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Background
Identification of the culprit genes underlying multifactorial diseases is one of the most important current challenges of molecular genetics. While recent advances in genomics research have accelerated the discovery of susceptibility genes, much remains to be learned about the functions of disease-associated genetic variants. Recently, M...
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Context 1
... 5 years after transplantation, 35.7% of patients with a CAV1 AA genotype graft devel- oped proteinuria vs 21.3% for AC and 14.3% of patients with CC genotype (P < 0.05) ( Table 1). In multivariate ana- lysis of the renal transplant function determinants, analysis of covariance for serum creatinine levels (expressed as log10-transformed, Table 2) showed a significant interaction between genotype and time post-transplant (P = 0.02) and between genotype and delayed graft function (DGF) (P = 0.003). In the group of patients that did not experience DGF, 3-month creatinine levels were similar for all CAV1 graft genotypes (P = 0.10). ...
Context 2
... donor age (P < 0.0001) was also an inde- pendent predictor of creatinine increase over time (P < 0.0001). Analysis of covariance for eGFR levels (expressed as log10-transformed) was consistent with the conclusions regarding serum creatinine levels (Table 2). Again, signifi- cant interactions were observed between genotype and time (P = 0.02) as well as between genotype and delayed graft function (P = 0.001). ...
Similar publications
New-onset diabetes mellitus after transplant is a common complication in renal allograft recipients. Recently, a high prevalence of diabetes mellitus has been reported in patients with chronic hepatitis C virus. The association between hepatitis C and diabetes mellitus is well demonstrated in the general population, but some controversy still exist...
Objectives:
Renal allograft function and graft survival depends on many factors, including the source of the graft, immunologic matching between donor and recipient, incidence of acute rejection, and recurrence of the original kidney disease. This work aimed to evaluate the effects of the original kidney disease on patient and graft survival.
Mat...
Citations
... 18 CAV1 function is also of potential interest in the context of kidney transplantation. [19][20][21] Indeed, 2 studies reported that donor CAV1 single nucleotide variation could influence graft fibrosis and longterm outcome after kidney transplantation. 20,21 In a recent study, Gambella et al 22 reported that Caveolin-1 is overexpressed in cABMR and could be a key marker in patients with cABMR. ...
... [19][20][21] Indeed, 2 studies reported that donor CAV1 single nucleotide variation could influence graft fibrosis and longterm outcome after kidney transplantation. 20,21 In a recent study, Gambella et al 22 reported that Caveolin-1 is overexpressed in cABMR and could be a key marker in patients with cABMR. Overexpression of CAV1 could thus be a compensatory mechanism to the fibrotic lesions induced by cABMR but both its kinetics and prognostic significance remain to be determined. ...
Background
The benefit of extracorporeal photopheresis on the course of kidney transplant rejection is unknown. The aim of our study was to investigate the variations in transcriptomics on graft biopsies when extracorporeal photopheresis was used to treat chronic humoral rejection after kidney transplantation.
Methods
We retrospectively analyzed the mRNA expression of 770 genes of interest in graft biopsies performed before and after treatment. Eight patients received an average of 23 extracorporeal photopheresis sessions over 4 mo between the 2 biopsies.
Results
Transcriptomic analysis of the graft biopsies identified a significant (adjusted P < 0.05) increase in CAV1 mRNA in all patients and a significant decrease in CD19 , IL21 , PAX5 , and S FTPA2 mRNAs in 7 of 8 patients.
Conclusions
In patients treated with extracorporeal photopheresis for chronic humoral rejection after renal transplantation, omic analysis of repeated biopsies shows a reduction in fibrotic and inflammatory transcriptomic biologicals markers.
... Cav-1 is the main scaffolding protein of caveolae: within the kidney, it is constitutively expressed by arterial smooth muscle cells, podocytes, mesangial cells, but not by endothelial cells [35,[46][47][48]. Conversely, injured endothelial cells significantly express Cav-1 [28][29][30][31][32][33][34][35]49] and its expression has been found to be associated with arterial stiffness, allograft fibrosis and failure [33,50,51]. ...
Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate marker of c-ABMR. Caveolin-1 expression was analyzed in a selected series of 22 c-ABMR samples and 11 controls. Caveolin-1 immunohistochemistry proved positive in peritubular and glomerular capillaries of c-ABMR specimens, irrespective of C4d status whereas all controls were negative. Multiplex gene expression profiling in c-ABMR cases confirmed Caveolin-1 overexpression and identified additional genes (n = 220) and pathways, including MHC Class II antigen presentation and Type II interferon signaling. No differences in terms of gene expression (including Caveolin-1 gene) were observed according to C4d status. Conversely, immune cell signatures showed a NK-cell prevalence in C4d-negative samples compared with a B-cell predominance in C4d-positive cases, a finding confirmed by immunohistochemical assessment. Finally, differentially expressed genes were observed between c-ABMR and controls in pathways associated with Caveolin-1 functions (angiogenesis, cell metabolism and cell–ECM interaction). Based on our findings, Caveolin-1 resulted as a key player in c-ABMR, supporting its role as a marker of this condition irrespective of C4d status.
... Regarding the remaining two genes, it has been suggested that CAV1 plays an important role in diabetic nephropathy [53,54]. More importantly, the genotype of CAV1 can affect the renal transplant outcome, which is consistent with our results [55]. On the other hand, Hence, a recent study suggested that CAV1 can be used as a biomarker to distinguish renal allograft tolerance from chronic antibody-mediated rejection [56]. ...
Allogeneic kidney transplantation (renal allograft) is the most effective treatment for advanced kidney disease. Previous studies have indicated that ferroptosis participates in the progression of acute kidney injury and renal transplant failure. However, few studies have evaluated the prognostic value of ferroptosis on renal transplantation outcomes. In this study, a total of 22 differentially expressed ferroptosis-related genes (DFGs) were identified, which were mainly enriched in infection-related pathways. Next, a ferroptosis-related gene signature, including GA-binding protein transcription factor subunit beta 1 (GABPB1), cyclin-dependent kinase inhibitor 1A (CDKN1A), Toll-like receptor 4 (TLR4), C-X-C motif chemokine ligand 2 (CXCL2), caveolin 1 (CAV1), and ribonucleotide reductase subunit M2 (RRM2), was constructed to predict graft loss following renal allograft. Moreover, receiver operating characteristic (ROC) curves (area under the ROC curve [AUC] > 0.8) demonstrated the accuracy of the gene signature and univariate Cox analysis suggested that the gene signature could play an independent role in graft loss (p < 0.05). Furthermore, the nomogram and calibration plots also indicated the good prognostic capability of the gene signature. Finally, immune-related and cytokine signaling pathways were mostly enriched in renal allograft patients with poor outcomes. Considered together, a ferroptosis-related gene signature and nomogram based on DFGs were created to predict the 1-, 2- and 3- year graft loss probability of renal allograft patients.The gene signature could serve as a valuable biomarker for predicting graft loss, contributing to improving the outcome of allogeneic kidney transplantation.
... It could have been interesting to provide surrogate markers, in particular long term eGFR, which would support the lack of impact of CAV1 rs4730751 SNP in their cohort. In the same way, Van der Hauwaert et al. could not find any impact on graft survival in a smaller cohort (475 kidney donors, AA genotype prevalence: 7.6%) 24 , however AA genotype exhibited a significant decrease in eGFR. As in the present study, information concerning ethnicity was missing which may interfere with the results. ...
... As in the present study, information concerning ethnicity was missing which may interfere with the results. As Van der Hauwaert et al. 24 , our results may suggest an impact on eGFR decrease as there was a trend of a higher slope decrease, using a linear mixed-model, for AA donors compared to non AA. Considering the low frequency of the allele, the absence of significance may be due to a lack of power. ...
... Furthermore, even if we could not find any difference on interstitial fibrosis-tubular atrophy in 3-months kidney biopsies score, we observed a significant higher percentage of globally scarred glomeruli in AA donors compared to non AA donors. This may be in line with the results of the previous studies on CAV1 genotype 11,24 , where AA donors related recipients, who had experienced a delayed graft functioning, had lower eGFRs at 3-months than non-AA donors related recipients, suggesting a decreased ability of renal recovery. In this study, AA genotype was also associated with several markers of fibrosis, with a higher risk of chronic allograft dysfunction 24 , interstitial fibrosis 24 or vascular fibrosis 11 . ...
Abstract Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR = 1.23 [0.74–2.05] and HR = 1.27 [0.84–1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.
... Donor CAV1 AA rs4739751 genotype of renal transplants are associated with worsening renal allograft function, survival as well as excess fi brosis upon histology in cohorts from Birmingham [74], Belfast [74], and France [75]. ...
p>Caveolin-1 is the essential structural formation for lipid raft formation. It has been ascribed to several disease processes in humans due to its ubiquitous distribution. Patients with chronic kidney disease suffer great morbidity and mortality where manipulation of caveolin-1 could lead to new potential therapeutic targets in this patient group. This review highlights caveolin-1 structure, signalling and provides examples of studies of caveolin-1 single nucleotide polymorphism in chronic kidney disease.</p
... Based on these findings, they concluded and confirmed that the CC genotype is associated with protection from adverse outcomes (Chand et al., 2013). Van der Hauwaert et al. (2015) found that patients receiving a graft carrying the CAV1 rs4730751 AA genotype had a significant decrease in estimated glomerular filtration rate and a significant increase in serum creatinine levels. Moreover, Table 5 Kidney allograft histopathological changes (i, t, v, ah, ci, cg, ct, cv, mm) iinterstitial infiltration, ttubulitis, vintimal arteritis, aharteriolar hyaline thickening, ciinterstitial fibrosis, cgglomerulopathy, cttubular atrophy, cv -fibrous intimal thickening, mmmesangial matrix increase. ...
Caveolin-1 is a phosphoprotein that plays a crucial role in tissue remodeling and fibrotic pathways, controlling fibroblast function, proliferation, and apoptosis. Here we aimed to examine the association between the CAV1 rs4730751 gene polymorphism and kidney graft function, graft histology, and graft survival. This study enrolled 270 Caucasian deceased - donor renal transplant recipients. We found no statistically significant associations between CAV1 rs4730751 and delayed graft function, acute rejection, or chronic allograft dysfunction, as well as creatinine values at 1-60 months after transplantation, the risk of graft loss, dialysis or death after transplantation, or histopathological changes in kidney allograft biopsies. Our findings do not support an association between the CAV1 gene rs4730751 polymorphism and kidney allograft function in our population. © 2017 Faculty of Health and Social Sciences, University of South Bohemia in Ceske Budejovice.
... In renal transplantation, donor CAV1 SNP rs4730751 has been associated with renal transplant organ survival, function and fibrosis (82,158). In haemodialysis dependent patients, this SNP has been associated with carotid intima medial thickness (159). ...
... However, the question remains as to whether this SNP's association relates to direct mechanistic causality, as the SNP is found on the noncoding intron of the CAV1 gene (Figure 7-1). In general, intronic SNP could be in linkage disequilibrium with another gene, however, rs4730751 is not in linkage disequilibrium with genetic variants in exons that may truncate or alter CAV1 protein (158). Thus its effect may be by influencing resulting transcripts or splicing (273). ...
... From the Lancet in July 2016, thirteen fibrotic genes predicting future fibrosis in renal allografts was found from examining the renal transplant biopsy transcriptome (275). A similar approach could be extended to see if any genetic differences can be found in biopsy tissue depending on patient's genotype in renal allografts as previously donor CAV1 SNP rs4730751 genotype predicted renal allograft survival and fibrosis (82,158). This could assist understanding of how variation with this SNP could lead to fibrotic change. ...
Renal disease is a major global public health issue that affects 10% of the general population with premature morbidity and mortality related to cardiovascular disease and infection. Interstitial fibrosis is a common hallmark of progressive kidney dysfunction. There remains a stubborn discrepancy in identifying which patients suffer adverse events because of their disease or resulting treatment. Investigation in patient genome variation may explain this discrepancy.
Caveolin-1 is the essential structural protein for caveolae that are ubiquitously distributed in fibroblasts, endothelial and epithelial cells. They act as molecular chaperones for transcellular signaling such as degradation of the activated TGFβ-1 receptor. In this thesis, caveolin-1 single nucleotide polymorphism rs4730751 CC genotype is shown to be associated with a better outcome in renal patients for arterial stiffness, and reduced mortality from cardiovascular disease, infection, malignancy in ANCA associated vasculitis. By inducing renal models of fibrosis in caveolin-1 knockout mice, deletion of caveolin-1 leads to increased fibrosis.
In conclusion, this polymorphism could be used as a marker of disease risk either in isolation or as part of a clinical risk score to counsel patients on the likely prognosis of their condition. Manipulation of caveolin-1 expression may be a therapeutic strategy in reducing renal fibrosis.
Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.
Few reports assessed endothelial activation biomarkers in kidney allograft biopsies using immunohistochemistry. This retrospective cohort study evaluated the association between posttransplant outcomes and the immunohistochemistry expression of Caveolin-1, Von Willebrand Factor (Vwf), and T-Cadherin in for-cause biopsies diagnosed as interstitial fibrosis and tubular atrophy of unknown etiology. Samples with antibody-mediated changes were excluded. The patients were followed for 3 years after the biopsy or until graft loss/death. Seventy-one (71) samples from 66 patients were included. Eighteen (25.4%) patients lost their grafts, mainly due to chronic rejection (33.3%). Caveolin-1 and T-Cadherin were not associated with graft loss. Vwf had good accuracy in predicting graft failure (AUC 0.637, 95% CI 0.486 to 0.788 P=0.101). The presence of more than 10% of Vwf positivity in the microvasculature (Vwf >10%) was associated with reduced death-censored graft survival (58.2% vs. 85.4% P=0.006), and this result was also observed in the subgroup presenting mild interstitial fibrosis (ci=1) (65.7% vs. 88.6% P=0.033). The multivariate analysis showed that Vwf >10% was an independent risk factor for graft loss (HR=2.88, 95% CI 1.03 to 8.02 P=0.043). In conclusion, Vwf might be an additional tool to predict allograft outcomes in kidney transplant recipients with interstitial fibrosis and tubular atrophy of unknown etiology, probably reflecting immune endothelial activation.
Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (p=1.6x10-8 -2.2x10-8 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; p=2x10-9 -3.7x10-8 ) and plasmacytoma variant translocation 1 (PVT1) genes (p=4.0x10-8 -7x10-8 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (p=2x10-9 -5x10-8 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.
