Impaired insulin sensitivity as an underlying mechanism linking hepatitis C and posttransplant diabetes mellitus in kidney recipients.

Aim of this study was to investigate the mechanism/s associating hepatitis C virus (HCV) infection and posttransplant diabetes mellitus in kidney recipients. Twenty HCV-positive and 22 HCV-negative kidney recipients, 14 HCV-positive nontransplant patients and 24 HCV-negative nontransplant (healthy) subjects were analyzed. A 3-h intravenous glucose tolerance test was performed; peripheral insulin sensitivity was assessed by minimal modeling. Pancreatic insulin secretion, hepatic insulin uptake, pancreatic antibodies and proinflammatory cytokines in serum (tumor necrosis factor-alpha, intereukin-6, high-sensitive C-reactive protein) were also assessed. HCV-positive recipients showed a significantly lower insulin sensitivity as compared to HCV-negative recipients (3.0 +/- 2.1 vs. 4.9 +/- 3.0 min(-1).microU.mL(- 1).10(4), p = 0.02), however, insulin secretion and hepatic insulin uptake were not significantly different. Pancreatic antibodies were negative in all. HCV status was an independent predictor of impaired insulin sensitivity (multivariate analysis, p = 0.008). The decrease of insulin sensitivity due to HCV was comparable for transplant and non-transplant subjects. No significant correlation was found between any of the cytokines and insulin sensitivity. Our results suggest that impaired peripheral insulin sensitivity is associated with HCV infection irrespective of the transplant status, and is the most likely pathogenic mechanism involved in the development of type 2 diabetes mellitus associated with HCV infection.

Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation.

The Symphony study showed that at 1 year posttransplant, a regimen based on daclizumab induction, 2 g mycophenolate mofetil (MMF), low-dose tacrolimus and steroids resulted in better renal function and lower acute rejection and graft loss rates compared with three other regimens: two with low-doses of cyclosporine or sirolimus instead of tacrolimus and one with no induction and standard cyclosporine dosage. This is an observational follow-up for 2 additional years with the same endpoints as the core study. Overall, 958 patients participated in the follow-up. During the study, many patients changed their immunosuppressive regimen (e.g. switched from sirolimus to tacrolimus), but the vast majority (95%) remained on MMF. During the follow-up, renal function remained stable (mean change: -0.6 ml/min), and rates of death, graft loss and acute rejection were low (all about 1% per year). The MMF and low-dose tacrolimus arm continued to have the highest GFR (68.6 +/- 23.8 ml/min vs. 65.9 +/- 26.2 ml/min in the standard-dose cyclosporine, 64.0 +/- 23.1 ml/min in the low-dose cyclosporine and 65.3 +/- 26.2 ml/min in the low-dose sirolimus arm), but the difference with the other arms was not significant (p = 0.17 in an overall test and 0.077, 0.039 and 0.11, respectively, in pair-wise tests). The MMF and low-dose tacrolimus arm also had the highest graft survival rate, but with reduced differences between groups over time, and the least acute rejection rate. In the Symphony study, the largest ever prospective study in de novo kidney transplantation, over 3 years, daclizumab induction, MMF, steroids and low-dose tacrolimus proved highly efficacious, without the negative effects on renal function commonly reported for standard CNI regimens.

Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program.

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

An outbreak of hospital-acquired Pseudomonas aeruginosa infection caused by contaminated bottled water in intensive care units.

This study describes an outbreak of Pseudomonas aeruginosa infections caused by contaminated bottled still water (BSW) in six intensive care units (ICUs) of a German university hospital. Clinical and environmental samples from these units were cultured and genotyped by amplified fragment-length polymorphism and pulsed-field gel electrophoresis analysis. Microbiological results were reviewed on a weekly basis to determine the number of P. aeruginosa infections and colonisations of ICU patients. Clinical specimens from 19 ICU patients--15 infections and four colonisations--yielded the same strain of P. aeruginosa. Furthermore, four of 103 environmental samples also yielded P. aeruginosa. However, only a P. aeruginosa strain isolated from unopened BSW was genetically identical to the P. aeruginosa strain isolated from the patients. In the 42-week period before the outbreak, the mean weekly number of new ICU patients infected or colonised with P. aeruginosa was 46.9 (95% CI 40.7-53.1)/1000 bed-days. During the 6-week period of the outbreak, the weekly number of new patients with P. aeruginosa was 88.9 (95% CI 54.3-122.2)/1000 bed-days. This number returned to the previous level after removal of the BSW. Thus, the microbiological and epidemiological findings revealed that the outbreak was related to BSW contaminated with P. aeruginosa. It was concluded that all untested BSW should be removed from ICUs.

Sexual dysfunction after simultaneous pancreas-kidney transplantation.

Simultaneous pancreas-kidney transplantation (SPK) is the treatment of choice for patients with type 1 diabetes mellitus and end-stage renal disease (ESRD) because it improves survival, is cost-effective, and can mitigate secondary complications of diabetes. Patient-reported outcomes such as quality of life (QoL) have recently received increased attention among transplant recipients. However, the impact of erectile dysfunction on patient QoL has not been investigated in this high-risk group with a history of diabetes and uremia. We applied the International Index of Erectile Function (IIEF) to describe the prevalence and severity of self-reported changes in erectile function after transplantation, comparing the quality of well-being (QWB) index of subgroups of 101 consecutive male SPK recipients with varying degrees of erectile function. Only 21% of patients did not suffer from erectile dysfunction; 18% were classified as mild erectile dysfunction, 31% as mild to moderate, 21% as moderate, and 9% as severe according to the IIEF scores. Forty-one percent of patients reported subjective overall improvement in erectile dysfunction compared with their pretransplant status; 7% considered their sexual function to be worse than before, and 51% did not note any change. The QWB index was highest among the group of patients without erectile dysfunction, decreasing gradually but significantly with increasing severity. A direct impact of erectile dysfunction on QoL, as well as a confounding effect of underlying vascular comorbidities, could explain this finding.

Relationship of hepatitis B or C virus prevalences, risk factors, and outcomes in renal transplant recipients: analysis of German data.

BACKGROUND: Chronic liver disease resulting from hepatitis B (HBV) and hepatitis C (HCV) virus infections is still a major concern in kidney recipients. Our aim was to evaluate the prevalences, risk factors, and impact of HBV and HCV infections in adult renal transplant recipients in Germany. MATERIALS AND METHODS: Data were collected on 1633 kidney recipients transplanted between 1989 and 2002 at the 21 German renal transplant centers participating in MOST, the prospective Multinational Observational Study in Transplantation. Subgroup analyses compared HBV- and HCV-positive patients vs those with HBV/HCV-negative serology at the time of transplantation. RESULTS: The prevalences of 4.4% (n = 72) for HBV and 5.8% (n = 94) for HCV showed a marked decline over the last 15 years. Retransplantations were significantly more common among HBV+ (29%) and HCV+ (36%) than HBV-/HCV- patients (12%). HCV+ patients experienced significantly longer dialysis times and received significantly more pretransplantation blood transfusions. Between all groups, no significant differences were observed in acute rejection rate at 12 months or in renal graft function up to 5 years posttransplantation (mean glomerular filtration rate: HBV+, 57.3 mL/min; HCV+, 58.5 mL/min; HBV-/HCV-, 59 mL/min). No progressive elevations in liver enzymes and bilirubin were noted during the 5-year observation period. CONCLUSIONS: HBV and HCV infections currently have a low prevalence among German kidney graft recipients. Long dialysis times, blood transfusions, and retransplantations were identified as risk factors for hepatitis infections. At 5 years posttransplantation, kidney and liver functions did not differ significantly between HBV+ and HCV+ vs HBV-/HCV- renal transplant recipients.

Erythropoietin in polycystic kidneys.

Erythropoietin (EPO) formation in kidneys of 18 patients with autosomal dominant polycystic kidney disease (ADPKD) was investigated. In 12 patients on hemodialysis and in 6 patients with preterminal renal failure serum, EPO was 29 +/- 7 and 16 +/- 1.5 mU/ml and hemoglobin concentrations were 11.0 +/- 0.6 and 12.7 +/- 1.2 g/dl, respectively. Cyst fluid from a total of 357 renal cysts was obtained by either in vivo aspiration or immediately after nephrectomy. The cysts contained variable concentrations of bioactive EPO from undectable values up to 3.2 U/ml. A pronounced enrichment of EPO was observed in cysts with sodium concentrations greater than 100 mmol/liter, suggesting an association with proximal tubular malformations. The EPO concentrations in the cysts were neither correlated with the protein concentration nor with the oxygen pressure of the cyst fluid. Using a cDNA probe for human EPO, mRNA for EPO was localized in stroma cells of the cyst walls by an in situ hybridization technique. Our findings suggest that single interstitial cells juxtaposed to proximal tubular cysts may produce EPO independent of the oxygen pressure inside the cysts, which ameliorates the anemia during end-stage polycystic kidney disease.

Immediate recovery of renal function after orthotopic liver transplantation in a patient with hepatorenal syndrome requiring hemodialysis for more than 8 months.

Severe liver dysfunction may lead to impairment of renal function without an underlying renal pathology. This phenomenon is called hepatorenal syndrome (HRS), which is associated with a poor prognosis showing a median survival of less than 2 months if renal replacement therapy is necessary. Liver transplantation is the best therapeutic option to regain renal function, but because of poor survival, these patients often die before transplantation. Herein we report a 37-year-old patient with ethyl-toxic liver cirrhosis who underwent hemodialysis due to HRS type I for more than 8 months. After living donor liver transplantation, diuresis immediately resumed, renal function soon recovered, and intermittent hemodialysis was stopped at 18 days after transplantation. Renal function was stable with a serum creatinine <2 mg/dL during the last 5 years posttransplantation. As far as we know, only a few cases of an anuric patient suffering from HRS have been reported with a survival beyond 8 months and full recovery of renal function after liver transplantation. This underlined that renal replacement therapy in HRS should be considered as a possible bridging method to liver transplantation even for longer periods.

Complication rate of pancreas retransplantation after simultaneous pancreas-kidney transplantation compared with pancreas after kidney transplantation.

Simultaneous pancreas kidney transplantation is currently the state of the art therapy for patients with type 1 diabetes mellitus and diabetic nephropathy. Up to 30% of patients loose the pancreas with a kidney graft that continues to function. Under those conditions, isolated pancreas retransplantation can be indicated. We compared the outcome of these patients with the outcome of patients undergoing primary pancreas after kidney transplantation. From 1998 to 2005, we performed 205 pancreas transplantations. Three patients were considered for isolated pancreas retransplantation; to date, two have received a new organ. One was retransplanted twice. In two cases, the reasons for the initial graft loss in the retransplantation group were pancreatitis with hemorrhagic bleeding and in the third case severe rejection. After retransplantation two of three patients lost their graft owing to bleeding and venous thrombosis. One of three organs was successfully transplanted and the patient does not require insulin. During the same time, three pancreas after kidney transplantations were performed; all are doing well und are free of insulin. The study despite the small number of cases shows a high complication rate after pancreas retransplantation. Nevertheless, pancreatic retransplantation should be considered in selected patients.

Tie2 receptor expression is stimulated by hypoxia and proinflammatory cytokines in human endothelial cells.

The tyrosine kinase receptor Tie2 (also known as Tek) plays an important role in the development of the embryonic vasculature and persists in adult endothelial cells (ECs). Tie2 was shown to be upregulated in tumors and skin wounds, and its ligands angiopoietin-1 and -2, although they are not directly mitogenic, modulate neovascularization. To gain further insight into the regulation of Tie2, we have studied the effect of hypoxia and inflammatory cytokines, two conditions frequently associated with neoangiogenic processes, on Tie2 expression in human ECs. Exposure to 1% O(2) led to a time-dependent significant rise of Tie2 protein levels in human coronary microvascular endothelial cells (HCMECs) and dermal microvascular ECs (HMEC-1) (3.2- and 2.5-fold within 24 hours), which was reversible after reoxygenation, and induced a less marked increase in human umbilical vein ECs (HUVECs; 1.7-fold). Hypoxia-conditioned medium and D-deoxyglucose did not change Tie2 expression, but desferrioxamine and cobalt, which are known to mimic hypoxia-sensing mechanisms, induced Tie2 at ambient oxygen tensions. Tumor necrosis factor-alpha induced Tie2 in a time- and dose-dependent fashion in all 3 EC types (HUVEC, 2.3-fold; HMEC-1, 2. 8-fold; and HCMEC, 3.0-fold; 10 ng/mL, 24 hours). Enhanced expression was also found after exposure to interleukin-1beta (1 ng/mL). Changes in Tie2 protein levels were paralleled by changes in mRNA expression. In accordance with these in vitro findings, immunohistochemistry revealed focal upregulation of Tie2 in capillaries at the border of infarcted human and rat myocardium. In conclusion, the data show that hypoxia and inflammatory cytokines upregulate Tie2, which may contribute to the angiogenic response in ischemic tissues.

Amelioration of anemia after kidney transplantation in severe secondary oxalosis.

INTRODUCTION: In small bowel disease such as M. Crohn, the intestinal absorption of oxalate is increased. Severe calcium oxalate deposition in multiple organs as consequence of enteric hyperoxaluria may lead to severe organ dysfunction and chronic renal failure. The management of hemodialyzed patients with short bowel syndrome may be associated with vascular access problems and oxalate infiltration of the bone marrow leading to pancytopenia. Although the risk of recurrence of the disease is very high after renal transplantation, it may be the ultimate therapeutic alternative in secondary hyperoxaluria. CASE: Here, we report a patient with enteric oxalosis due to Crohn's disease. He developed end-stage renal disease, erythropoietin-resistant anemia, oxalate infiltration of the bone marrow and severe vascular access problems. Following high-urgency kidney transplantation, daily hemodiafiltration of 3 hours was performed for 2 weeks to increase oxalate clearance. Despite tubular and interstitial deposition of oxalate in the renal transplant, the patient did not require further hemodialysis and the hematocrit levels normalized. DISCUSSION: Early treatment of hyperoxaluria due to short bowel syndrome is essential to prevent renal impairment. Declining renal function leads to a further increase in oxalate accumulation and consecutive oxalate deposition in the bone marrow or in the vascular wall. If alternative treatments such as special diet or daily hemodialysis are insufficient, kidney transplantation may be a therapeutic alternative in severe cases of enteric oxalosis despite a possible recurrence of the disease.

Acute renal failure after liver transplantation: incidence, etiology, therapy, and outcome.

Acute renal failure (ARF) was a frequent complication after orthotopic liver transplantation (OLT) when ARF was defined by a calculated glomerular filtration rate decrease of >50% or by a doubled serum creatinine above 2.5 mg/dL within the first week after OLT. We analyzed 1352 liver transplant recipients in retrospective fashion with regard to the incidence, etiology, therapy, and outcome of ARF; 162 patients developed ARF within the first week after OLT (12%), among whom 157 patients (97%) were recompensated by postoperative day 28. Altogether 52 patients (32%) received an average of 6 hemodialysis treatments, excluding the 5 patients (3%) who developed end-stage renal failure. Risk factors for this complication included hepatorenal syndrome type II, a glomerular filtration rate of <50 mL/min, and a diagnosis of hepatitis C.

Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas.

The transcription factor hypoxia-inducible factor (HIF)-1 is an important mediator of hypoxic adaptation of tumor cells and controls several genes that have been implicated in tumor growth. Oxygen-dependent degradation of HIF-1alpha, the regulatory subunit, requires binding to the von Hippel Lindau (VHL) protein. Because functional inactivation of the VHL tumor suppressor gene occurs in up to 70% of clear cell renal carcinomas, we investigated whether this results in overexpression of HIF-1alpha and its target genes. Immunoblotting revealed increased expression of HIF-1alpha in 24 of 32 (75%) clear cell renal carcinomas but only 3 of 8 non-clear cell renal tumors. Somatic mutations of the VHL gene were detected only in clear cell renal carcinomas that overexpressed HIF-1alpha. None of the HIF-1alpha-negative tumors displayed a VHL mutation. The level of HIF-1alpha mRNA was not different between tumors and adjacent kidney tissue. Immunohistochemistry revealed distinct patterns of nuclear staining for HIF-1alpha, depending on histological type and overall abundance of HIF-1alpha. In those clear cell renal carcinomas that showed increased expression on immunoblots, HIF-1alpha was expressed in almost all cells. In the remaining clear cell and in non-clear cell tumors, staining was focal; these different patterns thus were compatible with genetic stabilization in contrast to microenvironmental stimulation of HIF-1alpha as the primary mechanism. The mRNA expression of two known target genes of HIF-1alpha, vascular endothelial growth factor and glucose transporter 1, increased progressively with increasing amounts of HIF-1alpha in tumor extracts. In addition, glucose transporter 1 protein levels correlated with HIF-1alpha abundance. In conclusion, the data provide in vivo evidence for a constitutive up-regulation of HIF-1alpha in the majority of clear cell renal carcinomas, which leads to more widespread accumulation of this transcription factor than hypoxic stimulation. These observations are most likely linked to functional inactivation of the VHL gene product. Increased expression of HIF-1alpha is associated with alterations in gene expression patterns that are likely to contribute to tumor phenotype and progression.

Comparable kidney graft survival of type 1 diabetics treated with simultaneous pancreas-kidney transplantation and nondiabetic patients treated with cadaveric renal transplantation.

Simultaneous pancreas-kidney transplantation (SPK) is now a common treatment for insulin-dependent diabetic patients with end-stage renal disease. This study analyzed the patient and graft survival rates of 231 kidney transplantations (KTX) in nondiabetic patients and of 95 SPK in diabetic patients between January 1, 1998 and December 31, 2001. The SPK group showed significantly better patient and graft survival rates after 5 years than the KTX group (96% and 90% vs 85% and 75%, respectively; P < .05). Even the serum creatinine level during the first 2 years showed significantly lower levels in the SPK group (P < .01). The patients in the SPK group were significantly younger. They received organs from younger donors than the patients in the KTX group (P < .01). The cold ischemia time and the time on previous dialysis were also shorter in the SPK group (P < .01). However, the number of HLA mismatches was higher in the SPK patients (P < .01). Limiting the analysis to recipients younger than 60 years, donors younger than 58 years, and cold ischemia time to <19 hours, there was no difference in graft or patient survival. These data suggest that donor and recipient age as well cold ischemic time have a greater impact on early outcome and postoperative complications of renal transplants than HLA matching.

Accurate prediction of kidney allograft outcome based on creatinine course in the first 6 months posttransplant.

Most attempts to predict early kidney allograft loss are based on the patient and donor characteristics at baseline. We investigated how the early posttransplant creatinine course compares to baseline information in the prediction of kidney graft failure within the first 4 years after transplantation. Two approaches to create a prediction rule for early graft failure were evaluated. First, the whole data set was analysed using a decision-tree building software. The software, rpart, builds classification or regression models; the resulting models can be represented as binary trees. In the second approach, a Hill-Climbing algorithm was applied to define cut-off values for the median creatinine level and creatinine slope in the period between day 60 and 180 after transplantation. Of the 497 patients available for analysis, 52 (10.5%) experienced an early graft loss (graft loss within the first 4 years after transplantation). From the rpart algorithm, a single decision criterion emerged: Median creatinine value on days 60 to 180 higher than 3.1 mg/dL predicts early graft failure (accuracy 95.2% but sensitivity = 42.3%). In contrast, the Hill-Climbing algorithm delivered a cut-off of 1.8 mg/dL for the median creatinine level and a cut-off of 0.3 mg/dL per month for the creatinine slope (sensitivity = 69.5% and specificity 79.0%). Prediction rules based on median and slope of creatinine levels in the first half year after transplantation allow early identification of patients who are at risk of loosing their graft early after transplantation. These patients may benefit from therapeutic measures tailored for this high-risk setting.

Cyclosporine-based immunosuppressive strategies for kidney recipients: interim analysis of German data from the Multinational Observational Study (MOST).

INTRODUCTION: We collected data from kidney recipients with a functioning graft at German kidney transplant centers in order to analyze the efficacy of various cyclosporine (CsA)-based immunosuppressive strategies, the effects of different perioperative and maintenance regimens, and the impact of donor source on clinical outcome. METHODS: As part of the ongoing prospective Multinational Observational Study in Transplantation (MOST), data for both prospective and retrospective analysis were collected from kidney recipients over 18 years bearing a functioning graft that was transplanted at 21 German kidney transplant centers between 1987 and 2002. RESULTS: Data from 1223 renal graft recipients, including their CsA-based immunosuppressive regimens, were stratified as: 402 de novo patients (median 6.8 months posttransplant) and 821 patients on maintenance therapy (median 71 months posttransplant). Triple regimens with CsA + mycophenolate mofetil (MMF) + steroids (Ste) currently comprise the major perioperative immunosuppressive strategies in Germany (de novo 65%). IL-2 receptor antagonist (IL-2Ra) use is increasing (de novo 18%, maintenance 4%), while mono and dual regimen use de novo is declining (de novo 4%, maintenance 20%). Among 689 patients transplanted between 1987 and 2002 with outcome data, the mean incidence of acute rejection during the first posttransplant year was 21.6%. Rejection rates on initial therapy with CsA + MMF + Ste +/- antibodies (n = 517) averaged 17.8%. CONCLUSIONS: Between 1987 and 2002, CsA-based immunosuppression combined with MMF and Ste became the most commonly used strategy for both initial and maintenance therapy after kidney transplantation in Germany, yielding the low acute rejection rates particularly when combined with IL-2Ra.

Policy principles and implementation guidelines for private sector participation in the water sector--a step towards better results.

To achieve the Millennium Development Goals, all partners (public, private, NGOs) must be engaged for improving and expanding the water supply and sanitation services. Yet, high transaction costs, unclear role allocation and lack of trust and commitment put Private Sector Participation (PSP) at risk. The initiative "Policy Principles and Implementation Guidelines for Private Sector Participation in Sustainable Water Supply and Sanitation" contributes to equitable, effective, ecological and efficient PSP projects. Based on a multi stakeholder process, the Policy Principles are offering an open and transparent framework for the negotiation of valid, widely accepted and action-oriented solutions, while the Implementation Guidelines focus on success factors for building partnerships on the operational level.

Plasma levels of tumor necrosis factor (TNF) and soluble TNF receptors in kidney transplant recipients.

Tumor necrosis factor-alpha is elevated in plasma during kidney transplant rejection. However, the measurement and biological activity of TNF alpha is influenced by inhibitory soluble TNF receptors. We therefore determined plasma levels of TNF alpha and the 2 soluble TNF receptors, the 55-kDa TNF receptor (TNF-sR55) and the 75-kDa TNF receptor (TNF-sR75), by immunoassays in 25 patients before and daily after kidney transplantation. Plasma samples were retrospectively assigned to 3 groups: (1) patients with well-functioning grafts (n = 14); (2) patients with biopsy-proven graft rejections (n = 7 patients with 10 rejections); and (3) patients with episodes of CsA nephrotoxicity (n = 4 patients with 9 samples). On the day of biopsy-proven graft rejection, TNF alpha increased from 8.6 +/- 0.9 pg/ml to 14.8 +/- 3.5 pg/ml (P < 0.02), TNF-sR55 from 6.6 +/- 1.3 ng/ml to 9.0 +/- 1.2 ng/ml (NS), and TNF-sR75 from 10.3 +/- 1.0 ng/ml to 15.3 +/- 2.0 ng/ml (P < 0.01). During episodes of CsA toxicity, TNF alpha levels did not change, TNF-sR55 increased from 5.2 +/- 0.5 ng/ml to 10.5 +/- 0.5 ng/ml (P < 0.01), and TNF-sR75 increased from 10.2 +/- 0.8 ng/ml to 17.5 +/- 0.9 ng/ml (P < 0.01). There was a strong correlation between serum creatinine and plasma TNF-sR55 (r = 0.7, P < 0.001) and TNF-sR75 (r = 0.7, P < 0.001), but not with TNF alpha. Therefore, levels of TNF-sR55 and TNF-sR75 were corrected for serum creatinine. An index expressing TNF alpha over actively released soluble receptors (index = TNF alpha/(corr.TNF-sR55 + corr.TNF-sR75)) detected rejection episodes with a sensitivity of 70-80% and a specificity of 89%. We conclude that the measurement of plasma TNF alpha in combination with its soluble receptors is superior to isolated TNF alpha determinations in discriminating acute graft rejection from episodes of CsA toxicity in kidney transplant recipients.

Randomized, double-blind, one-year study of the safety and tolerability of cyclosporine microemulsion compared with conventional cyclosporine in renal transplant patients. International Sandimmun Neoral Study Group.

BACKGROUND: A microemulsion formulation of cyclosporine, Neoral, has been developed to overcome the problems associated with the poor and variable absorption of the traditional oil-based oral formulation, Sandimmune. The present study was conducted to compare the safety and tolerability of Neoral versus Sandimmune in maintenance renal transplant recipients over 1 year, and to assess the number of dose adjustments necessary to maintain trough cyclosporine concentrations within the desired therapeutic range. METHODS. Patients on Sandimmune were randomized to be converted to Neoral (n=373) or remain on Sandimmune (n=93) for 12 months. RESULTS: The proportion of patients needing dose increases to maintain cyclosporine trough levels within the desired range was significantly higher in the Sandimmune group during the first 3 months of the study, whereas the number of patients needing dose reductions was similar in both groups throughout the study period. There were no differences between the groups in terms of changes in blood pressure, serum creatinine levels, or other laboratory parameters. No significant differences in the incidence of adverse events known to be related to cyclosporine were observed between the treatment groups. More adverse events were causally related to Neoral than to Sandimmune by the investigators. However, overall, there were no clinically relevant differences between the treatment groups in the main safety and tolerability variables. CONCLUSIONS: The results of this study in maintenance renal transplant patients suggest that the improved pharmacokinetic characteristics of the microemulsion formulation of cyclosporine, Neoral, may facilitate the clinical management of cyclosporine immunosuppression, compared with the traditional formulation, Sandimmune. Furthermore, there is no evidence that the average improved bioavailability of Neoral has a negative impact on the main safety and tolerability variables, as no significant differences in graft function, the incidence of rejections, and most adverse events were seen.

Cytotoxic effector molecule gene expression in acute renal allograft rejection: correlation with clinical outcome; histopathology and function of the allograft.

BACKGROUND: Cytotoxic effector molecule expression in human renal allograft biopsies has been closely associated with acute rejection. Here we studied whether intragraft expression of perforin, granzyme B, and Fas ligand correlates with long-term clinical outcome of acute rejection episodes. Furthermore, we examined the relation to histopathology and function of the allograft during rejection. METHODS: Twenty-two human renal biopsies were quantified for mRNA expression of perforin, granzyme B, Fas ligand, and Fas with reverse transcription-polymerase chain reaction. Expression levels were correlated with clinical outcome after 12 months, Banff rejection grades, and allograft function in the course of acute rejection. RESULTS: Only Fas ligand, but not perforin or granzyme B, showed significantly higher up-regulation in seven samples with therapy-resistant acute rejections versus eight samples with therapy-sensitive acute rejection. We found no relation between cytotoxic marker expression and Banff rejection grades or serum creatinine peak levels. CONCLUSIONS: Fas ligand may be useful as an early marker of therapy-resistant acute rejection. Cells that express Fas ligand but not classical soluble cytotoxic molecules might influence clinical outcome of acute rejection episodes.