Background Obese kidney allograft recipients have worse results in kidney transplantation (KT). H... more Background Obese kidney allograft recipients have worse results in kidney transplantation (KT). However, there is lack of information regarding the effect of body mass index (BMI) variation after KT. The objective of the study was to evaluate the effects of body weight changes in obese kidney transplant recipients. Methods In this study we used data from the Catalan Renal Registry that included KT recipients from 1990 to 2011 (n = 5607). The annual change in post-transplantation BMI was calculated. The main outcome variables were delayed graft function (DGF), estimated glomerular filtration rate (eGFR) and patient and graft survival. Results Obesity was observed in 609 patients (10.9%) at the time of transplantation. The incidence of DGF was significantly higher in obese patients (40.4% versus 28.3%; P < 0.001). Baseline obesity was significantly associated with worse short- and long-term graft survival (P < 0.05) and worse graft function during the follow-up (P < 0.005). B...
Tacrolimus updated guidelines through population-based pharmacokinetics modeling: how to benefit ... more Tacrolimus updated guidelines through population-based pharmacokinetics modeling: how to benefit more from CYP3A pre-emptive genotyping prior to kidney transplantation Laure Elens, Jean-Baptiste Woillard, Michael Neely, Arnaud Capron, Ron Van Schaik, Teun van Gelder, Dennis Hesselink, Nuria Lloberas, Pierre Marquet, Vincent Haufroid (1.Universite catholique de Louvain, 2.CHU limoges, 3.Children’s Hospital Los Angeles, 4.Universite catholique de Louvain, 5.University Medical Centre Rotterdam, 6.University Medical Center Rotterdam, 7.University Medical Center Rotterdam, 8.University of Barcelona, 9.CHU Limoges, 10.Universite catholique de Louvain)
A validated CYP3A genotype classification system allows clustering patients into poor, intermedia... more A validated CYP3A genotype classification system allows clustering patients into poor, intermediate and extensive metabolizer phenotypes. However, substantial overlap exists between the clusters. A rare CYP3A4 allele, named CYP3A4*20 (rs67666821), has been specifically described in the Spanish population. The authors investigated the relevance of CYP3A4*20 testing to see if the above-mentioned metabolic CYP3A classification system can be improved. In a cohort of 204 kidney transplant recipients, one male patient carrying a CYP3A4*20 allele was detected. This patient was receiving very low doses of tacrolimus to maintain therapeutic levels from day 7 onward when compared with the majority of the patients. These data suggest that this patient should be regarded as a CYP3A-poor metabolizer.
Transplant international : official journal of the European Society for Organ Transplantation, Jan 2, 2018
Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recip... more Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients. Several single-nucleotide polymorphisms (SNPs) in the ANRIL gene pathway have been associated with cardiovascular events (CE). The main objective was to ascertain whether ANRIL (rs10757278) and CARD8 (rs2043211) SNPs could mediate susceptibility to CE. This was an observational follow-up cohort study of renal transplant recipients at Bellvitge University Hospital (Barcelona) from 2000 to 2014. A total of 505 recipients were followed up until achievement of a CE. Patients who did not achieve the endpoint were followed up until graft loss, lost to follow-up or death. Survival analysis was used to ascertain association between genetic markers, clinical data, and outcome. Fifty-three patients suffered a CE after renal transplantation. Results showed a significant association between ANRIL SNP and CE. Homozygous GG for the risk allele showed higher risk for CE than A carriers for the p...
Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose... more Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose 2,6-bisphosphate (Fru-2,6-P) and the enzyme responsible for its synthesis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). PFKFB3 gene, which encodes for the most abundant PFK-2 isoenzyme in proliferating tissues, has been found overexpressed during cell activation in several models, including immune cells. However, there is limited knowledge on the pathways underlying PFKFB3 regulation in human T-lymphocytes, and the role of this gene in human immune response. The aim of this work is to elucidate the molecular mechanisms of PFKFB3 induction during human T-lymphocyte activation by mitotic agents. The results obtained showed PFKFB3 induction during human T-lymphocyte activation by mitogens such as phytohemagglutinin (PHA). PFKFB3 increase occurred concomitantly with GLUT-1, HK-II, and PCNA upregulation, showing that mitotic agents induce a metabolic reprograming pr...
Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic ... more Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients. In a cohort of 272 kidney transplant recipients, associations between functional genetic variants (CYP3A4*22 and CYP3A5*3) and dose-adjusted predose Tac concentrations (C0) and daily doses of Tac at days 5-7 and 15 and 1, 3, 6 and 12 months after renal transplantation were evaluated. Patients were genotyped and clustered according to both CYP3A4*22 and CYP3A5*3 allelic status: poor (PM) (CYP3A4*22 carriers with CYP3A5*3/*3), intermediate (IM) (CYP3A4*1/*1 with CYP3A5*3/*3 or CYP3A4*22 carriers with CYP3A5*1 carriers) and extensive CYP3A-metabolizers (EM) (CYP3A4*1/*1 and CYP3A5*1 carriers). EM had an 88% lower dose-adjusted C0 compared with IM. PM had a 26% higher dose-adjusted C0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C0&amp;amp;amp;amp;gt;15 ng/ml) was significantly higher in PM (43.5%) compared with EM (0%) at days 5-7 after transplantation (P=0.01). About 30% of EM had subtherapeutic exposure (C0&amp;amp;amp;amp;lt;5 ng/ml) at days 5-7 after transplantation (P=0.001). The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure.
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection a... more Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics(®). Patients were genotyped for the CYP3A4(∗)22 and CYP3A5(∗)3 alleles and were classified into 3 different categories [poor-...
Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft... more Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft function (subclinical rejection) could permit more effective therapy and prevent later development of de novo anti-donor HLA antibodies and/or graft dysfunction. Here we tested whether quantifying posttransplant donor-specific alloreactive T-cells by IFN-γ ELISPOT assay noninvasively detects subclinical T-cell mediated rejection and/or predicts development of anti-donor HLA antibodies. Using an initial cross-sectional cohort of 60 kidney transplant patients with six-month surveillance biopsies, we found that negative donor-specific IFN-γ ELISPOT assays accurately ruled out the presence of subclinical T-cell mediated rejection. These results were validated using a distinct prospective cohort of 101 patients where donor-specific IFN-γ ELISPOT results at both three- and six-months posttransplant significantly differentiated patients with subclinical T-cell mediated rejection at six months, independent of other clinical variables (odds ratio 0.072, 95% confidence interval 0.008-0.653). The posttransplant donor-specific IFN-γ ELISPOT results independently associated with subsequent development of significant anti-donor HLA antibodies (0.085, 0.008-0.862) and with significantly worse two-year function (estimated glomerular filtration rate) compared to patients with a negative test. Thus, posttransplant immune monitoring by donor-specific IFN-γ ELISPOT can assess risk for developing subclinical T-cell mediated rejection and anti-donor HLA antibodies, potentially limiting the need for surveillance biopsies. Our study provides a guide for individualizing immunosuppression to improve posttransplant outcomes.
The Journal of clinical investigation, Jan 6, 2017
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutatio... more Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expres...
Background Obese kidney allograft recipients have worse results in kidney transplantation (KT). H... more Background Obese kidney allograft recipients have worse results in kidney transplantation (KT). However, there is lack of information regarding the effect of body mass index (BMI) variation after KT. The objective of the study was to evaluate the effects of body weight changes in obese kidney transplant recipients. Methods In this study we used data from the Catalan Renal Registry that included KT recipients from 1990 to 2011 (n = 5607). The annual change in post-transplantation BMI was calculated. The main outcome variables were delayed graft function (DGF), estimated glomerular filtration rate (eGFR) and patient and graft survival. Results Obesity was observed in 609 patients (10.9%) at the time of transplantation. The incidence of DGF was significantly higher in obese patients (40.4% versus 28.3%; P < 0.001). Baseline obesity was significantly associated with worse short- and long-term graft survival (P < 0.05) and worse graft function during the follow-up (P < 0.005). B...
Tacrolimus updated guidelines through population-based pharmacokinetics modeling: how to benefit ... more Tacrolimus updated guidelines through population-based pharmacokinetics modeling: how to benefit more from CYP3A pre-emptive genotyping prior to kidney transplantation Laure Elens, Jean-Baptiste Woillard, Michael Neely, Arnaud Capron, Ron Van Schaik, Teun van Gelder, Dennis Hesselink, Nuria Lloberas, Pierre Marquet, Vincent Haufroid (1.Universite catholique de Louvain, 2.CHU limoges, 3.Children’s Hospital Los Angeles, 4.Universite catholique de Louvain, 5.University Medical Centre Rotterdam, 6.University Medical Center Rotterdam, 7.University Medical Center Rotterdam, 8.University of Barcelona, 9.CHU Limoges, 10.Universite catholique de Louvain)
A validated CYP3A genotype classification system allows clustering patients into poor, intermedia... more A validated CYP3A genotype classification system allows clustering patients into poor, intermediate and extensive metabolizer phenotypes. However, substantial overlap exists between the clusters. A rare CYP3A4 allele, named CYP3A4*20 (rs67666821), has been specifically described in the Spanish population. The authors investigated the relevance of CYP3A4*20 testing to see if the above-mentioned metabolic CYP3A classification system can be improved. In a cohort of 204 kidney transplant recipients, one male patient carrying a CYP3A4*20 allele was detected. This patient was receiving very low doses of tacrolimus to maintain therapeutic levels from day 7 onward when compared with the majority of the patients. These data suggest that this patient should be regarded as a CYP3A-poor metabolizer.
Transplant international : official journal of the European Society for Organ Transplantation, Jan 2, 2018
Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recip... more Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients. Several single-nucleotide polymorphisms (SNPs) in the ANRIL gene pathway have been associated with cardiovascular events (CE). The main objective was to ascertain whether ANRIL (rs10757278) and CARD8 (rs2043211) SNPs could mediate susceptibility to CE. This was an observational follow-up cohort study of renal transplant recipients at Bellvitge University Hospital (Barcelona) from 2000 to 2014. A total of 505 recipients were followed up until achievement of a CE. Patients who did not achieve the endpoint were followed up until graft loss, lost to follow-up or death. Survival analysis was used to ascertain association between genetic markers, clinical data, and outcome. Fifty-three patients suffered a CE after renal transplantation. Results showed a significant association between ANRIL SNP and CE. Homozygous GG for the risk allele showed higher risk for CE than A carriers for the p...
Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose... more Lymphocyte activation is associated with rapid increase of both the glycolytic activator fructose 2,6-bisphosphate (Fru-2,6-P) and the enzyme responsible for its synthesis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). PFKFB3 gene, which encodes for the most abundant PFK-2 isoenzyme in proliferating tissues, has been found overexpressed during cell activation in several models, including immune cells. However, there is limited knowledge on the pathways underlying PFKFB3 regulation in human T-lymphocytes, and the role of this gene in human immune response. The aim of this work is to elucidate the molecular mechanisms of PFKFB3 induction during human T-lymphocyte activation by mitotic agents. The results obtained showed PFKFB3 induction during human T-lymphocyte activation by mitogens such as phytohemagglutinin (PHA). PFKFB3 increase occurred concomitantly with GLUT-1, HK-II, and PCNA upregulation, showing that mitotic agents induce a metabolic reprograming pr...
Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic ... more Tacrolimus (Tac) has a narrow therapeutic window and shows large between-patient pharmacokinetic variability. As a result, over-immunosuppression and under-immunosuppression are frequently encountered in daily clinical practice. Unraveling the impact of genetic polymorphisms on Tac pharmacokinetics may help to refine therapy. In this study, the associations of single-nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes (CYP3A) with Tac pharmacokinetics were investigated in renal transplant recipients. In a cohort of 272 kidney transplant recipients, associations between functional genetic variants (CYP3A4*22 and CYP3A5*3) and dose-adjusted predose Tac concentrations (C0) and daily doses of Tac at days 5-7 and 15 and 1, 3, 6 and 12 months after renal transplantation were evaluated. Patients were genotyped and clustered according to both CYP3A4*22 and CYP3A5*3 allelic status: poor (PM) (CYP3A4*22 carriers with CYP3A5*3/*3), intermediate (IM) (CYP3A4*1/*1 with CYP3A5*3/*3 or CYP3A4*22 carriers with CYP3A5*1 carriers) and extensive CYP3A-metabolizers (EM) (CYP3A4*1/*1 and CYP3A5*1 carriers). EM had an 88% lower dose-adjusted C0 compared with IM. PM had a 26% higher dose-adjusted C0 compared with IM. The percentage of patients with supratherapeutic Tac exposure (C0&amp;amp;amp;amp;gt;15 ng/ml) was significantly higher in PM (43.5%) compared with EM (0%) at days 5-7 after transplantation (P=0.01). About 30% of EM had subtherapeutic exposure (C0&amp;amp;amp;amp;lt;5 ng/ml) at days 5-7 after transplantation (P=0.001). The combined CYP3A4 and CYP3A5 genotype of renal transplant recipients has a major influence on the Tac dose required to reach the target exposure.
Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection a... more Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics(®). Patients were genotyped for the CYP3A4(∗)22 and CYP3A5(∗)3 alleles and were classified into 3 different categories [poor-...
Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft... more Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft function (subclinical rejection) could permit more effective therapy and prevent later development of de novo anti-donor HLA antibodies and/or graft dysfunction. Here we tested whether quantifying posttransplant donor-specific alloreactive T-cells by IFN-γ ELISPOT assay noninvasively detects subclinical T-cell mediated rejection and/or predicts development of anti-donor HLA antibodies. Using an initial cross-sectional cohort of 60 kidney transplant patients with six-month surveillance biopsies, we found that negative donor-specific IFN-γ ELISPOT assays accurately ruled out the presence of subclinical T-cell mediated rejection. These results were validated using a distinct prospective cohort of 101 patients where donor-specific IFN-γ ELISPOT results at both three- and six-months posttransplant significantly differentiated patients with subclinical T-cell mediated rejection at six months, independent of other clinical variables (odds ratio 0.072, 95% confidence interval 0.008-0.653). The posttransplant donor-specific IFN-γ ELISPOT results independently associated with subsequent development of significant anti-donor HLA antibodies (0.085, 0.008-0.862) and with significantly worse two-year function (estimated glomerular filtration rate) compared to patients with a negative test. Thus, posttransplant immune monitoring by donor-specific IFN-γ ELISPOT can assess risk for developing subclinical T-cell mediated rejection and anti-donor HLA antibodies, potentially limiting the need for surveillance biopsies. Our study provides a guide for individualizing immunosuppression to improve posttransplant outcomes.
The Journal of clinical investigation, Jan 6, 2017
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutatio... more Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expres...
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