Key results
In this prospective, multicenter cohort study including a total of 1112 hospitalized COVID-19 patients, we were able to evaluate for the first time the combined effect of kidney function and preformed antibody levels on COVID-19-related in-hospital mortality risk.
Following adjustment for potential confounding factors, patients with an eGFR of 60–89 ml/min, 30–59 ml/min, and < 30 ml/min had 4.5, 8.5, and 8.4 times higher odds of dying if anti-SARS-CoV-2 spike antibody levels were below the Youden index of 182BAU/ml. In patients with reduced eGFR, the combination of eGFR category and antibody levels was found to be a stronger predictor of in-hospital mortality than either factor alone.
umulative survival over time was better in patients with antibody levels < 1200BAU/ml compared to < 182BAU/ml, in particular for patients with low kidney function (eGFR < 30 ml/min, 30–59 ml/min).
This is in line with the incremental increase in protection with rising antibody levels in our data and previous studies14,16 and suggests that the threshold of 1200BAU/ml would be more conservative for protecting CKD patients in clinical practice.
Previous studies have linked the individual risk factors reduced kidney function and anti-SARS-CoV-2 spike antibodies to outcome in COVID-19 but did not evaluate the role of antibody levels in relation to kidney function in COVID-19 related mortality 6,9,16,18.
Our data suggest that the combination of these factors has a greater effect on COVID-19 mortality than each factor individually, potentially due to increased relevance of preformed antibody levels in patients with low kidney function. As reduced kidney function is often accompanied by low-grade systemic inflammation and increased levels of proinflammatory cytokines26, this may in part be caused by a mitigating effect of antibodies on elevated inflammation levels27 in patients with CKD.
Of note, our data indicate that, even though reduced kidney function is an independent risk factor, mortality risk did not differ significantly by kidney function if antibody levels were > 182BAU/ml. In contrast, in CKD patients with lower antibody levels, mortality risk nearly doubled with each 30 ml/min decrease in eGFR. This underlines the importance of regular booster vaccinations in patients with impaired kidney function.
Interpretation
In our data, COVID-19-associated 90-day mortality was highest in patients with an eGFR of < 30 ml/min and low antibody levels. While mortality rates progressively increased with decreasing kidney function, the same eGFR category (60-89 ml/min, 30-59 ml/min, < 30 ml/min) combined with low antibody levels exhibited significantly higher mortality rates than the eGFR category by itself.
In patients with decreased eGFR and higher antibody levels (> 182BAU/ml), mortality rates were found to be significantly lower in each eGFR category than for patients with lower antibody levels. While we also observed a trend towards a progressive increase in mortality rates with decreasing kidney function in patients with high antibody levels, this trend did not attain statistical significance, possibly due to the comparatively low number of events in this group.
Patients with an eGFR of 60–89 ml/min and high antibody levels registered significantly lower mortality rates than patients with lower antibody levels despite being more predisposed to adverse outcomes through higher age14. Accordingly, patients with an eGFR of 30–59 ml/min and high antibody levels exhibited significantly lower mortality rates despite having a substantially higher prevalence of CAD, CVD, and a higher number of comorbidities. Of note, survival did not differ significantly by eGFR in patients with high antibody levels.
CKD has been linked to a range of dysfunctions affecting both the innate and the adaptive immune system 28. While CKD is associated with increased levels of pro-inflammatory cytokines, including IL-6 and tumor necrosis factor alpha 29,30, many functions of the cellular immune system, such as adaptive T-cell responses, phagocytic functions or the capacity of dendritic cells to activate T-cells appear to be impaired in this patient group 28. In addition, the number of dendritic cells, naïve T-cells, as well as the number of naïve and memory B-cells may be reduced in CKD patients due to decreased output or increased apoptosis rates 28.
Given the critical role of T-cell mediated immunity in eliminating intra-cellular pathogens such as viruses 31, the impairment of adaptive T-cell responses in patients with CKD may be of particular relevance in COVID-19. As the impairment of immune functions appears to be in part dependent on the degree of uremia 28, the importance of preformed antibody levels in coping with a viral infection may increase with decreasing kidney function and its associated diminished cellular immune function.
Strengths and Limitations
One of the main strengths of this study is its high recruitment rate, which substantially reduces the risk of selection bias. In addition, this study is based on a hard endpoint (mortality), minimizing the risk of assessment bias32. Further, two different risk measures were provided, and all regression models were adjusted for known risk factors of adverse outcomes in COVID-19 which may have acted as confounders. These include age, obesity, SARS-CoV-2 variant, and the comorbidities type 2 diabetes, hypertension, coronary artery disease, heart failure, chronic obstructive pulmonary disease, and cerebrovascular disease.
All utilized laboratory parameters are widely available in clinical laboratories and have short turn-around times. Finally, previous studies show that the Roche anti-SARS-CoV-2 spike antibody assay is highly sensitive in the detection of neutralizing antibodies while maintaining this sensitivity over time33.
By design, this study centered on hospitalized COVID-19 patients, potentially limiting its applicability to outpatients. However, we deliberately chose to examine hospitalized patients because severe cases are highly likely to be admitted to a hospital. Given the observational character of this study, the thresholds used in this study should be verified in separate cohorts.
This study did not assess cellular immunity. Effective viral clearance requires the coordinated action of both humoral and cellular immune responses. In particular, T-cell mediated immunity is known to play a critical role in eliminating SARS-CoV-2 and establishing long-lasting immune memory 31. Both antibody and T-cell responses, in particular CD8 + T cells, have been shown to correlate with disease severity 14. However, measures of cellular immune responses are less readily available in routine clinical laboratories, more costly, and less firmly established as correlates of immunity in clinical practice 34. Nonetheless, future studies should investigate the interplay between T-cell immunity, preformed antibody levels, kidney function and outcome in COVID-19.
While results were still statistically significant for patients with an eGFR of < 30 ml/min, the relatively low patient number (n = 104) in this category should be taken into account. In addition, we did not observe a significant difference in COVID-19 related mortality by antibody level in patients with an eGFR > 90 ml/min. A potential reason for this may be the low number of events in this category.
Patients in this study were classified based on eGFR in order to evaluate how antibody levels in combination with kidney function affect outcome in COVID-19. As proteinuria was not routinely assessed on hospital admission, data on proteinuria was only available in part of the cohort. Future studies are warranted to assess whether proteinuria affects the relationship between antibody levels, kidney function, and COVID-19 related mortality.
Underlying kidney diseases, such as autoimmune and hereditary diseases, may affect both immune responses and outcome in COVID-19. However, in our data, exclusion of patients with these conditions did not alter the statistical significance of our findings. Due to the small number of patients within these subgroups, a robust subgroup analysis was not considered feasible. Future studies should investigate these patient subsets in greater detail to better understand if these diseases affect the association between antibody levels, kidney function, and outcome in COVID-19.
Both transplant patients and immunocompromised patients were considered eligible for inclusion in this study. However, none of the included patients had received a kidney transplant and the comparatively low number of immunocompromised CKD patients did not allow for a meaningful subgroup analysis.
While excluding these patients from the analysis did not affect the statistical significance of our results, future studies are required to address in how far our results are applicable to immunocompromised CKD patients.
This study evaluated the association between eGFR and anti-SARS-CoV-2 spike antibody levels at the time of hospital admission. While preformed antibody levels appear to indicate protection against severe COVID-19 and COVID-19 related mortality 15,16, the strength of the antibody response over the course of the disease correlates with disease severity, resulting in decreased prognostic utility of antibody levels later in the infection 15.
In addition, the strength of the immune response is highly variable, influenced not only by the severity of the infection but also by temporal dynamics throughout the course of the disease. Immune responses further exhibit substantial inter-individual variability 15,16. Thus, identifying individuals at increased mortality risk based on “weaker-than-normal” immune responses may be challenging to implement in clinical practice. Moreover, assessing anti-SARS-CoV-2 antibody levels in addition to kidney function on hospital admission may facilitate the early identification of high risk COVID-19 patients with CKD who may benefit from intensified treatment regimes. We therefore deemed it important to evaluate the prognostic utility of preformed antibody levels at the onset of COVID-19.
The emergence of new SARS-CoV-2 variants with multiple variants in the spike antigen has resulted in differing degrees of immune evasion from pre-existing antibodies35, associated with a corresponding loss in efficacy. Nonetheless, higher antibody levels were still found to retain their protective value36,37.
Further studies are warranted to investigate the interplay between kidney function, antibody levels, COVID-19 outcome, and other factors that may influence inflammatory responses such as statin treatment, oral antivirals, and certain comorbidities38,39. This question may be particularly relevant for patient subsets that are highly susceptible to severe courses of COVID-19.
Another question that should be investigated is whether anti-SARS-CoV-2 spike antibody levels may prevent acute kidney injury during COVID-19 and if this is the case, how high antibody levels need to be in order to effect this protection. Future studies should further evaluate whether preformed antibody levels confer protection from the transition to chronic kidney disease in long-COVID-19.
Previous studies have shown that vaccination status is a weaker predictor of outcome in COVID-19 than antibody levels15,16. Possible reasons are that antibody levels decline over time following a vaccination, the wide interindividual variability in the strength of antibody responses, and a general decline in the strength, quality and durability of antibody responses with age14. As kidney disease occurs more commonly with progressive age, the latter point is of particular interest in this patient group.
Moreover, our data suggest that adequate antibody levels are critical for survival in patients with impaired kidney function. Maintaining sufficiently high antibody levels is therefore of key importance in this patient group.
Our data indicate significant differences in COVID-19 related mortality in patients with impaired kidney function for both antibody thresholds employed in this study. Consistent with previous studies 16,17, we further found a decrease in mortality risk for every 250BAU/ml increase in antibody levels, that was present in all eGFR categories. Given the better cumulative survival, and in accordance with the incremental increase in protection with increasing antibody levels, the threshold of 1200BAU/ml is deemed more conservative for clinical practice.
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