Our analysis revealed that comorbidities were prevalent in COVID-19. Compared to those without, patients with preexisting CVD, CKD, COPD or liver disease sustained excess death. More importantly, our report highlights for the first time that deteriorated kidney function during hospitalization is a detrimental factor to excess death and partially mediates the facilitating effect of comorbidities, which provides novel insights into comorbidity-related excess death.
Our study described the characteristics of COVID-19 in a larger population with a wider range of comorbidities. In this study, 56.16% patients have at least one preexisting comorbidity. This is consistent with another published research in Wuhan (48%) (21). Although, a lower comorbidity rate (25.1%) was observed in a larger descriptive research in whole China (2). However, it’s surprised nearly 90% or even above 90% of the hospitalized COVID-19 patients were with at least one type of comorbidities in the US (22, 23). This difference may occur from various admission standards, but generally, comorbidities were quite common for hospitalized COVID-19 patients. For critical cases, comorbidities are even more prevalent; 77.02% in our research coincides with 73.5% in Canada (1).
Compared to COVID-19 patients without preexisting comorbidities, those with CVD, CKD, COPD or liver disease had greater excess death. The strength of correlation between different comorbidities and the prognosis, however, was inconsistent when compared with the previous researches (2, 5, 24). We do not find significant risk increase in hypertension and diabetes. The reasons for these inconsistences are still confusing. Thus, how these comorbidities accelerate in-hospital death is an urge problem remained to be solved.
In the current study, it’s shown that patients with comorbidities were more prone to experience deteriorated kidney function. Although there were some publications on kidney involvement and COVID-19 infection, they mainly focused on the phenomenon of higher mortality risk associated with comorbidities or kidney diseases or simply presented the prevalence of kidney injury during the disease course (5, 11, 13). Whereas, our mediation analysis demonstrates that the deteriorated kidney function exhibited different proportion of mediation effect on the accelerating role of comorbidities. The association of comorbidities and high in-hospital death could be partially explained by deteriorated kidney function, with a mediation effect ranging from 11% to 32% and highest for CKD. In line with previous findings (11, 13), deteriorated kidney function is prevalent in COVID-19 patients and strongly related to higher in-hospital death rate, especially in those with comorbidities. However, previous studies were focusing on acute kidney injury (11,13). While, in our research, any declines in kidney function were found associated with excess death independent of age, gender, smoking status, white blood cell counts and baseline serum creatinine. Although the highest risk occurred in patients with more than 50% decline of kidney function, those with more than 10% decline of kidney function ought not to be neglected. However, according to our findings, deteriorated kidney function is not the only mediator in comorbidities related excess death. Meanwhile, more detailed mechanism as well as the cause-effect relationship could not be confirmed for the retrospective nature of this study.
The pathogenesis of COVID-19 related kidney function deterioration and how it accelerates in-hospital death is largely unknown. It’s supposed to be related to direct viral infection or dysregulated immune response (10, 25, 26). SARS-CoV-2 enters cells by binding angiotensin-converting enzyme-2 (ACE2) (27, 28). Theoretically, the decrease of ACE2, caused by SARS-CoV-2 infection, would break the balance between ACE and ACE2. As a result, Renin-Angiotensin-Aldosterone system (RAAS) was positively regulated and angiotensin II type 1 receptor was over stimulated, which may further cause inflammation activation, endothelial injury and mitochondrial dysfunction (29, 30). The kidney and cardiovascular system are supposed as main victims for they are main targets of angiotensin II. These was astonishingly consistent with our findings, for we get the most mediating effect in CKD and CVD patients. Besides, drug-related kidney injury could be another important factor. According to “COVID-19 Diagnosis and Treatment Protocol of China”, many potential nephrotoxic drugs were proposed, including some kind of anti-virus drugs (examples: α-interferon, lopinavir and ribavirin), resochin and Chinese traditional medicine( examples: Angong Niuhuang pill, Tanreqing injection and Xingnaojing injection (16). It may be reasonable to speculate that the deteriorated kidney function could be a sign of renal involvement of SARS-COV-2 infection. And it may be somehow relevant to RAAS, which requires further investigations.
For now, kidney function hasn’t been emphasized in COVID-19 patients’ management both in China and Occident (16, 17, 31). These findings provide novel insights into comorbidities-related in-hospital death, which could be helpful in stratifying high-risk patients during this pandemic and advising prevention practices for high-risk patients. In other words, the decline of kidney function is likely considered as an important factor in risk stratification models for COVID-19. Thus, dynamic monitoring the kidney function is of paramount importance in COVID-19 patients, especially in those with preexisting comorbidities. Additionally, avoiding the occurrence of hypotension/hypoxemia or using nephrotoxic drugs, attenuating the synthesis of pro-inflammatory cytokines might help to lower the risk of jeopardizing the kidney function and improve chances of survival in patients with preexisting comorbidities.
But patients were not followed after discharge in this investigation. Hence, recovery of the kidney function and the full clinical course of these patients could not be further evaluated.