A. Yussim

A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients

BACKGROUND A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Cyclosporine, tacrolimus and sirolimus retain their distinct toxicity profiles despite low doses in the Symphony study

BACKGROUND Reducing side effects of immunosuppressive regimens has become a priority in transplantation medicine because of the large number of patients and grafts that succumb to infection in the short term and cardiovascular disease in the long term. The Symphony study was a 12-month prospective, randomized, open-label, multi-centre, four parallel arm study that aimed to evaluate the safety and efficacy of low-dose immunosuppressive regimens compared with a standard-dose regimen in renal transplant recipients. This sub-analysis focuses on specific toxicities observed with the low-dose regimens. METHODS Adult patients (n = 1645) scheduled to undergo renal transplantation received low-dose cyclosporine (CsA), tacrolimus (Tac) or sirolimus (SRL) in addition to daclizumab induction or standard-dose cyclosporine without induction. All patients received mycophenolate mofetil and corticosteroids. We evaluated the incidence of adverse events (AEs), tested specific group differences and assessed the relationship of selected AEs with drug levels. RESULTS The four arms had similar incidences of AEs, but serious AEs were more common with low-dose SRL and led to more discontinuations. Infections were the most common AEs, with the highest incidence in the standard-dose CsA group, in particular, cytomegalovirus (CMV) infections. Low-dose Tac had the most reports of new-onset diabetes, leucopenia and diarrhoea. Low-dose SRL negatively influenced triglycerides, wound healing, lymphocele and anaemia. We found only weak relationships between specific AEs and drug levels. CONCLUSIONS Despite the low doses, CsA, Tac and SRL retained distinct and different toxicity profiles. These findings may be of relevance for tailoring specific immunosuppressive regimens to patients with particular needs.

Increased expression of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy

BACKGROUND The goal of the current study was to examine the potential value of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes in the process of human kidney aging in vivo, and in the development of chronic allograft nephropathy (CAN). METHODS Expression of p16(INK4a) and p27(Kip1) CDKI genes was evaluated and compared in 20 normal human kidney tissues of different ages (range, 21 to 80 years) and in 9 chronically rejected kidney grafts. Age dependency of marker expression was analyzed by the Pearson correlation and linear regression. RESULTS Expression of p16 in cortical tubular (CTS) and interstitial (CIS) cells of normal kidney was age dependent (correlation coefficients: 0.608 and 0.726, 95% confidence interval [CI]: 0.227 to 0.828 and 0.417 to 0.884, respectively). Cortical tubular expression of p27 was also correlated with increasing age (0.672, 95% CI: 0.327 to 0.859). Linear regression analyses confirmed the linearity of marker relationship with age (coefficient of determination R(2):0.370, 0.452, and 0.527 for CIS p16, CTS p27, and CTS p16, respectively). The mean chronological and predicted graft ages (53 +/- 21 and 76 +/- 8.9 years, respectively) were significantly different (P = 0.0126). The glomeruli, tubules, and interstitial cells of rejected grafts expressed significantly higher levels of p16 and p27 than normal kidneys. Expression of p16 in glomerular and cortical interstitial cells was higher in grade 3 of CAN than in grade 2 (P = 0.013 and 0.004, respectively). CONCLUSION The results of the current study show that expression of p16(INK4a) and p27(Kip1) CDKI genes is increased in cortical cells of the aging human kidney and in chronic allograft rejection, supporting the senescence theory of CAN.

Kidney transplantation from living-unrelated donors: comparison of outcome with living-related and cadaveric transplants under current immunosuppressive protocols

OBJECTIVES Living-unrelated donors may become an additional organ source for patients on the kidney waiting list. We studied the impact of a combination of calcineurin inhibitors and mycophenolate-mofetil together with steroids on the outcomes of living-related (LRD), unrelated (LUR), and cadaver transplantation. METHODS Between September 1997 and January 2000, 129 patients underwent LRD (n = 80) or LUR (n = 49) kidney transplantation, and another 173 patients received a cadaveric kidney. Immunosuppressive protocols consisted of mycophenolate-mofetil with cyclosporine-Neoral (41%) or tacrolimus (59%) plus steroids. We compared the patient and graft survival data, rejection rate, and graft functional parameters. RESULTS LRD recipients were younger (33.6 years) than LUR (47.8 years) and cadaver (43.7 years) donor recipients (P <0.001). HLA matching was higher in LRD patients (P <0.001). Acute rejection developed in 28.6% of LUR versus 27.5% of LRD transplants and 29.7% of cadaver kidney recipients (P = not significant). The creatinine level at 1, 2, and 3 years after transplant was 1.63, 1.73, and 1.70 mg% for LRD patients; 1.48, 1.48, and 1.32 mg% for LUR patients; and 1.75, 1.68, and 1.67 mg% for cadaver kidney recipients (P = not significant), respectively. No difference in patient survival rates was found among the groups. The 1, 2, and 3-year graft survival rates were significantly better in recipients of LRD (91.3%, 90.0%, and 87.5%, respectively) and LUR transplants (89.8%, 87.8%, and 87.8%, respectively) than in cadaver kidney recipients (81.5%, 78.6%, 76.3%, respectively; P <0.01). CONCLUSIONS Despite HLA disparity, the rejection and survival rates of LUR transplants under current immunosuppressive protocols are comparable to those of LRD and better than those of cadaveric transplants.

Hepatic artery thrombosis in pediatric liver transplantation: Graft salvage after thrombectomy

Abstract: Hepatic artery thrombosis (HAT) is a devastating complication that may occur after orthotopic liver transplantation (OLT). A higher incidence has been reported in children. Salvage of the graft by thrombectomy has been suggested as an alternative to re‐transplantation. In this study we report the outcome of three children who underwent thrombectomy for HAT. Between January 1992 and June 1998, 14 children (< 17 yrs of age) underwent liver transplantation. Three developed HAT (one a whole‐liver graft recipient, age 17; two living‐related graft recipients, ages 4 and 4.5 yr). In the first patient, thrombosis of the hepatic artery was associated with scattered areas of parenchymal necrosis on computed tomography. In the two living‐related patients, HAT was found incidentally during re‐exploration for bleeding (day 2 and day 10). Thrombectomy was performed in all three patients. At 18–24 months after thrombectomy, all three children had normal graft function. In the first patient, complete regeneration of the liver has been documented by computed tomography and a late asymptomatic recurrent thrombosis is suggested by absence of arterial flow on Doppler examination. The hepatic artery is patent in the two living‐related recipients. One of these living‐related recipients developed ischemic bile duct stricture and underwent successful percutaneous balloon dilatation. We conclude that long‐term normal graft function can be achieved by thrombectomy in pediatric liver recipients with HAT, even in the presence of limited parenchymal damage.

Serum cholestasis markers as predictors of early outcome after liver transplantation

Abstract:  Background:  Early cholestasis is not uncommon after liver transplantation and usually signifies graft dysfunction. The aim of this study was to determine if serum synthetic and cholestatic parameters measured at various time points after transplantation can predict early patient outcome, and graft function.

BK polyoma virus nephropathy in kidney transplant recipient: the role of new immunosuppressive agents.

BK POLYOMA virus (BKV) is a newly described agent causing renal dysfunction and failure among kidney transplant recipients. The virus remains latent following primary exposure at childhood and becomes activated in immunocompromised states. Clinically, the virus rarely causes symptoms such as hemorrhagic cystitis in bone marrow transplant recipients. Although viral shedding is detected in urine specimens of many renal transplant recipients, only a few will develop BKV transplant nephropathy. This disease process is characterized by a rapidly progressive loss of graft function. Introduction of new and more aggressive immunosuppressive protocols may explain the emergence of this new infectious complication. We describe our experience with 7 patients with BKV nephropathy with specific attention to possible risk factors.

Nonfunctioning renal allograft embolization as an alternative to Graft nephrectomy: Report on seven years' experience

Purpose: Graft nephrectomy is the treatment of choice in patients with graft intolerance syndrome, but it is associated with high morbidity and mortality rates. Renal vascular embolization has been suggested as a possible alternative. The aim of this study was to evaluate the efficacy and safety of arterial embolization of these nonfunctioning transplanted kidneys. Methods: Twenty-six transplanted kidneys in 25 patients with irreversible renal graft rejection and graft intolerance who underwent arterial embolization at our center from August 1994 to April 2001 were analyzed for procedural success and long-term outcome. Embolization was performed with absolute alcohol or with polyvinyl alcohol (Ivalon) and coils. Results: Twenty-four of the 26 (92%) procedures were technically successful, but in one patient only partial occlusion of one of two renal arteries was achieved, and in another the renal artery was already completely occluded. There were two major complications: emphysematous pyelonephritis necessitating nephrectomy and groin abscess that was drained. Follow-up ranged from 8 to 84 months. Clinical success was achieved in 24 of the 26 procedures (92%), and only in one patient did embolization fail to relieve the symptoms, and nephrectomy was performed 3 months later. Conclusion: Renal vascular embolization is a simple, safe and effective technique for the treatment of nonfunctioning renal allografts associated with graft intolerance syndrome. We suggest that it be considered the treatment of choice.

New Immunosuppressive Agents for Maintenance Therapy in Organ Transplantation

SummaryTraditional cyclosporin-based immunosuppressive protocols are associated with relatively high incidences of early acute rejection and late graft loss due to chronic rejection. In addition, long-term immunosuppression with cyclosporin and corticosteroids has been associated with significant metabolic, infectious, malignant and cosmetic adverse effects. In the last decade, the goals of immunosuppression strategies have included not only short-term survival but also graft acceptance, with a low incidence of early acute rejection and minimal long-term toxicity.Tacrolimus and mycophenolate mofetil are 2 new immunosuppressive agents that have recently been approved for use. The mechanism of action and toxicity profile of tacrolimus are similar to that of cyclosporin. Tacrolimus reduces early acute rejection and is also effective in salvage of allografts with refractory rejection. A wide spectrum of adverse effects, including nephrotoxic, neurotoxic, gastrointestinal, metabolic and hematological effects, has been reported in association with tacrolimus but, unlike cyclosporin, this agent is not associated with hirsutism or gingival hyperplasia. Mycophenolate mofetil, an antimetabolite, has been effective in reducing early acute rejection and in treatment of refractory rejection when used in combination with cyclosporin instead of azathioprine. Its myelosuppressive and gastrointestinal toxicities are mild and reversible, but it may be associated with an increased risk of infections. Both agents permit early corticosteroid withdrawal.Other new immunosuppressive agents that act on different stages of the cell cycle but that have not yet been introduced for wide clinical use, including sirolimus (rapamycin), brequinar, mizoribine and gusperimus, are also discussed in this review

Single-bolus high-dose ATG for prophylaxis of rejection in renal transplantation--a prospective, randomized study.

Abstract Currently, most centers use antithymocyte globulin (ATG) for induction or treatment of acute rejection. In the literature, postponement of introduction of cyclosporin or delay in acute rejection following ATG induction are well documented [1‐4]. In contrast, data are very scant on the reduction of incidence of rejection or improvement of graft survival following ATG prophylaxis [5, 6]. The objective of this study was to compare the efficacy and safety of ATG high‐dose single‐bolus therapy with that of a standard cyclosporine‐based protocol in prophylaxis of acute rejection in renal transplantation in an adult population. Rabbit ATG (Fresenius, Oberursel) was administered intraoperatively (before revascularization) to 19 renal transplant recipients as a single intravenous injection in a dose of 9 mg/kg body weight (high dose, single bolus). Treatment results were compared with those of a control group comprising 19 recipients receiving the same cyclosporin‐Neoral‐based protocol as the study group. In all patients concomitant medication consisted of steroids and azathioprine. The incidence of acute rejection in the high‐dose ATG bolus group was 26%, compared with 58% in controls (P < 0.05). In the ATG treated group no grafts were lost to acute rejection in both high‐and low‐risk recipients, versus compared with a loss of 37% of rejecting grafts in controls. Though the observed difference in 1‐year graft survival between study and control groups (84.2% vs 73.6%) did not reach statistical significance, the same trend was also observed in patients (n = 9 and n = 12 respectively) who, at he time of this report, had completed a 2nd post‐transplantation year. The bolus and control groups had a similar incidence of complications and comparable renal function. We conclude that a single‐bolus high‐ATG protocol is efficient and safe in prophylaxis of renal allograft rejection.