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Living donor kidney transplantation (LDKT) is the best treatment option for end stage renal disease in terms of both patient and graft survival. However, figures on LDKT in Spain that had been continuously growing from 2005 to 2014, have experienced a continuous decrease in the last five years. One possible explanation for this decrease is that the significant increase in the number of deceased donors in Spain during the last years, both brain death and controlled circulatory death donors, might have generated the false idea that we have coped with the transplant needs. Moreover, a greater number of deceased donor kidney transplants have caused a heavy workload for the transplant teams. Furthermore, the transplant teams could have moved on to a more conservative approach to the information and assessment of patients and families considering the potential long-term risks for donors in recent papers. However, there is a significant variability in the LDKT rate among transplant centers and regions in Spain independent of their deceased donor rates. This fact and the fact that LDKT is usually a preemptive option for patients with advanced chronic renal failure, as time on dialysis is a negative independent factor for transplant outcomes, lead us to conclude that the decrease in LDKT depends on other factors. Thus, in the kidney transplant annual meeting held at ONT site in 2018, a working group was created to identify other causes for the decrease of LDKT in Spain and its relationship with the different steps of the process. The group was formed by transplant teams, a representative of the transplant group of the Spanish Society of Nephrology (SENTRA), a representative of the Spanish Society of Transplants (SET) and representatives of the Spanish National Transplant Organization (ONT). A self-evaluation survey that contains requests about the phases of the LDKT processes (information, donor work out, informed consent, surgeries, follow-up and human resources) were developed and sent to 33 LDKT teams. All the centers answered the questionnaire. The analysis of the answers has resulted in the creation of a national analysis of strengths, weaknesses, opportunities, threats (SWOT) of the LDKT program in Spain and the development of recommendations targeted to improve every step of the donation process. The work performed, the conclusions and recommendations provided, have been reflected in the following report: Spanish living donor kidney transplant program assessment: recommendations for optimization. This document has also been reviewed by a panel of experts, representatives of the scientific societies (Spanish Society of Urology (AEU), Spanish Society of Nephrology Nursery (SEDEN), Spanish Society of Immunology (SEI/GETH)) and the patient association ALCER. Finally, the report has been submitted to public consultation, reaching ample consensus. In addition, the transplant competent authorities of the different regions in Spainhave adopted the report at institutional level. The work done and the recommendations to optimize LDKT are summarized in the present manuscript, organized by the different phases of the donation process., (Copyright © 2022. Published by Elsevier España, S.L.U.)

The number of kidney transplant (KT) procedures with controlled donation after circulatory death (cDCD) donors has exponentially increased in Spain in recent years, with a parallel increase in donor and recipient acceptance criteria. The outcomes of cDCD-KT have been reported to be comparable to those of KT with donation after brain death (DBD) donors. However, studies in elderly recipients have yielded contradictory results. We performed a registry analysis of 852 KT recipients aged ≥65 years (575 in the DBD-KT group, 277 in the cDCD-KT group) in Catalonia, Spain. Clinical outcomes and survival were compared between DBD-KT and cDCD-KT recipients. The donor and recipient ages were similar between the two groups (71.5 ± 8.7 years for donors, 70.8 ± 4.1 years for recipients). Delayed graft function (DGF) was more frequent among cDCD-KT recipients, without a difference in the rate of primary nonfunction. The 3-year patient and death-censored graft survival rates were similar between DBD-KT and cDCD-KT recipients (78.8% vs. 76.4% and 90.3% vs. 86.6%, respectively). In multivariable analysis, previous cardiovascular disease and DGF were independent risk factors for patient death. The type of donation (cDCD vs. DBD) was not an independent risk factor for patient survival or graft loss. cDCD-KT and DBD-KT provide comparable patient and graft survival in elderly recipients., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: The treatment of coronavirus disease 2019 (COVID-19) is based on the patient's clinical status and levels of inflammatory biomarkers. The comparative activity of these biomarkers in kidney transplant (KT) patients with COVID-19 pneumonia from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and non-SARS-CoV-2 etiologies is unknown. The aim of this study was to compare the clinical presentation and inflammatory parameters at admission of KT patients with COVID-19 pneumonia and those with non-COVID-19 pneumonia over the same period., Methods: Biomarkers were measured and compared between KT patients with COVID-19 pneumonia (n = 57) and non-COVID-19 pneumonia (n = 20) from March 2020 to March 2021., Results: Both groups showed comparable demographics. The KT patients with COVID-19 had fewer neutrophils (6824 ± 5000 vs 8969 ± 4206; P = .09) than the non-COVID group, although there was no significant difference in the lymphocyte count. Non-COVID-19 pneumonia was associated with higher d-dimer (median, 921 [interquartile range (IQR), 495-1680] vs median, 2215 [IQR, 879-3934]; P = 0.09) and interleukin-6 (median, 35 [IQR, 20-128] vs median, 222 [IQR, 38-500]; P = 0.006) levels. The ferritin level was higher in the COVID-19 group (median, 809 [IQR, 442-1,330] vs median, 377 [IQR, 276-885]; P = 0.008). In multivariable analysis, only d-dimer (hazard ratio [HR], 1; 95% confidence interval [CI],1-1.002; P = .02) and ferritin (HR, 1; 95% CI, 0.9-0.9; P = .02) increase the statistic signification., Conclusion: COVID-19 pneumonia in KT patients shows a different presentation of inflammatory biomarkers than other non-COVID pneumonias. It could be useful to identify KT patients with COVID-19. More detailed studies are necessary to understand the presentation of biomarkers in KT with COVID-19., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Living donor kidney transplantation (LDKT) is the best treatment option for end stage renal disease in terms of both patient and graft survival. However, figures on LDKT in Spain that had been continuously growing from 2005 to 2014, have experienced a continuous decrease in the last five years. One possible explanation for this decrease is that the significant increase in the number of deceased donors in Spain during the last years, both brain death and controlled circulatory death donors, might have generated the false idea that we have coped with the transplant needs. Moreover, a greater number of deceased donor kidney transplants have caused a heavy workload for the transplant teams. Furthermore, the transplant teams could have moved on to a more conservative approach to the information and assessment of patients and families considering the potential long-term risks for donors in recent papers. However, there is a significant variability in the LDKT rate among transplant centers and regions in Spain independent of their deceased donor rates. This fact and the fact that LDKT is usually a preemptive option for patients with advanced chronic renal failure, as time on dialysis is a negative independent factor for transplant outcomes, lead us to conclude that the decrease in LDKT depends on other factors. Thus, in the kidney transplant annual meeting held at ONT site in 2018, a working group was created to identify other causes for the decrease of LDKT in Spain and its relationship with the different steps of the process. The group was formed by transplant teams, a representative of the transplant group of the Spanish Society of Nephrology (SENTRA), a representative of the Spanish Society of Transplants (SET) and representatives of the Spanish National Transplant Organization (ONT). A self-evaluation survey that contains requests about the phases of the LDKT processes (information, donor work out, informed consent, surgeries, follow-up and human resources) were developed and sent to 33 LDKT teams. All the centers answered the questionnaire. The analysis of the answers has resulted in the creation of a national analysis of strengths, weaknesses, opportunities, threats (SWOT) of the LDKT program in Spain and the development of recommendations targeted to improve every step of the donation process. The work performed, the conclusions and recommendations provided, have been reflected in the following report: Spanish living donor kidney transplant program assessment: recommendations for optimization. This document has also been reviewed by a panel of experts, representatives of the scientific societies (Spanish Society of Urology (AEU), Spanish Society of Nephrology Nursery (SEDEN), Spanish Society of Immunology (SEI/GETH)) and the patient association ALCER. Finally, the report has been submitted to public consultation, reaching ample consensus. In addition, the transplant competent authorities of the different regions in Spain have adopted the report at institutional level. The work done and the recommendations to optimize LDKT are summarized in the present manuscript, organized by the different phases of the donation process., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: In kidney transplantation, fibrosis represents the final and irreversible consequence of the pathogenic mechanisms that lead to graft failure, and in the late stages it irremediably precedes the loss of renal function. The invasiveness of kidney biopsy prevents this condition from being frequently monitored, while clinical data are rather unspecific. The objective of this study was to find noninvasive biomarkers of kidney rejection., Methods: We carried out proteomic analysis of the urinary Extracellular Vesicles (uEVs) from a cohort of kidney transplant recipients (n = 23) classified according to their biopsy-based diagnosis and clinical parameters as interstitial fibrosis and tubular atrophy (IFTA), acute cellular rejection (ACR), calcineurin inhibitors toxicity (CNIT) and normal kidney function (NKF)., Results: Shotgun mass spectrometry of uEV-proteins identified differential expression of several proteins among these different groups. Up to 23 of these proteins were re-evaluated using targeted proteomics in a new independent cohort of patients (n = 41) classified in the same diagnostic groups. Among other results, we found a differential expression of vitronectin (VTN) in patients displaying chronic interstitial and tubular lesions (ci and ct mean > 2 according to Banff criteria). These results were further confirmed by a pilot study using enzyme-linked immunosorbent assay (ELISA)., Conclusion: Urinary vitronectin levels are a potential stand-alone biomarker to monitor fibrotic changes in kidney transplant recipients in a non-invasive fashion.

The spleen is a secondary lymphoid organ with multiple functions including the removal of senescent red blood cells and the coordination of immune responses against blood-borne pathogens, such as malaria parasites. Despite the major role of the spleen, the study of its function in humans is limited by ethical implications to access human tissues. Here, we employed multiparameter flow cytometry combined with cell purification techniques to determine human spleen cell populations from transplantation donors. Spleen immuno-phenotyping showed that CD45 + cells included B (30%), CD4 + T (16%), CD8 + T (10%), NK (6%) and NKT (2%) lymphocytes. Myeloid cells comprised neutrophils (16%), monocytes (2%) and DCs (0.3%). Erythrocytes represented 70%, reticulocytes 0.7% and hematopoietic stem cells 0.02%. Extracellular vesicles (EVs) are membrane-bound nanoparticles involved in intercellular communication and secreted by almost all cell types. EVs play several roles in malaria that range from modulation of immune responses to vascular alterations. To investigate interactions of plasma-derived EVs from Plasmodium vivax infected patients (PvEVs) with human spleen cells, we used size-exclusion chromatography (SEC) to separate EVs from the bulk of soluble plasma proteins and stained isolated EVs with fluorescent lipophilic dyes. The integrated cellular analysis of the human spleen and the methodology employed here allowed in vitro interaction studies of human spleen cells and EVs that showed an increased proportion of T cells (CD4+ 3 fold and CD8+ 4 fold), monocytes (1.51 fold), B cells (2.3 fold) and erythrocytes (3 fold) interacting with PvEVs as compared to plasma-derived EVs from healthy volunteers (hEVs). Future functional studies of these interactions can contribute to unveil pathophysiological processes involving the spleen in vivax malaria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gualdrón-López, Díaz-Varela, Toda, Aparici-Herraiz, Pedró-Cos, Lauzurica, Lacerda, Fernández-Sanmartín, Fernandez-Becerra and del Portillo.)

Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients.

Plasmodium vivax is the most widely distributed human malaria parasite. Previous studies have shown that circulating microparticles during P. vivax acute attacks are indirectly associated with severity. Extracellular vesicles (EVs) are therefore major components of circulating plasma holding insights into pathological processes. Here, we demonstrate that plasma-derived EVs from Plasmodium vivax patients (PvEVs) are preferentially uptaken by human spleen fibroblasts (hSFs) as compared to the uptake of EVs from healthy individuals. Moreover, this uptake induces specific upregulation of ICAM-1 associated with the translocation of NF-kB to the nucleus. After this uptake, P. vivax-infected reticulocytes obtained from patients show specific adhesion properties to hSFs, reversed by inhibiting NF-kB translocation to the nucleus. Together, these data provide physiological EV-based insights into the mechanisms of human malaria pathology and support the existence of P. vivax-adherent parasite subpopulations in the microvasculature of the human spleen.

The SARS-CoV-2 (Covid-19) coronavirus pandemic is evolving very quickly and means a special risk for both immunosuppressed and comorbid patients. Knowledge about this growing infection is also increasing although many uncertainties remain, especially in the kidney transplant population. This manuscript presents a proposal for action with general and specific recommendations to protect and prevent infection in this vulnerable population such as kidney transplant recipients., (Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum β-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose ® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events., (© 2019 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Background: Direct-acting antivirals (DAA) allow effective and safe eradication of hepatitis C virus (HCV) in most patients. There are limited data on the long-term effects of all-oral, interferon-free DAA combination therapies in kidney transplant (KT) patients infected with HCV. Here we evaluated the long-term tolerability, efficacy, and safety of DAA combination therapies in KT patients with chronic HCV infection., Methods: Clinical data from KT patients treated with DAA were collected before, during, and after the treatment, including viral response, immunosuppression regimens, and kidney and liver function., Results: Patients (N = 226) were mostly male (65.9%) aged 56.1 ± 10.9 years, with a median time from KT to initiation of DAA therapy of 12.7 years and HCV genotype 1b (64.6%). Most patients were treated with sofosbuvir-based therapies. Rapid virological response at 1 month was achieved by 89.4% of the patients and sustained virological response by week 12 by 98.1%. Liver function improved significantly after DAA treatment. Tacrolimus dosage increased 37% from the beginning of treatment (2.5 ± 1.7 mg/d) to 1 year after the start of DAA treatment (3.4 ± 1.9 mg/d, P < 0.001). Median follow-up was 37.0 months (interquartile range, 28.4-41.9) and death-censored graft survival was 91.1%. Adverse events resulting from DAA treatment, especially anemia, were reported for 31.0% of the patients., Conclusions: Chronic HCV infection can be treated efficiently and safely with DAA therapy in KT patients. Most patients retained stable kidney function and improved liver function. Tacrolimus dose had to be increased in most patients, potentially as a result of better liver function., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) is a serious complication after kidney transplantation. FSGS relapse is suspected by a sudden increase in proteinuria but there is not an accurate noninvasive diagnostic tool to confirm this entity or to detect patients at risk. We aimed to validate the diagnostic performance of ApoA-Ib to detect FSGS relapses by measuring urinary ApoA-Ib in a retrospective cohort of 61 kidney transplanted patients (37 FSGS and 24 non-FSGS). In addition, to assess the ApoA-Ib predictive ability, ApoA-Ib was measured periodically in a prospective cohort of 13 idiopathic FSGS patients who were followed during 1 year after transplantation. ApoA-Ib had a sensitivity of 93.3% and a specificity of 90.9% to diagnose FSGS relapses, with a high negative predictive value (95.2%), confirming our previous results. In the prospective cohort, ApoA-Ib predated the recurrence in four of five episodes observed. In the nonrelapsing group (n = 9), ApoA-Ib was negative in 37 of 38 samples. ApoA-Ib has the potential to be a good diagnostic biomarker of FSGS relapses, providing a confident criterion to exclude false positives even in the presence of high proteinuria. It has also the potential to detect patients at risk of relapse, even before transplantation., (© 2018 Steunstichting ESOT.)

Background: Kidney transplantation (KTx) is the best therapeutic approach for chronic kidney diseases leading to irreversible kidney failure. Considering the origin of the graft, several studies have reported differences between living (LD) and deceased donors (DD) in graft and patient survival. These differences seem to be related to multiple factors including, donor age and time of cold ischemia among others. Many of transplanted organs come from old-aged DDs, in which pre-transplant biopsy is recommended. However, kidney biopsy has several limitations, and there is a need to develop alternatives to assess the status of a kidney before transplantation. As the analysis of urinary extracellular vesicles (uEVs) rendered promising results as non-invasive biomarkers of kidney-related pathologies, this pilot study aimed to investigate whether profiling uEVs of LDs and DDs may be of help to assess the quality of the kidney before nephrectomy., Methods: uEVs from 5 living donors and 7 deceased donors were isolated by size-exclusion chromatography, and their protein and miRNA content were analysed by liquid chromatography followed by mass spectrometry and next generation sequencing, respectively. Then, hierarchical clustering and venn diagrams were done with Perseus software and InteractiVenn tool. Specific EVs data bases were also used for Gene Ontology analysis., Results: Next generation sequencing revealed that uEVs from DDs contained less miRNAs than LDs, but most of the DD-expressed miRNAs were shared with LDs (96%). Only miR-326 (targeting the apoptotic-related Bcl2) was found significantly over-represented in LD. Focusing on the protein content, we detected a low intra-group correlation in both types of donors. Despite these differences, hierarchical clustering of either miRNA or protein data could not identify a differential profile between LDs and DDs. Of note, 90% of transplanted patients had a functional graft after a year from KTx., Conclusions: In this pilot study we found that, in normo-functional grafts, minor differences in uEVs profile could not discriminate between LDs and DDs.

Introduction: Secondary hyperparathyroidism (SHPT) and vitamin D deficiency are common at kidney transplantation and are associated with some early and late complications. This study was designed to evaluate whether paricalcitol was more effective than nutritional vitamin D for controlling SHPT in de novo kidney allograft recipients., Methods: This was a 6-month, investigator-initiated, multicenter, open-label, randomized clinical trial. Patients with pretransplantation iPTH between 250 and 600 pg/ml and calcium <10 mg/dl were randomized to paricalcitol (PAR) or calcifediol (CAL). The intention-to-treat population (PAR: n = 46; CAL: n = 47) was used for the analysis. The primary endpoint was the percentage of patients with serum iPTH >110 pg/ml at 6 months. Secondary endpoints were bone mineral metabolism, renal function, and allograft protocol biopsies., Results: The primary outcome occurred in 19.6% of patients in the PAR group and 36.2% of patients in the CAL group ( P  = 0.07). However, there was a higher percentage of patients with iPTH <70 pg/ml in the PAR group than in the CAL group (63.4% vs. 37.2%; P  = 0.03). No differences were observed in bone turnover biomarkers and bone mineral density. The estimated glomerular filtration rate was significantly higher in the CAL group than in the PAR group without differences in albuminuria. In protocol biopsies, interstitial fibrosis and tubular atrophy tended to be higher in the PAR group than in the CAL group (48% vs. 23.8%; P  = 0.09). Both medications were well tolerated., Conclusion: Both PAR and CAL reduced iPTH, but PAR was associated with a higher proportion of patients with iPTH <70 pg/ml. These results do not support the use of PAR to treat posttransplantation hyperparathyroidism.

Background: Chronic immunosuppression promotes nonmelanocytic squamous cell carcinoma (SCC) after kidney transplantation. Adaptive and innate immunity play a key role controlling tumor growth and are influenced by different immunosuppressive agents. We hypothesized that functional impairment of tumor-specific T cell responses due to calcineurin inhibitors (CNI) could contribute to SCC development, whereas conversion to mammalian target of rapamycin inhibitors (mTOR-i) could recover this protective immune response., Methods: Peripheral tumor-specific T cell responses against main SCC-derived antigens using the IFN-γ enzyme-linked immunospot assay and intratumor (IT) and circulating immune phenotypes (CD4 + T, CD8 + T, CD20 + B, CD56 + NK, FOXP3 + regulatory T [Treg] cells) were explored in a cross-sectional analysis in 59 kidney transplant patients with SCC on CNI (KT-CNI-SCC) or mTOR-i (KT-mTORi-SCC), 25 nontransplants developing SCC (NoKT-SCC) and 6 healthy controls. Moreover, 25 KT-CNI-SCC were switched to mTOR-i and evaluated after 12 months., Results: Kidney transplant patients showed lower IT infiltrates and tumor-specific T cell responses than NoKT-SCC, and intratumoral and circulating FOXP3 + Treg cells were higher in KT-mTORi-SCC (P < 0.05). Tumor-specific T cell responses were significantly lower in KT-CNI-SCC than KT-mTORi-SCC and NoKT-SCC and predicted SCC relapses (area under the curve = 0.837; P < 0.05). One-year after mTOR-i conversion, a significant increase in FOXP3 + Treg cell numbers and tumor-specific T cell responses were observed, reaching similar levels than KT-mTORi-SCC and NoKT-SCC patients., Conclusions: Tumor-specific T cell responses are strongly impaired in CNI-treated patients but recover after mTOR-i conversion, reducing SCC relapses.

Patients with chronic kidney disease (CKD) are characterized by a state of inflammation and oxidative stress that seems to improve after kidney transplantation (KT). Nevertheless, there is controversy regarding what is the best marker that better define inflammation and specially oxidative stress., Objective: To evaluate the biomarkers which are associated with improvements in inflammation and lipid peroxidation in patients who have undergone KT. To evaluate the relationship between inflammation, lipid peroxidation and mortality in KT., Patients: 196 KT (between 2003 and 2008). 67.9% men; median age: 51.9 years. Inflammation markers analyzed previous KT and 3 months after KT: c-reactive protein(CRP), interleukin 6(IL-6), tumor necrosis factor alpha(TNFα), soluble tumor necrosis factor receptor alpha(sTNFRα), soluble interleukin-2 receptor (sIL-2R). Lipid peroxidation markers analyzed: oxidized low-density lipoprotein (oxLDL) and anti-oxLDL antibodies. Calculation of glomerular filtration rate after KT: MDRD equation., Results: Following KT, there is a significant decrease in CRP (p = 0.006), IL-6 (p = 0.0037), TNFα (p < 0.0001), sTNFRα (p < 0.0001) and sIL-2R (p < 0.0001), while levels of oxLDL increase after KT (p < 0.0001) and there is not a significantly difference in anti-oxLDL. 12.8% of the patients had died in 2012. These patients had higher levels of IL-6 (p = 0.011) and sTNFRα (p < 0.006) after KT and a lower MDRD (p < 0.0001), hemoglobin (p = 0.012) and albumin (p = 0.007). We observed no statistically differences in the levels of markers previous KT. Of the patients who died, the 43.5% of them had anti-oxLDL antibody levels greater than 75th percentile (P 75 : 3781 UI/ml, p = 0.028). In the multivariate analysis, age (OR:1.12; p = 0.0129), MDRD (OR:0.92; p = 0.013) and P 75 of anti-oxLDL(OR: 5.19; p = 0.026) were independent risk factors for mortality. Independent risk factors for survival were: P 75 of IL-6 (HR: 2.45; p = 0.027), oxLDL (HR:19.85; p = 0.002) and anti-oxLDL (HR: 9.55; p = 0.003)., Conclusions: KT improved inflammation but not lipid oxidative state. KT patients who died had a higher inflammatory state (with higher levels of IL-6 and sTNFRα), a worse lipid oxidative state and a worse renal function 3 months after KT. Age, anti-oxLDL and renal function at 3 months after KT were independent risk factors for mortality.

Background: Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time., Methods: Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency., Results: One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively., Conclusions: In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Secondary hyperparathyroidism is a common complication in patients with chronic kidney disease and frequently persists after kidney transplantation. Paricalcitol, a selective vitamin D receptor activator, is indicated in the management of this disorder and recent evidences have suggested that this drug has other beneficial effects. Aiming to elucidate these effects, our study included 52 stable kidney transplant recipients randomized 2:1 to treatment with paricalcitol or to no treatment. Bone mineral parameters, kidney function and inflammatory status were assessed at baseline, at 3 and at 12 months. Moreover, a proteomic approach, based on magnetic beads technology coupled to MALDI-TOF mass spectrometry readout, was used to determine changes in patients' plasma peptidome. Patients treated with paricalcitol showed a significant decrease in parathyroid hormone and alkaline phosphatase levels, and an increase of bone mineral density and glomerular filtration rate. The proteomic analysis revealed a decrease in bradykinin after paricalcitol treatment, whereas 2 peptides identified as fragments of the complement factor C4 decreased only in those patients not treated with paricalcitol. These findings suggest that paricalcitol may offer additional benefits due to immunomodulatory effects via the kallikrein-kinin and complement systems., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Organ transplants in elderly recipients have increased over the past few years. This situation poses specific problems both in terms of organs and recipients; therefore, immunosuppressant regimens must be adapted accordingly. A previous study demonstrated good initial results in kidney transplant cases in which older donors and recipients (average ages of 64.4 years and 61.3 years) had received initial immunosuppressant therapy with daclizumab and mycophenolate mofetil as well as delayed introduction of reduced-dose tacrolimus. In this study we reviewed the long-term results in the same group of patients., Methods: An observational, retrospective multi-centre study carried out at a national level to determine survival rates and renal function in 126 patients included in the initial study (127 patients who survived the first year with a functioning graft, 123 treated according to protocol). We gathered data from the 2nd to the 6th year for 120, 118, 113, 102 and 62 patients, respectively. The evolution of renal function, relevant clinical data, and safety profiles were also analysed., Results: After five years, most patients continued with the initial immunosuppressant regimen: 92% tacrolimus and 80% mycophenolate mofetil; 48% had abandoned steroids and proliferation signal inhibitors had been introduced in 3%. Patient and graft survival (adjusted for patient death) after five years was 93.1% and 93.8%, respectively. The main cause of death was neoplasia (in 7 out of 10 cases) whilst graft loss was mainly due to death with a functioning graft. The other causes of death were 2 acute myocardial infarctions and a gastrointestinal haemorrhage. Renal function was moderately but significantly reduced with the passing of time (P<.001): average creatinine levels in the overall group of patients rose from 1.60 ± 0.50mg/dl after the 1st year to 1.63 ± 0.70 mg/dl at the end of study. MDRD dropped from 46.28 ± 15.64 ml/min after the 1st year to 45.69 ± 15.44 ml/min at the end of study (P<.01). Only two acute rejections were observed after the 1st year. There were 19 cardiovascular events registered in 12 patients., Conclusions: The regimen used in our study was useful and appropriate for elderly donor-recipient pairs as demonstrated by the good long-term survival results, continued optimum renal function, and acceptable safety profile.

Unlabelled: The aim of this study was to analyze the relationship between pre-transplant adiponectin (pre-ADP), abnormalities in glucose homeostasis (AGH) at three months post-transplantation, and preclinical atherosclerosis in non-diabetic patients prior to kidney transplantation (KT)., Methods: We carried out a multicenter study in 157 non-diabetic KT patients (66.5% men; age: 50±13 yr). Pre-ADP levels were analyzed using radioimmunoassay. Carotid ultrasound was performed to determine carotid intima-media thickness (c-IMT). Oral glucose tolerance test was carried out to classify patients according ADA criteria., Results: Of the patients, 52.8% had AGH. Median pre-ADP was 19.5 (14-27) μg/mL. An inverse correlation was found between ADP and HOMA index (r=-0.432; p<0.001). Median c-IMT was 0.6 (0.48-0.71) mm. Significant inverse correlation existed between ADP and c-IMT on both sides (p<0.05). Patients with c-IMT >0.6 mm had more AGH (p=0.012) and lower ADP levels (p=0.02). We performed a logistic regression analysis using preclinical atherosclerosis (c-IMT ≥0.6 mm) as dependent variable and sex, age, BMI, ADP, AGH, and HOMA index as independent variables of altered c-IMT. Age, pre-ADP, and AGH were independent risk factors for elevated c-IMT., Conclusions: Patients with AGH have a greater presence of preclinical atherosclerosis. ADP has an inverse relationship with AGH and is an independent marker of preclinical atherosclerosis., (© 2011 John Wiley & Sons A/S.)

This multicenter, open, phase IIIb study assessed short-term efficacy, safety and dose adjustments in adult stable renal transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients receiving unchanged tacrolimus BID for ≥ 12 weeks were enrolled, and after 6-weeks, converted from tacrolimus BID to QD (morning dose) on a 1 : 1 (mg : mg) total daily dose basis, for a further 12 weeks. Primary endpoint: change in steady-state creatinine clearance between treatment phases. Secondary endpoints: biopsy-proven acute rejection (BPAR), patient and graft survival, safety. 128 patients enrolled (mean age 48.9 years; time post-transplant 48.9 months); 91 evaluated for the primary endpoint. Mean total daily dose was 0.06 mg/kg (BID) and 0.07 mg/kg (QD); 79.1% required one/no dose changes post-conversion to maintain recommended blood-trough levels; average dose increase was small (0.6-0.7 mg/day) with more dose increases in patients on the lowest tacrolimus BID doses. Renal function remained stable and non-inferiority of tacrolimus QD against tacrolimus BID was demonstrated. There were no BPAR episodes; patient and graft survival were 100%. Adverse events were few; none led to dose modifications/discontinuation. Tacrolimus BID to tacrolimus QD conversion is straightforward and does not compromise renal function in stable kidney transplant patients in the short term., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

Background/aims: Statins are prescribed in kidney transplant recipients in order to manage dyslipidemia, a common complication in these patients. The efficacy of statins in reducing cholesterol levels has been accompanied by pleiotropic effects. Fifty-four kidney transplant patients were included in the present study, the objective of which was to ascertain the effect of 12 weeks of atorvastatin therapy (10 mg/day) on the patients' lipid profile, renal function, markers of inflammation and plasma peptide profile., Methods: Biochemical variables were determined with a routine clinical laboratory analyzer, and the proteomic approach was based on magnetic particle-assisted sample processing coupled to mass spectrometry readout., Results: Atorvastatin therapy improved the lipid profile of patients and caused significant changes in their plasma peptide profile; peptides with m/z 1063 and 1898 decreased after treatment and were identified as fragments derived from molecules involved in vascular inflammation, i.e. high-molecular-weight kininogen and complement factor C4, respectively., Conclusion: These findings may contribute to the growing body of evidence of the anti-inflammatory actions attributed to statins, by which these drugs could improve these patients' clinical status., (Copyright © 2011 S. Karger AG, Basel.)

Background. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) decrease cardiovascular mortality and slow the progression of renal disease in non-transplant patients, but their impact on kidney transplant outcome has not been well established.Methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered for the present study. Only adult (>/=18 years) recipients of a single kidney transplant functioning at the end of the first year were considered. A total of 4842 patients with clinical data about ACEI/ARB therapy were included.Results. During the initial 2 years after transplant, ACEI/ARB were less frequently used in the 1990 and 1994 cohorts than in 1998 and 2002 (15.1%, 24.6%, 33.5% and 45.1%, respectively; P < 0.001). During the first year, a total of 1063 patients (22.8%) received ACEI/ARB treatment, and graft survival (50.0% for treated patients and 51.4% for untreated, P = ns), death-censored graft survival (60.6% versus 63.5%, P = ns) and patient survival (68.8% versus 66.6%, P = ns) were not different. During the initial 2 years, 1472 patients (31.4%) received treatment with ACEI/ARB, and graft survival tended to be higher in treated patients (54.4% and 50.9%, P = 0.063). Since there was an interaction between ACEI/ARB treatment and year of transplant, graft survival was analysed in each cohort. Cox regression analysis including the propensity score for ACEI/ARB treatment showed an association between ACEI/ARB treatment and graft survival in the 2002 cohort (relative risk 0.36 and 95% confidence interval 0.17-0.75, P = 0.007). Death-censored graft survival (63.8% versus 63.1%, P = ns) and patient survival (68.1% and 66.5%, P = ns) were not significantly different.Conclusions. The use of ACEI/ARB during the initial 2 years after transplantation was associated with a better graft survival, but this effect was only observed in the 2002 cohort.

Objective: Patients on dialysis display increased inflammation (IF) and oxidative stress (OS). Diabetes mellitus (DM) may increase both processes. The role of transplantation in this situation is unknown. Herein we have assessed the evolution of IF and OS following grafting and its relationship to a prior diagnoses of DM and to kidney function at 1 year., Patients and Methods: This prospective study included 131 dialysis patients who underwent transplantation of mean age 54 +/- 12 years, including 68% men with 19.5% showing prior DM. The following markers of IF and OS were determined prior to and at 3 months after grafting: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), soluble TNFalpha receptor (sTNFalpha-R), soluble IL-2 receptor (sIL-2R), oxidized LDL (oxLDL), and anti-oxLDL antibodies (oxLDLab). The evolution (ratio) of these markers was assessed by dividing the values at 3 months by the prior ones. Modification of Diet in Renal Disease (MDRD) was determined at 12 months., Results: Patients with prior DM were older (P = .034). There were no differences in the pregrafting phase between diabetics and nondiabetics in relation to IF or OS. IF and OS showed a worse evolution postgrafting among patients with prior DM. At 1 year postgrafting renal function was greater in patients without prior DM (P = .022). There was an inverse correlation between the ratios of markers and kidney function at 1 year postgrafting: TNFalpha: r = -.235 (P = .012); sIL-2R: r = .441 (P < .001); and sTNFalpha-R: r = .225 (P = .017)., Conclusions: In the pregrafting phase, there were no differences between patients with or without DM in terms of IF and OS. These differences appeared in the postgrafting phase: patients with DM showed greater IF and OS, an increase that may explain the poor kidney function observed at 1 year among patients with DM.

Statins are prescribed to reduce posttransplant dyslipidemia, which is frequent among kidney graft recipients. Their efficacy to reduce cholesterol levels has been accompanied by pleiotropic effects. Proteomics is the study of the expressed complement of proteins in tissues or biological fluids. It includes the identification of changes in proteins that occur in various states, eg, after drug administration. Our study objectives were: (1) to analyze the effect of atorvastatin (10 mg/d) on lipid profile, renal function, proteinuria, and inflammation parameters, such as C-reactive protein (CRP), and (2) to use proteomics to ascertain whether this treatment modified the patients' urinary peptide profiles seeking to understand the molecular actions of the drug. Urinary peptide profiles, lipids, renal function parameters (creatinine clearance), proteinuria, and CRP were determined in 39 patients at baseline and at 12 weeks after atorvastatin treatment (10 mg/d). The peptide fraction of each sample acquired using magnetic beads was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Our results showed that treatment with atorvastatin produced a significant reduction in lipid profile, but did not modify renal function (creatinine clearance), proteinuria, or CRP. The proteomic study showed that statin treatment did not produce significant changes in the urinary peptidome, although there was a tendency for some peptides to increase or decrease after the treatment.

Objective: To evaluate the differences in perceived state of health (PSH) according to patient age younger or older than 60 years., Patients and Methods: One hundred sixty-two patients were entered on the waiting list for renal transplantation from July 2003 at 4 hospitals in California and were observed prospectively for 2 years. Data were obtained at baseline and at 3 and 12 months after transplantation. All patients answered a generic Perceived State of Health (PSH) questionnaire, the 36-item Short-Form Health Survey (SF-36), and the EuroQol (EQ-5D) questionnaire. Data were analyzed using the t test for independent variables and the chi(2) test for contingency tables., Results: Patients aged 60 years or older had higher PSH scores compared with those younger than 60 years on all dimensions of the SF-36 and on the 2 summary scores. Scores for the physical domains were significantly improved at all follow-up visits. After transplantation, scores for the EQ-5D were higher for older patients vs younger patients (mean [SD], 80 [16] vs 67 [14]; P = .01). The PSH score for the older patients was similar to that for the general population (>45 points). The PSH scores for the physical and mental health domains were worse for the younger patients compared with the general population; no differences were noted for clinical variables., Conclusion: Patients older than 60 years have higher PSH scores compared with patients younger than 60 years. However, scores for the younger patients were significantly improved at 1 year after transplantation.

Hepcidin is a hormone that regulates the intestinal absorption of iron and its release from the reticuloendothelium. The objective of this study was to determine the use of hepcidin for kidney disease patients with a diagnosis of iron deficiency pretransplantation by evaluating the soluble transferrin receptor (sRTfR-F) index as a marker for iron deficiency. This transverse study of 164 pretransplant patients determined hematometry and conventional markers related to iron metabolism, as well as soluble transferrin receptor (sTfR), its index (sTfR-F), and serum hepcidin concentrations. The following markers of inflammation (MIF) were also assessed C-reactive protein (hs-CRP), interleukin-6 (IL-6), soluble IL-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and soluble TNF-alpha receptor (s-TNF-alphaR). Among the studied patients, 11.4% showed an absolute iron deficiency with ferritin concentrations < 100 ng/mL, a mean hepcidin value of 120.7 +/- 38.5 ng/mL, and a mean sTfR-F value of 1.03 +/- 0.3; 18.2% of patients displayed a ferritin > 800 ng/mL with mean hepcidin and sTfR-F values of 147.5 +/- 36.6 ng/mL and 0.54 +/- 0.2, respectively. Iron deficiency was not observed in the other patients when considering the conventional markers: ferritin > 100 ng/mL and transferrin saturation (ST) > 20%. However, this study showed that determination of hepcidin concentrations together with M/F improved the identification of iron deficiency in pretransplant patients by 21.6%.

Background: Insulin-resistance hyperinsulinemia is a novel risk factor for renal disease in the general population. Glomerular hyperfiltration has been proposed as an early consequence of hyperinsulinemia., Methods: In this multicenter cohort study, we analyzed 202 patients without diabetes before or after renal transplantation during the first posttransplant year. Insulin was measured at 3 and 12 months. The majority of patients (91%) were on calcineurin inhibitors. Patients were classified as with persistent normo or hyperinsulinemia when situated below or above the median value of insulin (3 months: 9 muU/mL; 12 months: 8.74 muU/mL) at both periods. The 3 to 12 months percent change in calculated creatinine clearance (3-12 months DeltaCrCL) was calculated., Results: Patients with persistent hyperinsulinemia showed a higher increase in 3 to 12 months DeltaCrCL compared with those with persistent normoinsulinemia (12% [-20/40] vs. -0.03% [-12/18], P=0.035). We performed a multivariate linear regression analysis with the 3 to 12 months DeltaCrCL as the dependent variable and different factors that may induce hyperfiltration, including persistent hyperinsulinemia, as covariates. Persistent hyperinsulinemia was a risk factor for increased CrCL (beta 0.09, 95% CI 0.07/0.12, P=0.035)., Conclusion: In nondiabetic recipients during the first posttransplant year, hyperinsulinemia induced increments in CrCL. As this may herald future renal dysfunction, hyperinsulinemia should not be ignored as a potential target in this population.

This study assays therapy with basiliximab and different patterns of cyclosporin A (CsA) initiation in renal transplant (RT) recipients from expanded criteria donors (ECD) and at high risk of delayed graft function (DGF). A multicentre six-month open-label randomized trial with three parallel groups treated with basiliximab plus steroids, mycophenolate mofetil and different patterns of CsA initiation: early within 24 h post-RT at 3 mg/kg/d (Group 1; n = 38), and at 5 mg/kg/d (Group 2; n = 40), or delayed after 7-10 d at 5 mg/kg/d (Group 3; n = 36). There were no differences among groups in six months GFR (43.1 +/- 12, 48.0 +/- 14 and 47.2 +/- 17 mL/min, respectively), DGF (Group 1: 31%, Group 2: 37%, Group 3: 42%), nor biopsy-proven acute rejection, although clinically treated and biopsy-proven acute rejection was significantly higher in Group 3 (25%) vs. Group 1 (5.3%, p < 0.05). At six months no differences were observed in death-censored graft survival or patient survival. Induction therapy with basiliximab and three CsA-ME initiation patterns in RT recipients from ECD and at high risk of DGF presented good renal function and graft survival at six months. Late onset group did not achieve improvement in DGF rate and showed a higher incidence of clinically treated and biopsy-proven acute rejection.

Background: Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial., Methods: The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria., Results: A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33)., Conclusions: In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

Background and Objectives: Emerging information indicates that glucose metabolism alterations are common after renal transplantation and are associated with carotid atheromatosis. The aims of this study were to investigate the prevalence of different glucose metabolism alterations in stable recipients as well as the factors related to the condition., Design, Setting, Participants, & Measurements: A multicenter, cross-sectional study was conducted of 374 renal transplant recipients without pre- or posttransplantation diabetes. A standard 75-g oral glucose tolerance test was performed., Results: Glucose metabolism alterations were present in 119 (31.8%) recipients: 92 (24.6%) with an abnormal oral glucose tolerance test and 27 (7.2%) with isolated impaired fasting glucose. The most common disorder was impaired glucose tolerance (17.9%), and an abnormal oral glucose tolerance test was observed for 21.5% of recipients with a normal fasting glucose. By multivariate analysis, age, prednisone dosage, triglyceride/high-density lipoprotein cholesterol ratio, and beta blocker use were shown to be factors related to glucose metabolism alterations. Remarkably, triglyceride levels, triglyceride/high-density lipoprotein cholesterol ratio, and the proportion of recipients with impaired fasting glucose were already higher throughout the first posttransplantation year in recipients with a current glucose metabolism alteration as compared with those without the condition., Conclusions: Glucose metabolism alterations are common in stable renal transplant recipients, and an oral glucose tolerance test is required for its detection. They are associated with a worse metabolic profile, which is already present during the first posttransplantation year. These findings may help planning strategies for early detection and intervention.

Background: Tacrolimus-based immunosuppression, the most widely used regimen in kidney transplantation, increases the risk of new onset diabetes after transplantation (NODAT). However, the prevalence, evolution and risk factors of different prediabetic alterations: impaired fasting glucose, impaired glucose tolerance, and provisional diabetes, have not been established., Methods: In this multicenter and prospective study we evaluated 154 nondiabetic kidney transplant recipients receiving tacrolimus, mycophenolate mofetil and low dose steroids. An oral glucose tolerance test was performed 3 and 12 months after transplantation and prediabetes was defined by American Diabetes Association criteria., Results: Prediabetes was highly prevalent and showed little variation between 3 and 12 months (36% and 33%, respectively). Impaired glucose tolerance was the most frequent abnormality observed (23% and 25%, respectively) observed. In addition, 20% of recipients showed NODAT by 1 year. Multivariate analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.004-1.14), pretransplant body mass index (OR: 1.3, CI: 1.09-1.6) and triglyceride/high density lipoprotein-cholesterol ratio, a marker of insulin resistance, (OR: 1.4, CI: 1.05-1.9) were independent risk factors for prediabetes., Conclusion: One in two recipients with tacrolimus-based immunosuppresion showed prediabetes or NODAT by 1 year posttransplantation when properly investigated. Older age and high pretransplant body mass index and triglyceride/high density lipoprotein-cholesterol ratio were risk factors for prediabetes. These findings may help applying early interventions to prevent the disorder.

Background: Inflammation plays an important role in the pathogenesis of ischemic acute kidney injury (IAKI). In this study, we hypothesize that transplant recipients with pretransplant inflammation may have a greater chance of developing delayed graft function (DGF), an example of IAKI., Patients and Methods: We analyzed 178 patients who had undergone their first transplant using cadaveric donors. Blood samples were extracted from transplant recipients prior to transplantation. C-reactive protein (CRP) (nephelometry); interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) (automatized enzyme chemiluminescence immunometric assay); and pregnancy-associated plasma protein A (PAPP-A) (enzyme-linked immunosorbent assay) were determined using the pretransplant blood samples. The risk factors analyzed included cold ischemia, type and time of dialysis, donor and recipient age and HLA compatibility., Results: Sixty-one patients (34.3%) developed DGF. Pretransplant TNF-alpha (9.31 +/- 2.57 vs. 10.56 +/- 3.82 pg/mL; p=0.039) and PAPP-A (1.25 +/- 0.74 vs. 1.90 +/- 1.56 mU/L; p=0.002) were significantly elevated in the group of patients with DGF. Univariate analysis showed that PAPP-A, TNF-alpha, cold ischemia, type of dialysis (hemodialysis) and donor age were associated with DGF. Multivariate analysis showed that PAPP-A (p=0.006), cold ischemia (p=0.009) and type of dialysis (p=0.046) were independent risk factors for DGF., Conclusions: Pretransplant inflammation (TNF-alpha, PAPP-A) in transplant recipients could be a risk factor for the development of DGF.

Background: Abnormalities in glucose homeostasis (AGH) frequently occur in kidney transplantation and favor vascular lesions. The purpose of this study was to analyze whether C-reactive protein (CRP), adiponectin, and ghrelin are markers of AGH and indicators of carotid atherosclerosis in kidney transplant patients with fasting plasma glucose below 126 mg/dL., Methods: This was a cross-sectional study of 85 kidney transplant patients (59 men; mean age: 52.4 +/- 11.6 years; median posttransplant follow-up 31 (range 3-61) months). All patients underwent an oral glucose tolerance test. Abnormalities in glucose homeostasis were diagnosed following American Diabetes Association criteria. CRP, adiponectin, and ghrelin levels were determined. Doppler ultrasound of the carotid artery was performed to determine intima media thickness (IMT) and atheromatous plaque., Results: A total of 50.5% of patients had AGH (12.9% were diagnosed with new-onset diabetes mellitus after transplantation and 37.7% had impaired glucose tolerance or impaired fasting glucose), whereas 49.4% were normoglycemic. Patients with AGH were older (P=0.002), had greater carotid IMT (P=0.022), and lower ghrelin concentrations (P=0.017) than normoglycemic patients. Logistic regression analyses showed ghrelin to be an independent marker for AGH (P=0.012) and AGH to be related to greater IMT (P=0.041). No differences in adiponectin or CRP were found in relation to AGH or atherosclerosis; however, there was a positive correlation between adiponectin levels and prednisone dose (r=0.240; P=0.044)., Conclusions: A total of 50.5% of the study patients had abnormalities in glucose homeostasis. Patients with AGH had a higher percentage of preclinical atherosclerosis (greater carotid IMT). Ghrelin is an independent marker for abnormalities in glucose homeostasis.

Background: Renal insufficiency and renal transplant (RT) provoke a microinflammatory state that leads to increased atherosclerosis. It is not fully known whether calcineurin inhibitors (CNIs) play a role in the inflammation observed in these patients or whether any differences exist between CNIs., Objectives: The study aimed to establish differences in the inflammatory state of two groups treated with cyclosporine microemulsion (CyA) or tacrolimus (TC)., Patients and Methods: This prospective study included 81 RT patients divided into two groups according to the CNI: CyA group, n = 35 versus TC group, n = 46. The markers of inflammation (MIF) were determined preRT and at 3 and 12 months' postRT: C-reactive protein (CRP), serum amyloid protein A (SAA), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and pregnancy-associated plasma protein A (PAPP-A). Samples were collected in stable patients in the absence of rejection, active infection, or inflammatory processes., Results: No significant differences existed between the markers of inflammation in the two treatment groups prior to transplantation. At 3 months' posttransplant, patients treated with CyA showed significantly higher levels of IL-6 (P = .05), SAA (P = .03), and sIL-2R (P = .008) compared with patients treated with TC. These differences were maintained for IL-6 (P = .03) and sIL-2R (P = .027) at 12 months' posttransplant. A multivariate analysis at 3 months showed that only age [OR 10.1; CI (95% 2.6-38.4); P = .001], SAA [OR 4.8; IC (95% 1.4-16.5); P = .015], and sIL-2R [OR 4.9; IC (95% 1.5-16.2); P = .009] were independent predictors of the CNI used. At 12 months, age [OR 3.7; IC (95% 0.9-14.2] and sIL-2R [OR 6.04; IC (95% 1.5-23); P = .006] continued to be independent predictors., Conclusions: Patients treated with CyA displayed significantly higher levels of inflammatory markers (IL-6, SAA, sIL-2R) at 3 and 12 months' posttransplantation, independent of age, gender, time on dialysis, diabetes mellitus (preRT and de novo postRT), and renal function measured by serum creatinine.

Introduction: Proteinuria and dyslipidemia are nonimmune risk factors implicated in the deterioration of kidney function and associated with an increased risk of accelerated atherogenesis. Statin therapy, used for cholesterol reduction, has shown a renoprotective effect in animal models, particularly in cases of proteinuria. This may occur through lipid-independent mechanisms, such as improved endothelial dysfunction/vascular biology, reduced inflammatory cytokine production (transforming growth factor-beta 1 [TGF-beta1]), and regulation of fibrogenic responses. We studied mechanisms of action of agents, such as statins, to change proteinuria, inflammatory parameters, and TGF-beta1 plasma levels in relation to vascular tone., Methods: Fifty-six kidney transplant recipients (30 men and 26 women of overall mean age 54 +/- 13 years) were treated posttransplantation with atorvastatin (10 mg/d) for 12 weeks without renin-angiotensin-system blockade drugs. Inflammatory variables, biochemical parameters, lipid profile, renal function, and TGF-beta1 levels were determined at baseline and at 3 months. Vascular stiffness was evaluated using pulse wave velocity (PWV)., Results: Baseline TGF-beta1 plasma levels were higher among transplant recipients than healthy controls, namely 8.12 ng/mL (range, 5.82-13.12) to 2.55 (range, 1.78- 4.35) (P < .01). Furthermore, the levels remained higher after the treatment with atorvastatin, namely, 7.59 (range, 4.97-12.35) to 2.55 (range, 1.78-4.35) ng/mL (P < .01). Atorvastatin treatment significantly decreased total cholesterol as well as low-density lipoprotein cholesterol plasma levels, but did not modify mean blood pressure (MBP), proteinuria, creatinine clearance, or inflammatory factors. Reduction in TGF-beta1 plasma levels was statistically significant among patients with PWV >9.75 (m/s) (pathology reference value) namely, from 10.7 ng/mL (range, 7.02-13.98) to 6.7 (range, 3.96-11.94) (P = .038). Among older patients, atorvastatin significantly decrease TGF-beta1 plasma levels: from 9.5 ng/mL (range, 6.45-14.44) to 5.65 (range, 3.63-9.48; P < .05). The decreased TGF-beta1 was not related to changes in lipid profiles., Conclusions: Atorvastatin (10 mg/d) improved the lipid profile and moreover among older patients with worse PWV (>9.75 m/s), TGF-beta1 levels were significantly reduced. Our results suggested that statins displayed potent actions distinct from their hypolipidemic effects.

Unlabelled: Anti-CD25 monoclonal antibodies (MAbs) are directed against the IL-2 (CD-25) receptor, which is associated with the pathogenesis of diabetes mellitus (DM). Measuring CD25 on peripheral blood lymphocytes could be a new immunologic marker to identify patients with prediabetes., Objective: The study aimed to analyze whether administration of anti-CD25 MAbs was an independent risk factor for posttransplant diabetes mellitus (PTDM) in kidney transplant (KT) patients at 3 months after transplantation., Patients and Methods: Seventy-four stable, nondiabetic KT patients were included in the study. The overall sex distribution was 70% men and mean overall age, 52 +/- 10 years. Thirty-eight subjects where treated with anti-CD25 antibodies (basiliximab). The diagnosis of PTDM was made if patients required insulin or oral antidiabetic drugs and/or had glycemia >200 mg/dL at 120 minutes after an oral glucose tolerance test (75 g glucose). We determined the age, weight, body mass index, acute rejection, chronic hepatitis C virus (HCV) infection, and type of calcineurin inhibitor., Results: Thirty-four percent of patients developed PTDM. Patients treated with anti-CD25 antibodies were older (P = .022) and showed a greater incidence of PTDM (P = .041). The logistic regression analysis (dependent variable: PTDM; independent variables: age, anti-CD25, tacrolimus vs cyclosporine) showed that treatment with anti-CD25 is an independent risk factor for PTDM (P = .041; OR 3.28; CI 95% 1.04-10.31)., Conclusion: Patients treated with anti-CD25 MAbs showed greater incidence of PTDM.

In laboratory testing the reference change value (RCV) is used to detect changes in a patient's clinical status, even before clinical signs are evident. In a previous study we determined the biological variation (BV) of a number of constituents during early post-transplantation in kidney recipients to calculate useful RCVs for this purpose. RCVs for creatinine and urate were identified as the most suitable and were different from those calculated from the normal population. The aim of the current study was to determine the BV components at long-term following renal transplantation to predict potential crises in transplant recipients who have been stable for a number of years. BV components for creatinine and urate were calculated in a new group of 40 kidney transplanted patients (26 men and 14 women, 29-71 years old) who had been stable for period of 4 to 7 years following transplantation (long-term post-TR group). An average of 8 samples per patient was obtained during a period of 1-2 years. Results were compared with those from our described group of recently transplanted patients (short-term post-TR group). There were no statistically significant differences between the groups with regard to within-subject variation or within-subject plus analytical variation (CVI+A) for any of the constituents studied. Distribution of CVI+A values in long-term post-TR was comparable to that of short-term post-TR values. Independence between creatinine and urate was maintained at long-term. The fact that BV components for creatinine and urate were similar in short- and long-term post-TR and that independence was maintained implies that the short-term post-TR RCV can also be applied in long-term post-TR patients. The RCV for predicting crises in this population represents an optimization of laboratory reporting and could be a valuable tool for clinical decision making.

Background: Cardiovascular disease and chronic allograft nephropathy (CAN) are two of the main complications observed in patients after renal transplantation. Both appear to be manifestations of the same process, in which inflammation plays a determinate role. Pregnancy-associated plasma protein A (PAPP-A) has been shown to be a marker of acute coronary syndrome and cardiovascular pathology. The objective of this study was to demonstrate whether or not serum concentration of pretransplant PAPP-A is a marker of CAN and a predictor of posttransplant cardiovascular events., Methods: In all, 178 renal transplants (65% males; 53+/-12 years of age) followed up over the course of 49.3+/-33.6 months were used in this study. During the follow-up period, 19 patients developed CAN (diagnosed by renal biopsy) and 27 patients had a cardiovascular event. Previous to transplantation, the following were determined: ultrasensitive C-reactive protein (CRP) (nephelometry); interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) (immunofluorimetric automatized method), and ultrasensitive PAPP-A (ELISA)., Results: A positive correlation was found between PAPP-A and the inflammatory markers (PAPP-A vs. CRP, r=0.218; P=0.004; PAPP-A vs. IL-6, r=0.235; P<0.001; PAPP-A vs. TNF-alpha, r=0.372; P<0.001). The multiple regression analysis showed PAPP-A (relative risk [RR]: 6.4; 95% confidence interval [CI]:1.24-33.11; P=0.027) and CRP (RR: 6.05; 95% CI:1.21-29.74; P=0.028) to be predictors of posttransplant cardiovascular events and PAPP-A (RR: 4.27; 95% CI: 1.03-17.60; P=0.044) and TNF-alpha (RR: 5.6; 95% CI: 1.43-21.83; P=0.013) to be predictors of CAN., Conclusions: PAPP-A correlated with the inflammatory markers studied (CRP, IL-6 and TNF-alpha). Pretransplant serum concentration of PAPP-A is a predictor of posttransplant cardiovascular events and CAN.

Introduction: Various studies describe the pleiotropic antiinflammatory and antioxidant effects of atorvastatin, in addition to its hypolipemic effects. It has been suggested that statins modify glucose homeostasis via their antiinflammatory effects. A further hypothesis suggests that the incidence of posttransplantation diabetes is lower in statin-treated patients. This study sought to ascertain whether atorvastatin modifies glucose homeostasis, adiponectin, and inflammatory markers in kidney transplant recipients., Patients and Methods: Sixty-eight kidney transplant recipients (41 men, 27 women; mean age, 53 +/- 12 years) with stable renal function and dyslipidemia were treated with atorvastatin (10 mg/d) for 12 weeks. Glucose, insulin, homeostasis model assessment (HOMA-IR) index, adiponectin, tumor necrosis factor (TNF)-alpha, and serum C-reactive protein (CRP) concentrations were determined at baseline and at 3 months. The lipid profile, renal function parameters (creatinine, creatinine clearance, and proteinuria), as well as GOT, GPT, and CK were determined at baseline and at 3 months., Results: Treatment with atorvastatin achieved a statistically significant decrease in lipid profile. After 3 months of treatment, 74.6% of patients had total cholesterol and 78.7% low-density lipoprotein (LDL) cholesterol concentrations within reference range (<5.2 and 3.3 mmol/L, respectively). Furthermore, 47.5% of patients attained an LDL concentration <2.59 mmol/L. A greater reduction in total cholesterol (P = .05) and LDL cholesterol (P = .04) was achieved in patients with creatinine clearance <60 mL/min. Atorvastatin did not modify glucose homeostasis parameters, adiponectin, TNF-alpha, or CRP. At baseline and after 3 months of treatment, an inverse correlation was found between adiponectin and glucose, insulin, HOMA- IR index, and creatinine clearance, and a positive correlation was found between adiponectin and high-density lipoprotein (HDL) cholesterol., Conclusion: Atorvastatin at a dose of 10 mg/d in kidney transplant recipients does not modify glucose homeostasis or alter inflammatory markers, despite its hypolipemic effects. Its efficacy to reduce total cholesterol and LDL cholesterol was greater in patients with worse renal function.

The case of a Spanish kidney transplant patient who developed disseminated histoplasmosis approximately one year and a half after transplantation without having previously visited or travelled to endemic areas of histoplasmosis is presented. To our knowledge this is the first case of this disease in a kidney transplant patient in Spain without epidemiologic antecedent. The study of anti-histoplasm antibodies by complement fixation of the donor and recipient did not safely clarify the mechanism of contagion.

Background: New-onset diabetes mellitus after transplantation (NODAT) is a severe complication of kidney transplantation (KTx) with negative effects upon patient and graft survival. Several risk factors for NODAT have been described; however, the search for an early predictive marker is ongoing. It has recently been demonstrated that high concentrations of adiponectin (APN), which is an adipocyte-derived peptide with antiinflammatory and insulin-sensitizing properties, protect against future development of type 2 diabetes in healthy individuals. The purpose of this report was to study pretransplant insulin resistance and analyze pretransplant serum leptin and APN levels as independent risk factors for the development of NODAT., Methods: A total of 68 KTx patients were studied [mean age, 48 +/- 11 years; 70% males; body mass index (BMI), 25 +/- 3 kg/m]; 31 KTx patients with NODAT and 37 KTx patients without NODAT (non-NODAT) with similar age, sex, BMI, immunosuppression, and posttransplant time were studied. All patients received prednisone and calcineurin inhibitors (75% tacrolimus and 25% cyclosporine A), and 76% of patients received mycophenolate mofetil. Family history of diabetes mellitus was recorded. Pretransplant homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated from fasting plasma glucose and insulin. Pretransplant serum leptin and APN levels were determined by radioimmunoassay., Results: NODAT patients showed higher pretransplant plasma insulin concentrations [NODAT, 13.4 (11-22.7) microIU/mL; non-NODAT, 10.05 (7.45-18.4) microIU/mL; P=0.049], HOMA-IR index [NODAT, 4.18 (2.49-5.75); non-NODAT, 2.63 (1.52-4.68); P=0.043], and lower pretransplant serum APN concentration [NODAT, 8.78 (7.2-11.38) microg/mL; non-NODAT, 11.4 (8.56-15.27) microg/mL, P=0.012]. Inverse correlations between APN and BMI (r=-0.33; P=0.014) and APN and HOMA-IR index (r=-0.39; P=0.002) and between APN and NODAT (r=-0.31; P=0.011) were observed. Multiple logistic regression analysis showed the patients with lower pretransplant APN concentrations to be those at greater risk of developing NODAT [Odds Ratio=0.832 (0.71-0.96); P=0.01]., Conclusion: Pretransplant serum APN concentration is an independent predictive factor for NODAT development in kidney-transplanted patients.

The aim of the study presented here was to set up and standardize a semiquantitative polymerase chain reaction method for monitoring Epstein-Barr virus (EBV) DNA levels in blood and saliva samples from transplant recipients and to determine the value of these levels as an early marker for the development of post-transplant lymphoproliferative disorders. EBV DNA load was prospectively measured in 53 adult kidney transplant recipients. Results were correlated with clinical features and degree of immunosuppression. Healthy blood donors and patients with infectious mononucleosis were used as controls. Levels higher than 500 EBV DNA copies/75,000 peripheral blood mononuclear cells were found in all patients with infectious mononucleosis and in all patients with post-transplant lymphoproliferative disorder but in only 7.5% of transplant recipients without that complication.