Publications by authors named "Ignacio Revuelta"

46 Publications

Kidney Transplantation in Monoclonal Immunoglobulin Deposition Disease: A Report of 6 Cases.

Am J Kidney Dis 2021 May 4. Epub 2021 May 4.

Nephrology and Renal Transplantation Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain; Amyloidosis and Myeloma Unit.Hospital Clínic de Barcelona; Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Barcelona, Spain. Electronic address:

Monoclonal immunoglobulin deposition disease (MIDD) usually leads to kidney failure. Treatment of patients with a bortezomib-based regimen followed by autologous stem cell transplantation has been increasingly used, with improvements in the response rates and the allograft outcomes in kidney transplant recipients. The objective of this report was to analyze the outcomes of 6 patients who underwent kidney transplantation in our institution after treatment of MIDD between 2010 and 2019. Monoclonal immunoglobulin deposition disease was initially treated with Bortezomib-based therapy followed by high dose melphalan and autologous stem cell transplant (SCT) with complete hematologic response, although all patients remained on dialysis. During a median follow-up of 20.5 months from kidney transplant and 54 months from SCT, 1 patient experienced hematologic relapse and 2 had hematologic progression (one of them with MIDD relapse in the allograft) requiring treatment. The patient with organ relapse received Daratumumab monotherapy achieving complete hematologic response but graft failure. The other 5 patients had functional graft with median serum creatinine 1.68 mg/dl. These results support that, in patients with MIDD and sustained complete hematologic response, a kidney transplant can be considered. The optimal approach to treatment of hematologic relapse or recurrence of MIDD after kidney transplant remains to be determined.
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http://dx.doi.org/10.1053/j.ajkd.2021.02.337DOI Listing
May 2021

A hybrid data envelopment analysis-artificial neural network prediction model for COVID-19 severity in transplant recipients.

Artif Intell Rev 2021 Apr 23:1-32. Epub 2021 Apr 23.

Department of Nephrology and Renal Transplantation, Hospital Clínic, Villarroel 170 (Escala 10 - Planta 5), 08036 Barcelona, Spain.

In an overwhelming demand scenario, such as the SARS-CoV-2 pandemic, pressure over health systems may outburst their predicted capacity to deal with such extreme situations. Therefore, in order to successfully face a health emergency, scientific evidence and validated models are needed to provide real-time information that could be applied by any health center, especially for high-risk populations, such as transplant recipients. We have developed a hybrid prediction model whose accuracy relative to several alternative configurations has been validated through a battery of clustering techniques. Using hospital admission data from a cohort of hospitalized transplant patients, our hybrid Data Envelopment Analysis (DEA)-Artificial Neural Network (ANN) model extrapolates the progression towards severe COVID-19 disease with an accuracy of 96.3%, outperforming any competing model, such as logistic regression (65.5%) and random forest (44.8%). In this regard, DEA-ANN allows us to categorize the evolution of patients through the values of the analyses performed at hospital admission. Our prediction model may help guiding COVID-19 management through the identification of key predictors that permit a sustainable management of resources in a patient-centered model.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10462-021-10008-0.
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http://dx.doi.org/10.1007/s10462-021-10008-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062617PMC
April 2021

Adoption of a novel smart mobile-health application technology to track chronic immunosuppression adherence in solid organ transplantation: Results of a prospective, observational, multicentre, pilot study.

Clin Transplant 2021 May 16;35(5):e14278. Epub 2021 Mar 16.

Renal Transplant Unit, Nephrology Department, IDIBELL, Bellvitge University Hospital, Barcelona, Spain.

Background: Low adherence to chronic immunosuppression is associated with suboptimal transplantation outcomes. Mobile-health technology is a promising tool to monitor medication adherence, but data on patient engagement to these tools are lacking.

Methods: Prospective, observational, multicenter, 2-phase trial in kidney and liver transplant recipients, investigating the degree of engagement to TrackYourMed (TYM), a novel m-Health technology with a QR code-scan app to track immunosuppression adherence and its association with drug monitoring.

Results: Out of 204 consecutive transplant patients, 90 patients were eligible to participate. 61 (68%) used TYM regularly, 21 (23%) never or barely used it, 5 (5.5%) were irregular users, and 3 (3.3%) were lost to follow-up. 6-month total correct intakes (CIN) ranged between 69%-76%, 12%-19% intakes were out-of-time (OUT), and 9%-12% were missed (MIS). Notably, a rate of intakes out of the scheduled time higher than 20% in the 6 days prior to blood immunosuppressant trough levels was associated with a higher intra-patient variability (17 IQR 13-21% vs. 29 IQR 23%-36%, p = .001), and with a higher dose-adjustment (p < .001). At 1 year, 53(59%) patients were still active users of TYM.

Conclusions: Implementing m-Health technologies promoting immunosuppression adherence may be useful for a relevant number of transplant patients and help transplant physicians identifying erratic immunosuppression adherence.
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http://dx.doi.org/10.1111/ctr.14278DOI Listing
May 2021

A case of recurrent anemia due to chronic parvovirus B19 infection in a kidney transplant recipient. Can everolimus make a difference?

CEN Case Rep 2021 Feb 4. Epub 2021 Feb 4.

Department of Nephrology and Kidney Transplantation, Hospital Clinic, 170 Villarroel Street, 08036, Barcelona, Spain.

Parvovirus B19 (PB19) is a common infection among solid transplant recipients. Usually, it is asymptomatic, but sometimes it can become a real therapeutic challenge. We report a case of a kidney transplant recipient with relapsing pure red cell aplasia due to PB19 infection. Our patient was initially managed with standard treatment consisting of intravenous immunoglobulins and minimization of immunosuppressive treatment. However, when this approach became ineffective, conversion from tacrolimus to everolimus was done, with favorable results. This paper explores infection by PB19 in kidney transplant recipients and the potential benefits of a calcineurin inhibitor-free immunosuppression and the antiviral properties of mTOR inhibitors.
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http://dx.doi.org/10.1007/s13730-021-00575-0DOI Listing
February 2021

Psychosocial risk factors for impaired health-related quality of life in living kidney donors: results from the ELIPSY prospective study.

Sci Rep 2020 12 7;10(1):21343. Epub 2020 Dec 7.

Medical School, University of Barcelona, Barcelona, Spain.

Living kidney donors' follow-up is usually focused on the assessment of the surgical and medical outcomes. Whilst the psychosocial follow-up is advocated in literature. It is still not entirely clear which exact psychosocial factors are related to a poor psychosocial outcome of donors. The aim of our study is to prospectively assess the donors' psychosocial risks factors to impaired health-related quality of life at 1-year post-donation and link their psychosocial profile before donation with their respective outcomes. The influence of the recipient's medical outcomes on their donor's psychosocial outcome was also examined. Sixty donors completed a battery of standardized psychometric instruments (quality of life, mental health, coping strategies, personality, socio-economic status), and ad hoc items regarding the donation process (e.g., motivations for donation, decision-making, risk assessment, and donor-recipient relationship). Donors' 1-year psychosocial follow-up was favorable and comparable with the general population. So far, cluster-analysis identified a subgroup of donors (28%) with a post-donation reduction of their health-related quality of life. This subgroup expressed comparatively to the rest, the need for more pre-donation information regarding surgery risks, and elevated fear of losing the recipient and commitment to stop their suffering.
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http://dx.doi.org/10.1038/s41598-020-78032-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721886PMC
December 2020

Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts.

J Nephrol 2021 06 4;34(3):861-874. Epub 2020 Dec 4.

REMAR-IVECAT Group, "Germans Trias i Pujol Research Institute (IGTP)" Health Science Research Institute, Campus Can RutiCarretera de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Spain.

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.
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http://dx.doi.org/10.1007/s40620-020-00886-yDOI Listing
June 2021

The impact of functional delayed graft function in the modern era of kidney transplantation - A retrospective study.

Transpl Int 2021 Jan 28;34(1):175-184. Epub 2020 Nov 28.

Nephrology and Renal Transplant Department, Hospital Clínic, Barcelona, Spain.

The dialysis-based definition of Delayed Graft Function (dDGF) is not necessarily objective as it depends on the individual physician's decision. The functional definition of DGF (fDGF, the failure of serum creatinine to decrease by at least 10% daily on 3 consecutive days during the first week post-transplant), may be more sensitive to reflect recovery after the ischemia-reperfusion injury. We retrospectively analyzed both definitions in 253 deceased donor kidney transplant recipients for predicting death-censored graft failure as primary outcome, using eGFR < 25 ml/min/1.73 m as a surrogate end-point for graft failure. Secondary outcome was a composite outcome that included graft failure as above and also patient's death. Median follow-up was 3.22 [2.38-4.21] years. Seventy-nine patients developed dDGF (31.2%) and 127 developed fDGF (50.2%). Sixty-three patients fulfilled criteria for both definitions (24.9%). At multivariable analysis, the two definitions were significantly associated with the primary [HR (95%CI) 2.07 (1.09-3.94), P = 0.026 for fDGF and HR (95%CI) 2.41 (1.33-4.37), P = 0.004 for dDGF] and the secondary composite outcome [HR (95%CI) 1.58 (1.01-2.51), P = 0.047 for fDGF and HR (95%CI) 1.67 (1.05-2.66), P = 0.028 for dDGF]. Patients who met criteria for both definitions had the worst prognosis, with a three-year estimates (95%CI) of survival from the primary and secondary outcomes of 2.31 (2.02-2.59) and 2.20 (1.91-2.49) years for fDGF+/dDGF+, in comparison with the other groups (P < 0.01 for trend). fDGF provides supplementary information about graft outcomes on top of the dDGF definition in a modern series of kidney transplantation.
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http://dx.doi.org/10.1111/tri.13781DOI Listing
January 2021

Modeling patients as decision making units: evaluating the efficiency of kidney transplantation through data envelopment analysis.

Health Care Manag Sci 2021 Mar 18;24(1):55-71. Epub 2020 Sep 18.

Renal Transplant Unit, Department of Nephrology and Kidney Transplant, Hospital Clinic, Barcelona, Spain.

The main applications of Data Envelopment Analysis (DEA) to medicine focus on evaluating the efficiency of different health structures, hospitals and departments within them. The evolution of patients after undergoing a medical procedure or their response to a given treatment are not generally studied through this programming technique. In addition to the difficulty inherent to the collection of this type of data, the use of a technique that is mainly applied to evaluate the efficiency of decision making units representing industrial and production structures to analyze the evolution of human patients may seem inappropriate. In the current paper, we illustrate how this is not actually the case and implement a decision engineering approach to model kidney transplantation patients as decision making units. As such, patients undergo three different phases, each composed by specific as well as interrelated variables, determining the potential success of the transplantation process. DEA is applied to a set of 12 input and 6 output variables - retrieved over a 10-year period - describing the evolution of 485 patients undergoing kidney transplantation from living donors. The resulting analysis allows us to classify the set of patients in terms of the efficiency of the transplantation process and identify the specific characteristics across which potential improvements could be defined on a per patient basis.
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http://dx.doi.org/10.1007/s10729-020-09516-2DOI Listing
March 2021

Results and Lessons Learned on Robotic Assisted Kidney Transplantation.

Biomed Res Int 2020 2;2020:8687907. Epub 2020 Sep 2.

Department of Urology, Hospital Clínic, Barcelona 08036, Spain.

Introduction: Nowadays, minimally invasive surgery in kidney transplantation is a reality thanks to robotic assistance. In this paper, we describe our experience, how we developed the robotic assisted Kidney transplantation (RAKT) technique, and analyze our results. . This is a retrospective study of all RAKTs performed at our center between July 2015 and March 2020. We describe the donor selection, surgical technique, and analyze the surgical results and complications. A comparison between the first 20 cases and the following ones is performed.

Results: During the aforementioned period, 82 living donor RAKTs were performed. The mean age was 47.4 ± 13.4 and 50 (61%) were male. Mean body mass index was 25 ± 4.7 and preemptive in 63.7% of cases. Right kidneys and multiple arteries were seen in 14.6% and 12.2%, respectively. Mean operative and rewarming time was 197 ± 42 and 47 ± 9.6 minutes, respectively. Five cases required conversion to open surgery because of abnormal kidney vascularization. Two patients required embolization for subcapsular and hypogastric artery bleeding without repercussion. Three kidneys were lost, two of them due to acute rejection and one because venous thrombosis. Late complications requiring surgery included one kidney artery stenosis, one ureteral stenosis, two lymphoceles, and three hernia repairs. We noticed a significant reduction in time between the first 20 cases and the following ones from 248.25 ± 38.1 to 189.75 ± 25.3 ( < 0.05). With a mean follow-up time of 1.8 years (SD 1.3), the mean creatinine was 1.52 (SD 0.7) and RAKT graft survival was 98%.

Conclusions: The robotic approach is an attractive, minimally invasive method for kidney transplantation, yielding good results. Further studies are needed to consider it a standard approach.
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http://dx.doi.org/10.1155/2020/8687907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484686PMC
May 2021

Use of De Novo mTOR Inhibitors in Hypersensitized Kidney Transplant Recipients: Experience From Clinical Practice.

Transplantation 2020 08;104(8):1686-1694

Nephrology and Renal Transplant Department, Hospital Clínic, Barcelona, Spain.

Background: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment.

Methods: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3-8 ng/mL).

Results: Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277).

Conclusions: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.
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http://dx.doi.org/10.1097/TP.0000000000003021DOI Listing
August 2020

Endothelial-to-mesenchymal transition compromises vascular integrity to induce Myc-mediated metabolic reprogramming in kidney fibrosis.

Sci Signal 2020 06 9;13(635). Epub 2020 Jun 9.

Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of (which encodes Twist) or (which encodes Snail) in VE-cadherin or Tie1 endothelial cells inhibited the emergence of EndMT and improved kidney fibrosis in two different kidney injury/fibrosis mouse models. Suppression of EndMT limited peritubular vascular leakage, reduced tissue hypoxia, and preserved tubular epithelial health and function. Hypoxia, which was exacerbated by EndMT, resulted in increased Myc abundance in tubular epithelial cells, enhanced glycolysis, and suppression of fatty acid oxidation. Pharmacological suppression or epithelial-specific genetic ablation of Myc in tubular epithelial cells ameliorated fibrosis and restored renal parenchymal function and metabolic homeostasis. Together, these findings demonstrate a functional role for EndMT in the response to kidney capillary endothelial injury and highlight the contribution of endothelial-epithelial cross-talk in the development of kidney fibrosis with a potential for therapeutic intervention.
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http://dx.doi.org/10.1126/scisignal.aaz2597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790440PMC
June 2020

Successful use of nonantigen-specific immunoadsorption with antihuman Ig-columns in kidney graft antibody-mediated rejection.

J Clin Apher 2020 Jun 27;35(3):188-199. Epub 2020 Mar 27.

Nephrology and Renal Transplantation Department, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.

Introduction: Nonantigen-specific immunoadsorption (IA) has proven to be effective in acute antibody-mediated rejection (aAMR). However, there is a lack of solid studies evaluating the safety and efficacy of IA with antihuman Ig-columns in aAMR. For chronic-active AMR (cAMR), no studies have evaluated the efficacy of nonantingen-specific IA with antihuman Ig-columns. The purpose of this study was to evaluate the role of nonantigen-specific IA with antihuman Ig-columns in the treatment of both aAMR and cAMR in kidney transplantation.

Material And Methods: In retrospective and observational study, kidney graft and recipient survival rates were assessed after treatment of aAMR and cAMR with nonantigen-specific IA with Ig-Flex columns (Therasorb) between January 2012 and May 2018. Protocols included nonantigen-specific IA, rituximab, intravenous immunoglobulin, and rescue plasma exchange, if necessary.

Results: The study included 14 patients with AMR (acute in 9, chronic active in 5). For aAMR, mean follow-up was 13 ± 6 months, and patient and graft survival were, respectively, of 100% and 83%, with a mean increase in estimated glomerular filtration rate (eGFR) of 7.98 ± 12.96, 10.18 ± 16.71, and 11.43 ± 13.85 mL/min/1.72 m (P > .05) at 3, 12 months after treatment, and at the end of follow-up, respectively. For cAMR, mean follow-up was 14 ± 8 months, and patient and graft survival were, respectively, of 100% and 60%, with an average increase in eGFR of 4.30 ± 7.86, 5.64 ± 10.47, and 14.5 ± 7.86 mL/min/m (P > .05) at 3, 12 months after IA treatment, and at the end of the follow-up, respectively, although 40% did not respond and required chronic hemodialysis.

Conclusion: Nonantigen-specific IA with Ig-Flex columns was safe and effective for aAMR treatment in kidney transplantation. In cAMR, IA with Ig-Flex columns was associated with a satisfactory kidney graft survival, suggesting that IA could potentially offer some benefits supporting its indication in cAMR.
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http://dx.doi.org/10.1002/jca.21779DOI Listing
June 2020

Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation?

Am J Transplant 2020 Jul 9;20(7):1875-1878. Epub 2020 Apr 9.

Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain.

COVID-19 is novel infectious disease with an evolving understanding of its epidemiology and clinical manifestations. Immunocompromised patients often present atypical presentations of viral diseases. Herein we report a case of a COVID-19 infection in a solid organ transplant recipient, in which the first clinical symptoms were of gastrointestinal viral disease and fever, which further progressed to respiratory symptoms in 48 hours. In these high risk populations, protocols for screening for SARS-Cov2 may be needed to be re-evaluated.
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http://dx.doi.org/10.1111/ajt.15874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228209PMC
July 2020

Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial.

Clin Infect Dis 2020 12;71(9):2375-2385

Experimental Nephrology Laboratory, Bellvitge Biomedical Research Institute, IDIBELL, Hospitalet de Llobregat, Spain.

Background: Improving cytomegalovirus (CMV) immune-risk stratification in kidney transplantation is highly needed to establish guided preventive strategies.

Methods: This prospective, interventional, multicenter clinical trial assessed the value of monitoring pretransplant CMV-specific cell-mediated immunity (CMI) using an interferon-γ release assay to predict CMV infection in kidney transplantation. One hundred sixty donor/recipient CMV-seropositive (D+/R+) patients, stratified by their baseline CMV (immediate-early protein 1)-specific CMI risk, were randomized to receive either preemptive or 3-month antiviral prophylaxis. Also, 15-day posttransplant CMI risk stratification and CMI specific to the 65 kDa phosphoprotein (pp65) CMV antigen were investigated. Immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids in 80% of patients, whereas 20% received thymoglobulin induction therapy.

Results: Patients at high risk for CMV based on pretransplant CMI developed significantly higher CMV infection rates than those deemed to be at low risk with both preemptive (73.3% vs 44.4%; odds ratio [OR], 3.44 [95% confidence interval {CI}, 1.30-9.08]) and prophylaxis (33.3% vs 4.1%; OR, 11.75 [95% CI, 2.31-59.71]) approaches. The predictive capacity for CMV-specific CMI was only found in basiliximab-treated patients for both preemptive and prophylaxis therapy. Fifteen-day CMI risk stratification better predicted CMV infection (81.3% vs 9.1%; OR, 43.33 [95% CI, 7.89-237.96]).

Conclusions: Pretransplant CMV-specific CMI identifies D+/R+ kidney recipients at high risk of developing CMV infection if not receiving T-cell-depleting antibodies. Monitoring CMV-specific CMI soon after transplantation further defines the CMV infection prediction risk. Monitoring CMV-specific CMI may guide decision making regarding the type of CMV preventive strategy in kidney transplantation.

Clinical Trials Registration: NCT02550639.
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http://dx.doi.org/10.1093/cid/ciz1209DOI Listing
December 2020

Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice.

J Nephrol 2020 Jun 18;33(3):601-610. Epub 2019 Dec 18.

Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain.

Introduction: The TRANSFORM study demonstrated that an immunosuppression based on a combination of calcineurin inhibitors and de-novo mTOR inhibitors (mTORi) is safe and effective in kidney transplant recipients. However, data that validate this approach in clinical practice are currently missing.

Materials And Methods: Analysis of 401 kidney transplant recipients transplanted from June 2013 to December 2016. All patients received tacrolimus with prednisone in combination with either mycophenolate (n = 186) or mTORi (either everolimus or sirolimus, n = 215). A propensity score to receive mTORi was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age and sex of donor and recipient, BMI, previous transplants, diabetes, cPRA, dialysis before transplantation, dialysis vintage, type of donor, ABO-incompatibility, HLA-mismatches, induction and ischemia time. Median follow-up was 2.6 [1.9; 3.7] years.

Results: Cox-regression analysis suggests good results for mTORi versus MPA in terms of 1-year biopsy-proven acute rejection (BPAR, P = 0.063), 1-year graft loss (P = 0.025) and patient survival (P < 0.001). Results observed for BPAR and graft failure were largely attributed to those patients that would have been excluded by the TRANSFORM because of some exclusion criteria (52.9% of the population, P = 0.003 for 1-year BPAR and P = 0.040 for graft loss). In patients who met selection criteria for TRANSFORM, no effect of treatment for BPAR or graft failure was observed, while the beneficial effect on overall survival persisted.

Conclusions: In a real-life setting, a protocol based on de-novo mTORi with tacrolimus and prednisone could be employed as a standard immunosuppressive regimen and was associated with good outcomes.
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http://dx.doi.org/10.1007/s40620-019-00675-2DOI Listing
June 2020

Impact of Discards for Living Donor Kidney Transplantation in a Transplant Program.

Transplant Proc 2019 Dec 13;51(10):3222-3226. Epub 2019 Nov 13.

Nephrology and Renal Transplant Department, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), IDIBAPS, Barcelona, Spain; Barcelona University, Barcelona, Spain; Spanish Kidney Research Network, ISCIII-RETIC REDinREN RD016/0 009, Madrid, Spain. Electronic address:

Objective: Living donor kidney transplantation (LDKT) is the best treatment for end-stage renal disease. In this setting, a significant percentage of transplants are not undertaken because of medical and nonmedical reasons of both donors and recipients. However, the impact of these discards in a transplant program has not been identified thoroughly so far. Our objective was to clarify key reasons for exclusion of LDKTs and the consequences for the discarded transplant candidates in the following 5 years.

Methods: Analysis of donors' and recipients' characteristics of 781 couples evaluated in our hospital from January 2005 to December 2013. The consequences of discards in transplant candidates were analyzed in the cohort 2012 to 2013 (n = 106) and followed up until October 2018.

Results: In our study group, 402 (51.5%) LDKT couples were successfully donated, and 379 (48.5%) were excluded. Donor and transplant recipient candidates discarded were older at the evaluation (55.07 ± 12.14 years vs 51.73 ± 10.93 years, P < .001; 48.81 ± 14.05 years vs 44.62 ± 13.91 years, P < .001, respectively). The most frequent reason for kidney discard was medical contraindication found in the potential donor (47.5%; low eGFR, diabetes mellitus, impaired glucose tolerance, high blood pressure, cardiovascular pathology casually found during evaluation, and proteinuria). Of the discarded candidates from 2012 to 2013, 36.8% received a deceased donor kidney transplant, 17% a LDKT with another donor, 7.5% stayed on the waiting list, 18.9% died, 3.8% were excluded from the waiting list, and 14.2% were lost to follow-up.

Conclusions: In most cases, transplantation was not undertaken because of donor pathology. Fifty-three percent of the discarded patients were eventually transplanted, with a 31.4% probability to receive an organ from another living donor.
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http://dx.doi.org/10.1016/j.transproceed.2019.09.008DOI Listing
December 2019

Effect of immunosuppression in miRNAs from extracellular vesicles of colorectal cancer and their influence on the pre-metastatic niche.

Sci Rep 2019 08 1;9(1):11177. Epub 2019 Aug 1.

Laboratori Experimental de Nefrologia i Trasplantament (LENIT), IDIBAPS, Barcelona, Spain.

Colorectal cancer (CRC) occurs with more aggressiveness in kidney transplant recipients compared to the general population. Immunosuppressive therapy plays a crucial role in the development of post-transplant malignancy. Concretely, cyclosporine A (CsA) has intrinsic pro-oncologic properties, while several studies report a regression of cancer after the introduction of rapamycin (RAPA). However, their effect on the extracellular vesicle (EV) content from CRC cell lines and their relevance in the pre-metastatic niche have not yet been studied. Here, we investigated the effect of RAPA and CsA in EV-miRNAs from metastatic and non-metastatic CRC cell lines and the role of relevant miRNAs transferred into a pre-metastatic niche model. EV-miRNA profiles showed a significant upregulation of miR-6127, miR-6746-5p, and miR-6787-5p under RAPA treatment compared to CsA and untreated conditions in metastatic cell lines that were not observed in non-metastatic cells. From gene expression analysis of transfected lung fibroblasts, we identified 22 shared downregulated genes mostly represented by the histone family involved in chromatin organization, DNA packaging, and cell cycle. These results suggest that EV-miR-6127, miR-6746-5p and miR-6787-5p could be a potential epigenetic mechanism induced by RAPA therapy in the regulation of the pre-metastatic niche of post-transplant colorectal cancer.
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http://dx.doi.org/10.1038/s41598-019-47581-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672014PMC
August 2019

Postinfectious Acute Glomerulonephritis in Renal Transplantation: An Emergent Aetiology of Renal Allograft Loss.

Case Rep Transplant 2019 18;2019:7438254. Epub 2019 Mar 18.

Department of Nephrology and Renal Transplantation, Hospital Clínic, University of Barcelona, IDIBAPS, Barcelona, Spain.

Despite the high incidence of posttransplant infections, postinfectious acute glomerulonephritis (PIAGN) in renal allograft is a rare entity, without effective treatment and a bad prognosis. We describe two cases of PIAGN: the first one was developed 2 years after kidney transplantation, secondary to bacteremia with presence of extracapillary proliferation in biopsy. The patient was treated with methylprednisolone and plasma exchanges without response, remaining dialysis dependent. The second case was reported 5 years after kidney transplantation, secondary to influenza A infection. Kidney biopsy showed an IgA-dominant PIAGN and methylprednisolone boluses were initiated without clinical response, suffering a progressive worsening and loss of kidney graft. Due to the aggressive clinical course of this entity, PIAGN should be considered in the differential diagnosis of acute kidney graft failure in the context of an infection. Elderly patients have a higher risk of more severe acute renal dysfunction, requiring dialysis in a great proportion of cases.
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http://dx.doi.org/10.1155/2019/7438254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442439PMC
March 2019

Rituximab, plasma exchange and immunoglobulins: an ineffective treatment for chronic active antibody-mediated rejection.

BMC Nephrol 2018 10 11;19(1):261. Epub 2018 Oct 11.

Department of Nephrology and Renal Transplantation, ICNU, Hospital Clinic, Barcelona, Spain.

Background: Chronic active antibody-mediated rejection (c-aABMR) is an important cause of allograft failure and graft loss in long-term kidney transplants.

Methods: To determine the efficacy and safety of combined therapy with rituximab, plasma exchange (PE) and intravenous immunoglobulins (IVIG), a cohort of patients with transplant glomerulopathy (TG) that met criteria of active cABMR, according to BANFF'17 classification, was identified.

Results: We identified 62 patients with active c-aABMR and TG (cg ≥ 1). Twenty-three patients were treated with the combination therapy and, 39 patients did not receive treatment and were considered the control group. There were no significant differences in the graft survival between the two groups. The number of graft losses at 12 and 24 months and the decline of eGFR were not different and independent of the treatment. A decrease of eGFR≥13 ml/min between 6 months before and c-aABMR diagnosis, was an independent risk factor for graft loss at 24 months (OR = 5; P = 0.01). Infections that required hospitalization during the first year after c-aABMR diagnosis were significantly more frequent in treated patients (OR = 4.22; P = 0.013), with a ratio infection/patient-year of 0.65 and 0.20 respectively.

Conclusions: Treatment with rituximab, PE, and IVIG in kidney transplants with c-aABMR did not improve graft survival and was associated with a significant increase in severe infectious complications.

Trial Registration: Agencia Española de Medicametos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTR-INM-2017-01.
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http://dx.doi.org/10.1186/s12882-018-1057-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182805PMC
October 2018

Assessment of donor satisfaction as an essential part of living donor kidney transplantation: an eleven-year retrospective study.

Transpl Int 2018 12 10;31(12):1332-1344. Epub 2018 Sep 10.

Medical School, University of Barcelona, Barcelona, Spain.

Living kidney donors seem highly satisfied with donation. However, previous studies measure satisfaction by a single-item or by simply questioning donors' willingness to donate again or to recommend living donation. With the aim of analyzing whether satisfaction with donation is a multidimensional construct, thus allowing a more specific characterization of dissatisfied donors, 332 living kidney donors (2005-2015) answered a renewed version of the European Living Donation and Public Health Project satisfaction survey. Exploratory factor-analyses suggested that satisfaction was composed of three-factors: violation of donors' expectancies about donation; interference of donation on daily activities, and pain and discomfort. Donors reported high levels of satisfaction. However, cluster-analysis identified a subgroup characterized by a higher discrepancy between the expected and the actually experienced during donation, higher interference on daily activities, and higher pain and discomfort. Most of them considered that hospital discharge was premature, suffered economic losses and perceived worse health outcomes of their recipients. Single questions assessing donors' willingness to donate again or to recommend living donation were unable to differentiate between clusters. In summary, donor's satisfaction seems better characterized by three dimensions than by single questions.
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http://dx.doi.org/10.1111/tri.13334DOI Listing
December 2018

Combining Sensitive Crossmatch Assays With Donor/Recipient Human Leukocyte Antigen Eplet Matching Predicts Living-Donor Kidney Transplant Outcome.

Kidney Int Rep 2018 07 30;3(4):926-938. Epub 2018 Mar 30.

Kidney Transplant Unit, Nephrology Department, Bellvitge University Hospital, Barcelona University, Barcelona, Spain.

Introduction: Despite the different assays available for immune-risk stratification before living-donor kidney transplantation (LDKT), the precise type and number of tests to perform remain uncertain.

Methods: In a cohort of 330 consecutive LDKT patients, all of which were complement-dependent cytotoxicity (CDC)-crossmatch negative, we retrospectively analyzed the impact on main clinical outcomes of most sensitive immunoassays (complement-dependent cytotoxicity-panel-reactive antibody [CDC-PRA], flow cytometry crossmatch [FC-XM], donor-specific antibodies [DSAs], and their complement-binding capacity DSA-C3d]), together with donor/recipient HLA eplet matching. Mean follow-up was 67 months (range 24-190 months).

Results: Of 330 patients, 35 (11%) showed a CDC-PRA >20%; 17 (5%) FC-XM+; 30 (9%) DSA+, 18(5%) DSA-C3d+, with low overlapping results (10 patients positive in all donor-specific tests). Unlike HLA allele compatibility, the mean number of HLA class II eplet mismatches was higher in LDKT patients with positive baseline test results. DSA-C3d+ showed higher mean fluorescence intensity (MFI) DSA, with a cut-off MFI of 6192 accurately predicting complement fixation (area under the curve = 0.85,  = 0.008). Although all assays were associated with acute rejection (AR), only DSA-C3d+ (odds ratio [OR] = 6.64,  = 0.038) or high MFI-DSA (OR = 7.54,  = 0.038) independently predicted AR. Likewise, poorly HLA class II eplet-matched patients were at higher risk for AR, particularly patients with negative baseline test results (OR = 1.14,  = 0.019). Finally, previous AR and FC-XM+/DSA+, regardless of C3d positivity, independently predicted graft loss.

Conclusion: Combining FC-XM and solid-phase assays with the evaluation of donor/recipient HLA eplet mismatches, are most accurate tools for immune-risk stratification prior LDKT.
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http://dx.doi.org/10.1016/j.ekir.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035161PMC
July 2018

Pancreas outcomes between living and deceased kidney donor in pancreas after kidney transplantation patients.

Nephrol Dial Transplant 2018 11;33(11):2052-2059

Renal Transplant Unit, Nephrology and Kidney Transplantation Department, Hospital Clinic, Barcelona, Spain.

Background: Pancreas outcomes in pancreas after kidney transplantation (PAK) patients have been reported as being inferior to those of patients who receive simultaneous pancreas and kidney transplantation (SPK). The influence of the kidney donor (i.e. living versus deceased) has never been previously addressed.

Methods: We retrospectively analysed all pancreas transplants performed in a single centre since 2007 and compared the outcomes between those patients who had previously received a living-donor kidney transplant (pancreas transplantation after living-donor kidney transplantation, PAldK; n = 18) or a deceased-donor kidney transplant (pancreas transplantation after deceased-donor kidney transplantation, PAddK; n = 28), using SPK (n = 139) recipients as a reference.

Results: Pancreas survival was similar between all groups, but inferior for PAldK when including only those with a functioning graft at day 90 post-transplantation (P = 0.004). Pancreas acute rejection was significantly increased in PAldK (67%; 1.8 ± 1.4 episodes/graft) when compared with PAddK (25%) and SPK (32%) (P < 0.05) patients. In a multivariate Cox regression model including known risk factors for pancreas rejection, PAldK was the only predictor of acute rejection (hazard ratio 6.82, 95% confidence interval 1.51-30.70, P < 0.05). No association was found between donor-recipient HLA mismatches and graft rejection. Repeated HLA mismatches between kidney and pancreas donors (0 versus 1-6) did not correlate with pancreas graft rejection or survival in either PAK transplantation group (P > 0.05).

Conclusion: Pancreas graft outcomes are worse for PAldK when compared with PAddK and SPK patients.
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http://dx.doi.org/10.1093/ndt/gfy133DOI Listing
November 2018

Tofacitinib Halts Progression of Graft Dysfunction in a Rat Model of Mixed Cellular and Humoral Rejection.

Transplantation 2018 07;102(7):1075-1084

Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Background: The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation.

Methods: Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks.

Results: Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma.

Conclusions: Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.
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http://dx.doi.org/10.1097/TP.0000000000002204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228626PMC
July 2018

Histopathological evaluation of pretransplant donor biopsies in expanded criteria donors with high kidney donor profile index: a retrospective observational cohort study.

Transpl Int 2017 Oct 2;30(10):975-986. Epub 2017 Jun 2.

Nephrology and Renal Transplant Department, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain.

There is no consensus on the allocation of renal transplants from expanded criteria donors (ECD). The Kidney Donor Profile Index (KDPI) is used without the need for pretransplant donor biopsies (PTDB). We explored whether PTDB based on Remuzzi Score (RS) allows identification of those marginal kidneys in the highest calculated KDPI risk group (>91%) that appropriate for single transplantation. A retrospective study was conducted of 485 consecutive kidneys procured from a single center and transplanted if the RS was ≤4. We compared 5-year kidney and patients survival between KDPI groups and between RS <4 or =4 in the highest KDPI group. The median KDPI (interquartile range) was 71 (66-76) for KDPI <80% (n = 77), 86 (81-90) for KDPI 81-90% (n = 82), and 97 (94-100) for KDPI >91% (n = 205). Patient survival at 5 years was 85.7%, 85.3%, and 76.09% (P = 0.058) and death-censored graft survival was 84.4%, 86.5%, 73.6% (P = 0.015), respectively for each KDPI group. In >91% calculated KDPI group, there were no differences in graft survival depending on the RS (<4 vs. =4) (P = 0.714). The implementation of PTDB based on RS used for allocation of organs with the highest KDPI range could support to the acceptance of suitable organs for single transplantation with good patient and graft survival rate.
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http://dx.doi.org/10.1111/tri.12966DOI Listing
October 2017

Failed ABO incompatible high titers kidney transplant using bortezomib. Case report.

Nefrologia 2016 Nov - Dec;36(6):701-704. Epub 2016 Aug 25.

Nephrology, Hospital Clinic Barcelona, Barcelona, Spain; Laboratori Experimental de Nefrologia i Trasplantament (LENIT), CRB CELLEX, IDIBAPS, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.nefro.2016.05.022DOI Listing
April 2018

mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome.

Transplant Direct 2016 Feb 22;2(2):e65. Epub 2016 Jan 22.

Laboratori Experimental de Nefrologia I Trasplantament (LENIT), CRB CELLEX, Fundació Clínic, IDIBAPS, Barcelona, Spain.; Department of Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.

Background: Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β -cell toxicity.

Methods: Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression.

Results: After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated.

Conclusions: In conditions that require adaptive β -cell proliferation, SRL might reveal harmful effects by blocking β -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.
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http://dx.doi.org/10.1097/TXD.0000000000000576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946492PMC
February 2016

Role of HHV-8 and mTOR pathway in post-transplant Kaposi sarcoma staging.

Transpl Int 2016 Sep 7;29(9):1008-16. Epub 2016 Jul 7.

Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, Barcelona, Spain.

Kaposi's sarcoma (KS) is one of the most frequent transplant related tumors. Several pathways are involved; however, the impact of the molecular phenotype associated to the tumor stage and the behavior-depending resultant therapy is still unknown. The aim of our study was to analyze the role of HHV-8 and mTOR pathway in tumor stages of skin KS after renal transplantation. Twelve renal transplant recipients with cutaneous KS from five transplant centers (1980-2007) under reduction of immunosuppression or conversion to mTOR inhibitor were included. The expression of HHV-8, PTEN, TGFβ, VEGF, phospho-mTOR, and phospho-P70S6K in tumoral tissue was analyzed. KS lesions were classified as patch, plaque, and nodule state. HHV-8 infection was found in all tissue samples. KS lesions showed high activation of VEGF, p-mTOR and p-P70S6K, low PTEN, and null TGFβ expression. The only pathway activated in a staging-dependent manner was mTOR with higher p-mTOR and p-P70S6K expression in nodule versus patch stage. KS lesions disappeared after 5.24 months in all converted patients without any recurrence in 14.05 years of mean follow-up. The activation of mTOR pathway according to KS stages supports the rational of the mTOR inhibitor in post-transplant Kaposi.
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http://dx.doi.org/10.1111/tri.12800DOI Listing
September 2016