key: cord-0078162-kegsf4k5
authors: Song, Yuting; Mao, Dongdong; Zou, Rong; Hu, Yanglin; Luo, Dan; Liu, Hong; Tu, Can; Xiong, Fei
title: Patients with Chronic Kidney Disease Have Higher Acute Kidney Injury Morbidity than those without after SARS-CoV-2 Infection
date: 2021-11-29
journal: nan
DOI: 10.4103/imna.imna_24_21
sha: a157854ad42f0533f4dadb5bd4ec670f8861979b
doc_id: 78162
cord_uid: kegsf4k5

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) and acute kidney injury (AKI) increase the risk of serious disease and mortality in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients. This study evaluated the occurrence and outcome of AKI in CKD and non-CKD patients infected with SARS-CoV-2. SUBJECTS AND METHODS: We retrospectively analyzed the medical records of 845 patients with SARS-CoV-2 infection regarding the occurrence and outcome of AKI in a coronavirus disease-2019 (COVID-19)-designated hospital in Wuhan, China, from December 31, 2019, to March 20, 2020. RESULTS: Of the 845 COVID-19 patients, 91 had CKD and 754 had no CKD (non-CKD), of whom 22 and 14 developed AKI, respectively. Finally, 36 patients were included in the analysis. Older patients and those with cardiovascular or cerebrovascular diseases were more likely to develop AKI. More CKD patients progressed to critical illness (72.73%) than non-CKD patients (57.14%), but the degree of AKI in CKD patients was lesser than that in non-CKD patients. Higher urea nitrogen, creatinine, and proteinuria levels were observed in CKD patients. More non-CKD patients were treated with human albumin than CKD patients. The survival probability of CKD patients was lower than that of non-CKD patients, but it was not statistically significant. CONCLUSION: There were significant differences in the incidence rate of AKI after SARS-CoV-2 infection between CKD and non-CKD patients, and the clinical manifestations and treatments of AKI also differed. These results highlight the necessity of variable treatment methods for optimal clinical management.

The second outbreak of coronavirus disease-2019 (COVID-19) highlights considerable public health problems. The mortality rate of respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients after acute kidney injury (AKI) is consistently high (60%-90%). [1, 2] An early study found that chronic kidney disease (CKD) is a risk factor for severe COVID-19 and death, [2] indicating that CKD might be a risk for SARS-CoV-2 infection and death.

Several studies have reported the incidence and severity of AKI in COVID-19 patients, [3] [4] [5] but the clinical manifestations of CKD developing AKI after SARS-CoV-2 infection are not well-described, hindering treatment. Therefore, we aimed to identify the clinical characteristics and prognosis of AKI in SARS-CoV-2-infected patients and compare the clinical features of patients with and without CKD to provide a clinical reference for treating these patients.

This retrospective single-center study was performed in one of the largest designated hospitals for patients with severe COVID-19. Patients infected with SARS-CoV-2 and treated at the hospital from December 31, 2019, to March 20, 2020, were included. All patients were diagnosed with SARS-CoV-2 infection based on the Diagnosis and Treatment Protocols for Novel Coronavirus Pneumonia (Trial Version 7) guidelines. [6] Patients undergoing maintenance dialysis or renal transplantation were excluded. Clinical outcomes were monitored through May 5, 2020. This study followed the guidelines of the Declaration of Helsinki and was approved by the institutional ethics board of our institution.

Data on the baseline characteristics, clinical manifestations, laboratory results, treatments, and outcomes were obtained from the hospital's health information system and were recorded by standard electronic methods. The laboratory data consisted of renal function, electrolyte levels, and routine urine parameters.

SARS-CoV-2-infected cases were clinically classified as mild, moderate, severe, or critical based on the Diagnosis and Treatment Protocols for Novel Coronavirus Pneumonia (Trial Version 7) guidelines. [6] The Kidney Disease: Improving Global Outcomes guidelines were used to diagnose and classify AKI and CKD.

Disease progression was based on lung computed tomography (CT) imaging and defined as the expansion of the infected lesion or the appearance of new lesions at the second checkup. No progression was defined as no obvious enlargement or shrinkage of the infected lesions compared with the last checkup or some lesions were enlarged and others slightly reduced without obvious change overall. Remission was defined as the absorption or shrinkage of the infected lesion at the second checkup.

Nor mally distributed data were expressed as means ± standard deviations, and a t-test was used for between-group comparisons. Nonnormally distributed data were represented by medians and interquartile ranges (P25, P75), and the Wilcoxon test was used for between-group comparisons. Fisher's exact test was used for categorical variables. The overall survival between the CKD-AKI and CKD groups was compared by Kaplan-Meier analysis with the log-rank test. SPSS version 23.0 (IBM Corp., Armonk, NY, USA) and RevMan version 5.3 (Cochrane Collaboration, The Nordic Cochrane, Copenhagen) were used for the statistical analyses. P < 0.05 was considered statistically significant.

Chronic kidney disease patients infected with severe acute respirator y syndrome coronavirus-2 developed acute kidney injury more frequently than did nonchronic kidney disease patients

In total, 845 patients were diagnosed with SARS-CoV-2 infection, of whom 91 (10.77%) had CKD and 22 (24.18%) had AKI. Of the 754 (89.23%) non-CKD patients, 14 (1.86%) had AKI. In total, 36 (4.26%) patients with SARS-CoV-2 infection developed AKI and were included in the analysis. These results suggest that patients with SARS-CoV-2 infection can develop AKI, and CKD patients were more likely to develop AKI after being infected [ Figure 1 ].

The mean age of infected patients with AKI was 77.5 (66.5-85.75) years, and most were male. In total, 61.11% of patients had cardiovascular disease, 72.22% had cerebrovascular disease, 38.89% had diabetes, and 8.33% had cancer. The time from onset to admission for AKI was at least 1 week, with a mean of approximately 10 days. Angiotensin drugs were previously taken by 28% of the patients, and hypoglycemic drugs were previously taken by 13.89% of the patients.

Age, sex, time from onset to admission, and comorbidities did not differ between CKD and non-CKD patients. More CKD patients took oral angiotensin drugs before admission, but the difference was statistically insignificant [ Table 1 ].

Cough (61.11%), fatigue (50%), decreased appetite (82.76%), and decreased urine output (78.13%) were the main clinical symptoms of infected patients who developed AKI, followed by fever (47.22%), chest tightness (25%), edema (14.29%), and sore throat (11.11%). The mean oxygen saturation (by finger pulse oximeter) was 96% at admission, which was lower than the reference range. After admission, the mean maximum body temperature was 39°C, and the mean minimum 24-hour urine output was 500.00 ml. Overall, 27.78% of the patients developed severe disease, and 66.67% developed critical illness. Regarding the AKI stage, 33.33%, 36.11%, and 30.56% of the infected patients were at Stage 1, Stage 2, and Stage 3, respectively.

Among SARS-CoV-2-infected patients who developed AKI, the urine output 24-hour after admission was significantly lower in non-CKD patients than in CKD patients. Furthermore, non-CKD patients had a higher frequency of decreased urine output (92.31%), decreased appetite (90.91%), and diarrhea (21.43%). Cough (72.73%), fatigue (59.09%), edema (17.65%), and increased nocturia (12.50%) were more frequent in CKD patients, but the differences were not statistically significant.

Regarding clinical classification, more CKD patients (72.73%) progressed to critical illness than non-CKD patients. The AKI classification suggests that 40.91% of CKD patients were at Stage 1, 36.36% at Stage 2, and 22.73% at Stage 3 AKI. However, the clinical classification of non-CKD patients trended oppositely with the AKI grade: 35.71% of patients progressed to severe illness and 57.14% progressed to critical illness, and 21.43% were at AKI Stage 1, 35.71% were at Stage 2, and 42.86% were at Stage 3 [ Table 2 ]. It suggests that the relationship between the progression of CKD and AKI may not be as close as that of non-CKD patients.

Lung computed tomography of severe acute respiratory syndrome coronavirus-2-infected patients with acute kidney injury showed disease progression, and more than half had hematuria or proteinuria Lung CT re-examination indicated that only 37.04% of patients had lung lesion absorption, 22.22% had no significant improvement, and 40.74% had disease progression. Overall, 57.90% of patients had hematuria, 57.15% had proteinuria, and 20% had pathological casts in the urine test. After admission, the highest urinary nitrogen and creatinine levels were significantly higher than the normal values.

Comparing non-CKD patients and CKD patients who developed AKI, we found that CKD patients had significantly higher basal urea nitrogen and creatinine levels (P = 0.02 and P = 0.02, respectively). The proportion of CKD patients with proteinuria was also higher than non-CKD patients (P = 0.050). Lung CT re-examination showed the proportions of progression, no change, and remission in non-CKD patients were similar. However, 46.67% of CKD patients showed progression, whereas 40% showed remission. More pathological casts were also seen in the urine of CKD patients, but these differences were statistically insignificant [ Table 3 ].

Antibiotics (97.22%), Chinese medicine (88.89%), antiviral agents (86.11%), and human albumin (58.33%) were the primary treatment methods, followed by steroids (43.75%), diuretics (41.12%), and blood transfusion (31.25%). All three patients treated with continuous renal replacement therapy (CRRT) died. Overall, 41.67% of patients received noninvasive ventilation, 22.86% received invasive ventilation, and two patients (6.45%) received extracorporeal membrane oxygenation. Regarding outcomes, 44.66% of patients were discharged and 55.56% died.

Comparing non-CKD patients and CKD patients, we found that significantly more non-CKD patients were treated with human albumin infusion than CKD patients. Moreover, non-CKD patients were more likely to receive hormone therapy (P = 0.050). Regarding outcomes, CKD patients had a higher mortality rate (68.18%) than non-CKD patients (35.71%), but the difference was not statistically significant [ Table 4 ].

Survival analysis showed that the overall 1-and 2-month survival rates of CKD patients were lower than those of non-CKD patients, but the differences were not statistically significant [ Figure 2 ].

In this study, we investigated the clinical characteristics and prognosis of AKI in SARS-CoV-2-infected patients. We found that 4.26% of patients diagnosed with SARS-CoV-2 infection in a COVID-19-designated hospital in Wuhan, China, had AKI, consistent with a previous study, [7] but lower than that reported by Chan et al. [8] and Cheng et al. [2] This difference may be related to the lack of monitoring urine volume and fewer reviews of renal function in COVID-19 patients for various pandemic-related reasons.

Most SARS-CoV-2-infected patients with AKI were male and older than those without AKI. [8] However, there were no differences in age or sex between CKD and non-CKD patients in our study, which might be due to all included patients being infected with SARS-CoV-2 and developing AKI. Although age and sex are risk factors for SARS-CoV-2 infection, there were no differences between CKD and non-CKD patients who were infected.

Many SARS-CoV-2-infected patients who developed AKI had cardiovascular, cerebrovascular disease, or diabetes. A previous study reported that most SARS-CoV-2-infected patients had diabetes. [1] Thus, it is hypothesized that SARS-CoV-2 infection combined with circulatory system diseases has a greater effect on the kidney.

The duration from onset to admission of patients with SARS-CoV-2 infection who developed AKI was at least 1 week. The oxygen saturation level at admission was lower than normal, consistent with a previous study. [2] It was speculated that patients with AKI progressed rapidly, and the disease may have already progressed to a serious level before admission. In our study, after admission, the mean maximum body temperature reached 39°C, which may also be related to a higher likelihood of severe or critical disease progression among AKI patients. In addition to the typical clinical manifestations of pneumonia during hospitalization, the AKI patients also had characteristics of kidney disease, such as decreased appetite, reduced urine output, and edema, indicating that the kidney is a major target of SARS-CoV-2 attack.

Antiviral agents, antibiotics, Chinese medicine, and human albumin were the main treatments for AKI, consistent with the treatment for SARS-CoV-2-infected patients. Three patients were treated with CRRT with poor results. A previous study suggested that CRRT treatment could improve AKI. [9] In severe acute respiratory syndrome, the Middle East respiratory syndrome, and sepsis infections, CRRT has been proven to be an effective treatment. In particular, on the 7 th day of sepsis, using 6 L/h high throughput hemodiafiltration can effectively remove interleukin 6 and improve multiple organ failure. However, the therapeutic effect of CRRT on AKI development after SARS-CoV-2 infection remains questionable.

The clinical characteristics of AKI in patients with SARS-CoV-2 infection emphasize the AKI risk in elderly patients and those with cardiocerebrovascular disease or low oxygen saturation levels on admission. Kidney-related routine tests should be performed on admission, and specialized tests should be performed if signs of AKI appear. Finally, more treatments for kidney disease should be administered to SARS-CoV-2-infected patients who develop AKI.

The clinical manifestations of non-CKD patients with AKI and SARS-CoV-2 infection were more similar to AKI symptoms, such as decreased appetite and urine output. The frequency of diarrhea in non-CKD patients was slightly higher than that in CKD patients, and significantly more non-CKD patients were treated with human albumin than CKD patients. Thus, diarrhea caused by SARS-CoV-2 infection as well as the imbalances between water and electrolytes caused by reduced food intake may cause AKI in patients with non-CKD. Active nutritional support may improve the outcome of these patients.

The clinical classification of non-CKD patients was consistent with the AKI grade, suggesting that the degree of AKI in non-CKD patients may directly affect the severity of the clinical condition. In contrast, although many CKD patients progressed to critical illness, the trend was not consistent with the distribution of AKI grade, suggesting that diseases other than AKI affect disease progression in CKD patients.

CKD patients were significantly more likely to develop AKI than non-CKD patients. A previous study showed that SARS-CoV-2 mainly combines with angiotensin-converting enzyme 2 (ACE2) to invade human cells. [10] In addition to human type II alveolar epithelial cells and ciliary cells, cardiac endothelial cells and renal tubular cells also express ACE2. [11] Subsequently, Pan et al. performed single-cell sequencing analysis and found that the SARS-CoV-2-binding proteins, ACE2, and transmembrane protease serine 2 were abundantly expressed on renal tubular cells and podocytes, suggesting that the SARS-CoV-2 might directly damage several kinds of inherent kidney cells. [12] However, this hypothesis needs further verification. CKD patients themselves have primary or secondary kidney disease with varying degrees of cell damage, such as glomerular podocytes, mesangial cells, endothelial cells, and tubule cells. Su et al. conducted pathological examinations on the kidneys of those who died from SARS-CoV-2 infection. [13] Under electron microscopy, coronavirus particles were found in the proximal tubular endothelial cells, podocytes, and distal renal tubules. Furthermore, fluorescent analyses of the SARS-CoV-2 showed positive for coronavirus particles, confirming that the coronavirus was SARS-CoV-2. These results indicate that the SARS-CoV-2 might increase the impact on the kidneys to varying degrees and become a potential cause of AKI, regardless of primary or secondary CKD.

CKD patients infected with SARS-CoV-2 and with AKI had the worst prognosis. The basic health of CKD patients was below average, most of which had diseases, such as chronic obstructive pulmonary disease, diabetes, cardiovascular disease, cerebrovascular disease, and malignant tumors. A previous study indicated that CKD patients also had long-term chronic inflammation and internal environmental disturbance. [14] However, SARS-CoV-2 activates the innate immune system, which induces the secretion of inflammatory factors by macrophages and dendritic cells. [15] In severe cases, it can lead to inflammatory factor storms. [16] Therefore, after CKD patients are infected with the SARS-CoV-2, the virus may exacerbate the attack on the kidneys and internal environmental disturbances caused by oxidative stress products, inflammatory factors, and other pathological products. All of these factors increase the mortality rate of patients with AKI. Consistent with this, patients infected with SARS-CoV-2 may present with hypoxemia, acid-base balance disorder, respiratory failure, and sepsis. This study has several limitations. First, SARS-CoV-2-infected patients who developed AKI may have more urine abnormalities, but not all patients underwent urine tests. Second, because of the inconvenience of data collection due to special reasons during the pandemic, the sample size was small and some results showed a trend without statistical differences. Third, whether the renal function of infected patients will recover or develop into a chronic issue remains unknown.

CKD and non-CKD patients have significantly different AKI incidence rates after being infected with SARS-CoV-2. After AKI occurred, the clinical manifestations and treatment of those with and without CKD also differed. Moreover, the mortality rate of CKD patients may also be higher. These results highlight the importance of variable treatment 

Nil.

Fei Xiong is an Editorial Board Member of the journal. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study

Kidney disease is associated with in-hospital death of patients with COVID-19

Incidence and risk factors for acute kidney injury and its effect on mortality in patients hospitalized from COVID-19

Prevalence of kidney injury and associations with critical illness and death in patients with COVID-19

Incidence and outcomes of acute kidney injury in patients admitted to hospital with COVID-19: A retrospective cohort study

National Health Commission of the People's Republic of China. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7)

Factors associated with COVID-19-related death using OpenSAFELY

AKI in hospitalized patients with COVID-19

Anticoagulation strategies and filter life in COVID-19 patients receiving continuous renal replacement therapy: A single-center experience

Single-cell RNA sequencing analysis of human kidney reveals the presence of ACE2 receptor: A potential pathway of COVID-19 infection

Angiotensin-converting enzyme II in the heart and the kidney

Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: A study based on single-cell transcriptome analysis

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome

Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in Covid-19: Key therapeutic targets?

Cytokine storm and COVID-19: A chronicle of pro-inflammatory cytokines