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Background: The aim was to test the effectiveness of early home-based group education on knowledge and communication about renal replacement therapy (RRT)., Methods: We conducted a randomized controlled trial using a cross-over design among 80 end-stage renal disease (ESRD) patients. Between T0 and T1 (weeks 1-4) Group 1 received the intervention and Group 2 received standard care. Between T1 and T2 (weeks 5-8) Group 1 received standard care and Group 2 received the intervention. The intervention was a group education session on RRT options held in the patient's home given by social workers. Patients invited members from their social network to attend. Self-report questionnaires were used at T0, T1 and T2 to measure patients' knowledge and communication, and concepts from the Theory of Planned Behaviour such as attitude. Comparable questionnaires were completed pre-post intervention by 229 attendees. Primary RRT was registered up to 2 years post-intervention. Multilevel linear modelling was used to analyse patient data and paired t-tests for attendee data., Results: Statistically significant increases in the primary targets knowledge and communication were found among patients and attendees after receiving the intervention. The intervention also had a significant effect in increasing positive attitude toward living donation and haemodialysis. Of the 80 participants, 49 underwent RRT during follow-up. Of these, 34 underwent a living donor kidney transplant, of which 22 were pre-emptive., Conclusions: Early home-based group education supports informed decision-making regarding primary RRT for ESRD patients and their social networks and may remove barriers to pre-emptive transplantation., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands., Methods: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up., Results: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently., Conclusion: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

Background: The differential diagnosis of nephrotic syndrome is diverse. Systemic conditions and medication such as NSAIDs can cause this syndrome., Case Description: A 33-year-old male with Crohn's disease for which he was receiving adalimumab noticed he was gaining weight and had swollen ankles. Examination revealed nephrotic syndrome without renal insufficiency. Renal biopsy showed a membranous glomerulopathy. We excluded secondary causes of membranous glomerulopathy such as diabetes mellitus, systemic lupus erythematosus, viral infection or malignancy. We treated the patient with high-dose glucocorticoids on a weaning schedule and adalimumab was discontinued. This regimen resulted in complete remission. It is likely that the nephrotic syndrome with membranous glomerulopathy was associated with adalimumab., Conclusion: In patients with nephrotic syndrome based on membranous glomerulopathy both primary and secondary causes, such as use of medication, need to be excluded.

Background: Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction., Methods: A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001)., Results: During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization., Conclusion: Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.

Knowledge is a prerequisite for promoting well-informed decision-making. Nevertheless, there is no validated and standardized test to assess the level of knowledge among renal patients regarding kidney disease and all treatment options. Therefore, the objective of this study was to investigate the psychometric properties of such a questionnaire for use in research and practice. A 30-item list was validated in four groups: (1) 187 patients on dialysis, (2) 82 patients who were undergoing living donor kidney transplantation the following day, (3) the general population of Dutch residents (n = 515) and (4) North American residents (n = 550). The psychometric properties of the questionnaire were examined using multidimensional item response theory (MIRT). Norm references were also calculated. Five items were found to distort ability estimates (Differential item functioning; DIF). MIRT analyses were subsequently carried out for the remaining 25 items. Almost all items showed good discrimination and difficulty parameters based on the fitted model. Two stable dimensions with 21 items were retrieved for which norm references for the Dutch and North American, dialysis and transplantation groups were calculated. This study resulted in a thorough questionnaire, the Rotterdam renal replacement knowledge-test, which enables reliable testing of patient's knowledge on kidney disease and treatment options in clinic and research., (© 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Secondary hyperparathyroidism is an almost inevitable complication of advanced kidney failure. The introduction of the calcimimetic cinacalcet for the treatment of secondary hyperparathyroidism in patients on dialysis was based on its ability to reduce elevated levels of parathyroid hormone (PTH). Subsequent clinical studies confirmed the beneficial effects of cinacalcet on biochemical parameters reflecting mineral disturbances and bone disease. In this review we summarise the impact of cinacalcet on biochemical, intermediate and clinical outcomes. We also present previously unpublished mineral metabolism data from 144 Dutch dialysis patients treated with cinacalcet who participated in the pan-European ECHO observational study. Although secondary hyperparathyroidism tended to be more severe in our Dutch cohort, compared with the entire ECHO cohort, cinacalcet was nevertheless effective in reducing PTH in these patients. Two recent clinical studies evaluated, respectively, the efficacy of cinacalcet in improving the intermediate endpoint of cardiovascular calcifications (ADVANCE trial), and its impact on clinical outcomes, including all-cause mortality and cardiovascular events (EVOLVE trial). The ADVANCE trial provided evidence that cinacalcet may indeed improve calcification in both large arteries and cardiac valves. The EVOLVE trial, however, did not meet its clinical primary endpoint (time to all-cause mortality, myocardial infarction, hospitalisation for unstable angina, heart failure or a peripheral vascular event), although secondary and sensitivity analysis suggested a beneficial effect. The clinical implications of these important studies are also addressed in this review.

Background: Renal function is currently estimated using the Modification of Diet in Renal Disease (MDRD) formula, which is partly based on the serum creatinine level. Patients with impaired renal function are referred to nephrologists in accordance with the Dutch national transmural agreement for 'Chronic renal impairment'., Case Description: A 54-year-old woman without significant history was referred to analyse a coincidentally found decline in the estimated glomerular filtration rate (eGFR). The patient had no complaints and used no medication except creatine supplements. Additional diagnostic testing showed no abnormalities. After cessation of creatine supplementation, the calculated renal function normalized., Conclusion: Serum creatinine is a reflection of muscle mass. The use of creatine-containing dietary supplements, such as creatine ethyl ester, can influence serum creatinine levels and therefore the eGFR as calculated with the MDRD formula. The use of supplements deserves attention when taking the history.

In this article, an ethical analysis of an educational programme on renal replacement therapy options for patients and their social network is presented. The two main spearheads of this approach are: (1) offering an educational programme on all renal replacement therapy options ahead of treatment requirement and (2) a home-based approach involving the family and friends of the patient. Arguments are offered for the ethical justification of this approach by considering the viewpoint of the various stakeholders involved. Finally, reflecting on these ethical considerations, essential conditions for carrying out such a programme are outlined. The goal is to develop an ethically justified and responsible educational programme.

We investigated the relationship between cyclosporine exposure and the presence of cyclosporine-related side effects and assessed the advantage of the cyclosporine concentration 2 h post-dose (C(2)) over pre-dose concentration (C(0)) monitoring. Cyclosporine area-under-the-concentration-time curves were measured during the absorption phase (AUC(0-4 h)) in 49 liver, 28 heart and 26 kidney transplant recipients (time since transplantation >6 years) with or without cyclosporine-related side effects on maintenance therapy. The cyclosporine C(0) correlated well with AUC(0-4) (r=0.77), whereas C(2) levels correlated strongly with AUC(0-4) (r=0.92). Although we observed a trend towards higher CsA concentrations in transplant recipients with side effects than in patients without CsA toxicity, the large majority of those differences were not statistically significant. Thus, as cyclosporine exposure was not clearly related to the presence of side effects, and C(0) correlated fairly with AUC(0-4), the advantage of monitoring cyclosporine treatment using C(2) rather than C(0), may be limited for patients on cyclosporine maintenance therapy.

We have previously suggested that the in vitro donor-specific cytotoxic T-lymphocyte precursor (CTLp) assay can guide us to identify patients in which the immunosuppressive load can be tapered. In a clinical trial we had observed that a low (<10/10(6) PBMC) frequency of these CTLp was predictive for an uneventful rejection-free clinical course in patients that were converted from calcineurin inhibitors to mycophenolate mofetil or azathiopine. In the present prospective study in 81 stable kidney transplant recipients, already converted from calcineurin inhibitors, we measured CTLp frequencies and reduced the immunosuppressive load on a routine basis when CTLp were <10/10(6) PBMC. Donor-specific cytotoxicity could not be measured in 50/81 patients, while their reactivity against third-party lymphocytes was not impaired. These 50 patients were tapered in their immunosuppression. Only in one patient, who had stopped all his medication, was a rejection episode diagnosed. We conclude that in patients with a low donor-specific CTLp frequency it is safe to reduce the immunosuppression.

The introduction of cyclosporine (CsA) into clinical practice resulted in a dramatic reduction in the incidence and severity of acute rejection. As a result, short-term and medium-term kidney allograft survival increased greatly. However, the long-term patient and graft survival have not improved to a similar degree. This can partly be attributed to the side effects of CsA and partly to the fact that the use of CsA has not led to a reduced incidence of chronic allograft nephropathy. Thus, there has been a continuing search for strategies that minimize CsA toxicity but maintain adequate immunosuppression. This has resulted in the development of the CsA microemulsion formulation and improved methods for therapeutic drug monitoring. With the introduction of newer immunosuppressive drugs, early CsA withdrawal and CsA-free immunosuppressive therapy have become feasible. However, CsA weaning or complete avoidance is associated with a slightly higher risk of acute rejection, and the long-term efficacy and safety of such strategies remain to be established. Therefore, it is to be expected that in the near future CsA will remain part of the standard immunosuppressive regimen in many transplant centers.

Aims: To evaluate the effect of corticosteroids on tacrolimus pharmacokinetics., Methods: In a randomized trial, kidney transplant recipients were treated with tacrolimus and mycophenolate mofetil with either daclizumab (n = 31) or 3 months of prednisone (n = 34). Tacrolimus dose-adjusted predose concentrations (C0) at month 1-6 were compared between both groups and within the corticosteroid group before and after prednisone withdrawal., Results: At month 1 the tacrolimus dose-adjusted C0 in the corticosteroid group was 83 +/- 8 vs 119 +/- 17 ng ml-1 mg-1 kg-1 in the daclizumab group. The tacrolimus dose-adjusted C0 within the corticosteroid group at month 1 and 2 was 42% and 29% lower compared with month 4 (P < 0.001)., Conclusions: A higher tacrolimus dose is required to reach target concentrations when used in combination with corticosteroids.

Background: The calcineurin inhibitors cyclosporine (INN, cyclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1., Objective: Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics., Methods: Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype., Results: Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P <.0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P =.003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations., Conclusion: As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.

Viral infections constitute an important problem for transplant recipients and their physicians. Often the balance between adequate and over-immunosuppression is hard to find and therapeutic drug monitoring might be a welcome adjunct in the management of transplant patients. We report four renal transplant recipients with extra-ordinary presentations of viral disease who were all treated with mycophenolate mofetil and in whom high mycophenolic acid (MPA) trough levels were found. High MPA levels may reflect over-immunosuppression resulting in infectious complications.

Uncertainty exists regarding the necessity of continuing triple therapy consisting of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) after kidney transplantation (RTx). At 6 mo after RTx, 212 patients were randomized to stop CsA (n = 63), stop Pred (n = 76), or continue triple drug therapy (n = 73). The MMF dose was 1000 mg twice daily, target CsA trough levels were 150 ng/ml, and Pred dose was 0.10 mg/kg per d. Follow-up was until 24 mo after RTx. Biopsy-proven acute rejection occurred in 14 (22%) of 63 patients after CsA withdrawal compared with 3 (4%) of 76 in the Pred withdrawal group (P = 0.001) and 1 (1.4%) of 73 in the control group (P = 0.0001). Biopsy-proven chronic rejection was present in one patient in the control group, in nine patients after CsA withdrawal (P = 0.006 versus control group); and in four patients after discontinuation of Pred (NS). Graft loss occurred in two versus one patient after CsA or Pred withdrawal, respectively, and in two patients in the control group (NS). Patients who successfully withdrew CsA had a significantly lower serum creatinine during follow-up. Pred withdrawal resulted in a reduction in mean arterial pressure, and the total cholesterol/HDL ratio increased. In conclusion, rapid CsA withdrawal at 6 mo after RTx results in a significantly increased incidence of biopsy-proven acute and chronic rejection. Pred withdrawal was safe and resulted in a reduction in mean arterial pressure. However, patient and graft survival and renal function 2 yr after RTx were not different among groups.

Patients returning to haemodialysis or peritoneal dialysis after a failed kidney transplantation sometimes have a renal allograft left in situ for some urine production. Low-dose immunosuppressive medication is often continued in such patients. To evaluate the morbidity and mortality between patients in time periods with (group A) or without (group B) low-dose maintenance immunosuppression, the present study was initiated. In a multi-centre cohort study we analysed data from patient files, which showed failure after at least 3 months graft function between 10 August 1972 and 4 April 1996, including 197 kidney transplantations. A total of 1.7 versus 0.51 infections per patient year was found in groups A and B, respectively (odds ratio [OR]: 3.4, 95% confidence interval [CI]: 2.5-4.5). There was an increased mortality in group A compared to group B (OR 3.4, 95% CI: 1.8-6.3), both from infectious disease (OR 2.8, 95% CI: 1.1-7.0), and cardiovascular disease (OR 4.9, 95% CI: 1.8-13.5). Continuation of immunosuppressive medication did not lead to fewer rejections (defined as a painful, tender graft and/or haematuria and/or low-grade non-infectious fever). Transplantectomy-related morbidity and mortality were acceptable. The increase in morbidity and mortality associated with low-dose maintenance immunosuppression argues in favour of stopping these medicaments when failed renal allograft patients return to dialysis.

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection.

Mycophenolate mofetil is a new immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T- and B-lymphocytes. Superior efficacy of mycophenolate mofetil compared to azathioprine, in combination with cyclosporine and prednisone, in the prevention of acute rejection in organ transplantation has made mycophenolate mofetil one of the standard immunosuppressive drugs after transplantation. Mycophenolate mofetil also is an interesting candidate drug for many other, mainly auto-immune mediated diseases. The use of mycophenolate mofetil in several of these diseases is discussed. The definitive place of mycophenolate mofetil will depend on the results of randomised trials currently under way.

Background: The introduction of cyclosporine (CsA) in kidney transplantation has improved early graft survival. However, its long-term use is associated with impairment of renal function and increased cardiovascular risk factors. To avoid CsA-related long-term adverse effects, patients were converted to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation., Methods: Between September 1995 and January 1997, 64 stable renal transplant recipients on CsA and prednisone treatment were included in a prospective, randomized study. Patients were randomized for conversion of CsA to 2 mg/kg AZA (n=30) or 1 g of MMF twice daily (n=34). All patients remained on low-dose steroids. To decrease the total immunosuppressive load, a dose reduction in MMF and AZA was performed at 4 and again at 8 months after conversion. Mycophenolic acid trough levels were measured at regular intervals., Results: After conversion, a decrease in serum creatinine was found for both groups: for MMF, 132 to 109 micromol/L (P=0.016); and for AZA, 123 to 112 micromol/L (P<0.0001). After conversion, more acute rejections occurred in the AZA group (11/30) compared to the MMF group (4/34) (P=0.04). Dose reduction of MMF to 500 mg twice daily and of AZA to 1.0 mg/kg elicited three rejections in both groups. The incidence of side effects and infections were similar., Conclusion: Discontinuation of CsA spared renal function. In patients converted to MMF significantly less rejections occurred compared to patients converted to AZA. Furthermore, dose reduction of both AZA and MMF is possible in the majority (72%) of the patients.

Background: To reduce the side effects of long-term immunosuppressive therapy, stable renal transplant patients were routinely converted from cyclosporine to either azathioprine or mycophenolate mofetil. Thereafter, the azathioprine and mycophenolate mofetil dose was reduced to 75% at 4 months and to 50% at 8 months after conversion. We questioned whether the T-cell reactivity before conversion was able to predict which patients could be safely converted and tapered in their immunosuppressive load, while remaining free from acute rejection., Methods: Before conversion, the T-cell reactivity of peripheral blood mononuclear cells against donor and third-party spleen cells were tested in mixed lymphocyte cultures. We measured the frequency of donor and third-party reactive helper T-lymphocyte (HTLpf) and cytotoxic T-lymphocyte (CTLpf) precursors and their avidity for HLA class I antigens using limiting dilution analysis. Peripheral blood mononuclear cells were also stimulated with tetanus toxoid to test the general immune response., Results: The tetanus toxoid response, reactivity to donor and third-party cells as measured in mixed lymphocyte cultures and HTLpf, and the avidity of cytotoxic T-lymphocyte precursors were not predictive for the development of acute rejection. However, significant differences were found in donor-specific CTLpf before conversion, between patients with and without acute rejection after conversion in immunosuppression. The donor-specific CTLpf was significantly lower in patients without compared to those with acute rejection (P=0.01). Additionally, when no CTLpf was detectable before conversion, acute rejection did not occur after conversion. Acute rejection was only diagnosed in patients with detectable CTLpf before conversion., Conclusion: The number of donor-specific cytotoxic T-lymphocytes identifies patients in whom the immunosuppressive load can be safely reduced.

Twenty-seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil (MMF) and prednisone 1 year after transplantation. After conversion the patients were treated with a standard daily dose of 1 g MMF b.i.d. and 10 mg prednisone for 4 months. Thereafter, two MMF dose reductions were performed with a 4-month interval. Mycophenolic acid (MPA) trough levels were measured at regular intervals. A relation was found between MPA trough levels and MMF dose. The median MPA trough level for patients treated with 1 g MMF b.i.d. was 4.3 microg/ml (0.95-15.5) and 3.0 microg/ml (0.73-7.8) for patients treated with 750 mg b.i.d. (P = 0.0002). The MPA trough levels further decreased from 3.0 to 2.3 microg/ml (0.6-6.63) in patients treated with 500 mg MMF b.i.d. (P = 0.01). Dose reduction of MMF from 1 g to 750 mg b.i.d. could be performed without acute rejections. A further dose reduction to 500 mg b.i.d. elicited 3 rejections. Patients experiencing an acute rejection had a median MPA trough level of 2.3 microg/ml (1.26-3.38) compared to 3.8 microg/ml (1.48-6.52) in patients without an acute rejection (P = 0.25). We conclude that there is a significant relation between MPA trough levels and MMF dose. MPA trough levels were not predictive of rejection in the present study.

Background: Triple drug treatment consisting of mycophenolate mofetil (MMF), in a standard dose of 2 g daily, combined with cyclosporine (CsA) and prednisone, has become the standard immunosuppressive regimen after kidney transplantation in many centers. The need for therapeutic drug monitoring of mycophenolic acid (MPA) has not yet been established. Several drug interactions with MMF are known. We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients., Methods: Fifty-two patients were treated with 1 g of MMF twice daily, and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation. At 6 months after transplantation, 19 patients were randomized for continuation of triple therapy (group A), 19 patients discontinued CsA (group B), and 14 patients discontinued prednisone (group C). We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups., Results: MPA trough levels during treatment with CsA, MMF, and prednisone were significantly lower than those during treatment with MMF and prednisone only (group B); median levels were 1.87 mg/L (range: 0.56-5.27) vs. 3.16 mg/L (range: 0.32-7.78), respectively (P=0.002). MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation; group A median levels were 1.87 (range: 0.31-4.32) vs. 1.53 mg/L (range: 0.36-3.70), and group C median levels were 1.62 (range: 0.69-10.34) vs. 1.79 mg/L (range: 0.54-6.00), respectively. At 9 months after transplantation, patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy (P=0.001) or patients in whom steroids were withdrawn (P=0.014)., Conclusion: A significant increase of MPA trough levels was found after discontinuation of CsA (6 months after transplantation), resulting in almost a doubling of MPA trough levels at 9 months after transplantation. This resulted in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone.

Background: Both mycophenolate mofetil (MMF) and azathioprine (AZA) are immunosuppressive drugs that inhibit purine synthesis. In theory, MMF selectively inhibits lymphocyte proliferation, while AZA has well-known effects on red blood cells and thrombocytes as well. In renal transplant recipients we replaced CsA therapy by MMF in an attempt to reduce the immunosuppressive load 1 year after kidney transplantation. During this study we observed the effect of MMF on haematological parameters such as haemoglobin (Hb), leukocytes, and thrombocytes., Methods: One year after kidney transplantation 26 stable patients were converted from cyclosporin A (CsA) to MMF (2 g/day). Thereafter, these patients were tapered twice in their MMF dose from 2 g to 1.5 g (4 months after conversion) and from 1.5 to 1 g (8 months after conversion) per day. The Hb levels, leukocyte and thrombocyte counts, and mycophenolic acid (MPA) trough levels were routinely measured., Results: After conversion from CsA to MMF not only creatinine levels and the number of leukocytes, but also the haemoglobin (Hb) level significantly decreased in 21/26 patients (P=0.0004). In eight patients the Hb level dropped more than 1 mmol/l (=1.61 g/dl). Only in two of eight patients was an explanation for blood loss found. The effect on Hb level did not ameliorate after the first MMF dose reduction to 1.5 g/day. After tapering the MMF dose to 1 g/day, the Hb approached the pre-conversion level. Not only the MMF dose but also the mycophenolic acid (MPA) trough level correlated with the Hb level., Conclusions: After conversion from CsA to MMF 1 year after kidney transplantation, a decrease in Hb level and leukocyte count was observed. The MPA trough level correlated also with the Hb level. The effect on the Hb level was reversible after dose reduction. This finding suggests that MMF exerts a negative effect on erythropoietic cells.

Background: Combining cyclosporin (CsA) and prednisone with mycophenolate mofetil (MMF) results in a significant reduction in the rate of biopsy-proven acute rejection after kidney transplantation. This is achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring of the pharmacologically active metabolite mycophenolic acid (MPA) will lead to improved safety and efficacy is unclear., Methods: We monitored MPA trough levels in 18 kidney transplant recipients treated with CsA, prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated with prednisone and MMF only, in a cross-sectional study. All patients were at least 3 months after transplantation with stable graft function. All patients were treated with 2 g MMF for at least 3 months and 10 mg prednisone., Results: The MPA trough levels in the CsA-treated patients were significantly lower (P<0.0001; Mann-Whitney) than those in patients on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40 mg/l respectively)., Conclusions: Although all patients were treated with an identical MMF dose, a significant difference was found in the MPA trough levels between CsA- vs non-CsA-treated patients. This suggests that CsA influences the MPA trough level. The level at which CsA affects the MPA trough levels is unclear.

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.

Background: Failed renal allografts are sometimes left in situ for additional clearance and urine production during hemodialysis or peritoneal dialysis, and low-dose immunosuppressive medication is often continued in such patients. We compared the morbidity and mortality due to infections between patients with (group A) or without (group B) low-dose immunosuppression (i.e., transplantectomy)., Methods: In a hospital-based cohort study, we analyzed data from patient files. We evaluated 37 patients who received 42 kidney transplantations between May 1975 and November 1995., Results: A total of 2.28 vs. 0.68 infections/patient-year were found in groups A and B, respectively. The odds ratio of one or two infections developing for patients in group A compared with group B was 14.2 (95% confidence interval, 1.4-143.4; P<0.025) and 4.3 (95% confidence interval, 1.1-17.3; P<0.04). A total of five lethal infections were found in group A; no lethal infections were found in group B., Conclusions: The increase in serious and life-threatening infections associated with even low-dose immunosuppression argues in favor of discontinuation of these drugs. The removal of failed renal allografts should be considered.

The case history of a haemodialysis patient with fever and rigors is presented. This diagnostic problem turned out to be a hypersensitivity reaction to azathioprine, with identical complaints recurring after a rechallenge with azathioprine, findings which resolved on discontinuation of this drug. The more extended indications for use of azathioprine warrant attention to the possibility of side-effects like drug fever.

A pilot study was performed on the storage of plasma and cryosupernatant plasma at 4 degrees C for up to 28 days. Eight bags, four of CPD fresh-frozen plasma (FFP) and four of CPD cryosupernatant plasma (CSP, plasma without cryoprecipitate), were sampled during storage for assays of pH; factors V, VIII, IX, and XI; fibrinogen; prothrombin time; activated partial thromboplastin time (APTT); plasma protein electrophoresis; viscosity; and C1q binding. No changes were found in viscosity or the plasma protein electrophoretic pattern, and there was no detectable immune complex formation. The fibrinogen concentration remained constant, and the prothrombin time showed a gradual increase of 2.5 seconds for both groups of plasma. The labile coagulation factor V decreased gradually for FFP and CSP to 58 and 64 percent of its initial value, respectively (51 +/- 8% and 54 +/- 6% of the value of fresh pooled plasma). Factor VIII decreased to 36 percent of its initial value in FFP (48 +/- 14% of fresh pooled plasma). In CSP, factor VIII decreased after 28 days to 7 percent of its initial value (7 +/- 1% of fresh pooled plasma). The APTT increased for FFP from 28 to 35.8 +/- 1.1 seconds and for CSP from 36 to 49.5 +/- 4.9 seconds. The only chemical change observed for both plasmas was a rise in pH, from 7.27 to 7.56, after 28 days. The results of this pilot study indicate that FFP can be stored at 4 degrees C for 28 days with sufficient recovery of coagulation factors to maintain hemostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

The accuracy of clinical diagnosis and fine-needle aspiration biopsy (FNAB) was evaluated in a total of 495 patients of whom 183 were operated upon within 6 months after FNAB and 312 were not. Operated patients were divided into three subgroups with high, moderate or low suspicion of malignant neoplasms on clinical grounds. Histological examination revealed an overall malignant neoplasm rate of 23%. The rate, i.e. the positive predictive value, was 74% for the subgroup with high clinical suspicion, vs 14% and 10% respectively for the subgroups with moderate and low clinical suspicion. The sensitivity of a high clinical suspicion was 60% and the specificity 93%. The overall sensitivity of FNAB was 93% in the operated group and probably not less than 87% in all patients studied; specificity was 71% and 84% respectively for these groups. The overall positive predictive value of a positive cytology result (malignant or uncertain) was 48%. In the subgroups with moderate or low clinical suspicion which are more representative of a non-university setting, the average predictive value was 27%. In our opinion all patients in the group with high clinical suspicion need surgical treatment, regardless of the FNAB result; those with lower degrees of clinical suspicion and malignant or uncertain FNAB result should also undergo diagnostic surgical exploration.