Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro.

BACKGROUND: Antibody-mediated response in solid organ transplantation is critical for graft dysfunction and loss. The use of immunosuppressive agents partially inhibits the B-lymphocyte response leading to a risk of acute and chronic antibody-mediated rejection. This study evaluated the impact of JAK3 and PKC inhibitors tofacitinib (Tofa) and sotrastaurin (STN), respectively, on B-cell proliferation, apoptosis, and activation in vitro. METHODS: Human B cells isolated from peripheral blood of healthy volunteers were cocultured with CD40 ligand-transfected fibroblasts as feeder cells in the presence of interleukin (IL) 2, IL-10, and IL-21. The cocultures were treated with immunosuppressants Tofa, STN, and rapamycin (as a control), to analyze the proliferation and apoptosis of B cells by means of Cyquant and flow cytometry, respectively. CD27 and IgG staining were applied to evaluate whether treatments modified the activation of B cells. RESULTS: Tofa and STN were able to inhibit B-cell proliferation to the same extent as rapamycin, without inducing cell apoptosis. After 6 days in coculture with feeder cells, all B cells showed CD27 memory B-cell phenotype. None of the immunosuppressive treatments modified the proportion between class-switched and non-class-switched memory B cells observed in nontreated cultures. The high predominance of CD27+CD24+ phenotype was not modified by any immunosuppressive treatment. CONCLUSIONS: Our results show that Tofa and STN can suppress B-cell antibody responses to an extent similar to rapamycin, in vitro; therefore these compounds may be a useful therapy against antibody-mediated rejection in transplantation.

Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.

Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors.

Desensitization Before Living Donor Kidney Transplantation in Highly HLA-Sensitized Patients: A Single-Center Study.

BACKGROUND: Renal transplantation in highly sensitized patients represents a major clinical challenge leading to long periods on the waiting list. When a living donor is available, the use of different strategies to desensitize recipients with preformed human leukocyte antigen antibodies can allow a successful transplantation. METHODS: We performed a retrospective observational study including all living donor kidney transplantation (LDKT) with desensitization (DS) from 2008 to 2014 in our transplant unit. The rates of rejection and graft survival were evaluated. DS consisted of plasma exchange (PE), rituximab (RTX), and intravenous immunoglobulin (IVIG) induction with thymoglobulin and maintenance immunosuppression with tacrolimus, corticosteroids, and mycophenolate mofetil. RESULTS: From 2008 to 2014, we performed 368 LDKT, with 31 receiving desensitization. Seven cases from a clinical trial were excluded. Demographic data and outcomes were recorded. All of the patients received RTX + PE + IVIG. DS was performed for positive complement-dependent cytotoxicity cross-match (4.2%), T-cell- and/or B-cell-positive flow cytometry cross-match (87.5%) and presence of donor-specific antibodies alone (8.3%). We identified 23 episodes of rejection in 12 patients (50%); 79% were antibody-mediated rejections (AMR). Graft failure was 12.5%, with a mean time to graft loss of 229 ± 203 days. Mean follow-up was 37 ± 27 months, and graft survival was 91% and 86% at 1 and 5 years, respectively. CONCLUSIONS: Desensitization in LDKT appears to offer an acceptable option for highly sensitized patients. In our series, 41% presented an AMR and 12.5% showed transplant glomerulopathy in protocol and/or indication biopsies. However, short-term outcomes and graft survival were satisfactory.

Desensitization in ABO-Incompatible Kidney Transplantation With Low ABO Iso-Agglutinin Titers.

BACKGROUND: In ABO-incompatible (ABOi) kidney transplantation (KT) with low iso-agglutinin (IG) titers (IGT), standard pre-conditioning treatment might be excessive. To try to answer this question, we evaluated the pre-conditioning requirements of a group of ABOi KT with low ABO IGT in our center. Our main objective was to assess desensitization requirements for ABOi KT with low IGT (<16) at Hospital Clinic of Barcelona from 2006 to 2014. METHODS: A retrospective study of desensitization (rituximab and plasma exchange [PE]) requirements for ABOi KT with IGT <16 was conducted. RESULTS: One and 5 years after KT, patient survival was 100%. Renal graft survival was 90% at 1 and 5 years after KT. Mean PE performed before KT was 1.7 (standard deviation [SD], 1.703); 50% of the patients did not receive PE after transplantation, 30% received 2 sessions of PE, and 20% received only 1. The average is 0.8 (SD, 0.91).Follow-up IG determinations remained with low titers (≤8/8). No rebounds of titers were observed during the first 4 to 6 months after transplantation. CONCLUSIONS: Recipients with IGT ≤8 required none or only 1 PE session to reach acceptable titers (titers ≤4) to perform ABOi KT safely. This information is useful to assess the possibility of a minimized desensitization protocol in ABOi KT donors with low titers of IG to reduce adverse effects, reduce cost, and simplify pre-transplant logistics.

Pre-Emptive Retransplantation in Patients With Chronic Kidney Graft Failure.

INTRODUCTION: The aim of this study was to compare the group of patients receiving a new kidney transplant before starting dialysis again (pre-reTR) with a group of patients receiving a new kidney transplant after restarting dialysis (reTR). METHODS: This retrospective cohort included all the kidney retransplantations (second transplantations) between 2000 and 2012 performed at our center and their follow-up until July 2014. We analysed graft and patient survival, rejection rates, and immunologic parameters of these patients. RESULTS: We studied 18 patients who had pre-reTR and 83 who had reTR. In the pre-reTR group no patient had panel-reactive assay (PRA) >10% at any time. In the reTR group 26.5% had PRA >10% at the time of transplantation (P = .014) and 54.2% had a historical highest PRA >10% (P < .001). The rejection rate was 11.1% in the pre-reTR group and 27.7% in the reTR group during the first year post-retransplantation (P = .227). Patient survival rate was 100% in the pre-reTR group at 5 years of follow-up, whereas in the reTR group at 1 year it was 95.2% and 85.9% at 5 years after retransplantation. Allograft survival at 1 and 5 years was 88% and 89%, respectively, in the pre-reTR group. On the other hand, in the reTR group it was 89% after the first year and 65% at 5 years post-retransplantation. CONCLUSION: Pre-emptive renal retransplantation is a feasible option that should be assessed in patients with kidney graft failure and may help to minimize the morbidity associated with dialysis reinitiation.

Living Donor Transplantation: Long-Term Evolution Related to Age Matching.

The lack of donors is favoring living kidney donor (LKD) transplantation worldwide, quite often beyond the classic age-matching rules. We analysed renal function (RF) at 1 and 5 years in all donor and recipients as well as death-censored graft and patient survival. LKD recipients were divided into 4 subgroups: young recipients-young donors (YR-YD; N = 355), elderly recipients-young donors (ER-YD; N = 13), young recipients-elderly donors (YR-ED; N = 67), and elderly recipients-elderly donors (ER-ED; N = 38). "Elderly" was defined as ≥60 years. RF was better in those who received a young allograft (YR-YD/ER-YD) at any time (P < .001). There was a trend toward higher proteinuria among the recipients of an old allograft (YR-ED/ER-ED) at any time (P = not significant [NS]). However, our population showed low levels of proteinuria and this was not a risk factor for graft failure. Logistic regression model showed that creatinine level at 1 year is a good predictor of graft losses. Graft survival was worse in the allografts from elderly donors (P < .001). Analysing the young recipients, renal survival was inferior in those who received an old kidney (YR-ED; P < .00005) as well as mortality rates at 14 years (P = .03). The RF of young (N = 295) and elderly donors (N = 98) was optimal with no progression to ESRD or deaths registered during follow-up. In conclusion, young recipients of elderly kidneys pay the price of a worse RF, allograft prognosis, and patient prognosis. The pair YR-ED is a doable option, but we recommend age matching when it is possible.

Association between individual and combined SNPs in genes related to innate immunity and incidence of CMV infection in seropositive kidney transplant recipients.

In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients.

Economic analysis of the treatment of end-stage renal disease treatment: living-donor kidney transplantation versus hemodialysis.

INTRODUCTION: End-stage renal disease (ESRD) is a major public health problem in the Spanish health system. Kidney transplantation is the treatment of choice, offering better survival and cost-effectiveness than other alternatives. This study aimed to compare the cost of living-donor kidney transplantation (LDKT) during the first year after transplantation with that of hemodialysis (HD). METHOD: A prospective, descriptive study of cost and efficacy was performed in the Hospital Clinic in Barcelona from January to December 2011. We included 106 patients (57 undergoing HD and 49 receiving a LDKT). The costs of LDKT (donor and recipient) and HD were calculated based on our economic database program. RESULTS: The mean age of recipients and donors was 46 ± 15 and 52 ± 10 years, respectively, and 67% of the recipients were men. In HD patients, the mean age was 67 ± 11 years and 62% were men. The total cost of LDKT was €29,897.91 (€8,128.44 for donors and €21,769.47 for recipients). The total cost of HD was €43,000.88 (€37,917 for HD and related procedures plus €5,082 for transport). LDKT represented a savings of €13,102.97 per patient/year and the payback period was less than 1 year. Quality-adjusted life years were higher in LDKT than in HD patients. CONCLUSION: LDKT is cost effective during the first year after transplantation and is associated with enhanced quality of life. From both the medical and economic points of view, pre-emptive LDKD should be encouraged in Spain to reduce the health budget for ESRD.

Polyclonal versus monoclonal induction therapy in a calcineurin inhibitor-free immunosuppressive therapy in renal transplantation: a comparison of efficacy and costs.

BACKGROUND: Induction therapy in renal transplantation reduces the incidence of acute rejection (AR) in expanded criteria donation (ECD) and donation after cardiac death (DCD). We compared the efficacy of Thymoglobulin (Sanofi-Aventis, Spain), ATG Fresenius (ATG-Fresenius, Spain), and Simulect (Novartis Farm, Spain) in a calcineurin-free protocol in ECD and DCD renal transplantation by evaluating patient survival, graft survival, and AR at 1 year and overall costs. METHODS: An observational retrospective study was performed using our database of 289 consecutive cadaveric ECD renal transplant recipients (n = 178) and DCD recipients (n = 111) from April 1999 to December 2011. Induction therapy consisted of Simulect, Thymoglobulin, and ATG Fresenius. Calcineurin-inhibitor (CNI)-free maintenance therapy consisted of mycophenolate mofetil or sodium and steroids. RESULTS: There were no differences in the patients' demographic characteristics or patient and graft survival. One-year AR rates were equivalent (ECD: 10%, 19.1%, 17.7% versus DCD: 14.3%, 7.1%, 16.7%). Leukopenia and thrombopenia were significantly more frequent in the ECD group treated with polyclonal induction. The average total cost of transplantation was higher in the ECD group but there were no significant differences in the average total cost between ECD and DCD: 39,970.31 ± 7,732€ versus 35,058.34 ± 6,801€ (P = NS). CONCLUSION: Our study shows the same efficacy with polyclonal and monoclonal antibody induction and a CNI-free treatment regimen in ECD and DCD renal transplantation with no differences in overall costs at 1 year after transplantation.

Wnt pathway activation in long term remnant rat model.

Progression of chronic kidney disease (CKD) is characterized by deposition of extracellular matrix. This is an irreversible process that leads to tubulointerstitial fibrosis and finally loss of kidney function. Wnt/ ß-catenin pathway was reported to be aberrantly activated in the progressive damage associated with chronic organ failure. Extensive renal ablation is an experimental model widely used to gain insight into the mechanisms responsible for the development of CKD, but it was not evaluated for Wnt/ ß-catenin pathway. This study aimed to elucidate if the rat 5/6 renal mass reduction model (RMR) is a good model for the Wnt/ ß-catenin activation and possible next modulation. RMR model was evaluated at 12 and 18 weeks after the surgery, when CKD is close to end-stage kidney disease demonstrated by molecular and histological studies. Wnt pathway components were analyzed at mRNA and protein level. Our results demonstrate that Wnt pathway is active by increase of ß-catenin at mRNA level and nuclear translocation in tubular epithelium as well as some target genes. These results validate the RMR model for future modulation of Wnt pathway, starting at shorter time after the surgery.

Elimination of large uremic toxins by a dialyzer specifically designed for high-volume convective therapies.

BACKGROUND: Unlike conventional hemodialysis treatments, which rely almost solely on diffusion-related mechanisms for solute removal, hemodiafiltration (HDF) allows more efficient removal of higher molecular weight toxins due to convective transport mechanisms. To facilitate the removal of these toxins in HDF treatment modalities, dialyzers with highly efficient high-flux membranes are necessary. This study assessed the large uremic toxin removal ability of a high-flux dialyzer (FX CorDiax 60) specifically designed to facilitate convective therapies compared with a standard high-flux dialyzer (FX 60). METHODS: In an open, randomized, cross-over, single-center, controlled, prospective clinical study, 30 adult chronic hemodialysis patients were treated by post-dilution online HDF with the FX 60 or the FX CorDiax 60 dialyzer. All other dialysis parameters were kept constant in both study arms. The reduction rate (RR) of blood urea nitrogen, phosphate, ß2-microglobulin (ß2-m), myoglobin, prolactin, α1-microglobulin, α1-acid glycoprotein, albumin and total protein as well as the elimination into dialysate was intraindividually compared for the two dialyzer types. RESULTS: For FX CorDiax 60 versus FX 60, the RR was significantly higher for blood urea nitrogen (86.23 ± 4.14 vs. 84.89 ± 4.59%, p = 0.015), ß2-m (84.67 ± 3.79 vs. 81.30 ± 4.82%, p < 0.0001), myoglobin (75.23 ± 10.48 vs. 58.60 ± 12.1%, p < 0.0001), prolactin (72.96 ± 9.68 vs. 56.91 ± 13.01%, p < 0.0001) and α1-microglobulin (20.89 ± 18.27 vs. 13.60 ± 12.50%, p = 0.016). There were no significant differences in the RR for phosphate, α1-acid glycoprotein, albumin and total protein. Mass removal was significantly higher with the FX CorDiax 60 than with the FX 60 for ß2-m (0.26 ± 0.09 vs. 0.24 ± 0.09 g, p = 0.0006), myoglobin (1.83 ± 0.89 vs. 1.51 ± 0.76 mg, p = 0.0017), prolactin (0.17 ± 0.13 vs. 0.14 ± 0.08 mg, p = 0.02) and albumin (4.25 ± 3.49 vs. 3.01 ± 2.37 g, p = 0.03). CONCLUSIONS: This study demonstrates that treating patients with an FX CorDiax 60 instead of an FX 60 dialyzer in post-dilution HDF mode significantly increases the elimination of middle molecules.

Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.

Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.

Cinacalcet treatment for stable kidney transplantation patients with hypercalcemia due to persistent secondary hyperparathyroidism: a long-term follow-up.

BACKGROUND: Cinacalcet is an effective treatment for hypercalcemia due to persistent hyperparathyroidism (HPT) in patients who have undergone kidney transplantation (KT). Few data are available about their long-term follow-up. OBJECTIVE: We aimed to evaluate the long-term efficacy of cinacalcet in functioning stable KT subjects with hypercalcemia secondary to persistent HPT. MATERIAL AND METHODS: Twenty-three patients (6 men) with a stable KT showed persistent hypercalcemia (>12 months) secondary to HPT (parathyroid hormone by radioimmunoassay [iPTH] > 150 pg/mL). The mean age was 54 ± 13 years. Time after KT to beginning cinacalcet treatment was 36.5 ± 37.9 (range 12 to 172) months. Initial cinacalcet doses were 30 mg/d. Median follow-up was 53 ± 7.4 months (range 42 to 60 months). We determined serum calcium, phosphorus, alkaline phosphatase, iPTH, creatinine, and immunosuppressant concentrations at baseline as well as 3, 6, and 12 months and after every 6 months thereafter. RESULTS: Initial serum calcium was 11 ± 0.65 mg/dL and mean calcium during treatment, 10.25 ± 0.81 mg/dL (P < .001). Initial serum phosphorus was 2.8 ± 0.58 mg/dL and mean value serum phosphorus during the treatment period, 3.13 ± 0.6 mg/dL (P = 0.015). Initial iPTH was 260 ± 132 pg/mL and during the treatment period; 237 ± 131 pg/mL (P = ns). There was no change in renal function nor in immunosuppressant blood levels. Doses of cinacalcet at the end of the follow-up were 40.4 ± 18.9 mg/d. CONCLUSION: Cinacalcet was effective for long-term control of hypercalcemia related to persistent HPT for patients with stable KT.

Cinacalcet de novo in persistent hypercalcemia after kidney transplantation secondary to hyperparathyroidism: long-term follow-up and effect of withdrawal.

BACKGROUND: Secondary hyperparathyroidism that persists after kidney transplantation (KT), is the main cause of hypercalcemia. Cinacalcet has been used to control hypercalcemia in KT patients. OBJECTIVE: The aim of this study was to evaluate the effect of de novo cinacalcet in KT patients with hypercalcemia and the evolution after its withdrawal. METHODS: This observational study included 41 KT patients (17 men) with persistent hypercalcemia (>6 months), defined as serum calcium (sCa) ≥10.5 mg/dL, and a mean age of 51.1 ± 13.3 years with a functional allograft for >12 months. The time after surgery to begin cinacalcet was 33 months (range, 12.5-81.3). The initial dose of cinacalcet was 30 mg/d. In a subgroup of 14 patients cinacalcet was stopped after 1 year. We studied the evolution of serum levels of calcium, phosphorus, intact pathyroid hormone (iPTH), and serum creatinine. RESULTS: Calcemia normalized in all patients (sCa <10.2 mg/dL). iPTH decreased (basal 267 ± 212 pg/mL vs final: 219 ± 160 pg/mL; P = ns) Serum phosphorus increased (basal 2.85 ± 0.48 mg/dL vs final 3.16 ± 0.50 mg/dL; P = ns). Renal function remained stable (basal creatinine 1.49 ± 0.48 vs final 1.47 ± 0.32 mg/dL; P = ns). After stopping cinacalcet, in group 1 calcemia persisted at normal levels in 50% (n = 7), but the drug had to be reintroduced in the other 50% after 10 ± 7.9 months. No adverse events were documented. CONCLUSIONS: Cinacalcet is an effective alternative for the treatment of hypercalcemia in patients with persistent hyperparathyroidism after KT. Once the treatment is started, there is presently no invice to disclose to who tolerate its withdrawal or the time to do so.

Withdrawal of cinacalcet at the time of renal transplantation is not a risk factor for allograft calcifications in the early posttransplantation period.

BACKGROUND: Secondary hyperparathyroidism is a relevant problem in patients on dialysis. Cinacalcet in regular clinical practice increases the percentage of patients achieving treatment targets for PTH, Ca and P. We evaluated allograft calcification in serial protocol biopsies after transplantation among patients receiving Cinacalcet on dialysis but discontinued after surgery. METHODS: This retrospective single-centre study included kidney allograft recipients who were receiving Cinacalcet for more than 6 months before surgery and had it withdrawn thereafter. The 46 patients including 17 women showed a mean overall age of 54 ± 30 years. Protocol graft biopsy was performed at 3 and at 12 months. Biochemical analyses at the time of biopsy included blood levels of creatinine, phosphorus, calcium, alkaline phosphatases, iPTH, and proteinuria. RESULTS: Any biopsy showed nephrocalcinosis either intratubular calcifications, or in the parenchyma. There were no changes in calcemia (10.22 ± 0.7 to 10.27 ± 0.7 mg/dL), in alkaline phosphatase (259 ± 119.6 to 255 ± 122.3 mg/dL) nor in iPTH (317 ± 220.2 to 320 ± 168.8 pg/mL) between 3 and 12 months respectively. There was a slight but non-significant increase in serum phosphorus (2.79 ± 0.8 to 3.22 ± 0.9 mg/dL), serum creatinine (1.53 ± 0.6 to 1.84 ± 1.2 mg/dL) and proteinuria (528 ± 603 to 879 ± 1398 mg/24h) between 3 and 12 months respectively. CONCLUSIONS: Withdrawal of Cinacalcet at the time of renal transplantation was not a risk factor for allograft calcifications in the early post-transplant period.

Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.

Mixed cryoglobulinaemia not related to hepatitis C virus, mesangiocapillary glomerulonephritis and lymphoplasmocytic lymphoma.

Kidney involvement associated to lymphoma is a known phenomenon but frequently not characterized due to the low frequency with which biopsies are realized in these patients. Several histological patterns can co-exist and happen unnoticed without a biopsy. Parenchyma infiltration in kidney for lymphoma has been found in 34% (post-mortem) and 14% (pre-mortem) and have low incident of clinical manifestations. Other patterns of renal injury are associated to lymphoma and minimal changes disease is especially related with Hodgkin's lymphoma. Renal lesions associated to paraprotein in lymphoplasmacytic lymphoma are an exceptional association, in spite of in 20% of them, appear cryoglobulinemia. There are a few cases reported in the literature with different histological patterns: light-chain disease, amyloidosis, and immunotactoid glomerulopathy related with kidney injury in patients with lymphoma. A 39-year-old male presented an association among paraproteinemia, membrano-proliferative glomerulonephritis no hepatitis C virus related and lymphoplasmacytic lymphoma with renal infiltration. This case emphasized the variety of renal lesions that lymphomas could trigger and the value of the nephropathology in the diagnosis and outcome of the hematologic diseases with paraproteinemia.

Preemptive use of Mammalian target of rapamycin inhibitors in living donor transplantation.

UNLABELLED: Sirolimus (SRL) has demonstrated beneficial impacts on the development of chronic allograft dysfunction (CAD). In living donor transplantation, strategies mostly seek to prevent graft dysfunction and respond to a decline in renal function. The present study focused on proactive, preemptive SRL administration for patients with repeated renal transplantations and those engrafted with an extended criteria donor organ. MATERIAL AND METHODS: This retrospective, monocenter study describes 7 renal transplant recipients with stable graft function receiving SRL within the first year posttransplantation and 3 recipients of second transplantations who started SRL treatment before obtaining their repeat grafts. RESULTS: A proactive use of SRL revealed stable renal function parameters at 1 year after SRL introduction: Creatinine 1.33 ± 0.21 mg/dL; Modification of Diet in Renal Disease (MDRD) equation glomerular filtration rate, 57 ± 19 mL/min; PU 452 ± 338 mg/24 hours. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over the 1-year follow-up. SRL administration before retransplantation provided good graft survival and renal function with a creatinine of 1.2 ± .32 mg/dL, MDRD of 60 ± 28 mg/dL, and PU 502 ± 432 mg/24 hour. Cell counts, hemoglobin concentrations, as well as triglyceride and total cholesterol levels did not differ over 1-year follow-up. CONCLUSION: Preemptive SRL-induction before signs of graft deterioration or chronic injury may be a useful approach to prevent CAD.

Kidney transplantation and waiting list for renal transplantation for human immunodeficiency virus patients.

INTRODUCTION: The aim of this study was to evaluate the experience of a renal transplantation unit in the management of human immunodeficiency virus (HIV)-infected patients with end-stage renal disease (ESRD). METHODS: A prospective study was performed between 2005 and 2010 among 23 patients with ESRD. RESULTS: In this study 83% of HIV-infected patients with ESRD were included on the waiting list for renal transplantation with 4 patients in a clinical evaluation phase. During the follow-up, 52% of waiting list patients (n = 11) received a renal transplant, and 1 patient underwent a simultaneous kidney-pancreas transplantation. Among the waiting list group we observed a significant later exclusion (43%; n = 3). Among the transplanted group there was a high but clinically inconsequential prevalence of acute tubular necrosis (36%; n = 4) and acute rejection episodes (36%; n = 4). The renal function showed a serum creatinine of 1.1 mg/dL at a follow-up of 24 + 12 months. All patients on the waiting list and after the transplantation are prescribed combined antiretroviral treatment (cART) with a low viral load <50 with CD4 >200. CONCLUSIONS: HIV-infected patients with ESRD should be considered to be candidates for renal transplantation if they meet the HIV inclusion criteria. Renal transplantation in adequately selected HIV-infected patients is a safe procedure with acceptable patient and graft survivals.