In our study, we added new information and insights on the contribution of kidney dysfunction in COVID-19. We investigated and characterized several risk factors in COVID-19, with a specific focus on the relationship between age and kidney dysfunction on progression and severity of the disease. The most interesting results of our study, in a population of COVID-19 hospitalized patients, are the importance of AKI as independent risk factor for mortality, the identification of key variables for risk assessment of patients, and the evidence that the influence of baseline GFR on the clinical outcomes decreases with age, and it seems to not represent a major risk factor for elderly patients.
AKI occurred in one-third of hospitalized COVID-19 patients with a wide range among different studies, probably due to differences in study populations examined [11–14]. Based on the literature, incidence of AKI seems to be higher in COVID-19 patients compared to SARS-CoV2 negative patients [15–16] confirming that it is not an epiphenomenon in severe or critical disease. CKD is a well-known risk factor for AKI and poor outcomes in different clinical settings and is frequently observed in the elderly that appear to be at higher risk of developing severe or critical COVID-19 disease as do other patients affected by comorbidities associated with kidney dysfunction (diabetes, CVD, and hypertension) [17]. This is why it is challenging to discriminate between association and causality of CKD and poor outcome in COVID-19.
Also, a precise risk assessment in COVID-19 patients is essential to allocate health resources during the pandemic emergency.
A recent study performed on the Danish population [5], which differentiated between pre-existing CKD and AKI through national healthcare registries, showed an increasing risk for severe disease in CKD population. Although these findings appear in contrast with our data, the mean age in this study was significantly lower compared to our sample (57.6 y vs. 69.1 y), which shows this could be due to demographic differences of the populations studied. However, the risk for severe disease or death was weak for early stages of CKD and when the variable “age” was included in the regressive model [5]. Previous studies have reported a significant influence of age on the association between CKD and disease progression. The same influence was not found for mortality, but this may be due to a markedly younger median age, compared to our sample [18].
Beyond COVID-19, various studies investigated the relationship between eGFR and clinical outcomes in the elderly, and the role of reduced GFR in this population is still debated among nephrologists [8]. Some studies demonstrated that in elderly patients a GFR < 60 mL/min is not associated with increased risk for mortality or progression to end stage kidney disease (ESKD) [19–20], while a meta-analysis found a U shape curve in the relationship between GFR and mortality for older age group (> 65 years) with a higher risk for GFR > 115 mL/min [21].
Thus, a lower limit for CKD definition in the elderly has been proposed (e.g. eGFR < 45 mL/min) [15], and different GFR equations have been developed and validated in this population. Recent studies evaluated the performance of different and more used equations for eGFR and found various pitfalls, limitations, and conflicting results in the association with short- and long-term hard outcomes [9, 22–23].
To investigate the correlation between age and kidney dysfunction, we firstly analysed age as a dichotomous variable, and we showed that it influences mortality but not the composite endpoint, performed to evaluate the severity of the disease. However, analysing the single outcomes of the composite endpoint, we found a positive, but not significant, correlation with the need for high flux oxygen therapy (FiO2 > 60%; OR 1.83 95% IC 0.96–3.5). Conversely, we demonstrated an inverse correlation between age and C-PAP and age and EIT. A speculative reason for this evidence could be that elderly patients experiment a higher rate of mortality despite a slightly increased risk for severe or critical disease. This could partially be due to a minor eligibility of elderly patients to more invasive therapeutic approaches, and maybe to a reduced availability of medical resources during the pandemic outbreak. The non-randomized nature of this study, however, does allow us to clarify the reasons.
Age and AKI confirmed their important role as independent risk factors for COVID-19 mortality. In this relationship, eGFR acted as possible confounder with an effect of diminishing the hazard risk of death in patients over 70 years.
We did not show a significant impact of pharmacologic treatment on disease progression or mortality, with the exception of steroids. Indeed, all the drugs used were positively correlated with the severity of disease, probably because patients affected by pauci-symptomatic diseases were not referred to pharmacologic treatment. Steroid treatment, on the other hand, seemed to have a beneficial effect (OR 0.45 95% IC 0.19–1.07), consistent with previous reports [24].
We also developed a predictive analysis with a very high accuracy for AKI and mortality in the subset of patients < 70 years. Interestingly, in patients ≥ 70 years the model showed a worse accuracy, and a worse accuracy of BIS-1 formula compared to CKD-EPI and MDRD. Although BIS-1 formula has been specifically developed in the elderly population, the diagnostic and predictive performance of this equation did not show significant superiority compared to CKD-EPI and/or MDRD[17]. In our population, MDRD showed the best predictive value, for AKI, severity of the disease and mortality, while BIS-1, which identifies almost twice the amount of CKD compared to other formula (28.7 % vs 16.6 %) showed the worst performance compared to MDRD and CKD-EPI.
The worse accuracy of our predictive analysis in patients ≥ 70 years could be due to a lack of variables of interest in the older population, such as albuminuria and BMI, and the reduced influence of our variables in the elderly, including GFR.
In conclusion, this study confirms the important role of AKI in COVID-19 progression. We believe that frequent sCr measurements should be performed in hospitalized patients to achieve an early detection of AKI, in order to identify patients at high risk for mortality and morbidity. Moreover, our study diminishes the role of a pre-existing CKD in COVID-19 patients, especially in the elderly patients, where its contribution, compared with age and AKI, results of minor relevance.
Reasons behind this evidence are partially speculative. GFR estimation based on sCr levels is actually the most feasible method in the clinical routine but it presents strong bias in specific clinical conditions. Indeed, low sCr levels could be measured in fragile and sarcopenic patients. In this specific population, GFR could be artifactually higher. CKD is a well-recognized negative prognostic factor for mortality and CVD morbidity, but also malnutrition inflammation syndrome (MIS), in which creatinine generation is very low, is a strong CVD risk factor and correlates with mortality [25].
Moreover, as we discussed above, our population was characterized by a high percentage of elderly patients and a relatively high mean GFR value, which, in this setting, became prognostically relevant when under 45 mL/min.
Our study has several limitations: first of all, we were not able to collect previous creatinine values of patients, thus causing possible overlapping of CKD and AKI. Moreover, we missed important variables such as albuminuria, proteinuria, BMI and fragile state index. In particular, nutritional status and body mass assessment is essential to further investigations into the relationship between CKD and clinical outcomes in the older old affected by COVID-19.
Finally, the evaluation of the severity, through the composite endpoint, was affected by a bias of eligibility of older patients to invasive treatments, due to clinical decision making, and probably influenced by the availability of healthcare resources during the COVID-19 outbreak in Italy.