Post COVID-19 condition imposes significant burden in patients with advanced chronic kidney disease: A nested case-control study.

BACKGROUND: The burden of post COVID-19 condition (PCC) is not well studied in patients with advanced kidney disease. METHODS: A large prospective cohort of SARS-CoV-2 vaccinated patients with chronic kidney disease stages G4-G5 (CKD G4/5), on dialysis, and kidney transplant recipients (KTR) were included. Antibody levels were determined after vaccination. Presence of long-lasting symptoms was assessed in patients with and without prior COVID-19 and compared using logistic regression. In patients with prior COVID-19, PCC was defined according to the WHO definition. RESULTS: Two hundred sixteen CKD G4/5 patients, 375 dialysis patients, and 2005 KTR were included. Long-lasting symptoms were reported in 204/853 (24%) patients with prior COVID-19 and in 297/1743 (17%) patients without prior COVID-19 (aOR: 1.45 (1.17-1.78)], P < 0.001). PCC was prevalent in 29% of CKD G4/5 patients, 21% of dialysis patients, and 24% of KTR. In addition, 69% of patients with PCC reported (very) high symptom burden. Odds of PCC was lower per 10-fold increase in antibody level after vaccination (aOR 0.82 [0.70-0.96], P = 0.01) and higher in case of COVID-19 related hospital admission (aOR 4.64 [2.61-8.25], P = 0.003). CONCLUSIONS: CKD G4/5 patients, dialysis patients, and KTR are at risk for PCC with high symptom burden after SARS-CoV-2 vaccination, especially if antibody levels are low and in case of hospitalization due to COVID-19.

Incidence and Severity of COVID-19 in Relation to Anti-Receptor-Binding Domain IgG Antibody Level after COVID-19 Vaccination in Kidney Transplant Recipients.

Kidney transplant recipients (KTRs) elicit an impaired immune response after COVID-19 vaccination; however, the exact clinical impact remains unclear. We therefore analyse the relationship between antibody levels after vaccination and the risk of COVID-19 in a large cohort of KTRs. All KTRs living in the Netherlands were invited to send a blood sample 28 days after their second COVID-19 vaccination for measurement of their IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD IgG). Information on COVID-19 was collected from the moment the blood sample was obtained until 6 months thereafter. Multivariable Cox and logistic regression analyses were performed to analyse which factors affected the occurrence and severity (i.e., hospitalization and/or death) of COVID-19. In total, 12,159 KTRs were approached, of whom 2885 were included in the analyses. Among those, 1578 (54.7%) became seropositive (i.e., anti-RBD IgG level >50 BAU/mL). Seropositivity was associated with a lower risk for COVID-19, also after adjusting for multiple confounders, including socio-economic status and adherence to COVID-19 restrictions (HR 0.37 (0.19-0.47), p = 0.005). When studied on a continuous scale, we observed a log-linear relationship between antibody level and the risk for COVID-19 (HR 0.52 (0.31-0.89), p = 0.02). Similar results were found for COVID-19 severity. In conclusion, antibody level after COVID-19 vaccination is associated in a log-linear manner with the occurrence and severity of COVID-19 in KTRs. This implies that if future vaccinations are indicated, the aim should be to reach for as high an antibody level as possible and not only seropositivity to protect this vulnerable patient group from disease.

Adherence to preventive measures after SARS-CoV-2 vaccination and after awareness of antibody response in kidney transplant recipients in the Netherlands: a nationwide questionnaire study.

Background: Kidney transplant recipients (KTRs) were advised to tightly adhere to government recommendations to curb the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) because of a high risk of morbidity and mortality and decreased immunogenicity after vaccination. The aim of this study was to analyse the change in adherence to preventive measures after vaccination and awareness of antibody response, and to evaluate its effectiveness. Methods: In this large-scale, national questionnaire study, questionnaires were sent to 3531 KTRs enrolled in the Dutch RECOVAC studies, retrospectively asking for adherence to nine preventive measures on a 5-point Likert scale before and after SARS-CoV-2 vaccination and after awareness of antibody response. Blood samples were collected 28 days after the second vaccination. Antibody response was categorised as non-responder (≤50 BAU/mL), low-responder (>50 ≤ 300 BAU/mL) or high-responder (>300 BAU/mL), and shared with participants as a correlate of protection. Participants of whom demographics on sex and age, blood samples and completed questionnaires were available, were included. Our study took place between February 2021 and January 2022. The primary outcome of adherence before and after vaccination was assessed between August and October 2021 and compared via the Wilcoxon signed rank sum test. Logistic regression analysis was performed to estimate the association between antibody response and non-adherence, and adherence on acquiring SARS-CoV-2 infection. This study is registered at ClinicalTrials.gov (NCT04841785). Findings: In 2939 KTRs (83%) who completed the first questionnaire on adherence to preventive measures, adherence was higher before than after vaccination (4.56, IQR 4.11-4.78 and 4.22, IQR 3.67-4.67, p < 0.001). Adherence after awareness of antibody response was analysed in 2399 KTRs (82%) of whom also blood samples were available, containing 949 non-responders, 500 low-responders and 950 high-responders. Compared to non-responders, low- and high-responders reported higher non-adherence. Higher adherence was associated with lower infection rates before and after vaccination (OR 0.67 [0.51-0.91], p = 0.008 and OR 0.48 [0.28-0.86], p = 0.010). Interpretation: Adherence decreased after SARS-CoV-2 vaccination and in KTRs who were aware of a subsequent antibody response compared with those without. Preventive measures in this vulnerable group seem to be effective, regardless of vaccination status. This study starts a debate on sharing antibody results with the patient and future studies should elucidate whether decreased adherence in antibody responders is justified, also in view of future pandemics. Funding: The Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation.

Differences in mental health status during the COVID-19 pandemic between patients undergoing in-center hemodialysis and peritoneal dialysis.

BACKGROUND: The mental health of dialysis patients during the COVID-19 pandemic may have been modulated by dialysis modality. Studies comparing mental health of in-center hemodialysis and peritoneal dialysis patients during the first 2 years of the pandemic are lacking. METHODS: We conducted repeated cross-sectional and multivariable regression analyses to compare the mental health of in-center hemodialysis and peritoneal dialysis patients from March 2019 until August 2021 using data from the Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes. The study period was divided into one pre-pandemic and six 3-month pandemic periods (period 1-period 6). Mental health was assessed with the Mental Component Summary score of the 12-item Short Form health survey and mental symptoms of the Dialysis Symptom Index. RESULTS: We included 1274 patients (968 on in-center hemodialysis and 306 on peritoneal dialysis). Mental Component Summary scores did not differ between in-center hemodialysis and peritoneal dialysis patients. In contrast, in-center hemodialysis patients more often reported nervousness during period 3 (27% vs 15%, P = 0.04), irritability and anxiety during period 3 (31% vs 18%, P = 0.03, 26% vs. 9%, P = 0.002, respectively) and period 4 (34% vs 22%, P = 0.04, 22% vs 11%, P = 0.03, respectively), and sadness in period 4 (38% vs 26%, P = 0.04) and period 5 (37% vs 22%, P = 0.009). Dialysis modality was independently associated with mental symptoms. CONCLUSIONS: In-center hemodialysis patients more often experienced mental symptoms compared to peritoneal dialysis patients from September 2020 to June 2021, which corresponds to the second lockdown of the COVID-19 pandemic. Mental health-related quality-of-life did not differ between in-center hemodialysis and peritoneal dialysis patients. TRIAL REGISTRATION NUMBER: Netherlands Trial Register NL6519, date of registration: 22 August, 2017.

Impact of immunosuppressive treatment and type of SARS-CoV-2 vaccine on antibody levels after three vaccinations in patients with chronic kidney disease or kidney replacement therapy.

Background: Patients with chronic kidney disease (CKD) or kidney replacement therapy demonstrate lower antibody levels after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination compared with healthy controls. In a prospective cohort, we analysed the impact of immunosuppressive treatment and type of vaccine on antibody levels after three SARS-CoV-2 vaccinations. Methods: Control subjects (n = 186), patients with CKD G4/5 (n = 400), dialysis patients (n = 480) and kidney transplant recipients (KTR) (n = 2468) were vaccinated with either mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech) or AZD1222 (Oxford/AstraZeneca) in the Dutch SARS-CoV-2 vaccination programme. Third vaccination data were available in a subgroup of patients (n = 1829). Blood samples and questionnaires were obtained 1 month after the second and third vaccination. Primary endpoint was the antibody level in relation to immunosuppressive treatment and type of vaccine. Secondary endpoint was occurrence of adverse events after vaccination. Results: Antibody levels after two and three vaccinations were lower in patients with CKD G4/5 and dialysis patients with immunosuppressive treatment compared with patients without immunosuppressive treatment. After two vaccinations, we observed lower antibody levels in KTR using mycophenolate mofetil (MMF) compared with KTR not using MMF [20 binding antibody unit (BAU)/mL (3-113) vs 340 BAU/mL (50-1492), P < .001]. Seroconversion was observed in 35% of KTR using MMF, compared with 75% of KTR not using MMF. Of the KTR who used MMF and did not seroconvert, eventually 46% seroconverted after a third vaccination. mRNA-1273 induces higher antibody levels as well as a higher frequency of adverse events compared with BNT162b2 in all patient groups. Conclusions: Immunosuppressive treatment adversely affects the antibody levels after SARS-CoV-2 vaccination in patients with CKD G4/5, dialysis patients and KTR. mRNA-1273 vaccine induces a higher antibody level and higher frequency of adverse events.

Mycophenolic Acid Exposure Determines Antibody Formation Following SARS-CoV-2 Vaccination in Kidney Transplant Recipients: A Nested Cohort Study.

Despite (repeated) boosting, kidney transplant recipients (KTRs) may remain at increased risk of severe COVID-19 since a substantial number of individuals remain seronegative or with low antibody titers. In particular, mycophenolic acid use has been shown to affect antibody formation negatively and may be an important modifiable risk factor. We investigated the exposure-response relationship between mycophenolic acid 12-hour area under the curve (AUC0-12h ) exposure and seroconversion including antibody titers after vaccination using mRNA-1273 SARS-CoV-2 vaccine (Moderna) in 316 KTRs from our center that participated in the national Dutch renal patients COVID-19 vaccination - long term efficacy and safety of SARS-CoV-2 vaccination in kidney disease patients vaccination study. After two vaccination doses, 162 (51%) KTRs seroconverted. KTRs treated with mycophenolic acid showed less seroconversion and lower antibody titers compared with KTRs without mycophenolic acid (44% vs. 77%, and 36 binding antibody units (BAU)/mL vs. 340 BAU/mL; P < 0.001). The mean mycophenolic acid AUC0-12h exposure was significantly lower in KTRs who seroconverted compared with KTRs who did not (39 vs. 29 mg⋅h/L; P < 0.001). High mycophenolic acid exposure (±90 mg⋅h/L) and no exposure to mycophenolic acid resulted in a seroconversion rate ranging from 10% to 80%. Every 10 mg⋅h/L increase in mycophenolic acid AUC0-12h gave an adjusted odds ratio for seroconversion of 0.87 (95% confidence interval (CI), 0.79-0.97; P = 0.010) and 0.89 (95% CI, 0.85-0.93; P < 0.001) for KTRs on dual and triple maintenance immunosuppressive therapy, respectively. Higher mycophenolic acid AUC0-12h correlated with lower antibody titers (R = 0.44, P < 0.001). This study demonstrates the exposure-response relationship between gold standard mycophenolic acid exposure and antibody formation to support interventional studies investigating mycophenolic acid adjustment to improve antibody formation after further boosting.

Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS­CoV­2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response. Methods: Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome. Results: The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model' 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA); chronic lung disease, heart failure, and diabetes; increased age; shorter time after transplantation; lower body mass index; lower kidney function; no alcohol consumption; ≥2 transplantations; and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations. Conclusions: In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies.

The Clinical Frailty Scale as a triage tool for ICU admission of dialysis patients with COVID-19: an ERACODA analysis.

BACKGROUND: Several guidelines recommend using the Clinical Frailty Scale (CFS) for triage of critically ill coronavirus disease 2019 (COVID-19) patients. This study evaluates the impact of CFS on intensive care unit (ICU) admission rate and hospital and ICU mortality rates in hospitalized dialysis patients with COVID-19. METHODS: We analysed data of dialysis patients diagnosed with COVID-19 from the European Renal Association COVID-19 Database. The primary outcome was ICU admission rate and secondary outcomes were hospital and ICU mortality until 3 months after COVID-19 diagnosis. Cox regression analyses were performed to assess associations between CFS and outcomes. RESULTS: A total of 1501 dialysis patients were hospitalized due to COVID-19, of whom 219 (15%) were admitted to an ICU. The ICU admission rate was lowest (5%) in patients >75 years of age with a CFS of 7-9 and highest (27%) in patients 65-75 years of age with a CFS of 5. A CFS of 7-9 was associated with a lower ICU admission rate than a CFS of 1-3 [relative risk 0.49 (95% confidence interval 0.27-0.87)]. Overall, mortality at 3 months was 34% in hospitalized patients, 65% in ICU-admitted patients and highest in patients >75 years of age with a CFS of 7-9 (69%). Only 9% of patients with a CFS ≥6 survived after ICU admission. After adjustment for age and sex, each CFS category ≥4 was associated with higher hospital and ICU mortality compared with a CFS of 1-3. CONCLUSIONS: Frail dialysis patients with COVID-19 were less frequently admitted to the ICU. Large differences in mortality rates between fit and frail patients suggest that the CFS may be a useful complementary triage tool for ICU admission in dialysis patients with COVID-19.