Use of mycophenolate mofetil in immunosuppressive protocols in elderly renal transplant recipients.
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Aged↗
Biomedical subjects
David W Johnson
Publications and source records attributed to David W Johnson.
Cyclosporine excretion into breast milk.
Although many female patients of childbearing age who are receiving cyclosporine have successful pregnancies, these women may be advised not to breast-feed. During recent years, cases of uneventful pregnancies and subsequent successful breast-feeding have been reported in the literature. The infant's blood cyclosporine concentration was usually very low. Based on these findings and the lack of detectable adverse effects, some investigators have suggested that women on cyclosporine may breast-feed, challenging the conventional view that cyclosporine is contraindicated during breast-feeding. Here, we report our experience with cyclosporine use during breast-feeding in five mother-infant pairs. We show a wide range of infant exposures to the drug in milk, noting that one of the infants had therapeutic blood concentrations of cyclosporine despite relatively low concentrations of the drug in milk.
Cyclosporine↗
Patient management by cyclosporine C2 monitoring: not enough science yet to justify the practice.
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Complement C2↗
A single-centre experience of post-renal transplant lymphoproliferative disorder.
Post-transplant lymphoproliferative disorder (PTLD) complicates 1 to 10% of all transplantations. Previous clinicopathological studies of PTLD have been limited by small numbers, short follow-up times, outdated data, heterogeneity of pooled solid-organ transplant results, and selective inclusion of early-onset disease. We therefore undertake here a retrospective analysis and identify all cases of PTLD that complicated renal transplantation at the Princess Alexandra Hospital between 30 June 1969 and 31 May 2001. Tumour samples were subsequently retrieved for pathological review and for Epstein-Barr virus-encoded RNA in situ hybridisation (EBER-ISH). Of 2,030 renal transplantation patients, 29 (1.4%) developed PTLD after a median period of 0.5 years (range 0.1 to 23.3 years). PTLD patients were more likely to have received cyclosporine (76% versus 62%, P<0.05), tacrolimus (10% versus 2%, P<0.05) and OKT3 (28% versus 10%, P<0.01). As the burden of immunosuppression increased from dual, to triple, to OKT3 therapy, the risks of early onset, extensive-stage, polymorphic, Epstein-Barr virus (EBV)-associated and fatal PTLD progressively increased. The majority of patients presented with an extra-nodal mass (45%), were afebrile (76%), and had stage-IV disease (60%). EBER-ISH was positive in 58%. Actuarial 5-year disease-free survival was 53.7%. The independent predictors of mortality on multivariate Cox regression were polymorphic histology (HR 7.4, 95% CI 1.5-37) and an international prognostic index (IPI) >1 (HR 2.7, 95% CI 1.1-6.8). Compared with other treatments, chemotherapy was associated with higher survival rates (100% versus 18% at 3 years, P=0.0001). In conclusion, PTLD is more likely, occurs earlier, and is more often fatal, in the setting of intensive immunosuppression. Nevertheless, excellent long-term outcomes are achievable with early recognition and institution of appropriate treatment.
Humans↗
Clinicians' attitudes to clinical practice guidelines.
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Attitude of Health Personnel↗
In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure.
Caveolae and their proteins, the caveolins, transport macromolecules; compartmentalize signalling molecules; and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.
Acute Kidney Injury↗
Analysis of isomeric long-chain hydroxy fatty acids by tandem mass spectrometry: application to the diagnosis of long-chain 3-hydroxyacyl CoA dehydrogenase deficiency.
Acetyl trimethylaminoethyl ester iodide derivatives have been used to selectively analyze isomeric long-chain hydroxy fatty acids by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The binary derivatives of 2-, 3-, 12- and 16-hydroxypalmitic acids afford remarkably different product ion spectra. Further discrimination between isomers is possible by acylating with pivaloyl chloride. 2- and omega-Hydroxy long-chain fatty acids form pivaloyl esters in quantitative yield whereas other secondary alcohols only partially react. Cotton-based filter paper used for blood collection contains substantial amounts of esterified long-chain hydroxy fatty acids. From the product ion spectra of the acetyl trimethylaminoethyl esters the hydroxydocosanoic and -tetracosanoic acids are >90% omega-hydroxy. All remaining saturated and unsaturated hydroxy acids are >90% 2-hydroxy acids. A method for the quantification of free 3-hydroxypalmitic acid in plasma by ESI-MS/MS for the diagnosis of long-chain 3-hydroxyacyl CoA dehydrogenase deficiency (LCHAD) is described. Median plasma concentrations of 0.43 micromol/L (control, n = 22) and 12.2 micromol/L (LCHAD, n = 3) were obtained from 5 microL plasma samples.
3-Hydroxyacyl CoA Dehydrogenases↗
Correlates of subclinical left ventricular dysfunction in ESRD.
BACKGROUND: Abnormalities of the left ventricle are common in patients with end-stage renal disease (ESRD) both before and after the start of renal replacement therapy. The purpose of this study is to identify possible causes of subclinical left ventricular (LV) dysfunction in patients with ESRD. In particular, we sought to determine whether the presence of ESRD was itself associated with dysfunction independent of LV hypertrophy and coronary artery disease. METHODS: Assessment of cardiovascular risk factors and dialysis adequacy was completed in 145 unselected patients with ESRD who were recruited from the renal dialysis unit and compared with age- and sex-matched controls. Among the 68 patients with ESRD who had undergone a dobutamine stress echocardiogram with normal findings, regional cardiac function was quantified by myocardial Doppler velocity, LV volumes and mass were measured using three-dimensional echocardiography, and vascular function was assessed using brachial artery reactivity (BAR). RESULTS: LV diastolic velocity was impaired in patients with ESRD, but there was no significant difference in systolic velocity compared with control patients of similar age. Age, diabetes mellitus, hypertension, and LV mass were independent predictors of diastolic velocity (model R2 = 0.45; P < 0.001), whereas age and risk factor number were predictors of systolic velocity (model R2 = 0.19; P = 0.002). Increasing risk factor number had no significant relationship with LV mass or volume. There was no detected association between BAR and incremental risk factors (P = 0.51). CONCLUSION: Subclinical LV dysfunction occurs in patients with ESRD, but is evidenced as abnormal myocardial diastolic, rather than systolic, function. Correlates of abnormal function are age, diabetes mellitus, hypertension, and LV mass, rather than ESRD alone, dialysis adequacy, or abnormal endothelial function.
Adult↗
The frequency of complications associated with the use of multiple-dose activated charcoal.
STUDY OBJECTIVE: The objective of this study was to determine the frequency of complications associated with the use of multiple-dose activated charcoal. METHODS: The study population was drawn from 8 tertiary care hospitals in 4 North American cities. Medical records of all inpatients between March 1993 and March 1998 with a discharge diagnosis of poisoning (International Classification of Diseases, 9th edition, Clinical Modification codes 960-989.9) were reviewed to select patients who had received multiple-dose activated charcoal (defined as > or =2 doses administered within 12 hours). Medical records of patients who received multiple-dose activated charcoal were reviewed for patient demographics and clinical information regarding the occurrence of pulmonary aspiration, gastrointestinal obstruction, hypernatremia, hypermagnesemia, corneal abrasion, and other complications associated with the use of multiple-dose activated charcoal. RESULTS: We reviewed 6,258 medical records, identifying 878 patients who received multiple-dose activated charcoal. We judged 5 (0.6%; 95% confidence interval [CI] 0.1% to 1.1%) patients to have had clinically significant pulmonary aspiration and none (0%; upper 95% CI 0.3%) to have had gastrointestinal obstruction. None of the patients with pulmonary aspiration died or had residual sequelae recorded. Hypernatremia (peak serum sodium >145 mEq/L [145 mmol/L]) was documented in 53 (6.0%; 95% CI 4.4% to 7.6%) patients, of whom 5 (0.6%; 95% CI 0.1% to 1.1%) had a serum sodium concentration of greater than 155 mEq/L (155 mmol/L). Hypermagnesemia (peak serum magnesium >2.5 mg/dL [1.0 mmol/L]) was documented in 27 (3.1%; 95% CI 2.0% to 4.2%) patients, of whom 3 (0.3%; 95% CI 0.1% to 1.0%) had peak values that were greater than 3.75 mg/dL (1.5 mmol/L). One patient had a corneal abrasion (0.1%; 95% CI 0% to 0.6%). No other complications were identified. CONCLUSION: Clinically significant complications associated with the use of multiple-dose activated charcoal occur infrequently.
Adolescent↗
Can interpersonal competition be constructive within organizations?
An empirical analysis was conducted on the conditions under which competition can be constructive. The participants were 64 managers and 28 employees from organizations in mainland China. They were asked to describe specific incidents of competition between them and their fellow employees and rate on a 7-point Likert-type scale the conditions that they perceived affected the outcomes. The incidents could involve either a physical activity or an intellectual task or both. Results showed that the variables related to constructive competition included the fairness of the rules, the motivation to win, having an advantage that enhanced one's chances of winning, a strong positive relationship among competitors, and a history of confirming each other's competence. By controlling these factors, the constructiveness of competition may be enhanced.
Adult↗
Quantification of glutamine in dried blood spots and plasma by tandem mass spectrometry for the biochemical diagnosis and monitoring of ornithine transcarbamylase deficiency.
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Blood Specimen Collection↗
The effect of obesity on renal transplant outcomes.
BACKGROUND: Although obesity has been associated with improved survival on dialysis, its effects on renal transplant outcomes remain unclear. Previous studies have reported conflicting findings and have been limited by the use of outdated patient data, univariate analyses, and liberal transplant selection criteria. The present study aimed to evaluate the effect of obesity on renal transplant outcomes in a rigorously screened population. METHODS: A retrospective analysis was undertaken of all patients transplanted at the Princess Alexandra Hospital from 1 April 1994 to 31 March 2000. Patients were rigorously screened for cardiovascular disease before acceptance for transplantation. The effects of obesity on renal transplant outcomes were assessed by logistic and multivariate Cox regressions. RESULTS: Of the 493 patients transplanted, 59 (12%) were obese (body mass index [BMI] 30 kg/m ). Obese patients were more likely to experience superficial wound breakdown (14% vs. 4%, P<0.01) and complete wound dehiscence (3% vs. 0%, P<0.01). Wound infections also tended to be more frequent in obese recipients (15% vs. 8%, P=0.11). There were no significant differences between the two groups with respect to operative duration, postoperative complications, hospitalization, delayed graft function, or acute rejection episodes. Five-year actuarial survival rates were comparable between the two groups with respect to graft survival (83% vs. 84%, P=NS) and patient survival (91% vs. 91%, P=NS). On multivariate analysis, BMI was an independent risk factor for wound breakdown (odds ratio 1.21, 95% CI 1.09-1.34, P<0.001), but not for other posttransplant complications, hospitalization, graft loss, or patient survival. CONCLUSIONS: The only significant adverse effect of obesity on renal transplant outcomes was an increase in wound complications, which were generally of minor consequence. Provided that adequate care is taken to avoid transplanting patients with significant cardiovascular disease, obese recipients can achieve excellent long-term patient and graft survivals that are on par with their nonobese counterparts. Denying patients access to renal transplantation on the basis of obesity per se does not appear to be justified.
Adult↗
Is mycophenolate mofetil less safe than azathioprine in elderly renal transplant recipients?
BACKGROUND: Mycophenolate mofetil (MMF) is a potent immunosuppressive agent that has been shown to be superior to azathioprine in preventing early acute rejection in the general renal transplant population. However, it is uncertain whether these benefits also apply to older renal transplant recipients, who are known to be more susceptible to infectious complications and have considerably lower rates of rejection and immunological graft loss. METHODS: A retrospective analysis was undertaken of all elderly (> or =55 years old) renal transplant recipients who underwent renal transplantation at the Princess Alexandra Hospital (1994-2000) and received either MMF (n=60) or azathioprine (n=55) in combination with prednisolone and cyclosporin. Data were analyzed on an intention-to-treat basis using a multivariate Cox proportional hazards model. RESULTS: The azathioprine- and MMF-treated groups were well matched at baseline with respect to demographic characteristics, end-stage renal failure causes and transplant characteristics. Compared with the MMF cohort, azathioprine-treated patients experienced a shorter time to first rejection [hazard ratio (HR) 4.47, 95% CI 1.53-13.1, P<0.01]. However, azathioprine-treated patients were also less likely to develop opportunistic infections (HR 0.11, 95% CI 0.03-0.41, P=0.001). No differences were observed between the two groups with respect to hospitalization rates, intensive care admissions, hematological complications, or posttransplant malignancies. Actuarial 2-year survival rates for the azathioprine- and MMF-treated patients were 100 and 87%, respectively (P<0.001). The principal cause of death in the MMF cohort was infection. Using a multivariate Cox regression analysis of patient survival, an adjusted hazard ratio of 0.01 (95% CI 0.001-0.08, P=0.001) was calculated in favor of azathioprine. Overall graft survival also tended to be better in patients receiving azathioprine (HR 0.27, 95% CI 0.06-1.33, P=0.11), CONCLUSIONS: In elderly renal transplant recipients, the combination of MMF, cyclosporin, and prednisolone appears to result in a worse outcome compared with the less potent combination of azathioprine, cyclosporin, and prednisolone. Future prospective studies need to specifically evaluate the risk/benefit ratios of newer, more potent immunosuppressive protocols, such as MMF-based regimens, in this important and sizeable patient subgroup.
Aged↗
Interleukin-1beta induces human proximal tubule cell injury, alpha-smooth muscle actin expression and fibronectin production.
BACKGROUND: Tubulointerstitial lesions, characterized by tubular injury, interstitial fibrosis and the appearance of myofibroblasts, are the strongest predictors of the degree and progression of chronic renal failure. These lesions are typically preceded by macrophage infiltration of the tubulointerstitium, raising the possibility that these inflammatory cells promote progressive renal disease through fibrogenic actions on resident tubulointerstitial cells. The aim of the present study, therefore, was to investigate the potentially fibrogenic mechanisms of interleukin-1beta (IL-1beta), a macrophage-derived pro-inflammatory cytokine, on human proximal tubule cells (PTC). METHODS: Confluent, quiescent, passage 2 PTC were established in primary culture from histologically normal segments of human renal cortex (N = 11) and then incubated in serum- and hormone-free media supplemented with either IL-1beta (0 to 4 ng/mL) or vehicle (control). RESULTS: IL-1beta significantly enhanced fibronectin secretion by up to fourfold in a time- and concentration-dependent fashion. This was accompanied by significant (2.5- to 6-fold) increases in alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor beta (TGF-beta1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1beta. NG-methyl-l-arginine (L-NMMA; 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1beta-stimulated fibronectin secretion. In contrast, a pan-specific TGF-beta neutralizing antibody significantly blocked the effects of IL-1beta on PTC fibronectin secretion (IL-1beta, 268.1 +/- 30.6 vs. IL-1beta+alphaTGF-beta 157.9 +/- 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1beta 81.0 +/- 6.7% vs. IL-1beta+alphaTGF-beta 93.4 +/- 2.1%, of control values, P < 0.01). CONCLUSION: IL-1beta acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote alpha-smooth muscle actin expression. These actions appear to be mediated by a TGF-beta1 dependent mechanism and are independent of nitric oxide release.
Actins↗
Interleukin-1beta stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-beta-dependent mechanism.
One of the hallmarks of progressive renal disease is the development of tubulointerstitial fibrosis. This is frequently preceded by macrophage infiltration, raising the possibility that macrophages relay fibrogenic signals to resident tubulointerstitial cells. The aim of this study was to investigate the potentially fibrogenic role of interleukin-1beta (IL-1beta), a macrophage-derived inflammatory cytokine, on cortical fibroblasts (CFs). Primary cultures of human renal CFs were established and incubated for 24 hours in the presence or absence of IL-1beta. We found that IL-1beta significantly stimulated DNA synthesis (356.7% +/- 39% of control, P <.003), fibronectin secretion (261.8 +/- 11% of control, P <.005), collagen type 1 production, (release of procollagen type 1 C-terminal-peptide, 152.4% +/- 26% of control, P <.005), transforming growth factor-beta (TGF-beta) secretion (211% +/- 37% of control, P <.01), and nitric oxide (NO) production (342.8% +/- 69% of control, P <.002). TGF-beta (1 ng/mL) and the phorbol ester phorbol 12-myristate 13-acetate (PMA, 25 nmol/L) produced fibrogenic effects similar to those of IL-1beta. Neither a NO synthase inhibitor (N(G)-methyl-l-arginine, 1 mmol/L) nor a protein kinase C (PKC) inhibitor (bis-indolylmaleimide 1, 1 micromol/L) altered the enhanced level of fibronectin secretion or DNA synthesis seen in response to IL-1beta treatment. However, addition of a TGF-beta-neutralizing antibody significantly reduced IL-1beta-induced fibronectin secretion (IL-1beta + IgG, 262% +/- 72% vs IL-1beta + alphaTGF-beta 156% +/- 14%, P <.02), collagen type 1 production (IL-1beta + IgG, 176% +/- 28% vs IL-1beta + alphaTGF-beta, 120% +/- 14%, P <.005) and abrogated IL-1beta-induced DNA synthesis (245% +/- 49% vs 105% +/- 21%, P <.005). IL-1beta significantly stimulated CF DNA synthesis and production of fibronectin, collagen type 1, TGFbeta, and NO. The fibrogenic and proliferative action of IL-1beta on CF appears not to involve activation of PKC or production of NO but is at least partly TGFbeta-dependent.
Antibodies↗
Effects of conflict resolution training integrated into a high school social studies curriculum.
The authors examined the effectiveness of conflict resolution and peer mediation training among California high school students. The authors randomly assigned 2 of 4 classes to receive 5 weeks of conflict resolution and peer mediation training integrated into the required social studies curriculum. The remaining 2 classes studied the same social studies curriculum for an identical amount of time (105 min every other day) without conflict resolution and peer mediation training. The authors investigated 2 issues. The 1st was the effectiveness of the conflict resolution and peer mediation training. The trained students, compared with the untrained students, learned the integrative negotiation and peer mediation procedures better, applied the procedures more completely, chose an integrative over a distributive approach to negotiation, and developed more positive attitudes toward conflict. The 2nd issue was the impact of the training program on academic achievement. Integrating conflict resolution and peer mediation training into an academic course promoted higher achievement, greater long-term retention of the academic learning, and greater transfer of academic learning in social studies to language arts.
Adolescent↗
Neutrophil dysplasia characterised by a pseudo-Pelger-Huet anomaly occurring with the use of mycophenolate mofetil and ganciclovir following renal transplantation: a report of five cases.
AIM: The pseudo-Pelger-Huet (PH) anomaly has been associated with a variety of primary haematological disorders, infections and drugs. Recently, the development of dysgranulopoiesis characterised by a pseudo-PH anomaly has been reported in two patients with the use of mycophenolate mofetil (MMF) in the setting of heart and/or lung transplantation. We present a further five cases of MMF-related dysgranulopoiesis characterised by a pseudo-PH anomaly occurring after renal transplantation. METHODS: All patients were receiving standard immunosuppression protocols for renal transplantation, including a combination of MMF, steroids and either cyclosporin or tacrolimus. Oral ganciclovir was also used for cytomegalovirus prophylaxis in each case. RESULTS: Development of dysplastic granulopoiesis occurred a median of 96 days (range 66-196 days) after transplantation. Moderate or severe neutropaenia (<1.0 x 10(9)/l) developed in three cases, and appeared to be directly correlated with the percentage of circulating neutrophils present with dysplastic morphology. Resolution of dysgranulopoiesis occurred in all cases only after dose reduction and/ or cessation of both MMF and ganciclovir. CONCLUSIONS: In our series, the observed dysplastic granulopoiesis appeared related to the combination of MMF and ganciclovir, rather than MMF alone. Further study is required to determine the exact incidence and pathogenesis of this pattern of bone marrow toxicity.
Antiviral Agents↗