HCV-positive kidney transplant patients treated with direct-acting antivirals maintain stable medium-term graft function despite persistent reduction in tacrolimus trough levels.

Background/aim: Direct-acting antivirals (DAAs) have improved the treatment of HCV-positive kidney transplant recipients (KTRs). However, their medium-term follow-up effects on graft function are conflicting. This study aimed to analyze how the interplay between DAAs, calcineurin inhibitors (CNI), and HCV eradication impacts 12-month kidney graft function. Methods: This double-center retrospective study with a prospective follow-up enrolled 35 KTRs with HCV treated with DAAs for 12 weeks. We compared three parameters: estimated glomerular filtration rate (eGFR), 24-h proteinuria, and CNI trough levels at three time points: baseline, end of treatment (EOT), and 12 months later. Results: Kidney allograft function remained stable when comparing baseline and 12-month post-treatment values of eGFR (60.7 versus 57.8 ml/min; p = 0.28) and 24-h proteinuria (0.3 versus 0.2 g/24 h; p = 0.15), while tacrolimus (Tac) trough levels underwent a statistically significant decline (6.9 versus 5.4 ng/ml; p = 0.004). Using an ongoing triple Tac-based maintenance therapy as a conservative measure, a dose escalation of Tac was applied only in seven patients. No variation in CyA and mTOR levels was detected. Conclusion: DAA therapy is safe and effective in HCV-positive KTRs. It also produces a persistent significant reduction in Tac trough levels that does not influence graft function at 12 months.

Management of patients with a failed kidney transplant: what should we do?

The number of kidney transplant recipients returning to dialysis after graft failure is steadily increasing over time. Patients with a failed kidney transplant have been shown to have a significant increase in mortality compared with patients with a functioning graft or patients initiating dialysis for the first time. Moreover, the risk for infectious complications, cardiovascular disease and malignancy is greater than in the dialysis population due to the frequent maintenance of low-dose immunosuppression, which is required to reduce the risk of allosensitization, particularly in patients with the prospect of retransplantation from a living donor. The management of these patients present several controversial opinions and clinical guidelines are lacking. This article aims to review the leading evidence on the main issues in the management of patients with failed transplant, including the ideal timing and modality of dialysis reinitiation, the indications for an allograft nephrectomy or the correct management of immunosuppression during graft failure. In summary, retransplantation is a feasible option that should be considered in patients with graft failure and may help to minimize the morbidity and mortality risk associated with dialysis reinitiation.

Recurrent urinary tract infections in kidney transplant recipients during the first-year influence long-term graft function: a single-center retrospective cohort study.

Urinary tract infections (UTIs) after kidney transplantation are associated with significant morbidity. However, data on the impact of UTI on graft survival are controversial. We conducted a retrospective cohort study of 380 kidney transplant patients. Recipients with symptomatic UTIs during the first year after transplantation were categorized into three groups: early (< 3 episodes from months 1st to 6th), late (< 3 episodes during months 7th to 12th) and recurrent (≥ 3 episodes throughout the whole first year). Graft function at three years was considered the primary outcome. Symptomatic UTIs occurred in 184 (48.4%) kidney transplant recipients during the first year; 83 (21.8%) patients developed early UTIs, 50 (13.2%) late UTIs and 51 (13.4%) recurrent UTIs. We observed a significant improvement in graft function after three years in all patients (P < 0.001) except those who had recurrent UTIs. A Kaplan-Meier analysis showed that recipients with recurrent UTIs had worse graft outcome (eGFR value < 60 mL/min/1.73 m2) (P = 0.01). Recurrent UTIs was an independent predictor of graft function at three years in a model adjusted for DGF and episodes of acute rejection (Hazard Ratio, 2.2; 95% CI, 1.3 to 3.5; P = 0.001). Recurrent symptomatic UTIs during the first year after transplantation have negative impact on long-term graft function.

Updates on urinary tract infections in kidney transplantation.

Urinary tract infection (UTI) represents the most common infection after kidney transplantation; it is associated with an increased risk for acute kidney rejection and impaired graft function in the early post-transplant period. Kidney transplant recipients with UTIs are often clinically asymptomatic due to the immunosuppressive therapy; however, asymptomatic bacteriuria may progress to acute pyelonephritis, bacteremia and urosepsis, particularly in the early post-transplant period, that are independent risk factors for short and long-term graft and patient survival. This article reviews the definitions, incidence, risk factors and the management of UTI in kidney transplant recipients; furthermore, the main controversial and still unanswered questions, regarding the causes of recurrent UTIs, adequate use of antibiotics to avoid antibiotic resistance, dosing and timing for prophylaxis and treatment of symptomatic infections, are also discussed. The emerging definition of urinary microbiota introduces new concepts in understanding the complexity of the disease and might represent the future target for therapeutic interventions.

A single-center cohort study to define the role of pretransplant biopsy score in the long-term outcome of kidney transplantation.

BACKGROUND: The role of pretransplant biopsy in defining the quality of kidney grafts is still debated. The aim of this study was to investigate the influence of pretransplant biopsy score on long-term graft outcome. METHODS: In a retrospective cohort study, we analyzed 372 recipients of single kidney transplantation (SKT) from deceased donors between 1997 and 2007, with an available pretransplant biopsy. We evaluated 5- and 10-year graft survival, incidence of delayed graft function, and estimated glomerular filtration rate at 1 and 5 years. RESULTS: Graft survival at 5 and 10 years was significantly better for recipients with a score of 0 compared to transplants with a score of 1 to 5, whereas we did not observe any significant difference among transplants with a score of 1 through 4. Survival of kidneys with a score of 5 was significantly worse compared to grafts with a score of 1 to 4. In a multivariate Cox model, only pretransplant histological score was significantly associated with graft survival. Transplants with a score of 0 and 5 had the best and the worst graft function, respectively, both at 1 and 5 years, whereas we did not observe any difference among patients with a score of 1 through 4. In a multivariate logistic regression, pretransplant histological score was independently associated with the prevalence of an estimated glomerular filtration rate less than 30 mL/min at 5 years. Finally, delayed graft function rate was significantly higher in recipients with a score of 5 compared to patients with a score of 1 to 4 and score of 0. CONCLUSIONS: Our data suggest that 1) pretransplant histological score may predict long-term graft outcome and 2) allocation of kidneys with a score of 4 to SKT provides an acceptable long-term graft function and survival.

Increasing relevance of donor-specific antibodies in antibody-mediated rejection.

One of the major concerns in organ transplantation is the early detection of humoral rejection, through improved diagnostic and prognostic biomarkers. Long-term survival of renal allografts is significantly lower in recipients developing donor-specific anti-HLA antibodies (DSAs) either pretransplant or posttransplant. Patients can form antibodies following blood transfusions, pregnancies or previous transplants. DSAs can lead to endothelial damage through complement-dependent or independent pathways. Universal testing of kidney transplant patients and careful monitoring of graft function if DSAs are detected are recommended. Since there are different techniques to detect DSAs presence and serum levels, nephrologists have to face challenges in their interpretation due to variable sensitivity and specificity. Moreover, other biomarkers of rejection (T-cell reactivity, gene expression pattern modulation, early features of immunological damage in protocol renal biopsies) may be adopted together with DSAs detection tools, thus providing a global approach to the issue. To date, however, there are no well-defined strategies of intervention in cases of humoral graft damage. Future resolution of both interpretative and therapeutic concerns will make DSAs monitoring a very effective way to predict incoming immunological events. Therefore, an operative protocol for DSAs detection in renal recipients has been illustrated.

The European Union Interreg Program: Italian-Albanian experience with kidney transplants.

INTRODUCTION: A collaboration between the Regional Health Agency of Puglia (ARES), the Italian Ministry of Health and the Albanian Ministry of Health, was realized in 2008. One of the areas of interest was to promote the performance of kidney transplants in Albania by Albanian medical staff, funded with nearly 2 million euros. The program included two major goals: to transmit the required know-how to health care staff and to upgrade the Albanian facilities and equipment to the standards necessary for successful transplantation. MATERIALS AND METHODS: During the year 2008, two couples of Albanian patients were transplanted at the Department of Emergency and Organ Transplantation-Urology Unit in Bari, Italy. The surgical procedures were performed by mixed surgical teams, with the active participation of Albanian medical staff under the guidance of the Italian colleagues. The first kidney transplant was performed at the end of January 2008 and the second in June 2008. Both surgical procedures and post-transplant periods were clinically uneventful. RESULTS: After returning to Albania the trained team started to carry out team-work, preparing the patients for the first kidney transplantation. The first donor-patient couple was prepared for kidney transplantation at the end of 2008. On the 26th March 2009 the first kidney transplant was performed by the Albanian medical team, with the active participation of 2 Italian urologists from the University of Bari. CONCLUSIONS: Appropriate training, equipment, and infrastructure are necessary to build a rational, functional national system for organ transplantation. Continuous exchange of ideas and data on kidney transplantation between Albania and Italy will probably contribute to extend such forms of cooperation to the western Balkans in the near future.

Immunohistochemical characterization of glomerular and tubulointerstitial infiltrates in renal transplant patients with chronic allograft dysfunction.

BACKGROUND: The term chronic allograft nephropathy (CAN) was deleted in the Eighth Banff Classification and two new categories were introduced: chronic T-cell-mediated rejection (CTMR) and chronic active humoral rejection (CAHR). The aim of this study was to revise our CAN cases diagnosed in the last 4 years, analyse allograft survival rates and identify types of infiltrating cells in the different settings. METHODS: Seventy-nine patients with biopsy-proven CAN were examined and classified into four groups according to the Banff 2005 criteria: CTMR, CAHR, chronic calcineurin inhibitor toxicity (CNITOX) and interstitial fibrosis and tubular atrophy not otherwise specified (NOS). CD4, CD8, CD20, CD68, CD103, Foxp3 and IL-17 protein expression and C4d deposits were investigated. RESULTS: We diagnosed 20 CTMR, 13 CAHR, 28 CNITOX, and 18 NOS. Death-censored graft survival at 4 years from renal biopsy was worse in CAHR compared with the other types of chronic injury. Glomerular CD8(+) cells were increased in CTMR vs CNITOX and NOS. Interstitial CD4(+) and CD8(+) cells were increased in CTMR vs CNITOX. CD68(+) cells in glomerular and peritubular capillaries were higher in CAHR vs CNITOX, CTMR and NOS. CD103(+) cells were higher in cases with tubulitis than in those without. T regulatory and T helper 17 cells were rarely observed in the different settings. CONCLUSIONS: Graft survival was worse in patients with CAHR. The presence of any grade transplant glomerulopathy and chronic allograft vasculopathy are poorer prognostic factors. Infiltrating CD8(+), CD103(+) and CD4(+) cells may help to differentiate CTMR from other types of chronic injury, thus improving diagnostic/prognostic features of biopsy in patients with chronic allograft dysfunction.

[Selection and follow-up of living donor kidney transplant recipients]. / Selezione e follow-up del ricevente di trapianto di rene da donatore vivente.

The objectives of pre-transplant assessment are: a) to ensure that transplantation is technically possible; b) to ensure that the recipient's chances of survival are not compromised by transplantation; c) to ensure that graft survival is not limited by premature death; d) to ensure that pre-existing conditions are not exacerbated by transplantation; e) to identify measures to be taken to minimize perioperative and postoperative complications; f) to inform patients of the likely risks and benefits of transplantation. During the long-term follow-up of living donor kidney transplant recipients, clinicians have to pay attention to the possible recurrence of the primary renal disease, to the identification and, if possible, prevention of noncompliance, and, finally, to immunological monitoring.

Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is characterized by deposition of extracellular matrix (ECM) in all renal compartments. PAI-1 seems to play a pivotal role in ECM turnover in CAN. Rapamycin has been shown to improve long-term graft survival in patients with CAN. The aim of the study was to evaluate the molecular mechanisms underlying the beneficial effects of rapamycin on CAN progression at glomerular and tubulointerstitial level. METHODS: After a biopsy-proven CAN diagnosis (T0), 18 patients on calcineurin inhibitors (CNI) were randomly assigned in a 2:1 ratio to continue CNI (6 patients) or to receive rapamycin (RAPA; 12 patients). After 2 years of treatment (T24), all patients underwent a second renal biopsy. Morphometric analysis was conducted at T0 and at T24. PAI-1 expression was evaluated at T0 and T24 by immunohistochemistry. We evaluated the effect of rapamycin on PAI-1 gene expression in cultured proximal tubular cells incubated with CD40L or thrombin, two potential CAN pathogenic mediators. RESULTS: The RAPA group showed a significant regression of glomerulosclerotic lesions and only a 26% increase in interstitial fibrosis after 2 years compared to baseline, whereas the CNI group showed progression of glomerulosclerosis and 112% increase in fibrosis. Glomerular and tubulointerstitial PAI-1 expression was reduced compared to the baseline in the RAPA group, while they were unchanged in the CNI group. In vitro data showed that rapamycin significantly reduced PAI-1 gene expression induced by both CD40L and thrombin in proximal tubular epithelial cells. CONCLUSIONS: These data suggest that rapamycin may modulate ECM deposition in CAN reducing PAI-1 expression.

The treatment of chronic hepatitis C with peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed patients awaiting renal transplant.

BACKGROUND/AIMS: We undertook a pilot study to investigate the efficacy and safety of peginterferon alfa-2a (40 kDa) plus ribavirin in haemodialysed chronic HCV patients awaiting renal transplant. METHODS: Patients received peginterferon alfa-2a 135 microg/week plus ribavirin 200 mg/day for 24 or 48 weeks (genotype non-1 and 1, respectively). The dose of ribavirin was tailored according to plasma concentrations and to haemoglobin levels. Outcomes in treated patients were compared with those of a matched untreated control group. RESULTS: Thirty-five patients received treatment, while 35 served as untreated controls. Thirty patients completed treatment; patients were withdrawn due to transplantation (n=2), severe anaemia (n=1), dermatitis (n=1) and non-response (n=1) resulting in a drop-out rate of 14%. Overall, 34/35 treated patients were HCV RNA negative at week 4 and had undetectable RNA at the end of treatment, compared with none of the untreated controls (ETR 97% vs 0%; p<0.001). Moreover, all achieved sustained virological response after 24 weeks of treatment-free follow-up versus no control patients (SVR 97% vs 0 %; p<0.001). CONCLUSIONS: In this study, we have shown for the first time in a large cohort of patients that HCV-patients on haemodialysis can be treated successfully with peginterferon alfa-2a (40 kDa) plus ribavirin.

Sirolimus interferes with iron homeostasis in renal transplant recipients.

BACKGROUND: Sirolimus is an immunosuppressive drug whose use is frequently associated with anemia. A pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we investigated whether sirolimus may influence iron homeostasis and serum levels of hepcidin, a key mediator of inflammation-related anemia. METHODS: To this purpose, 42 consecutive transplanted patients with biopsy-proven chronic allograft nephropathy were randomized (2:1 ratio) to receive either a 40% cyclosporine reduction (group A, 14 patients) or immediate cyclosporine withdrawal and sirolimus introduction (group B, 28 patients). Hemoglobin levels and iron status were evaluated 6 months before and after randomization. RESULTS: The two groups had similar hemoglobin levels and iron status at baseline. We did not observe any significant change in hemoglobin and iron status in group A patients after randomization. On the contrary, we observed a significant reduction of hemoglobin without any change of red blood cell count after sirolimus introduction, with a significant reduction of mean corpuscular volume and mean corpuscular hemoglobin. Serum iron and transferrin saturation (TSAT) levels were markedly reduced after the switch, while ferritin serum concentrations remained stable. Although sirolimus-induced anemia was recently suggested to resemble inflammation-related anemia, hepcidin serum levels were similar in the two groups after randomization. None of group A and eight of group B patients presented a TSAT <20 and were given iron supplementation after randomization, in all of them oral iron therapy did not influence either hemoglobin or serum iron levels. CONCLUSION: We demonstrated that sirolimus-induced anemia is independent of the drug antiproliferative effect and does not present the features of inflammation-related anemia. This event may be due to the direct influence of sirolimus on iron homeostasis.

Rapamycin for treatment of chronic allograft nephropathy in renal transplant patients.

Chronic allograft nephropathy (CAN) represents the main cause of renal allograft loss after 1 yr of transplantation. Calcineurin inhibitor (CNI) use is associated with increased graft expression of profibrotic cytokines, whereas rapamycin inhibits fibroblast proliferation. The aim of this randomized, prospective, open-label, single-center study was to evaluate the histologic and clinical effect of rapamycin on biopsy-proven CAN. Eighty-four consecutive patients who had biopsy-proven CAN and received a transplant were randomized to receive either a 40% CNI reduction plus mycophenolate mofetil (group 1; 50 patients) or immediate CNI withdrawal and rapamycin introduction with a loading dose of 0.1 mg/kg per d and a maintaining dose aiming at through levels of 6 to 10 ng/ml (group 2; 34 patients). The follow-up period was 24 mo. At the end of follow-up, 25 patients (group 1, 10 patients; group 2, 15 patients) underwent a second biopsy. CAN lesions were graded according to Banff criteria. alpha-Smooth muscle actin (alpha-SMA) protein expression was evaluated in all biopsies as a marker of fibroblast activation. Graft function and Banff grading were superimposable at randomization. Graft survival was significantly better in group 2 (P = 0.0376, chi2 = 4.323). CAN grading worsened significantly in group 1, whereas it remained stable in group 2. After 24 mo, all group 1 biopsies showed an increase of alpha-SMA expression at the interstitial and vascular levels (P < 0.001); on the contrary, alpha-SMA expression was dramatically reduced in group 2 biopsies (P = 0.005). This study demonstrates that rapamycin introduction/CNI withdrawal improves graft survival and reduces interstitial and vascular alpha-SMA expression, slowing down the progression of allograft injury in patients with CAN.

Sirolimus for Kaposi's sarcoma in renal-transplant recipients.

BACKGROUND: Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treatment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects. METHODS: We stopped cyclosporine therapy in 15 kidney-transplant recipients who had biopsy-proven Kaposi's sarcoma and began sirolimus therapy. All patients underwent an excisional biopsy of the lesion and one biopsy of normal skin at the time of diagnosis. A second biopsy was performed at the site of a previous Kaposi's sarcoma lesion six months after sirolimus therapy was begun. We examined biopsy specimens for vascular endothelial growth factor (VEGF), Flk-1/KDR protein, and phosphorylated Akt and p70S6 kinase, two enzymes in the signaling pathway targeted by sirolimus. RESULTS: Three months after sirolimus therapy was begun, all cutaneous Kaposi's sarcoma lesions had disappeared in all patients. Remission was confirmed histologically in all patients six months after sirolimus therapy was begun. There were no acute episodes of rejection or changes in kidney-graft function. Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells. The expression of VEGF was increased in Kaposi's sarcoma cells and even more so in normal skin cells around the Kaposi's sarcoma lesions. CONCLUSIONS: Sirolimus inhibits the progression of dermal Kaposi's sarcoma in kidney-transplant recipients while providing effective immunosuppression.

Conversion to C2 monitoring of cyclosporine A exposure in maintenance kidney transplant recipients: results at 3 years.

BACKGROUND: It has been suggested that conversion from monitoring cyclosporine A (CsA) trough level to the level 2 hours after the morning dose (C2 ) may have clinical benefits in maintenance adult renal transplant recipients, but evidence supporting such a suggestion presently is very limited. METHODS: We enrolled 188 maintenance patients to investigate the clinical impact of the adjustment of CsA dose according to C2 levels over 3 years (target, 800 ng/mL). RESULTS: Patient and graft survival rates were 100% and 98.4%, respectively. C2 monitoring led to a reduction in CsA dose in 49.4% of patients and an increase in more than 20% of patients without an increase in acute rejection risk and clinically overt nephrotoxicity. Patients in the greatest quartile of C2 levels showed the lowest serum creatinine levels (P = 0.009), the greatest creatinine clearance values (P = 0.0006), and the lowest prevalence of chronic allograft nephropathy (P = 0.01). By means of multivariate analysis, C2 levels were the most relevant independent predictors of graft deterioration (change in serum creatinine level from baseline to end of study > or =0.5 mg/dL [> or =44 micromol/L]). Receiver operating characteristic analysis showed an inflection point of mean C2 level versus risk for graft deterioration at less than 661 ng/mL. CONCLUSION: In maintenance renal transplant recipients, conversion to C2 monitoring is a seemingly safe option with good graft performance after 3 years. Mean C2 levels greater than 661 ng/mL seem to be associated with better long-term graft function and a lower prevalence of biopsy-proven chronic allograft nephropathy, at least during a 3-year follow-up.

Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin.

Ischemia-reperfusion (I-R) injury in transplanted kidney, a key pathogenic event of delayed graft function (DGF), is characterized by tubular cell apoptosis and interstitial inflammation. Akt-mammalian target of rapamycin-S6k and NF-kappaB-inducing kinase (NIK)-NF-kappaB axis are the two main signaling pathways regulating cell survival and inflammation. Rapamycin, an immunosuppressive drug inhibiting the Akt axis, is associated with a prolonged DGF. The aim of this study was to evaluate Akt and NF-kappaB axis activation in patients who had DGF and received or not rapamycin and in a pig model of I-R and the role of coagulation priming in this setting. In graft biopsies from patients who were not receiving rapamycin, phosphorylated Akt increased in proximal tubular, interstitial, and mesangial cells with a clear nuclear translocation. The same pattern of activation was observed for S6k and NIK. However, in rapamycin-treated patients, a significant reduction of S6k but not Akt and NIK activation was observed. A time-dependent activation of phosphatidylinositol 3-kinase, Akt, S6k, and NIK was observed in the experimental model with the same pattern reported for transplant recipients who did not receive rapamycin. Extensive interstitial and glomerular fibrin deposition was observed both in pig kidneys upon reperfusion and in DGF human biopsies. It is interesting that the activation of both Akt and NIK-NF-kappaB pathways was induced by thrombin in cultured proximal tubular cells. In conclusion, the data suggest that (1) coagulation may play a pathogenic role in I-R injury; (2) the Akt axis is activated after I-R, and its inhibition may explain the prolonged DGF observed in rapamycin-treated patients; and (3) NIK activation in I-R and DGF represents a proinflammatory, rapamycin-insensitive signal, potentially leading to progressive graft injury.

Cyclosporin exposure correlates with 1 year graft function and histological damage in renal transplanted patients.

BACKGROUND: Cyclosporin (CsA) level obtained 2 h after the morning dose (C(2)) has been shown to accurately predict total CsA exposure and acute rejection (AR) risk, whereas conventional trough levels (C(0)) do not. The impact of C(2) monitoring on long-term kidney graft function, independent from AR risk, is still unclear, however, and it was assessed in the present study. METHODS: We enrolled 39 CsA-treated renal transplant recipients and used 1 year graft function and histological structure as surrogate markers of graft outcome. CsA dose was adjusted according to C(2) levels. RESULTS: In the first 7 days after grafting, 40-51% of patients failed to reach target C(2) levels; nevertheless, at 1 year the incidence of AR was only 2.5% and graft and patient survival was 100%. The decrease of serum creatinine (12-6 months) was associated with significantly higher C(2) levels over time (P = 0.0003) and lower intrapatient variability of CsA relative absorption (CV) (P = 0.0006). One year graft biopsy showed chronic tubulointerstitial lesions in 54.5% of patients. Both C(2) mean levels and the percentage CV independently predicted the severity of chronic histological lesions (R = 0.69, P<0.0001). CONCLUSIONS: Higher C(2) levels, within the proposed target range values, seem to be associated with better renal function and structure.

Addition of sirolimus to cyclosporine delays the recovery from delayed graft function but does not affect 1-year graft function.

Delayed graft function (DGF) has long been identified as one of the main correlates of poor graft survival in cadaveric renal transplantation, but the factors that affect its onset and duration are not fully elucidated. The impact of two immunosuppressive protocols on the incidence and length of DGF among kidney transplant recipients of a suboptimal organ was evaluated. Patients were randomly treated with corticosteroids (CS); low-dose cyclosporine (CsA) and sirolimus (SRL; group 1; n = 42); or CS, full-dose CsA, and mycophenolate mofetil (group 2; n = 48). All recipients received immunoprophylaxis with basiliximab. After 3 mo, group 1 discontinued CsA and continued with SRL, whereas group 2 continued the same treatment. The incidence of DGF was similar in the two groups (group 1 = 52.4%; group 2 = 58.3%), whereas its duration was significantly higher in the group 1 (19.0 +/- 6.0 versus 10.3 +/- 3.2 d; P = 0.001). Both groups showed 100% actuarial graft and patient survival at 1-yr. Among DGF patients, serum creatinine (sCr) at discharge was significantly worse in group 1 (sCr, 3.0 +/- 1.0 versus 1.5 +/- 0.2 mg/dl; calculated creatinine clearance, 31.2 +/- 9.3 versus 61.1 +/- 10 ml/min; P = 0.001). During the first year, the former group displayed a significant improvement of graft function, such that at 1-yr, no difference could be measured between groups (sCr, 1.8 +/- 0.5 versus 1.7 +/- 0.4 mg/dl; calculated creatinine clearance, 51.5 +/- 10.2 versus 53.3 +/- 9.4 ml/min). In conclusion, in de novo renal transplanted patients, the administration of SRL, in combination with low-dose CsA, is associated with a delayed recovery from DGF but does not worsen 1-yr graft function.

Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients.

BACKGROUND: Chronic allograft nephropathy (CAN) represents the most common cause of late graft loss. Nephrotoxicity from chronic use of calcineurin inhibitors (CNI) has the potential to contribute to CAN. The present investigation aimed to evaluate the impact of early CNI withdrawal on kidney graft function and structure at 1 year in sirolimus (SRL)-treated patients. METHODS: Forty consecutive kidney transplant recipients were initially treated with corticosteroids, cyclosporine A (CsA), and SRL (2 mg/day). After 3 months, patients were randomly assigned to either continue the same treatment (group I) or to withdraw CsA and continue SRL (group II). All patients underwent kidney graft biopsy immediately after graft reperfusion (0-hr biopsy) and 12 months after engraftment. RESULTS: Baseline graft biopsy showed a higher degree of renal damage in group II patients (total score, 4+/-1.6 vs. 2+/-0.9; P<0.05). Twelve months after engraftment, CAN was diagnosed in 55% of all patients, of whom 64% were in group I and 36% in group II. CAN lesions were scored as moderate to severe in 90% of group I patients but only 32% of group II patients (P<0.05). A vascular score greater than or equal to 2 occurred in 90% of group I patients and in 38% of group II patients (P<0.05). At 1 year, group I patients showed a significantly worse kidney graft function (serum creatinine, 2.0+/-0.3 vs. 1.3+/-0.3 mg/dL; creatinine clearance, 54+/-14 vs. 66+/-17 mL/min; both P<0.002). CONCLUSIONS: These results suggest that early withdrawal of CsA is a safe option, which allows a significant reduction of chronic histologic damage, particularly vascular injury, of cadaveric kidney allografts.