scholarly journals Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial

2020 ◽  
Vol 9 (10) ◽  
pp. 3216
Author(s):  
Manuela Yepes-Calderón ◽  
Camilo G. Sotomayor ◽  
Daniel Guldager Kring Rasmussen ◽  
Ryanne S. Hijmans ◽  
Charlotte A. te Velde-Keyzer ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Collagen Type ◽  
Interstitial Fibrosis ◽  
Controlled Trial ◽  
Kidney Transplant Recipients ◽  
Tubular Atrophy ◽  
Post Hoc Analysis ◽  
Non Invasive ◽  
Collagen Type Vi ◽  
Post Hoc

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

scholarly journals P1761SIDE EFFECTS OF MTOR INHIBITORS DEPEND ON THE BASELINE METABOLIC STATUS OF KIDNEY TRANSPLANT RECIPIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
David Cucchiari ◽  
Alicia Molina-Andujar ◽  
Enrique Montagud-Marrahi ◽  
Jordi Rovira ◽  
Fritz Diekmann
Keyword(s):  
Kidney Transplantation ◽  
Side Effects ◽  
Kidney Transplant ◽  
De Novo ◽  
Mtor Inhibitors ◽  
Metabolic Status ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background and Aims Biologically, the cellular activity of the mTOR complexes depends on the balance between the catabolic and the anabolic inputs. Hence, we hypothesized that the metabolic side effects of mTOR inhibitors (mTORi) in kidney transplantation depend on the baseline metabolic status of the patient. Method The analysis included all the patients that have been transplanted in our Center between June 2013 to December 2016, completed one year of follow-up and did not change medication during the first year after kidney transplantation (per-protocol population, n=298). Outcomes chosen include de novo diabetes, 1-year difference from baseline in glycated hemoglobin (HbA1c), triglycerides and total cholesterol. Kidney transplant recipients were treated either with an mTORi (either Sirolimus or Everolimus, n=134) or Mycophenolic Acid (MPA, n=164). Both drugs were always accompanied by tacrolimus and steroids. Patients were stratified according to the treatment received (mTORi versus MPA) and the baseline metabolic status (diabetes mellitus type 2 and obesity). Differences among groups were analyzed with exact Fisher test and ANOVA test with LSD post-hoc analysis. Results We observed a strong difference for 1-year change in HbA1c depending on the baseline metabolic status of the patients (P&lt;0.001 between groups, Figure 1a). The worst results were observed for patients with baseline diabetes. Among these, obese patients treated with mTORi had the higher increase in HbA1c (3.04 ± 1.18% from baseline, P&lt;0.01 with all groups at post-hoc analysis). De-novo diabetes was more frequent in patients taking mTORi (23.4 vs. 13.1%), albeit not significantly (P=0.100) and without differences taking into account obesity as a covariate. Triglycerides increased substantially in patients without baseline diabetes and treated with mTORi (P&lt;0.05). Surprisingly, in diabetic patients no differences were observed in triglycerides between mTORi and MPA groups (Figure 1b). There were no differences in the increase in total cholesterol among groups (P=0.155) (Figure 1c). Conclusion We observed that the 1-year increase in HbA1c and triglycerides attributable to mTORi after kidney transplantation depends on the baseline metabolic status of the patients. We propose that the metabolic side effects of mTORi depend on the balance between anabolic and catabolic inputs of every kidney transplant recipient.

scholarly journals Association between medication adherence and intrapatient variability in tacrolimus concentration among stable kidney transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyunmin Ko ◽  
Hyo Kee Kim ◽  
Chris Chung ◽  
Ahram Han ◽  
Seung-Kee Min ◽  
...  
Keyword(s):  
Medication Adherence ◽  
Kidney Transplant ◽  
Controlled Trial ◽  
Self Report ◽  
Tacrolimus Concentration ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Post Hoc Analysis ◽  
Intrapatient Variability ◽  
Post Hoc

AbstractThis study analyzed the association between medication adherence and the intrapatient variability (IPV) of tacrolimus concentrations among kidney transplant recipients through a post hoc analysis of the dataset from a recently conducted randomized controlled trial. Among 138 patients enrolled in the original trial, 92 patients with ≥ 5 months of medication event monitoring system (MEMS) use and ≥ 4 tacrolimus trough values were included in this post hoc analysis. The variability of tacrolimus trough levels was calculated using coefficient variation (CV) and mean absolute deviation. Adherence was assessed using MEMS and self-report via the Basal Assessment of Adherence to Immunosuppressive Medication Scale. There were no statistically significant differences in the CV [median 16.5% [interquartile range 11.6–25.5%] and 16.0% [11.5–23.5%], respectively, P = .602] between the nonadherent (n = 59) and adherent groups (n = 33). There was also no significant correlation between the CV and adherence detected by MEMS (taking adherence, ρ = − 0.067, P = .527; dosing adherence, ρ = − 0.098, P = .352; timing adherence, ρ = − 0.113, P = .284). Similarly, adherence measured by self-report did not significantly affect the IPV (P = .452). In this post hoc analysis, nonadherent behavior, measured through electronic monitoring or self-report, did not affect the IPV.

scholarly journals Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts

2020 ◽  
Author(s):  
Laura Carreras-Planella ◽  
David Cucchiari ◽  
Laura Cañas ◽  
Javier Juega ◽  
Marcella Franquesa ◽  
...  
Keyword(s):  
Differential Expression ◽  
Kidney Transplant ◽  
Interstitial Fibrosis ◽  
Calcineurin Inhibitors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Tubular Atrophy ◽  
Non Invasive ◽  
Noninvasive Biomarkers

Abstract Background In kidney transplantation, fibrosis represents the final and irreversible consequence of the pathogenic mechanisms that lead to graft failure, and in the late stages it irremediably precedes the loss of renal function. The invasiveness of kidney biopsy prevents this condition from being frequently monitored, while clinical data are rather unspecific. The objective of this study was to find noninvasive biomarkers of kidney rejection. Methods We carried out proteomic analysis of the urinary Extracellular Vesicles (uEVs) from a cohort of kidney transplant recipients (n = 23) classified according to their biopsy-based diagnosis and clinical parameters as interstitial fibrosis and tubular atrophy (IFTA), acute cellular rejection (ACR), calcineurin inhibitors toxicity (CNIT) and normal kidney function (NKF). Results Shotgun mass spectrometry of uEV-proteins identified differential expression of several proteins among these different groups. Up to 23 of these proteins were re-evaluated using targeted proteomics in a new independent cohort of patients (n = 41) classified in the same diagnostic groups. Among other results, we found a differential expression of vitronectin (VTN) in patients displaying chronic interstitial and tubular lesions (ci and ct mean > 2 according to Banff criteria). These results were further confirmed by a pilot study using enzyme-linked immunosorbent assay (ELISA). Conclusion Urinary vitronectin levels are a potential stand-alone biomarker to monitor fibrotic changes in kidney transplant recipients in a non-invasive fashion.

scholarly journals Endotrophin, a collagen type VI-derived matrikine, reflects the degree of renal fibrosis in patients with IgA nephropathy and in patients with ANCA-associated vasculitis

2021 ◽  
Author(s):  
Nadja Sparding ◽  
Federica Genovese ◽  
Daniel Guldager Kring Rasmussen ◽  
Morten Asser Karsdal ◽  
Michaela Neprasova ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Kidney Function ◽  
Renal Fibrosis ◽  
Collagen Type ◽  
Validation Cohort ◽  
Interstitial Fibrosis ◽  
Matrix Remodeling ◽  
Tubular Atrophy ◽  
Anca Associated Vasculitis ◽  
Collagen Type Vi

Abstract Background Renal fibrosis is the hallmark of chronic kidney disease (CKD) and characterized by an imbalanced extracellular matrix remodeling. Endotrophin (ETP) is a signaling molecule released from collagen type VI (COL VI). ETP can be measured by the PRO-C6 assay, which quantifies the levels of COL VI formation. ETP levels were previously associated with mortality and disease progression in patients with CKD. We hypothesized that serum and urinary ETP levels correlate with the degree of interstitial fibrosis in kidney biopsies from patients with IgA nephropathy (IgAN) and patients with ANCA-associated vasculitis (AAV). Methods We examined a cohort of 49 IgAN and 47 AAV patients. A validation cohort of 85 IgAN patients was included. ETP was measured in serum (S-ETP) and urine (U-ETP/Cr) samples, taken on the same day before renal biopsy was performed, using the ELISA PRO-C6. The biopsies were evaluated for interstitial fibrosis and tubular atrophy according to the Banff and MEST-C scores. Results S-ETP and U-ETP/Cr levels correlated with kidney function, increased with CKD severity, correlated with the extent of interstitial fibrosis and gradually increased with increasing degree of interstitial fibrosis and tubular atrophy. ETP outperformed the known fibrosis biomarker Dickkopf-3 for discrimination of patients with high fibrotic burden. The association of S-ETP and U-ETP/Cr with the level of kidney fibrosis was confirmed in the validation cohort. Conclusions We demonstrated that high levels of circulating and excreted ETP are not only indicative of lower kidney function, but also reflect the burden of fibrosis in the kidneys.

scholarly journals Effect of a Multidomain Lifestyle Intervention on Estimated Dementia Risk

2021 ◽  
pp. 1-6
Author(s):  
Alina Solomon ◽  
Ron Handels ◽  
Anders Wimo ◽  
Riitta Antikainen ◽  
Tiina Laatikainen ◽  
...  
Keyword(s):  
Lifestyle Intervention ◽  
Intervention Study ◽  
Controlled Trial ◽  
Control Group ◽  
Post Hoc Analysis ◽  
Randomized Controlled ◽  
Dementia Risk ◽  
Geriatric Intervention ◽  
Prevention Potential ◽  
Post Hoc

We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60–77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was –0.16 (95 %CI –0.31 to 0.00) (p = 0.013), corresponding to a relative dementia risk reduction between 6.04–6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.

scholarly journals Validation of the pediatric refractory septic shock definition: post hoc analysis of a controlled trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luc Morin ◽  
Karthik Narayanan Ramaswamy ◽  
Muralidharan Jayashree ◽  
Arun Bansal ◽  
Karthi Nallasamy ◽  
...  
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Neonatal Intensive Care ◽  
Controlled Trial ◽  
Receiver Operating Curve ◽  
Double Blind ◽  
Post Hoc Analysis ◽  
Prognostic Accuracy ◽  
Refractory Septic Shock ◽  
Post Hoc

Abstract Background The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) developed and validated a definition of pediatric refractory septic shock (RSS), based on two septic shock scores (SSS). Both bedside SSS (bSSS) and computed SSS (cSSS) were found to be strongly associated with mortality. We aimed at assessing the accuracy of the RSS definition on a prospective cohort from India. Methods Post hoc analysis of a cohort issued from a double-blind randomized trial that compared first-line vasoactive drugs in children with septic shock. Sequential bSSS and cSSS from 60 children (single-center study, 53% mortality) were analyzed. The prognostic value of the ESPNIC RSS definition was tested for 28-day all-cause mortality. Results In this septic shock cohort, RSS was diagnosed in 35 patients (58.3%) during the first 24 h. Death occurred in 30 RSS patients (85.7% mortality) and in 2 non-RSS patients (8% mortality), OR = 60.9 [95% CI: 10.5–676.2], p < 0.001 with a median delay from sepsis onset of 3 days [1.0–6.7]. Among patients diagnosed with RSS, the mortality was not significantly different according to vasopressors randomization. Diagnosis of RSS with bSSS and cSSS had a high discrimination for death with an area under the receiver operating curve of 0.916 [95% CI: 0.843–0.990] and 0.925 [95% CI: 0.845–1.000], respectively. High prognostic accuracy of the bSSS was found in the first hours following intensive care admission. The best interval of prognostication occurs after the 12th hour following treatment initiation (AUC 0.973 [95% CI: 0.925–1.000]). Conclusions The ESPNIC refractory septic shock definition accurately identifies, within the first 6 h of septic shock management, children with lethal outcome.

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