Juan Carlos Ruiz San Millán

Practical recommendations for the early use of m‐TOR inhibitors (sirolimus) in renal transplantation

m‐TOR inhibitors (e.g. sirolimus) are well‐tolerated immunosuppressants used in renal transplantation for prophylaxis of organ rejection, and are associated with long‐term graft survival. Early use of sirolimus is often advocated by clinicians, but this may be associated with a number of side‐effects including impaired wound‐healing, lymphoceles and delayed graft function. As transplant clinicians with experience in the use of sirolimus, we believe such side‐effects can be limited by tailored clinical management. We present recommendations based on published literature and our clinical experience. Furthermore, guidance is provided on sirolimus use during surgery, both at transplantation and for subsequent operations.

Prediction at First Year of Incident New-Onset Diabetes After Kidney Transplantation by Risk Prediction Models

OBJECTIVE Our aim was to analyze the performance of two scores developed for predicting diabetes in nontransplant populations for identifying kidney transplant recipients with a higher new-onset diabetes mellitus after transplantation (NODAT) risk beyond the first year after transplantation. RESEARCH DESIGN AND METHODS We analyzed 191 kidney transplants, which had at least 1-year follow-up posttransplant. First-year posttransplant variables were collected to estimate the San Antonio Diabetes Prediction Model (SADPM) and Framingham Offspring Study–Diabetes Mellitus (FOS-DM) algorithm. RESULTS Areas under the receiver operating characteristic curve of FOS-DM and SADPM scores to predict NODAT were 0.756 and 0.807 (P < 0.001), respectively. FOS-DM and SADPM scores over 75 percentile (hazard ratio 5.074 and 8.179, respectively, P < 0.001) were associated with NODAT. CONCLUSIONS Both scores can be used to identify kidney recipients at higher risk for NODAT beyond the first year. SADPM score detects some 25% of kidney transplant patients with an eightfold risk for NODAT.

Predictive factors of allosensitization in renal transplant patients switched from calcineurin to mTOR inhibitors

Conversion of kidney‐transplant recipients from calcineurin inhibitors to mTOR inhibitors has been suggested to be a risk factor for increased alloimmune response. We have analyzed the development of new HLA‐antibodies (HLA‐Abs) early after conversion in 184 patients converted in stable phase at our hospital and compared with a control group of nonconverted comparable 63 transplants. Using single‐antigen solid‐phase immunoassay analysis, a preconversion and a 3–6 months postconversion sera were prospectively analyzed in every patient for the appearance of new HLA‐Abs. Renal function at 2 years postconversion and cumulative graft survival were compared between groups. In 16 patients, new HLA‐Abs (3‐DSA and 13‐NonDSA), not present at the moment of conversion, were detected (8.7% vs. 3.1% in the control group). The type of mTORi used, type of CNI preconversion, the presence of steroids, time of conversion, or indication for conversion did not have influence on this effect but the presence of HLA‐Abs before conversion highly correlated with the appearance of new specificities. Patients with de novo HLA‐Abs showed a trend to worst graft function and survival. In conclusion, conversion to mTORi can be followed by early appearance of de novo HLA‐Abs, especially in patients with HLA‐Abs preconversion, and this complication should be screened early after conversion.

Intermediate steroid withdrawal after renal transplantation and anti-HLA antibodies (HLA-Abs) development

INTRODUCTION Steroid withdrawal in renal transplantation is desirable to avoid their adverse effects. However, by decreasing the immunosuppression, could lead to an increased risk for the development of HLA-Abs. OBJECTIVE Evaluate the relationship between steroid withdrawal and development of HLA-Abs in renal transplantation. METHODS We analyzed sera by Luminex from 182 kidney transplants performed from 1998 to 2011, before and two years after transplantation. All the patients had a pretransplant PRA (panel reactive of antibodies) <20% by complement-dependent cytotoxicity (CDC) and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF). We compared a group of steroid withdrawal at 7 months (group-I; n=130) and another control with non-withdrawal (group-II; n=52). RESULTS 22 patients (16.9%) in group-I and 11 patients in group-II (21.1%) had HLA-Abs after two years (pNS). Despite excluding patients with PRA >20%, we detected HLA-Abs pretransplant by Luminex in 11.5% of patients in both groups, of which, 66.6%, versus 53% (p 0.058), developed new specificities, with a similar percentage of donor specific antibodies (DSA) in both groups (33.33% vs 36.36%), pNS. In the subgroup without pretransplant HLA-Abs (group-I; n=115, group-II; n=45), 6.08% developed de novo HLA-Abs, being DSA 3.4% (Group-I) versus 7.69% in group II with 3.84% DSA (pNS). CONCLUSIONS Steroid withdrawal at 7 months of renal transplantation does not entail a higher risk in terms of HLA-Abs development in patients without pretransplant HLA-Abs and treatment with tacrolimus and MMF, although larger studies are needed to confirm these findings.

High Levels of Monocyte-Myeloid-Derived Suppressor Cell Frequencies Prior Kidney Transplantation are Related with Risk of Acute Rejection

Introduction Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that expand after inflammation and are able to suppress innate and adaptive immune responses in different settings. Based on their phenotype could be divided in early (eMDSC), Monocytic (M-MDSC), poli-morpho nuclear (PMN-MDSC) with different functions. The MDSCs can expand regulatory T cells after kidney transplantation (KT) and potentially could be involved in allograft tolerance. The aim of the work was to analyze MDSC subsets in end-stage renal disease and correlate with further clinical events after KT. Materials and Methods 31 patients on waiting list were recruited in our hospital. MDSC subsets were measured in peripheral blood by flow cytometry prior KT and prospectively clinical events were recorded. MDSC were studied as detailed previously (1). Results A total of 12 (38.7%) developed acute rejection post-KT. No differences in sensitization status or previous transplant between AR and No rejection groups. The frequency of M-MDSC: MDSC4 (CD33+CD11b+CD14+HLADR-/low) within peripheral blood mononuclear cells was statistically higher in AR group vs No rejection 1.76 (1.1-2.5) vs 0.18 (0.09-0.74), p=0.0014. The other M-MDSC subsets, MDSC1 (CD14+CD124+), MDSC7 (CD15-CD14+CD33highDRlow) were increased in AR group, p=0.01 and p=0.06 respectively. No differences between PMN-MDSC and eMDSC between the groups were found. Figure. No caption available. Discussion The inflammation prior kidney transplantation can induce the expansion of M-MDSCs, and the patients with increased number of MDSC-4 are at risk of suffering an acute rejection episode after KT Conclusion The measurement of MDSC could identify KT patients at risk of acute rejection, although these findings should be confirmed in large and multicenter studies Reference (1) Mandruzzato et al. Cancer Immunol Immunother (2016); 65: 161 ISCiii (FIS16/00386). REDinREN RD16/0009/0027. IDIVAL (NEXTVAL 16/022).

Can Regulatory T Cells Help Us as a Biomarker of Long-Term Kidney Graft Survival?

IDIVAL. Background Immunosuppression regimens effectively control acute rejection and decrease graft loss in the first year after transplantation; but long-term graft attrition rates remain stable beyond this point, due to a combination of drug toxicities and the emergence of chronic alloimmune responses. It is known that regulatory T cells (Tregs) play a role in limiting kidney transplant rejection and can potentially promote transplant tolerance. Despite this, there are a few prospective studies that prove the role of peripheral Tregs on long-term graft outcome.The aim of our study was to analyze the influence of 1-year peripheral blood Tregs on long-term death censored graft survival. Methods and Materials Prospectively monitored peripheral blood Tregs by flow cytometry in Kidney Transplant Recipient (KTR) between 2005 and 2011. A total of 133 KTR were included in the study and followed up to 4 years after transplantation. Death censored graft survival was determined retrospectively in January-2017. Results Follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death censored graft loss (DCGL). One-year peripheral Tregs were 17.4 ± 16.9 cells/mm3. Patients with high Tregs above the median value (14.57 cells/mm3) showed better death-censored graft survival (5-year 92.5% vs. 81.4%, Log-rank p = 0.030). One-year Tregs showed AUC-ROC of 63.1% (95%CI 52.9-73.2%, p = 0.026) for predicting DCGL. After multivariate Cox’s regression analysis, a high number of peripheral blood Tregs was a protective factor for DCGL (HR 0.961, 95%CI 0.924-0.998, p = 0.041) irrespectively of 1-year proteinuria and renal function. Conclusion A high number of peripheral blood Tregs at 1-year after kidney transplantation relates to a better long-term graft outcome. This relationship was independent of other significant 1-year variables. In this sense, peripheral blood Tregs can be useful as a biomarker to predict graft outcomes and to tailor immunosuppression.

Hepatitis C Virus Infection in Kidney Transplant Recipients: Final Results from a Spanish Multicenter Study

Grupo Español De Actualizacion En Trasplante. Background HCV is a relevant negative prognosis factor for graft and transplant recipient survival.New direct-acting antivirals(DAA)allow us to solve this problem in an effective way.It is crucial to know their real impact in our daily practice. Methods Observational,retrospective and prospective study.We analyze treatment results with DAA,in kidney transplant(KT)recipients from 15 hospitals,regarding effectiveness,tolerance and impact on immunosuppression and renal function-proteinuria in a short-medium term. Results Until November 2017,226 KT recipients were included (9combined liver- kidney transplants).69.7%male; average age 54.2±9yo;KT length 11.4±10years. More than 50%showed stage 3-4 chronic kidney disease. Immunosuppressive therapies: tacrolimus(70%) or cyclosporine (18%) with MMF(76%). Predominant genotype was 1b(68.1%), 1a(13.8%),3(7.8 %), 4(6%) and 2(4.3%);51% had grade 3-4 of fibrosis, 17% portal hypertension. The main DAA used was sofosbuvir(91%)combined with ledipasvir(55%), simeprevir(14%)or daclatasvir(13%);in 9 cases(7%)the combination of paritaprevir-ritonavir-ombitasvir-dasabuvir(3D)was employed;18% were treated with Ribavirin as coadjuvant. Side effects were limited,23.5 %,and without relevance, except for anemia caused by Ribavirin.2 patients interrupted the treatment, due to neurotoxicity caused by the interaction between 3D and tacrolimus and anemia caused by Ribavirin (both had virological response).All the patients that completed the treatment (213)are alive and show virological response in 98% of cases and with SVR-12.Liver function analysis improved: 74%normal vs 21% before the treatment (p<0.001). Renal function did not change significantly. Tacrolimus level at the end was lower with respect to the beginning (6.6 vs 7.3 ng/ml, p=0.03), in spite of a slight increase in the dose (3.5 vs 2.6 mg/day p=0.01). Conclusions DAA are highly effective in KT patients, with good tolerance,making it possible to solve the problem and having a good chance to improve the prognosis in our patients.The use of DAA in these patients requires special control and coordination with hepatologists, especially when 3D or Ribavirin is used.

Relationship Between the Histological Findings Obtained by 1-Year Protocol Biopsies and Kidney Transplant Failure Score (KTFS)

Background Progressive reduction in acute rejection rates has led to an improvement of kidney graft survival throughout the first year, but long-term graft attrition rates remain stable beyond this point. Predicting the outcomes of kidney transplant recipients at 1-year would be useful in order to identify those for whom interventions may be needed. On one hand, it is known that allograft histology obtained by 1-year protocol biopsies is independently related to death-censored graft survival. On the other hand, several clinical risk scores, such as Kidney Transplant Failure Score (KTFS), have shown a good ability to predict long-term graft outcome. The aim of our study was to analyze the relationship between 1-year histologic findings of protocol biopsies and KTFS. Methods/Materials Between 2012 and 2016, 85 protocol biopsies were performed at 1-year post-transplant in our center and each biopsy was scored according to Banff criteria. KTFS was calculated taking into account 8 pre- and post-transplant clinical and analytical variables. Results Mean KTFS was 6.3 ± 1.7. KTFS related to t (r = 0.256, p = 0.018), i (r = 0.299, p = 0.005), ci (r = 0.326, p = 0.002), ct (r = 0.341, p = 0.001) and ah (r = 0.265, p = 0.014), but not with g, v, cg, cv, ptc or mm. Mean KTFS values were higher in patients with higher scores of t (p = 0.046), i (p = 0.008), ct (p = 0.007) and ci (p = 0.009). After multivariate linear regression analysis, both i (&bgr; 0.507, 95%CI 0.011-1.004, p = 0.045) and ci (&bgr; 0.460, 95%CI 0.034-0.886, p = 0.035) related to higher KTFS, but only 14.7% of total variation in KTFS was explained by histologic scores. Conclusion A clinical scoring system predictive of long-term kidney graft survival such as KTFS relates to both acute and chronic histologic findings in 1-year protocol biopsies, although the degree of correlation was weak. Both clinical scores and histologic variables provide additional information to predict renal graft outcome.

The Coefficient of Variability is the Same in the mTOR-inhibitors?

Background Intrapatient trough levels variability of immunosuppressive drugs must be considered as a prognostic factor. Many studies demonstrate the relationship between the high intrapatient variability of calcineurin inhibitors (CNI) levels and poor long-term renal graft outcome. Recent studies suggest a lower variability when using once-daily tacrolimus compared to the classical twice-daily formulation. Our objective is to analyze the intrapatient variability observed in the blood levels of mTOR-inhibitors (mTORi) and to compared the variability of sirolimus (SRL) with that of everolimus (EVL) in transplant patients converted to an iMTORi. Methods We analyzed 256 adult renal transplant patients converted to an mTORi between Jan-2009 and Dec-2015 in two Spanish transplant centers. The mean post-transplant conversion time was 51,6 months. One hundred and seventeen werw converted to SRL and 139 to EVL. Coefficient of variation (CV) was calculated using at least 3 blood trough levels between 3 and 18 months postconversion. Conversions in the first postransplant year (121) and later (135) were analized separatedly. CV was correlated with graft evolution (graft survival and/or renal function). Results The mean and median CV of the entire group was 25,6∓13,0% and 23,7∓12,1%. SRL and EVL mean CV was 23,8% and 27,1% (p=0,04). Inthe subgroup of late conversions (>1 y) SRL and EVL-CV was 23,0% and 29,0% (p=0,008). 59,8% vs 41,7% of patients converted to SRL and EVL respectively had a CV below the median (p=0,004). No differences in graft evolution could be demonstrated between patients with high and low CV at a mean follow-up of 58,5∓21,4 months. Conclusions We suggest that SRL has a lower CV than EVL. This difference should probably have a prognostic significance but we have not found differences in the long-term follow-up. This might probably be a consequence of that most patients were converted in the stable postransplant phase.