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Research Interests: Business, Economics, Economic Theory, Risk Management, Applied Economics, and 14 moreCredit Rating, Counterparty Risk, Credit Risk, Financial Studies, State Space, Default Risk, Derivative, Bond, Markov chain, Term Structure, Markov model, Finance and Investment Banking Area, Finance and Investment Banking, and Credit derivative
Research Interests: Cardiology, Kidney transplantation, Medicine, Linear models, Humans, and 15 moreInternal Medicine, Blood Pressure, Female, Male, Cyclosporine, Middle Aged, Adult, Chi Square Distribution, Calcineurin, Calcineurin inhibitors, Immunosuppressive Agents, Diastole, Antihypertensive agents, Medical and Health Sciences, and Heart atria
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The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We... more
The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An add...
Research Interests: Risk, Kidney transplantation, Medicine, Humans, Female, and 15 moreMale, Incidence, Cadaver, Health Care Rationing, Middle Aged, Time Factors, Proportional hazards model, Major histocompatibility complex, Graft Rejection, Proportional Hazards Models, Acute Disease, Human leukocyte antigen, Medical and Health Sciences, Tissue and organ procurement, and hazard ratio
Evaluating prognostic determinants and results of renal transplantation. Descriptive study. Leiden University Hospital, The Netherlands. Follow-up of all 1289 patients who had a kidney transplantation in Leiden University Hospital between... more
Evaluating prognostic determinants and results of renal transplantation. Descriptive study. Leiden University Hospital, The Netherlands. Follow-up of all 1289 patients who had a kidney transplantation in Leiden University Hospital between March 1966 and December 1994. The following determinants were investigated: age and sex of donors and recipients. HLA matching, type of immunosuppression, presensitization, presence of diabetes mellitus, and living or post-mortem donor. Renal transplantation was very successful during the first few years, one-year graft survival dropped to 50% during the second decade and gradually increased to almost 90% during the last years. 5-year and 10-year graft survival were 65% and 50% respectively. The mean age of recipients increased from 32.8 years to 45.7 years, that of donors from 24.9 to 37.9 years. Duration of dialysis before transplantation increased from 19.7 months to 35.7 months. The introduction of cyclosporine and matching on the HLA-DR locus ...
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We propose that tissue-specific alloantigens are of importance in interstitial and vascular rejection. To study this hypothesis we took the following approaches: multivariate analysis on our database (N = 482) was performed, the... more
We propose that tissue-specific alloantigens are of importance in interstitial and vascular rejection. To study this hypothesis we took the following approaches: multivariate analysis on our database (N = 482) was performed, the specificity of T cells cultured from kidneys with rejection was analyzed, and non-anti-HLA antibodies reactive with endothelium were studied. First we observed that in a cohort study of 482 patients receiving a cadaveric renal allograft 76 (15.8%) patients developed vascular rejection and 115 (23.9%) developed interstitial rejection. The incidence of vascular rejection was increased in patients with delayed graft function, HLA-DR mismatches, a prolonged cold ischemia period, and previous transplantations. Next we examined 40 graft infiltrating cell (GIC) lines cultured from renal biopsies taken during rejection episodes. Thirteen GIC lines reacted in a donor-specific fashion to proximal tubular cells (PTEC) but not to donor splenocytes. These GIC recognize p...
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The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We... more
The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An add...
Research Interests: Risk, Kidney transplantation, Medicine, Humans, Female, and 15 moreMale, Incidence, Cadaver, Health Care Rationing, Middle Aged, Time Factors, Proportional hazards model, Major histocompatibility complex, Graft Rejection, Proportional Hazards Models, Acute Disease, Human leukocyte antigen, Medical and Health Sciences, Tissue and organ procurement, and hazard ratio
Research Interests: Kidney transplantation, Gene expression, Biopsy, Humans, Internal Medicine, and 15 moreFemale, Drug Resistance, Male, Immunosuppression, Clinical Sciences, Graft Rejection, Genetic Markers, Logistic Models, Gene Expression Regulation, Acute Disease, Immunosuppressive Agents, Kidney biopsy, Adrenal cortex hormones, Medical and Health Sciences, and Acute Allograft rejection
Evaluating prognostic determinants and results of renal transplantation. Descriptive study. Leiden University Hospital, The Netherlands. Follow-up of all 1289 patients who had a kidney transplantation in Leiden University Hospital between... more
Evaluating prognostic determinants and results of renal transplantation. Descriptive study. Leiden University Hospital, The Netherlands. Follow-up of all 1289 patients who had a kidney transplantation in Leiden University Hospital between March 1966 and December 1994. The following determinants were investigated: age and sex of donors and recipients. HLA matching, type of immunosuppression, presensitization, presence of diabetes mellitus, and living or post-mortem donor. Renal transplantation was very successful during the first few years, one-year graft survival dropped to 50% during the second decade and gradually increased to almost 90% during the last years. 5-year and 10-year graft survival were 65% and 50% respectively. The mean age of recipients increased from 32.8 years to 45.7 years, that of donors from 24.9 to 37.9 years. Duration of dialysis before transplantation increased from 19.7 months to 35.7 months. The introduction of cyclosporine and matching on the HLA-DR locus ...
Research Interests:
We propose that tissue-specific alloantigens are of importance in interstitial and vascular rejection. To study this hypothesis we took the following approaches: multivariate analysis on our database (N = 482) was performed, the... more
We propose that tissue-specific alloantigens are of importance in interstitial and vascular rejection. To study this hypothesis we took the following approaches: multivariate analysis on our database (N = 482) was performed, the specificity of T cells cultured from kidneys with rejection was analyzed, and non-anti-HLA antibodies reactive with endothelium were studied. First we observed that in a cohort study of 482 patients receiving a cadaveric renal allograft 76 (15.8%) patients developed vascular rejection and 115 (23.9%) developed interstitial rejection. The incidence of vascular rejection was increased in patients with delayed graft function, HLA-DR mismatches, a prolonged cold ischemia period, and previous transplantations. Next we examined 40 graft infiltrating cell (GIC) lines cultured from renal biopsies taken during rejection episodes. Thirteen GIC lines reacted in a donor-specific fashion to proximal tubular cells (PTEC) but not to donor splenocytes. These GIC recognize p...
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Research Interests:
Research Interests: Kidney transplantation, Gene expression, Biopsy, Humans, Internal Medicine, and 15 moreFemale, Drug Resistance, Male, Immunosuppression, Clinical Sciences, Graft Rejection, Genetic Markers, Logistic Models, Gene Expression Regulation, Acute Disease, Immunosuppressive Agents, Kidney biopsy, Adrenal cortex hormones, Medical and Health Sciences, and Acute Allograft rejection
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In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of... more
In 1995 - 1996, we switched from a once-daily Sandimmune dose to a twice-daily dose regimen of Neoral. Concurrent with the switch we changed our target trough level from 100 microg/l at 24 hours to the generally accepted 12-hour level of 150 microg/l. We performed a retrospective cohort study to assess cyclosporine toxicity following this switch and to identify risk factors for nephrotoxicity. Of 212 patients with a stable graft function pre-conversion clinical parameters at 1 and 12 months post-conversion were compared with those at time of conversion. Cyclosporine nephrotoxicity was defined as a significant decline of the reciprocal of the serum creatinine concentration over time post-conversion in the absence of other obvious causes for declining graft function. Risk factors of cyclosporine nephrotoxicity were assessed using logistic regression analysis. The mean cyclosporine trough level rose from 87 microg/l at the time of conversion to 139 microg/l at 12 months post-conversion...
Research Interests: Kidney diseases, Kidney transplantation, Medicine, Humans, Female, and 15 morePubmed, Male, Cyclosporine, Risk factors, Renal Function, Clinical Sciences, Middle Aged, Clinical Nephrology, Retrospective Studies, Risk Factors, Nephrotoxicity, Logistic Models, Creatinine, Calcium Channel Blockers, and Immunosuppressive Agents
Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term... more
Acute rejection is a major complication after renal transplantation and the most important risk factor for chronic rejection. We investigated whether the timing of the last treated acute rejection episode (ARE) influences long-term outcome and compared the risk profiles of early versus late ARE. A cohort of 654 patients who underwent cadaveric renal transplants (1983-1997) that functioned for more than 6 months was studied. In 384 of 654 transplant recipients, one or more treated AREs were documented; the last ARE occurred in 297 of 384 transplant recipients within 3 months and in 87 of 384 after 3 months. Applying multivariate logistic regression analysis, we compared the predictor variables of the two groups with transplants without AREs. Ten-year graft survival rates censored for causes of graft loss other than chronic rejection were 94%, 86%, and 45% for patients without ARE, with early ARE, and with late ARE, respectively. Delayed graft function, odds ratio (OR) 2.37 (1.55-3.62...
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Research Interests: Immunology, Complement activation, Kidney transplantation, Innate immunity, Disease susceptibility, and 15 moreComplement System, Complication, Humans, Female, Male, Immunosuppression, Kidney Transplant, Adult, Bacteremia, Biological markers, Bacterial infections, Complement, Cytomegalovirus Infections, mannose binding lectin, and Medical and Health Sciences
Research Interests: Kidney transplantation, Treatment Outcome, Medicine, Transplantation, Humans, and 15 moreKidney, Pancreas, Female, Male, Kidney Transplant, Adult, Time Factors, Retrospective Studies, Blood Transfusion, Graft Rejection, Chronic Kidney Failure, Pancreas Transplantation, Severity of Illness Index, Acute Disease, and Medical and Health Sciences
Research Interests: Kidney transplantation, Enzyme Inhibitors, Medicine, Biopsy, Prospective studies, and 15 moreHumans, Female, Feasibility Studies, Male, Immunosuppression, AUC, Middle Aged, Calcineurin, Graft Rejection, Calcineurin inhibitors, Area Under the Curve, Mycophenolate mofetil, Glomerular Filtration Rate, Acute Disease, and Medical and Health Sciences
Cardiovascular disease is both a major threat to the life expectancy of kidney transplant recipients and an important determinant of late allograft loss. Obesity is an important risk factor for cardiovascular disease. We investigated the... more
Cardiovascular disease is both a major threat to the life expectancy of kidney transplant recipients and an important determinant of late allograft loss. Obesity is an important risk factor for cardiovascular disease. We investigated the relation between both pretransplant and 1-year posttransplant body mass index (BMI) with patient and renal graft survival in a cohort of 1810 adult patients. Sixty-one percent of all patients were men; median age (interquartile range [IQR]) was 46 years (35-56 years); median (IQR) pretransplant BMI was 23.0 kg/m (20.8-25.6 kg/m); 1 year after transplantation, the median (IQR) BMI had increased 1.6 kg/m (0.3-3.2 kg/m) and median (IQR) follow-up time was 8.3 years (5.3-12.0 years). We categorized BMI as follows: less than or equal to 20, more than 20 to less than or equal to 25 (normal), more than 25 to less than or equal to 30, and more than 30 (obesity) kg/m. Using a Cox proportional hazards model, after adjustment for cardiovascular risk factors, the relative risks (95% confidence intervals) of death and death-censored graft failure during all follow-up for pretransplant obesity compared with normal BMI were 1.22 (0.86-1.74) and 1.34 (1.02-1.77), respectively; for obesity 1 year after transplantation compared with normal BMI, it was 1.39 (1.05-1.86) and 1.39 (1.10-1.74), respectively; and for change in BMI (per 5 kg/m increment) during the first year after transplantation, it was 1.23 (1.01-1.50) and 1.18 (1.01-1.38), respectively. One year posttransplant BMI and BMI increment are more strongly related to death and graft failure than pretransplant BMI among kidney transplant recipients. Patients with BMI more than 30 kg/m compared with a normal BMI have approximately 20% to 40% higher risk for death and graft failure.
Research Interests: Epidemiology, Kidney diseases, Kidney transplantation, Evolution, Cardiovascular disease, and 15 moreHumans, Internal Medicine, Female, Male, Life Expectancy, Body Mass Index, Kidney Transplant, Adult, Cardiovascular Risk Factor, First Year, Confidence Interval, Immunosuppressive Agents, Graft failure, Medical and Health Sciences, and Cox proportional hazards model
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Research Interests: Membrane Proteins, Medicine, Humans, Kidney, Female, and 15 moreMale, Fibrosis, Clinical Sciences, Nephropathy, Prognosis, Multivariate Regression, Biological markers, Disease Progression, Proteinuria, Membrane Protein, IgA nephropathy, Glomerulosclerosis, Cytotoxic T cells, Glomerular Filtration Rate, and Human leukocyte antigen
Research Interests: Gastroenterology, Dialysis, Adolescent, Biopsy, Conversion, and 15 moreBlood Pressure, Chronic Disease, Female, Cyclosporine, Clinical Sciences, Aged, Adult, Cardiovascular Risk Factor, Cardiovascular Diseases, Autoantibodies, Azathioprine, Acute rejection, Glomerular Filtration Rate, Chronic Allograft Nephropathy, and Cause of death
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Research Interests: Nephrology, Surgery, Complement activation, Kidney transplantation, Medicine, and 15 moreHumans, Female, Male, Risk factors, Low, Clinical Sciences, Middle Aged, Adult, Risk Factors, Chronic Kidney Failure, Pancreas Transplantation, Predictive value of tests, mannose binding lectin, Diabetic nephropathies, and hazard ratio
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Summary Background and objectives Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during... more
Summary Background and objectives Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during acute rejection is regarded as an inferior prognostic sign. This case-control study investigated the prognostic role of mere C4d staining for graft outcome during an ARE in a well defined cohort of similarly ARE-treated patients. Design, setting, participants, & measurements All kidney transplant recipients in the authors' center from January 1, 1995 to December 31, 2005 were reviewed. From these patients, 151 had a clinical ARE. Paraffin and/or frozen material was available for 128 patients showing a histologically proven ARE within the first 6 months after transplantation. All ARE patients were treated similarly with high-dose pulse steroids and in the case of steroid unresponsiveness with anti-thymocyte globulin. Biopsies were scored according...
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ABSTRACT
Research Interests: Kidney transplantation, Medicine, Complement System, Transplantation, Humans, and 15 moreInternal Medicine, Female, Male, American, Risk factors, Kidney Transplant, Adult, Prognosis, Complement, Risk Factors, Graft Rejection, Enzyme Linked Immunosorbent Assay, Cohort Studies, mannose binding lectin, and Medical and Health Sciences
Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute... more
Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (p < 0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC = 0.88, p < 0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (p = 0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that nonresponse to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor.
Research Interests: Kidney transplantation, Medicine, In Situ Hybridization, Humans, Internal Medicine, and 15 moreFemale, Drug Resistance, Male, Metallothionein, Cohort, Middle Aged, Biological markers, Graft Rejection, Gene expression profiling, Case Control Studies, Cohort Studies, Methylprednisolone, real time polymerase chain reaction, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
Kidney transplant recipients have high cardiovascular risk and an unfavorable cardiovascular risk profile, which frequently includes hyperlipidemia. Although the use of HMG-CoA reductase inhibitors (statins) is associated with improved... more
Kidney transplant recipients have high cardiovascular risk and an unfavorable cardiovascular risk profile, which frequently includes hyperlipidemia. Although the use of HMG-CoA reductase inhibitors (statins) is associated with improved survival in the general population, the effects of these drugs on the survival of kidney transplant recipients have not been established. In this study, we determined which factors were associated with the use of statins in a population of 1,574 adult, kidney allograft recipients, transplanted in one institution. A risk factor analysis of patient survival was done with a primary focus on the possible relationship between statin use and survival. The percent of patients treated with statins increased progressively from 1982 to 1996. Statins were used significantly more often in whites (30%) than in blacks (20%, P = 0.001) and in older individuals. These differences in statin use were not due to differences in lipid levels among the patient groups. As expected, the group of patients treated with statins had significantly higher serum lipid levels than untreated patients. Patient survival was significantly better in patients treated with statins than in untreated patients. That relationship became apparent, however, only after controlling for three additional factors: recipient age, transplant year, and serum cholesterol levels. In a multivariable Cox survival model, patient survival was associated significantly with statin use (hazard ratio [HR] = 0.76; confidence interval [CI], 0.6 to 0.96; P = 0.02), recipient age (HR = 1.05; CI, 1.04 to 1.06; P < 0.0001), and transplant year (HR = 1.05; CI, 1.01 to 1.08; P = 0.001). The serum cholesterol level was not associated significantly with patient survival in this model, but cholesterol significantly modified the relationship between statin use and patient survival. Renal transplant recipients treated with statins have a 24% better survival than patients who do not receive these drugs.
Research Interests: Cardiovascular Risk, Insulin Resistance, Humans, African American, Diabetes mellitus, and 15 moreHyperlipidemia, Cox Regression, Blood Pressure, Cholesterol, Female, American, African Americans, Clinical Sciences, Adult, Age Factors, European Continental Ancestry Group, Chronic Kidney Failure, General Population, Confidence Interval, and hazard ratio
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In this thesis we present novel methods to improve the limitations in Optical Coherence Tomography (OCT). They are divided into two parts. The first part deals with the axial resolution limitation in OCT systems. We give a description of... more
In this thesis we present novel methods to improve the limitations in Optical Coherence Tomography (OCT). They are divided into two parts. The first part deals with the axial resolution limitation in OCT systems. We give a description of the Fourier Domain OCT (FDOCT), and then we show theoretically how to enhance the axial resolution in a particular case of a two-layer sample where one of the two layers is moving continuously, while these two layers are separated by a distance lower than the physical axial resolution. The second part of the thesis demonstrates a novel full theoretical model that uses the second order autocorrelation interferometry technique in nonlinear optics to eliminate the strong background DC, and therefore enhance the imaging contrast. A femtosecond laser emits the light at 1300nm wavelength, it travels through a polarized beam splitter which divides the light in two orthogonal polarizations, one will probe the reference and the other will probe the sample. B...
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This article provides a Markov model for the term structure of credit risk spreads. The model is based on Jarrow and Turnbull (1995), with the bankruptcy process following a discrete state space Markov chain in credit ratings. The... more
This article provides a Markov model for the term structure of credit risk spreads. The model is based on Jarrow and Turnbull (1995), with the bankruptcy process following a discrete state space Markov chain in credit ratings. The parameters of this process are easily estimated using observable data. This model is useful for pricing and hedging corporate debt with imbedded options, for pricing and hedging OTC derivatives with counterparty risk, for pricing and hedging (foreign) government bonds subject to default risk (e.g., municipal bonds), for pricing and hedging credit derivatives, and for risk management. This article presents a simple model for valuing risky debt that explicitly incorporates a firm's credit rating as an indicator of the likelihood of default. As such, this article presents an arbitrage-free model for the term structure of credit risk spreads and their evolution through time. This model will prove useful for the pricing and hedging of corporate debt with We would like to thank John Tierney of Lehman Brothers for providing the bond index price data, and Tal Schwartz for computational assistance. We would also like to acknowledge helpful comments received from an anonymous referee. Send all correspondence to