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.

First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

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.

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.

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.

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.

Uncontrolled donation after circulatory death: A cohort study of data from a long-standing deceased-donor kidney transplantation program.

Despite good long-term outcomes of kidney transplants from controlled donation after circulatory death (DCD) donors, there are few uncontrolled DCD (uDCD) programs. This longitudinal study compares outcomes for all uDCD (N = 774) and all donation after brain death (DBD) (N = 613) kidney transplants performed from 1996 to 2015 at our center. DBD transplants were divided into those from standard-criteria (SCD) (N = 366) and expanded-criteria (N = 247) brain-dead donors (ECD). One-, 5-, and 10-year graft survival rates were 91.7%, 85.7%, and 80.6% for SCD; 86.0%, 75.8%, and 61.4% for ECD; and 85.1%, 78.1%, and 72.2% for uDCD, respectively. Graft survival was worse in recipients of uDCD kidneys than of SCD (P = .004) but better than in transplants from ECD (P = .021). The main cause of graft loss in the uDCD transplants was primary nonfunction. Through logistic regression, donor death due to pulmonary embolism (OR 4.31, 95% CI 1.65-11.23), extrahospital CPR time ≥75 minutes (OR1.94, 95%CI 1.18-3.22), and in-hospital CPR time ≥50 minutes (OR 1.79, 95% CI 1.09-2.93) emerged as predictive factors of primary nonunction. According to the outcomes of our long-standing kidney transplantation program, uDCD could help expand the kidney donor pool.

In vivo diagnosis with purified tropomyosin in mite and shellfish allergic patients.

BACKGROUND: Tropomyosin is the most studied shellfish allergen and has been involved in cross-reactivity among different invertebrates (crustacean, mollusks, mites, insects, and nematodes). OBJECTIVE: To determine the relevance of tropomyosin in mite- and shellfish-sensitized patients using tropomyosin skin testing. METHODS: Patients were divided into 3 groups: group M included mite allergic patients (ie, individuals with respiratory symptoms and a positive result on skin prick testing [SPT] to house dust mites), group S included shellfish allergic patients (ie, individuals who reported symptoms with shellfish), and group MS included mite- and shellfish allergic patients (ie, individuals who simultaneously fulfilled the inclusion criteria for groups M and S). Tropomyosin was purified from shrimp, characterized, and used in SPT for diagnosis in the patient population. RESULTS: Eight hundred fifty patients were included in the study: 790 (92.9%) in group M, 21 (2.5%) in group S, and 39 (4.6%) in group MS. Tropomyosin was purified from shrimp with a purity higher than 95%. Forty-two individuals tested positive to tropomyosin: the prevalence was 2.7% in group M, 28.6% in group S, and 38.5% in patients of group MS. Twenty-one (50%) of the tropomyosin-positive individuals had symptoms with shellfish, and 3 (14.3%) reported anaphylaxis. CONCLUSION: The prevalence of tropomyosin was low in mite-sensitized patients (2.7 %) and high in shellfish allergic patients (28.6%). The higher prevalence of tropomyosin was found in patients sensitized to both mite and shellfish (38.5%). The selection of tropomyosin-sensitized patients by SPT might help in the choice of appropriate treatments or management for these patients.

The relationship between dysfunctional family patterns and symptom severity among adolescent patients with eating disorders: A gender-specific approach.

The objective of the authors in this study was to identify factors related to dysfunctional family functioning that may be associated with the severity of symptoms among adolescent patients with an eating disorder (ED) at first-contact care. A total of forty-eight mothers and forty-five fathers of fifty patients with EDs were recruited from an ED unit in Madrid, Spain, between October 2011 and July 2012. Parents completed self-report assessments related to family functioning and psychological wellbeing. Patients went through clinical interviews and completed a self-report questionnaire assessing symptom severity. Compared to fathers, mothers showed higher levels of anxiety and emotional over-involvement and perceived to a greater degree the positive and negative aspects of their experience as caregivers. Regarding the relationship between family functioning and symptom severity, mothers' perceptions of their family relationships as enmeshed and less adaptive, along with anxiety, accounted for 39% of variance in the severity of ED symptoms. Anxiety and symptom accommodation by the fathers accounted for 27% of variance in the symptom severity. Interventions that help parents to cope with their caregiving role should target behavioral, cognitive, and emotional aspects of their functioning and be gender-specific, to improve the outcome of ED in patients.

Use of the Hospital Anxiety and Depression Scale in Spanish caregivers.

BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is widely used in the assessment of anxiety and depression, but there are scarce data about its psychometric properties in caregivers of older relatives. OBJECTIVE: The goal of this study was to analyse the factor structure of the HADS to verify its suitability to assess emotional symptomatology in family caregivers of old people, its internal consistency and confirming its relation with the General Health Questionnaire (GHQ-12) and an index of disease and physical complaints. METHODS: One hundred and seventy-five family caregivers (25 men and 150 women) aged 32-86, who were taking care of at least one older person in a situation of dependence, were recruited for this study. A descriptive, comparative, correlational design was employed. The scientific adequacy of the questionnaire and its structure were analysed using confirmatory factor analysis. The scores obtained in the GHQ and in an index of disease and physical complaints were used as external criteria to assess the adequacy of the HADS for caregivers. RESULTS: Higher levels of anxiety and depression than in the normal population were obtained. The reliability/internal validity of the questionnaire was adequate. A bifactor model, with one subscale for anxiety and one for depression, provides the best fit to the data. The subscales were related to GHQ-12 and index of diseases/physical complaints. CONCLUSIONS: The HADS was shown to be useful to assess the presence of anxiety and depression in family caregivers, and the original two-dimensional model is the most adequate.

The GHQ-12 for the assessment of psychological distress of family caregivers.

This study examined the utility of the 12-item General Health Questionnaire (GHQ-12) to assess the psychological distress of family caregivers. To accomplish this goal, a sample of 172 caregivers, 25 men and 147 women, aged 56.6 (SD = 13.7) completed self-report questionnaires and provided data on demographic factors. Univariate and bivariate models adjust adequately, although the two-factor model (anxiety/depression and social dysfunction) presented a better fit. Relative caregivers scored higher in psychological distress (anxiety and depression levels) on the GHQ-12 than did the normal population. In conclusion, the GHQ-12 is a sensitive instrument to detect the presence of anxiety and depression in relative caregivers, and the external validity of the instrument is generally adequate. The GHQ-12 seems particularly appropriate for research and clinical and health intervention in caregivers. Implications and limitations of these results are discussed, along with suggestions for future research.

Benefits of Best Practice Guidelines in Spine Fusion: Comparable Correction in AIS with Higher Density and Fewer Complications.

BACKGROUND: There is significant variability in surgeons' instrumentation patterns for adolescent idiopathic scoliosis surgery. Implant density and costs are difficult to correlate with deformity correction, safety, and quality of life measures. MATERIALS AND METHODS: Two groups of postoperative adolescents were compared based on exposure to a best practice guidelines program (BPGP) introduced to decrease complications. Hybrid and stainless steel constructs were dropped, and posterior-based osteotomies, screws, and implant density were increased to 66.8 ± 12.03 vs. 57.5 ± 16.7% (p < 0.001). The evaluated outcomes were: initial and final correction, rate of correction loss, complications, OR returns, and SRS-22 scores (minimum two-year follow-up). RESULTS: 34 patients were operated on before BPGP and 48 after. The samples were comparable, with the exceptions of a higher density and longer operative times after BPGP. Initial and final corrections before BPGP were 67.9° ± 22.9 and 64.6° ± 23.7; after BPGP, the corrections were 70.6° ± 17.4 and 66.5° ± 14.9 (sd). A regression analysis did not show a relation between the number of implants and postoperative correction (beta = -0.116, p = 0.307), final correction (beta = -0.065, p = 0.578), or loss of correction (beta= -0.137, p = 0.246). Considering screw constructs only (n = 63), a regression model controlled for flexibility continued to show a slight negative effect of density on initial correction (b = -0.274; p = 0.019). Only with major curve concavity was density relevant in initial correction (b = 0.293; p = 0.038), with significance at 95% not being achieved for final correction despite a similar beta (b = 0.263; p = 0.069). Complications and OR returns dropped from 25.6% to 4.2%. Despite this, no difference was found in SRS-22 (4.30 ± 0.432 vs. 4.42 ± 0.39; sd) or subdomain scores pre- and post-program. FINDINGS: Although it appears counterintuitive that higher density, osteotomies, and operative time may lead to fewer complications, the study shows the value of best practice guidelines in spinal fusions. It also shows that a 66% implant density leads to better safety and efficacy, avoiding higher costs.

Complications associated with surgical treatment for pediatric spine deformities: A single center 10-years experience.

INTRODUCTION: The surgical treatment for pediatric spine deformity is complex and often associated with complications, which generates important clinical and economic impact. Herein the authors analyze the prevalence of complications in surgery for pediatric spine deformity, the correlation between complications and several risk factors, and present a preventive algorithm for these events. MATERIAL AND METHODS: We collected for analysis the data regarding pediatric patients with spine deformities surgically treated in our institution through a 10 years period with 100% revision rate and a 24-month minimum follow-up were included. The statistical analysis was performed using SPSS Statistics 23. RESULTS: 70 complications (33,4%) were identified in 56 patients (26,7%), of which 38 (54,2%) were acute and 32 (45,7%) late complications. Pulmonary complications (7.1%), surgical site infection (6.6%) and junctional kyphosis (4.3%) were the most frequent events. Scoliosis etiology was especially correlated with general complications (p < 0.05) and early complications (p < 0.01). A logistic regression model identified preoperative hemoglobin (Exp =1.476; P=0.044), fused levels (Exp =-0.677; P=0.023) and titanium implants (Exp =0.257, P < 0.000) as relevant factors for complications. Area under the curve was 0.744, and, when using the best cutting point, the model was capable of predicting absence of complications in 84% of cases, and its occurrence in 56%. DISCUSSION: Pulmonary complications, surgical site infection and junctional events were identified as the most frequent complications after pediatric scoliosis surgery. By developing high risk protocols to decrease these events, patient safety will be significantly enhanced. Risk assessment makes part of this process and our predictive model by identifying two modifiable factors and including another that relates to procedure invasiveness may help avoiding complications and improve outcomes. ctors for complications. Area under the curve was 0.744, and, when using the best cutting point, the model was capable of predicting absence of complications in 84% of cases, and its occurrence in 56%.

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.

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.

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.

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.

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.

Serum level of fibroblast growth factor 23 in maintenance renal transplant patients.

BACKGROUND: The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients. METHODS: We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1-4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation. RESULTS: FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = -0.487; P < 0.001), PTH (r = -0.444; P < 0.001), serum phosphate levels (r = -0.315; P < 0.001) and fractional excretion of magnesium (r = -0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003). CONCLUSIONS: Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.

Limited-sampling strategy for mycophenolic acid in renal transplant recipients reciving enteric-coated mycophenolate sodium and tacrolimus.

BACKGROUND: Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. STUDY DESIGN: Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). RESULTS: The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). CONCLUSIONS: : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.