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Background: Hemophagocytic syndrome (HPS) combines febrile hepatosplenomegaly, pancytopenia, hypofibrinemia, and liver dysfunction. It is defined by bone marrow and organ infiltration by activated, nonmalignant macrophages phagocytizing blood cells. HPS is often caused by an infectious or neoplastic disease and has rarely been described in renal transplant recipients., Methods: We retrospectively analyzed 17 cases of HPS after cadaveric renal transplantation (13 men and 4 women, age 41+/-8 years). The median time between transplantation and hemophagocytosis was 52 days. Eleven patients (64%) had received antilymphocyte globulins during the 3 months before presentation., Results: Fever was present in all patients, and hepatosplenomegaly was present in 9 of 17 patients. Other nonspecific clinical findings included abdominal, neurologic, and respiratory symptoms. Laboratory tests showed anemia (hemoglobin 6.1+/-1.3 g/dL), thrombocytopenia (34,000+/-32,000/mm3), and leukopenia (1,700+/-1,400/mm3). Elevated liver enzymes were present in 12 of 17 patients, and cholestasis was present in 10 of 17 patients. Elevated triglycerides and ferritin were noted in 75% and 86% of cases, respectively. HPS was related to viral infection in nine patients (cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and human herpesvirus 8), bacterial infection in three patients (tuberculosis and Bartonella henselae), and other infections in two patients (toxoplasmosis and Pneumocystis carinii pneumoniae). Posttransplant lymphoproliferative disease was present in two patients. Despite large-spectrum anti-infectious treatment and dramatic tapering of immunosuppression, death occurred in eight patients (47%). Graft nephrectomy was performed in four of the nine surviving patients., Conclusions: We report here the largest series of HPS after renal transplantation. This rare disease is usually secondary to herpes viridae infections, mostly cytomegalovirus and Epstein-Barr virus in severely immunocompromised patients. Despite aggressive treatment, the prognosis remains poor.

Ciclosporin is associated with significant toxicity, including nephrotoxicity, and with an increased risk of cardiovascular events. Many attempts have been made to wean patients from ciclosporin. Before the availability of new immunosuppressive drugs, the acute rejection rate observed after ciclosporin withdrawal did not permit the widespread use of withdrawal regimens even though meta-analysis did not show that they adversely affected patient or graft survival. Nevertheless, maintenance therapy with azathioprine and corticosteroids has not become routine practice. The introduction of mycophenolate mofetil and subsequently sirolimus has increased the number of clinical studies of the effects of ciclosporin withdrawal. In stable patients, this withdrawal is associated with a small but significant increase in the incidence of acute rejection episodes. Declining renal function and other forms of ciclosporin-related toxicity have improved. However, this improvement was also observed when ciclosporin was only reduced (and not withdrawn), which did not increase the risk of acute rejection. More precise definition of the patients who could benefit from ciclosporin-withdrawal may help to optimise the immunosuppressive regimen in this setting. In patients with chronic allograft deterioration, ciclosporin withdrawal together with mycophenolate mofetil introduction has been shown to improve renal function significantly in many small studies, and a large prospective randomised study. For the time being, ciclosporin withdrawal is a good therapeutic option for patients with declining renal function and signs of chronic ciclosporin nephrotoxicity on renal biopsy. Finally, recent preliminary studies have reported the results of complete avoidance of calcineurin inhibitors after renal transplantation. These results are promising as regards the incidence of acute rejection, renal function and safety, but need confirmation in larger trials with a longer follow-up. Nevertheless, it has become clear that the concept of an immunosuppressive regimen with little or no nephrotoxicity after renal transplantation is more and more important and plays a crucial part in tailoring immunosuppression to the needs of specific patient populations.

Background: Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation., Methods: We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment., Results: The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level., Conclusions: We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.

Background: Tacrolimus pharmacokinetic characteristics vary greatly among individuals. Tacrolimus is a substrate of cytochrome p450 (CYP), of subfamily CYP3A. CYP3A activity is the sum of the activities of the family of CYP3A genes, including CYP3A5. Subjects with the CYP3A5*1/*1 genotype express large amounts of CYP3A5. Heterozygotes (genotype CYP3A5*1/*3) also express the enzyme. We postulated that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations., Methods: CYP3A5 genotype was evaluated in 80 renal transplant recipients and correlated with the daily tacrolimus dose and concentration-to-dose ratio., Results: The frequency of the homozygous CYP3A5*1 genotype (CYP3A5*1/*1) was 5%, and 11% of subjects were heterozygous (CYP3A5*1/*3). The mean doses required to obtain the targeted concentration-to-dose ratio were significantly lower in patients with the CYP3A5*1/*1 genotype., Conclusions: Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.

Background: MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C2) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here., Methods: MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C2 targets of 1.6 to 2.0 microg/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C2 targets and prophylactic administration of antibodies., Results: At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 micromol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C2 levels greater than 1.6 microg/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11)., Conclusions: Patient management by C2 monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C2 monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.

The Kaplan-Meier (KM) method is commonly used to estimate the incidence of an event over time. It assumes independence between the event of interest and any competing event that precludes the event of interest to occur. However, when the competing event is death without the event of interest, censoring these patients will affect the incidence of the event of interest by modifying the number of exposed patients, so that KM results will be misleading. Three prospective cohorts were studied: (1) 657 renal transplant recipients, (2) 262 children with acute leukemia who received bone marrow transplants, and (3) 8,353 intensive care patients. The main outcome measures were kidney graft loss, leukemia relapse, and ICU-acquired infection, respectively, with death before the main outcome as the competing event. The incidence of each main outcome was overestimated by the KM method. The magnitude of overestimation ranged from 3% to 30%, and varied with baseline patient characteristics and follow-up duration, with most of this variation being related to the rate of the competing event. A competing-risk approach must be used to analyze the risk of events other than death in cohort studies, particularly when mortality rates are high.

Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of thiopurine drugs. A genetic polymorphism is responsible for large inter-individual differences observed in TPMT activity. We report a new HPLC technique, which avoids an extraction step and the use of radioactive reagents, based on the conversion of 6-mercaptopurine (6-MP) to 6-methylmercaptopurine (6-MMP) using S-adenosyl-L-methionine (SAM) as methyl donor in red blood cell lysates (RBC). Intra- and inter-assay variation, within-day, within-run, between-day, and between-run variations showed high precision. The formation of 6-MMP was linear with respect to the lysate concentration and time. In a blinded assay of 61 samples, the results of HPLC method correlated with those of the radiochemical method (r2=0.82, P<0.0001). Using a cut-off point of 8.5 nmol/h/ml packed RBC, positive predictive value of HPLC was 100% for heterozygous patients. Because of the absence of extraction step, this new HPLC technique of TPMT activity determination reduces analysis variation and is time-saving. This rapid, sensitive, and reproducible method is suitable for routine monitoring of TPMT activity and for fundamental studies.

Background: Renal relapse in lupus nephritis has been shown to have ominous prognostic significance with the majority of patients progressing to doubling of serum creatinine (CRX2). However, not all patients do so. This report explores the roles of response of inflammation to therapy and of glomerular scarring and interstitial fibrosis and their potential reversal to outcome of renal relapse., Methods: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy, as well as subsequent biopsies for clinical indications, were studied. The relationships of morphologic factors to renal relapse and its outcome as well as to CRX2 and end-stage renal disease (ESRD) were analyzed. Cox proportional hazards modeling was used to assess association of morphologic variables with outcomes., Results: Renal interstitial fibrosis and glomerular segmental scarring were partially reversible in 17 and 11 patients, respectively. This decline was associated with an excellent prognosis, with only one patient in each group (5.9% and 9.1% respectively) progressing to CRX2. All 18 patients who progressed to CRX2 either failed to respond to therapy (7 patients) as defined by normalization of serum creatinine (SCr) and reduction of proteinuria to < or =1 g/day, or relapsed after initial response (11 patients), as defined by recent rise of SCr > 50% and/or proteinuria > 3.5 g/day. However, relapse also occurred in 11 of 47 other patients without progression to CRX2. These patients showed a greater initial response of inflammation and deposits to therapy and fibrous lesions partially reversed in the period prior to relapse, so that active lesions were superimposed on a lower level of chronic lesions. By contrast, chronic lesions mounted steadily in those who progressed to CRX2. Cox proportional hazards modeling indicated a strong association of inflammatory variables with renal relapse, CRX2 and ESRD. However, the extent of immunoglobulin deposits was not significantly associated with any outcome. Finally, we found that failure of disease to remit also is associated with a high rate of CRX2 (64.8% vs. 13.0%, P = 0.00034)., Conclusions: Interstitial fibrosis and glomerular scarring in systemic lupus erythematosus are partially reversible, and this reversal is attended by an excellent outcome. The outcome of renal relapse is determined by the initial response of inflammatory and chronicity elements to therapy, those with prior partial reversal of interstitial and glomerular scarring having a good outcome, and those in whom fibrotic lesions have continued to increase and have a poor outcome. Inflammatory variables appear to be more important in determining outcome than immunoglobulin deposits.

Henoch-Schönlein Purpura nephritis (HSPN) has been extensively studied in children but, its natural history in adults is much less known. A cohort of 250 adults suffering HSP was retrospectively analyzed for a median follow-up period of 14.8 yr. All patients had biopsies consistent with HSP (predominant IgA mesangial deposits) associated with purpura, bowel angina, and/or abdominal pain. At presentation, palpable purpura was present in 96% of patients, and arthritis was reported in 61%, and gastrointestinal involvement in 48%. Thirty-two percent of the patients showed renal insufficiency (Creatinine clearance [CrCl] <50 ml/min), usually associated with proteinuria (99%) and/or hematuria (93%). Endocapillary glomerulonephritis was the most frequent lesion on renal biopsy (61%). At the end of follow-up, patient survival was only 74%. The first cause of death was carcinoma (most of them of respiratory or digestive tract). Regarding renal function, 11% of patients reached end-stage renal failure, 13% exhibited severe renal failure (CrCl <30 ml/min), and 14% moderate renal insufficiency (CrCl <50 ml/min). Clinical remission defined as the absence of proteinuria, hematuria, and a normal renal function was achieved in only 20%. This is a retrospective study; therefore, it is not possible to demonstrate any steroid and/or cyclophosphamide efficacy in diminishing the incidence of renal insufficiency. Multivariate analysis demonstrated that renal function impairment and proteinuria level at presentation and, on renal biopsy, the degree of interstitial fibrosis, percentage of sclerotic glomeruli, and presence of glomeruli with fibrinoid necrosis were associated with a poor renal prognosis. The data indicate that clinical presentation of HSPN in adults is severe and its outcome relatively poor, worse than in children. Identification of clinical and histologic prognostic factors may permit the design of appropriate therapeutic prospective studies.

Background: In selected young patients with type 1 diabetes mellitus and end-stage renal failure, simultaneous pancreas and kidney (SPK) transplantation is the treatment of choice. We conducted a retrospective, case-controlled study to compare the function, survival and pathology of renal allografts after SPK and kidney-alone (KA) transplantations., Methods: We studied 26 consecutive SPK patients and 67 KA controls matched for time of transplantation. Renal function was assessed by routine evaluation of serum creatinine and its course by the 1/serum creatinine vs time curve. Histologic evaluation of early biopsies (0-3 months post-transplantation, n=63), intermediate biopsies (3 months-1 year, n=75) and late biopsies (after 1 year, n=35) were performed by two independent reviewers., Results: SPK and KA recipients differed significantly with regard to donor and recipient age, time on the waiting list, HLA sensitization, renal cold ischaemia time (CIT) and the incidence of delayed graft function. Acute rejection was more frequent after SPK than KA (54 vs 27%; P=0.01), despite higher trough levels of calcineurin inhibitors. After SPK and KA, actuarial patient and renal allograft survival and renal function were comparable at 1 and 4 years. Severe chronic lesions, especially vascular lesions, and calcineurin-inhibitor nephrotoxicity were more frequent in intermediate and late biopsies in the SPK group., Conclusions: We confirmed that patient and graft survival is comparable between SPK and KA recipients. Despite the use of optimal organs and shorter CIT in SPK, renal graft function was not different in the two groups. Histologic chronic lesions were more severe in SPK than in KA recipients. This might be caused by acute rejection episodes or be due to more severe nephrotoxicity after SPK, because of higher doses of calcineurin inhibitors, or higher sensitivity to calcineurin-inhibitor nephrotoxicity.

Background: Chronic allograft nephropathy is the main cause of long-term kidney graft loss. The plasminogen activator inhibitor type 1 (PAI-1) is a potential fibrogenic molecule whose secretion is regulated by several metabolic, inflammatory, and genetic factors. We aimed to determine whether PAI-1 secretion in renal transplant patients is correlated with the decline in renal function after transplantation., Methods: Renal transplant patients (145 male/71 female) were included in the study 1-27 years after transplantation (median of follow-up: 7.35 years). At inclusion, routine clinical and biological data were collected, the 4G/5G polymorphism of the recipient PAI-1 gene was determined, and the PAI-1 plasma level was measured., Results: The mean rate of decline in renal function was -4.26+/-0.30 ml/min/year. By multiple linear regression analysis, the rate of decline in renal function was significantly correlated with proteinuria (P=0.0176), occurrence of late acute rejection episodes (P=0.0001), and PAI-1 plasma level (P=0.0051). In addition, PAI-1 plasma level was also significantly correlated with body mass index (P=0.038), insulin (P<0.0001), platelet count (P<0.0001), and fibrinogen (P=0.024). The PAI-1 gene polymorphism tested did not influence the rate of decline in renal function after transplantation nor the plasma level of PAI-1 antigen., Conclusion: We conclude that PAI-1, whose secretion is determined in large part by metabolic and inflammatory factors, may be implicated in the rate of decline in renal function after transplantation.

Minimization protocols: The goal of minimization protocols is to reduce the load of immunosuppressant agents after transplantation. Besides the basic medical objective of reduced deleterious effects of long-term immunosuppression, minimization also has an economic impact. Discontinuation of corticosteroid therapy: Results obtained with different minimization protocols have shown that any interruption of corticosteroid therapy, even if associated with the new immunosuppressants, should be conducted carefully in selected patients, tapering off late after transplantation. Mycophenolate-mofetil (MMF): MMF withdraw may be risked and the beneficial effect of discontinuation remains to be demonstrated. Calcineurin inhibitors: Most immunosuppression protocols use cyclosporine. The benefit obtained by totally discontinuing cyclosporine in stabilized patients does not outbalance the risks induced by withdrawal. However, in this population, MMF can be useful for tapering down cyclosporine. In patients with altered renal function, introduction of MMF or sirolimus can allow a reduction in dosage or complete withdrawal of cyclosporine.

Objective: The authors report their preliminary experience of a manually assisted laparoscopic bilateral nephrectomy technique for refractory hypertension in renal transplant recipients., Material and Methods: Between April and May 1999, 2 laparoscopic bilateral nephrectomies were performed with manual assistance using the Hand-Port. One patient was operated 4 months before renal transplantation and the other was operated 13 months after renal transplantation. Both patients presented severe hypertension refractory to several antihypertensive drugs. An 8 cm midline supra-umbilical incision and 3 trocars were necessary. One hand was introduced into the abdominal cavity via the Hand-Port at the beginning of the operation. The intra-abdominal hand assisted all phases of dissection of the kidney and control of vessels. The renal vessels and ureter were clipped. The kidneys were removed by the intra-abdominal hand through the supra-umbilical incision., Results: Operating times were 200 min and 130 min. Blood loss was 220 ml. No conversion was performed. The duration of major postoperative analgesics was 3 days. Length of hospital stay was 6 days and 7 days. There were no complications. Blood pressure was controlled by bilateral nephrectomy in both cases, with significant reduction of antihypertensive therapy. One year after the operation, both patients were satisfied with the aesthetic result., Conclusions: Laparoscopic bilateral nephrectomy manually assisted by the Hand-Port is an alternative to open bilateral nephrectomy. Larger series are necessary to evaluate the morbidity of this technique.

Glucocorticoïds, calcineurin inhibitors (especially tacrolimus) and the combination of both are responsible for the occurrence of diabetes mellitus after organ transplantation. These drugs induce both insulin resistance and insulinopenia. Risks factors are well identified: high doses of immunosuppressive drugs, genetic background, age and weight excess. Long-term consequences seem to be as deleterious as those of other types of diabetes mellitus. Modulating the doses of immunosuppressive drugs is efficient in decreasing insulin requirement in transplant recipients but only individualization of immunosuppression taking risks factors into account will permit to decrease the incidence of this side-effect.

Thiopurine methyltransferase (TPMT) is implicated in the metabolism of azathioprine. The consequences of differential TPMT activity induction by azathioprine on the long-term results after renal transplantation were investigated. The erythrocyte TPMT activity in 82 patients on days 0, 7, and 30 was prospectively evaluated. Because various patterns of TPMT activity variation were noted, the population was subsequently divided between inductors (n = 47) and noninductors (n = 35). Data regarding patient and graft survival and acute rejection episodes were collected. Renal allograft assessment was performed at 3 mo and 2 yr to evaluate the renal function and the histologic lesions on routine biopsies. Data regarding azathioprine-related toxicity also were collected. In a subgroup of patients (n = 19), azathioprine blood levels were determined at day 7 and day 30. The graft survival censoring death was statistically improved in TPMT inductor patients when compared with non-TPMT inductors (P < 0.05). Among TPMT inductors, an acute rejection episode was observed in 34% of the patients versus 69% among non-TPMT inductors (P = 0.002). At 3 mo, serum creatinine was significantly lower among TPMT inductors when compared with non-TPMT inductors (123.1 +/- 7.6 and 161.4 +/- 13.9 micromol/L, respectively; P = 0.01). On routine allograft biopsies at 2 yr (n = 61), grade 2 or 3 chronic lesions were present in 19% versus 25%, respectively (P = NS). At days 7 and 30, the azathioprine blood levels were higher among patients who experienced acute rejection (P < 0.02). TPMT activity induction was observed in 57% of renal transplant recipients who received azathioprine. This induction was associated with better graft outcome. The appropriate conversion from azathioprine, which is a pro-drug, into 6-mercaptopurine could explain both better graft outcome and TPMT induction. Assessing the ability of azathioprine metabolism at an individualized level before transplantation may allow a more accurate choice among the different immunosuppressive treatments.

New insights have been recently obtained about pharmacokinetic and pharmacodynamic characteristics of mycophénolate mofetil (MMF). One of the already described MPA metabolite, the acylglucuronide of MPA may be both active and responsible for some side-effects. Glucuronidation is mediated by at least two uridine diphosphate glucuronosyltransferase (UGT) forms, namely UGT1A8 and UGT1A10 whose variability could explain the inter- and intra-individual variability of MMF metabolism. MPA pharmacokinetic data in dialyzed patients or in patients with chronic renal failure are now available. After renal transplantation, MPA levels vary between immediate post-transplant period, at three months and at two years. The target enzyme is inosine monophosphate dehydrogenase (IMPDH). The genes of the two IMPDH isoforms have been cloned. The bicyclic ring system of MPA packs underneath the hypoxanthine ring of IMPDH, thereby trapping this covalent intermediate of the enzymatic reaction. After renal transplantation, a randomized trial has shown that clinical efficacy is correlated with MPA AUC but side effects are correlated with MMF dosage. When associated with cyclosporine, there is a significant decrease of MPA level. Better knowledge of MMF metabolism, of variability factors and target levels to reach in clinical practice should allow a better use of MMF.

Background: Cyclosporine A (CsA) nephrotoxicity is a nonimmunologic factor of chronic allograft dysfunction (CAD) in kidney transplant recipients. Mycophenolate mofetil (MMF) may allow CsA dosage reduction or even complete withdrawal in selected populations with CsA nephrotoxicity or CAD. The aim of the present study was to evaluate the efficacy and safety of CsA withdrawal after azathioprine (AZA)-MMF conversion in a population of stable renal transplant recipients., Methods: Twenty-eight first cadaver kidney recipients were included. AZA was then discontinued, MMF was introduced and after 4 months CsA was completely withdrawn. All patients underwent inuline clearance measurement and renal biopsy at inclusion and at the end of the follow-up (40 wk)., Results: CsA was completely discontinued in 20 patients. No patient lost his graft during the study period, but 1 patient experienced a reversible acute rejection episode. Inuline clearance improved significantly in the whole series. At the end of follow-up, histological worsening was observed in 50% of patients without any specific risk factor. In these patients, inuline clearance did not improve. Systolic blood pressure, the need for anti-hypertensive drugs and HDL cholesterol improved., Conclusion: In stable kidney transplant recipients, CsA withdrawal after AZA replacement by MMF switch was safe with regard to acute rejection. It improved blood pressure and the lipid profile, but, in 50% of patients was associated with histologic deterioration.

Objective: To evaluate the feasibility and complications of manually assisted laparoscopic live donor kidney harvesting., Material and Method: Since June 1999, all related live donor kidney harvests have been performed by manually assisted laparoscopy. The patient is placed in the lumbotomy position and an 8 cm midline periumbilical incision is made. The assistant's hand is introduced through a watertight port (HandPort). Three trocars are used. The assistant presents the structures to be dissected and controls the ureter. The artery is clipped and the vein is stapled or clipped, depending on its diameter. The kidney is extracted via the midline incision and washed., Results: Five kidney harvests were performed (three right kidneys and two left kidneys) with a mean operating time of 220 +/- 30 minutes. Conversion was necessary in one case following the intraoperative discovery of two right renal veins. Warm ischaemia lasted 5 minutes for the first patient and one to two minutes for the other four non-converted patients. Blood losses were minimal. The mean duration of major analgesia was 2.4 days and the mean length of hospital stay was 7.2 days. Complications were: bacteriuria in 2 cases and prolonged lymphorrhoea in 1 case. One transplanted kidney had to be removed because of immediate thrombosis of the recipient iliac artery. With a mean follow-up of 6 months (1 to 12 months), no ureteric or venous complications have been observed in the 4 evaluable transplanted kidneys., Conclusion: An intra-abdominal hand during laparoscopic live donor kidney harvesting simplifies dissection, ensures intraoperative security and allows rapid extraction of the kidney.

The emergence of a resistant strain is a theoretical threat after extensive use of antiviral drugs. We report the emergence of a ganciclovir-resistant cytomegalovirus (CMV) strain in a kidney transplant recipient during oral ganciclovir maintenance treatment. The patient was treated by oral ganciclovir for 2 months after successful treatment of CMV primary infection by intravenous ganciclovir. He developed a new episode of CMV infection with no clinical response to intravenous ganciclovir. The CMV isolate exhibited both phenotypic and genotypic resistance to ganciclovir. The CMV isolate was constituted of a mixture of strains, with and without a mutation at codon 460 of the UL97 gene. The clinical condition improved when mycophenolate mofetil (MMF) was discontinued, and a short course of intravenous globulin was added to ganciclovir. The emergence of the CMV strain could be secondary to more potent immunosuppression provide by MMF or subtherapeutic level obtained during oral ganciclovir treatment. We believe that ganciclovir resistance must be part of the differential diagnosis when a patient relapses or fails to respond to ganciclovir treatment.

Background: Cystatin C has recently been proposed as an alternative marker of glomerular filtration rate. The diagnostic value of plasma cystatin C for the longitudinal assessment of kidney function after renal transplantation, however, has not been addressed., Methods: Renal function was evaluated in 30 adults receiving renal transplants (46 +/- 9 years, mean +/- SD) and in 56 healthy controls (38 +/- 10 years) using cystatin C. Plasma cystatin C was determined daily starting the day of surgery and for 3 weeks after surgery by an immunonephelometric assay., Results: Plasma concentration significantly decreased during the first week (-44% vs -29% for creatinine). Plasma cystatin C correlated with plasma creatinine (r = 0.741; P <0.0001) and the reciprocal of the creatinine clearance estimated by the Cockcroft-Gault formula (r = 0.882; P <0.001). In all three cases of acute renal impairment, the increase in plasma cystatin C values was more prominent than that of creatinine., Conclusions: Plasma cystatin C is an alternative and accurate marker of allograft function in adult transplant patients. Increased sensitivity compared with creatinine for the detection of acute reduction in glomerular filtration rate allows in some cases a more rapid diagnosis of acute rejection or treatment nephrotoxicity.

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.

Background: The aim of the present study was to describe the histologic features disclosed by protocol kidney transplant biopsies in patients who experienced neither acute rejection nor acute renal failure during the 2 years after transplantation., Methods: We studied 10 recipients of HLA-identical kidneys from living-related donors and 31 recipients of cadaveric kidneys. They were selected because, during the 2 years after transplantation, they did not experience clinical acute or chronic rejection, their renal function was normal and stable, and they underwent a protocol kidney biopsy at 3 months and at 2 years after transplantation., Results: Histologic chronic allograft nephropathy was present in 25% of patients at 3 months and in 50% at 2 years, but was absent in the recipients of HLA-identical kidneys. Histologic worsening was associated with increased donor age, the presence of asymptomatic grade I acute rejection at 3 months, and an increased cyclosporine trough level., Conclusions: Protocol biopsies contribute important information that could be used to improve the prophylaxis of chronic allograft nephropathy.

Influence of viral liver diseases on the occurrence of azathioprine hepatitis was evaluated in 21 kidney transplant recipients. Diagnosis of azathioprine hepatitis was always based on jaundice, which disappeared after azathioprine withdrawal in 18 patients and after azathioprine dose reduction in 3 patients. Histopathological diagnosis of azathioprine toxicity was ascertained in 14 patients. Rechallenge with azathioprine performed in 4 patients, within 2-4 months after the first jaundice episode, resulted in relapse of jaundice in all cases. Viral hepatitis B virus and hepatitis C markers were present in all 20 tested patients (serum hepatitis B surface antigen in 6 patients and anti-HCV antibodies in 17 patients). Biopsy-proven chronic hepatitis was observed in 18 patients, including 14 chronic active hepatitis, 3 chronic persistent hepatitis and cirrhosis in 1. In kidney transplant recipients, azathioprine hepatitis seems to be facilitated or induced by hepatitis B virus or hepatitis C virus chronic hepatitis. Azathioprine reduction or withdrawal should therefore be combined with the diagnostic evaluation and the treatment of viral liver diseases.

Thiopurine methyltransferase (TPMT), one of the enzymes involved in azathioprine metabolism, exhibits a wide range of activity in the normal population. We prospectively evaluated the monitoring of erythrocyte TPMT activity (using a radiochemical method) in kidney transplant recipients with regard to the efficacy of azathioprine. Three patterns in TPMT activity variation were observed. In group 1 patients, TPMT activity rose as early as 8 days after transplantation and steadily until month 3. In group 3 patients, TPMT activity remained unchanged. In group 2 patients, TPMT activity rose at month 1 after transplantation. Interestingly, the incidence of acute rejection was significantly (P < 0.01) different among the 3 groups, with the lowest incidence in group 1 and the highest in group 3. We hypothesized that TPMT activity increase was induced by azathioprine in the patients with the lowest incidence of acute rejection. The inducibility of TPMT activity would then appear to be an interesting marker of azathioprine-induced immunosuppression.