Imaging Biomarkers in Young Patients With ADPKD.
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ABSTRACT:
SUBMITTER: Yang X
PROVIDER: S-EPMC10577310 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Imaging Biomarkers in Young Patients With ADPKD.
Yang Xinyi X Wang Wei W Gitomer Berenice B Cadnapaphornchai Melissa A MA Xing Fuyong F Chonchol Michel M
Kidney international reports 20230722 10
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Project description:BackgroundAutosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups.MethodsThis pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46-56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD).ResultsHt-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly.ConclusionAge-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.
| S-EPMC10539251 | biostudies-literature
Project description:From serum samples of non-dialyzed and dialyzed patients with ADPKD and healthy control total RNA was isolated and miRNA expression was evaluated. Circulating microRNAs (miRNA) are important intercellular communication compounds. We investigated the influence of ADPKD (autosomal dominant polycystic kidney disease) and hemodialysis on the profile of serum miRNAs. We found 37 significant circulating miRNA that differ between ADPKD patients (dialyzed and non-dialyzed) and healthy controls. Bioinformatic analysis revealed strongest connections between those miRNAs and KEGG pathway: MicroRNAs in cancer. We selected 3 miRNAs with highest and 3 with lowest fold change in comparison of dialyzed and non-dialyzed patients and compared their expression in paired pre-/post-dialysis samples. All up-regulated miRNAs (miR-532-3p, miR-320b, miR-144-5p) were not significantly altered by hemodialysis. From down-regulated miRNAs miR-27a-3p was shown to be significantly lower after dialysis in both total and exosomal fraction. MiR-20a-5p was down-regulated after dialysis only in the exosomal fraction whereas miR-16-5p was unaltered by hemodialysis. MiR-16-5p was selected as the best circulating biomarker of ADPKD with miR-22-3p, let-7i-5p and miR-24-3p as following best ones. Circulating representatives of miR-17 family (new drug target of ADPKD (Hajarnis et al. 2017)) sharing the same seed region (miR-20a-5p, miR-93-5p and miR-106a-5p) showed significantly lowered expressed in sera of dialyzed patients vs non-dialyzed ones and their exosomal fraction dropped after hemodialysis. We concluded that serum miRNA among ADPKD patients differ substantially depending on the stage of CKD. These alterations show possible links with cancer. The exosomal fraction of miRNA was more affected by dialysis than total fraction of miRNAs suggesting their dynamically changing functional role.
2018-06-30 | GSE101811 | GEO
Project description:Background and objectivesThis study aimed to compare Total kidney volume (TKV) measurements using US-ellipsoid (US-EL) and MRI-ellipsoid (MRI-EL) in patients with autosomal-dominant-polycystic-kidney-disease (ADPKD). It also evaluated whether the agreement between right (RKV) and left (LKV) kidney volume measurements differed.MethodsRetrospective analysis of a prospective data-base that included consecutive patients diagnosed with ADPKD. Total kidney volumes by 3D-US-EL were compared with those by MRI-EL. Bland-Altman-plots, Passing-Bablok-regression, and the concordance-correlation-coefficient (CCC) were used to compare right (RKV), left (LKV), and TKV measurements.ResultsThirty-two ADPKD patients, 14(43.7%) women, were included. Mean measured (mGFR) and estimated (eGFR) glomerular-filtration-rate (GFR) were 86.5 ± 23.9 mL/min and 78.9 ± 23.6 mL/min, respectively. Compared with MRI-EL, TKV (Mean difference: - 85.9 ± 825.6 mL; 95%CI - 498.5 to 326.7 mL; p = 0.6787), RKV (Mean difference: - 58.5 ± 507.7 mL; 95%CI - 312.2 to 195.2 mL; p = 0.6466), and LKV (Mean difference: - 27.4 ± 413.5 mL; 95%CI - 234.1 to 179.2 mL; p = 0.7918) were lower with US-EL than with MRI-EL, although without significant differences. According to Passing and Bablok-regression analysis, the Spearman correlation-coefficient was 0.96 (95%CI 0.92 to 0.98); 0.91 (95%CI 0.82 to 0.96), and 0.94 (95%CI 0.87 to 0.97) in the RKV, LKV, and TKV, respectively; p < 0.0001 each, respectively. CCC of RKV, LKV, and TKV measurements were 0.95, 0.89, and 0.94, respectively. The mGFR and eGFR showed statistically significant negative correlations with TKV measured by both MRI-EL (p = 0.0281 and p = 0.0054, respectively) and US-EL (p = p = 0.0332 and p = 0.0040, respectively).ConclusionsThis study found that ultrasound-based ellipsoid kidney volume measurements strongly correlated with MRI-based measurements, suggesting that ultrasound is a reliable, accessible alternative for assessing kidney volume, particularly when MRI is unavailable.
| S-EPMC11814422 | biostudies-literature
Project description:Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and enlargement and dysfunction of the kidneys. The Consortium of Radiologic Imaging Studies of the Polycystic Kidney Disease (CRISP) cohort revealed that 89.1% had either a PKD1 or PKD2 mutation. Of the CRISP patients with a genetic cause detected, mutations in PKD1 accounted for 85%, while mutations in the PKD2 accounted for the remaining 15%. Here, we report exome sequencing of 16 Saudi patients diagnosed with ADPKD and 16 ethnically matched controls. Methods: Exome sequencing was performed using combinatorial probe-anchor synthesis and improved DNA Nanoballs technology on BGISEQ-500 sequencers (BGI, China) using the BGI Exome V4 (59 Mb) Kit. Identified variants were validated with Sanger sequencing. Results: With the exception of GC-rich exon 1, we obtained excellent coverage of PKD1 (mean read depth = 88) including both duplicated and non-duplicated regions. Of nine patients with typical ADPKD presentations (bilateral symmetrical kidney involvement, positive family history, concordant imaging, and kidney function), four had protein truncating PKD1 mutations, one had a PKD1 missense mutation, and one had a PKD2 mutation. These variants have not been previously observed in the Saudi population. In seven clinically diagnosed ADPKD cases but with atypical features, no PKD1 or PKD2 mutations were identified, but rare predicted pathogenic heterozygous variants were found in cystogenic candidate genes including PKHD1, PKD1L3, EGF, CFTR, and TSC2. Conclusions: Mutations in PKD1 and PKD2 are the most common cause of ADPKD in Saudi patients with typical ADPKD. Abbreviations: ADPKD: Autosomal dominant polycystic kidney disease; CFTR: Cystic fibrosis transmembrane conductance regulator; EGF: Epidermal growth factor; MCIC: Mayo Clinic Imaging Classification; PKD: Polycystic kidney disease; TSC2: Tuberous sclerosis complex 2.
| S-EPMC6735335 | biostudies-literature
Project description:BACKGROUND:Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. METHODS:The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. RESULTS:A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. CONCLUSIONS:The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.
| S-EPMC5810027 | biostudies-literature
Project description:IntroductionTolvaptan slowed estimated glomerular filtration rate (eGFR) decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) in TEMPO 3:4 and REPRISE trials. Tolvaptan effects in subjects with eGFR 15 to 24 ml/min per 1.73 m2 were not investigated. This post hoc analysis retrospectively investigated eGFR decline in REPRISE versus an open-label, phase 3b extension trial (open-label extension [OLE] NCT02251275) in subjects who received placebo in REPRISE and tolvaptan in OLE with eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2, respectively.MethodsOne data subset comprised subjects with OLE baseline eGFR 15 to 29 ml/min per 1.73 m2 who had received placebo in REPRISE and began tolvaptan in OLE. The second comprised subjects who had received tolvaptan in REPRISE and were matched to REPRISE placebo-treated subjects for REPRISE baseline characteristics. Annualized eGFR slopes in REPRISE versus OLE were compared within the REPRISE placebo (i.e., placebo vs. tolvaptan treatment) and tolvaptan (i.e., 2 periods of tolvaptan treatment) subsets.ResultsMean annualized eGFR slopes (ml/min per 1.73 m2) during tolvaptan treatment in OLE versus placebo treatment in REPRISE were -3.4 versus -5.2 for subjects with OLE baseline eGFR 15 to 29 (difference, 1.7; P < 0.001), -3.6 versus -5.4 with baseline eGFR 15 to 24 (difference, 1.8; P < 0.001), and -3.3 versus -4.9 with baseline eGFR 25 to 29 (difference, 1.6; P < 0.001). In REPRISE tolvaptan subjects who continued tolvaptan in OLE, treatment effect was maintained (no difference between mean annualized eGFR slopes).ConclusionInitiating or maintaining tolvaptan therapy significantly delayed eGFR decline in subjects with baseline eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m2.
| S-EPMC8343715 | biostudies-literature
Project description:BackgroundRecent work suggests that dysregulated cellular metabolism may play a key role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The TAME-PKD clinical trial is testing the safety, tolerability, and efficacy of metformin, a regulator of cell metabolism, in patients with ADPKD. This study investigates the cross-sectional association of urinary metabolic biomarkers with ADPKD severity among TAME-PKD trial participants at baseline.MethodsConcentrations of total protein, targeted metabolites (lactate, pyruvate, succinate, and cAMP), and key glycolytic enzymes (pyruvate kinase M2 [PKM2], lactate dehydrogenase A [LDHA], and pyruvate dehydrogenase kinase 1 [PDK1]) were measured by ELISA, enzymatic assays, and immunoblotting in baseline urine specimens of 95 TAME-PKD participants. These analytes, normalized by urinary creatinine or osmolality to estimate excretion, were correlated with patients' baseline height-adjusted total kidney volumes (htTKVs) by MRI and eGFR. Additional analyses were performed, adjusting for participants' age and sex, using multivariable linear regression.ResultsGreater htTKV correlated with lower eGFR (r=-0.39; P=0.0001). Urinary protein excretion modestly correlated with eGFR (negatively) and htTKV (positively). Urinary cAMP normalized to creatinine positively correlated with eGFR. Among glycolytic enzymes, PKM2 and LDHA excretion positively correlated with htTKV, whereas PKM2 excretion negatively correlated with eGFR. These associations remained significant after adjustments for age and sex. Moreover, in adjusted models, succinate excretion was positively associated with eGFR, and protein excretion was more strongly associated with both eGFR and htTKV in patients <43 years old.ConclusionsProteinuria correlated with ADPKD severity, and urinary excretion of PKM2 and LDHA correlated with ADPKD severity at baseline in the TAME-PKD study population. These findings are the first to provide evidence in human urine samples that upregulated glycolytic flux is a feature of ADPKD severity. Future analysis may reveal if metformin treatment affects both disease progression and the various urinary metabolic biomarkers in patients throughout the study.
| S-EPMC8312696 | biostudies-literature
Project description:IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst enlargement, leading to kidney failure. Sirtuin-1 is upregulated in ADPKD and accelerates disease progression by deacetylating p53. Niacinamide is a dietary supplement that inhibits sirtuins at high doses.MethodsWe conducted an open-label, single-arm intervention trial (study 1, N = 10), and a randomized, double blinded, placebo-controlled trial (study 2, N = 36) to assess the biological activity and safety of niacinamide. Patients with ADPKD were given 30 mg/kg oral niacinamide or placebo, for 12 months. The primary endpoint was the ratio of acetylated p53 to total p53 protein in peripheral blood mononuclear cells (PBMCs).ResultsThere was no sustained effect of niacinamide on acetylated/total p53 in either study and no difference between placebo and niacinamide arms. There was no difference in the change in height-adjusted total kidney volume over 12 months between niacinamide and placebo. Niacinamide was generally well tolerated. The most common adverse effects were nausea, diarrhea, gastroesophageal reflux, headache, and acneiform rash but there was no difference in their incidence between niacinamide and placebo.ConclusionsIn conclusion, niacinamide is safe and well-tolerated in patients with ADPKD. However, we were unable to detect a sustained inhibition of sirtuin activity over 12 months of treatment, and there was no signal to suggest a beneficial effect on any efficacy measure.
| S-EPMC7403550 | biostudies-literature
Project description:IntroductionCystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD.MethodsThis is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records.ResultsDifferences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at <47, 47-61, or >61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients.ConclusionHtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age.
| S-EPMC7938061 | biostudies-literature
Project description:IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic nephropathy and has striking familial variability of disease severity.MethodsTo better comprehend familial phenotypic variability, we analyzed clinical and pedigree data on 92 unrelated ADPKD kindreds with ≥2 affected individuals (N = 292) from an Irish population. All probands underwent genetic sequencing. Age at onset of kidney failure (KF), decline in estimated glomerular filtration rate (eGFR), predicting renal outcome in polycystic kidney disease (PROPKD) score, and imaging criteria were used to assess and grade disease severity as mild, intermediate, or severe. One mild and 1 severe case per family defined marked intrafamilial variability of disease severity.ResultsMarked intrafamilial variability was observed in at least 13% of the 92 families, with a higher proportion of families carrying PKD1-nontruncating (PKD1-NT) variants. In families with ≥2 members affected by KF, the average intrafamilial age difference was 7 years, and there was no observed difference in intrafamilial variability of age at KF between allelic groups. The prespecified criteria showed marked familial variability in 7.7%, 8.4%, and 24% for age at KF, the PROPKD score, and imaging criteria, respectively. In our multivariate mixed-effects model, the intrafamilial variability in kidney survival was independent of the measured genotypic factors associated with prognosis and survival (P = <0.001).ConclusionUsing objective measures, we quantified marked intrafamilial variability in ADPKD disease phenotype in at least 13% of families. Our findings indicate that intrafamilial phenotypic variability remains incompletely understood and necessitates a more thorough identification of relevant clinical and genotypic factors.
| S-EPMC10928004 | biostudies-literature