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Kathleen Claes

Publications and source records attributed to Kathleen Claes.

29 records · Page 2Linked to original sources
PubMed2004

Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients.

INTRODUCTION: Tacrolimus and mycophenolate mofetil are effective drugs characterized by specific toxicity profiles that may compromise their long-term use in renal transplant recipients. Clinicians, therefore, need reliable drug monitoring tools for relating efficacy and toxicity to drug exposure. Study design We conducted a prospective 12-month pharmacokinetic study of tacrolimus and mycophenolic acid in 100 de novo recipients. The aim was to examine whether tacrolimus and mycophenolic acid exposure parameters (predose trough blood concentration [C(0)], area under the concentration curve from 0 to 12 hours [AUC(0-12)], maximum blood or plasma concentration [C(max)], and dose) would reflect clinical efficacy and toxicity at different time points after transplantation (7 days, 6 weeks, and 3, 6, and 12 months). RESULTS: Initially, after grafting, the tacrolimus AUC(0-12) was higher in recipients with infection (P =.01 on day 7, P =.02 at week 6), whereas the mycophenolic acid AUC(0-12) was not different. There was no difference in tacrolimus exposure between patients who had arterial hypertension or hyperlipidemia and those who did not. Patients with tacrolimus nephrotoxicity received a higher drug dose (P =.03) and had higher drug clearance (P =.02). From 3 months, recipients with anemia or leukopenia had higher mycophenolic acid AUC(0-12) (anemia, P =.03 at month 3 and P =.01 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year) and C(0) (anemia, P =.001 at month 3 and P =.001 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year). Finally, for recipients who did not simultaneously have a target tacrolimus AUC(0-12) of 150 ng x h/mL and a mycophenolic acid AUC(0-12) of 45 mg x h/L by day 7, the incidence of acute rejection tended to be higher (26.3%) compared with patients who reached both target values (7.7%) (P =.07). CONCLUSIONS: Pharmacokinetic exposure parameters of tacrolimus and mycophenolic acid are related to specific drug-induced side effects in a time-dependent fashion. In addition, this study has provided a conceptual basis for defining a combined target therapeutic window for tacrolimus and mycophenolic acid based on sparse AUC(0-12) measurements.

Area Under Curve↗
PubMed2004

A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition due to heterozygous germline mutations in DNA mismatch repair genes, in particular MLH1, MSH2 and MSH6. Recently, a syndrome was recognized in which children develop haematological malignancies, solid tumours and signs of neurofibromatosis type 1 due to bi-allelic MMR gene mutations in MLH1, MSH2 and PMS2. Here we describe the child of healthy consanguineous parents who had café-au-lait spots, oligodendroglioma, and rectal cancer. The patient was homozygous for the MSH6 mutation c.3386_3388delGTG in exon 5 which has a predicted pathogenic effect. Germline NF1 gene mutation testing was negative. The rectal tumour showed microsatellite instability and absence of MSH6 staining, whereas the brain tumour was MSI stable and showed normal immunohistochemical expression of MSH6. Apparently, not only MLH1, MSH2 and PMS2, but also MSH6 is involved in the syndrome of childhood cancer and signs of neurofibromatosis type 1.

Base Pair Mismatch↗
PubMed2004

Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study.

BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.

Adult↗
PubMed2004

Time-related clinical determinants of long-term tacrolimus pharmacokinetics in combination therapy with mycophenolic acid and corticosteroids: a prospective study in one hundred de novo renal transplant recipients.

BACKGROUND: Tacrolimus is an efficient primary immunosuppressive drug in renal transplantation but its long-term use is associated with calcineurin-inhibitor-related toxicity. The specific characteristics of the inter-relationship between dose, concentration and clinical (side-)effects for tacrolimus have not yet been identified and extensive long-term pharmacokinetic studies are presently lacking. OBJECTIVE: To establish the characteristics of the long-term pharmacokinetics of tacrolimus, to determine the time-dependent factors that influence the pharmacokinetics within the first critical post-transplant year and to identify a more appropriate way of monitoring drug exposure in clinical practice. STUDY DESIGN: A prospective pharmacokinetic study of tacrolimus was conducted in 100 de novo renal allograft recipients during the first year post-transplantation. METHODS: Area under the concentration-time curve (AUC) blood samplings for tacrolimus were performed on days 7, 42, 90, 180 and 360 for all patients. Model-independent pharmacokinetic parameters for tacrolimus were calculated and dose-corrected when appropriate: AUC12, peak plasma concentration (Cmax), pre-dose trough concentration (C0), time to Cmax, average steady-state blood concentration, steady-state total body clearance, terminal half-life, volume of distribution and an estimate for tacrolimus bioavailability was derived from additional steady-state intravenous clearance data. The association between tacrolimus pharmacokinetic parameters and different clinical variables was evaluated on days 7, 42, 90, 180 and 360. The clinical variables were either donor-related (e.g. donor age), transplantation-related (e.g. delayed graft function), recipient-related (e.g. bodyweight), biochemical (e.g. serum albumin), therapeutic variables (e.g. corticosteroid dose) or disease variables (e.g. liver dysfunction). RESULTS: Long-term tacrolimus dose-corrected exposure (AUC12, C0) is characterised by a late significant increase towards the end of the first year post-transplantation as the result of a significant increase in tacrolimus bioavailability (p < 0.05) and a slow decrease in tacrolimus steady-state clearance. Consequently, tacrolimus dose-requirements corrected for bodyweight decrease significantly in the first postoperative year (p < 0.05), in part because of the simultaneous tapering of the corticosteroid dose which significantly affects tacrolimus bioavailability (p < 0.05). Other clinical variables that significantly influenced tacrolimus administration, exposure and bioavailability in a time-related fashion were identified in this study (renal allograft function [p < 0.05], liver dysfunction [p < 0.05], diarrhoea [p < 0.05]), while the clinical relevance of other variables was considerably moderated by our findings (serum albumin, haematocrit). Time-unrelated variables proved to be of significant continuing clinical importance for tacrolimus dose-exposure pharmacokinetics throughout the first post-transplant year (recipient age [p < 0.05], gender [p < 0.01] and donor-receptor gender mismatch [p < 0.05]), while donor hypotension (p < 0.05) and cold ischaemia time (p < 0.05) also proved significant although at present the reasons for this are unknown. Finally, using multiple stepwise regression analysis we demonstrated that classical assessment of tacrolimus exposure by monitoring pre-dose trough blood concentration (or any other single concentration sampling timepoint) is not the most reliable method and that abbreviated AUC measurements may constitute a more accurate clinical tool for (therapeutic) monitoring of drug exposure. CONCLUSION: Tacrolimus pharmacokinetics in the first year after renal transplantation are characterised by a specific time-dependent evolution. The identification of clinical variables that determine tacrolimus pharmacokinetics is an important aid in the development of reliable drug monitoring strategies using abbreviated AUC measurements.

Adrenal Cortex Hormones↗
PubMed2003

Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2.

About 4% of all BRCA1 and BRCA2 alterations reported to the Breast Information Core database are splice site variants. Only a limited number of them have been studied at the RNA level. By BRCA1 and BRCA2 mutation analysis of breast/ovarian cancer families, we identified two novel and eight previously reported potential splice site mutations, never characterized at the cDNA level before. RT-PCR was performed to determine whether these variants disrupted correct splicing. To ensure efficient detection of transcripts containing premature termination codons, a nonsense-mediated mRNA decay inhibitor was added to the lymphoblastoid cell lines of the patients before RNA extraction. We found that BRCA1 IVS3+3A>C, 4304G>A (in the last codon of exon 12), and IVS19+2delT and BRCA2 IVS6+1G>A, IVS23-2A>G, and IVS24+1G>A lead to aberrant transcripts in lymphocytes. Therefore, they were considered to be true pathogenic mutations, predisposing carriers to cancers of the hereditary breast/ovarian cancer syndrome. BRCA2 IVS24-16T>C is a frequent polymorphism in linkage disequilibrium, with a polymorphic stop codon in exon 27, K3326X. BRCA1 IVS2-14C>T and BRCA2 IVS9-5insT and IVS25+9A>C represent rare variants, not disrupting normal splicing in blood lymphocytes. However, some of the alterations may act differently, qualitatively and/or quantitatively, in breast or ovarian tissues. The data provided in this paper allowed more accurate risk estimation of patients and relatives carrying the mutations described herein and have facilitated genetic counseling. Furthermore, our study is important for a better understanding of splicing mechanisms and revealed new patterns of alternative splicing in BRCA1 and BRCA2.

Adult↗
PubMed2002

Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1 exon 5 increase alternative transcript levels in the 5' end of the BRCA1 gene.

We report two novel mutations in the splice sites of BRCA1 exon 5: IVS5+3A>G, a Belgian founder mutation, and IVS3-6T>G, identified in one family with a strong family history of breast cancer. Real-time RT-PCR showed that IVS3-6T>G leads to a fivefold increase of the BRCA1-Deltaex5 (isoform with an in frame skip of exon 5) ratio to the total BRCA1 expression level. IVS5+3A>G results in a 10-fold increase of the BRCA1-Delta22ntex5 ratio (isoform with an out of frame skip of the last 22 nucleotides of exon 5) and a twofold increase of the BRCA1-Deltaex5 ratio. These altered ratios are most likely to result from increased expression of the alternative transcripts, although we cannot completely rule out a small decrease of the total BRCA1 expression level due to highly variable BRCA1 levels in cultured cell lines. In order to explore the functional significance of the isoforms, we evaluated their prevalence in normal tissues and cancer cell lines. The BRCA1-Delta22ntex5 ratio was significantly higher in an ovarian cancer cell line compared to normal ovarian tissue. Our findings suggest that revealing the defects caused by some splice mutations requires accurate quantitative methods. We hypothesize that disruption of alternative transcript ratios of BRCA1 may be a dominant mechanism affecting predisposition to hereditary breast and/or ovarian cancer.

Alternative Splicing↗
PubMed2002

An uncommon tumor in a renal graft recipient: a diagnostic and therapeutic challenge.

The development of malignancies after solid organ transplantation represents an increasing clinical problem complicating the long-term follow-up of transplant recipients. In this case report the authors describe the rare triple combination of a simultaneous hepatocellular carcinoma with a glucagonoma and a splenic hamartoma in a renal allograft recipient. It is not only the first published report of a glucagonoma occurring after renal transplantation but serves also as an illustration of the therapeutic decision making in the setting of the immune-compromised host. This case report also illustrates the different imaging modalities that can be used for the diagnosis of neuroendocrine tumors.

Carcinoma, Hepatocellular↗
PubMed2002

Cessation of steroids in stable renal transplant patients: the Leuven experience.

Because of the major long-term impact of steroids on the quality of life of renal allograft recipients, physicians are attempting to avoid, reduce or eliminate steroids from the immunosuppressive regimen after renal transplantation. In 311 stable renal transplant recipients, transplanted more than one year and with low immunological risk for rejection, an attempt was made to stop steroids. A permanent cessation of steroids succeeded in 274. Cessation of steroids in stable renal transplant patients resulted in a transient rise of serum creatinine over 3 months. This was reflected in a decreased GFR in the first month. A concomitant change in potassium and weight suggested a minor mineralocorticoid deficiency as plausible explanation. After 4 years, serum creatinine again rose slightly; however, this was not reflected in a decreased GFR. This might reflect a metabolic phenomenon rather than immunological one because patients with acute rejection were excluded from this group and also because there was a small rise in weight and blood pressure noted after the second year following cessation of steroids. Only a mild and transient drop in lipids was present after cessation of steroids. Steroid withdrawal was unsuccessful in 12% of patients, and was twice as high in female patients as in males. Adrenal cortical deficiency was the most prominent reason (3%); acute rejection developed in only 5 patients (1.6%) and chronic rejection was documented in only 4 (1.3%). A better graft and patient survival rate and similar renal function, degree of proteinuria and blood pressure 10 years after renal transplantation (and 6 years after cessation of steroids) compared with patients in whom steroids were never stopped, are very promising despite the selection bias. Although longer follow-up is needed to determine whether stopping steroids will result in altered long-term transplant function, these results are reassuring that steroids can be withdrawn in stable renal transplant patients with a low immunological risk in order to diminish the long-term morbidity associated with corticosteroid therapy.

Adrenal Cortex Hormones↗