THE CLINICAL FRAILTY SCALE IS USEFUL FOR ICU TRIAGE IN DIALYSIS PATIENTS WITH COVID-19-AN ERACODA ANALYSIS

BACKGROUND AND AIMS: during the COVID-19 pandemic, several guidelines have recommended the use of the Clinical Frailty Scale (CFS) for triage of critically ill patients with COVID-19 in case of shortage in ICU resources. However, no data on using CFS assessment for ICU triage for dialysis patients is yet available. This study evaluates whether CFS is associated with mortality rates in a cohort of hospitalized dialysis patients with COVID-19. METHOD: the analyses are based on data of the European Renal Association COVID-19 Database (ERACODA). Dialysis patients who presented with COVID-19 between 1 February 2020 and 30 April 2021 and with complete information on CFS and vital status at 3 months were included. Study outcomes were hospital and ICU admission rates and hospital and ICU mortality at 3 months after hospital admission. Cox regression analyses were performed to assess the association of CFS category (≤5 versus ≥ 6) and study outcomes in line with Dutch ICU triage guidelines for COVID-19. Furthermore, additional subgroup analyses were performed to assess the association between CFS and 3-month mortality by age category (<65, 65-75 and >75 years). RESULTS: among a total of 2206 dialysis patients (mean age = 67.2 (14.1) years, male sex = 61%), 1694 (77%) had CFS ≤ 5 and 514 (23%) had CFS ≥ 6. Hospitalization rate was comparable in patients with CFS ≤ 5 and in patients with CFS ≥ 6 (67 and 71%, respectively), whereas the rate of ICU admission was higher in patients with CFS ≤ 5 than in patients with CFS ≥ 6 (16 versus 9%, p = 0.001). Among 1501 hospitalized patients, 3-month mortality was 26% of patients with CFS ≤ 5 and 59% in patients with CFS ≥ 6 (P < 0.001). Multivariate analysis with adjustment for patient demographics, smoking status and BMI revealed that CFS ≥ 6 was associated with hospital mortality [aHR 2.27 (1.88-2.74) versus CFS ≤ 5;P < 0.001) with a significant interaction for age (P = 0.029). aHR was 4.00 (2.56-6.37;CFS ≥ 6 versus CFS ≤ 5;P < 0.001) in patients < 65 years, aHR was 1.87 (1.33-2.64;CFS ≥ 6 versus CFS ≤ 5;P < 0.001) in patients 65-75 years and aHR was 2.12 (1.64-2.75;CFS ≥ 6 versus CFS ≤ 5;P < 0.001) in patients >75 years. Among 219 ICU admitted patients, 3-month mortality was 60% of the patients with CFS ≤ 5 and 91% in the patients with CFS ≥ 6, respectively. Multivariate analysis with adjustment for patient demographics, smoking status and BMI revealed that CFS ≥ 6 was associated with ICU mortality [aHR 1.80 (1.17-2.77);CFS ≥ 6 versus CFS ≤ 5;P = 0.002]. CONCLUSION: more frail dialysis patients with CFS ≥ 6 who are hospitalized for COVID-19 were less often admitted to the ICU, but in case they were admitted to the ICU they have a very high mortality of 91% in this cohort study. In fit to mildly frail dialysis, patients who were admitted to the ICU, mortality rates are lower. The association between frailty and hospital mortality is interacted by age with the strongest association in patients younger than 65 years. These findings suggest that CFS may be a useful complementary triage tool for ICU admission of dialysis patients during the ongoing COVID-19 pandemic.

A COMPARATIVE STUDY OF PATIENT MORTALITY DURING FIRST AND SECOND WAVES OF COVID-19 PANDEMIC IN DIALYSIS PATIENTS AND KIDNEY TRANSPLANT RECIPIENTS

BACKGROUND AND AIMS: Patients on kidney replacement therapy (KRT) are at a particularly high risk of mortality from COVID-19. In this study, we investigated COVID-19 mortality in KRT patients in the first and second waves of the pandemic and potential reasons for any difference in mortality between the two waves. METHOD: Data from the European Renal Association COVID-19 Database (ERACODA) of KRT patients who presented between 1 March 2020 and 28 February 2021 with COVID-19 were analyzed. The cut-off for dividing the first and second waves was set for 1 August 2020. The primary study outcome was 28-day mortality. Multivariable Cox proportional-hazards regression analysis was used to examine the relationship between the pandemic waves and mortality with follow-up time starting at the date of presentation. Dialysis patients and kidney transplant recipients were analyzed separately. RESULTS: Among 3004 dialysis patients (1253 in the first and 1751 in the second wave), the 28-day mortality was 24.3% in the first wave and 19.6% in the second wave (P = .002). Compared with the first wave, in the second wave, identification of patients with limited to no symptoms was higher (14.3% versus 24.8%;P < .001), hospitalization was lower (71.3% versus 44.3%;P < .001), but in-hospital mortality was similar (30.4% versus 30.7%;P = .92) (Fig. 1). Crude hazard ratio (HR) for 28-day mortality in the second wave was 0.77 (95% CI: 0.66, 0.89). However, in a fully adjusted model, when correcting for differences in patient and disease characteristics, including the reason for COVID-19 screening and disease severity, the HR for mortality in the second wave was 0.93 [95% confidence interval (95% CI): 0.79-1.10]. When follow-up was chosen to start at the date of first symptoms to account for possible lead-time bias, crude HR for 28-day mortality in the second wave was 0.90 (95% CI: 0.75-1.07) and the fully adjusted HR was 0.98 (95% CI: 0.81-1.18). Among 1035 kidney transplant recipients (475 in the first and 560 in the second wave), results were essentially similar except that patients in the second wave were younger (55.6 years versus 58.2 years;P = .002), and crude HR for 28-day mortality from the date of first symptoms was 0.66 (95% CI: 0.47-0.93), whereas the fully adjusted HR was 1.02 (95% CI: 0.70-1.49). CONCLUSION: Among patients on KRT with COVID-19, 28-day mortality rates were lower in the second wave compared with the first wave. However, a greater proportion of patients with minimal symptoms, lead-time bias in dialysis patients, and younger age in kidney transplant recipients possibly explain the lower mortality during the second wave. Any improvement in patient management during the second wave may not be the main reason for lower mortality. (Table Presented).

HIGHER ANTIBODY RESPONSE AFTER 2 VACCINATIONS WITH MRNA-1273 AS COMPARED WITH BNT162B2 AND AZD1222 IN HIGH-RISK KIDNEY PATIENTS

BACKGROUND AND AIMS: Lower antibody responses after SARS-Cov-2 vaccination have been reported in patients with severely impaired kidney function or patients with kidney replacement treatment. We compared humoral responses and reported adverse events of three vaccines (mRNA-1273, BNT162b2 and AZD1222) in kidney transplant recipients (KTRs), dialysis patients, patients with CKD stages G4-G5 and control subjects without kidney disease. METHOD: KTRs, dialysis patients and patients with CKD stages G4-G5 were vaccinated with either mRNA-1273, BNT162b2 or AZD1222 during the Dutch SARSCoV- 2 vaccination program. Control subjects were all vaccinated with mRNA-1273. Blood samples were obtained at 1 month after two vaccinations by home-based finger prick tests and were analysed for the presence of IgG antibodies against the receptorbinding domain of the spike protein of SARS-CoV-2 using the Sanquin anti-SARSCoV- 2 RBD IgG ELISA assay. Primary endpoints were the antibody titer and reported systemic adverse events (AEs) at 1 month after the second vaccination. Multivariate regression analysis was performed on the difference between vaccines with respect to antibody titer and AEs after correction for sex, ethnicity, BMI, eGFR, dialysis vintage, transplantation characteristics and use of immunosuppressive drugs. RESULTS: A total of 2468 KTRs, 480 dialysis patients, 400 patients with CKD stages G4-G5 and 186 control subjects were enrolled. KTRs had lower antibody titers (66 [8-573] BAU/mL) in comparison to dialysis patients [1375 (431-2896) BAU/mL], patients with CKD stages G4-G5 [2097 (828-4077) BAU/mL] and control subjects [3713 (2291-6451) BAU/mL]. mRNA-1273 demonstrated a higher antibody titer compared with BNT162b2 in KTR [72 (9-638) versus 21 (6-128) BAU/mL;P < .001), dialysis patients [1675 (573-3031) versus 636 (216-1416) BAU/mL;P < .001] and patients with CKD stages G4-G5 [2879 (1425-5311) versus 1063 (389-1939) BAU/mL;P < .001). In a similar pattern, mRNA-1273 demonstrated a higher antibody titer compared with AZD1222 (P < .001 in all groups). Multivariate analysis revealed that BNT162b2 and AZD1222 were significantly associated with lower antibody levels compared with mRNA-1273 in all 3 patient groups. BNT162b2 demonstrated less frequently systemic AEs compared with mRNA-1273 in KTRs (12% versus 27%;P < .001), dialysis patients (12% versus 29%;P = .007) and in patients with CKD G4- G5 (18% versus 67%, P < .001). AZD1222 demonstrated less systemic AEs compared with mRNA-1273 only in patients with CKD stages G4-G5 (39% versus 67%;P = .03). Multivariate analysis revealed that BNT162b2 was associated with fewer systemic AEs in only dialysis patients (P = .04) and patients with CKD stages G4-G5 (P = .02). CONCLUSION: mRNA-1273 demonstrated significantly higher antibody levels at 1 month after 2 vaccinations as compared with BNT162b2 and AZD1222 in high-risk patients with kidney disease. BNT162b2 was associated with a fewer systemic AEs in dialysis patients and patients with CKD stages G4-G5, although these AEs were mild and self-limiting. mRNA-1273 may therefore be considered as the preferred SARS-CoV-2 vaccine in high-risk patients with kidney disease. Whether the higher antibody response following vaccination with mRNA-1273 sustains and results in a better protection against COVID-19 is yet to be analysed.

DEVELOPMENT AND VALIDATION OF A MULTIVARIABLE PREDICTION MODEL FOR NONSEROCONVERSION AFTER SARS-COV-2 VACCINATION IN KIDNEY TRANSPLANT RECIPIENTS

BACKGROUND AND AIMS: Kidney transplant recipients (KTRs) are still at risk of fatal COVID-19 disease after SARS-CoV-2 vaccination, even after a third booster vaccination. With the spread of new SARS-CoV-2 variants, great urgency exists for a better understanding of the factors that impact the immune response in these patients. Our aim was to predict nonseroconversion after SARS-CoV-2 vaccination to understand the factors that may disrupt the humoral response in KTRs. METHOD: A multivariable logistic regression model was developed and validated that uses routinely available clinical and laboratory information to predict nonseroconversion after two doses of SARS-CoV-2 mRNA vaccination in KTRs. KTRs were prospectively enrolled to the Dutch REnal patients COVID-19 VACcination (RECOVAC) consortium, specifically to the Immune Response (IR) study with four participating university medical centres in the Netherlands. The discovery cohort consisted of three participating centres (Amsterdam UMC, Radboud UMC Nijmegen and Erasmus MC Rotterdam), and the validation cohort of patients treated in UMC Groningen. A large second validation set from the RECOVAC consortium (LESS-CoV- 2) was used to test a more simplified version of the model without lymphocyte counts. All participants received two doses of the mRNA-1273 COVID-19 vaccine (Moderna) and had no history of SARS-CoV-2 infection. Participants were classified as responder or non-responder based on seroconversion at day 28 following the second vaccination with a threshold for seropositivity based on receiver operator curve analysis set at S1-specific IgG antibody concentration ≥10 BAU/mL. RESULTS: The discovery cohort included 215 KTRs of which 126 responders and 89 non-responders. After backward selection, 6 out of 19 factors remained predictive for nonseroconversion: increased age, lower lymphocyte count, lower estimated glomerular filtration rate (eGFR), shorter time after transplantation, not using steroids and the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) (Figure 1). The area under the curve (AUC) of the receiver operating characteristics was 0.83 (95% confidence interval 0.78-0.89) in the discovery cohort after adjustment for optimism and 0.84 (0.74-0.94) in external validation of the UMC Groningen cohort (n = 73), and 0.75 (0.72-0.77) in external validation of the LESS-CoV-2 dataset (n = 2484). In addition, MMF/MPA appeared to have a dose-dependent unfavourable association with the S1 IgG antibody titer (Figure 2). CONCLUSION: Six predictors allow for a better understanding of the process of the development of the humoral response in KTRs. These predictors could be applied to individualized patient counseling and treatment strategy during the COVID-19 pandemic and future innovative vaccine trial design for this complex patient group. (Figure Presented).

Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.

BACKGROUND: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. METHODS: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). DISCUSSION: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

Long-term efficacy and safety of SARS-CoV-2 vaccination in patients with chronic kidney disease, on dialysis or after kidney transplantation: a national prospective observational cohort study.

BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.

Association of obesity with 3-month COVID-19-related mortality in ESKD patients

Background: In the general population obesity is associated with increased risk of mortality. However, in ESKD patients obesity is associated with lower risk of mortality, particularly in dialysis patients (i.e. the obesity paradox). In COVID-19 patients, obesity exhibits a similar association with mortality as observed in the non-COVID-19 general population. Given the obesity paradox, we questioned the association of obesity with mortality in ESKD patients with COVID-19. Methods: Data from the European Renal Association COVID-19 Database (ERACODA) were analysed. Association of BMI (kg/m2), divided into: <18.5 (lean), 18.5-24.9 (normal weight), 25-29.9 (overweight), 30-34.9 (obese I) and ≥35 (obese II), with 3-month mortality was investigated using Cox proportional-hazards regression. Results were investigated for the total population and, dialysis patients and kidney transplant recipients separately. Results: In 3160 ESKD patients (mean age: 65 years, male: 61%), 99 patients were lean, 1151 normal weight (reference group), 1160 overweight, 525 obese I and 225 obese II. During follow-up of 3 months, 28%, 20%, 21%, 23% and 27% of patients died in the lean, normal weight, overweight, obese I and obese II category, respectively. In fully adjusted model, the HRs for 3-month mortality were 1.65 (95% CI:1.10, 2.47), 1.07 (95% CI:0.89, 1.28), 1.17 (95% CI:0.93, 1.46) and 1.71 (95%CI:1.27, 2.30) in lean, overweight, obese I and obese II vs normal weight patients (Figure). Results were similar among dialysis patients and transplant recipients (p-interaction=0.99). Conclusions: In ESKD patients with COVID-19, dialysis patients or kidney transplant recipients, obesity is associated with an increased risk of mortality at 3 months. This is contrary to obesity paradox generally observed in dialysis patients. There is need to investigate why in dialysis patients with COVID-19 the survival benefit of obesity is lost.

Three-month clinical, functional, and mental outcomes in kidney transplant recipients surviving COVID-19

Background: Kidney transplant patients are at high risk for COVID-19 related mortality. However, limited data are available on longer term clinical, functional and mental outcomes in patients that survive COVID-19. Methods: Data from adult kidney transplant patients that presented with COVID-19 between February 1st, 2020 and January 31st, 2021 were retrieved from the ERACODA database. Data from patients with complete data for vital status, hospitalization and/or ICU admission was used for this analysis. Results: 912 patients were included with a mean age of 56.7 (±13.7) years. 26.4% were not hospitalized, 57.5% hospitalized, and 16.1% hospitalized and ICU admitted. Three-months survival was 82.3% overall and 98.8%, 84.2% and 49.0% resp. in each group. Three-months acute rejection, need for dialysis / CVVH at any time point, and graft failure occurred in the overall group in 1.0%, 2.6% and 1.8% resp., and in 2.1%, 10.6% and 10.6% of ICU admitted patients resp. Of the surviving patients 83.3% had reached their prior functional status within 3 months. Of patients that had not yet reached their prior functional status, it was expected that 79.6% still would do so within the coming year. 94.4% had reached their prior mental status. Of patients that had not yet reached their prior mental status, it was expected that 80% of patients would do so within the coming year. Conclusions: In patients alive at three-months follow-up, graft loss was rare, and most patients had reached their pre-COVID-19 functional and mental status. Clinical, functional, and mental outcomes in kidney transplant recipients three months after being diagnosed with COVID-19. Data of 487 patients were available for analysis of graft function related outcomes. Data of 450 patients were available for functional and mental status outcomes.

COVID-19 related mortality in kidney transplant and dialysis patients: A comparative, prospective registry based study

BACKGROUND AND AIMS: Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics. METHOD: Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening. RESULTS: A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects. CONCLUSION: In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.