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Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease.

ABSTRACT: Long-term clinical outcomes in children with very-early onset (VEO; diagnosis in utero or within the first 18 months of life) autosomal dominant polycystic kidney disease (ADPKD) are currently not well understood. We conducted a longitudinal retrospective cohort study to assess the association between VEO status and adverse clinical outcomes.Seventy patients with VEO-ADPKD matched (by year of birth, sex and race/ethnicity) to 70 patients with non-VEO-ADPKD who participated in research at the University of Colorado were studied. Kaplan-Meier survival analysis was performed. The predictor was VEO status, and outcomes were progression to end-stage renal disease (ESRD), development of hypertension, progression to estimated glomerular filtration rate (eGFR <90 ml/min/1.73 m2), glomerular hyperfiltration (eGFR ?140 ml/min/1.73 m2) and height-adjusted total kidney volume (htTKV) measured by MRI ?600 ml/m.Median follow-up was until 16.0 years of age. There were only 4 ESRD events during the follow-up period, all in the VEO group (p < 0.05). VEO patients were more likely to develop hypertension (hazard ratio, HR 3.15, 95% CI 1.86-5.34; p < 0.0001) and to progress to eGFR <90 ml/min/1.73 m2 (HR 1.97, 95% CI 1.01-3.84; p < 0.05) than non-VEO patients. There was no difference between groups in the development of glomerular hyperfiltration (HR 0.89, 95% CI 0.56-1.42; p = 0.62). There were only 7 patients who progressed to htTKV ?600 ml/m, 4 in the VEO group and 3 in the non-VEO group (p < 0.01).Several clinical outcomes are worse in patients with VEO-ADPKD compared to non-VEO ADPKD. Children with VEO-ADPKD represent a particularly high-risk group of ADPKD patients.

SUBMITTER: Nowak KL

PROVIDER: S-EPMC5098215 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease.

Nowak Kristen L KL Cadnapaphornchai Melissa A MA Chonchol Michel B MB Schrier Robert W RW Gitomer Berenice B

American journal of nephrology 20160823 3

<h4>Background</h4>Long-term clinical outcomes in children with very-early onset (VEO; diagnosis in utero or within the first 18 months of life) autosomal dominant polycystic kidney disease (ADPKD) are currently not well understood. We conducted a longitudinal retrospective cohort study to assess the association between VEO status and adverse clinical outcomes.<h4>Methods</h4>Seventy patients with VEO-ADPKD matched (by year of birth, sex and race/ethnicity) to 70 patients with non-VEO-ADPKD who ...[more]

PMID: 27548646

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Project description:BACKGROUND AND OBJECTIVES:In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ?1 year (mean±SD, 4.6±2.8; range, 1.1-11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up. RESULTS:Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, -2.20±2.18 ml/min per 1.73 m2 per year) and from month 1 (mean±SD, -1.97±2.44 ml/min per 1.73 m2 per year) compared with controls (mean±SD, -3.50±2.09 ml/min per 1.73 m2 per year; P<0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. CONCLUSIONS:Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.

Project description:BACKGROUND & AIMS:Polycystic 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. METHODS:We 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). RESULTS:We 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. CONCLUSIONS:Hepatomegaly 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.

Project description:Hypertension 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.In 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.The 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).In 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.).

Project description:Background and objectivesTolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety.Design, setting, participants, & measurementsSubjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter.ResultsAmong 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538-924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan (i.e., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%-1.1%/0.0%-0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%-2.0%/0.0%-1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred.ConclusionsNo new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations.Clinical trial registry name and registration numberOpen Label Extension of TEMPO 3:4, NCT02251275.

Dataset Information

Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease.

Publications

Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease.

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