Development of an Information Guideline for Kidney Transplant Recipients in a Clinical Trial: Protocol for a Modified Delphi Method.

BACKGROUND: Renal transplantation is the treatment of choice for most cases of end-stage renal disease. Recipients need to lead a healthy lifestyle to minimize the potential side effects of immunosuppressive drugs and improve transplant outcomes. There is not much evidence about the best way to increase adherence to healthy lifestyles in kidney transplant recipients, so one of the objectives set by the nursing team is to train people to acquire the necessary skills and tools to be able to take care of themselves. In this sense, the consensual development of appropriate materials may be useful and of interest. OBJECTIVE: The aim of this study was to develop an information guide for adults with kidney transplants to be assessed in a subsequent clinical trial as an intervention to increase adherence to healthy habits. METHODS: We used a 3-step, methodological, sequential approach: (1) training from a group of experts and item consensus; (2) review of the medical literature available; and (3) use of the Delphi technique with on-site meetings. A total of 5 nurses from the Community of Madrid Kidney Transplantation Unit in Spain were asked to participate. The patients' lifestyle factors that, according to the medical literature available and experts' opinions, have the greatest impact on the survival of the transplanted organ and the recipients themselves were all described. RESULTS: After using the modified Delphi method to reach a consensus on the items to be included and the information needed in each, an information guide for adult kidney transplant patients was developed. This guide facilitates the structuring of health care, information, and recommendations necessary for effective self-care for each person. The result is considered to be an easy-to-understand tool, useful for transplant doctors and nurses, in simple language, with information based on the latest scientific-medical evidence published to date, aspects of which will be evaluated in a clinical trial designed for this purpose. CONCLUSIONS: Currently, this guide is the main intervention variable of a clinical trial (registered on ClinicalTrials.gov; NCT05715580) aimed at improving compliance with healthy habits in kidney transplant recipients in the Community of Madrid, Spain. The method used in its development has been useful and agile, and the result is a guide that can be easily updated periodically following the same procedure. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46961.

Management of immunosuppressive therapy in kidney transplant recipients with COVID-19. A multicentre national study derived from the Spanish Society of Nephrology COVID registry.

INTRODUCTION: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated. OBJECTIVES: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis. MATERIAL AND METHODS: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis. RESULTS: renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years. The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased. Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7 ±â€¯0.8, 2.1 ±â€¯1.2 and 1.8 ±â€¯1 mg/dl respectively (p < 0.001). 56.9% of the patients (N = 350) were monitored for anti-HLA antibodies. 94% (N = 329) had no anti-HLA changes, while 6% (N = 21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N = 9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant. CONCLUSIONS: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis.

Manejo de la inmunosupresión en pacientes trasplantados de riñón con COVID19. Estudio multicéntrico nacional derivado del registro COVID de la Sociedad Española de Nefrología / Management of immunosuppressive therapy in kidney transplant recipients with COVID-19. A multicentre national study derived from the Spanish Society of Nephrology. COVID registry

Introducción: La infección por SARS-CoV2 ha impactado de forma importante en los pacientes con trasplante renal causando una elevada mortalidad en los primeros meses de la pandemia. La reducción intencionada de la inmunosupresión se ha postulado como uno de los pilares en el manejo de la infección ante la falta de un tratamiento antiviral dirigido. Esta se ha modificado de acuerdo con la situación clínica de los pacientes, y su efecto sobre la función renal o los anticuerpos anti-HLA a medio plazo no ha sido evaluado. Objetivos: Evaluar los cambios de inmunosupresión realizados durante la infección por SARS-CoV2, así como la función renal y los anticuerpos anti-HLA de los pacientes trasplantados de riñón a los 6 meses del diagnóstico de COVID19. Material y métodos: Estudio retrospectivo, multicéntrico nacional (30 centros) de pacientes trasplantados de riñón con COVID19 desde el 01/02/20 al 31/12/20. Se recogieron las variables de la historia clínica y se incluyeron en una base de datos anonimizada. Se utilizó el programa estadístico SPSS para el análisis de resultados. (AU)

Introduction: SARS-CoV-2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient's clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated. Objectives: Evaluate the management of immunosuppressive therapy made during SARS-CoV-2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID-19 diagnosis. Material and methods: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis. (AU)

Sodium-glucose cotransporter-2 inhibitor therapy in kidney transplant patients with type 2 or post-transplant diabetes: an observational multicentre study.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have cardioprotective and renoprotective effects. However, experience with SGLT2is in diabetic kidney transplant recipients (DKTRs) is limited. Methods: This observational multicentre study was designed to examine the efficacy and safety of SGLT2is in DKTRs. The primary outcome was adverse effects within 6 months of SGLT2i treatment. Results: Among 339 treated DKTRs, adverse effects were recorded in 26%, the most frequent (14%) being urinary tract infection (UTI). In 10%, SGLT2is were suspended mostly because of UTI. Risk factors for developing a UTI were a prior episode of UTI in the 6 months leading up to SGLT2i use {odds ratio [OR] 7.90 [confidence interval (CI) 3.63-17.21]} and female sex [OR 2.46 (CI 1.19-5.03)]. In a post hoc subgroup analysis, the incidence of UTI emerged as similar in DKTRs treated with SGLT2i for 12 months versus non-DKTRs (17.9% versus 16.7%). Between baseline and 6 months, significant reductions were observed in body weight [-2.22 kg (95% CI -2.79 to -1.65)], blood pressure, fasting glycaemia, haemoglobin A1c [-0.36% (95% CI -0.51 to -0.21)], serum uric acid [-0.44 mg/dl (95% CI -0.60 to -0.28)] and urinary protein:creatinine ratio, while serum magnesium [+0.15 mg/dl (95% CI 0.11-0.18)] and haemoglobin levels rose [+0.44 g/dl (95% CI 0.28-0.58]. These outcomes persisted in participants followed over 12 months of treatment. Conclusions: SGLT2is in kidney transplant offer benefits in terms of controlling glycaemia, weight, blood pressure, anaemia, proteinuria and serum uric acid and magnesium. UTI was the most frequent adverse effect. According to our findings, these agents should be prescribed with caution in female DKTRs and those with a history of UTI.

Role of mTOR inhibitor in the cellular and humoral immune response to a booster dose of SARS-CoV-2 mRNA-1273 vaccine in kidney transplant recipients.

Background: Immunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved. Methods: Prospective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination. Results: Among COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p<0.001) and the percentage of S-protein-specific IFNγ-producing CD8-T cells (r=0.198, p=0.049) was observed. Factors related to the humoral response in naïve KTR were: lymphocytes count pre-vaccination >1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p<0.001], mTOR inhibitors [6.40 (1.37-29.86), p=0.018]. Infected KTR developed a stronger serologic response than naïve patients (96.8 vs 75.2%, p<0.001). Conclusions: KTR presented poor cellular and humoral immune responses following vaccination with mRNA-1273. The immunosuppression degree and kidney function of these patients play an important role, but the only modifiable factor with a high impact on humoral immunogenicity after a booster dose was an immunosuppressive therapy including a mTOR inhibitor. Clinical trials are required to confirm these results.

Genome-wide association study biomarkers in T-cell mediated rejection: selective effect according to the Banff classification.

BACKGROUND: A genome-wide association study (GWAS) in kidney transplant recipients reported the association of two polymorphisms located in the PTPRO gene and upstream of the CCDC67 (DEUP1) gene with increased risk of acute T cell-mediated rejection (TCMR). We aimed at replicating the assessment of mentioned associations and additionally ascertaining the influence of treatment and clinical features of the patients. METHODS: The polymorphisms, PTPRO-rs7976329 and CCDC67-rs10765602 were genotyped by TaqMan chemistry in 641 consecutive kidney transplant recipients. The diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. Associations were evaluated by Chi-square test or Fisher's exact test when necessary and multivariate logistic regression. RESULTS: Considering the GWAS study we only replicated the association of the PTPRO-rs7976329*C allele in the Banff grade < II subjects. However, the homozygous mutant genotypes of both polymorphism seemed to increase the risk of TCMR Banff grade < II in the overall cohort and after stratification by Thymoglobulin induction therapy. In the multivariate analysis, we confirmed the association of PTPRO-rs7976329 with TCMR Banff grade < II, independently of the Thymoglobulin induction therapy and of CCDC67-rs10765602 only in the group of patients not receiving Thymoglobulin induction therapy. No association of these polymorphisms with TCMR Banff grade ≥ II was observed in either the overall cohort or in the subgroups stratified by Thymoglobulin therapy. CONCLUSIONS: Our study shows that the increased risk of TCMR related to polymorphisms PTPRO-rs7976329 and CCDC67-rs10765602 previously reported in a GWAS was replicated only in homozygous patients who presented TCMR Banff grade < II and for the minor allele of either polymorphism.

Efficacy and safety of oral fosfomycin for asymptomatic bacteriuria in kidney transplant recipients: Results from a Spanish multicenter cohort.

Current guidelines recommend against systematic screening or treating asymptomatic bacteriuria (AB) among kidney transplant (KT) recipients, although the evidence regarding episodes occurring early after transplantation or in the presence of anatomical abnormalities is inconclusive. Oral fosfomycin may constitute a good option for the treatment of post-transplant AB, particularly due to the emergence of multidrug-resistant (MDR) uropathogens. Available clinical evidence supporting its use in this specific setting, however, remains scarce. We performed a retrospective study in 14 Spanish institutions from January 2005 to December 2017. Overall, 137 episodes of AB diagnosed in 133 KT recipients treated with oral fosfomycin (calcium and trometamol salts) with a test-of-cure urine culture within the first 30 days were included. Median time from transplantation to diagnosis was 3.1 months (interquartile range [IQR]: 1.1 - 10.5). Most episodes (96.4% [132/137]) were caused by gram-negative bacteria (GNB), and 56.9% (78/137) were categorized as MDR (extended-spectrum ß-lactamase-producing Enterobacterales [20.4%] and carbapenem-resistant GNB [2.9%]). Rate of microbiological failure at month 1 was 40.1% (95% confidence interval [95%CI]: 31.9 - 48.9) for the whole cohort and 42.3% (95%CI: 31.2 - 54.0) for episodes due to MDR pathogens. Previous urinary tract infection (odds ratio [OR]: 2.42; 95%CI: 1.11 - 5.29; P-value = 0.027) and use of fosfomycin as salvage therapy (OR: 8.31; 95%CI: 1.67 - 41.35; P-value = 0.010) were predictors of microbiological failure. No severe treatment-related adverse event were detected. Oral fosfomycin appears to be a suitable and safe alternative for the treatment (if indicated) of AB after KT, including those episodes due to MDR uropathogens.

Live donor kidney transplantation. Situation analysis and roadmap.

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.

Clinical Effectiveness of SARS-CoV-2 Vaccination in Renal Transplant Recipients. Antibody Levels Impact in Pneumonia and Death.

BACKGROUND: Few studies have described the clinical impact of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in renal transplant recipients (RTRs) in the context of omicron variant and the third vaccine dose. Antibody titer has been tried to relate to the prediction of outcomes related to SARS-CoV-2, but it results controversially in these populations. METHODS: All patients with positive SARS-CoV-2 polymerase chain reaction followed at a RTRs reference center from March 15, 2020, to March 15, 2022, were considered for analysis. Cases were analyzed by vaccination status. Breakthrough cases were then analyzed by nonantibodies (<20 arbitrary unit [AU]/mL), low (20-100 AU/mL), and high antibody titers (>100 AU/mL) against SARS-CoV-2 spike protein. Outcomes included pneumonia and mortality. We used logistic regression multivariable to assess for confounders. RESULTS: Among 186 RTRs with coronavirus disease 2019, 50.5% (n = 94) were vaccinated versus 49.5% (n = 92) unvaccinated. Of the vaccinated patients, 67.02% developed a high antibody titer (>100 AU/mL) but 14.89% achieved a low antibody titer and 18.08% nonantibodies. Pneumonia-free survival (day 20) was 95% in high antibody titer but 40% in unvaccinated RTRs. Survival in RTRs at day 60 was similar in the unvaccinated group compared with nonantibodies breakthrough cases (82%) but 92% in the low antibody titer group (relative risk, 0.027; 95% confidence interval, 0.002-0.479; P = 0.014). Only patients with >100 AU/mL showed a 100% survival on day 60 postinfection. CONCLUSIONS: Vaccinated RTRs who achieve at least a low antibody titer (>20 AU/mL) had better results in terms of pneumonia and mortality than unvaccinated RTRs. Antibody titer >100 AU/mL associate with even better results than patients with lower antibody titers.

[Management of immunosuppressive therapy in kidney transplant recipients with COVID19. A multicentre national study derived form the S.E.N. COVID registry.] / Manejo de la inmunosupresión en pacientes trasplantados de riñón con COVID19. Estudio multicéntrico nacional derivado del registro COVID de la S.E.N.

INTRODUCTION: SARS CoV2 infection has had a major impact on renal transplant patients with a high mortality in the first months of the pandemic. Intentional reduction of immunosuppressive therapy has been postulated as one of the cornerstone in the management of the infection in the absence of targeted antiviral treatment. This has been modified according to the patient`s clinical situation and its effect on renal function or anti-HLA antibodies in the medium term has not been evaluated. OBJECTIVES: Evaluate the management of immunosuppressive therapy made during SARS-CoV2 infection, as well as renal function and anti-HLA antibodies in kidney transplant patients 6 months after COVID19 diagnosis. MATERIAL AND METHODS: Retrospective, national multicentre, retrospective study (30 centres) of kidney transplant recipients with COVID19 from 01/02/20 to 31/12/20. Clinical variables were collected from medical records and included in an anonymised database. SPSS statistical software was used for data analysis. RESULTS: 615 renal transplant recipients with COVID19 were included (62.6% male), with a mean age of 57.5 years.The predominant immunosuppressive treatment prior to COVID19 was triple therapy with prednisone, tacrolimus and mycophenolic acid (54.6%) followed by m-TOR inhibitor regimens (18.6%). After diagnosis of infection, mycophenolic acid was discontinued in 73.8% of patients, m-TOR inhibitor in 41.4%, tacrolimus in 10.5% and cyclosporin A in 10%. In turn, 26.9% received dexamethasone and 50.9% were started on or had their baseline prednisone dose increased.Mean creatinine before diagnosis of COVID19, at diagnosis and at 6 months was: 1.7±0.8, 2.1±1.2 and 1.8±1 mg/dl respectively (p<0.001).56.9% of the patients (N=350) were monitored for anti-HLA antibodies. 94% (N=329) had no anti-HLA changes, while 6% (N=21) had positive anti-HLA antibodies. Among the patients with donor-specific antibodies post-COVID19 (N=9), 7 patients (3.1%) had one immunosuppressant discontinued (5 patients had mycophenolic acid and 2 had tacrolimus), 1 patient had both immunosuppressants discontinued (3.4%) and 1 patient had no change in immunosuppression (1.1%), these differences were not significant. CONCLUSIONS: The management of immunosuppressive therapy after diagnosis of COVID19 was primarily based on discontinuation of mycophenolic acid with very discrete reductions or discontinuations of calcineurin inhibitors. This immunosuppression management did not influence renal function or changes in anti-HLA antibodies 6 months after diagnosis.

Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

BACKGROUND: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population. METHODS: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351). RESULTS: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010). CONCLUSIONS: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.

Hemophagocytic syndrome triggered by donor-transmitted toxoplasmosis as a complication in same-donor recipients of renal transplantation: Case report and review of the literature.

BACKGROUND: Hemophagocytic syndrome (HPS) is an infrequent complication of transplantation caused by an inflammatory response with a benign proliferation of macrophages and defective lytic capability of T lymphocytes and NK cells that can lead to multiorgan failure. Transplant patients are particularly exposed as a result of the increased risk of both infections and malignancies derived from immunosuppressive drugs. There is no consensus for therapy or immunosuppression; mortality is high. We report a case and present a review of all cases of HPS occurring in solid organ transplant recipients.  CASE REPORT: We report two cases of infection by Toxoplasma gondii transmitted by the kidney allograft. One of the recipients was seronegative before transplantation and developed disseminated primary toxoplasmosis. An immune reaction compatible with an HPS ensued. Both were treated with Trimethoprim/sulfamethoxazole, immunosuppression was tapered, and after a 2-week period a complete response was obtained. CONCLUSION: HPS presents therapeutic challenges in the context of transplantation. If HPS is suspected, the search of a very likely underlying infection should be central to the management.

Live donor kidney transplantation. Situation analysis and roadmap. / Trasplante renal de donante vivo. Análisis de situación y hoja de ruta.

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.

Association of Polymorphisms in T-Cell Activation Costimulatory/Inhibitory Signal Genes With Allograft Kidney Rejection Risk.

The genes CD28, CD86 and CTLA-4 conform the costimulatory (CD28-CD86) or inhibitory (CTLA-4-CD86) signal in T-cell activation. T-cell immune response has a critical role in allograft rejection, and single nucleotide polymorphisms (SNPs) located in these genes have been widely analyzed with controversial results. We analyzed a group of SNPs located in the three genes: CD28: rs3116496; CD86: rs1129055; and CTLA-4: rs231775 and rs3087243 in a cohort of 632 consecutively recruited kidney transplanted subjects. All polymorphisms were genotyped by TaqMan chemistry and the diagnosis of rejection was confirmed by biopsy and categorized according to the Banff classification. The analyses showed a statistically significant protective effect to T cell-mediated rejection (TCMR) in carriers of the CTLA-4 rs3087243*G allele, especially in patients with TCMR Banff ≥2 in the overall cohort and in patients without thymoglobulin induction therapy. Both associations were corroborated as independent factors in the multivariate analysis. Interestingly, associations with rejection were not found for any SNP in patients with thymoglobulin induction therapy. As expected, considering the major role of these genes in T-cell activation, no effect was observed for antibody-mediated rejection (ABMR). In conclusion, the SNP rs3087243 located in the CTLA-4 gene may be considered a useful independent biomarker for TCMR risk especially for severe TCMR in patients who did no received thymoglobulin induction therapy.

Predictors of severe COVID-19 in kidney transplant recipients in the different epidemic waves: Analysis of the Spanish Registry.

SARS-CoV-2 infection has produced high mortality in kidney transplant (KT) recipients, especially in the elderly. Until December 2020, 1011 KT with COVID-19 have been prospectively included in the Spanish Registry and followed until recovery or death. In multivariable analysis, age, pneumonia, and KT performed ≤6 months before COVID-19 were predictors of death, whereas gastrointestinal symptoms were protective. Survival analysis showed significant increasing mortality risk in four subgroups according to recipient age and time after KT (age <65 years and posttransplant time >6 months, age <65 and time ≤6, age ≥65 and time >6 and age ≥65 and time ≤6): mortality rates were, respectively, 11.3%, 24.5%, 35.4%, and 54.5% (p < .001). Patients were significantly younger, presented less pneumonia, and received less frequently specific anti-COVID-19 treatment in the second wave (July-December) than in the first one (March-June). Overall mortality was lower in the second wave (15.1 vs. 27.4%, p < .001) but similar in critical patients (66.7% vs. 58.1%, p = .29). The interaction between age and time post-KT should be considered when selecting recipients for transplantation in the COVID-19 pandemic. Advanced age and a recent KT should foster strict protective measures, including vaccination.

Use of tocilizumab in kidney transplant recipients with COVID-19.

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed.

Oral fosfomycin for the treatment of lower urinary tract infections among kidney transplant recipients-Results of a Spanish multicenter cohort.

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 ß-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.

Impacts of Interleukin-18 Polymorphisms on the Incidence of Delayed-Onset Cytomegalovirus Infection in a Cohort of Kidney Transplant Recipients.

BACKGROUND: The incidence of cytomegalovirus (CMV) infection in solid organ transplant recipients may be reduced by antiviral prophylaxis, but this strategy may lead to delayed-onset CMV infection. The proinflammatory cytokine interleukin (IL)-18 plays a major role in viral host defense responses. This study examines the impacts of 2 single-nucleotide polymorphisms (SNPs) in the promoter region of the IL-18 gene, -607C/A (rs1946518) and -137G/C (rs187238), on the incidence of delayed-onset CMV infection in patients undergoing kidney transplant. METHODS: This retrospective study analyzed 2 IL-18 SNPs in consecutive adult kidney transplant recipients using real-time polymerase chain reaction with TaqMan probes. Participants were enrolled over the period 2005-2013 and stratified according to their IL-18 SNP genotype. The concordance index (Harrell's c-index) was used as a measure of the discriminatory power of the predictive models constructed with bootstrapping to correct for optimistic bias. RESULTS: Seven hundred nine patients received transplants in the study period, and 498 met selection criteria. Cytomegalovirus infection and disease incidence were 38% and 7.5%, respectively. In multivariate competing risk regression models, carriers of the -607C/-137G haplotype who received prophylaxis showed a higher incidence of CMV replication after antiviral agent discontinuation (hazard ratio = 2.42 [95% confidence interval, 1.11-5.26]; P = .026), whereas CMV disease was not observed in those given prophylaxis who were noncarriers of this polymorphism (P = .009). CONCLUSIONS: Our findings suggest that the -607C/-137G IL-18 haplotype is associated with a higher incidence of postprophylaxis CMV replication. The prior identification of this polymorphism could help select alternative measures to prevent delayed-onset CMV infection in these patients.

Trasplante renal con órganos procedentes de donación tras parada circulatoria controlada: resultados del estudio multicéntrico GEODAS-3 / Kidney transplant from controlled donors following circulatory death: Results from the GEODAS-3 multicentre study

Introducción: Varios países eu:ropeos disponen de programas de donación tras parada cardiaca controlada (cDCD). Veintidós centros participan en el grupo GEODAS, cuyos resultados clínicos presentamos desde una perspectiva nefrológica. Métodos: Estudio multicéntrico retrospectivo observacional con inclusión sistemática de todos los trasplantes renales (TR) procedentes de cDCD, siguiendo protocolos locales de extracción e inmunosupresión. Resultados: Se incluyó a 335 donantes tras cDCD (edad media 57,2 años) fallecidos mayoritariamente por eventos cardiovasculares. Se analizan 566 receptores (edad media de 56,5 años; el 91,9% con primer trasplante renal), con una mediana de seguimiento de 1,9 años. La terapia de inducción fue casi universal (timoglobulina 67,4%; simulect 32,8%) con mantenimiento con prednisona-MMF-tacrolimus (91,3%) o combinaciones con mTOR (6,5%). El tiempo medio de isquemia fría (CIT) fue 12,3 h. Hubo un 3,4% de fallo primario del injerto (n = 19), asociado fundamentalmente al tiempo de isquemia fría (solo el CIT ≥ 14 h se asoció a fallo primario del injerto). La función retrasada del injerto (DGF) fue 48,8%. Los factores de riesgo para la DGF fueron: CIT ≥ 14 h OR 1,6, procedencia de hemodiálisis (vs. diálisis peritoneal) OR 2,1 y edad del donante OR 1,01 (por año). Veintiún pacientes fallecieron con injerto funcionante (3,7%), con una supervivencia de paciente e injerto (censurada para muerte) al segundo año del 95% y del 95,1%, respectivamente. El filtrado glomerular estimado al año de seguimiento fue 60,9ml/min. Conclusiones: El CIT es un factor modificable para mejorar la incidencia del fallo primario del injerto en trasplante renal procedente de cDCD. El trasplante renal con cDCD tiene mayor incidencia en la función retrasada del injerto, pero igual supervivencia de paciente e injerto que la referencia histórica para donación en muerte encefálica. Los resultados son satisfactorios para continuar promoviendo este tipo de donación. Conclusiones: El CIT es un factor modificable para mejorar la incidencia del fallo primario del injerto en trasplante renal procedente de cDCD. El trasplante renal con cDCD tiene mayor incidencia en la función retrasada del injerto, pero igual supervivencia de paciente e injerto que la referencia histórica para donación en muerte encefálica. Los resultados son satisfactorios para continuar promoviendo este tipo de donación

Introduction: Many European countries have transplant programmes with controlled donors after cardiac death (cDCD). Twenty-two centres are part of GEODAS group. We analysed clinical results from a nephrological perspective. Methods: Observational, retrospective and multicentre study with systematic inclusion of all kidney transplant recipients from cDCD, following local protocols regarding extraction and immunosuppression. Results: A total of 335 cDCD donors (mean age 57.2 years) whose deaths were mainly due to cardiovascular events were included. Finally, 566 recipients (mean age 56.5 years; 91.9% first kidney transplant) were analysed with a median of follow-up of 1.9 years. Induction therapy was almost universal (thymoglobulin 67.4%; simulect 32.8%) with maintenance with prednisone-MMF-tacrolimus (91.3%) or combinations with mTOR (6.5%). Mean cold ischaemia time (CIT) was 12.3 h. Approximately 3.4% (n = 19) of recipients experienced primary non-function, essentially associated with CIT (only CIT ≥ 14 h was associated with primary non-function). Delayed graft function (DGF) was 48.8%. DGF risk factors were CIT ≥ 14 h OR 1.6, previous haemodialysis (vs. peritoneal dialysis) OR 2.1 and donor age OR 1.01 (per year). Twenty-one patients (3.7%) died with a functioning graft, with a recipient and death-censored graft survival at 2-years of 95% and 95.1%, respectively. The estimated glomerular filtration rate at one year of follow-up was 60.9 ml/min. Conclusions: CIT is a modifiable factor for improving the incidence of primary non-function in kidney transplant arising from cDCD. cDCD kidney transplant recipients have higher delayed graft function rate, but the same patient and graft survival compared to brain-dead donation in historical references. These results are convincing enough to continue fostering this type of donation

De Novo IgA Nephropathy in a Renal Allograft.

Posttransplant glomerulonephritis is a complication of kidney transplant that can impair graft function and long-term graft survival. De novo immunoglobulin A disease in kidney allografts appears to be much less common than the recurrent disease, and in most cases it is diagnosed in protocol biopsies with no clinical evidence of disease or in association with other renal transplant pathologies such as chronic rejection. We present a case of de novo immunoglobulin A nephropathy presenting with overt proteinuria, microscopic hematuria, and progressive deterioration of renal function 30 months after renal transplant.