Institute of Mathematics of the Academy of Sciences of the Czech Republic provides access to digi... more Institute of Mathematics of the Academy of Sciences of the Czech Republic provides access to digitized documents strictly for personal use. Each copy of any part of this document must contain these Terms of use. This paper has been digitized, optimized for electronic delivery and stamped with digital signature within the project DML-CZ: The Czech Digital Mathematics Library http://project.dml.cz časopis pro pěstování matematiky, roč. 10! (1976), Praha
Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through the... more Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through therapeutic drug monitoring (TDM). Home-based dried blood spot (DBS) sampling has the potential to replace conventional TDM sampling at the clinic. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify tacrolimus and mycophenolic acid in DBS and clinically validated for abbreviated area under the concentration-time curve (AUC) monitoring using an innovative volumetric DBS sampling device. METHODS Clinical validation was performed by direct comparison of paired DBS and whole blood (WB) (tacrolimus) and plasma (mycophenolic acid) concentrations and AUCs. Agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and DBS-to-WB predictive performance. TDM dosing recommendations based on both methods were compared to assess clinical impact. RESULTS Paired tacrolimus (n = 200) and mycophenolic acid (n = 192) DBS and WB samples were collected from 65 kidney(-pancreas) transplant recipients. Differences for tacrolimus and mycophenolic acid were within ±20% for 84.5% and 76.6% of concentrations and 90.5% and 90.7% of AUCs, respectively. Tacrolimus and mycophenolic acid dosing recommendation differences occurred on 44.4% and 4.7% of occasions. Tacrolimus DBS dosing recommendations were 0.35 ± 0.14 mg higher than for WB and 8 ± 3% of the initial dose. Mycophenolic acid DBS dosing recommendations were 23.3 ± 31.9 mg lower than for plasma and 2 ± 3.5% of the initial dose. CONCLUSIONS Tacrolimus and mycophenolic acid TDM for outpatient renal transplant recipients, based on abbreviated AUC collected with a DBS sampling device, is comparable to conventional TDM based on WB sampling. Patient training and guidance on good bloodspotting practices is essential to ensure method feasibility.
Background. Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) ha... more Background. Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. Methods. A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n ¼ 21) and patients with IgAN (n ¼ 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. Results. Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. Conclusions. Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.
Patient variability in clinical response to the calcineurin inhibitors (CNIs) ciclosporin A and t... more Patient variability in clinical response to the calcineurin inhibitors (CNIs) ciclosporin A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize therapy from a pharmacokinetic perspective. In contrast, no genetic variants have been found to clearly relate to ciclosporin A exposure. Despite therapeutic drug monitoring aimed at individualizing CNI therapy, patients still suffer from acute or chronic rejection and CNI toxicity. To further optimize CNI therapy future research may incorporate genetic polymorphisms in proteins involved in CNI pharmacodynamics (i.e. drug target). Proteins potentially relevant for drug response are calcineurin and the CNI binding proteins immunophilins. Moreover, since the expression of the nuclear factor of activated T-cells (NFAT) is reduced after calcineurin inhibition, genetic polymorphisms in the genes encoding NFAT may also be interesting candidates for studying inter-patient differences in CNI efficacy and toxicity. In addition, the existence of isoforms and differences in tissue distribution of the calcineurin protein could potentially explain variable drug response. At present, the focus has been on the metabolism of CNIs and not on variability in the drug target. Therefore, future improvements in CNI therapy are likely to occur from a systems pharmacology approach taking into account genetic markers for both CNI pharmacokinetics and pharmacodynamics.
Background Controversy remains about the interaction between mycophenolate mofetil (M MF) and the... more Background Controversy remains about the interaction between mycophenolate mofetil (M MF) and the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (TACR). The need to double the dose of MMF in case of CsA co-administration to achieve the same mycophenolic acid (MPA) levels as in TACR co-administration, has been attributed to either inhibition by CsA of the enterohepatic cycle, or an inhibition of glucuronidation to mycophenolate glucuronide (MPAG) by TACR. We explored these interactions clinically in 64 kidney transplant patients. Methods Plasma MPA/MPAG curves were determined during the first year post transplantation. Using nonlinear mixed effect modelling, MPA/MPAG data were fitted to a fourcompartment model, in which a rate constant describing transfer from the fourth to the first compartment (k41), and therefore enterohepatic recycling, could be introduced. Results MPA and MPAG plasma concentrations were adequately described by a four-compar tment model, which was significantly improved by introduction of k41 in case of TACR co-administration (minimum value of the objective function decreased by 181 points, P < 0.0001). Using this model, no statistically significant difference was observed in clearance of MPA between TACR and CsA co-administration (11.9 and 14.1 l h-1 , respectively). Total clearance of MPAG was lower in case of CsA co-administration (1.45 and 0.92 l h-1 , respectively), while there was no difference in renal clearance of MPAG (1.09 and 0.92 l h-1 , respectively). Conclusions Our study supplies supportive clinical evidence that inhibition of the enterohepatic cycle in case of CsA co-administration explains some of the differences observed in PK of MMF when co-administered with either TACR or CsA. This finding may have clinical consequences for the immunosuppressive management of kidney transplant patients.
Background. Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of... more Background. Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C 0h monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (ts0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreaskidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics. Methods. A two-compartment model with lag time and first-order absorption was calculated using a PK software package from data of 20 KTA and SPKT recipients and validated prospectively in 20 KTA and 20 SPKT recipients. Calculated population PK parameters were individualized for each of the remaining 40 patients based on their CsA dosing and on one or a combination of measured CsA blood concentrations using the Bayesian fitting method. AUCs were calculated from individualized PK parameters. AUCs were also calculated using previously published LSMs. Relationships between AUCs calculated by the models and the 'golden standard' AUC (trapezoidal rule) were investigated by Pearson correlation test. Results and conclusions. A population two-compartment model is presented to reliably estimate the CsA AUC in KTA and SPKT recipients. The performance of the model to estimate the AUC is comparable to the performance of two published LSMs in KTA patients, but markedly better in SPKT patients. Combined with Bayesian fitting, the model is very flexible since sampling times are not rigid and can be varied as long as dosing and sampling times are recorded accurately. The model has already proven to be clinically useful and is currently used to further investigate CsA in an integrated pharmacokineticupharmacodynamic model.
Recently, several B cell-related markers have been described to be upregulated during operational... more Recently, several B cell-related markers have been described to be upregulated during operational tolerance in kidney allograft recipients. Little data exist on these markers during allograft rejection. In this study, we investigated regulation-associated B-cell phenotypes in peripheral blood mononuclear cells (PBMCs) of kidney transplant recipients with (n=21) and without (n=22) acute rejection (AR). We also determined expression levels of the B cell-related genes, MS4A1, TCL1A, and CD79B, in PBMCs and isolated B cells. Patient samples were analyzed before transplantation at discharge and at time of AR before initiation of antirejection therapy or at matching timepoints in patients with stable graft function. On transplantation, the peripheral CD19CD24CD38 transitional B cell subset strongly declined, regardless of the subsequent occurrence of AR. In contrast, the CD19CD27CD24 subset remained stable after transplantation in both patients groups. MS4A1 gene expression levels in PBMC were comparable between patient groups at all timepoints. In contrast, TCL1A expression levels increased in stable patients, but decreased in patients at the time of AR in both PBMC and isolated B cells. CD79B expression levels in stable patients were unaltered after transplantation in PBMC but showed an increase in the B cell fraction at discharge. At the time of AR, CD79B gene expression was significantly lower compared to stable patients, being most apparent in the B-cell fraction. These results suggest that, in addition to being markers for immunologic unresponsiveness, gene expression levels of TCL1A and CD79B may also identify immune activation in the setting of kidney transplantation.
Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted i... more Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted in increased rates of delayed graft function (DGF) and primary nonfunction. Here, we used Nuclear Magnetic Resonance (NMR) spectroscopy to analyze the urinary metabolome of DCD transplant recipients at multiple time points (days 10, 42, 180, and 360 after transplantation). The aim was to identify markers that predict prolonged duration of functional DGF (fDGF). Forty-seven metabolites were quantified and their levels were evaluated in relation to fDGF. Samples obtained at day 10 had a different profile than samples obtained at the other time points. Furthermore, at day 10 there was a statistically significant increase in eight metabolites and a decrease in six metabolites in the group with fDGF (N = 53) vis-à-vis the group without fDGF (N = 22). In those with prolonged fDGF (≥21 days) (N = 17) urine lactate was significantly higher and pyroglutamate lower than in those with limited fDGF (<21 days) (N = 36). In order to further distinguish prolonged fDGF from limited fDGF, the ratios of all metabolites were analyzed. In a logistic regression analysis, the sum of branched-chain amino acids (BCAAs) over pyroglutamate and lactate over fumarate, predicted prolonged fDGF with an AUC of 0.85. In conclusion, kidney transplant recipients with fDGF can be identified based on their altered urinary metabolome. Furthermore, two ratios of urinary metabolites, lactate/fumarate and BCAAs/ pyroglutamate, adequately predict prolonged duration of fDGF.
Despite excellent short-term graft survival after renal transplantation, the long-term graft outc... more Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejecti...
The warm and cold ischemia times were 46.7612.4 (26-117) and 172.3686.7 (41-780) minutes respecti... more The warm and cold ischemia times were 46.7612.4 (26-117) and 172.3686.7 (41-780) minutes respectively. Pts received triple immunosuppression. Initial immunosuppression mainly (80; 62.0%) consisted of prednisolone, cyclosporine A (generics, oral solutions) and mycophenolate mofetil. Induction therapy used selectively (29; 22.5%), mainly in highly sensitized pts (ATG in 2 and Basiliximab in 27 pts). Complications: Overall, 58 (45.0%) pts had 92 episodes of acute rejection, median on 12 th day after KT. All pts received methylprednisolone pulses, 5 in addition ATG. Twelve pts (9.3%) had acute tubulonecrosis, 10 of them received HD. Prophylaxis of cytomegalovirus (CMV) infection is not routinely done due to high cost. Twenty-two pts (17.1%) had CMV disease that was successfully treated. Complications included also pulmonary tuberculosis (1), chickenpox (5), herpes zoster (9) and measles (1). Nine pts (7%) had oncological complications, two of them died. Sixteen (12.4%) pts lost their grafts and were back on HD. The causes were rejection (8), mainly as a result of noncompliance (7), chronic transplant nephropathy (3), surgical complications (2), reduction of immunosuppression in case complications (2) and hyperhomocysteinemia (1). One, 3-, 5-and 10-year graft survival rate is 96.1%, 93.4%, 92.4% and 88.5% respectively. Nine pts (7%) died with functioning grafts due to cardio-vascular (3), oncological complications (2), gastro-intestinal bleeding (2) and systemic amyloidosis (2). Pts' 1-, 3-5-and 10-year survival is 98.4%, 97.5%, 95.3% and 89.8% respectively. CONCLUSIONS: KT is the optimal treatment of ESRD also in countries with limited resources. Pts' non-compliance can be ruled out by psycho-social adaptation and use of convenient forms of medications (capsules instead of oral solutions). LRKT program alone is far from covering all the demand for KT and must be complemented by deceased donor transplantation.
A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and period... more A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was admitted because of chronic diarrhoea. During admission she developed a rapidly progressive nephrotic syndrome. Reactive amyloid A (AA) amyloidosis was confirmed after colonic and renal biopsy which showed deposition of amyloid. After initial treatment with high-dosed corticosteroids, therapy was switched to anakinra, an IL-1 receptor antagonist, but her symptoms persisted. After cessation of anakinra, a marked exacerbation of the intestinal symptoms was noted. Nine months after the initial diagnosis of reactive amyloidosis without any amelioration of the symptoms and a decreasing quality of life, our patient declined further treatment and died soon after. This case demonstrates that AA amyloidosis does occur in patients with HIDS and can present with intestinal symptoms and proteinuria. Once amyloidosis is diagnosed the goal of treatment is to prevent furthe...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 19, 2015
Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes ... more Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, re...
Institute of Mathematics of the Academy of Sciences of the Czech Republic provides access to digi... more Institute of Mathematics of the Academy of Sciences of the Czech Republic provides access to digitized documents strictly for personal use. Each copy of any part of this document must contain these Terms of use. This paper has been digitized, optimized for electronic delivery and stamped with digital signature within the project DML-CZ: The Czech Digital Mathematics Library http://project.dml.cz časopis pro pěstování matematiky, roč. 10! (1976), Praha
Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through the... more Tacrolimus and mycophenolic acid dosing after renal transplantation is individualized through therapeutic drug monitoring (TDM). Home-based dried blood spot (DBS) sampling has the potential to replace conventional TDM sampling at the clinic. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to quantify tacrolimus and mycophenolic acid in DBS and clinically validated for abbreviated area under the concentration-time curve (AUC) monitoring using an innovative volumetric DBS sampling device. METHODS Clinical validation was performed by direct comparison of paired DBS and whole blood (WB) (tacrolimus) and plasma (mycophenolic acid) concentrations and AUCs. Agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and DBS-to-WB predictive performance. TDM dosing recommendations based on both methods were compared to assess clinical impact. RESULTS Paired tacrolimus (n = 200) and mycophenolic acid (n = 192) DBS and WB samples were collected from 65 kidney(-pancreas) transplant recipients. Differences for tacrolimus and mycophenolic acid were within ±20% for 84.5% and 76.6% of concentrations and 90.5% and 90.7% of AUCs, respectively. Tacrolimus and mycophenolic acid dosing recommendation differences occurred on 44.4% and 4.7% of occasions. Tacrolimus DBS dosing recommendations were 0.35 ± 0.14 mg higher than for WB and 8 ± 3% of the initial dose. Mycophenolic acid DBS dosing recommendations were 23.3 ± 31.9 mg lower than for plasma and 2 ± 3.5% of the initial dose. CONCLUSIONS Tacrolimus and mycophenolic acid TDM for outpatient renal transplant recipients, based on abbreviated AUC collected with a DBS sampling device, is comparable to conventional TDM based on WB sampling. Patient training and guidance on good bloodspotting practices is essential to ensure method feasibility.
Background. Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) ha... more Background. Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. Methods. A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n ¼ 21) and patients with IgAN (n ¼ 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. Results. Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. Conclusions. Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.
Patient variability in clinical response to the calcineurin inhibitors (CNIs) ciclosporin A and t... more Patient variability in clinical response to the calcineurin inhibitors (CNIs) ciclosporin A and tacrolimus partly results from differences in CNI exposure. For tacrolimus drug interactions and genetic variability relate to tacrolimus exposure. Patients carrying the CYP3A5*1 allele have an increased tacrolimus metabolism, hence lower drug exposure. Adjusting the tacrolimus dose to this genotype is a tool to optimize therapy from a pharmacokinetic perspective. In contrast, no genetic variants have been found to clearly relate to ciclosporin A exposure. Despite therapeutic drug monitoring aimed at individualizing CNI therapy, patients still suffer from acute or chronic rejection and CNI toxicity. To further optimize CNI therapy future research may incorporate genetic polymorphisms in proteins involved in CNI pharmacodynamics (i.e. drug target). Proteins potentially relevant for drug response are calcineurin and the CNI binding proteins immunophilins. Moreover, since the expression of the nuclear factor of activated T-cells (NFAT) is reduced after calcineurin inhibition, genetic polymorphisms in the genes encoding NFAT may also be interesting candidates for studying inter-patient differences in CNI efficacy and toxicity. In addition, the existence of isoforms and differences in tissue distribution of the calcineurin protein could potentially explain variable drug response. At present, the focus has been on the metabolism of CNIs and not on variability in the drug target. Therefore, future improvements in CNI therapy are likely to occur from a systems pharmacology approach taking into account genetic markers for both CNI pharmacokinetics and pharmacodynamics.
Background Controversy remains about the interaction between mycophenolate mofetil (M MF) and the... more Background Controversy remains about the interaction between mycophenolate mofetil (M MF) and the calcineurin inhibitors cyclosporin (CsA) and tacrolimus (TACR). The need to double the dose of MMF in case of CsA co-administration to achieve the same mycophenolic acid (MPA) levels as in TACR co-administration, has been attributed to either inhibition by CsA of the enterohepatic cycle, or an inhibition of glucuronidation to mycophenolate glucuronide (MPAG) by TACR. We explored these interactions clinically in 64 kidney transplant patients. Methods Plasma MPA/MPAG curves were determined during the first year post transplantation. Using nonlinear mixed effect modelling, MPA/MPAG data were fitted to a fourcompartment model, in which a rate constant describing transfer from the fourth to the first compartment (k41), and therefore enterohepatic recycling, could be introduced. Results MPA and MPAG plasma concentrations were adequately described by a four-compar tment model, which was significantly improved by introduction of k41 in case of TACR co-administration (minimum value of the objective function decreased by 181 points, P < 0.0001). Using this model, no statistically significant difference was observed in clearance of MPA between TACR and CsA co-administration (11.9 and 14.1 l h-1 , respectively). Total clearance of MPAG was lower in case of CsA co-administration (1.45 and 0.92 l h-1 , respectively), while there was no difference in renal clearance of MPAG (1.09 and 0.92 l h-1 , respectively). Conclusions Our study supplies supportive clinical evidence that inhibition of the enterohepatic cycle in case of CsA co-administration explains some of the differences observed in PK of MMF when co-administered with either TACR or CsA. This finding may have clinical consequences for the immunosuppressive management of kidney transplant patients.
Background. Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of... more Background. Therapeutic drug monitoring of cyclosporin A (CsA) is an obvious necessity because of its unpredictable absorption and narrow therapeutic window. The use of limited sampling models (LSMs) has improved the estimation of the systemic exposure [area under curve (AUC)] compared with C 0h monitoring, but these equations are rigid and not reliable in patients with an abnormal absorption profile. We developed and validated a limited sampling (ts0, 2 and 3 h) strategy, based on a compartmental population pharmacokinetic (PK) model for CsA after kidney transplantation alone (KTA) and simultaneous pancreaskidney transplant (SPKT) recipients, a group of patients with unpredictable absorption kinetics. Methods. A two-compartment model with lag time and first-order absorption was calculated using a PK software package from data of 20 KTA and SPKT recipients and validated prospectively in 20 KTA and 20 SPKT recipients. Calculated population PK parameters were individualized for each of the remaining 40 patients based on their CsA dosing and on one or a combination of measured CsA blood concentrations using the Bayesian fitting method. AUCs were calculated from individualized PK parameters. AUCs were also calculated using previously published LSMs. Relationships between AUCs calculated by the models and the 'golden standard' AUC (trapezoidal rule) were investigated by Pearson correlation test. Results and conclusions. A population two-compartment model is presented to reliably estimate the CsA AUC in KTA and SPKT recipients. The performance of the model to estimate the AUC is comparable to the performance of two published LSMs in KTA patients, but markedly better in SPKT patients. Combined with Bayesian fitting, the model is very flexible since sampling times are not rigid and can be varied as long as dosing and sampling times are recorded accurately. The model has already proven to be clinically useful and is currently used to further investigate CsA in an integrated pharmacokineticupharmacodynamic model.
Recently, several B cell-related markers have been described to be upregulated during operational... more Recently, several B cell-related markers have been described to be upregulated during operational tolerance in kidney allograft recipients. Little data exist on these markers during allograft rejection. In this study, we investigated regulation-associated B-cell phenotypes in peripheral blood mononuclear cells (PBMCs) of kidney transplant recipients with (n=21) and without (n=22) acute rejection (AR). We also determined expression levels of the B cell-related genes, MS4A1, TCL1A, and CD79B, in PBMCs and isolated B cells. Patient samples were analyzed before transplantation at discharge and at time of AR before initiation of antirejection therapy or at matching timepoints in patients with stable graft function. On transplantation, the peripheral CD19CD24CD38 transitional B cell subset strongly declined, regardless of the subsequent occurrence of AR. In contrast, the CD19CD27CD24 subset remained stable after transplantation in both patients groups. MS4A1 gene expression levels in PBMC were comparable between patient groups at all timepoints. In contrast, TCL1A expression levels increased in stable patients, but decreased in patients at the time of AR in both PBMC and isolated B cells. CD79B expression levels in stable patients were unaltered after transplantation in PBMC but showed an increase in the B cell fraction at discharge. At the time of AR, CD79B gene expression was significantly lower compared to stable patients, being most apparent in the B-cell fraction. These results suggest that, in addition to being markers for immunologic unresponsiveness, gene expression levels of TCL1A and CD79B may also identify immune activation in the setting of kidney transplantation.
Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted i... more Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted in increased rates of delayed graft function (DGF) and primary nonfunction. Here, we used Nuclear Magnetic Resonance (NMR) spectroscopy to analyze the urinary metabolome of DCD transplant recipients at multiple time points (days 10, 42, 180, and 360 after transplantation). The aim was to identify markers that predict prolonged duration of functional DGF (fDGF). Forty-seven metabolites were quantified and their levels were evaluated in relation to fDGF. Samples obtained at day 10 had a different profile than samples obtained at the other time points. Furthermore, at day 10 there was a statistically significant increase in eight metabolites and a decrease in six metabolites in the group with fDGF (N = 53) vis-à-vis the group without fDGF (N = 22). In those with prolonged fDGF (≥21 days) (N = 17) urine lactate was significantly higher and pyroglutamate lower than in those with limited fDGF (<21 days) (N = 36). In order to further distinguish prolonged fDGF from limited fDGF, the ratios of all metabolites were analyzed. In a logistic regression analysis, the sum of branched-chain amino acids (BCAAs) over pyroglutamate and lactate over fumarate, predicted prolonged fDGF with an AUC of 0.85. In conclusion, kidney transplant recipients with fDGF can be identified based on their altered urinary metabolome. Furthermore, two ratios of urinary metabolites, lactate/fumarate and BCAAs/ pyroglutamate, adequately predict prolonged duration of fDGF.
Despite excellent short-term graft survival after renal transplantation, the long-term graft outc... more Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejecti...
The warm and cold ischemia times were 46.7612.4 (26-117) and 172.3686.7 (41-780) minutes respecti... more The warm and cold ischemia times were 46.7612.4 (26-117) and 172.3686.7 (41-780) minutes respectively. Pts received triple immunosuppression. Initial immunosuppression mainly (80; 62.0%) consisted of prednisolone, cyclosporine A (generics, oral solutions) and mycophenolate mofetil. Induction therapy used selectively (29; 22.5%), mainly in highly sensitized pts (ATG in 2 and Basiliximab in 27 pts). Complications: Overall, 58 (45.0%) pts had 92 episodes of acute rejection, median on 12 th day after KT. All pts received methylprednisolone pulses, 5 in addition ATG. Twelve pts (9.3%) had acute tubulonecrosis, 10 of them received HD. Prophylaxis of cytomegalovirus (CMV) infection is not routinely done due to high cost. Twenty-two pts (17.1%) had CMV disease that was successfully treated. Complications included also pulmonary tuberculosis (1), chickenpox (5), herpes zoster (9) and measles (1). Nine pts (7%) had oncological complications, two of them died. Sixteen (12.4%) pts lost their grafts and were back on HD. The causes were rejection (8), mainly as a result of noncompliance (7), chronic transplant nephropathy (3), surgical complications (2), reduction of immunosuppression in case complications (2) and hyperhomocysteinemia (1). One, 3-, 5-and 10-year graft survival rate is 96.1%, 93.4%, 92.4% and 88.5% respectively. Nine pts (7%) died with functioning grafts due to cardio-vascular (3), oncological complications (2), gastro-intestinal bleeding (2) and systemic amyloidosis (2). Pts' 1-, 3-5-and 10-year survival is 98.4%, 97.5%, 95.3% and 89.8% respectively. CONCLUSIONS: KT is the optimal treatment of ESRD also in countries with limited resources. Pts' non-compliance can be ruled out by psycho-social adaptation and use of convenient forms of medications (capsules instead of oral solutions). LRKT program alone is far from covering all the demand for KT and must be complemented by deceased donor transplantation.
A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and period... more A 62-year-old woman with a history of genetically confirmed hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was admitted because of chronic diarrhoea. During admission she developed a rapidly progressive nephrotic syndrome. Reactive amyloid A (AA) amyloidosis was confirmed after colonic and renal biopsy which showed deposition of amyloid. After initial treatment with high-dosed corticosteroids, therapy was switched to anakinra, an IL-1 receptor antagonist, but her symptoms persisted. After cessation of anakinra, a marked exacerbation of the intestinal symptoms was noted. Nine months after the initial diagnosis of reactive amyloidosis without any amelioration of the symptoms and a decreasing quality of life, our patient declined further treatment and died soon after. This case demonstrates that AA amyloidosis does occur in patients with HIDS and can present with intestinal symptoms and proteinuria. Once amyloidosis is diagnosed the goal of treatment is to prevent furthe...
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, Jan 19, 2015
Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes ... more Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, re...
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