The Hypothesis of the COVID-19 Role in Acute kidney Injury: A Literatures Review

Introduction

Up to now, two main groups of β-coronavirus have been recognized:1-Human coronavirus which includes 6 types of virus and, in most cases, results in mild illness without significant complications.

2-Zoonotic coronavirus consists of 3 types of the virus; severe acute respiratory syndrome (SARS), recognized in 2003, and the Middle East respiratory syndrome (MERS), introduced in 2012; both of these viruses resulted in respiratory infection and recently coronavirus disease 2019 (COVID-2019) infection that results in pandemic respiratory infection (1).

Bat is the primary host in all three strains. The intermediate host for SARS is a civet and for MERS is a camel, but the Intermediate host for COVID-19 is debated, and the first suspected origin was the seafood market recently, pangolin is suggested as the main intermediate host (2, 3) and the final host for 3 viruses is human. COVID-19 infection is the most virulent strain that resembles up now that emerged in December 2019. According to the last update of the world health organization (WHO), the coronavirus has brought up 53,000,000 infected cases and about 1,300,000 deaths up to November 2020 (4).

COVID-19 infection is accompanied by moderate to severe disease in 20% of patients, and the remaining have mild symptoms (5). The incidence of acute kidney failure increases with the severity of the disease. The kidney disease improving global outcome (KDIGO) definition was used to identify acute kidney injury (AKI); the peak serum creatinine value of more than 1.5. The evidence shows that AKI increases mortality 4 to 5 times (5, 6). 

Methods

Searching in databases such as PubMed, Scopus, Embase, Medline, and Web of science for all retrospective, prospective, and review articles with these keywords; covid-19, coronavirus plus kidney disease or acute tubular necrosis (ATN), or acute kidney injury. We have chosen the English literature between Nov. 2019 till Nov. 2020.

Summary of researches

In the study by Pie et al., they evaluated 333 patients with COVID-19 contamination and revealed that about 75% of them had acute kidney injury or abnormal tests in their urinalysis. Among those patients, thirty-five patients had acute kidney damage, but sixteen had finally gained normal renal function. Death was significantly higher among patients with acute renal failure (about 10 times higher) (6).

They concluded that although renal involvement is joint in these patients, and most of them recovered without any sequel, it can result in increased mortality (7).

In an exciting study in the USA(NYC) by Yamada et al., they evaluated 3391 patients and discovered about 6% had chronic renal failure. This category of patients needs a ventilator, and the death rate (especially in advanced age above eighty years old) is higher (8).

In another contradictory study by Wung et al., they assessed the medical archives of 116 patients from January 14 to February 13, 2020. Incidence of uremia was mentioned in about ten percent, and only seven percent of patients had proteinuria. They quoted that acute kidney injury is infrequent in these patients and does not accompany a significant sequel (9).

Among patients with AKI exact mechanism of kidney injury is disputed. In the study by Su et al., the autopsy was done on twenty-six patients for renal specimens. Nine patients displayed evidence of acute kidney injury in laboratory assessment. They surveyed the sample by light microscopy, electron microscope, and immunohistochemical (IHC) staining. In light microscopy, they detected proximal tubular damage. In electron microscopy, they detected groups of virus-like spots with distinct spears in the tubular epithelium, and finally, IHC staining was positive in the tubular segment of specimens. They concluded that this virus directly invades the kidney tissue (10).

In a different study by Rossi et al., as a case report in the evaluation of kidney specimens, the only part of the kidney that was involved by the virus was the tubular segment, and other parts of the kidney were not involved by the virus. Interestingly, no virus was observed in the electron microscope (EM) evaluation. They concluded that ATN is related mainly to pre-renal causes rather than direct injury to the tubule by a viral infection, and we should not rely only on morphologic findings (11).

In the study by Diao et al., they hypothesized the combined mechanism of direct kidney injury by a virus and an exaggerated immune response to the virus contributed to ATN in infected patients because they found evidence of virus particles and simultaneously the presence of inflammatory cells in renal specimens that result in tubular damage (12, 13).

In a conflicting study by Miller et al., they mentioned that usually, direct involvement of kidneys by viral infection is associated with viruria, but they did not observe this finding in infected patients. Additionally, they mentioned that the manifestation of the virus in kidney specimens only reveals the viral entrance to the kidney and does not mean pathologic involvement of the renal system, so multifactorial etiology (viral invasion and pre-renal etiology) may have essential roles (14).

Discussion

AKI is prevalent in patients with coronavirus infection (between 5-50% in non-admitted and admitted patients, respectively(15). The death rate was reported to be significantly higher among patients with acute renal failure (about 10 times higher) (6). It could be a consequence of severe pulmonary involvement and multiple organ dysfunction. In a study by Cheng et al., they assessed 701 patients and revealed that the incidence of ATN was about five percent. Also, they discovered that AKI is more common in patients with pre-existing renal failure (12% vs. 4 %) (6).

A large study by Richardson (USA-NYC), 5700 cases were assessed, revealing that AKI incidence was 5-7.5%. The incidence of AKI was fifty percent in patients who needed intensive care units. The main risk factors for AKI were male sex, hypertension (HTN), and diabetes mellitus (15).

Conditions like HTN, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), chronic kidney disease (CKD), morbid obesity, and immunosuppression have been linked with increasing death(16, 17). Two studies from china declared that the mortality rate will increase with age (about 1.5 percent between 50–60 years to about 15 percent in 80 years) (18, 19).

In the very clarifying study from Italy, data from the Italian Health Institute specified that about half of the patients had three or more comorbid conditions, the remaining had one or more comorbid diseases, and about one percent had no previous illness. The comorbid illnesses were HTN, DM, and CKD, decreasing the prevalence. Interestingly prevalence of chronic kidney disease was more common than pulmonary disease among fatal cases of viral infection (20).

There are some challenges to the pathophysiology of kidney injury, if the mechanism of pathogenesis is identified, then the protocols and some preventive or therapeutic measures could be designed to care for these patients and decrease mortality.

The exact role of the angiotensin-converting enzyme (ACE) in the pathogenesis of infection is largely studied, and it is mentioned that the ACE-2 receptor is frequently expressed in the lung, GI system, liver, and kidney. Consequently, viruses can contaminate these organs. The study by Qi et al., discovered that the most frequent site for this factor was the renal proximal tubular segment (21). It is recommended that there is renal tropism for viruses, especially renal tubules that result in ATN. As mentioned earlier, some researchers cited that they discovered the virus in kidney tissue analysis by EM and believed in the virus's direct effect on the kidney that results in AKI. Rossi et al. did not find a virus in the kidney and believed in ATN due to pre-renal cause (11). Diao et al., in their investigation, cited that the combined mechanism of viral tissue invasion and exaggerated immune system response (cytokine storm) may lead to AKI (12, 13).

A multifactorial mechanism could be considered for AKI in covid infection in patients requiring a ventilator due to acute respiratory distress syndrome (ARDS). There is a hypo-perfusion state that results in AKI; in some patients idea of rhabdomyolysis due to the cytotoxic effect of the virus on the muscle, tissue hypoxia, and drug toxicity proposed (10).

The study by Batlle et al., quoted that hypercoagulability can result in obstructing the microvasculature of the kidney (22).

AKI may have been caused by a cytokine storm. In this situation, the immune system concurrently damages the virus and normal organs such as the kidney.

Based on the multifactorial mechanism of AKI, we should have considered probable causes of AKI and acted in a stepwise manner. In critically ill patients needing ventilation support, fever and insensible fluid loss can result in pre-renal volume depletion, so careful fluid monitoring to prevent hypo-perfusion and rhabdomyolysis is essential. Some studies mentioned that if conventional treatments for acute kidney damage are unsuccessful, hemodialysis can be started (23).

Conclusions

In critically ill patients, managing hypercoagulability states that can result in complications such as microvasculature thrombosis in the kidney and other organs should be considered. In severe inflammatory response due to cytokine storm in very ill patients, the treatment that lessens the immune system could be considered to decrease AKI and, consequently, mortality.

Authors’ contributions

AM is responsible for study conception, writing the manuscript, and providing data; SMKA supervised the process and edited the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Acknowledgments

Special thanks to the Urology Research Center (URC), Tehran University of Medical Sciences (TUMS).

Conflict of interest

The authors declare that there are no conflicts of interest regarding the publication of this manuscript.

Funding

The authors received no financial support for this research.

Ethical statement

Not applicable.

Data availability

Not applicable.

Abbreviations