Kidney transplantation from donors with viral B and C hepatitis.

INTRODUCTION: The success of renal transplantation as a treatment for end-stage renal disease has created a chronic shortage of donor organs. We present our experience in transplanting kidneys from donors with hepatitis B virus (HBV) or hepatitis C virus (HCV) among matched serology-positive recipients. MATERIALS AND METHODS: From January 2002 to November 2005, 44 patients with end-stage renal disease and HCV seropositivity underwent kidney transplantation. In 28 transplants in HCV+ recipients, the donor was HCV+ (DC+/RC+) and in 16 of these cases the donor (one living donor) was HCV- (DC-/RC+). In the same period 14 patients with HBV infection and HbsAg seropositivity underwent kidney transplantation: eight received their graft from a cadaveric HbsAg-positive donor (DB+/RB+), while six patients received their graft from an HbsAg-negative donor. RESULTS: Viral reactivation was higher among DC+/RC+ (21.4%) than DC-/RC+ patients (6%). Graft survivals were 90% and 88% for DC+/RC+ and DC-/RC+, respectively; patient survivals were 100% for DC+/RC+ and 94% for DC-/RC+. Among the group of DB+/RB+, all the patients developed an HBV-DNA positivity in the early postoperative period. Patient and graft survivals were 100% in both groups. CONCLUSIONS: Our results suggest that HBV- and HCV-positive donors can be considered as an alternative donor source, because their kidneys are allocated to the matched serology-positive recipients, shortening their time on the waiting list.

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Improved attainment of NKF classified lipid target levels after conversion from cyclosporine to tacrolimus in renal graft recipients.

In an open, prospective, multicenter study, stable renal graft recipients were converted to tacrolimus because of cyclosporine-related side effects. Seventy-five patients were switched primarily because of hyperlipidemia. After the switch to tacrolimus, mean total cholesterol was reduced by 15% at month 6. One hundred seventy-seven additional patients were switched primarily for other indications: hypertrichosis, gingival hyperplasia, and arterial hypertension, and these symptoms also improved after the switch. In this analysis, serum lipid levels were categorized according to a modified standard classification of lipid parameters for renal transplant patients (published by the NKF Work Group). The aim was to estimate the proportion of patients reaching normal lipid levels after the conversion to tacrolimus therapy. In patients with primary indication hyperlipidemia, the proportion with normal cholesterol levels increased significantly from 5.6% at baseline to 37.5% at month 6 (P < .05). For LDL cholesterol, the increase was from 54.1% at baseline to 64.9% at month 6, and for triglycerides the improvement was from 25.4% to 33.8%. HDL cholesterol levels remained stable. Similar changes of lipid parameters were also observed in the subgroups of patients converted to tacrolimus primarily because of other indications. After conversion from cyclosporine to tacrolimus, a significantly higher proportion of stable renal graft recipients reached normal total cholesterol levels. For LDL cholesterol and triglycerides, a trend for normalization was observed. Thus, the improvement of serum lipid levels resulted for many patients in a change to a better level class and improved or normalized their cardiovascular risk parameters.

A randomized trial of steroid avoidance in renal transplant patients treated with everolimus and cyclosporine.

In this randomized trial renal transplant recipients were treated with basiliximab, everolimus 3 mg/day, low-dose CsA. At transplantation, patients were randomized to stop steroids at the seventh day (group A) or to continue oral steroids in low doses (group B). Of the 113 patients enrolled, 65 were randomized to group A and 68 to group B. All patients were followed for 2 years. During the study 28 (43%) group A patients required reintroduced corticosteroids. One patient died, in group B. The Graft survival rate was 97% in group A and 90% in group B. There were more biopsy-proven rejections in group A (32% vs 16%; P = .044). The mean creatinine clearance was 54 +/- 21 mL/min in group A vs 56 +/- 22 mL/min in group B. Mean levels of serum cholesterol tended to be lower in group A, but the difference was of borderline significance (191 +/- 91 vs 251 +/- 188 mg/dL; P = .07). Vascular thrombosis (0 vs 5) and pneumonia requiring hospitalization (2 vs 7) tended to be more frequent in group B. Only three cases of CMV infection (1 vs 2) occurred. An immunosuppressive therapy with everolimus and low-dose CsA allows one to obtain excellent renal graft survival and stable graft function at 2 years. Early interruption of steroids in patients treated with this regimen may increase the risk of acute rejection, but neither affects graft survival nor graft function, while possibly reducing the risk of hyperlipemia and vascular thrombosis. About 60% of patients given everolimus and low-dose CsA can definitively stop steroids after 1 week.

Addition of sirolimus to cyclosporine in long-term kidney transplant recipients to withdraw steroid.

The aim of this study was to evaluate the feasibility of a steroid-free maintenance immunosuppression regimen in long-term renal transplant (KTx) recipients after addition of sirolimus (SRL) to cyclosporine (CsA)-based immunosuppression. A multicenter, prospective pilot study of steroid withdrawal (SW) was initiated for KTx patients. SW was divided into three phases: (A) conversion to a SRL + CsA + steroid regimen; (B) steroid tapering and withdrawal; and (C) maintenance with SRL + CsA. Primary endpoints of the study were incidence of acute biopsy-proven rejection (AR) and safety. In the A and B phases of the study 42 KTx patients (132 +/- 75 months post-Tx) were entered into the study, 18 of 42 (43%) with severe, acute side effects due to the CsA + SRL combination. These side effects were reversible with reduction of CsA or with suspension of the SRL/CsA combination. An amendment was introduced in the protocol to drastically reduce the CsA exposure to <50 ng/mL (trough) at the time of SRL addition. After this amendment, 39 other KTx patients entered the study and only 3 of 39 (8%) were discontinued because of toxic side effects. In the overall cohort of 81 KTx patients, the incidence of AR after SW was low (n = 5, 6.1%), all occurring within the first 3 months after SW. These findings indicate: (1) addition of SRL to very low-maintenance CyA exposure allows safe SW in KTx; (2) with the SRL + CsA combination, the incidence of AR after SW is low in long-term KTx patients; and (3) in the first 3 months after SW strict monitoring for early diagnosis and treatment of AR is mandatory.

Design of a trial comparing sirolimus plus mycophenolate mofetil versus sirolimus plus cyclosporine.

We present the study design of a prospective, multicenter, randomized trial aimed at comparing the effects of two different combinations of sirolimus. Renal transplant recipients will be allocated to receive either sirolimus and mycophenolate mofetil (group A) or sirolimus and cyclosporine (group B). The primary endpoint will be the graft function at 3, 6, 12, 24, 36, 48, and 60 months. A number of secondary endpoints will also be considered. To obtain a significant difference in the primary endpoint 180 patients will be enrolled.

Determinants of enhanced thromboxane biosynthesis in renal transplantation.

BACKGROUND: Despite great improvement in patient and graft survival, the long-term morbidity and mortality in renal transplant recipients (RTRs) are still significant, with a high incidence of cardiovascular disease-related deaths. METHODS: We investigated thromboxane (TXA2) biosynthesis and endothelial and coagulative activation in 65 patients who received a renal transplant. RESULTS: The rate of TXA2 biosynthesis (urinary 11-dehydro-TXB2 excretion largely reflects platelet TXA2 production in vivo) was significantly (P < 0.0001) higher in RTRs than in healthy subjects. Plasma von Willebrand factor (vWF) and thrombin-antithrombin (TAT) complexes were significantly higher (P < 0.001) in RTRs compared with controls. Urinary 11-dehydro-TXB2 directly correlated with plasma vWF and cholesterol. We next examined the relative influence of cyclosporine A (CsA) on TXA2 biosynthesis and endothelial activation, comparing a group of RTRs not receiving CsA with an age- and sex-matched group of patients treated with CsA. Urinary excretion of 11-dehydro-TXB2 and plasma levels of vWF were significantly increased in RTRs who received CsA compared with those who did not. After an overall follow-up of 120 months, RTRs who experienced cardiovascular events had a higher frequency of abnormal plasma levels of vWF than patients who remained event free. CONCLUSION: Renal transplantation is associated with in vivo platelet activation highly related to endothelial activation. This is particularly evident in CsA-treated patients. Administration of drugs that are able to reduce or eliminate thromboxane-dependent platelet activation in vivo may be beneficial to reduce the risk of cardiovascular events in RTRs.

Carotid atherosclerosis in renal transplant recipients: relationships with cardiovascular risk factors and plasma lipoproteins.

BACKGROUND: Renal transplant recipients have an increased incidence of cardiovascular disease, but less data exist about cerebrovascular atherosclerosis. In this study, we assessed the prevalence of carotid lesions as evaluated by B-mode ultrasonography in a group of renal transplant recipients, and we evaluated univariate and multivariate relationships between common risk factors and plasma lipoproteins and carotid lesions. METHODS: Fifty-seven renal transplant recipients and 113 age- and gender-matched controls underwent a complete clinical visit for the evaluation of risk factors present. In all subjects, a blood sample was collected for lipoprotein determination, and an ultrasound high-resolution B-mode imaging examination of the common carotid arteries was performed. RESULTS: We found that among renal transplant recipients, there was a significantly increased prevalence of subjects with plaque in comparison with controls (24.6% vs. 6.2%, P<0.001). At multiple analysis, carotid lesions were independently associated with age, hypertension, diabetes, smoking habit, and the presence of cardiovascular disease in controls and with age and hypertension in renal transplant recipients. Neither the lipid profile nor the presence of dyslipidemias was related to carotid score in renal transplant recipients, whereas a nonsignificant trend was observed in controls. Finally, in transplant patients, we did not find any association between carotid lesions and high-density lipoprotein subfractions. CONCLUSIONS: Age and hypertension are the main predictors of extracranial cerebrovascular atherosclerosis after renal transplantation. Because carotid lesions may represent a useful predictive marker of clinical events in nontransplant subjects, carotid artery evaluation by B-mode ultrasound might be routinely included in the management of renal transplant patients.

Plasma (total and ionized), erythrocyte and platelet magnesium levels in renal transplant recipients during cyclosporine and/or azathioprine treatment.

We evaluated total and ionized plasma magnesium levels, and erythrocyte and platelet magnesium concentrations from two groups of renal transplant recipients treated either with cyclosporine, azathioprine and prednisolone (group CAP, n = 8) or with azathioprine and prednisolone (group AP, n = 13), and in a group of age- and sex-matched healthy subjects (n = 10). Reduced plasma (total and ionized), erythrocyte and platelet magnesium concentrations were found in both CAP and AP groups with respect to controls (CAP: total plasma Mg median 0.61 vs 0.86 mmol/L, p < 0.01, ionized plasma Mg median 0.43 vs 0.58 mmol/L, p < 0.001, erythrocyte Mg median 2.18 vs 2.56 mmol/L, p < 0.05, platelet Mg median 1.75 vs 2.84 mmol/10(8) cells, p < 0.001; AP: total plasma Mg median 0.62 vs 0.86 mmol/L, p < 0.01, ionized plasma Mg median 0.48 vs 0.58 mmol/L, p < 0.001, erythrocyte Mg median 2.30 vs 2.56 mmol/L, p < 0.05, platelet Mg median 1.75 vs 2.84 mumol/10(8) cells, p < 0.001), while no difference was found between the two groups of transplant recipients as regards plasma and intracellular magnesium levels. Magnesium fractional excretion was higher in transplant recipients than in the control group (Mg fractional excretion median AP 18.6 per cent and CAP 12.8 per cent vs controls 3.5 per cent), whereas no difference was found between patients and control subjects for urinary magnesium 24h excretion. Moreover, in the whole group of transplant recipients (n = 21), urinary magnesium showed an inverse correlation with platelet (rs = -0.54, p < 0.05) and ionized plasma magnesium (rs = -0.48, p < 0.05), and time after transplantation showed a negative correlation with platelet magnesium concentrations (rs = -0.73, p < 0.001), and a direct correlation with fractional magnesium excretion (rs = 0.53, p < 0.05). Finally, a direct relationship between platelet magnesium and ionized plasma magnesium was also detected in the whole group of transplant recipients (rs = 0.47, p < 0.05). Both intraplatelet magnesium depletion and ionized plasma magnesium reduction induced by immunosuppressive therapy could be involved in the increased risk from atherosclerotic disease in renal transplant recipients.

HDL subfractions distribution in renal transplant recipients: lack of evidence of a reduction of HDL2 particles.

Since the high rate of cardiovascular disease in renal transplant recipients, alterations of lipoprotein profile in such patients were extensively evaluated, but the HDL subclass profile was not completely clarified. Renal transplant recipients usually show normal to high plasma levels of HDL cholesterol, even if some investigations suggested a persistence of low HDL2 levels: this was not useful in terms of cardiovascular protection. We designed this study in order to evaluate HDL subfractions distribution in renal transplant recipients. We studied 55 renal transplant recipients, treated with prednisone, azathioprine and/or cyclosporine, and 34 healthy normolipidemics as controls. In all subjects cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, apolipoproteins A-I and B levels and HDL subfractions, as determined by nondenaturing polyacrylamide gradient gel electrophoresis, were assayed. Renal transplant recipients had cholesterol, triglycerides, LDL cholesterol and apolipoproteins A-I and B levels significantly higher than controls; HDL cholesterol levels were slightly, but not significantly, increased in comparison with controls (respectively 51.1 +/- 15.5 and 46.1 +/- 10.8 mg/dl). Multivariate analysis showed that only the time since transplantation was significantly associated with HDL cholesterol levels. When HDL subfractions were analyzed, renal transplant recipients presented significantly lower levels of HDL3a and HDL3b and, in males, higher levels of HDL2b than controls. HDL cholesterol levels were positively correlated with HDL2b levels in both renal transplant recipients and controls, and negatively correlated with HDL3b in controls. In conclusion, in renal transplant recipients, we failed to demonstrate any decrease of HDL2 particles. On the basis of a nonatherogenic HDL profile, we suggest that the increased cardiovascular risk in renal transplant recipients might be accounted for by other risk factors.

[Effects of cyclosporin A on various indices of cholestasis in kidney transplant recipients]. / Effetti della ciclosporina A su alcuni indici di colestasi nei trapiantati renali.

A cholestatic syndrome has been reported as one of the main side effects of CyA therapy. The aim of the present study was to evaluate frequency and degree of severity of the cholestatic syndrome in a group of patients with renal transplant treated with CyA. In 55 patients we evaluated both clinical: jaundice, pruritus, presence of biliary lithiasis and biochemical parameters: total serum biliary salts (TBS), total bilirubin (TB), alkaline phosphatase (AP), gammaglutamyl transpeptidase (GGT), transaminase (AST, ALT), cholesterol (CT), triglycerides (TG), HDL-cholesterol (HDL-C) and compared them with a control group matched for sex and age. In the transplant patients significantly higher values of TBS, TB, AP (p < 0.05) were found; 55% of the patients had above mean values of at least one of the classical parameters of liver function and an higher frequency of biliary lithiasis was also found, in the absence of the classical risk factors. However, none of the patients presented severe signs of hepatic disease and to date it has never been necessary to stop treatment. In conclusion, our study shows that the dosage of CyA used at present is quite safe; however, it is necessary to monitor in these patients some parameters of liver function to prevent the minor side effects we observed from progressing into more serious damage.

Lipoprotein (a) levels in end-stage renal failure and renal transplantation.

Some previous studies have documented an increase in lipoprotein (a) [Lp(a)] levels in renal diseases. Here, we report data in subjects with end-stage renal failure treated with hemodialysis (HD) or with continuous ambulatory peritoneal dialysis (CAPD) and in renal transplant recipients (RTR), compared with a group of normolipidemic controls (C). Lp(a) levels were significantly increased in HD and CAPD patients in comparison with C, while they were only slightly increased in RTR. Both HD and CAPD patients showed Lp(a) levels higher than in RTR, but no difference was found between the subjects of the two dialysis procedures. The prevalence of Lp(a) levels > 25 mg/dl was significantly higher in HD and CAPD patients, but not in RTR, in comparison with C. Moreover, Lp(a) levels did not change after HD. When patients were divided according to their fasting lipid levels in normolipidemics and hyperlipoproteinemics, no difference was found for Lp(a) levels in any group. Mechanisms underlying the increase in Lp(a) levels in these patients are not known. It is possible to suggest an active role of the kidney in the Lp(a) metabolism or that uremic plasma contains some factors affecting Lp(a) metabolism.

Pancreatic enzymes in chronic renal failure and transplant patients.

The aim of the present study was to determine the frequency and degree of elevated serum levels of Total Amylase (TA), Pancreatic Amylase (PA), and Lipase (L) activity in patients with chronic renal failure (CRF) on conservative therapy; CRF on periodical hemodialysis (HD); in renal transplant (RT) and in a control Group (C). Mean values were significantly higher in all groups than Group C for TA (p < 0.005), PA (p < 0.0001) and L (p < 0.0001). A statistically significant correlation was found between TA and L vs creatininemia values in CRF patients, but only up to a certain level (creatininemia < 6 mg %) (p < 0.03 and p < 0.05), above which there was no correlation. The enzyme most frequently over the maximum normal limit was PA, both in the total CRF group (51%), in the hemodialysis patients (65%), and in the RT patients (55%); but only a few patients had values two times higher than the normal limits: 15% in the total CRF, 14% is the hemodialysis, and 10% in the RT groups, respectively. These results suggest that the increase in serum pancreatic enzyme during chronic renal pathology is slight but frequently occurs. It is possible that in these patients together with the renal excretion impairment there could also be some subclinical pancreatic damage; its genesis could also depend on the pharmacological treatment used (diuretics, immunosuppressive drugs) commonly adopted in these pathologies.

Serum trypsin in chronic renal failure and transplant patients.

The frequency and degree of elevated serum levels of trypsin (T) and correlation with other pancreatic enzymes were determined in several groups of patients with renal disease, i.e., patients with chronic renal failure (CRF), hemodialysis patients (HD), renal transplant recipients (RT), and in a control (C) group. Mean values of T were significantly higher in all other groups than in the C group (p less than 0.0001). A statistically significant correlation between T and creatininemia levels was found only for the RT group (p less than 0.0001). Correlations between T versus pancreatic amylase and T versus lipase activity were found to be statistically significant in the CRF and RT groups (p less than 0.01), but not in the HD group. Most patients in all groups had T values higher than the maximum value observed in the controls and, of them, most had very elevated values. The results suggest that in chronic renal pathology there are frequent and significant increases in serum T levels, circulating in parallel with the other pancreatic enzymes. It is possible that, together with the renal excretion impairment, there could also be subclinical pancreatic damage or a dysfunction of the other means of elimination of T that can be responsible for, or contribute to, the serum increase in the enzyme.