Ellipro scores of donor epitope specific HLA antibodies are not associated with kidney graft survival.

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants.

Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation.

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.

Visual interstitial fibrosis assessment as continuous variable in protocol renal transplant biopsies.

AIMS: In current renal transplant pathology practice, interstitial fibrosis is visually assessed in categories according to the Banff classification. As this has a moderate reproducibility, which is little ameliorated by morphometric analysis, we investigated whether visual renal fibrosis assessment is feasible on a continuous scale, i.e. as a percentage of affected area of the cortex. METHODS AND RESULTS: Protocol renal biopsies taken at transplantation (n = 125), three (n = 73) and 12 months (n = 88) after transplantation were visually scored in categories (Banff) and percentages for interstitial fibrosis (ci). Interobserver variation (ICC and weighted κ) was assessed, and morphometric analysis on Sirius red-stained sections was performed. Correlations between the different methods and their association with donor age and eGFR 1 and 5 years post-transplant were analysed using Pearson's or Spearman's rho. Interobserver agreement was equivalent for Banff and %ci (κ = 0.713 versus ICC = 0.792), and for Banff IF/TA and %IF/TA (κ = 0.615 versus ICC = 0.743). Both Banff and %ci were associated with Sirius red morphometry in 3 and 12 months. With all three methods, a significant correlation was found between donor age and fibrosis in the implantation biopsy and between fibrosis in the 12 months' biopsy and eGFR at 1 and 5 years (eGFR at 1 year: Sirius red ρ = 0.487, %ci ρ = 0.393, Banff ρ = 0.413, all P < 0.01, eGFR at 5 years: Sirius red ρ = 0.392, %ci ρ = 0.333, Banff ρ = 0.435, all P < 0.01). CONCLUSION: Interstitial fibrosis assessment on a continuous scale can be used next to scoring in categories according to the Banff classification in protocol renal transplant biopsies.

T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation.

CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.

Endothelial dysfunction and low-grade inflammation in the transition to renal replacement therapy.

INTRODUCTION: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce. METHODS: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology. RESULTS: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter. CONCLUSIONS: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation.

Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients.

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long-term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995-2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6-month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA-B plus 1 HLA-DR, or 2 HLA-DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low-risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.

Antibodies against ARHGDIB are associated with long-term kidney graft loss.

The clinical significance of non-HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large-scale studies incorporating analysis of multiple non-HLA antibodies simultaneously. We developed a multiplex non-HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non-HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased-donor kidney (N = 3276) but not in recipients of a living-donor kidney (N = 1496). At 10 years after deceased-donor transplantation, recipients with anti-ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death-censored covariate-adjusted graft survival compared to the anti-ARHGDIB-negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32-2.53; P = .0003). These antibodies occur independently from donor-specific anti-HLA antibodies (DSA) or other non-HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non-HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti-ARHGDIB antibodies in all patients awaiting deceased-donor transplantation.

A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival.

BACKGROUND: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. METHODS: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. RESULTS: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). CONCLUSION: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term.

Toward a Sensible Single-antigen Bead Cutoff Based on Kidney Graft Survival.

BACKGROUND: There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody. METHODS: To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants. RESULTS: First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background. CONCLUSIONS: With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.

Effect of initial immunosuppression on long-term kidney transplant outcome in immunological low-risk patients.

BACKGROUND: Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. METHODS: We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. RESULTS: Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P < 0.0001) and CsA/Pred (64%, P < 0.0001). CONCLUSION: These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival.

Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients.Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay.Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P=0.93). Patients without DSA had a 10-year graft survival of 78%.Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.

PIRCHE-II Is Related to Graft Failure after Kidney Transplantation.

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.

Development and Validation of a Multiplex Non-HLA Antibody Assay for the Screening of Kidney Transplant Recipients.

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.

No evidence for progressive deterioration in stimulated insulin secretion in renal transplant recipients after 12years tacrolimus exposure.

AIMS: Tacrolimus (Tac) inhibits insulin secretion in a Tac-trough blood level dependent way early post-transplant in renal transplant recipients (Rtx). It is unknown whether long-term exposure results into a progressive beta cells dysfunction. METHODS: Two independent cohorts of Tac-treated non-diabetic Rtx, previously participating in glucose metabolism studies using intravenous Glucose Tolerance Test (ivGTT) were included: Fifty-eight Rtx were tested by ivGTT cross-sectional between 0.25 and 12.6years post-transplant. Factors related to glucose metabolism parameters were explored by multilinear regression analysis. Eighteen non-diabetic Rtx tested by ivGTT 6months post-transplant were retested at 12years. The glucose metabolism outcome parameters were also adjusted according to the results of the cross-sectional study. RESULTS: Multivariate analysis showed 'Age', 'BMI' and 'use of steroids' to be significantly related, in different combinations, to the glucose metabolism parameters 'insulin resistance', 'fasting insulin level' and 'stimulated insulin secretion'. However 'time on tacrolimus' wasn't related to any parameter. In the longitudinal study, none of the glucose metabolism parameters (either analyzed crude or adjusted) deteriorated clinically or statistically significant. Numerically, 'stimulated insulin secretion' even increased. CONCLUSIONS: Chronic Tac exposure does NOT lead to a progressive decrease in 'stimulated insulin secretion' between 6months and 12years post renal transplant in our population of 18 patients.

Development and Pretesting of a Questionnaire to Assess Patient Experiences and Satisfaction with Medications (PESaM Questionnaire).

BACKGROUND: The aim of this study was to develop, together with the Lung Foundation Netherlands and Dutch Kidney Patients Association, patients and clinicians, a measure to evaluate patient experiences with the orphan drugs pirfenidone (for idiopathic pulmonary fibrosis [IPF]) and eculizumab (for atypical haemolytic uraemic syndrome [aHUS]), as well as a generic measure of patient experiences and satisfaction with medications. METHODS: Development of the Patient Experiences and Satisfaction with Medications (PESaM) questionnaire consisted of four phases: literature review (phase I); focus groups and individual patient interviews (phase II); item generation (phase III); and face and content validity testing (phase IV). Literature review aimed to identify existing disease-specific and generic patient experience measures to provide guidance on the domains of medication use relevant to patients, the number of items and type of response categories, and to generate an initial pool of items. Subsequent focus groups and patient interviews were conducted to gain insight into the perceived effectiveness of the therapies, the burden of side effects, and how the medication impacted on a patient's daily life. Focus groups and interviews were recorded and transcribed verbatim. Coding was carried out by highlighting passages in the text and assigning each passage a code representing the following predefined categories: (1) perceived effectiveness; (2) side effects; (3) ease of use; and (4) impact of medication. Using data from phase I and II, a panel of experts selected items relevant for inclusion in the questionnaire. Individual patient interviews with IPF and aHUS patients (n = 18), using a retrospective verbal probing technique, were conducted to assess face validity, time needed to fill out the questionnaire, and content validity. RESULTS: The PESaM questionnaire that was developed consisted of two disease-specific modules that assessed patient experiences with pirfenidone for the treatment of IPF, and eculizumab for the treatment of aHUS, a generic module, applicable to any medication, and a module to assess patient expectations. Review of the literature identified multiple disease- or medication-specific questionnaires and two generic patient satisfaction questionnaires. Common domains across most questionnaires were effectiveness, side effects, ease of use and overall satisfaction. Patient interviews revealed the social impact (e.g. unable to go outside) of side effects such as photosensitivity associated with pirfenidone and the risk of infection associated with eculizumab. Each PESaM module focuses on patients' perceived effectiveness of the medication, side effects, and ease of use, and the impact these aspects have on physical and emotional health and daily life. The generic module additionally includes items related to satisfaction with the medication. Individual interviews with patients in phase IV confirmed, in general, that questions and response options of the modules were clear and content validity was good. The mean time to complete the modules ranged from 6 min for the disease-specific (aHUS) module to 9 min for the generic module. CONCLUSIONS: We developed the PESaM questionnaire to quantitatively assess patient experiences and satisfaction with medications. A validation study is currently underway to examine the psychometric properties of the PESaM questionnaire.

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

OBJECTIVE: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. DESIGN: Systematic review and meta-analysis of individual patient data. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. ELIGIBILITY: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. RESULTS: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. CONCLUSIONS: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Immunosuppressive regimen and interstitial fibrosis and tubules atrophy at 12 months postrenal transplant.

BACKGROUND AND OBJECTIVES: Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil. RESULTS: Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001). CONCLUSIONS: These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Early loss of peritubular capillaries after kidney transplantation.

Inflammation, interstitial fibrosis (IF), and tubular atrophy (TA) precede chronic transplant dysfunction, which is a major cause of renal allograft loss. There is an association between IF/TA and loss of peritubular capillaries (PTCs) in advanced renal disease, but whether PTC loss occurs in an early stage of chronic transplant dysfunction is unknown. Here, we studied PTC number, IF/TA, inflammation, and renal function in 48 patients who underwent protocol biopsies. Compared with before transplantation, there was a statistically significant loss of PTCs by 3 months after transplantation. Fewer PTCs in the 3-month biopsy correlated with high IF/TA and inflammation scores and predicted lower renal function at 1 year. Predictors of PTC loss during the first 3 months after transplantation included donor type, rejection, donor age, and the number of PTCs at the time of implantation. In conclusion, PTC loss occurs during the first 3 months after renal transplantation, associates with increased IF and TA, and predicts reduced renal function.

Glucose metabolism before and after conversion from cyclosporine microemulsion to tacrolimus in stable renal recipients.

BACKGROUND: Tacrolimus is more diabetogenic than cyclosporine. However, this difference is only discernible in the first few months after renal transplantation. In randomized trials, investigating the effects of immunosuppression after renal transplantation, no increase in diabetes mellitus has been reported. However, no sensitive technique was used in these trials, so subclinical alteration of glucose metabolism cannot be excluded. METHODS: We, therefore, decided to use an intravenous glucose tolerance test (IV-GTT), to investigate whether conversion from cyclosporine-based immunosuppression, with a median trough level of 120 microg/l, to tacrolimus-based immunosuppression with a median trough level of 6.5 microg/l influences glucose metabolism and whether patients on steroids behave differently from those not on steroids. RESULTS: Thirty stable, non-diabetic patients, transplanted 10 or more years earlier, were converted from cyclosporine to tacrolimus without changing their concomitant medication. IV-GTT's were performed before and 2.5 months after the conversion. Before conversion, 40% of the patients had an abnormal glucose disappearance rate (kG): in 7%, kG was below 0.8 (abnormal range) and in 34%, kG was between 0.8 and 1.2 (indeterminate range). After conversion, stimulated insulin production, kG, HbA1C and fasting glucose did not change significantly. Insulin resistance (HOMA-R) of the whole group increased significantly, mainly due to a rise in HOMA-R in patients on steroids (n = 18). None of these patients developed overt diabetes mellitus. CONCLUSIONS: Some 40% of long-term cyclosporine-treated patients had an abnormal glucose metabolism. Conversion from cyclosporine to tacrolimus does not negatively influence stimulated glucose metabolism or insulin resistance in stable, steroid-free renal transplant recipients. However, in patients receiving steroids, conversion leads to an increase in insulin resistance while insulin output remains the same.

High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation.

Morbidity and mortality due to cardiovascular disease are major problems after renal transplantation. The effects of three immunosuppressive protocols on cardiovascular end points were investigated in a single-center, randomized, parallel (1-1-1) group. Acute rejection was a secondary safety endpoint. Groups were as follows: group one, tacrolimus+sirolimus; group two, tacrolimus+mycophenolate mofetil (MMF); group three, sirolimus+MMF+daclizumab. All groups received two days methylprednisolone only. The Ethical Committee demanded an interim analysis when 50% of the patients were included. In this analysis, 54 patients with a median follow-up of 9.2 months were studied. The Kaplan-Meyer analysis showed a difference in rejection free survival between group one (82%) and group three (34%, P=0.03) and between groups one and two (tacrolimus-based, 76%) and group three (calcineurin-free, 34%, P=0.04). Calcineurin-free immunosuppression with two days of steroids only showed an unacceptable high incidence of acute rejection and re-rejection, and the study had to be stopped.