The incidence of acute renal failure and high mortality rate in elderly patients hospitalized with community acquired pneumonia

Community acquired pneumonia is associated with high mortality and health care costs, especially in old age. The clinical presentation of pneumonia in the elderly may be asymptomatic or atypical. One of the known complication is an acute kidney injury. The purpose of our study was to estimate the incidence of this complication in elderly patients hospitalized with pneumonia in our geriatric hospital. From a group of 180 elderly patients hospitalized with community-acquired pneumonia 34.4 % developed acute kidney injury. In this group, 51.6 % of patients died compared to 14.4 % in the group of patients without acute kidney injury ( p < 0.001). The lower level of e-GFR was significantly associated with mortality (p < 0.001): out of seven patients with e-GFR level of 15 – 29 mg/mmol, five patients died (71.4 %). Elderly patients with community-acquired pneumonia suffering acute kidney injury experienced worse in-hospital outcomes; mortality rate was significantly higher in our study. We found a relationship between low level of e-GFR and mortality. Clinicians should be alert for early detection and prevention of kidney injury in patients admitted with pneumonia.


Introduction
Community acquired pneumonia (CAP) is a leading cause of infectious death globally (Naghavi et al., 2017;Liu et al., 2017). The incidence of pneumonia increases with age and is associated with high morbidity, mortality, and health care costs. The number of patients hospitalized with CAP in the USA is estimated to have increased to 1 million (14.4 for 100.000 population) in 2020, with similarly large increases globally. In addition, pneumonia in USA was one of the top ten most expensive conditions seen during inpatient hospitalizations. (Bartlett et al., 2000;Jain et al., 2015; Centers for Disease Control and Prevention, 2020; American Thoracic Society, 2019) The highest pneumonia mortality rates in 2017 were among people aged 70 and older. 1.13 million (261 out of 100,000) people died in this age group due to pneumonia (Centers for Disease Control and Prevention, 2020).
For US seniors, hospitalization for pneumonia has a greater risk of death compared to any of the other top 10 reasons for hospitalization (American Thoracic Society, 2019).
The clinical presentation of pneumonia in the elderly patient may differ from younger patients. Asymptomatic or atypical clinical presentations such as exacerbation of chronic diseases (eg. heart failure, chronic obstructive pulmonary disease) are more frequent presenting manifestations in older adults. Absence of fever, hypoxemia, tachycardia, elevation of leukocytes or respiratory symptoms do not rule out a pneumonia diagnosis (Halter et al., 2017).
The most common atypical manifestations are altered mental status, acute functional impairment, falls, loss of consciousness, generalized weakness, anorexia, dehydration, or urinary incontinence.
These changes may hinder an appropriate diagnosis of sepsis and impact adequate early treatment. A study of González-Castillo has shown that the undisturbed vital signs such as heart rate and temperature in older patients with suspected infection delays antibiotic administration and increases the likelihood of hospitalization with the need for intensive care and incidence of complication (González-Castillo et al., Abbreviations: CAP, Community acquired pneumonia; AKI, Acute Kidney Injury; eGFR, estimated Glomerular Filtration Rate.

2014).
Frequent complication of CAP is an acute kidney injury (AKI); the incidence of AKI in CAP patients was reported to range from 18 to 34 % (González-Castillo et al., 2014;Akram et al., 2010;Murugan et al., 2010). Previously reported patients with AKI coexisted with pneumonia were worse than patients with either pneumonia were alone (Chawla et al., 2017). AKI is not uncommon even among patients diagnosed with non-severe CAP (up to 25 % of patient). Kidney injury was associated with increased short-and long-term mortality (Murugan et al., 2010;Bellomo et al., 2012). However, the impact of AKI on in-hospital outcomes of CAP patients in the geriatric population remains unclear. The purpose of this study was to examine the incidence of AKI in elderly patients hospitalized in our multilevel geriatric hospital with CAP and to compare the results with data of patients with CAP and preserved kidney function.

Materials and methods
The study was performed in a university affiliated multilevel geriatric hospital with onsite full laboratory and radiological department. All patients were admitted into an acute geriatric ward from the community or nursing homes. The hospital's ethical committee approved the study.

Design and study population
Data were collected retrospectively from patients' computerized files for the years 2019 and 2020. The inclusion criteria were patients with a primary diagnosis of CAP and preserved kidney function, defined as estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73m 2 .
The minimal inclusive age was 65. Patients with impaired renal function, advanced cancer, terminal liver disease and pressure sores above grade 3 were excluded. Accordingly, 180 patients were included in the study. The participants were categorized into two groups: A-patient's with CAP and AKI, detected during first five days of hospitalization, and the second, group B -CAP without AKI.
The following information was retrieved from the files: demographics data, pre-existing chronic conditions, medication use, clinical laboratory and radiological features with emphasis on the relationship between presence of pneumonia and onset of renal dysfunction. The information retrieved from the patients' files was recorded on data worksheets and then transferred for statistical analysis.

Definitions
The diagnosis of CAP based on a clinical picture and detection of new inflammatory infiltrative changes on chest radiography, performed in emergency room on hospitalization day. AKI was defined by a rise in the serum creatinine concentration during five days from admission by The primary outcome was in-hospital acute kidney injury, and the secondary -mortality during hospitalization.

Statistical analysis
Data are presented as mean ± SD for continuous variables and frequency and percent for discrete variables. To tests for associations with AKI Chi-square were applied for discrete variables, and grouped t-test for continuous variables. Fisher's exact test of probability for small number analysis was used when expected frequencies were fewer than 5 cases. For continuous variables grouped t-tests were used. A two-tailed p-value <0.05 was considered as significant. The data were analyzed using SPSS 28 software (IBM Inc).

Results
The sample included 180 patients, of them 104 (57.8 %) women. The mean age was 87.9 years (range 67 to 106 years, SD = 7.6). Most patients were hospitalized from the community (74 %) and the rest from nursing homes (26 %). The demographic data presented in Table 1. During hospital stay 59 patients (33 %) died. Most common comorbidity and medications are presented in Tables 2 and 3, respectively.
The most common antibiotic treatment prescribed to patients was Ceftriaxone (135 patients, 75 %). In addition, there is high incidence treatment by Roxithromycin (32 patients, 17.8 %) and Ciprofloxacin (21 patients, 11.7 %). There were not statistically significant difference between two groups in antibiotic treatment (Table 3).
There were 62 (34.4 %) patients in-group A (CAP and AKI) and the rest of patients were in group B (CAP no AKI). No significant difference in age (p = 0.36) and sex (p = 0.9) were detected between two groups. Among the baseline comorbidities and laboratory tests there were not statistically significant difference between A and B groups.

Discussion
The main finding of our study -old patients suffering AKI experienced significantly worse in-hospital outcomes; mortality rate in geriatric patients with CAP and AKI was significantly higher compared to other studies. Moreover, we found a relationship between low level of e-GFR and mortality. The highest mortality (71.4 %) was in patients with e-GFR below 30 mg/mmol. Akram et al. demonstrated that AKI was significantly associated with 30-day mortality (OR, 1.46; 95 % CI, 1.04-2.04) (Akram et al., 2010). Murugan et al. reported a 1.29-fold increased risk of death in patients with CAP who developed AKI (HR, 1.29; 95 % CI; 1.03-1.60) (Murugan et al., 2010). Chen et al. found that in patients with AKI in-hospital mortality rate was higher than the non-AKI group (23,5 % versus 4.9 %; P < 0.001), (Chen et al., 2021). Chawla et al. reported a significantly shorter time to death in such patients (HR, 1.17; 95 % CI; 1.13-1.20), (Chawla et al., 2017). They observed that patients with pneumonia and AKI had highest mortality (51.3 %) compared to patients with pneumonia alone (42.7 %).
We report an incidence of AKI in 34.4 % of patients with CAP admitted to hospitalization, this is slightly higher than in previous studies, which found incidences ranging from 18 to 34 % (Akram et al., 2010;Murugan et al., 2010;Murugan et al., 2012;Chen et al., 2021). In a Scottish study (Akram et al., 2010) in cohort of 1241 patient with CAP  (Murugan et al., 2010). In prospective observational study observed 27.6 % of patients with CAP had AKI (Latief et al., 2021). In this study, patients with AKI had significantly higher baseline comorbidities of chronic kidney and coronary artery disease, higher level of uric acid, bilirubin and LDH in addition to elevated creatinine, BUN and lower albumin level compared to the non-AKI group (Latief et al., 2021). The difference from our study -preserved renal function on admission in our study. In Jain et al. study the risk factors included male gender, BMI >30 kg/m 2 , hypertension and use of angiotensin converting enzyme-inhibitors or angiotensin receptor blocker's (Jain et al., 2017). Lin et al. revealed elevated AKI among patients with pneumonia and diabetes, hypertension, congestive heart failure, cirrhosis and stroke (Lin et al., 2016). Serov et al. observed AKI more frequently with altered consciousness and abnormal liver function tests (Serov et al., 2016). In another study, predisposing factors to AKI in CAP patients were old age, hemodynamic disorders, diabetes mellitus, and prior urinary tract diseases (Serov et al., 2019).
In recent years, lung-kidney crosstalk has become a topic of increasing interest as pertaining to the critically ill patients, but the mechanisms of pneumonia-induced kidney failure are unclear (Hepokoski et al., 2018). Preclinical and clinical studies have demonstrated multiple relevant lung-kidney interaction (Hepokoski et al., 2017;Chawla et al., 2014). For example, chronic obstructive pulmonary disease and ventilator-induced lung injury promote endothelial inflammation in the lung and kidney (Husain-Syed et al., 2016;Chawla et al., 2014). The development of renal injury in patients with pulmonary disease is important clinically, as acute kidney injury is associated with not only increased mortality, but also with poor long-term functional outcomes (Huang et al., 2014). To reveal the mechanisms of persistent renal sequelae following pneumococcal pneumonia, Huang et al. reviewed the relevant studies and propose that acute sepsis causes the initial renal injury and the host immune response, and additional underlying comorbid diseases may contribute to secondary renal insults (Huang et al., 2014). Systemic hypotension and hypoxemia may result in peritubular hypoxia. Tissue hypoxia in the presence of various cytokines induces fibrosis-related processes (Zeisberg and Neilson, 2010). The cell wall of pneumococci, a major virulence determinant, triggers host inflammatory responses and induces the production of cytokines (Tuomanen et al., 1995;Panichi et al., 2002. Fried et al., 2004 showed that an increased level of inflammation or prothrombotic markers, such as Creactive protein, fibrinogen, and factor VII, are predictors of the deterioration of renal function in elderly patients. An addition, some studies have suggested that tumor-necrosis factor-α (Tu le et al., 2007) and soluble urokinase-type plasminogen activator receptor (Cunha, 1991) may induce renal interstitial fibrosis. Others describe in their studies cases of atypical bacterial community pneumonia that associated with renal parenchymal disease (Cunha, 1991;Sharma et al., 2017). Finally, the use in these patients of antibiotics such as macrolide (Mortensen et al., 2014) or aminoglycosides (Coca et al., 2012) can also contribute to development of AKI. Conversely, renal injury may also worsen pulmonary function via multiple mechanisms including uremic toxins, acid and/or electrolyte imbalance, inflammation, and oxidative stress (Husain-Syed et al., 2020).
In summary, the mechanism of pneumonia-induced kidney injury is unclear, so need further research and expanding knowledge of this subject, that can help find novel strategies aimed to improve understanding of the relationship between the lung and kidney injury. We believe that these strategies can improve short-and long-term outcomes of patients with CAP and AKI.

Conclusion
There is a high incidence of AKI in elderly patients hospitalized for CAP in our study similar to that reported in literature. It was important for us to implement this study, because we hope that impact of the results may be important on practice and policy, such as attention on euvolemic patient's state, avoidance of nephro-toxic medications in high-risk patients. Prognosis of AKI patients markedly worsens compared with patients without AKI. Clinicians should be alert for early detection and prevention of AKI in patients admitted with CAP diagnosis. We have a suggestion for further studies in this field with more participants.

Study limitation
There were several limitation in our study. First, it was a singlecenter retrospective study with small sample size. Second, our study has the limitation from using routinely collected data. Due to the nature of dataset, the association of severity of CAP with AKI could not be assessed. Since the etiology and pathogenesis of AKI is often multifactorial, confounding factors like nephrotoxic medication, fluids in-take and hemodynamic status of patient could have influenced the development of AKI and its course. Third, AKI was defined by serum creatinine  level only, unfortunately, we did not use the urine output data, according to KDIGO criteria.
No identification was made on the etiological agent responsible for CAP, so it was impossible to separate bacterial CAP from viral. We did not have a data regarding pneumococcal or influenza vaccines, so we could not identify a relationship between vaccinations and AKI.
The additional limitation in our study-there was no classification of renal status upon admission (patients who developed AKI might have been at higher risk).
The study and the manuscript were prepared in compliance with ethical standards. The study has ethical approval. It was retrospective study and there was not needed informed consent of participants.

Funding
No funding in this study.

Declaration of competing interest
No conflict of interest.