A randomized trial of everolimus and low-dose cyclosporine in renal transplantation: with or without steroids?

This multicenter, randomized, prospective, controlled trial (EVIDENCE study) aimed to determine short-term effects of early steroid withdrawal in renal transplant patients initially treated with everolimus, low-dose cyclosporine (CsA), and steroids. Patients were randomized to standard triple therapy with CsA, everolimus twice daily and steroids (group A), steroid-free immunosuppression (group B), or triple therapy once daily (group C). However, since patient enrollment was slower than expected, group C randomization was prematurely discontinued. The primary end point was treatment failure rate (composite end point of death, graft loss, biopsy-proven acute rejection, and loss to follow-up) between randomization and month 12. Patients evaluable for the primary end point included 139 randomized patients. According to intention-to-treat analysis, 2.8% of patients in group A and 14.7% in group B experienced treatment failure (95% upper confidence limit 19.7%). As this was higher than the predefined noninferiority limit of 10%, noninferiority could not be proved. No conclusive statements can be made on noninferiority of the steroid withdrawal regimen vs the standard regimen in these patients. Additional studies with longer follow-up are required to determine the efficacy of steroid-free immunosuppression in renal transplant recipients receiving everolimus.

Using metabolomics to monitor kidney transplantation patients by means of clustering to spot anomalous patient behavior.

BACKGROUND: NMR spectroscopy-based metabolomics is a system approach used to investigate the metabolic profile of biological fluids with multivariate data analysis tools. The aim of this study was to examine the kidney graft recovery process noninvasively through the examinations of urine samples using (1)H NMR spectroscopy combined with chemometric tools. METHODS: Urine samples were treated as the source of metabolites reflecting the pathological and clinical conditions of patients with transplanted kidneys. We observed 15 subjects (9 males and 6 females) during the graft recovery process and initial days thereafter. The patients provided at least 9 samples each, applying advanced statistical methods of analysis: Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis PLS-DA). RESULTS: The PCA model (for all subjects exp. var. PC1 13.96% and PC2 9.88%) allowed us to clearly designate 3 stages of recovery: initially the kidney is not working; in the second stage, it regains functions, and the third stage includes follow-up during hospitalization. PCA analysis of a single patient follows graft recovery based on biochemical (metabolites) information, assigning the appropriate recuperation stage. CONCLUSIONS: NMR spectroscopy together with chemometric analysis allow monitoring of kidney graft recovery to identify patients who are not progressing within the normal range.

Conversion of stable kidney transplant recipients from a twice-daily to once-daily everolimus regimen.

Once-daily everolimus administration is a further option to improve compliance to immunosuppressive therapy. We randomized 23 stable kidney transplant recipients already on everolimus therapy to receive a single daily morning dose or to continue the twice-daily regimen. The everolimus levels evaluated after 2 weeks showed a slight reduction from 5.13 +/- 1.61 ng/mL at baseline to 4.76 +/- 1.61 ng/mL, which was not statistically significant. After 2 weeks we also evaluated cyclosporine (CsA) levels together with renal function parameters, neither of which showed episodes, any difference between the converted versus twice-daily groups. We did not record any adverse event, such as an infection, an acute rejection episode, or graft loss, over the 6-month study period. Single dosing of everolimus is possible and safe and may achieve better patient compliance to multiple-drug immunosuppressive therapy.

Excellent long-term results in de novo renal transplant recipients treated with proliferation signal inhibitors and reduced calcineurin inhibitors exposure.

BACKGROUND: A new class of immunosuppressants, proliferation signal inhibitors (PSI)--sirolimus and everolimus--has the potential to prevent chronic allograft nephropathy (CAN). This retrospective analysis reports a 6-year practice using PSI at a single center, comparing a regimen based on reduced-dose calcineurin inhibitors (CNI) and PSI versus full-dose CNI and mycophenolic acid (MPA). METHODS: The study population included 70 patients (group A) who received de novo PSI therapy in combination with reduced dose of CNI, standard steroids, and basiliximab induction, and 216 patients (group B) with full-dose CNI, MPA, steroids, and basiliximab induction. RESULTS: No statistically significant differences were recorded in the baseline donor and recipient characteristics. A difference was observed in cold ischemia time, which could represent a bias for the analysis. No differences were recorded in actuarial patient survival, delayed graft function, biopsy-proven acute rejection rates, and renal function analysis. A significant difference was recorded in the actuarial graft survival rate at years 2, 3, and 4 (P< .01), as well as overall graft survival rates (P= .025). DISCUSSION: The reduction of cold preservation time seemed to be an important factor to improve both short- and long-term renal function. This regimen revealed a long-term trend toward better renal function and graft survival. The use of PSI with reduced doses of CNI seems to be indicated for suboptimal grafts, especially when a reduced quality of the kidney is associated with prolonged cold ischemia time.

Analysis of posttransplant diabetes mellitus prevalence in a population of kidney transplant recipients.

AIM: The onset of posttransplant diabetes mellitus (PTDM) among kidney recipients is associated with an increased risk of graft failure and death. Minimizing the risk of PTDM is a priority for long-term improvement in survival rates. We sought to evaluate the prevalence of PTDM and impaired fasting glucose (IFG) among a population of kidney transplant recipients to identify the risk factors and to evaluate graft and patient survivals. METHODS: We analyzed 250 consecutive Caucasian patients who received kidney allografts in our center between May 2000 and December 2005, with a median follow-up of 32 months (range, 1-78 months). RESULTS: We observed altered glucose metabolism in 17% of patients; specifically, the prevalences of PTDM and IFG were 12.2% and 4.8%, respectively. Patients who developed PTDM or IFG were overweight (BMI, 26.4+/-3.4 and 28.1+/-3.4 kg/m(2), respectively), whereas the normal glucose (NG) group's BMI was 23.8+/-3.5 kg/m(2) (P= .002 and P= .004, respectively). Prevalence of acute rejection was higher in the PTDM and IFG patients compared with the NG patients (60.7%, 63.6%, and 32.1%, respectively; P= .006; P< .04), while no difference was observed in terms of graft and patient overall survival. CONCLUSION: In our series of patients, we showed that being overweight represents a major risk factor for the development of PTDM, which results in an increased acute rejection rate. These results confirmed the importance of appropriate weight control among patients undergoing kidney transplantation, which should also be strictly monitored for all risk factors associated with the development of impaired glucose metabolism.

Diffusion tensor imaging in patients with primary cervical dystonia and in patients with blepharospasm.

Diffusion tensor imaging (DTI) analyses the movement of water molecules within the cerebral white matter thus providing information on ultrastructural brain changes. We studied 18 patients with cervical dystonia (CD), 16 with blepharospasm (BSP) and 35 years age-matched healthy controls. DTI data were obtained with a Philips 1.5 Tesla scanner and then processed to obtain maps of fractional anisotropy (FA) and mean diffusivity (MD). Twenty-three square regions of interest of uniform size were positioned on the FA maps and then automatically transferred to the MD maps. FA and MD values in the corpus callosum, left and right putamen, right caudate, left and right pre-frontal cortical area and left supplementary motor area in CD patients differed significantly from those in healthy controls. No significant regional differences were found between patients with BSP and healthy controls. In the CD group, age, duration and severity of dystonia did not correlate with regional FA/MD values, whereas the duration of botulinum toxin treatment correlated significantly with the MD value in the right-pre-frontal cortex. The abnormal DTI findings in patients with CD suggest the presence of brain ultrastructural changes in adult-onset primary CD.

Long-term outcome of renal transplantation from marginal donors.

Long-term survival of kidneys from suboptimal donors is known to be not as good as that from optimal ones. However, the shortage of donors has led many transplant centers to consider accepting older donors with comorbidities. We analyzed 238 patients who received deceased donor renal transplants in the period 2000-2005. The recipients were matched to be no more than 15 years older or younger than the corresponding donors. Among them 125 received a single and 18 a double transplantation from donors considered marginal, according to UNOS criteria for expanded criteria donor (ECD). Most kidneys were evaluated with a pretransplant biopsy, using the scoring system introduced by Karpinski in 1999. The analysis indicated clearly better results in the non-ECD group: both patients and graft survival rates were 10% higher at 1, 2, and 3 years. However, the ECD group showed satisfactory outcomes, confirming the utility of this procedure. The long-term survival rates of single or double grafts from marginal donors are satisfactory, confirming the practice of allocating kidneys after a preimplantation histological evaluation, allowing expansion of the donor pool and providing older patients access to the waiting lists.

Cytomegalovirus infection with multiple colonic perforations in a renal transplant recipient.

Cytomegalovirus (CMV) continues to be potentially the most important pathogen affecting organ transplant recipients. Severe gastrointestinal complications have been reported to occur in about 10% of renal transplant recipients, sometimes with dramatic presentations. We report the case of a 57-year-old CMV-seropositive woman with end-stage renal failure who developed CMV-related colonic multiple perforation 30 days after cadaveric CMV-positive renal transplantation. CMV pp65 antigenemia test and CMV-PCR had always been negative on all the weekly controls routinely performed in the postoperative period. Only after the sudden onset of this complication did the antigenemia and PCR become positive. The relationship between infection and perforation has been established beyond any doubt, as the histology of the resected colonic segment revealed florid CMV infection with evidence of typical inclusions in both macrophages and endothelial cells. Colonic perforations are often fatal in transplant recipients because of inability to contain the perforation, and only a rapid diagnosis and an aggressive surgical treatment can improve the prognosis.

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.

Kidney transplantation from donors aged 65 years or more as single or dual grafts.

AIM: The organ shortage and aging donor population force transplant centers to accept donors previously considered unusable for kidney transplantation. We report the experience of two Italian transplant centers with single (SKTx) and dual (DKTx) kidney transplantation from donors aged 65 years or more. METHODS: The study population comprised 75 SKTx (mean donor age 70.5 years) and 28 DKTx (mean donor age 75.0 years). Kidneys from donors with a calculated admission creatinine clearance <50 mL/min, a Karpinski's score on kidney biopsy between 5 and 7, or both were allocated to DKTx. Grafts with better function or lower biopsy scores were employed for SKTx. RESULTS: Delayed graft function occurred in 45.3% of SKTx and in 39.3% of DKTx. After a mean follow-up period of 30.0 +/- 19.5 months, the acute rejection rate was 24.0% in SKTx and 7.1% in DKTx. Mean serum creatinine was 1.8 +/- 0.9 and 1.8 +/- 1.3 mg/dL in SKTx, and 1.8 +/- 1.6 mg/dL and 1.3 +/- 0.2 mg/dL in DKTx at 1 and 5 years, respectively. Patient survival was 93.3% and 91.2% in SKTx, and 92.9% and 92.9% in DKTx at 1 and 5 years, respectively. Graft survival was 92.0% and 88.3% in SKTx, and 89.3% and 89.3% in DKTx at the same time intervals. Keeping preservation time below 16 hours and avoiding calcineurin inhibitors were both associated with improved graft survival and function. CONCLUSION: Careful donor selection, short preservation time, and tailored immunosuppression allow safe and efficient use of elderly donor kidneys.

Standardized psychological evaluation pre- and posttransplantation: a new option.

A multicenter study was undertaken involving three teams in Italy to obtain a homogeneous psychological evaluation of patients needing organ transplantations. After a preliminary formulation of a common questionnaire individualizing 22 items, yielding a final score from 0 to 44, 294 forms were analyzed for correlations between variables. The sample responses were related to individual variables as well as by cluster analysis to aggregate typical profiles. Clustering of variables was observed in three areas that showed two variables (no. 6, "ongoing psychotic disturbances" and no. 10 "drugs") to be separate. Area 1 ("psychopathology") highlights psychic disturbances, cognitive disorders, and unhealthy behavioral styles; area 2 ("anxia") correlates anxious symptoms to pretransplant examinations and waiting time; area 3 ("depression") ties personal emotional resources and affective factors. Cluster analysis of the sample identified four groups: Group 1 (16.6%) "at risk;" mean score 25.2 (range 16-31); Group 2 (21.7%) "intermediate-at risk," mean score 32 (range 25-38); Group 3 (29.6%) "intermediate-ideal," mean score 35.3 (range 26-40); and Group 4 (31.9%) "ideal candidate," mean score 40.7 (range 36-44). The two "intermediate" groups were studied for mean values for area 1; namely, a cut-off value of 1.78 constituted a better or worse prognostic factor to assign the patient to either Group 2 or 3. Using a uniform method of psychological evaluation before transplantation reduced single operator subjectivity, obtaining comparable results in different transplant centers and allowing planning interventions for at-risk patients.

Surgical endarterectomy for suprarenal iliac artery stenosis in renal allograft recipient.

Aortoiliac surgery performed in renal transplant recipients carries the risk of inducing a prolonged period of ischemia that can threaten organ survival. Recently, endovascular techniques have been increasingly applied but the rate of complications and recurrences remains significant. We report the case of a kidney heterotopic allotransplant recipient who presented with a history of new-onset arterial hypertension, right lower limb claudication, and allograft dysfunction related to a long, eccentric, and ulcerated plaque causing hemodynamic stenosis of suprarenal iliac artery that was successfully managed with surgical endarterectomy. Despite new advances in less invasive procedures such as transluminal angioplasty and stent implantation, surgical endarterectomy of suprarenal iliac artery may be safely performed in selected heterotopic kidney transplant recipients. It allows for complete removal of the plaque, with better long-term results, and does not preclude subsequent endovascular or surgical procedures; therefore it should be considered a therapeutic option in this clinical setting.

Tacrolimus is highly effective in both dual and triple therapy regimens following renal transplantation. Spanish and Italian Tacrolimus Study Group.

This open, multicenter, randomized, parallel-group study evaluated the efficacy and safety of tacrolimus-based dual and triple therapy regimens. For this 3-month study (with 12-month follow up), 491 adult renal transplant patients were randomized and received either dual therapy (tacrolimus/corticosteroids; 246 patients) or triple therapy (tacrolimus/corticosteroids/azathioprine; 245 patients). Patient survival rates at months 3 and 12 were 99.2 (dual) vs 99.6% (triple) and 97.8 vs 98.7%, respectively. Graft survival rates at months 3 and 12 were 94.1 (dual) vs 95.4% (triple) and 92.8 vs 93.3%, respectively. After 3 months, the incidences of treated acute rejection were 28.8 (dual) and 29.7% (triple); and 7.6 (dual) and 5.4% (triple) for corticosteroid-resistant acute rejections. Between months 4 and 12, three new first rejections were reported, (dual: 2, triple: 1). For leukopenia (1.3 vs 11.7%; P < 0.001) and anemia (14.8 vs 23.0%, P = 0.026), significantly higher incidences were reported in the triple therapy group. The incidence of de novo insulin-dependent diabetes was 5.6 (dual) and 4.0% (triple) at month 3. In terms of efficacy, no difference between the treatment groups was observed.

Effects of prolonged exposure to pancreatic glucagon on the function, antigenicity and survival of isolated human islets.

BACKGROUND: Certain clinical conditions are associated with inappropriately high levels of circulating glucagon. To date, little information is available about the direct effects of prolonged exposure of human islet cells to pancreatic glucagon. In the present study we evaluated the function, antigenicity and survival of human islets exposed for 24 h to human pancreatic glucagon. METHODS: We prepared human islets of Langerhans by collagenase digestion and density-gradient purification, incubated them for 24 h with 44 or 430 pmol/l pancreatic glucagon at physiological (5.5 mmol/l) glucose level, and evaluated their insulin release function, which was then compared with that obtained from islets kept at high (11.1 mmol/l) glucose concentration. In addition, aliquots of the islets were evaluated to assess their chemotactic properties towards human monocyte-macrophage cells, and their potency to induce cytokine release from human lymphocytes. Finally, survival of the islet cells cultured under varying conditions was evaluated, and an assessment was performed of mRNA expression of Bcl-2 and Bax proteins. RESULTS: The insulin secretion results demonstrated that, compared to the control islets, the islets previously exposed to either 44 or 430 pmol/l glucagon exhibited changes in insulin release in response to glucose, consisting of augmented secretion at low glucose challenge, and no further significant increase at high glucose stimulation, similar to the effects observed with islets pre-cultured with high glucose. These effects were reversible, as documented by the recovery of normal islet sensitivity to glucose after an additional 24-h culture in medium lacking glucagon. Compared to control islets, the culture medium from islets pre-cultured with high glucagon or high glucose showed an increased chemotactic potency towards human monocyte-macrophage cells. In addition, human lymphocytes released a greater amount of tumour necrosis factor alpha when co-cultured with the islets pre-exposed to high glucagon or high glucose, whereas no significant difference was observed (in comparison with control islets) as regards the release of gamma-interferon, interleukin-2 and interleukin-10. The TUNEL technique and RT-PCR showed, respectively, no major difference in cell survival and expression of mRNA encoding for Bcl-2 and Bax protein between control islets and islets kept for 24 h in the presence of high glucagon or high glucose. CONCLUSIONS: Our results show that in vitro exposure of human islets to pancreatic glucagon for 24 h causes changes in the function and antigenicity of isolated human islets that are similar to the changes observed after pre-culture with increased glucose levels. Under our experimental conditions, these changes were not accompanied by any evidence of cytotoxicity.

Lymphokine release from human lymphomononuclear cells after co-culture with isolated pancreatic islets: effects of islet species, long-term culture, and monocyte-macrophage cell removal.

This study evaluated the release of Th1 and Th2 cytokines from human lymphomononuclear cells (LMC) in response to purified human (HI) or bovine (BI) islets, and the role of long-term (3-4 weeks) islet culture and removal of monocyte-macrophage cells. The results showed that HI and BI caused a similar increase of the release of gamma interferon (IFN), IL-2 and IL-6 from LMC, whereas BI had a more marked effect than HI on IL-10 release. Culturing the islets had possible positive effects (reduction of IFN and IL-2), but also potentially negative effects (increase of TNF). Removal of monocyte-macrophage cells determined a significant reduction of IL-6, IL-10 and TNF production in response to xeno-islets.

Fate of kidneys from the same donor grafted into different recipients: do they behave similarly and are they influenced by donor-related factors?

BACKGROUND: The fate of paired kidneys might be similar and could therefore reflect the influence of donor-related factors on graft outcome. PATIENTS AND METHODS: To verify whether two kidneys retrieved from a single donor and grafted into different recipients have similar short, and middle-term outcomes we investigated the clinical outcome of 103 pairs of cadaveric kidneys grafted into 206 recipients. We evaluated the influence of donor-related factors such as age, sex and cause of death, and of the storage solution and method of harvesting. The incidence of delayed graft function was considered as the short-term outcome and serum creatinine levels at two years as the middle-term outcome. We evaluated the difference from expected frequencies in the incidence of delayed graft function and the incidence of similar serum creatinine levels in each pair of recipients. Univariate analysis of possible risk factors was made by the t-test, chi2 test and Fisher test, as appropriate. Multivariate analysis was done by logistic regression analysis with a forward stepwise variable selection. RESULTS: Delayed graft function was seen in both recipients from the same donor 2.5 times more than the expected frequency (p<0.001). Serum creatinine levels were similar in both recipients with a higher frequency than expected (p<0.01). Multivariate analysis showed that donor-related factors on graft function were age, cause of death and storage solution. CONCLUSIONS: Paired kidneys have similar performances in both the short and the long term. Major donor-related factors in delayed graft function are age and the storage solution. Major donor-related factors in graft function are age and cause of death.

Donor and recipient postoperative complications in living related kidney transplantation. A multicentric study.

BACKGROUND: Living related kidney transplantation is considered a gold standard of renal transplantation in order to overcome end-stage renal disease within the same family members. Living donation, albeit decreasing cadaveric donor shortage, exposes donors to the risk of surgical complications. METHODS: In order to assess the postoperative complication rate in donors and recipients, we reviewed retrospectively 90 consecutive living related kidney transplants in a multicentric study. All nephrectomies were performed extraperitoneally through a left flank incision. RESULTS: Major perioperative complications (first 3 weeks after surgery) occurred in 12 subjects: these included bleeding (2.2%), symptomatic pneumothorax (1.1%), iliac thrombophlebitis (3.3%), iliac artery dissection (1.1%), laparotomic dehiscence (2.2%), perirenal hematoma (1.1%), renal artery stenosis (1.1%), urinary fistula (1.1%). Minor perioperative complications took place in 8 cases. One recipient died. Donor postoperative major complications occurred in 2 subjects. CONCLUSIONS: On the basis of these results we conclude that living related kidney transplantation is an important treatment of end stage renal disease, due to the associated low major complication rate and the high feasibility of this methodology.