptan.
| S-EPMC10286436 | biostudies-literature
Project description:BackgroundPrevious clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed.Study designLongitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials.Setting & participants494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments.MeasurementsLongitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation.PredictorsDemographic, clinical, laboratory, and imaging features of participants.OutcomesProbability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories.ResultsMost (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations.LimitationsRelatively short follow-up of a clinical trial population.ConclusionsAlthough many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.
| S-EPMC5916329 | biostudies-literature
Project description:Background & aimsPolycystic liver disease (PLD), the most common extrarenal manifestation of autosomal-dominant polycystic kidney disease (ADPKD), has become more prevalent as a result of increased life expectancy, improved renal survival, reduced cardiovascular mortality, and renal replacement therapy. No studies have fully characterized PLD in large cohorts. We investigated whether liver and cyst volumes are associated with volume of the hepatic parenchyma, results from liver laboratory tests, and patient-reported outcomes.MethodsWe performed a cross-sectional analysis of baseline liver volumes, measured by magnetic resonance imaging, and their association with demographics, results from liver laboratory and other tests, and quality of life. The data were collected from a randomized, placebo-controlled trial underway at 7 tertiary-care medical centers to determine whether the combination of an angiotensin I-converting enzyme inhibitor and angiotensin II-receptor blocker was superior to the inhibitor alone, and whether low blood pressure (<110/75 mm Hg) was superior to standard blood pressure (120-130/70-80 mm Hg), in delaying renal cystic progression in 558 patients with ADPKD, stages 1 and 2 chronic kidney disease, and hypertension (age, 15-49 y).ResultsWe found hepatomegaly to be common among patients with ADPKD. Cysts and parenchyma contributed to hepatomegaly. Cysts were more common and liver and cyst volumes were greater in women, increasing with age. Patients with advanced disease had a relative loss of liver parenchyma. We observed small abnormalities in results from liver laboratory tests, and that splenomegaly and hypersplenism were associated with PLD severity. Higher liver volumes were associated with a lower quality of life.ConclusionsHepatomegaly is common even in early stage ADPKD and is not accounted for by cysts alone. Parenchymal volumes were larger, compared with liver volumes of patients without ADPKD or with those predicted by standardized equations, even among patients without cysts. The severity of PLD was associated with altered biochemical and hematologic features, as well as quality of life. ClinicalTrials.gov identifier: NCT00283686.
| S-EPMC4267913 | biostudies-literature
Project description:BackgroundHypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease.MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume.ResultsThe annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002).ConclusionsIn early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).
| S-EPMC4343258 | biostudies-literature
Project description:Background and objectivesTolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.Design, setting, participants, & measurementsThe trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.ResultsNo differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%).ConclusionsTolvaptan has been used safely in combination with statins in clinical trials.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.
| S-EPMC7269222 | biostudies-literature
Project description:Rationale & objectivePain is a frequent complication of autosomal dominant polycystic kidney disease (ADPKD) and includes back and abdominal pain. We hypothesized that in adults with early- and late-stage ADPKD, overweight and obesity are independently associated with greater self-reported back, abdominal, and radicular pain at baseline and that weight loss would be associated with decreased pain over a follow-up period.Study designPost hoc analysis of pooled data from 2 randomized trials.Setting & participantsParticipants in the HALT-PKD study A or B. 867 individuals were included in a cross-sectional analysis. 4,248 observations from 871 participants were included in a longitudinal analysis.PredictorOverweight and obesity (cross-sectional); annual change in weight as a time-varying predictor (longitudinal).OutcomePain (Likert-scale responses; cross-sectional); annual change in pain (binary outcome of worsening pain or not worsening; longitudinal).Analytical approachMultivariable ordinal logistic regression (cross-sectional); generalized estimating equation analysis (longitudinal).ResultsParticipants were aged 42±10 years and baseline estimated glomerular filtration rate was 71±26 mL/min/1.73 m2. Back, abdominal, and radicular pain were reported more frequently in individuals with increasing body mass index category (all P < 0.05 for trend). After multivariable adjustment, obesity was associated with increased odds of greater back and radicular pain, but not abdominal pain. Associations remained similar after further adjustment for baseline height-adjusted kidney and liver volume (study A only, n = 457); back pain: OR, 1.88 (95% CI, 1.15-3.08); and radicular pain: OR, 2.92 (95% CI, 1.45-5.91). Longitudinally (median follow-up, 5 years), weight loss (annual decrease in weight ≥ 4%) was associated with decreased adjusted odds of worsening back pain (OR, 0.87 [95% CI, 0.76-0.99]) compared with the reference group (stable weight).LimitationsPost hoc, associative analysis.ConclusionsIn early- and late-stage ADPKD, obesity was associated with greater back and radicular pain independent of total kidney/liver volume. Mild weight loss was associated with favorable effects on back pain.
| S-EPMC8350824 | biostudies-literature
Project description:Little is known about the genes involved in the initial cyst formation and disease progression in autosomal dominant polycystic kidney disease (ADPKD). To uncover the genetic determinants and molecular mechanisms of ADPKD, we analyzed 4-point time-series DNA microarrays from Pkd1L3/L3 mice to generate high-resolution gene expression profiles at different stages of disease progression. We found different characteristic gene expression signatures in the kidneys of Pkd1L3/L3 mice compared to age-matched controls during the initial phase of the disease. By postnatal week 1, the Pkd1L3/L3 kidney already had a distinctive gene expression pattern considerably different from the corresponding normal controls. The genes differentially expressed, either induced or repressed, in ADPKD are important in immune defense, cell structure and motility, cellular proliferation, apoptosis and metabolic processes, and include members of three pathways (Wnt, Notch, and BMP) involved in morphogenetic signaling. Further analysis of the gene expression profiles from the early stage of cystogenesis to end stage disease identified a possible gene network involved in the pathogenesis of ADPKD. A total of 13 microarray data sets were generated with RNA samples from age-matched control and disease littermates at the four time points, with at least three biological replicates for each time point (PNW1, n = 3; PNW2, n = 4; PNW3, n = 3; PNW3.5, n = 3). 13 2-color experiments including: 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 1 4 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 2 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 3 3 replicates of: Wt mice vs. Pkd1L3/L3 mice at PNW 3.5
2008-12-28 | E-GEOD-13452 | biostudies-arrayexpress