Risk Of Chronic Allograft Nephropathy Research Articles

DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway

Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end‐stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft‐stable cohort, patients who experienced AR‐induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft‐related inflammatory injuries. These results revealed that changes in methylation accompany AR‐induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival.

Current evidence on vitamin D deficiency and kidney transplant: What's new?

Kidney transplant is the treatment of choice for end-stage chronic kidney disease. Kidneys generate 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D (calcidiol) for circulation in the blood to regulate calcium levels. Transplant patients with low calcidiol levels have an increased risk of metabolic and endocrine problems, cardiovascular disease, type 2 diabetes mellitus, poor graft survival, bone disorders, cancer, and mortality rate. The recommended calcidiol level after transplant is at least 30ng/mL (75nmol/L), which could require 1000-3000IU/d vitamin D3 to achieve. Vitamin D3 supplementation studies have found improved endothelial function and acute rejection episodes. However, since kidney function may still be impaired, raising calcidiol levels may not lead to normal calcitriol levels. Thus, supplementation with calcitriol or an analog, alfacalcidiol, is often employed. Some beneficial effects found include possible improved bone health and reduced risk of chronic allograft nephropathy and cancer.

Delayed kidney graft function: from mechanism to translation

In as many as 50% of cases the immediate post-kidney transplant course is complicated by delayed graft function that is most commonly related to ischemia and reperfusion injury. In addition to the acute complications related to renal failure and the associated economic impact of prolonged hospitalization, the development of delayed graft function is associated with an increased risk of chronic allograft nephropathy and shortened allograft survival. Challenges in understanding its mechanisms include the complexity, as contributors are derived from both the donor and the recipient. This acute kidney injury is modulated and caused by a complex interplay of events that lead to hypoxic and ischemic injury as well as to altered repair mechanisms. New therapies primarily seek to suppress the inflammatory homing of adaptive immune cells to the kidney, limit cell death, and/or interrupt detrimental signaling of necrosis. Although there are several promising novel targets and innovative therapeutics available, many challenges remain in their translation from bench to bedside. Identifying organs at risk and clearly defined end points will be critical in designing interventional trials.

Immunosuppression (IST) Can Be Safely Ceased During Chemotherapy For Post-Transplant Lymphoproliferative Disorders (PTLD) In Renal Transplant Patients

IntroductionThe optimal reduction of IST in renal transplant patients with PTLD is uncertain. As chemotherapy used to treat PTLD is inherently immunosuppressive, IST may be able to be stopped during this time without compromising graft function. Subsequent long-term reduction of IST is important to reduce PTLD relapse, but may increase long-term risk of graft rejection. MethodsWe performed a retrospective matched cohort study of adult renal transplant patients where IST was ceased during chemotherapy and then resumed at lower dose (calcineurin inhibitor at 50%, prednisolone <6mg daily, no third agent). Outcomes were compared to renal transplant patients without PTLD, matched for creatinine at the equivalent time post-transplant that PTLD was diagnosed in the cases, as well as age, gender, year of transplant and age at transplant. The primary endpoint of time to renal deterioration, defined as the time from PTLD diagnosis (cases) or study entry (controls) to a 25% increase in creatinine, was analysed using competing risk survival analyses. Additional endpoints were time to renal allograft failure requiring dialysis or re-transplant and overall survival. Results24 cases were identified: median age at PTLD diagnosis 45yrs; 75% male; median time to onset of PTLD post-transplant was 9 years. 22 cases received CHOP-like chemotherapy and 2 received primary CNS lymphoma protocols, 7 received concurrent rituximab and 4 had consolidation radiation therapy. 88% attained complete remission. Five patients have relapsed. The 5 yr overall survival for the cases was 71% with a median follow-up of survivors of 11.9 years.The 24 PTLD cases were compared to 84 well matched controls. There were 11 deaths in the cases and 5 in the controls. Three cases recommenced dialysis, compared to 3 controls (HR 2.5, p=0.27). The 5 yr rate of 25% increase in creatinine was 36% in cases and 20% in controls (HR 1.8, p=0.098). Of the 11 cases with ≥25% increase in creatinine, only 1 of these occurred within 6 months of IST cessation in the setting of rapidly progressive PTLD and early death. Only 2 of these 11 cases received rituximab. In contrast 5 of the 7 patients given rituximab did not develop a ≥25% deterioration in renal function. ConclusionsIST can be safely ceased during chemotherapy for PTLD in renal transplant patients. Whilst long-term reduction in IST is necessary to reduce PTLD relapse, this is associated with a trend to increased risk of chronic allograft nephropathy. Prospective trials are needed to address the ideal reduction of IST in PTLD. Disclosures:No relevant conflicts of interest to declare.

Authors' Reply to Knight and Morris

We would like to thank the authors Knight and Morris for sharing their interpretation of our article (1). However, to clarify any possible confusion: nowhere in the article, we concluded that “early steroid withdrawal in the first week after transplantation is less safe than withdrawal beyond 3 months after transplantation” as the authors point out in their letter. As far as the interpretation regarding the acute rejection data is concerned, we have merely stated that in the meta-analysis of Knight and Morris (2), “the incidence of acute rejection was increased in the first three groups (steroid avoidance and steroid withdrawal before 7 days and between 7 days and 1 year) but not in the fourth (steroid withdrawal after 1 year).” However, we did not conclude from these observations that it would be “safer to withdraw steroids beyond 1 year posttransplant” (1). The broad and overlapping confidence intervals for the calculated relative risks would indeed not allow for drawing this conclusion, as rightfully pointed out by the authors (2). Moreover, in our article, we state that “although steroid avoidance and withdrawal regimens after kidney transplantation were associated with higher rates of acute rejection, this did not result in inferior patient or graft survival” (1). We want to take this opportunity to reiterate the exact conclusions of our article, which were 3-fold. First, in our opinion, withdrawal of steroids between 3 and 6 months posttransplant can be safely performed in selected patients (and this in contrast to the Kidney Disease: Improving Global Outcomes guidelines [3]). Second, although early discontinuation may be safe in patients who are at low immunologic risk, we believe that markers should be identified and evaluated to correctly identify this subset of patients and—given recent data concerning increased risk of chronic allograft nephropathy after early steroid withdrawal (4)—more studies focusing on long-term outcome should be performed before this approach is promoted as a standard practice care (as in the Kidney Disease: Improving Global Outcomes guidelines [3]). Finally, we are strongly convinced that future studies in this field should focus on long-term renal outcome (and not solely on acute rejection as a surrogate marker), cardiovascular outcome, and patient outcome. Ben Sprangers Yves Vanrenterghem Division of Nephrology Department of Medicine University Hospitals Leuven Leuven, Belgium

Where Did We Leave Off in 2008? Conclusions From The 8th International Symposium

Although short-term outcomes following kidney transplantation have improved in recent years, allograft viability beyond 1 year has changed little since the introduction of cyclosporine (CsA)-based immunosuppression. Chronic allograft nephropathy (CAN) is a continuing threat to improved long-term outcomes, and regimens that involve calcineurin inhibitors (CNI) are implicated as a result of the progressive fibrosis they promote in renal allografts. Although strategies to reduce the nephrotoxic effects of CNI exposure have shown some success, alternative approaches to reducing nephrotoxicity and graft failure are needed. Sirolimus (SRL) suppresses immune reactions in a mechanism distinct from that of other immunosuppressants and may therefore hold potential for reducing the risk of CAN and improving long-term graft survival. The Rapamune Maintenance Regimen study randomized patients at 3 months either to continue with a regimen of SRL, CsA, and steroids or to have CsA withdrawn and the dose of SRL increased. Patients who were randomized to CsA withdrawal had superior graft and patient survival, demonstrated improved renal function, better blood pressure control, and a lower rate of skin and nonskin posttransplantation malignancy. A key barrier to the wider clinical implementation of SRL in kidney transplantation has, however, been the understanding of its optimal incorporation into standard immunosuppressive protocols. The CONVERT study examined the late conversion (approximately 3 years posttransplantation) from CNI to SRL. Late conversion was associated with inferior outcomes in patients with poor graft function or significant proteinuria following conversion. In addition, a number of short-term adverse events, such as prolongation of delayed graft function and abnormal wound healing, have been more commonly associated with de novo approaches. In designing the optimal approach to achieving long-term CNI-free immunosuppression with SRL, it should therefore be considered how these adverse events may be avoided or minimized. This brings into focus the optimal timing for the introduction of SRL and the potential for a two-stage approach to immunosuppression, minimizing the different short- and long-term risks to both the graft and the patient.

Renal cortex neuronal nitric oxide synthase in response to rapamycin in kidney transplantation

Decreased renal neuronal nitric oxide synthase (nNOS) is present in various chronic kidney diseases although there is relative little known in chronic allograft nephropathy (CAN). Female sex increases the risk of acute rejection and calcineurin-inhibitor toxicity but decreases the risk of CAN. Rapamycin (RAPA) is an alternative immunosuppress although there is no information whether it is effective in females. We therefore investigated the efficacy of RAPA in both sexes and the impact of RAPA on renal cortex structure and nNOS expression. Male (M) and female (F) F344 kidneys were transplanted into same sex Lewis (ALLO) or F344 (ISO) recipients and treated with 1.6 mg/kg/day of RAPA for 10 days. Grafts were removed for renal histology and endothelial (e)NOS and neuronal (n)NOS protein measurements at 22 weeks. All ALLO rats survived without acute rejection. ALLO F survived with mild proteinuria and CAN at 22 weeks similar to ALLO M, while ISO F had better outcome than ISO M. Cortical nNOSα was undetectable in all RAPA groups; however, nNOSβ transcript and protein were compensatory increased. Both ALLO and ISO F showed higher medullary nNOSα but lower cortical eNOS abundance than M groups. In male ALLO RAPA decreased renal cortical nNOSα but increased nNOSβ expression. This may represent compensatory upregulation of nNOSβ when nNOSα-derived NO is deficient.

Early experience with conversion to sirolimus in a pediatric renal transplant population

Sirolimus is an immunosuppressive agent that offers potentially significant benefits for young transplant patients facing life-long treatment. Its action of reducing cell proliferation may reduce the risk of chronic allograft nephropathy and posttransplant neoplasia. Twenty-nine children were converted from calcineurin inhibitors to sirolimus after renal transplantation and followed for a minimum of 12 months. Glomerular filtration increased transiently in those converted before 12 months after transplantation but not in those converted later, when chronic histological changes had developed. Mild acute rejection occurred after conversion in 10%, and side effects led to cessation of sirolimus in 31%. Anemia occurred in 55% of patients and responded well to darbepoetin. Most side effects (anemia, hypercholesterolemia, mouth ulcers, and myalgias) became less severe with time. The number of antihypertensive drugs required decreased significantly on sirolimus. Although side effects are frequent on sirolimus, in the majority of children, they are mild enough to allow the patient to continue taking the drug, and for these children the long-term benefits are potentially valuable.

Calcineurin inhibitor sparing in renal transplantation

Purpose of review The aim of this review is to report on the current state of calcineurin inhibitor-sparing therapies. The influence of mammalian target of rapamycin inhibitors in combination with low-dose or no calcineurin inhibitors on long-term allograft survival and function are discussed. Calcineurin inhibitor-sparing therapies without mammalian target of rapamycin inhibitors are also discussed. Recent findings The withdrawal of calcineurin inhibitors 3 months after transplantation and continuous therapy with sirolimus and prednisolone gives an adequate long-term allograft survival rate 4 years after transplantation. Low-dose calcineurin inhibitors together with everolimus seems to be superior to a full-dose calcineurin inhibitor-based therapy 3 years after transplantation, but adequately powered studies with hard endpoints are still needed. If mammalian target of rapamycin inhibitors are not tolerated (up to 30% of patients), other strategies such as antimetabolite (mycophenolate mofetil, azathioprine)-based therapy or antibody therapies (that is belatacept) may be utilized to facilitate calcineurin inhibitor withdrawal. Summary New immunosuppressive regimens have made it possible to withdraw or completely avoid cyclosporine or tacrolimus in selected patients at high risk of chronic allograft nephropathy and calcineurin inhibitor toxicity.

Recipient age and risk of chronic allograft nephropathy in primary deceased donor kidney transplant

Single center and registry data studies have had conflicting results regarding the impact of recipient age on chronic allograft nephropathy (CAN). We tested the hypothesis that advanced recipient age is a risk factor for graft failure due to CAN. All patients who underwent primary deceased donor kidney transplant between January 1, 1995 and December 31, 2000 recorded in the United Network of Organ Sharing (UNOS) database were analyzed for the occurrence of death censored graft loss and by two different definitions of graft loss due to CAN. Kaplan-Meier analysis based on the recipient age, and Cox proportional hazard regression was used to estimate the independent effect of recipient age on the three endpoints of interest. For all endpoints, after age of 9 years, the risk of graft loss declined with each successive decade increase in age. This pattern of risk was similar for both Caucasian and African-American recipients, although for any given age the risk of graft loss was always higher in African-American recipients. Analysis of UNOS data does not support the hypothesis that advanced recipient age is a risk factor for CAN.

Immunosuppressive treatment and progression of histologic lesions in kidney allografts

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. Although short-term results are excellent, long-term graft survival has not improved substantially in recent times. Chronic allograft nephropathy (CAN) and death with a functioning graft are the most important causes of graft loss. Recent evidence shows that nephrotoxicity of calcineurin inhibitors contributes to CAN, and the introduction of non-nephrotoxic drugs such as mycophenolate mofetil (MMF) and mammalian target of rapamycin inhibitors may provide new immunosuppressive strategies to improve long-term results after renal transplantation. MMF decreases the risk of developing chronic allograft failure and is useful for treating established CAN, because it has a beneficial effect on allograft fibrosis. Treatment with sirolimus (SRL), a basic immunosuppressive drug given in association with MMF, may offer better renal function, decrease the prevalence of CAN, and downregulate expression of genes responsible for the progression of CAN than treatment with cyclosporine A (CsA). SRL also permits an early elimination of CsA from SRL-CsA-steroid regimens and shows better renal function and improved renal histology without risk of rejection. Notably, this approach improves graft survival at 4 years. Further multicenter studies are needed to determine whether both approaches produce similar results by comparing immunosuppression caused by SRL-based and tacrolimus (TAC)-based treatments. Because TAC is the most commonly used anticalcineurin drug, it is important to compare the effects of steroid-TAC-SRL treatment with and without elimination of TAC. Finally, although caution is needed, the use of non-nephrotoxic immunosuppressive treatment may change the natural history of CAN.

High CXCL10 Expression in Rejected Kidneys and Predictive Role of Pretransplant Serum CXCL10 for Acute Rejection And Chronic Allograft Nephropathy

Several experimental models have shown that CXCL10 is required for initiation and development of graft failure caused by both acute and chronic rejection. CXCL10 expression and distribution was investigated in tissue specimens obtained from 22 patients suffering from acute rejection (AR) or chronic allograft nephropathy (CAN) by using in situ hybridization. Furthermore, pretransplantation sera of 316 cadaveric kidney-graft recipients were tested retrospectively for serum CXCL10 levels by a quantitative sandwich immunoassay. Bioptic specimens obtained from patients with CAN were characterized by wide CXCL10 expression not only at level of infiltrating inflammatory cells but also of vascular, tubular, and glomerular structures. In addition, assessment of pretransplant serum CXCL10 levels in 316 graft recipients and stratification of patients in three groups according to serum CXCL10 levels (<100 pg/mL, n=163; 100-150 pg/mL, n=69; >150 pg/mL, n=84) showed highly significant differences in 5-year survival rates for the two extreme groups (95.7% vs. 79.7%, P=0.0002). Accordingly, patients who developed severe, early AR (277.14+/-65.08 p=0.004) and those who developed CAN also showed increased pretransplant serum CXCL10 levels (193.2+/-36.9, P=0.03). Multivariate analysis demonstrated that among the analyzed variables, CXCL10 (relative risk [RR] 2.801) and delayed graft function (RR 3.728) had the highest predictive power of graft loss. These results suggest that pretransplant serum CXCL10 levels greater than 150 pg/mL confer an increased risk of early, severe, AR and subsequent CAN, finally resulting in renal-allograft failure. This finding might be used for the individualization of immunosuppressive therapies.

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.

Variable cyclosporine exposure: a risk factor for chronic allograft nephropathy and graft loss?

Background Following the introduction of ciclosporine (CsA), the 2-year survival of transplanted kidneys improved from less than 60% to over 80%. Though the introduction of this drug resulted in a marked improvement in graft survival, its use was not without problems. Variable absorption and a narrow therapeutic index resulted in the need for measurements of CsA blood concentrations to tailor the drug dose to maximize therapeutic efficacy while minimizing toxicity. Methods Data were available from the LOTESS study of 4948 transplant patients receiving Neoral with at least 5 years' follow-up. Potential risk factors associated with outcome in renal transplant recipients treated with CsA were explored: the primary outcome variable was graft loss. A stepwise binary logistic regression analysis was used to identify donor, recipient, and treatment variables related to outcome. Results In the initial analysis, chronic rejection was the only significant predictor of graft loss. The relative risk (RR) of graft loss was 16.9 (95% CI = 13.9–20.4). Further analysis identified four independent risk factors for chronic rejection cadaveric donor (RR, 1.50; 95% CI = 1.05–2.15), older donor (RR, 1.02; 95% CI = 1.01–1.02), younger recipient (RR, 1.02; 95% CI = 1.02–1.03), and variable predose CsA concentration (RR, 1.25; 95% CI = 1.06–1.48). Conclusion With the UK kidney transplant waiting list at about 5000 patients and only 1658 transplants performed during 2002, it is important maximize graft survival. For example, perhaps marginal donors (age>55) can be matched to older recipients without increasing the risk of chronic allograft nephropathy and therefore graft loss. Variable predose CsA concentrations may arise from at least three different sources: adherence to treatment, drug formulation, and individual variation in absorption. Therefore, it is important to emphaze to patients that erratic compliance may increase their risk of graft loss. Second, although only one CsA formulation is marketed in the UK, when generic forms of CsA are introduced it will be important to demonstrate consistent delivery of CsA from these new formulations. Third, improved monitoring of CsA using a C2 rather than a predose blood concentration measurement may be used to reduce intra-individual variations in drug exposure.

The impact of donor age on the results of renal transplantation.

The use of elderly donors is becoming more frequent. An increase in the donor's age is associated with a greater incidence of delayed graft function (DGF), chronic allograft nephropathy (CAN) and worse graft survival. Poor renal graft function is a risk factor for cardiovascular (CV) complications and, finally, for mortality of the patients. A total of 3365 adult patients transplanted in 1990 (n = 824), 1994 (n = 1075) and 1998 (n = 1466) with a functioning graft after the first year were included. The impact of donor age on renal function, DGF, acute rejection and other clinical factors was evaluated according to two donor and recipient age categories: young (< 60 years old) and elderly (> or =60 years old). Additionally, donor age was categorized by decades for the analysis of patient and graft survival, acute rejection and CV mortality. Donor mean age significantly increased during the three transplantation periods. A total of 478 out of 3365 donors were older than 60 years. Elderly donors showed an increased risk of DGF (38.9 vs 28.8%) and CAN (56.8 vs 46.2%). Mean serum creatinine at 3 and 12 months and proteinuria were significantly higher in the old donor group. Incidence and severity of acute rejection were similar in both groups. Graft and patient survival were significantly lower in the old donor group. Also, risk of mortality due to CV events was also significantly higher. A linear increase in risk of graft loss, patient death or CV mortality was observed when donor age was divided into 10 year increase subsets. Donor age is a strong predictor of CAN and graft loss. Patient survival is also affected by donor age, particularly by a higher risk of CV mortality.

Experience with cyclosporine in the canary islands

Cyclosporine (CsA) is currently the basis of most immunosuppressive protocols after solid organ transplantation. The introduction of Neoral, a new microemulsion formulation of CsA, and more recently a range of adjunctive immunosuppressants have further enhanced short-term efficacy and tolerability of CsA-based immunosuppression. In addition, Neoral C 2 monitoring has been shown to have advantages not only in the early posttransplant period, but also for maintenance transplant patients. The major long-term disadvantage associated with CsA is the development of nephrotoxicity and chronic allograft nephropathy (CAN), which is the second major cause of graft failure. Thus, strategies to reduce the risk of CAN include CsA-sparing protocols, use of C 2 level monitoring, introduction of non-nephrotoxic adjunctive immunosuppressants, and optimal management of additional risk factors. Other important side effects related to CsA-based immunosuppression include hypertension, diabetes, and hyperlipidemia. Optimal management of these conditions may lead to significant reduction of cardiovascular-related morbidity and mortality following solid organ transplantation.

Pretransplant and early posttransplant predictors of chronic allograft nephropathy in cadaveric kidney allograft?a single-center analysis of 1112 cases

This retrospective series reviews risk factors for chronic allograft nephropathy (CAN) based on the 10-year experience of a single institution. One thousand one hundred and twelve primary cadaveric renal transplant recipients whose graft survived for more than 6 months were followed for a mean of 4.6 years. The data were analyzed using the multivariate Cox proportional hazards model. CAN was defined as an irreversible rise of serum creatinine (SCr) by 30% in the absence of other causes and occurred in 42% of the patients. The risk of CAN was significantly increased in patients who experienced late rejections. Recipients of organs from donors that were older than 50 years and from such who died secondary to cerebrovascular accident were at increased risk of incurring CAN. Early markers of progression to CAN found at 6 months after transplantation included SCr levels of greater than 1.8 mg/ml, proteinuria, hypoalbuminemia, and hypertension. In conclusion, immune and non-immune factors affect progression to CAN in renal allograft recipients.

Conversion from cyclosporine to azathioprine at three months reduces the incidence of chronic allograft nephropathy

Conversion from cyclosporine to azathioprine after renal transplantation has been shown to be beneficial in terms of allograft function, cardiovascular risk factor profile, and the incidence of gout. A higher incidence of acute rejection, however, has also been reported and uncertainty still exists about the long-term outcome after conversion. We report on the extended follow-up of an open-label, randomized trial that examined conversion to azathioprine as early as three months after transplantation. One hundred twenty-eight patients were enrolled in this single-center study. Three months after transplantation they were randomly assigned to continue cyclosporine treatment (N = 68), or they were converted to azathioprine (N = 60). The steroid dose was temporarily increased in the patients who were converted. Patient survival was not different in the two groups. Graft survival tended to be lower (64.7% vs. 76.5% at 15 years) in the cyclosporine continuation group (P = 0.14) when data were analyzed on an intention to treat basis. The graft survival of the patients that stayed on their assigned treatment was significantly higher in the azathioprine arm, starting at two years' post-transplantation. The glomerular filtration rate was significantly higher in the patients who were converted to azathioprine. More allograft biopsies were taken from patients remaining on cyclosporine for suspicion of cyclosporine-related nephrotoxicity and prompted a high rate of late conversions (19%). The relative risk of chronic allograft nephropathy was significantly higher in the group that continued cyclosporine [relative risk, 4.3 (95% CI, 1.4 to 12.9); P = 0.009]. Conversion to azathioprine reduced the need of blood pressure and lipid-lowering drugs. Conversion to a calcineurin inhibitor-free immunosuppressive regiment three months after renal transplantation improved allograft function, reduced the need of cardiovascular risk factor-controlling medication, and reduced the incidence of chronic allograft nephropathy.

Assessment of cyclosporine therapeutic monitoring with C 2 concentrations in stable renal allograft recipients

The optimal long-term C 2 target to minimize the risk of chronic allograft nephropathy (CAN) has not yet been established in a prospective study. Furthermore, it is not known whether the target is the same in patients who also receive mycophenolate mofetil (MMF). We determined the 2-hour postdose concentration (C 2) in a cohort of 65 maintenance renal transplant patients. The mean C 0 level was 0.12 μg/mL and the C 2 was 0.62 μg/mL. The overexposed patients are 14%. There was a good correlation between C 0 and C 2, and between C 2 and the cyclosporine (CsA) dose. Patients receiving MMF display lower levels of C 0 and C 2, lower dosages of CsA, and higher levels of plasma creatinines. We did not observe significant differences on relating the level of absorption to patient age and sex, creatinine level, CsA dose, or coadministration of MMF. In conclusion, there is a low incidence of overexposed patients. C 2 levels of approximately 0.6 μg/mL (and possibly may be sufficient in renal transplant patients. somewhat lower [0.5 μg/mL] in patients receiving MMF) Patients who display slow or fast absorption of CsA do not have any apparent characteristic.

Significance of cytomegalovirus infection in renal transplantation

The aim of this study was to establish the relationship between vascular lesion chronic allograft nephropathy (CAN) and the presence of cytomegalovirus (CMV) in kidney transplanted patients. We studied 259 consecutive kidney transplant recipients with a minimum follow-up of 6 months; the induction immunosuppressive therapy included a calcineurin inhibitor, mycophenolate mofetil, steroids, and the use of an antilymphocyte serum if the patients developed delayed graft function. CMV early antigen detection (pp65) was performed on a weekly basis between days 30 and 90 post transplantation. Prophylactic treatment was administered in the donor +/recipient-risk group, and preemptive therapy delivered for positive antigenemia namely 3 days of intravenous [IV] gancyclovir [GCV] plus 11 days of oral therapy [in the case of infection], or 14 days of IV GCV [in the case of disease]). An acute kidney allograft rejection episode preceded CMV in 64.3% of the patients, and CMV preceded acute rejection in 35.7% of the cases. We conclude that CMV disease is an independent risk factor for CAN. CMV infection is probably associated with CAN, suggesting that the greater the viral load, the higher the risk of CAN. It may be advisable to perform universal prophylaxis to lower the viral load and CAN.