Luc De Pauw

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia Fangchi)

BACKGROUND Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients

High levels of tumor necrosis factor-alpha, interleukin-2, and gamma-interferon appeared in the circulation of kidney transplant recipients after the first injection of the monoclonal antibody OKT3. This initial injection was systematically followed by fever. The three cytokines were released in all patients (n = 9), with peak serum levels of tumor necrosis factor occurring 1 hr after OKT3 injection and those of interleukin-2 and gamma-interferon after 2 hr. Cytokines were not released after the second and third OKT3 injections, when CD3+ cells had disappeared from blood. These findings suggest that circulating cytokines are released by T cells after activation by OKT3. These cytokines are probably involved in the systematic reactions observed after injection of OKT3.

Reduction of left ventricular diameter and mass after surgical arteriovenous fistula closure in renal transplant recipients.

Background. Left ventricular hypertrophy and dilatation is a frequent finding in kidney transplant recipients, which may be favored by the persistent patency of arteriovenous fistula. The purpose of the current study was to prospectively investigate whether surgical closure of the fistula allows reduction of abnormalities of left ventricular morphology in stable renal transplant patients. Furthermore, we studied the ability of preoperative echocardiographic and noninvasive hemodynamic measurements, including the effects of a temporary occlusion of the fistula, to predict postoperative left ventricular diameter and mass reduction. Methods. Seventeen kidney transplant recipients referred for surgical arteriovenous fistula closure were prospectively studied. Standard echocardiographic parameters, heart rate, and blood pressure were assessed preoperatively at baseline and during an acute pneumatic fistula occlusion. These measurements were repeated 3 to 10 weeks after surgical closure. Six kidney transplant recipients with patent arteriovenous fistulas referred for routine echocardiographic follow-up served as a control group. Results. Surgical fistula closure decreased left ventricular end-diastolic diameter and mass indexes (29.9±2.4 to 27.4±2.1 mm/m2, P <0.001, and 141±37 to 132±39 g/m2, P <0.05, respectively), whereas no changes were seen in controls after a similar delay. Postoperative left ventricular end-diastolic diameter and mass reductions correlated best with the increases in total peripheral resistance (r =0.85, P <0.0001) and mean arterial blood pressure (r =0.64, P =0.006) during pneumatic occlusion, respectively. Conclusions. Surgical closure of arteriovenous fistula reduces left ventricular diameter and mass in kidney transplant recipients. Increases in blood pressure and total peripheral resistance induced by temporary fistula occlusion are the best predictors of these morphological changes.

Absence of deleterious effect on long-term kidney graft survival of rejection episodes with complete functional recovery.

BACKGROUND Rejection episodes (RE) exert a detrimental influence on long-term kidney graft outcome. However, the impact of the severity of those RE on graft survival and the factors that could predict this impact are ill defined. The present retrospective study was undertaken on adult patients who received 582 cadaver kidney transplants at our center during the last 12 years, to assess the impact on graft survival of RE occurring during the first year after transplantation and to uncover the factors associated with the severity of those RE. METHODS Three grades of rejection were defined: (1) rejection without loss of graft function (benign rejection); (2) rejection followed by partial loss of graft function (severe rejection); and (3) rejection with return to dialysis (irreversible rejection). The grafts were distributed among four groups: (1) grafts free of rejection; (2) grafts with benign RE (only grade 1 RE); (3) grafts with severe RE (one or more grade 2 RE); and (4) grafts with irreversible (grade 3) RE. RESULTS Multivariate analyses revealed that (1) the occurrence of RE during the first posttransplant year (group 1 versus groups 2, 3, and 4) was significantly associated with primary immunosuppression with CsA rather than with OKT3 monoclonal antibody, the number of HLA-B + DR mismatches, and the younger recipients age; (2) in patients with rejection, OKT3 monoclonal antibody prophylaxis was less often used in patients with irreversible RE (group 4) than in those with reversible RE (group 2, benign, and group 3, severe); and (3) no single factor was able to differentiate patients with benign RE (group 2) from those with severe RE (group 3). For grafts still functioning 1 year after transplantation, long-term graft survival was similar in grafts with either no RE or benign RE, but it was significantly lower (P<0.0001) in grafts with severe RE: 8-year survival rates were 89% and 60%, respectively. The decline in graft survival after 1 year was significantly correlated with the serum creatinine value but not with the dose of cyclosporine at 1 year. CONCLUSIONS Benign RE occurring during the first year after transplantation and resulting in no loss of graft function do not exert a detrimental influence on long-term kidney graft outcome. In contrast, the prognosis of grafts with severe RE during the same period of time is much poorer.

CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation.

AIMS This prospective study investigated the effect of genetic polymorphisms in a biotransformation enzyme (CYP3A5) and a transporter protein (ABCB1) on tacrolimus (Tac) whole blood concentrations in renal transplantation, and more specifically on peripheral blood mononuclear cell (PBMC) drug concentrations, after renal transplantation. MATERIALS & METHODS A total of 96 renal transplant recipients were genotyped for the exon 11 (1199G>A), 21 (3435C>T) and 26 (2677G>T/A) polymorphisms in the ABCB1 gene and for the intron 3 polymorphism in the CYP3A5 gene. Tac blood and PBMC concentrations were determined at day 7 after transplantation and at steady state, and then compared with recipient genotypes. RESULTS & CONCLUSION The ABCB1 1199G>A, 3435C>T and 2677G>T/A SNPs, appeared to reduce the activity of P-glycoprotein towards Tac, increasing Tac PBMC concentrations. The impact of ABCB1 genetic polymorphisms on Tac blood concentrations was negligible. As increased Tac intracellular concentrations might in turn enhance immunosuppressive status and prevention or rejection, ABCB1 recipient genotyping might be useful to better individualize the Tac immunosuppressive therapy in renal transplantation.

Evidence that pentoxifylline reduces anti-CD3 monoclonal antibody-induced cytokine release syndrome.

Pretreatment with pentoxifylline (PTX), a methylxanthine known for its beneficial effects on tissue lesions induced by the injection of endotoxin or recombinant cytokines, was shown to decrease the systemic release of tumor necrosis factor and interleukin 2 occurring after the administration of the anti-CD3 monoclonal antibody 145–2C11 in mice. In parallel, PTX attenuated the hypothermia and the rise in blood urea nitrogen observed in this model. The protective effect of PTX on the toxicity of 145–2C11 was confirmed by the reduction of the mortality among D-galactosamine-sensitized animals. The mitigation by PTX of the release of cytokines did not affect the immunosuppression entailed by 145–2C11 as assessed by the unmodified cytotoxic T lymphocytes (CTL) unresponsiveness against alloantigens measured 48 hr after the injection of the mAb. In vitro experiments on human peripheral blood leu

A pilot trial of recombinant human interleukin-10 in kidney transplant recipients receiving OKT3 induction therapy.

BACKGROUND We conducted a randomized, double-blind, placebo-controlled, rising single-dose study to investigate the effects of recombinant human (rh) interleukin (IL) 10 in renal transplant patients who received OKT3 as induction therapy. METHODS Patients received 0.1 (n=6), 1 (n=6), or 10 microg/kg (n=3) rhIL-10 or placebo (n=6) intravenously 30 min before the first injection of 5 mg of OKT3. We monitored IL-10 serum levels, the effect of rhIL-10 on OKT3-induced cytokine production, clinical toxicity, and the incidence of immunization against OKT3. RESULTS Serum IL-10 levels in the three experimental groups reached 0.8+/-0.2, 7.9+/-1.3, and 118.6+/-7.3 ng/ml (mean+/-SEM), respectively, 30 min after rhIL-10 injection. Peak plasma levels of tumor necrosis factor-alpha (TNF-alpha) were reduced from 2953+/-1599 pg/ml in patients injected with OKT3 and placebo to 447+/-155, 703+/-246, and 459+/-246 pg/ml in patients injected with 0.1, 1, and 10 microg/kg rhIL-10, respectively. Values for 24-hr TNF-alpha area under the curve decreased from 8988+/-3551 pg x hr/ml in control patients to 2284+/-494, 3950+/-955, and 2420+/-931 pg x hr/ml for the 0.1, 1, and 10 microg/kg rhIL-10 dose groups, respectively (P=0.045). There was also a trend toward reduced plasma levels of IL-2, IL-8, and interferon-gamma in rhIL-10-pretreated patients. Although none of the patients who received placebo or 0.1 or 1 microg/kg rhIL-10 developed an IgM antibody response directed against OKT3 during the first 10 days, this occurred in all three patients who received the highest rhIL-10 dose. In two of these patients, neutralization of OKT3 was associated with a reversible acute rejection episode. CONCLUSIONS Pretreatment with doses of up to 1 microg/kg rhIL-10 is safe and reduces the release of TNF-alpha induced by OKT3. However, higher doses might promote early sensitization to OKT3.

Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines

Background: Tacrolimus (Tac) metabolism is mainly mediated by the cytochrome P450 3A (CYP3A) subfamily. Recently, it has been reported that kidney transplant recipients carrying the CYP3A4*22 decrease-of-function allele require lower Tac doses and are more at risk of Tac overexposure than CYP3A4*1/*1 patients. This effect was shown to be independent of the CYP3A5*3 allelic status. However, the pharmacokinetic (PK) parameters assessed in previous studies were limited on single time point whole blood trough concentrations (C0) during routine follow-up of the patient after transplantation. Methods: Our study investigates the impact of the CYP3A4*22 allele on Tac PK [C0, area under the time vs concentration curve (AUC0–12h), apparent clearance (Cl/F), Cmax, and dose requirement], time to achieve target C0, and creatinine clearance (CrCl) in 96 kidney transplant recipients considering the 2 first weeks after the graft. All patients were genotyped for both the CYP3A4*22 and the CYP3A5*3 polymorphisms. Results: CYP3A4*22 carriers had higher Tac C0 during the first week with significant longer exposures to C0 > 15 ng/mL. These patients showed reduced Tac Cl/F but higher dose-adjusted AUC0–12h and Cmax and were at increased risk of C0 > 20 ng/mL. These effects were independent from CYP3A5*3 genotype: clustering patients according to both CYP3A4*22 and CYP3A5*3 allelic status did increase the predictive value of the genotype to explain interindividual differences in Tac PK. During the second week after transplantation, CrCl was on average 9.5 mL/min higher for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (P = 0.007), suggesting that Tac overexposure in CYP3A4*22 carriers might provide a renal function benefit. Conclusions: Our study confirms the decreased CYP3A4 activity toward Tac for CYP3A4*22 carriers early after transplantation and provides evidence for refining genotype-based dosage by adding the CYP3A4*22 genotype information to the CYP3A5*3 allelic status.

Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation

BACKGROUND:  During liver transplantation (LT), profound activation of the fibrinolytic system can contribute significantly to perioperative bleeding. Prophylactic administration of antifibrinolytic agents has been shown to reduce blood loss and the need for allogeneic transfusion in these conditions.

Biotransformation enzymes and drug transporters pharmacogenetics in relation to immunosuppressive drugs: impact on pharmacokinetics and clinical outcome

Immunosuppressive drugs commonly used after organ transplantation to prevent acute rejection including tacrolimus, cyclosporine, sirolimus, and mycophenolic acid are characterized by a narrow therapeutic index and broad interindividual variability in their pharmacokinetics. Adequate immunosuppression aims to reach an optimal benefit–risk ratio. Therapeutic drug monitoring represents a crucial step in routine practice to maintain blood concentrations within the target window, because the bioavailability of these drugs depends on their absorption, distribution, biotransformation, and elimination. Single nucleotide polymorphisms (SNPs) in genes encoding biotransformation enzymes (CYP3A) and drug transporters (ABCB1) have opened up a promising way for the selection of individual dosages. The relationship of these SNPs with immunosuppressive drug pharmacokinetics was extensively studied after kidney, liver, heart, and lung transplantations. Patient susceptibility to nephrotoxicity in the long term was also reported in relation to some SNPs, which could allow effective assessment of individual risk and selection of treatment according to patient parameters. Further studies are needed to provide evidence that a genetic analysis combined with therapeutic drug monitoring has the potential to optimize drug use after transplantation.