Negative immune responses to two-dose mRNA COVID-19 vaccines in renal allograft recipients assessed with simple antibody and interferon gamma release assay cellular monitoring.

Studies are urgently needed to characterize immunogenicity, efficacy, and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in kidney transplant (KT) recipients, excluded from major clinical trials. Complex ELISPOT and other cellular response techniques have been applied, but simpler tools are needed. An easy-to-use real-world monitoring of SARS-CoV-2 IgG antibodies against the Spike protein and QuantiFERON® SARS-CoV-2 IFNγ release assay (IGRA) were performed at baseline and 28 days after the second dose in KT recipients and controls (dialysis patients and healthy ones). All healthy controls and >95% dialysis controls became positive for anti-S IgG antibodies, while only 63.3% of KT patients seroconverted with a very low antibody level. A positive IGRA was documented in 96.9% of controls, 89.3% peritoneal dialysis, 77.6% hemodialysis, 61.3% of KT patients transplanted more than 1 year ago and only 36% of those transplanted within the previous 12 months. Overall, 100% of healthy controls, 95.4% of dialysis patients and 78.8% KT recipients developed any immune response (humoral and/or cellular) against SARS-CoV-2. KT patients showed low rates of immune responses to mRNA Coronavirus infectious disease 2019 vaccines, especially those with recent transplantations. Simple humoral and cellular monitoring is advisable, so that repeated doses may be scheduled according to the results.

COVID-19 in elderly kidney transplant recipients.

The SARS-Cov-2 infection disease (COVID-19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID-19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti-retroviral and tocilizumab. Short-term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D-dimer, C-reactive protein, and IL-6 at their first tests. COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate.

COVID-19 in Grade 4-5 Chronic Kidney Disease Patients.

INTRODUCTION: Chronic kidney disease (CKD) increases the risk of mortality during coronavirus disease 2019 (COVID-19) episodes, and some reports have underlined the high incidence and severity of this infection in dialysis patients. Information on COVID-19 in nondialysis CKD patients is not available yet. CASE REPORTS: Here we present 7 patients with grade 4-5 CKD who developed symptomatic COVID-19; they comprise 2.6% of our 267 advanced CKD patients. The estimated GFR was between 12 and 20 mL/min during the month prior to COVID-19. The 3 major symptoms were fever, cough, and dyspnea, and 5 patients showed bilateral pneumonia. Hydroxychloroquine, azithromycin, ceftriaxone, and steroids were the most frequently prescribed drugs. Two patients needed noninvasive mechanical ventilation. All patients showed minimal to moderate kidney function deterioration during admission, with an eGFR decline below 5 mL/min in 6 cases. No patient required acute dialysis. Six patients were discharged alive and remained dialysis free athe t the time of reporting, and one 76-year-old patient died. CONCLUSIONS: COVID-19 affects grade 4-5 CKD patients, but prognosis may be acceptable if prompt supportive measures are applied. These findings should be confirmed in larger cohorts, and further observations will be needed to understand the full spectrum of clinical features and the optimal approach to COVID-19 in patients with advanced CKD.

Determination of free serotonin and its metabolite 5-HIAA in blood human samples with consideration to pre-analytical factors.

Significant differences have been reported over the years in measuring physiological levels of free circulating serotonin (f5-HT) in platelet-poor plasma (PPP). This work shows that there are crucial pre-analytical factors in sample manipulation that can provoke an artifactual release of 5-HT from platelets, and that, even when the sample is accurately processed to obtain PPP, f5-HT levels are approximately 2.8 times higher than those of f5-HT in blood. An alternative methodology consisting of ex vivo blood microdialysis coupled to high-performance liquid chromatography-electrochemical detection is proposed and validated. It is considered the most accurate technique to measure physiological circulating f5-HT and its metabolite 5-hydroxyindoleacetic acid (f5-HIAA), owing to its sensitivity (limits of quantification of 0.08 ng/mL) and reliability since there is no sample manipulation. The f5-HT and f5-HIAA levels in blood and in PPP were studied in control subjects, hypertensive and end-stage renal disease patients, who have a deregulated serotonergic system. This work reveals that blood is the best matrix to determine f5-HT concentrations, and the clinical relevance of the accuracy of f5-HT determination is discussed.

Dynamics of Humoral and Cellular Responses in Renal Transplant Recipients Receiving 3 Doses of SARS-CoV-2 mRNA Vaccine.

BACKGROUND: The original SARS-CoV-2 vaccination regimen (2 doses) induces insufficient short-term response in kidney transplant (KT) recipients. This study assessed the response to a third dose and the long-term immunogenicity after 2 doses in KT. METHODS: We analyzed the dynamics of the humoral and cellular response by monitoring SARS-CoV-2 IgG antibodies against the Spike-protein (IgG-Spike) and QuantiFERON SARS-CoV-2 IFN-γ release assay 6 mo after the second dose (T2) and 28 d after the third dose of mRNA vaccines (T3) to KT and controls (dialysis patients and healthy individuals). RESULTS: At T2, the percentage of IgG-Spike+ KT and dialysis patients decreased (KT 65.8%-52.6%, hemodialysis 92.6-81.5%, and peritoneal dialysis 100%-90%), whereas 100% of healthy controls remained positive. About the cellular response, the percentage of responders decreased in all groups, especially in KT (22.4%-9.2%, P = 0.081). At T3, 92% of KT, 94%-98% of dialysis patients, and 100% of healthy controls were IgG-Spike+. In terms of antibody titers, patients and controls showed a reduction between T2 and T3 and about 80% of dialysis patients and 100% of controls achieved high titers after the third dose (>1479.5 Binding Antibody Units/mL), whereas this percentage was only 50% in KT. With respect to the cellular response, only KT displayed a significant rise after the third dose. CONCLUSIONS: The third dose of mRNA vaccine improves both humoral and cellular responses, but less effectively in KT compared with dialysis patients and healthy controls.

Mortality in Hemodialysis Patients with COVID-19, the Effect of Paricalcitol or Calcimimetics.

BACKGROUND: In COVID-19 patients, low serum vitamin D (VD) levels have been associated with severe acute respiratory failure and poor prognosis. In regular hemodialysis (HD) patients, there is VD deficiency and markedly reduced calcitriol levels, which may predispose them to worse outcomes of COVID-19 infection. Some hemodialysis patients receive treatment with drugs for secondary hyperparathyroidism, which have well known pleiotropic effects beyond mineral metabolism. The aim of this study was to evaluate the impact of VD status and the administration of active vitamin D medications, used to treat secondary hyperparathyroidism, on survival in a cohort of COVID-19 positive HD patients. METHODS: A cross-sectional retrospective observational study was conducted from 12 March to 21 May 2020 in 288 HD patients with positive PCR for SARS-CoV2. Patients were from 52 different centers in Spain. RESULTS: The percent of HD patients with COVID-19 was 6.1% (288 out of 4743). Mortality rate was 28.4% (81/285). Three patients were lost to follow-up. Serum 25(OH)D (calcidiol) level was 17.1 [10.6-27.5] ng/mL and was not significantly associated to mortality (OR 0.99 (0.97-1.01), p = 0.4). Patients receiving active vitamin D medications (16/94 (17%) vs. 65/191(34%), p = 0.003), including calcimimetics (4/49 (8.2%) vs. 77/236 (32.6%), p = 0.001), paricalcitol or calcimimetics (19/117 (16.2%) vs. 62/168 (36.9%); p < 0.001), and also those on both paricalcitol and calcimimetics, to treat secondary hyperparathyroidism (SHPTH) (1/26 (3.8%) vs. 80/259 (30.9%), p < 0.001) showed a lower mortality rate than patients receiving no treatment with either drug. Multivariate Cox regression analysis confirmed this increased survival. CONCLUSIONS: Our findings suggest that the use of paricalcitol, calcimimetics or the combination of both, seem to be associated with the improvement of survival in HD patients with COVID-19. No correlation was found between serum VD levels and prognosis or outcomes in HD patients with COVID-19. Prospective studies and clinical trials are needed to support these findings.

Clinical Profiles in Renal Patients with COVID-19.

The COVID-19 pandemic has led to frequent referrals to the emergency department on suspicion of this infection in maintenance hemodialysis (MHD) and kidney transplant (KT) patients. We aimed to describe their clinical features comparing confirmed and suspected non-confirmed COVID-19 cases during the Spanish epidemic peak. Confirmed COVID-19 ((+)COVID-19) corresponds to patient with positive RT-PCR SARS-CoV-2 assay. Non-confirmed COVID-19 ((-)COVID-19) corresponds to patients with negative RT-PCR. COVID-19 was suspected in 61 patients (40/803 KT (4.9%), 21/220 MHD (9.5%)). Prevalence of (+)COVID-19 was 3.2% in KT and 3.6% in MHD patients. Thirty-four (26 KT and 8 MHD) were (+)COVID-19 and 27 (14 KT and 13 MHD) (-)COVID-19. In comparison with (-)COVID-19 patients, (+)COVID-19 showed higher frequency of typical viral symptoms (cough, dyspnea, asthenia and myalgias), pneumonia (88.2% vs. 14.3%) and LDH and CRP while lower phosphate levels, need of hospital admission (100% vs. 63%), use of non-invasive mechanical ventilation (36% vs. 11%) and mortality (38% vs. 0%) (p < 0.001). Time from symptoms onset to admission was longer in patients who finally died than in survivors (8.5 vs. 3.8, p = 0.007). In KT and MHD patients, (+)COVID-19 shows more clinical severity than suspected non-confirmed cases. Prompt RT-PCR is mandatory to confirm COVID-19 diagnosis.

Starting hemodialysis with catheter and mortality risk: persistent association in a competing risk analysis.

PURPOSE: The vascular access (VA) used at hemodialysis (HD) inception is involved in the mortality risk. We analyzed the survival of incident patients over time according to the initial VA and the VA profile of patients who died during the first year of follow-up. METHODS: Data of VA were obtained from 9956 incident HD patients from the Catalan Registry. RESULTS: Over 12 years, 47.9% of patients initiated HD with a fístula, 1.2% with a graft, 15.9% with a tunneled catheter and 35% with an untunneled catheter. Regarding fistula use, the hazard ratio of death for all-causes over time when applying a multivariate competing risk model was 1.55 [95% confidence interval (CI): 1.42-1.69] and 1.43 (95% CI: 1.33-1.54) for patients with tunneled and untunneled catheter, respectively. During the first year of follow-up, the crude all-cause mortality rate (deaths/100 patient-years) was higher during the early (first 120 days) compared to the late (121-365 days) period: 18.3 (95% CI: 16.8-19.8) versus 15.4 (95% CI: 14.5-16.5). Regarding fistula use, for patients using untunneled and tunneled catheter, the odds ratio of death in the early period for all-causes was 3.66 (95% CI: 2.80-4.81) and 2.97 (95% CI: 2.17-4.06), for cardiovascular causes it was 2.76 (95% CI: 1.90-4.01) and 1.84 (95% CI: 1.17-2.89) and for infection-related causes it was 6.62 (95% CI: 3.11-14.05) and 4.58 (95% CI: 2.00-10.52), respectively. CONCLUSIONS: Half of all incident patients in Catalonia are exposed to excessive mortality risk related to catheter and this scenario can be improved by early fistula placement.

Vascular access for incident hemodialysis patients in Catalonia: analysis of data from the Catalan Renal Registry (2000-2011).

PURPOSE: Arteriovenous fístula is the best vascular access (VA) for hemodialysis. We analyzed the VA used at first session and the factors associated with the likelihood to start hemodialysis by fistula in 2000-2011. METHODS: Data of VA type were obtained in 9,956 incident hemodialysis patients from the Catalan Registry. RESULTS: Overall, 47.9% of patients initiated hemodialysis with a fistula, 1.2% with a graft, 15.9% with a tunneled catheter and 35% with an untunneled catheter. The percentage of incident patients with fistula and catheter has remained stable at around 50% over the years. The likelihood to start hemodialysis with fistula was significantly lower in females [adjusted odds ratio: 0.69, 95% confidence interval (CI): 0.61-0.75], patients aged 18-44 years (0.78, 95% CI: 0.64-0.94), patients with comorbidity (0.67, 95% CI: 0.60-0.75) and tended to be lower in patients aged over 74 years (0.89, 95% CI: 0.78-1.01). The probability to use fistula was significantly higher in patients with polycystic kidney disease (2.08, 95% CI: 1.63-2.67), predialysis nephrology care longer than 2 years (4.14, 95% CI: 3.63-4.73) and steady chronic kidney disease (CKD) progression (10.97, 95% CI: 8.41-14.32). During 1 year of follow-up, 67.2% and 59.6% of patients using untunneled and tunneled catheter changed to fistula, respectively. CONCLUSIONS: Starting hemodialysis by fistula was related with nonmodifiable patient characteristics and modifiable CKD practice processes, such as predialysis care duration. Half of the incident patients were exposed annually in Catalonia to potential catheter complications. This scenario can be improved by optimizing the processes of CKD care.

Efficacy of influenza A H1N1/2009 vaccine in hemodialysis and kidney transplant patients.

BACKGROUND AND OBJECTIVES: Data are needed to assess safety and efficacy of the 2009 pandemic influenza A H1N1 vaccine in renal patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We prospectively evaluated seroconversion, predictors of response, and vaccine safety in renal patients. Hemagglutination inhibition tests to detect serum antibodies against a new influenza A-H1N1 virus were performed in 79 transplant patients, 48 hemodialysis patients, and 15 healthy workers before and 1 month after vaccination. Healthy controls and 88 of 127 renal patients were vaccinated. Seroconversion was defined as at least 2 dilutions increase in titer. RESULTS: We excluded 19 individuals seroprotected (≥1/40) against the novel H1N1 in the initial sample. Efficacy rate in the 96 vaccinated individuals was 43.7% (42 of 96 seroconverted versus four of 27 nonvaccinated patients, P = 0.007). For vaccinated subgroups, efficacy was 41.8% in transplant patients (P = 0.039 versus nonvaccinated), 33.3% in hemodialysis patients (P = 0.450), and 81.8% in controls. Healthy controls showed better response to vaccine than transplant (P = 0.021) and dialysis (P = 0.012) patients. For the transplant subgroup, longer time after transplantation (P = 0.028) was associated with seroconversion, but no influence was found for age, gender, renal function, or immunosuppression. In the hemodialysis subgroup, younger age was associated with response (55.7 ± 20.8 versus 71.6 ± 10.1 years, P = 0.042), but other specific variables, including Kt/V or time on dialysis, were not. No serious adverse events were reported, and kidney function was stable. CONCLUSION: The novel influenza A 2009 H1N1 vaccine was safe in renal patients, although administration of a single dose of adjuvanted vaccine induced a poor response in these patients.