Coronavirus: Kidney Damage Caused by COVID-19

Authors: C. John Sperati, M.D., M.H.S. Posted May 28, 2022 John’s Hopkins Health

COVID-19 Kidney Damage: A Known Complication

Some people suffering with severe cases of COVID-19 will show signs of kidney damage, even those who had no underlying kidney problems before they were infected with the coronavirus. Signs of kidney problems in patients with COVID-19 include high levels of protein or blood in the urine and abnormal blood work.

Studies indicate more than 30% of patients hospitalized with COVID-19 develop kidney injury, and more than 50% of patients in the intensive care unit with kidney injury may require dialysis. Sperati says early in the pandemic, some hospitals were running short on machines and sterile fluids needed to perform dialysis.

“As general treatments for patients with COVID-19 have improved, the rates of dialysis have decreased. This has helped to alleviate shortages, although intermittent supply chain disruptions remain a concern.

“Many patients with severe COVID-19 are those with co-existing, chronic conditions, including high blood pressure and diabetes. Both of these increase the risk of kidney disease,” he says.

But Sperati and other doctors are also seeing kidney damage in people who did not have kidney problems before they got infected with the virus.

How does COVID-19 damage the kidneys?

The impact of COVID-19 on the kidneys is complex. Here are some possibilities doctors and researchers are exploring:

Coronavirus might target kidney cells

The virus itself infects the cells of the kidney. Kidney cells have receptors that enable the new coronavirus to attach to them, invade, and make copies of itself, potentially damaging those tissues. Similar receptors are found on cells of the lungs and heart, where the new coronavirus has been shown to cause injury.

Too little oxygen can cause kidneys to malfunction

Another possibility is that kidney problems in patients with the coronavirus are due to abnormally low levels of oxygen in the blood, a result of the pneumonia commonly seen in severe cases of the disease.

Cytokine storms can destroy kidney tissue

The body’s reaction to the infection may be responsible as well. The immune response to the new coronavirus can be extreme in some people, leading to what is called a cytokine storm.

When that happens, the immune system sends a rush of cytokines into the body. Cytokines are small proteins that help the cells communicate as the immune system fights an infection. But this sudden, large influx of cytokines can cause severe inflammation. In trying to kill the invading virus, this inflammatory reaction can destroy healthy tissue, including that of the kidneys.

COVID-19 causes blood clots that might clog the kidneys

The kidneys are like filters that screen out toxins, extra water and waste products from the body. COVID-19 can cause tiny clots to form in the bloodstream, which can clog the smallest blood vessels in the kidney and impair its function.

Prevalence of organ impairment in Long COVID patients 6 and 12 months after initial symptoms

Authors:  Pooja Toshniwal PahariaMar 24 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study posted to the medRxiv* preprint server, researchers assessed the prevalence of organ impairment in long coronavirus disease 2019 (COVID-19) six months and a year post-COVID-19 at London and Oxford.

Multi-organ impairment associated with long COVID-19 is a significant health burden. Standardized multi-organ evaluation is deficient, especially in non-hospitalized patients. Although the symptoms of long COVID-19, also known as post-acute sequelae of COVID-19 (PASC), are well-established, the natural history is poorly classified by symptoms, organ impairment, and function.

About the study

In the present prospective study, researchers assessed organ impairment in long COVID-19 patients six months and a year after the onset of early symptoms and correlated them to their clinical presentation.

The participants were recruited based on specialist referral or the response to advertisements in sites such as Mayo Clinic Healthcare, Perspectum, and Oxford from April 2020 to August 2021, based on their COVID-19 history.

The study was conducted on COVID-19 patients who recovered from the acute phase of the infection. Their health status, symptoms, and organ impairment were assessed. The symptoms assessed comprised cardiopulmonary, severe dyspnoea, and cognitive dysfunction. Biochemical and physiological parameters were analyzed at baseline and post-organ impairment. The radiological investigation comprised multi-organ magnetic resonance imaging (MRI) performed in the long COVID-19 patients and healthy controls.

Over a year, the team prospectively investigated the symptoms, organ impairment, and function, especially dyspnea, cognitive dysfunction, and health-related quality of life (HRQoL). They also evaluated the association between organ impairment and clinical symptoms.

Patients with symptoms of active pulmonary infections (body temperature >37.8°C or ≥3 coughing episodes in a day) and hospital discharges in the previous week or >4 months were excluded from the study. Asymptomatic patients and those with MRI contraindications such as defibrillators, pacemakers, devices with metal implants, and claustrophobia were removed.

Participants with impaired organs, as diagnosed by blood investigations, incidental findings, or MRI, were included in the follow-up assessments. Every visit comprised blood investigations, MRI scanning, and online questionnaire surveys, which were to be filled out beforehand. In addition, a sensitivity analysis was performed that excluded patients at risk of metabolic disorders (including body mass index (BMI) ≥30 kg/m2, diabetes, and hypertension)

Results

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Out of 536 participants, the majority were middle-aged (mean age 45 years), female (73%), White (89%), and healthcare workers (32%). About 13% of the COVID-19 patients hospitalized during the acute phase of the infection completed the baseline evaluation. A total of 331 patients (62%) had incidental findings, organ impairment, or reduction in the symptoms from the baseline at both the time points.

Cognitive dysfunction (50% and 38%), poor HRQoL (EuroQOL <0.7 in 55% and 45%), and severe dyspnea (36% and 30%) were observed at six months and one year, respectively. On follow-up, the symptoms were reduced, especially cardiopulmonary and systemic symptoms, whereas fatigue, dyspnea, and cognitive dysfunction were consistently present. The greatest impact on quality of life was related to pain and difficulties performing routine activities. Almost every patient took time off work due to COVID-19. The symptoms were largely associated with obese women, young age, and impairment of a single organ.

At baseline, fibrous inflammation was observed in the pancreas (9%), heart (9%), liver (11%), and kidney (15%). Additionally, increased volumes of the spleen (8%), kidney (9%), and liver (7%) were observed. Moreover, reduced lung capacity (2%), excess adipose deposits in pancreatic tissues (15%) and liver (25%) were observed. High liver fibro-inflammation was associated with cognitive dysfunction at follow-up in 19% and 12% of patients with and without cognitive dysfunction, respectively. Low liver fat was more likely in those without severe dyspnoea at both time points. Increased liver volumes at follow-up were associated with lower HRQoL scores.

The prevalence of multi and single-organ impairment was 23% and 59% at baseline, respectively, and persisted in 27% and 59% of the participants on follow-up assessments. Most of the organ impairments were mild. However, they did not improve substantially between visits. Notably, participants without organ impairment had the lowest symptom burden.

Most biochemical parameters were normal except creatinine kinase (8% and 13%), lactate dehydrogenase (16% and 22%), mean cell hemoglobin concentration (21% and 15%), and cholesterol (46% and 48%), at six months and a year post-COVID-19, respectively. These biochemical markers increased from the baseline on follow-up assessments.

Conclusion

To summarize, organ impairment was detected in 59% of the patients at six months post-COVID-19 and persisted in 59% at one-year follow-up. This has significant implications on the quality of life, symptoms, and long-term health of the patients. These observations highlight the requirement for enhanced preventive measures and integrated patient care to decrease the long COVID-19 burden.

Journal reference:

Pancreatic damage in COVID‐19: Why? How?

Authors: Ferhat Bacaksız, 1 Berat Ebik, 1 Nazım Ekin, 1 and Jihat Kılıc 2

Int J Clin Pract. 2021 Aug 6 : e14692.doi: 10.1111/ijcp.14692 [Epub ahead of print] PMCID:  PMC8420122PMID: 34331821

Abstract

Object

We aimed to evaluate the elevation of amylase and lipase enzymes in coronavirus disease 2019 (COVID‐19) patients and their relationship with the severity of COVID‐19.

Method

In this study, 1378 patients with COVID‐19 infection were included. Relation of elevated amylase and lipase levels and comorbidities with the severity of COVID‐19 was analysed. The effects of haemodynamic parameters and organ failure on pancreatic enzymes and their relations with prognosis were statistically analysed.

Results

The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. Of all patients, 687 (49.9%) had mild and 691 (50.1%) patients had severe COVID‐19 infection. Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. According to univariate and multivariate analyses, elevated amylase levels were significantly associated with the severity of COVID‐19 (odds ratio [OR]: 4.37; P < .001). Moreover, diabetes mellitus (DM; OR: 1.82; P = .001), kidney failure (OR: 5.18; P < .001), liver damage (OR: 6.63; P < .001), hypotension (OR: 6.86; P < .001) and sepsis (OR: 6.20; P = .008) were found to be associated with mortality from COVID‐19.

Conclusion

Elevated pancreatic enzyme levels in COVID‐19 infections are related to the severity of COVID‐19 infection and haemodynamic instability. In a similar way to other organs, the pancreas can be affected by severe COVID‐19 infection.

What’s known

  • It has been suggested that COVID‐19 can cause pancreatic damage.
  • There are a limited number of studies related to the possibility of an increase in the level of pancreatic enzymes in COVID‐19 patients.

What’s new

  • COVID‐19 does not directly cause pancreatic damage.
  • Pancreatic enzyme elevation in patients with COVID‐19 develops in the advanced stages of the disease caused by multiple organ dysfunction and shock.

1. INTRODUCTION

Coronavirus disease 2019 (COVID‐19) infection was initially considered to attack only the upper respiratory tract, but was later found to potentially affect almost all systems. This is caused by the angiotensin‐converting enzyme 2 (ACE2) receptors that coronavirus binds to in order to enter the cells. These receptors are also commonly available in the gastrointestinal system such as in hepatic, pancreatic and colonic cells.12

Recent studies have shown that COVID‐19 infection can cause damage to the pancreas caused by the high expression of ACE2 receptors from the pancreatic tissue.3 Additionally, it has also been reported that hyperglycaemia can occur because of pancreatic islet cell damage in patients with COVID‐19 and that severe patients with COVID‐19 should be followed up closely in terms of pancreatic damage.45

In this study, we evaluated the amylase and lipase elevations in patients with COVID‐19 in order to investigate the relationship between pancreatic enzyme elevations and the severity of COVID‐19 infection and to identify the underlying conditions.Go to:

2. PATIENTS AND METHODS

The study included 1378 patients with COVID‐19 infection who presented to our hospital between March and December 2020. Clinical characteristics including temperature, blood pressure, laboratory parameters, treatments and comorbidities were monitored throughout hospitalisation. In addition to other laboratory parameters, amylase and lipase levels were also studied in order to determine the ratio of patients with elevated pancreatic enzymes. Values above 105 U/L for amylase and 65 IU/L for lipase were considered high.6 Patients with pancreatitis were identified according to the Atlanta criteria.7

Additionally, pancreatic enzyme elevation in COVID‐19 infection was investigated with regard to the severity of disease. Patients were divided into two groups based on the severity of their COVID‐19 symptoms: mild (n = 687) and severe (n = 691). Patients with fever, headache, loss of taste and smell and generalised myalgia without tachypnoea (oxygen saturation >92%) were considered to have a mild infection, whereas patients on invasive or non‐invasive respiratory support or with deteriorated haemodynamic conditions were considered to have severe COVID‐19 infection.8

The causes of pancreatic enzyme elevation were compared between patients with mild and severe COVID‐19 infection and between surviving and non‐surviving patients. Relation between elevated pancreatic enzymes and metabolic parameters, haemodynamic findings, single and multiple organ failures was also examined.910

Hypotension was evaluated based on mean arterial pressure (MAP). A MAP value of 60‐110 mmHg was accepted as normal, <60 mmHg as hypotensive and >110 mmHg as hypertensive.11

Liver damage was determined according to the 2019 European Association for the Study of the Liver (EASL) guidelines, based on the upper limits of normal (ULN) serum alanine aminotransferase activity (ALT) and serum alkaline phosphatase activity (ALP), as follows: ALT ≥5 × ULN or ALP ≥2 ULN [in the absence of known bone pathology] or ALT ≥3 ULN with simultaneous increase of total bilirubin concentration ≥2 ULN.12 Kidney injury was determined according to the RIFLE (Risk, Injury, Failure, Loss of kidney function and End‐stage kidney disease) criteria.13

The study was conducted in accordance with the Helsinki Declaration and the study protocol was approved by the local ethics committee (No: 611, Date: 16 October 2020).

2.1. Statistical analysis

Data were analysed using SPSS 26.0 for Windows (Armonk, NY: IBM Corp.). Normal distribution of data was assessed using Kolmogorov‐Smirnov, Shapiro‐Wilk test, coefficient of variation, skewness and kurtosis. Continuous variables were expressed as mean and standard deviation (SD), and categorical variables were expressed as percentages (%). Student t test and Mann‐Whitney U‐test were used in paired groups to compare pancreatic enzymes and disorders of other organs between patients with severe and mild COVID‐19 infection. ANOVA test was used for parameters homogeneously distributed in triple groups. Bonferroni correction was used to determine the significant results in groups. Welch’s ANOVA and Kruskal‐Wallis tests were performed for non‐homogeneous parameters. Pearson and Spearman correlation coefficients were used to analyse the relationship between pancreatic enzyme elevation and other parameters. Univariate and multivariate analyses were performed to determine the factors associated with pancreatic enzyme elevation. All tests were bilateral and a P‐value of <.05 was considered significant.Go to:

3. RESULTS

The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. The prevalence of kidney failure, DM, ischaemic hepatitis and sepsis was significantly higher in patients with severe COVID‐19 compared with patients with mild disease. Moreover, amylase and lipase levels were also higher in patients with severe COVID‐19 (Table 1).

TABLE 1

Demographic data and biochemical parameters of patients with mild and severe COVID‐19

Mild COVID‐19±SDSevere COVID‐19±SDP
N687 (49.9%)691 (50.1%)
Age60.2 (29‐84)65 (51‐86)<.001
Gender F/M356/331322/369.053
Amylase (U/L)82.6 ± 50.4264.7 ± 292.0<.001
Lipase (IU/L)59.7 ± 51.279.0 ± 24.2.045
ALT (IU/L)70.4 ± 60.282.7 ± 56.4<.001
AST (IU/L)61.6 ± 40.7180 ± 135.5<.001
ALP (IU/L)84.1 ± 35.4133.2 ± 107.2.295
GGT (IU/L)54.2 ± 51.579.4 ± 58.9.099
T.Bil (mg/dL)0.67 ± 0.331.95 ± 1.53<.001
LDH (IU/L)411.9 ± 2101137 ± 248.7<.001
Urea (mg/dL)45.7 ± 26.9187.0 ± 92.8<.001
Creatinine (mg/dL)0.89 ± 0.493.74 ± 1.96<.001
Glucose (mg/dL)138 ± 85.0290 ± 135<.001
WBC (cell/µL)9840 ± 448518 422 ± 6039<.001
Lymphocyte (cell/µL)1993 ± 6651655 ± 946<.001
CRP (mg/L)107.8 ± 67.2217.9 ± 69.1<.001
Procalcitonin (ng/mL)1.04 ± 4.658.03 ± 19.7<.001

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Abbreviations: ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase WBC, white blood cell, CRP, C reactive protein; ALT, alanine transaminase; AST, aspartate transaminase; LDH, lactate dehydrogenase; SD, standard deviation.

Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. Amylase and lipase elevation was found to be related to the severity of COVID‐19 infection in the remaining patients. The development of DM, kidney failure, hypotension and ischaemic hepatitis was found to be related to mortality from COVID‐19 infection. However, there was no relationship between lymphopenia and elevated amylase levels (Table 2). On the other hand, patients older than 65 years were more likely to have (1.89 times) elevated increased enzyme levels.

TABLE 2

Relationship between amylase level in COVID‐19 patients and gender, comorbid status, severity and consequence of COVID‐19, haemodynamic status, other organ failures and laboratory parameters

FeatureAmylase (normal)Amylase (1‐3 times)Amylase (more than 3 times)P‐values
N/%1062 (77.0%)261 (19.0%)55 (4.0%)
Gender
Female (678%‐49.2%)565 (83.3%)100 (14.8%)13 (1.9%)<.001
Male (700%‐50.8%)497 (71.0%)161 (23.0%)42 (6.0%)
COVID‐19 severity
Mild COVID‐19 (687%‐49.9%)612 (89.1%)71 (10.3%)4 (0.6%)<.001
Severe COVID‐19 (691%‐50.1%)450 (65.1%)190 (27.5%)51 (7.4%)
COVID‐19
Healing (909%‐66.0%)793 (87.2%)109 (12.0%)7 (0.8%)<.001
Death (469%‐34.0%)269 (57.4%)152 (32.4%)48 (10.2%)
Diabetes
Absent (866%‐62.8%)703 (81.2%)143 (16.5%)20 (2.3%)<.001
Available (512%‐32.6%)359 (70.1%)118 (23.0%)35 (6.9%)
Kidney failure
Absent (934%‐67.8%)808 (86.5%)114 (12.2%)12 (1.3%)<.001
AKI (316%‐22.9%)186 (58.8%)101 (32.0%)29 (9.2%)
CRF (128%‐9.3%)68 (53.1%)46 (36.0%)14 (10.9%)
Blood pressure
Normal (810%‐58.8%)727 (89.7%)76 (9.4%)7 (0.9%)<.001
Hypotension (466%‐33.8%)260 (55.8%)161 (34.5%)45 (9.7%)
Hypertension (102%‐7.4%)75 (73.6%)24 (23.5%)3 (2.9%)
ALT
Normal (562%‐40.8%)488 (86.8%)65 (11.6%)9 (1.6%)<.001
1‐3 times (488%‐35.4%)389 (79.7%)86 (17.6%)13 (2.7%)
3‐5 times (135%‐9.8%)89 (65.9%)37 (27.4%)9 (6.7%)
5‐10 times (65%‐4.7%)36 (55.4%)20 (30.8%)9 (13.8%)
>10 times (61%‐4.4%)32 (52.5%)26 (42.6%)3 (4.9%)
>1000 (IU/L) (67%‐4.9%)28 (41.8%)27 (40.3%)12 (17.9%)
AST
Normal (468%‐34.0%)428 (91.4%)36 (7.7%)4 (0.9%)<.001
1‐3 times (564%‐40.9%)454 (80.5%)98 (17.4%)12 (2.1%)
3‐5 times (121%‐8.8%)76 (62.8%)38 (31.4%)7 (5.8%)
5‐10 times (71%‐5.1%)35 (49.3%)27 (38.0%)9 (12.7%)
More than 10 times (45%‐3.3%)22 (48.9%)16 (35.6%)7 (15.5%)
>1000 (IU/L) (109%‐7.9%)47 (43.1%)46 (42.2%)16 (14.7%)
ALP
Normal (966%‐70.1%)737 (76.3%)191 (19.8%)38 (3.9%).092
1‐2 times (234%‐17.0%)176 (75.2%)45 (19.2%)13 (5.6%)
More than 2 times(178%‐12.9%)149 (83.7%)25 (14.0%)4 (2.3%)
GGT
Normal (909%‐66%)722 (79.4%)158 (7.4%)29 (3.2%).072
1‐2 times (254%‐18.4%)173 (68.1%)62 (24.4%)19 (7.5%)
More than 2 times (215%‐15.6%)167 (77.7%)41 (19.1%)7 (3.2%)
Total Bilirubin
Normal (1059%‐76.9%)860 (81.2%)171 (16.2%)28 (2.6%)<.001
1‐2 times (257%‐18.6%)172 (66.9%)68 (26.4%)17 (6.7%)
More than 2 times (62%‐4.5%)30 (48.4%)22 (35.5%)10 (16.1%)
LDH
Normal (<225 IU/L) (161%‐11.7%)157 (97.5%)4 (2.5%)0 (0.0%)<.001
Normal‐1000 (IU/L) (969%‐70.3%)788 (81.3%)158 (16.3%)23 (2.4%)
1000‐2250 (IU/L) (148%‐10.7%)79 (53.4%)55 (37.2%)14 (9.4%)
>2250 (IU/L)(100%‐7.3%)38 (38.0%)44 (44.0%)18 (18.0%)
Lymphocyte levels
Normal (724%‐52.5%)581 (80.3%)119 (16.4%)24 (3.3%).120
Mild lymphopenia (489%‐35.5%)360 (73.6%)111 (22.7%)18 (3.7%)
Severe lymphopenia (165%‐12.0%)121 (73.3%)31 (18.8%)13 (7.9%)

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Abbreviations: AKI, Acute kidney injury; ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase; ALT, alanine transaminase; AST, aspartate transaminase; CRF, Chronic renal failure; LDH, lactate dehydrogenase.

The prevalence of elevated amylase was 2.04 times higher in men than that in women. Hypotension (odds ratio [OR]: 6.63), sepsis (OR: 6.20), ischaemia‐related liver damage (OR: 6.63) and renal failure (OR: 5.18) were found to be significantly associated with pancreatic enzyme levels (Table 3).

TABLE 3

Analysis of factors affecting enzyme elevation in COVID‐19 patients with elevated amylase and lipase

FeatureUnivariateMultivariate
OR95% ClP valueOR95% ClP value
Age1.891.46‐2.44.0011.721.40‐2.11.001
Gender2.041.57‐2.64.0011.861.50‐2.31.001
COVID‐19 Severity4.373.28‐5.81<.0013.762.90‐4.88<.001
Death from COVID‐195.083.89‐6.64<.0014.233.33‐5.36<.001
Diabetes1.821.41‐2.35.0011.721.40‐2.11.001
Kidney failure5.183.95‐6.79<.0013.783.00‐4.75<.001
Liver damage6.634.56‐9.64<.0013.092.43‐3.94<.001
Hypotension6.864.50‐10.40<.0015.673.90‐8.22<.001
Sepsis6.203.83‐10.05.0082.882.24‐3.70.003
Pancreatitis21.22.54‐166.7.0058.024.54‐86.3.026

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A very strong positive correlation was found between amylase and lipase levels in all patients (r: .828, P < .001), which implicates that the increased amylase in COVID‐19 patients is caused by the pancreas. A weak correlation was found between amylase level and age or gender. Likewise, a weak but statistically significant correlation was found between amylase level and DM. A strong correlation was detected between the amylase level and the severity of COVID‐19. Additionally, the presence of liver damage, renal failure, hypotension and multiple organ dysfunction syndrome (MODS) in these patients was moderately correlated with amylase level (Figure 1).FIGURE 1

Correlation between amylase level and risk factors in COVID‐19 patients with hyperamylasaemiaGo to:

4. DISCUSSION

We found that 23% of patients with COVID‐19 infection had pancreatic enzyme elevations, and we also detected a relationship between pancreatic enzyme elevation and the severity of COVID‐19 infection, haemodynamic instability and MODS.

Although 10.9% of patients with mild COVID‐19 infection had elevated amylase levels, this rate was 34.9% in patients with severe COVID‐19 infection. It was also revealed that the causes of pancreatic enzyme elevation were hypotension and ischaemia in patients with severe COVID‐19 infection. Elevated amylase levels were detected in 10.3% and 44.2% of patients with a normal MAP and low MAP (<60 mmHg), respectively. Out of 316 patients with a high amylase level, 36.7% of the patients recovered and 63.3% of them died. Moreover, 53% of patients with ischaemic hepatitis had both amylase and lipase elevations. We consider that after the development of shock in the body, pancreatic damage occurs in addition to hepatic and intestinal injury as a result of the decrease in blood flow to the gastrointestinal system.

A study investigating the relationship between COVID‐19 infection and pancreas reported pancreatic damage in 1%‐2% and 17% of patients with mild and severe infection, respectively. The authors suggested that pancreatic damage can be exacerbated by systemic inflammation.14151617 Amylase and lipase elevation suggestive of pancreatic damage has been reported in 8.5%‐17.3% of patients with COVID‐19. Moreover, higher enzyme levels have been reported in severe COVID‐19 patients.14151617 Likewise, in two previous autopsy studies, five of 11 (45.5%) and two of eight (25%) cases were detected with focal pancreatitis with haemorrhagic and necrotic changes in the pancreas. These changes had no clinical manifestations and were attributed to ischaemia and end‐organ damage.1819 In the light of our data, we consider that pancreatic damage is the most important cause of amylase and lipase elevations. The exact pathophysiology of pancreatic damage remains unclear, while the most widely accepted hypothesis points to pancreatic ischaemia.202122 If septicaemia progresses towards septic shock, not only in COVID‐19 but also in other infections, the resulting hypotension and vasodilation reduce blood flow to organs. To protect blood flow to vital organs such as the brain and heart, blood flow to the celiac, superior and inferior mesenteric arteries are reduced as a part of the protective mechanism. Afterwards, this is followed by renal and iliac arteries. This is the neurohormonal mechanism protecting vital organs. Gastrointestinal system is the target organ of shock and hypotension. As a result, the blood flow to the liver, pancreas and the entire gastrointestinal system is reduced, thereby causing symptoms such as nausea, vomiting, distension, ileus, or diseases such as ischaemic hepatitis.

Pancreas is supplied well by pancreatic arteries that stem from the splenic, gastroduodenal and superior mesenteric arteries. Amylase, lipase, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) are released into the bloodstream caused by the ischaemia resulting from decreased blood flow to the pancreas.23 This damage is mainly caused by haemodynamic deterioration, not by the virus itself. Similarly, in our study, elevated amylase and lipase levels were found to be associated with haemodynamic parameters and hypotension.

Although increased amylase and lipase levels might have clinical importance, it seems highly unlikely to use these parameters as prognostic indicators in clinical practice, mainly because enzyme elevation occurs during the intensive care period when the disease is severe and requires mechanical ventilation. At this stage, most patients have single or multiple organ failure and require vasopressor support.

In conclusion, although ACE2 receptors are expressed highly in pancreatic tissue, pancreatic enzyme elevations occurring in COVID‐19 infection might be associated with the severity of disease and haemodynamic instability. If the opposite was the case, we would have seen too many cases of pancreatitis, mainly because the pancreas has ACE2 receptors. As a matter of fact, despite the huge number of COVID‐19 cases, which has exceeded 100 million, pancreatitis has remained only at the level of case reports.2425Go to:

Notes

Bacaksız F, Ebik B, Ekin N, Kılıc J. Pancreatic damage in COVID‐19: Why? How? Int J Clin Pract. 2021;00:e14692. 10.1111/ijcp.14692 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

DATA AVAILABILITY STATEMENT

Data may be made available upon request to the corresponding author.

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Acute Kidney Injury in COVID-19

Authors: Marta GłowackaSara LipkaEwelina Młynarska,*Beata Franczyk, and Jacek RyszHajime Nagasu, Academic Editor

Int J Mol Sci. 2021 Aug; 22(15): 8081.Published online 2021 Jul 28. doi: 10.3390/ijms22158081 PMCID: PMC8347536PMID: 34360866

Abstract

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy.

1. Introduction

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and it originated in Wuhan, China, in December 2019. As of 4 March 2021, approximately 84,230,049 cases have been discovered worldwide, causing an ongoing global pandemic [1]. Such a large number of confirmed cases is related to the way the virus is transmitted, which is close human-to-human contact through droplets or aerosol via coughs, sneezes or talking. Infection may also occur by touching contaminated surfaces and then touching routes of transmission such as the mouth, eyes or nose [2]. COVID-19 disease mainly affects the respiratory system, which in more severe cases is manifested by pneumonia, hypoxemia and acute respiratory distress syndrome. Although the main focus is on the pulmonary features, physicians must be aware of complications that SARS-CoV-2 infection carries to other organs, including the kidneys [3]. Acute kidney injury (AKI) is the most common kidney manifestation among patients hospitalized with COVID-19. According to KDIGO, AKI is defined as any of the following: (1) an increase in serum creatinine (SCr) by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 h; or (2) an increase in SCr ≥ 1.5 times of baseline within the prior 7 days; or (3) urine volume < 0.5 mL/kg/hour for 6 h. AKI can be also staged for severity according to KDIGO: stage (1) increase in SCr to 1.5–1.9 times baseline or by ≥0.3 mg/dL; stage (2) increase SCr to 2.0–2.9 times baseline; stage (3) increase SCr to 3.0 times baseline or increase in serum creatinine to ≥4.0 mg/dL (≥353.6 mmol/L) or initiation of renal replacement therapy [4]. Moreover, AKI development is far more frequent in severe and critically ill patients and is associated with poor prognosis and higher mortality [5,6,7]. Therefore, understanding the underlying pathophysiology of kidney injury in the course of COVID-19 is crucial for early recognition of the damage and the implementation of optimal treatment.

2. Epidemiology

With 84,230,049 cases of SARS-CoV-2 infection globally, at least one third is asymptomatic [8]. Among those COVID-19 patients who experience symptoms, about 80% develop mild to moderate symptoms, while 20% of cases present with severe symptoms over the course of the disease, of whom 6% become critically ill [9]. The overall mortality rate of COVID-19 patients is around 3% but, in the critically ill group, it can reach 50% [10].

The incidence of acute kidney injury in COVID-19 varies in different case reports. Studies in China [5,10,11] have shown that AKI occurred in 5% to 29% within a median of 7–14 days after admission, whereas reports from the United States [6,12,13] have shown greater rates reaching from 37% to 57% in COVID-19 positive patients. However, the onset of AKI in the US was observed much earlier—either upon admission or within 24 h of admission. Another study from Brazil also showed a high occurrence of AKI in 56% of COVID-19 patients, of which 67% developed stage 3 AKI [14].

Fisher et al. [13] presented a comparison report between 3345 patients with COVID-19 and 1265 patients without COVID-19 during the same hospitalization period. AKI development in the COVID-19 (+) group was higher than in the COVID-19 (−) group (57% and 37%, respectively), and a significant number of patients positive for COVID-19 had stage 3 AKI compared with patients negative for COVID-19 (17.2% vs. 7.3%). Moreover, 4.9% of the patients positive for COVID-19 required renal replacement therapy (RRT) compared with 1.6% of those negative for COVID-19. Other US studies reported RRT necessity in up to 19% of patients with COVID-19, while in Brazil it was up to 47% of patients.

The results of incidence of AKI in COVID-19 patients are presented in Table 1.

Table 1

Incidence of AKI in COVID-19 patients.

All PatientsAKIStages of AKIRRT in Patients with AKI
AKI 1AKI 2AKI 3
Yang, X. [10]5215 (29%)
Pei, G. [5]33322 (6.6%)4 (18.2%)7 (31.8%)11 (50%)
Cheng, Y. [11]70136 (5.1%)13 (1.9%)9 (1.3%)14 (2%)
Chan, L. [12]39931835 (45.9%)387 (21%)199 (10.8%)491 (26.7%)347 (19%)
Hirsch, J.S. [6]54491993 (36.6%)927 (46.5%)447 (22.4%)619 (31.1%)14.3%
Fisher, M. [13]33451903 (56.9%)942 (49.5%)387 (20.3%)574 (30.2%)164 (4.9%)
Costa, R.L.D. [14]10257 (55.9%)10 (17.5%)9 (15.8%)38 (66.7%)27 (47.4%)
Ferlicot, S. [15]471 (2.2%)3 (6.4%)2 (4.3%)41 (87.2%)30 (63.8%)

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3. Mechanism of SARS-CoV-2 Cellular Kidney Infection

It is now a well-known fact that the main target of SARS-CoV-2 is the lungs; more precisely, type II pneumocytes. More and more studies published to date have proved that not only the lungs are exposed to infection, but so are the heart, liver, gastrointestinal tract, bone marrow and kidneys [3,16] Multiorgan tropism is due to the fact that SARS-CoV-2 gains access to the cells through an endogenous viral receptor angiotensin converting enzyme 2 (ACE2) [17].

In order for SARS-CoV-2 to enter the host, cells are required to bind its transmembrane spike (S) glycoprotein to cellular receptor ACE2. S consists of two subunits, each with a different function. S1 is responsible for binding to the host cell receptor, while S2 is used to fuse the viral membrane with the membrane of the infected cell [18,19]. Spike then requires proteolytic priming to be activated, which is granted by serine protease TMPRSS2. Therefore, ACE2 and TMPRSS co-expression is a key determinant for the entry of SARS-CoV-2 into host cells [20,21]. Once SARS-CoV-2 is in the cytosol of the infected cell, the translation of its RNA and virion synthesis begins. It has been proven that genomic replication and virion assembly occur within the double vesicles of the endoplasmic reticulum (ER) and the Golgi complex [22].

We can therefore conclude that susceptible kidney cells are those that express ACE2. Using RNA-Seq sequencing techniques, scientists were able to determine which kidney cell types comprised the ACE2 gene. The data show that ACE2 mRNA is mostly expressed in proximal tubular epithelial cells and podocytes [20,21]. This would concur with a report by Braun F. et al., who managed to isolate SARS-CoV-2 from epithelial cells of an autopsied kidney [23].

4. Pathophysiology

The best understood mechanism of kidney damage induced by SARS-CoV-2 is direct cellular infection. However, there are also few possible reasons for acute renal failure, such as inflammatory damage caused by cytokine storm, AKI related to acute respiratory distress syndrome (ARDS), kidney–lung crosstalk theory, hypovolemia and collapsing glomerulopathy [24,25,26].

4.1. Direct Cellular Infection

As mentioned before, SARS-CoV-2 penetrates through angiotensin converting enzyme 2. The highest concentration of ACE2 in the kidneys was proven to be located in proximal tubular epithelial cells and podocytes [20,21,27]. Therefore, the direct infection of kidney cells by SARS-CoV-2 virus is the most likely mechanism for the development of acute kidney injury. Autopsy data also speak to this mechanism of AKI because many researchers found virus-like particles in epithelial cells of kidneys [24].

4.2. Cytokine Storm and AKI Related to ARDS

The abnormal immune response associated with SARS-CoV-2 is also a likely mechanism for the development of acute renal failure. At the root of these irregularities lies the cytokine storm and leukopenia [24]. Sepsis, a hemophagocytic syndrome, can lead to a so-called “cytokine storm”, which is a cytokine release syndrome (CRS). The most crucial cytokine responsible for this pathology is IL-6 [25]. IL-6 also occurs in ARDS complications of COVID-19. AKI in CRS is on intrarenal inflammation, increased vascular permeability, volume depletion and cardiomyopathy grounds. Cardiomyopathy can cause stasis in the renal veins, resulting in renal hypotension and hypoperfusion, leading to a reduction in the glomerular filtration rate. This phenomenon is called the syndrome type 1, which is manifested by endothelial damage, pleural effusions, edema, intra-abdominal hypertension, third-space fluid loss, intravascular fluid depletion and hypotension [28]. Moreover, other complications of COVID-19, such as right and left ventricular failure, can cause AKI. The first one leads to blood stagnation in the kidneys, whereas the second one to reduced cardiac output and then to renal hypoperfusion [24]. There are five causes of AKI in ARDS: hemodynamic instability, hypoxemia/hypercapnia, acid-base dysregulation, inflammation and neurohormonal effects [25].

4.3. Lung–Kidney Crosstalk Theory

The occurrence of kidney dysfunctions in COVID-19 patients might be explained by the kidney–lung crosstalk theory. This is due to the increased concentration of cytokines in the blood, the release of which is promoted by lung injury. Elevated levels of cytokines, especially IL-6, cause an increase in alveolar capillary permeability and pulmonary hemorrhage, and may even lead to distant-end organ dysfunction as damage to vascular endothelium in the kidneys. As a consequence, it leads to secondary hypoxia of the kidney and further damage to its structures. In patients who did not have chronic kidney disease or AKI, the research has shown that most of them manifested ARDS and/or AKI after developing pneumonia, which also testifies to the presence of lung–kidney crosstalk [28].

4.4. Hypovolemia

An incorrect distribution of fluids, especially hypovolemia (a consequence of fever and tachypnea), may affect the kidneys. This condition causes renal hypoperfusion and, consequently, renal failure. Endothelial damage, loss of fluid into the third space and hypotension provoke renal hypoperfusion. Virus cells and cytokines produced by the organism destroy the endothelium, which causes edema, ascites and hydrothorax, which in turn leads to hypotension and a loss of fluids to the third space. The amount of circulating fluid is reduced and this damages the kidneys in the prerenal mechanism. [28] Many patients infected with SARS-CoV2 have gastrointestinal symptoms that greatly increase the loss of fluid and further dehydration of the patient, mainly leading to pre-renal AKI [25]. In hemodynamically unstable patients, the venous flow deteriorates. Rhabdomyolysis (a condition involving the rapid dissolution of damaged or injured skeletal muscle), metabolic acidosis (increased level of hydrogen ions in the systemic circulation, which results in a reduction in the level of serum bicarbonate) and hyperkalemia (serum or plasma potassium level greater than 5.0 mEq/L to 5.5 mEq/L) are also associated with this condition. This has a significant impact on the degradation of kidney function and, later on, on the occurrence of AKI. [28] Therefore, optimizing hemodynamic is crucial to kidneys health.

4.5. Collapsing Glomerulopathy

Collapsing glomerulopathy (CG) is a histological term for focal segmental glomerulosclerosis defined by segmental or global glomerular collapse correlated with podocyte proliferation, whose typical feature is proteinuria. CG has been associated with various factors, but the essential one is the presence of Apolipoprotein 1 (APOL1) genotype, namely alleles G1 and G2 [29]. Since the COVID-19 outbreak, there have been several case reports presenting COVID-19 patients with CG, in which authors speculated about the possible mechanisms linking it to SARS-CoV-2 infection. Kissling et al. [30] suggested direct viral toxicity on tubular cells as a pathomechanism of acute tubular necrosis in COVID-19 patients with G1 variant of APOL1 gene, based on post-mortem kidney examination. In another report, Peleg et al. [31] failed to detect viral particles in kidney tissue; thus, cytokine storm was presumed as a cause of collapsing glomerulopathy in COVID-19 patients. Both theories are possible, especially with high-risk alleles of the APOL1 gene.

5. Histopathology

Many autopsies have been carried out since the beginning of the pandemic on COVID-19 patients, especially in the search of complications the SARS-CoV-2 virus carries to the human cells. Histopathological examinations used, among others, light microscopy, electron microscopy and immunofluorescence.

COVID-19 patients with AKI rarely showed clinical symptoms. The kidneys were often atypical in macroscopic examination, sometimes enlarged. However, microscopic examination of the subjects showed acute tubular injury (ATI), tubulointerstitial injury and glomerular injury, but nevertheless mild in relation to the degree of AKI and blood creatinine concentration [15,32]. Other notable observations were: fibrosis, congestion of the glomeruli and periurethral capillaries and the presence of glomerular fibrin. In addition, changes in the kidneys included atherosclerosis, foci of ischemia, benign chronic glomerular and tubulointerstitial lesions. Moreover, microscopy revealed the presence of isometric vacuolization in the renal tubules as an important diagnostic point. These changes in COVID-19 patients confirm direct viral infection into cells as a mechanism of AKI. Moreover, they correlate with the presence of double-membrane-covered vesicles that contain vacuoles and may be an indicator of active SARS-CoV-2 infection [32,33].

Acute tubular injury (ATI) is the constant condition found in COVID-19 patients with AKI. ATI is characterized by the loss of the brush rim, degeneration of the vacuole, flattening of the lumen of the tubule, cellular inclusions as well as necrosis and detachment of the epithelium. These changes can be well observed in samples subjected to light microscopy. The presence of hemosiderin and fibrin in the renal tubules has been rarely observed [15,23,32]. However, no aggregated platelets were observed at all. Electron microscopy revealed corona-like virus-like cells in the proximal part of the renal tubules and in podocytes. Erythrocytes were present in the lumen of the periurethral vessels [23]. The footprint of interferon in capillaries in electron microscopy indicates a cytokine storm as a mechanism for kidney damage. The visible swelling of the endothelial cells is also evidence of damage to the endothelium [15]. The most frequent histological observations are presented in Table 2.

Table 2

The most common histopathological observations in COVID-19.

Morphological DataNephron SegmentsPathophysiological Mechanism
Epithelial necrosisProximal tubulesDirect viral infections, hemodynamic disorders, rhabdomyolysis
Cellular debrisLumen of tubules
MyoglobinTubulesRhabdomyolysis
Corona-like virusesPodocytes, tubulesDirect viral infections
Isometric vacuolizationTubules
Loss of brush border, flattening, damageTubulesDirect viral infections, cytokine storm
Swelling of endothelial cellsGlomerulus

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6. Clinical Features

As mentioned before, COVID-19 can be manifested as a mild or moderate infection or a severe or critical illness. Mild or moderate symptoms include cough, fever, fatigue, dyspnea and smell and taste loss. Severe COVID-19 cases additionally present with hypoxia and >50% lung infiltration on imaging. The critical course of the disease includes respiratory failure, SIRS and/or multiple organ failure [9].

Although the main feature of COVID-19 is pneumonia, we focused our research on renal dysfunction. The most frequently reported disorder of the kidney was acute kidney injury (AKI). In researched studies [5,6,11,12,13,16], the end point of AKI was defined by the “Kidney Disease: Improving Global Outcomes (KDIGO)” criteria explained above. These findings indicate that increase in serum creatinine in COVID-19 patients at admission can be a negative prognostic factor in AKI development. In addition, majority of patients who developed AKI presented with hematuria and proteinuria, although these were more frequent in severe or critically ill patients (Table 3).

Table 3

Laboratory data in AKI patients with COVID-19.

Pei, G. [5n = 35Cheng, Y. [11n = 53Chan, L. [12n = 656Hirsch, J.S. [6n = 1993Li, Z. [34n = 147
Proteinuria84%26.0%88/147 (60%)
negative4/35 (11.4%)16/53 (30.2%)168 (26.0%)31 (21%)
+24/35 (68.6%)21/53 (39.6%)206 (31.9%)39 (27%)
++/+++7/35 (20.0%)16/53 (30.2%)194 (30.0%)15 (10%)
+++78 (12.1%)3 (2%)
p0.002<0.001
Hematuria81%46.1%71/147 (48%)
negative14/35 (40.0%)25/53 (47.2%)196 (36.2%)21 (14%)
+13/35 (37.1%)16/53 (30.2%)96 (17.7%)21 (14%)
++/+++8/35 (22.9%)12/53 (22.6%)148 (27.3%)16 (11%)
+++102 (18.8%)13 (9%)
p0.007<0.001
Serum creatinine
Serum creatinine, mg/dL0.79 (0.64–0.95)1.49 ± 0.441.42 (0.95–2.25)1.23 (0.91, 1.8)0.75 (0.61–0.93)
Peak serum creatinine, mg/dL1.84 ± 1.232.23 (1.40, 4.12)
Blood urea nitrogen
Blood urea nitrogen, mg/dL12.04 (9.0–16.0)30.8 ± 19.631 (18–51)23.0 (14.75, 37.0)0.01

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+—slight; ++—average; +++—significant.

More research is needed to determine whether the occurrence of AKI affects subsequent renal function. A study with a follow-up period of 3 weeks from the onset of the infection presented no improvement in kidney functions in 89.5% of COVID-19 patients who developed AKI [5]. Another study shows that 46% of COVID-19 patients who had AKI at discharge did not recover to baseline serum creatinine levels [12]. Therefore, the assumption that AKI may lead to CKD is possible but needs further investigation.

7. Risk Factors of AKI Development

Most of the patients who experience the severe or critical course of COVID-19 have pre-existing conditions. The most common comorbidities are hypertension and other cardiovascular disorders, diabetes mellitus and obesity. They are considered to be the major risk factors for developing a more severe, if not critical, course of COVID-19 [35]. A meta-analysis by Henry and Lippi pointed out that patients with chronic kidney failure must also take precautions in exposure to SARS-CoV-2 virus, since CKD increases the risk of a severe course of the disease [36].

In our research, we focused on the variables that specifically led to AKI occurrence in COVID-19 patients. Hirsch et al. analyzed possible risk factors associated with AKI development which included older age, diabetes, hypertension, cardiovascular disease and respiratory failure, the last one being the most important factor [6]. In another study, there was an association between older age and male sex as a primary risk factors of developing AKI [13]. Thus, not only do comorbidities play a role in the incidence of AKI, but so do non-modifiable factors such as age and gender. The results of variable correlations with AKI development are presented in Table 4.

Table 4

The correlation between age, sex, comorbid conditions and AKI development.

Pei, G. [5n = 19Chan, L. [12n = 1835Hirsch, J.S. [6n = 1993Fisher, M. [13n = 1903
Age (years)64.0 ± 8.171 (61–81)69.0 (58.0, 78.0)67.1 (15.3)
Sex (%)
Men14 (73.7)1270 (63.7)1091 (57.3)
Women734 (40)812 (42.7)
Hypertension (%)9 (47.4)820 (45)1292 (64.8)
Diabetes mellitus (%)8 (42.1)568 (31)830 (41.6)569 (29.9)
Chronic kidney disease (%)339 (18)287 (15.1)
ACEI/ARB treatment history (%)4(21.1)655 (32.9)195 (10.2)
Coronary artery disease (%)289 (14.5)
Congestive heart failure (%)244 (13)208 (10.4)87 (4.6)
Liver disease (%)99 (5)42 (2.1)
Peripheral vascular disease (%)194(11)61 (3.1)
Cancer (%)133 (6.7)38 (2.0)
Obesity (%)739 (37.1)

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Furthermore, the issue of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) in patients with COVID-19 infection and putative risk of AKI in COVID19 is worth addressing. The clinical use of ACEI and ARB was controversial at the beginning of the pandemic. Some researchers proposed, based on the mechanism of SARS-CoV-2 infection, that administering ACEI and ARB could aggravate the course of the disease. This speculation has been dismissed by several observational studies, as well as international societies such as The Council on Hypertension of the European Society of Cardiology. ACEI and ARB therapy should not be discontinued in the mild and/or moderate course of COVID-19 infection [37,38].

8. Impact of AKI Development on Hospitalization and Mortality Rate

In order to assess the impact of AKI development in patients with COVID-19 on the course of hospitalization and mortality rate, we have compiled the data from five different case reports and compared AKI patients with patients without AKI (Figure 1Figure 2 and Figure 3). The occurrence of AKI in COVID-19-positive patients resulted in a significantly increased number of admissions to the intensive care unit (ICU) in comparison to COVID-19 patients without AKI. In the same group of patients, the need for mechanical ventilation was also more noticeable. What stands out the most in our sheet is the fatality rate, which ranges from 33.3% up to 86.4% in COVID-19 patients with AKI in comparison to COVID-19 patients without AKI, which varies from 5.6% to 9.3%. Therefore, patients with COVID-19 who develop AKI are at significantly higher risk of severe or critical course of the disease, respiratory failure and consequent mechanical ventilation. Moreover, AKI incidence undeniably increases the mortality rate in COVID-19 patients.

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Figure 1

Intensive care unit admission in patients with AKI and no AKI [6,12,13].

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Figure 2

The need for mechanical ventilation in patients with AKI and no AKI [6,12,13,14].

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Figure 3

In-hospital death in patients with AKI and no AKI [5,6,12,13,14].

9. Clinical Handling

There is no specific treatment for AKI caused by COVID-19, and it has to be based on KDIGO and other guidelines. Prevention of AKI mainly consists of individual fluid therapies (balanced crystalloids), discontinuation or reduction in nephrotoxic drugs and, in the case of hypovolemia, the use of vasopressors. It is important to monitor kidney function with laboratory tests such as serum creatinine and urea levels.

Treatment should be systemic. We use antiviral drugs, antibiotics, corticosteroids, renin–angiotensin inhibitors, statins and anticoagulants. Drug therapy reduces the risk of developing AKI and causes a milder disease course [39].

10. Renal Replacement Therapy

Renal replacement therapy (RRT) is needed in up to 64% of critically ill COVID-19 patients who develop AKI (Table 1) [6,12,13,14,15]. It is due to abnormal concentrations of electrolytes and volume overload resistance to pharmacological treatment. The earliest studies suggested that, in hemodynamically unstable patients with COVID-19, the recommended approach was continuous RRT (CRRT) [28]. However, clinicians observed a significantly increased incidence of circuit clotting in COVID-19 patients, leading to prolonged time of treatment, as well as the unnecessary use of resources [24,40]. Therefore, we must take caution in choosing the most safe and effective strategy.

Ramirez-Sandoval, J.C. et al. [41] reported the viability and safety of prolonged intermittent renal replacement therapy (PIRRT) as a treatment option in COVID-19 patients with AKI. The use of low-molecular-weight heparin (LMWH) in systemic anticoagulation and unfractionated heparin (UFH) in regional anticoagulation was adapted and shown to reduce the incidence of the circuit clotting observed in up to 13% of ICU patients with COVID-19 infection. These findings were later confirmed in a report by Di Mario, F. et al. [42], who tested the effectiveness of sustained low-efficiency dialysis (SLED), which is a modality of PIRRT. However, in this study, the applied anticoagulation was regional citrate anticoagulation (RCA) protocol, and it significantly lowered dialysis interruption by circuit clotting to 6.1%. Moreover, the advantages of RCA over systemic heparin anticoagulation protocols have been demonstrated in a comparative study by Arnold, F. et al. [43] Taking into account these reports, we can assume that SLED with RCA protocol is the safest and most efficient way of AKI management in hemodynamically unstable COVID-19 patients.

11. Conclusions

Acute kidney injury is common amongst patients with SARS-CoV-2 infection, especially critically ill ones, and is without a doubt associated with higher mortality. There are numerous possible pathomechanisms which are still being investigated, but the most probable ones are direct cellular invasion, ARDS, cytokine storm and hypovolemia. Histopathological reports showed that most COVID-19 patients with AKI presented acute tubular damage, sometimes with necrosis and collapsing glomerulopathy. The most important steps that should be taken in AKI prevention are the following: minimizing the risk of hypovolemia and monitoring serum creatinine levels in the early stages of COVID-19 infection, especially in regard to the high-risk patients at an older age with diabetes mellitus, hypertension and cardiovascular diseases. However, when, despite our best efforts, COVID-19 patients are hemodynamically unstable, the safest and most efficient way of AKI management is SLED with RCA protocol. The evidence related to COVID-19 is changing dynamically and we are still in need of more research for establishing the optimal treatment of AKI in COVID-19 infection. Furthermore, physicians must be aware that patients who recover from AKI induced by SARS-CoV-2 require monitoring of their kidneys on follow-up, as there is rising evidence showing eGFR decreases among patients with a history of COVID-19-associated AKI [44].

Author Contributions

All authors (M.G., S.L., E.M., B.F., J.R.) were involved in the preparation of this article and J.R. revised the final version. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used in this article are sourced from materials mentioned in the References section.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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COVID-19 vaccination followed by activation of glomerular diseases: does association equal causation?

Authors: Nicholas L. Li,1P. Toby Coates,2 and Brad H. Rovin1,∗

Kidney Int. 2021 Nov; 100(5): 959–965.Published online 2021 Sep 14. doi: 10.1016/j.kint.2021.09.002 PMCID: PMC8437826PMID: 34534551

To date, >4 billion doses of the various severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have been administered worldwide in response to the coronavirus disease 2019 (COVID-19) pandemic. Even as widespread vaccination campaigns have contributed to declining case rates, adverse events are appearing beyond those originally reported in the clinical trials of vaccine efficacy and safety. Of particular relevance to the kidney is the increasing number of reports of de novo or reactivation of glomerular diseases (Table 1 12345678910111213141516171819202122232425). The occurrence of glomerular disease after immunization against influenza, pneumococcus, and hepatitis B has been reported in the past.262728 The reported patients developed acute onset nephrotic syndrome following vaccination, and kidney biopsies were consistent with a minimal change disease (MCD) pattern of injury. Although temporal association (median onset of 12 days) with vaccination and disease onset suggested a vaccine-related induction of immune injury, the pathophysiological mechanisms responsible have not been determined.

Table 1

Summary of reported cases of glomerular disease activation with COVID-19 vaccination

DiseaseAge, yr, median (range)% Female (n)Vaccine typeNo. of casesDe novo or flareaMaintenance immune therapyTemporal association to vaccination, dTreatmentOutcomeCOVID-IgG responseReferences
IgAN38 (13–52)58 (7 of 12)Pfizer–BioNTech, Moderna12De novo, 7 flareNo, or steroids, mycophenolic acid, calcineurin inhibitor in transplant patient1–2RASi, steroids, cyclophosphamideSpontaneous resolution, renal response to immunotherapyPositive1234567
MCD61 (22–”early 80s”)36 (4 of 11)Pfizer–BioNTech, Moderna, Astra Zeneca11De novo, 4 flareNo, or steroids, calcineurin inhibitor, rituximab1–13 (median, 7)Steroids, calcineurin inhibitorRenal response to immunotherapy in most casesPositive891011121314151617
MN68 (66–70)50 (1 of 2)Pfizer–BioNTech, Sinovac2De novo (anti-THSD7A+), 1 flare (anti-PLA2R+)No7–14RASiNRPositive18,19
AAN78 (52–81)33 (1 of 3)Moderna, Pfizer–BioNTech3De novoNo14Steroids, cyclophosphamide, plasma exchangeRenal responsePositive3,20,21
Anti-GBM60 (60–”older female”)100 (2 of 2)Moderna2De novoNo1–14Steroids, cyclophosphamide, plasma exchangeNo recoveryNR6,22
IgG4-RD660 (0 of 1)Pfizer–BioNTech1FlareRituximab14Steroids, rituximabRenal responsePositive23
LN42100 (1 of 1)Pfizer–BioNTech1FlareHydroxychloroquine7Steroids, mycophenolate mofetilPartial responsePositive24
Scleroderma renal crisis34100 (1 of 1)Pfizer–BioNTech1De novoNo1RASiResponsePositive25

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AAN, anti–neutrophil cytoplasmic antibody–associated nephritis; anti-GBM, anti–glomerular basement membrane antibody disease; COVID, coronavirus; COVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; IgG4-RD, IgG4-related disease; LN, lupus nephritis; MCD, minimal change disease; MN, membranous nephropathy; NR, not reported; PLA2R, phospholipase A2 receptor; RASi, renin-angiotensin system inhibitor; THSD7a, thrombospondin type-1 domain-containing 7A.aDe novo indicates disease development in a patient not known to have a prior glomerular disease; flare indicates activation of a known, but controlled, glomerular disease.

After vaccination against COVID-19, reports of exacerbation, and in some cases, new onset of glomerular diseases began arriving at Kidney International and other nephrology journals. Although the development of de novo glomerular disease is intriguing, increased patient awareness of symptoms after vaccination may have prompted medical attention, revealing a previously undiagnosed kidney disease as opposed to a de novo disease. Indeed, chronicity on the kidney biopsy may suggest the glomerular disease preceded COVID-19 vaccination. Although nearly all approved vaccine platforms have been implicated, cases have been far more common after the mRNA-based vaccines, Pfizer–BioNTech BNT162b2 and Moderna mRNA1273 (Table 1). Of course, this may simply reflect more widespread use of these mRNA vaccines. Another interesting feature of COVID-19 vaccine-associated glomerular disease (CVAGD) is that most cases appear to be either IgA nephropathy (IgAN) or MCD (Table 1). The timing of IgAN activation is generally within a day or two after receiving the second dose of BNT162b2 or mRNA1273, whereas MCD appears to occur at a median of 7 days after the first dose (Table 1). Although these associations do not prove causation, we suggest that the volume of cases of MCD and IgAN and the consistent time course of events indicate a direct role of the mRNA vaccines in these 2 glomerular diseases. Several other glomerular diseases have occurred in smaller numbers following vaccination, sometimes quickly (scleroderma renal crisis), but more often after about 2 weeks (e.g., membranous nephropathy, anti–neutrophil cytoplasmic antibody–associated vasculitis, anti–glomerular basement membrane disease, and IgG4 renal disease). Given the small number of cases of these immune-mediated glomerular diseases, and the longer time to their appearance, it is difficult to be certain that they were activated by the vaccines. Nonetheless, considering these cases in aggregate, it appears that the COVID-19 vaccines can (re)activate autoantibody-mediated kidney disease.

It is not clear how COVID-19 vaccines, and in particular the mRNA vaccines, induce MCD, IgAN, and other autoimmune kidney diseases. mRNA-based vaccine technology has been available for some time, although the SARS-CoV-2 vaccines were the first to be investigated in large-scale phase 3 randomized trials. It has been previously demonstrated that this vaccine technology promotes more potent immune responses than inactivated viral vaccines and even natural infection. A comparison of the immune responses to the COVID-19 vaccine platforms is given in Table 2 29303132333435. This ability of the mRNA vaccines to enhance virus-specific responses over and above more traditional vaccines has likely contributed to the high efficacy in preventing disease from SARS-CoV-2, as well as the viral variants that have evolved during this pandemic. BNT162b2 or mRNA1273 deliver lipid nanoparticle encapsulated mRNA encoding the full-length SARS-CoV-2 spike protein. These vaccines were found to be safe and efficacious in preventing severe COVID-19 in both clinical trial and real-world conditions, although patients with known autoimmune diseases were not included in the initial trials.36 These lipid nanoparticle–mRNA vaccines stimulate robust antigen-specific T-cell responses, including T follicular helper (Tfh) cells, and potent germinal center B-cell responses, leading to durable neutralizing antibody production.37

Table 2

Immune responses to SARS-CoV-2 vaccine platforms

VaccineExample manufacturerT-cell responsesB-cell responsesCytokine responsesReferences
LNP-mRNAPfizer–BioNTech, ModernaAntigen-specific Th1-biased CD4+ response, CD8+ IFNɣ, IL-2Prolonged S-specific germinal center B-cell responsesIFNɣ, IL-2, type I interferon via toll-like receptor-7293031
Adenovirus-DNAAstraZeneca, Janssen/Johnson & JohnsonAntigen-specific Th1-biased CD4+ response, monofunctional and cytotoxic CD8+ responseIgG1/IgG3 predominant, low IgG2/IgG4IFNɣ, TNFα, IL-2, type 1 interferon via toll-like receptor-931,32
Inactivated whole virusSinovac BiotechTh1-biased response with minimal Th2RBD-specific binding antibody and neutralizing antibody productionIFNɣ, TNFα, IL-233,34
Recombinant protein subunitNovavaxTh1-biased response with minimal Th2S-binding antibody and neutralizing antibody productionIFNɣ, TNFα, IL-235

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IFNγ, interferon gamma; IL-2, interleukin 2; LNP, lipid nanoparticle; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th1, T-helper cell 1; Th2, T-helper cell 2; TNFα, tumor necrosis factor alpha.

In the cases of IgAN, disease symptoms occurred right after vaccination, suggesting a rapid immune mechanism, such as a memory recall response or mobilization of cells positioned to secrete galactose-deficient IgA1 antibodies. Although purely speculative, we wonder if the COVID-19 vaccines can robustly stimulate the gut-associated lymphoid tissue (Peyer patches) responsible for IgA1 production, as they do in other lymphoid tissues. IgA1 hyperresponsiveness has been observed in patients with IgAN following influenza vaccination.38 In the case of COVID-19 vaccination, circulating IgA responses following administration have been observed to be similar in kinetics to IgG responses, with levels reaching a plateau 18 to 21 days after first mRNA dose, and further increases after a second dose peaking at 7 days after dose.39 The temporal associations with hematuria onset following vaccination on the order of days argues against the contribution of spike protein-specific IgA molecules from participating in disease. However, it is known that patients with IgAN have increased circulating galactose-deficient IgA1, and perhaps bystander activation of the immune system with mRNA COVID-19 vaccination may act as a trigger for the formation of immune complexes and subsequent glomerular injury.

In contrast, the development of MCD following vaccination takes some time, suggesting a role for cellular immunity. Central to the pathogenesis of MCD is the development of podocyte injury due to dysregulated T-cell activation.29 The COVID-19 mRNA vaccines trigger enhanced Tfh responses that peak 7 days after immunization. A potential contribution to the pathogenesis of MCD by Tfh cells has been suggested by observations that circulating subsets of Tfh cells are increased in patients with MCD, and the frequency of these populations is reduced in patients who are successfully treated with steroids.40 Given these findings, and the reported onset of disease at a time point that correlates with Tfh response, perhaps mRNA vaccine-induced alterations in the Tfh population and/or their associated cytokine profile in a susceptible individual could promote podocyte injury and the development of nephrotic syndrome and MCD.

The later appearing cases of autoantibody-mediated glomerular disease may be due to the induction of vaccine-associated autoimmunity. Vaccine-associated autoimmunity has been postulated to occur by antigen-specific and nonspecific mechanisms. Antigen-specific triggers for vaccine-mediated autoimmunity are thought to be secondary to molecular mimicry. That is, exposure to a non–self-antigen, such as SARS-CoV-2 spike protein, could elicit responses directed against host tissues if there was sufficient sequence homology to allow for cross-recognition. The SARS-CoV-2 spike protein shares homology with several human proteins, which may then be subject to off-target immune attack after vaccination.41 Consistent with the mimicry hypothesis, it has been suggested that homologous sequences between human alveolar surfactant-related proteins and SARS-CoV-2 spike glycoproteins contribute to host immune attack and the subsequent pulmonary pathology seen with COVID-19 infection.42 Similarly, mimicry of viral antigens with host proteins has been proposed to contribute to immune attack in the central nervous system, exacerbating neurologic complications in COVID-19.43

Antigen nonspecific mechanisms of autoimmunity with vaccination are thought to occur through bystander activation. In this model, the vaccine-stimulated immune response may trigger cellular damage and exposure of normally hidden self-antigens, which are then recognized by host immunity. Alternatively, by this model, innate immune responses may upregulate cytokine signaling and self-antigen presentation by antigen-presenting cells to potentially autoreactive T cells. Either of these mechanisms could conceivably contribute to the development of glomerular disease in response to vaccination, with perhaps different disease phenotypes resulting from each.

Interestingly, to date, there has been only one report of an exacerbation of lupus nephritis (LN) after COVID-19 vaccination, and this was with the BNT162b2 vaccine. This paucity of cases is somewhat unexpected. Tfh cells, robustly activated by mRNA-based COVID-19 vaccines, are important for autoantibody development in lupus.44 Germinal center and peripheral leukocyte cytokine profiles after vaccination are reminiscent of cytokine profiles from lupus patients, with especially high levels of interferon-α, interleukin-6, and tumor necrosis factor-α.45 In the reported case, a patient with known class V LN in remission developed nephrotic syndrome following the first vaccine injection, and kidney biopsy revealed International Society of Nephrology/Renal Pathology Society class II and V LN with an activity index of 0. Given the robust immune activation achieved with the mRNA vaccines, it is surprising that in this case immune complex deposits were limited to the subepithelial compartment and there was no development of proliferative LN. The absence of proliferative LN cases may arguably be because many patients who have lupus nephritis are maintained on long-term immunosuppression. Most patients who developed CVAGD were not on immunosuppression (Table 1). Perhaps a baseline level of immunosuppression is sufficient to blunt the immune response to mRNA vaccination and prevent autoimmune reactions. This is supported by the observation that solid organ transplant patients on various forms of immune suppression, including those typically used in lupus nephritis, such as glucocorticoids and mycophenolate mofetil, demonstrate a weaker response to 2 doses of BNT162b2 vaccination.46 However, considering the few reports of patients on immunosuppression who still developed glomerular injury after vaccination, including one kidney transplant patient, being on immunosuppression is clearly not the only factor determining who will develop kidney disease with these vaccines. Ultimately, there are likely individual patient-specific factors involved that determine whether vaccination results in immune protection or autoimmune injury.

In the published cases of CVAGD, glomerulonephritis was often managed with the usual therapeutic options for these diseases, frequently leading to a clinical response (Table 1). Although evidence is limited, we support a management strategy of CVAGD that is consistent with the conventional therapy of glomerular diseases not associated with vaccination, including the use of immunosuppression if typical indications develop. It is not unreasonable to extrapolate from the management of glomerulonephritis in general, given the presumption in CVAGD that the same disease mechanisms and pathways of vaccine-independent glomerular disease are activated by COVID-19 vaccination. However, management decisions should be tailored to individual cases given the rarity of these events.

As the worldwide COVID-19 vaccination campaign continues to accelerate, it is probable that we will continue to see CVAGD. Not all cases have been, or will be, reported, there is likely reporting bias, and the number of patients with known glomerular disease who have been vaccinated is not known, so the true incidence of CVAGD will be difficult to determine. As multiple doses of vaccines are now being offered, close observation to watch for an increase in CVAGD will be needed. However, in the context of the billions of doses of COVID-19 vaccine that have been administered, the relatively small number of cases thus far suggests a low incidence. Care providers should consider the possibility of glomerulonephritis in patients who develop gross hematuria or edema after vaccination to aid in the prompt diagnosis and management of these diseases. The possibility of CVAGD should not, however, prompt vaccine hesitancy. Most reported cases were easily managed and resolved on their own or responded to typical therapy. Also, COVID-19 infection itself has been linked to the development of immune-mediated kidney diseases.47 The benefits of COVID-19 vaccination appear to greatly outweigh the risks of glomerular disease occurrence or recurrence, and vaccination remains the best method of preventing the morbidity and mortality associated with SARS-CoV-2 infection. Therefore, we are offering vaccination to all of our patients with glomerular diseases, with the following considerations.

Patients in remission and off all immunosuppression should be followed up closely after vaccination and be told to report hematuria or swelling immediately for early intervention. For patients undergoing active immunosuppressive treatment with anti-metabolites (e.g., mycophenolate mofetil or azathioprine), cytotoxic drugs (e.g., cyclophosphamide), anti–B-cell therapies (e.g., rituximab), and costimulation blockers (e.g., abatacept), antibody response to COVID-19 vaccines is likely to be poor.48 , 49 It is probably reasonable to postpone vaccination until these intensive therapies have been tapered or completed. Timing is also important for anti-CD20 B-cell therapies as these have prolonged effects after dosing. For such patients, it is important to continue all preventative measures in place before vaccines were available, and all individuals within the patient’s “bubble” should be vaccinated to provide an additional layer of protection. Finally, it is difficult to speculate on the management of patients who develop CVAGD after the first injection of an mRNA-based vaccine. Checking SARS-CoV-2 antibody response after the first dose may provide some confidence that the patient developed an immune response and may not need the second dose, but of course this does not equate with protection against COVID-19. A change in vaccine platform could also be considered for a second dose. Alternatively, if the CVAGD was mild and readily resolved, administration of the follow-up dose could be considered.

The Immunonephrology Working Group of the European Renal Association–European Dialysis and Transplant Association recently published recommendations on the use of COVID-19 vaccines in patients with autoimmune kidney diseases and supports the vaccination of all individuals without known contraindications.50 However, these recommendations did not advise on whether vaccination with one vaccine platform was preferable to another. Despite the higher number of reports of glomerular disease activation or reactivation with mRNA COVID-19 vaccines compared with the traditional vaccines, it remains difficult to make a recommendation against the mRNA platform. As CVAGD has been seen with non-mRNA vaccines, avoiding Pfizer–BioNTech or Moderna vaccines does not completely eliminate autoimmune risk. Furthermore, the differences in efficacy between the various vaccines cannot be overlooked. Ultimately, as with all decisions in medicine, theoretical risks must be balanced against known benefits of interventions, and discussions between care providers and patients in this regard are important.Go to:

Disclosure

All the authors declared no competing interests.

See the article “A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination” in Kidney Int, volume 100 on page 238.See the article “Minimal change disease and acute kidney injury following the Pfizer-BioNTech COVID-19 vaccine” in Kidney Int, volume 100 on page 461.See the article “Relapse of primary membranous nephropathy after inactivated SARS-CoV-2 virus vaccination” in Kidney Int, volume 100 on page 464.See the article “Post-vaccinal minimal change disease” in Kidney Int, volume 100 on page 459.See the article “Minimal change disease following the Moderna mRNA-1273 SARS-CoV-2 vaccine” in Kidney Int, volume 100 on page 463.See the article “Histologic correlates of gross hematuria following Moderna COVID-19 vaccine in patients with IgA nephropathy” in Kidney Int, volume 100 on page 468.See the article “Anti-GBM nephritis with mesangial IgA deposits after SARS-CoV-2 mRNA vaccination” in Kidney Int, volume 100 on page 471.See the article “Relapse of minimal change disease following the AstraZeneca COVID-19 vaccine” in Kidney Int, volume 100 on page 459.See the article “Relapse of class V lupus nephritis after vaccination with COVID-19 mRNA vaccine” in Kidney Int, volume 100 on page 941.See the article “Letter regarding “Minimal change disease relapse following SARS-CoV-2 mRNA vaccine”” in Kidney Int, volume 100 on page 458.See the article “A case of membranous nephropathy following Pfizer–BioNTech mRNA vaccination against COVID-19” in Kidney Int, volume 100 on page 938.See the article “Minimal change disease relapse following SARS-CoV-2 mRNA vaccine” in Kidney Int, volume 100 on page 457.See the article “Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy” in Kidney Int, volume 99 on page 1487.See the article “ANCA glomerulonephritis after the Moderna COVID-19 vaccination” in Kidney Int, volume 100 on page 473.See the article “Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine” in Kidney Int, volume 100 on page 465.See the article “IgA nephropathy presenting as macroscopic hematuria in 2 pediatric patients after receiving the Pfizer COVID-19 vaccine” in Kidney Int, volume 100 on page 705.See the article “Gross hematuria following SARS-CoV-2 vaccination in patients with IgA nephropathy” in Kidney Int, volume 100 on page 466.See the article “Is COVID-19 vaccination unmasking glomerulonephritis?” in Kidney Int, volume 100 on page 469.See the article “De novo vasculitis after mRNA-1273 (Moderna) vaccination” in Kidney Int, volume 100 on page 474.See the article “Scleroderma renal crisis following mRNA vaccination against SARS-CoV-2” in Kidney Int, volume 100 on page 940.This article has been cited by other articles in PMC.

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COVID-19 and chronic kidney disease: a comprehensive review

Authors: Inah Maria D. Pecly,1Rafael B. Azevedo,1Elizabeth S. Muxfeldt,1,2Bruna G. Botelho,1Gabriela G. Albuquerque,1Pedro Henrique P. Diniz,1Rodrigo Silva,1 and Cibele I. S. Rodrigues3

J Bras Nefrol. 2021 Jul-Sep; 43(3): 383–399.Published online 2021 Apr 9. doi: 10.1590/2175-8239-JBN-2020-0203PMCID: PMC8428633PMID: 33836039

Abstract

Kidney impairment in hospitalized patients with SARS-CoV-2 infection is associated with increased in-hospital mortality and worse clinical evolution, raising concerns towards patients with chronic kidney disease (CKD). From a pathophysiological perspective, COVID-19 is characterized by an overproduction of inflammatory cytokines (IL-6, TNF-alpha), causing systemic inflammation and hypercoagulability, and multiple organ dysfunction syndrome. Emerging data postulate that CKD under conservative treatment or renal replacement therapy (RRT) is an important risk factor for disease severity and higher in-hospital mortality amongst patients with COVID-19. Regarding RAAS blockers therapy during the pandemic, the initial assumption of a potential increase and deleterious impact in infectivity, disease severity, and mortality was not evidenced in medical literature. Moreover, the challenge of implementing social distancing in patients requiring dialysis during the pandemic prompted national and international societies to publish recommendations regarding the adoption of safety measures to reduce transmission risk and optimize dialysis treatment during the COVID-19 pandemic. Current data convey that kidney transplant recipients are more vulnerable to more severe infection. Thus, we provide a comprehensive review of the clinical outcomes and prognosis of patients with CKD under conservative treatment and dialysis, and kidney transplant recipients and COVID-19 infection.

Keywords: Renal Insufficiency, Chronic; Renal Dialysis; Peritoneal Dialysis; Mortality; Morbidity:

Introduction

In December 2019, cases of atypical pneumonia began to rise in the city of Wuhan, located in the providence of Hubei, China1. In March 2020, amid initiation of global spread, the World Health Organization (WHO) declared the outbreak a pandemic, caused by SARS-CoV-2, a new positive-strand RNA virus from the coronoviridae family, being from the same family of the viruses responsible for the severe acute respiratory syndrome (SARS) in 2002 and the middle east respiratory syndrome (MERS) in 20122  4. In Brazil, until mid-September, the country surpassed 4,100,000 confirmed cases and 130,000 deaths due to the disease2 , 3. The etiological agent of COVID-19 is more infectious than SARS and MERS, with a basic number of reproductions (R0) ranging from 2-3.55  7. Moreover, besides a high transmission rate, authors postulate that a crucial factor regarding the transmission of COVID-19 infection is the high level of SARS-CoV-2 present in the upper respiratory tract, even among pre-symptomatic patients, contributing to the global spread of the disease5  8.

From a pathophysiological perspective, COVID-19, especially in severe forms, is characterized by an overproduction of inflammatory cytokines due to cytokine storm triggered by viral infection, leading to systemic inflammation and a prothrombotic state9 , 10. Thus, besides lung involvement, other organ complications are observed in patients with SARS-CoV-2 infection such as kidney damage leading to acute kidney injury (AKI)11, raising concerns regarding the clinical outcomes and prognosis of patients with preexisting comorbidities such as chronic kidney disease (CKD), end-stage kidney disease (ESKD), and kidney transplant recipients under immunosuppression therapy.

A meta-analysis including 73 studies evaluating the association between multi-organ dysfunction and COVID-19 development revealed that patients with CKD were more likely to develop severe SARS-CoV-2 infection (OR 1.84 [95%CI 1.47-2.30])12. Hence, besides disease severity, it is imperative to evaluate the clinical outcomes, prognosis, and mortality associated with COVID-19 infection in patients with history of CKD, CKD on maintenance dialysis, and kidney transplant recipients (Figure 1).

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Figure 1COVID-19 in patients with Chronic Kidney Disease. Brief summary of the key points regarding SARS-CoV-2 infection in patients with prior CKD undergoing conservative or dialytic therapy.

Methodology

A thorough scoping review based on the PubMed electronic bibliographic database was performed between April and September 2020, using the following Mesh terms: “Renal” OR “Kidney”, OR “Hemodialysis”, OR “Peritoneal Dialysis”, OR AND “Chronic Kidney Disease” AND “Kidney Transplant Recipients” AND “COVID-19”, with adoption of the PICO strategy and classification of the level of evidence.

The guiding question to construct the review was: what is the latest scientific evidence regarding SARS-CoV-2 in patients with COVID-19 and chronic kidney disease? Articles diverging from the central theme were excluded from the review. After exclusion, 90 articles were selected and cited directly or via cross-reference in the present review.Go to:

Integrated Discussion

Patients with ckd under conservative treatment and covid-19

In 2017, CKD affected around 10.0% of the global population. In Brazil, more than 10 million presented the disease in its different stages, with 139,691 undergoing dialysis of which 93.2% in hemodialysis in 201913  15. In addition to the high prevalence, CKD remarkably increases morbimortality and is associated with higher infection risk, mainly respiratory, and a more precise comprehension of the prognosis and the clinical evolution of CKD patients infected by COVID-19 is crucial16. In a study evaluating the early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy, the prevalence of CKD amongst hospitalized patients with COVID-19 was 11.8%17.

De Lusignan et al. in a recent cross-sectional study describing the risk factors for SARS-CoV-2 infection among 3,802 patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network found that individuals with CKD were more likely to test positive for COVID-19 (68 [32.9%] of 207 with CKD vs. 519 [14.4%] of 3595 without CKD; OR 1.91 [CI95% 1.31-2.78])18.

The high incidence of kidney involvement observed in hospitalized patients with COVID-19 might be also due to the presence of previous chronic kidney impairment. Cheng et al., in a prospective analysis of 701 patients with COVID-19, demonstrated that in comparison with patients with normal serum creatinine (SCr), patients admitted with elevated SCr presented higher leukocyte count (9.5±8.0 vs. 7.2±7.4 x 109/L, p=0.005), lower lymphocyte count (0.8±0.5 vs. 0.9±0.5 x 109/L, p=0.015), lower platelet count (191±94 vs. 216±84 x 109/L, p=0.014), prolonged partial thromboplastin time >42s (54.2 vs. 40.4%, p=0.029), higher D-dimer levels (>0.5mg/L) (89.8 vs. 75.3%, p=0.002), increased procalcitonin (≥0.5ng/mL) (29.3 vs. 6.9%, p<0.001), increased lactose dehydrogenase (LDH) (458±254 vs. 364±180, p=0.001), and the incidence of AKI was significantly higher in patients with elevated baseline SCr (11.9 vs. 4.0%, p=0.001). Furthermore, patients with COVID-19 and elevated baseline SCr presented higher prevalence of intensive care unit (ICU) admission (12.8 vs. 10.0%, p=0.382) and mechanical ventilation (21.8 vs. 12.8%, p=0.012). After univariate Cox regression analysis, elevated baseline SCr increased the risk of in-hospital death by almost three-fold (HR 2.99 [CI95% 2.00-4.47], p<0.001). CKD per se is associated with a proinflammatory state, inferring that patients with chronic kidney impairment and COVID-19 might evolve with a more pronounced cytokinetic storm, resulting in more severe systemic inflammation and hypercoagulability, being an important risk factor for acute kidney injury, severe illness, and mortality19.

The prospective analysis performed by Cheng et al. conjectures that previous chronic kidney impairment might have a negative impact on the clinical evolution and fatality risk of COVID-1919. Moreover, an analysis of the international Health Outcome Predictive Evaluation for COVID-19 registry (HOPE-COVID-19) evaluating the impact of renal function on admission and mortality in 758 patients with SARS-CoV-2 infection revealed a CKD prevalence of 8.5% amongst infected patients, and 30.0% had kidney dysfunction upon admission (eGFR <60mL/min/1.73m2)20. Patients were allocated into three groups according to the eGFR upon admission: absence of significant renal failure (eGFR >60mL/min/1.73m2), moderate renal failure (eGFR 30-60mL/min/1.73m2), and severe renal failure (eGFR <30mL/min/1.73m2). Patients with kidney dysfunction upon hospital admission presented a higher incidence of complications such as sepsis (11.9 vs. 26.4 vs. 40.8%, p<0.001) and respiratory failure (35.4 vs. 72.2 vs. 62.0%, p<0.001). Moreover, the incidence of AKI during admission was 19.7%, and patients with more severe kidney dysfunction upon admission were more susceptible for kidney function worsening during hospitalization (eGFR> 60mL/min/1.73m2 = 5.2% vs. eGFR 30-60mL/min/1.73m2= 31.8% vs. eGFR<30mL/min/1.73m2= 56.0%, p<0.001). Kaplan-Meier survival landmark analysis according to GFR demonstrated that the survival probability after 20 days was remarkably lower in patients with eGFR<30mL/min/1.73m2 (22.8%) and eGFR 30-60mL/min/1.73m2 (27.2%) compared to patients with absence of significant renal failure during hospital admission (71.7%). After Cox multivariate regression analysis, worse kidney function during hospital admission was an independent factor for in-hospital mortality as eGFR 30-60mL/min/1.73m2 increased in two-fold the risk of death (HR 2.205 [95%CI 1.573-3.091], p<0.001) and eGFR<30mL/min/1.73m2 increased almost five-fold the risk for in-hospital death amongst COVID-19 patients (HR 4.925 [95%CI 2.152-5.244], p<0.001)20.

Another prospective cohort study including 1,821 patients admitted to a University reference hospital in Spain revealed that 43.5% of patients with elevated SCr levels on hospital arrival had previous history of CKD and that the raw in-hospital mortality rate was higher in patients with increased SCr (32.4%), patients with previous CKD (41.1%), and patients who developed AKI during hospitalization (15.9%) compared to patients with normal SCr (5.8%). Additionally, the Kaplan-Meier analysis of cumulative incidence for in-hospital death revealed that patients with previous history of CKD and patients with elevated SCr levels on admission presented higher 20 day-mortality than patients with normal baseline creatinine. Elevated SCr on hospital admission (HR 4.07 [95%CI 3.07-5.39]) and previous history of CKD (HR 4.17 [95%CI 3.08-5.66]) were also associated with higher in-hospital death in the univariate Cox regression analysis. Thus, these studies accentuate that history of previous kidney impairment during hospital admission seems to be an independent risk factor for worse prognostic, urging that CKD history and kidney function must be screened during triage in patients with confirmed or suspected COVID-1919  21.

In an initial meta-analysis by Henry and Lippi published in March including four studies involving a total of 1,389 patients infected by SARS-CoV-2, the presence of CKD tripled the risk of patients developing severe disease [OR 3.03 (95%CI 1.09-8.47)]. Despite the low heterogeneity between the studies, none specifically evaluated and considered CKD as a pre-existing disease or obtained statistical significance, creating uncertainties about this association22. Nonetheless, the association between CKD and more severe COVID-19 was strengthened and clarified by subsequent studies.

Abrishami et al. in a single-center study evaluating the clinical and radiological characteristics of 43 adult CKD patients with confirmed COVID-19 in Iran, described that patients with CKD are vulnerable to a more severe form of COVID-19 and are predisposed to a higher mortality rate than the general population. The mean age of patients was 60.65±14.36 years and the most frequent CKD stage was IIIa (44.2%) and the least common was stage IV (4.7%), highlighting that amongst the total 43 CKD patients with COVID-19, 38 (88.4%) were discharged and 5 (11.6%) died on follow-up. The most prevalent symptoms were dyspnea (65.1%) and cough (60.5%). Laboratory evaluation revealed that leukopenia, leukocytosis, and thrombocytopenia were observed in 7 (16.3%), 4 (9.3%), and 12 (27.9%) patients, respectively. Moreover, LDH serum levels were significantly higher in CKD patients who died (740.2 ± 452.9 vs. 355 ± 127.5 IU/L). No significant laboratory alteration was observed across the CKD stages (p>0.05). Regarding CT scan findings, bilateral lung involvement was observed in 93.0% of the patients, the most common pattern of lung involvement was ground glass opacification (35.9%) and reticular pattern (16.3%), and the prevalence of pleural and pericardial effusion were 20.0 and 14.0%, respectively. Moreover, ground glass opacification was significantly higher in patients who died in comparison to survivors (60.0% vs. 31.5%). Regarding the analysis by CKD groups, the extent of lung involvement evaluated by total lung score significantly differ (p>0.05). On admission, 58.1% of CKD patients had severe COVID-19 and the mean duration of hospitalization was 11.65± 6.67 days, being more prolonged in patients with stage V CKD (15.4±6.4 days) and patients who died (16.6. ±8.38 days), despite lack of statistical significance (p>0.05)23. Thus, despite a high prevalence of severe disease and high mortality, higher CKD stage was not significantly associated to a worse prognosis23.

HOPE-COVID-19 investigators also demonstrated that from the 758 patients included in the study, patients with poorer kidney function (GFR 30-60mL/min/1.73m2 and GFR <30mL/min/1.73m2) on hospital admission had more adverse clinical manifestations and laboratory findings compared to patients with absence of significant renal failure (GFR >60mL/min/1.73m2)19. Shortness of breath (55.8 vs. 59.8 vs. 67.2%), tachypnea (19.0 vs. 28.1 vs. 39.9%) and, oxygen saturation on admission <92% (30.5 vs. 59.8 vs. 52.8%) were more frequent in patients with lower GFR during hospital admission. Furthermore, regarding laboratory profile, patients with poorer kidney function evolved with more significant D-dimer elevation (61.% vs. 79.% vs. 65.8%), and procalcitonin elevation (19.5 vs. 26.5 vs. 48.7%). More impaired kidney function during hospital admission was associated with a notably higher incidence of AKI (6.7 vs. 43.4 vs. 86.3%) and acute respiratory distress syndrome (ARDS) (35.4 vs. 72.2 vs. 62.0%). The prospective analysis from Spain corroborates these findings as patients with CKD presented increased inflammatory biomarker values such as CRP (113.7 vs. 65.6 mg/L, p=0.009) and ferritin (1132 vs 8721ng/mL, p=0.04), and altered coagulation markers as elevated D-dimer (>1.7mg/dL (%) (56.5 vs. 34.7%, p<0.001) and prolonged activated partial thromboplastin time (46.1 vs. 38.5 s, p<0.001) than non-CKD patients with COVID-1920 , 21.

A nationwide retrospective case-control study including 2,019,961 individuals evaluating the effect of underlying comorbidities on the severity of COVID-19 in Korea reported that CKD and ESKD were associated with severe COVID-19 (OR 2.052-2.178)24. Furthermore, a meta-analysis and systematic review including 34 studies also demonstrated that CKD (OR 3.02 [95%CI 2.23-4.08]) was associated with more severe and fatal outcomes among patients with COVID-1925. Fried et al. in an observational cohort study assessing clinical characteristics and outcomes of 11,271 patients with COVID-19 hospitalized in 245 hospitals across 38 different states in the United States revealed that CKD was associated with a higher need for mechanical ventilation (OR 1.22 [95%CI 1.05-1.43])26. Moreover, a cross-sectional study of 212,802 confirmed COVID-19 cases from Mexico demonstrated that comorbidities such as previous history of CKD increased the severity of COVID-19. The study found a correlation between CKD and a higher risk of hospitalization (OR 2.54 [95%CI 2.36–2.73]), ICU admission (OR 1.12 [95%CI 0.97-1.29]), and endotracheal intubation (OR 1.30 [1.15-1.48])27.

Besides more adverse clinical outcomes and heightened severity, CKD also seems to be associated with a higher mortality in patients with SARS-CoV-2 infection. Williamson et al. recently described the factors associated with COVID-19-related death using primary records of 17,278,392 adults pseudonymously linked to 10,926 COVID-19 related deaths with a secure health analytics platform from NHS England called OpenSAFELY28. The study emphasizes the significance of CKD as an important risk factor for COVID-19 mortality, as estimated hazard ratios from a multi-variable model associated CKD with eGFR 30-60 (HR 1.33 [95%CI 1.28-1.40]) and eGFR <30 (HR 2.52 [95%CI 2.33-2.72]) as a risk factor for mortality in patients with COVID-1928.

A retrospective observational cohort study evaluating the risk factors associated with mortality among 3,988 critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission in the region of Lombardy in Italy revealed a high mortality in patients with CKD. Among the first 1,715 patients, the prevalence of CKD was 3.1% and of 52 patients with CKD admitted to the ICU, 41 died (78.8%) and 11 were discharged from ICU (21.2%). Regarding mortality in the hospital setting, 44 patients with CKD died (84.6%) and 7 were discharged from the hospital (13.5%). Analyzing the full cohort of 3,988 patients, 87 patients had previous history of CKD (2.2%) and 71 with CKD died (81.6%). After univariate analysis, CKD was associated with higher mortality (HR 2.78 [2.19-3.53], p<0.001) in patients with COVID-19 admitted to the ICU29.

An analysis of 3,391 patients positive for COVID-19 in the Mount Sinai hospital in New York demonstrated that without adjusting for age groups, patients with CKD had a higher risk of mortality (RR 2.51 [95%CI 1.82-3.47], p<0.001) and intubation (RR 2.05 [1.40-3.01], p<0.001). Moreover, amongst CKD patients, a significantly higher rate of death was observed in patients with atrial fibrillation (OR 2.13 [95%CI 1.03-4.43]), heart failure (OR 2.09 [1.16-3.77]), and ischemic heart disease (IHD) (OR 2.87 [1.04-3.36])30. Fang et al. in a meta-analysis and systematic review including 61 studies also associated CKD with higher mortality (RR 7.10 [3.14-16.02], p<0.001), increasing by seven-fold the risk of death in patients with SARS-CoV-2 infection31. Thus, CKD seems to be an important risk factor for disease severity and higher in-hospital mortality27  34.

The interaction between SARS-CoV-2 and the RAAS system raised concerns regarding the use of RAAS inhibitors during the COVID-19 pandemic, due to the possibility of enhanced virulence and infectivity, worsening the prognosis of these patients. Nonetheless, despite ACE-2 being later identified as a receptor for SARS-CoV-2 cell invasion, evidence initially suggesting that the use of RAAS blockers might increase the expression of ACE-2 in the heart and kidneys were not confirmed35.

In a retrospective study with 12,594 individuals who underwent COVID-19 tests, the use of RAAS inhibitors was not associated with a higher risk of contamination nor a worse evolution of the disease among patients infected by SARS-CoV-236. In another case-control study, Mancia et al. evaluated the impact of RAAS inhibitors in the severity of the disease in 6,272 patients who tested positive for COVID-19, in comparison with the control group of the target population37. Analogously, no association between the use of these anti-hypertensive agents and a more severe evolution of COVID-19 was demonstrated36 , 37.

Correspondingly, a meta-analysis of the effects of RAAS blockers (ACE inhibitors and angiotensin 2 AT1 receptor blockers) in patients with COVID-19 compared 308 individuals using RAAS blockers and 1,172 individuals undergoing treatment with other antihypertensive drugs38. Severity of disease, risk of hospitalization, and death were the main outcomes of interest assessed. Patients with COVID-19 who were taking RAAS blockers had a lower risk of developing severe illness (44.0%), lower risk of death (62.0%), and reduced hospitalization (19.0%), although reduced hospitalization did not obtain statistical significance38  41.

Therefore, the initial assumption of a potential increase in infectivity and morbimortality in patients with CKD, hypertension, and/or heart failure undergoing treatment with RAAS blockers during the COVID-19 pandemic and the lack of robust scientific data evidencing a deleterious impact, prompted national and international societies to issue positions urging RAAS inhibitors maintenance in patients with formal indication. Additionally, a non-deleterious impact of RAAS blockers in SARS-CoV-2 clinical evolution has been proven by subsequent papers37 , 38 , 42  46.

The BRACE CORONA trial, the first multi-center randomized controlled study evaluating the safety of ACE inhibitors and ARBs on hospitalized patients with mild to moderate COVID-19 in 659 enrolled patients from 29 distinct sites in Brazil, revealed that among patients with COVID-19 infection undergoing chronic ACEi/ARB therapy, suspending ACEi/ARB did not improve the number of days alive and hospital discharge in 30 days (21.9 vs. 22.9, p=0.009), and a similar 30-day mortality rate was observed in COVID-19 patients who continued or suspended ACEi/ARB therapy (2.8 vs. 2.7%, p=0.95), highlighting that there is no clinical benefit from ACEi inhibitor/ARB treatment interruption in hospitalized patients with mild to moderate COVID-1947.

Studies are still required for a better comprehension of the peculiarities, clinical outcomes, and prognosis of non-dialytic CKD patients with COVID-19, elucidating questions about comorbidities as confounding factors and their immunological profile, to obtain the best possible outcomes for these patients. The main findings of studies involving individuals with CKD under conservative treatment are summarized in Table 1.

Table 1

Summary of the major studies regarding CKD under conservative treatment and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Uribarri et al.758Cohort  1.Mortality risk:
  (Kaplan-Meier survival curve):
  -eGFR > 60mL/ min/1.73 m2 = 71.7%
  – eGFR 30-60 mL/ min/1.73 m2 = 27.2%
 HTN (48.9%)– eGFR < 30mL/ min/1.73 m2 = 22.8%
66.0DLP (38.7%)2. Risk factors on admission associated with in-hospital death (multivariate regression):
±18.0DM (21.9%)– Age: (HR 1.034 [CI95%1.021-1.048]; p<0.001)
 CKD (8.5%)– SatO2 <92.0%: (HR 3.310 [2.362-4.369]; p<0.001)
  – eGFR 30-60: (HR 2.205 [1.473-3.091]; p<0.001)
  – eGFR < 30 (HR 4.925 [2.152-5.244]; p<0.001)
Ji et al.219,961Retrospective HTN (22.2%) 
47.05DM (14.2%)1. Severe COVID-19: (multivariate analysis)
±18.0CAD (4.2%)-CKD/ESKD: (OR 2.052-2.178)
 CKD (1.0%) 
Fried et al.11,721Retrospective  1. Severe COVID-19:
 HTN (46.7%)-Mechanical ventilation
> 60DM (27.8 %)(15.2% vs. 11.6%; p<0.001)
(67.3%)CVD (22.6 %)(OR 1.22 [CI95% 1.05-1.43]).
 CKD (4.3%)2.Mortality:
  -CKD (OR 1.66 [CI95% 1.45-1.91]).
Hernández-Galdamez et al.212,802Cross-sectional  1. Severe COVID-19:
  Hospitalization:
 HTN (20.12%)i. CKD (OR 2.54).
45.7DM (16.44%)ii. ICU admission:
±16.3CVD (2.35%)CKD (OR 1.12).
 CKD (2.17%)iii. Intubation:
  CKD (OR 1.30).
  2. Mortality:
  – CKD (OR 2.31).
Williamson et al.17,278,392Cohort18-39 (34.2%)  
40-49 (16.5%) 1.Mortality:
50-59 (17.7%)HTN (34.3%)Kidney function:
60-69 (13.8%)CVD (6.8%)i). eGFR 30-60 (HR 1.33 [1.28-1.40]).
70-79 (11.2%) ii) eGFR <30 (HR 2.52 [2.33-2.72]).
>80 (6.5%)  
Grasselli et al.3,988RetrospectiveHTN (41.2%)1.Mortality:
DM (12.9%)– CKD (OR 2.78 [95%CI 2.19-3.53];p<0.001).
CVD (13.4%)

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DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; DLP, dyslipidemia; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ICU, intensive care unit.

Patients with ckd in dialytic therapy and covid-19

Evidence concerning management of CKD patients on dialysis therapy infected with SARS-CoV-2 is still scarce. While these are high-risk patients due to the presence of comorbidities, especially hypertension, cardiopathies, left ventricular hypertrophy, diabetes mellitus, among others, it is not yet clear if dialysis therapy per se is associated with a worse prognosis in patients infected with SARS-CoV-2, although infections in general can decompensate underlying CKD48  52.

In a recent analysis of 37,852 patients in hemodialysis (HD) in Brazil, 1,291 patients were positive for SARS-CoV-2 infection and 357 patients died. Authors postulate that the incidence, mortality, and fatality rates in HD patients were 341/10,000 patients, 94/10,000 patients, and 27.7%, respectively, raising concerns regarding the vulnerability of this group amid the COVID-19 pandemic53.

Implementing social distancing in patients requiring dialysis is difficult due to need of frequent visits to dialysis clinics and direct contact with special care teams of clinics and hospitals, increasing the risk of COVID-19 dissemination and consequently the vulnerability of this group50 , 51.

Initial Chinese case report studies revealed that patients with CKD on dialysis, presented moderate clinical manifestations, with fever as the most prevalent symptom, whilst only a small group of CKD patients developed cough. A study carried out in Zhongnan hospital, Wuhan, described diarrhea as the most frequent manifestation in these patients52. Another study reported gastrointestinal manifestation as the most important initial complaint among patients on dialysis treatment, and due to the atypical symptomatology, the authors emphasized the importance of individualized patient approach to optimize COVID-19 diagnostic accuracy in this peculiar group with uncertain prognosis52  54.

Authors initially hypothesized that the presence of atypical clinical manifestations and a possible less severe evolution of COVID-19 in CKD patients undergoing dialysis was due to the immunodepression status of these patients, inferring that this group of patients might not develop the usual severe immune dysregulation and consequent cytokinetic storm of critical SARS-CoV-2 infection. This could be due to these patients evolving with more significant lymphopenia and lower serum cytokines when compared to infected patients without history of kidney disease55. Nevertheless, recent retrospective and observational studies with more robust epidemiological and clinical data of COVID-19 patients undergoing dialysis demonstrated an increased risk for adverse clinical outcomes and higher mortality in this group of patients.

Xiong et al., in a retrospective multicenter study evaluating the clinical characteristics of 131 patients undergoing hemodialysis with SARS-CoV-2 infection, revealed that the most common symptoms were fever (51.9%), fatigue (45.0%), cough (37.4%), sputum production (29.0%), and dyspnea (26%). Furthermore, 40 (30.5%) patients evolved with acute organ injury and dysfunction, including 24 (28.2%) with cardiac injury, 16 (15.5%) with liver dysfunction, 16 (13.8%) with ARDS, and 9 (9.6%) with cerebrovascular event. Regarding radiologic findings, the most common abnormalities revealed in CT scans were ground-glass or patchy opacities (82.1%) with bilateral lung involvement (86.7%), but foci of consolidation was uncommon (4.3%). Laboratory data revealed that the median levels of hemoglobin and lymphocytes were 105 x 109 cells/L (IQR 91.0-118.0) and 0.7 x 109 cells/L (IQR 0.5-1.1), respectively, and the majority of the patients had normal white cell and platelet counts56.

ESKD on chronic hemodialysis is also associated with higher short-term mortality, worse clinical evolution, and increased severity. A retrospective cohort study with 114 hospitalized patients on chronic hemodialysis with COVID-19 in New York demonstrated that 13.0% required ICU admission, 17.0% required mechanical ventilation, and in-hospital death occurred in 28.0% of these patients, being 87.0% of those who required ICU care57. Likewise, Valeri et al. retrospectively analyzing the clinical presentation and outcomes of 59 hospitalized patients with ESKD and COVID-19 revealed that 18 patients (31%) died in a median of 6 days after hospital admission, including 75.0% of patients who required mechanical ventilation. Moreover, patients who died presented higher initial median values of white blood cell count (7.5 vs. 5.7 x 1000/µL; p=0.04), lactate dehydrogenase (507 vs. 312 U/L; p=0.04), and C-reactive protein (CRP) (163 vs. 30.3 mg/L; p=0.01) in comparison to survivors58.

Tortonese et al. in a retrospective cohort study describing the demographics and clinical course of 44 patients on maintenance dialysis with COVID-19 in the Paris region also showed a correlation with worse outcomes and higher SARS-CoV-2 infection severity. The main coexisting comorbidities were hypertension (97.7%), dyslipidemia (59.1%), diabetes mellitus (50.0%), and obesity (34.1%), whilst the most prevalent symptoms were fever and chills (79.5%) and cough and shortness of breath (29.5%). Diarrhea, a frequent symptom in preliminary case reports, was present in 13.6% of patients59.

Laboratory evaluation revealed that most dialyzed ESKD patients with COVID-19 during hospitalization presented anemia (77.3%), hyperfibrinogenemia (77.3%), hyperferritinemia (70.5%), increased D-dimer levels (56.8%), lymphopenia (54.5%), and increased CRP levels (52.3%), depicting a more profound inflammatory and thrombotic profile. Moreover, aggravation of hematological and inflammatory markers was more remarkable in patients requiring oxygen therapy. Chest computed tomography scan performed in all 41 patients demonstrated a high prevalence of bilateral ground-glass opacities with or without consolidations (80.5%) and severe radiological findings were present in 31.7% of the cases59.

The retrospective analysis also demonstrated that COVID-19 in dialyzed patients was associated with a higher mortality rate, complications, and prolonged hospitalization. The median duration of hospitalization was 12 days (IQR 7-18) and the median length of stay in ICU was 10 days (IQR 7-21). Concerning severe adverse events, 27.3% of ESKD dialytic patients required mechanical ventilation, 27.3% evolved with ARDS, and 22.7%, with hemodynamic instability. In comparison with non-dialyzed patients, ESKD dialyzed patients presented higher mortality (27.3 vs. 12.9%, p=0.006), increased need for intensive care (34.1 vs. 22.7%, p=0.04) and remarkably higher in-ICU mortality (60.0 vs. 20.7%, p=0.002). After univariate Cox survival analysis, ARDS (HR 4.44 [95%CI 1.40-14.03], p=0.01), neutrophil count ≥10g/L (HR 4.49 [1.34-14.93], p=0.01), thrombocytopenia (HR 6.06 [1.64-22.49], p=0.003), metabolic acidosis (HR 11.18 [1.43-87.51], p=0.02), LDH levels ≥ 2 times the upper normal limit (HR 3.99 [1.26-12.63], p=0.016), blood CRP level ≥ 175mg/L (HR 13.06 [1.68-101.41], p<0.001), and D-dimer level > 4000 U/I (HR 4.44 [1.11-11.03], p=0.03) were associated with higher risk of death, being potential prognostic factors for mortality in hospitalized ESKD dialytic patients with COVID-1959.

A report from the Brescia renal COVID task force on the clinical characteristics and short-term outcomes of hemodialysis patients with SARS-CoV-2 infection also revealed a significant association with disease severity and in-hospital mortality. From a total of 94 patients, 57 (60.0%) required hospitalization after a median time from symptom onset of 4 days (IQR, 1-7) and from positive RT-PCR test results of 4 days (IQR, 1-3). Furthermore, 45 patients (79.0%) developed ARDS and 24 patients (42.0%) died after a median of 9 days (IQR, 7-10) from symptom onset. Among patients who died, the most frequent cause of death was respiratory failure secondary to ARDS (63.05%). Among survivors, 11 patients (19.0%) were discharged after a median of 8 days from admission (IQR, 6.5-13) and 15 days (IQR, 12.5-17.5) from onset of symptoms. After univariate logistic regression analysis, heart failure (OR 6.22 [CI95% 1.85-28.6]; p=0.007), ischemic heart disease (OR 5.61 [1.65-25.9]; p=0.01), fever at disease diagnosis (OR 18.2 [5.6-82.44]; p= 0.000013), shortness of breath at diagnosis (OR 18.17 [4.8-119.5]; p = 0.0002), myalgia or fatigue at diagnosis (OR 5.6 [1.65-25.9]; p = 0.01), infiltrates at the baseline chest X-ray (OR 4.4 [1.67-13]; p = 0.004), higher aspartate aminotransferase levels (OR 2.81 [1.08-7.6]; p= 0.04), and higher C-reactive protein levels (OR 4.68 [1.83-12.7]; p = 0.002) were associated with higher chance of developing ARDS during hospitalization. Additionally, ischemic heart disease (OR 3.11 [1.02-9.6]; p= 0.05), fever at disease diagnosis (OR 18.7 [3.62-343]; p = 0.005), cough at disease diagnosis (OR 3.5 [1.28-9.7]; p= 0.01), shortness of breath at disease diagnosis (OR 5.3 [2-15]; p= 0.001), and higher C-reactive protein level at disease diagnosis (OR 6.0 [2.1-19]; p = 0.001) were associated with higher mortality among hospitalized patients60.

Wang et al. in a retrospective single-center case series study in Zhongnan Hospital of Wuhan University evaluated the clinical outcomes of maintenance hemodialysis patients with COVID-19 and the impact of proactive chest CT scans. From 202 HD patients, 7 (3.5%) were diagnosed with SARS-CoV-2 infection, being 5 patients by RT-PCR and 2 patients diagnosed by RT-PCR as a result of screening 197 asymptomatic HD patients by chest CT scan. Regarding chest CT findings, 13 patients presented ground-glass opacity, but only 2 patients (15.0%) were confirmed to have COVID-19 by RT-PCR. Among the 7 patients with confirmed infection, all of them presented bilateral lung involvement. Lymphocytopenia (86%), elevated LDH (75%), elevated D-dimer (83%), elevated CRP (100%), and elevated procalcitonin (100%) were the most prevalent laboratory findings in infected HD patients. Moreover, 4 patients (57.0%) received oxygen therapy, 1 patient received noninvasive and invasive mechanical ventilation (14.0%), 1 patient developed ARDS (14.0%), and 3 patients died61. Additionally, another retrospective analysis of 31 hemodialysis patients with COVID-19 revealed an association with more severe illness and more adverse outcomes as 58.1% of patients presented organ dysfunction including ARDS (25.8%), acute heart failure (22.6%), and septic shock (16.1%)62. Besides worse clinical outcomes, a retrospective analysis of 14 consecutive patients on HD or with advanced CKD who initiated HD after COVID-19 diagnosis in South Korea demonstrated a prolonged median length of hospital and ICU stay in these patients, being 22.0 days and 6.0 days, respectively63.

The clinical outcomes of patients requiring chronic peritoneal dialysis (PD) associated with SARS-CoV-2 infection is also a concern for nephrologists. Sachdeva et al. in a case series study including 419 hospitalized patients with ESKD, 11 patients were on chronic PD (2.6%). Regarding clinical manifestations, the most prevalent symptoms were fever (64.0%), diarrhea (55.0%), shortness of breath (45.0%), cough (45.0%), and myalgias (36.0%). Majority of the patients presented bilateral opacities (82.0%) during initial chest imaging. Moreover, 3 patients (27.0%) were admitted to the ICU requiring mechanical ventilation. The length of hospital stay ranged from 2 to 23 days with a median of 9 days. Two patients died (18.0%) and 9 were discharged from the hospital (82.0%). Further studies with longer follow-up and a larger population are required for a more precise analysis concerning the clinical outcomes of chronic PD patients with COVID-1964.

Hence, SARS-CoV-2 infection in ESKD patients on maintenance dialysis seems to be associated with worse clinical outcomes, more profound inflammatory and thrombotic profile, more severe radiological findings, prolonged hospitalization, and higher fatality rate57  61 , 63.

Considering the hazardous context of SARS-CoV-2 infection, in order to attenuate the spread of the virus in CKD patients undergoing dialysis, a series of safety measures were adopted by hemodialysis centers and clinics to efficiently operate throughout the pandemic (Table 2)65  72. Nonetheless, Corbett et al. in a cohort study evaluating the epidemiology of COVID-19 in dialysis centers in the United Kingdom revealed that COVID-19 caused an abrupt epidemic in patients and healthcare workers. From the cohort of 1,530 patients with established kidney failure treated with dialysis in satellite units, 300 patients (19.6%) developed COVID-1973. In contrast, a study analyzing the incidence, clinical outcomes, and risk factors for mortality of COVID-19 in the French national cohort of dialysis patients demonstrated that the prevalence of COVID-19 varied from less than 1.0 to 10.0%74. Nevertheless, among 1,621 infected patients, 344 died (20.0%) and 9.0% were admitted to the ICU, highlighting that the mortality of ICU patients was higher compared to patients that did not require intensive care (35.0 vs. 15.5%). Risk factors for infection in dialysis patients were male sex (OR 1.2 [95%CI 1.1-1.4]), diabetes (OR 1.3 [1.1-1.4]), patients in need of assistance for transfer (OR 1.5 [1.3-1.8]), and patients treated in a self-care unit (OR 1.3 [1.0-1.6]). Moreover, at-home dialysis was associated with a lower SARS-CoV-2 infection probability (OR 0.6 [0.4-0.8])74. Despite lower incidence of SARS-CoV-2 infection compared with data from Corbett et al., patients on maintenance dialysis with COVID-19 presented high mortality, being imperative to reinforce health team protection and feasible logistics to secure patient safety and access to this indispensable treatment during this critical period65 , 70  74. High-risk of SARS-CoV-2 transmission, increased rates of hospitalization, and heightened morbimortality associated with ESKD patients on hemodialysis increased the support for home-based dialysis during the COVID-19 pandemic, particularly for PD modality75. The main findings of studies involving individuals with CKD under dialysis treatment are summarized in Table 3.

Table 2

Safety measures for dialysis centers during COVID-19 pandemic

GroupMain recommendations
Hemodialysis patients1. Education
 ✓ Patients should call dialysis clinics beforehand, optimizing specific individualized arrival logistics mitigating COVID-19 risk.
 ✓ Patients should inform healthcare team of the presence of suspected COVID-19 symptoms before arrival.
 ✓ Patients should be instructed on the proper use of PPE.
 ✓ Patients should be instructed to safely self-isolate.
 2. Screening
 ✓ Temperature screening for all patients upon arrival in dialysis clinics, being mandatory before and after sessions.
 ✓ All patients should perform hand hygiene upon arrival in dialysis clinics.
 ✓ All patients should wear personal protective equipment at all times during dialysis sessions.
 ✓ Single use dialyzers of confirmed and/or suspected patients should be disposed.
 ✓ All symptomatic dialytic patients must undergo rt-PCR screening test for COVID-19.
 ✓ Symptomatic patients must be kept in isolation during dialysis sessions (6 ft of separation).
 ✓ Patients with signs of critical infection must be immediately referred to a hospital.
Healthcare team3. Education
 ✓ PPE training for appropriate use.
 ✓ PPE use at all times (isolation gown, gloves, mask, and eye protection).
 ✓ Be vigilant towards COVID-19 symptoms.
 ✓ Implementation of disinfection routine of all dialysis stations.
 ✓ Emphasize and enhance dialytic patient’s knowledge regarding SARS-CoV-2 risks and infectivity.
 ✓ Staying home if symptomatic.
 4. Screening
 ✓ Body temperature measurement and symptom triage before contacting and assisting patients.
 ✓ Symptomatic employees must be isolated and submitted to specific protocol.
 ✓ All symptomatic healthcare workers should undergo rt-PCR screening test before patient assistance.

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PPE: personal protective equipment.

Table 3

Summary of the major studies regarding CKD under dialysis and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Xiong et al.7,154Retrospective  1. Clinical Manifestations:
 CVD (68.7%)-Fever (51.9%), fatigue (45.0%), cough (37.4%), sputum (29.0%), and dyspnea (26.0%).
63.1DM (22.9%)2. Clinical Evolution:
(13.4)COPD (3.8%)-Acute organ dysfunction (30.5%),
 Cancer (1.5%)– Cardiac injury (28.2%),
  – Liver dysfunction (15.5%),
  – ARDS (13.8%).
Fisher et al.114Cohort  1. Severe COVID-19:
 HTN (90.0%)-ICU admission (13.0%).
64.5DM (67.0%)-Mechanical ventilation (17.0%).
(55.0-73.0)CVD (55.0%)2. Mortality:
 Cancer (12.0%)-In-hospital death (28.0%):
  -ICU (87.0%).
  – General floor (19.0%).
Valeri et al.59Retrospective  1.Severe COVID-19:
  – Mechanical ventilation (14.0%).
 HTN (98.0%)2. Mortality:
63.0DM (69.0%)– In-hospital death: (31.0%).
(56-70)CAD (46.0%)– Laboratory profile of patients who died compared to survivors:
 PD (17.0%)– WBC (507 vs. 312 U/L; p=0.04).
  – CRP (163.0 vs. 80.3 mg/L; p=0.01).
  – LDH (507 vs. 312 U/L; p=0.04).
Tortonese et al.44Retrospective  1. Mortality
 HTN (97.7%)Dialyzed x non-dialyzed:
61.0DM (50.0%)1.1 Fatality Rate:
(51.5-72.5)DLP (59.1%)-Patients requiring oxygen therapy: (36.4%); ICU patients: (60.0%); Non-dialyzed patients: (12.9%); Dialyzed patients: (27.3%).
 Obesity (34.1%)1.2 Risk factors for mortality (Multivariate Cox analysis):
  – Cough (HR 5.18); thrombopenia ≤120g/L (HR 10.22); LDH ≥2N (HR 5.97); CRP ≥175mg/L (HR 19.53).
Alberici et al.94Retrospective  1. Risk factors for ARDS:
 HTN (93.0%)-History of IHD (OR 7.5); fever at diagnosis (OR 17.0); Dyspnea at disease onset (OR 20).
72.0DM (43.0%)2. Risk factors for mortality:
(62.0-79.0)CAD (17.0%)– Fever (OR 18.7); cough (OR 4.0); Increased CRP (OR 5.6).
 Cancer (12.0%)
Cécile et al.1,621Cohort  1. Severe COVID-19:
 DM (50.8%)-ICU admission (9.0%).
71.9CAD (27.2%)-Mechanical ventilation (51.0%).
(60.8-81.0)COPD (15.5%)2. Mortality:
 Cancer (9.3%)-Outpatients (8.5%):
  -Hospitalized (22.4%).
  – ICU (34.0% vs. 15.5%).

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DM: diabetes mellitus; HTN: hypertension; CVD: cardiovascular disease; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; PD: pulmonary disease; DLP: dyslipidemia; IHD: ischemic heart disease; ICU: intensive care unit.

Kidney transplant recipients and covid-19

Evidence on the management and prognosis of kidney transplant recipients with COVID-19 is limited to case reports. In the vast majority of cases, the withdrawal or reduction of immunosuppressive therapy and the maintenance or introduction of corticosteroids were advocated, due to their immunomodulatory, anti-inflammatory, and vascular properties, which provide immunological protection to the renal allograft. However, while the ideal time for the reintroduction of immunosuppressive agents is quite uncertain, a prolonged reduction in immunosuppression increases the risk of graft rejection76  84.

Moreover, a significant part of preliminary reports show that kidney transplant recipients with COVID-19 have typical clinical symptoms, with fever and cough being quite recurrent76 , 78 , 84. There are also reports that, in addition to fever and cough, patients presented diarrhea and viral conjunctivitis77 , 85. Another important aspect observed in early case reports concerns radiographic alterations with unilateral or bilateral infiltrates during admission of these patients, of which most require ventilatory support, given the rapid decompensation observed among patients who develop ARDS77  84. Pulmonary complications, infectious or otherwise, are known to be an important cause of morbidity in patients undergoing immunosuppression86.( )It is also important to note that almost all patients in these reports presented comorbidities such as hypertension, diabetes, cancer, obesity, chronic respiratory diseases, and cardiovascular diseases, and some described the development of acute kidney injuries after hospital admission.

Devresse et al. described the clinical outcomes and mortality in a single center case series of 22 cases of COVID-19 in a cohort of 1,200 kidney transplant recipients in Belgium. From a total of 22 patients, 18 (82.0%) required hospitalization, and chest CT scan during admission performed in 15 patients revealed mild involvement in 3 patients (20.0%), moderate involvement in 8 patients (53.0%), severe involvement in 2 patients (13.0%), extensive involvement in 1 patient (7.0%), and critical involvement in 1 patient (7.0%). During hospital admission, the median baseline GFR was 45 (15-95) mL/min/1.73m2, median CRP was 56 (1.5-314) mg/L, and median lymphocyte count was 730 (50-1440)/µL. Moreover, 11 patients required supplemental oxygen therapy and 2 were admitted to the ICU requiring mechanical ventilation. Despite a small number of patients and a short follow-up period, after a period of 18 days, 13 (72.0%) of the 18 patients who required hospitalization were discharged from the hospital after a median of 10 days, however 3 (17.0%) patients were still hospitalized and 2 patients died (11.1%)87.

In another case series study with 12 patients evaluating the clinical course, imaging features, and clinical outcomes of COVID-19 infection in kidney transplant recipients, the most common symptoms were fever (75.0%), cough (75.0%), and dyspnea (41.7%), and only 1 patient had gastrointestinal symptoms. Leukopenia was observed in 4 patients (33.3%), leukocytosis in 1 patient (8.3%), CRP was elevated in 10 patients (83.3%), and creatine phosphokinase was elevated in five patients (55.0%). During hospital admission, mean BUN was 82.9±55.2 mg/dL and creatinine was 2.30±1.09 mg/dL. Initial CT scan on hospital admission revealed bilateral lung involvement in eight patients and unilateral involvement in four patients, the lower lobes were compromised in 11 patients, and a combination of consolidation and ground glass opacities (GGO) was the most prevalent pattern on the chest CT scan (75.05%). The authors postulate that interlobular septal thickening, multilobular patterns, consolidative lesions, and a high score for lung involvement were more prevalent among patients with more adverse outcomes and ARDS. Regarding clinical outcomes, 10 patients were admitted to the ICU, 9 were intubated, and 8 died of severe COVID-19 pneumonia and ARDS. The median length of hospital stay was 15 days (IQR 8.0-1.5) being longer in patients who died (18.0 days, IQR 12.3-21.5)88.

A prospective study assessing the clinical outcomes and the incidence of SARS-CoV-2 infection among 1,216 kidney transplant recipients revealed that patients with kidney transplant have a high risk of severe COVID-19. The most frequent symptoms were fever (77.0%) and cough (58.0%), and 60 patients (91.0%) required hospitalization. Furthermore, 15 patients (22.0%) required mechanical ventilation being transferred to the ICU. Notably, dyspnea was the most frequent symptom in patients admitted to the ICU, being observed in 12 of 15 (80.0%) patients in the invasive mechanical ventilation group compared with 27.0% in the non-invasive group. Also, the majority of patients requiring invasive mechanical ventilation had bilateral and multifocal lung opacities on chest x-ray or CT scan. The mortality rate related to COVID-19 disease in the cohort of kidney transplant population was 1.0%, nonetheless 16 of 66 (24.05%) kidney transplant recipients positive for COVID-19 died. After univariate logistic regression analysis, non-white ethnicity (OR 2.17 [95%CI 1.23-3.78], p=0.007), obesity (OR 2.19 [1.19-4.05, p=0.01), asthma and chronic pulmonary disease (OR 3.09 [1.49-6.41], p=0.002), and diabetes (OR 3.33 [1.92 to 5.77], p<0.001) were independently associated with COVID-19 in kidney transplant recipients89. Caillard et al. in a registry-based observational study including 279 transplant recipient patients with COVID-19 in France demonstrated a high 30-day mortality rate among this patient population (22.8%). Moreover, multivariable analysis identified age >60 years, cardiovascular disease, and dyspnea as independent risk factors for mortality in hospitalized patients90.

Studies are controversial due to their heterogeneity and a large number of confounders that influence the outcome of each case, such as the age of patients, time of transplantation, medications, and comorbidities. The future challenge is to identify the main clinical markers of poor prognosis in patients with kidney transplant, with additional studies with longer follow-up periods and more robust populations of immunosuppressed kidney transplant recipients. Table 4 summarizes the main findings of studies involving kidney transplant recipients.

Table 4

Summary of the major studies regarding kidney transplant recipients and COVID-19

AuthorNDesignAge (years)ComorbiditiesMajor findings
Devresse et al.22Cohort  1. Clinical manifestations: .
 HTN (78.0%)-Fever (78.0%), cough (67.0%), dyspnea (39.0%), digestive symptoms (28.0%), neurologic symptoms (16.0%)
57.0DM (22.0%)2. Radiological presentation on CT:
(41.0-73.0)CVD (22.0%)-Mild (20.0%), moderate (53.0%), severe (13.0%), extensive (7.0%), critical (7.0%).
 Obesity (22.0%)
Abrishami et al.12Case series 0 (14.0%)1. Clinical manifestations:
66.01 (22.0%)
(57.0-76.0)2 (25.0%)-Fever (75.0%), cough (12.0%), dyspnea (41.7%).
 3 (13.0%)2. Radiological presentation on CT:
 >4 (21.0%)– Bilateral involvement (66.7%), GGO (100.0%), consolidation (75.0%), interlobular septal thickening (41.7%).
Elias et al.1216Prospective56.4 ±13.4DM (16.0%)1. Factors associated with COVID-19 in patients with KT (multivariate analysis):
– Non-White ethnicity (OR 2.17 [CI95% 1.23-3.78]; p=0.007), obesity (OR 2.19 [CI95% 1.19-4.05];p=0.01), asthma and COPD (OR 3.09 [CI95% 1.49-6.41; p=0.002), diabetes (OR 3.33 [CI95% 1.92-5.77];p<0.001).
Caillard et al279Observational  1.Clinical manifestations:
  -Symptoms: Fever (80.0%), cough (63.6%), diarrhea (43.5%), dyspnea (40.3%), and anosmia (14.1%).
  2.Laboratory profile:
  -CRP, mg/L (62 [27-144]); procalcitonin, ng/mL (0.20 [0.14-0.48]); lymphocyte count, x109 (0.66 [0.40-0.96]); platelet count, x109/L (178 [145-238); thrombocytopenia, <150 x109/L (54 [29%]); creatinine, µmol/L (176 [131-244]).
  3.Radiographic profile:
 HTN (90.1%)-Lung infiltrates on chest CT were detected in 87.0% of patients.
61.6DM (41.3%)4.Clinical outcomes:
(50.8-69.0)CVD (36.2%)-Complications: Acute kidney injury (43.6%), bacterial coinfection (23.5%), renal replacement therapy (11.1%), viral coinfection (2.1%), fungal coinfection (2.5%).
 Cancer (15.5%)5.Severe COVID-19:
  -Oxygen therapy (72.4%), mechanical ventilation (29.6%), vasopressor support (11.1%).
  -ICU (36.0%); median interval between hospitalization and ICU admission was 4 days [1-25 days].
  Risk factors: >60yr (HR 1.63), BMI>25 kg/m2 (HR 1.80), diabetes (HR 1.73), dyspnea (HR 2.28), fever (HR 1.77), procalcitonin >0.2 (HR 3.19), SatO2 <95.0% (HR 2.47).
  6.Mortality: -30-day mortality rate: 22.8%
  Risk factors: age >60yr (HR 3.81), History of CVD (HR 2.04), dyspnea on hospital admission (HR 2.35).

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DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; BMI, body mass index; COPD, chronic obstructive pulmonary disease; ICU: intensive care unit.Go to:

Conclusion

CKD under conservative treatment or maintenance dialysis seems to be associated with more adverse clinical outcomes, more severe disease, higher mortality, and poorer prognosis in patients with COVID-19 infection. Further studies are still required to elucidate the prognosis and clinical evolution of transplant kidney recipients. History of CKD must be taken into consideration during risk stratification of patients with confirmed or suspected COVID-19. Early detection of kidney abnormalities, optimal hemodynamic support when indicated, and avoiding nephrotoxic drugs with a risk-benefit judgement are essential steps to ensure a better evolution of these patients during hospitalization.Go to:

Acknowledgements

This study was supported by research grants from the Conselho Brasileiro de Desenvolvimento Científico e Tecnológico (CNPq, Distrito Federal, Brazil) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil). The sponsors have no role in study design, data collection and analysis, results interpretation or in preparation, review and approval of the manuscript.Go to:

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Review of COVID-19, part 1: Abdominal manifestations in adults and multisystem inflammatory syndrome in children

Authors: Devaraju Kanmaniraja,a,⁎ Jessica Kurian,a Justin Holder,a Molly Somberg Gunther,a Victoria Chernyak,b Kevin Hsu,a Jimmy Lee,a Andrew Mcclelland,a Shira E. Slasky,a Jenna Le,a and Zina J. Riccia

Abstract

The coronavirus disease 2019 (COVID -19) pandemic caused by the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has affected almost every country in the world, resulting in severe morbidity, mortality and economic hardship, and altering the landscape of healthcare forever. Although primarily a pulmonary illness, it can affect multiple organ systems throughout the body, sometimes with devastating complications and long-term sequelae. As we move into the second year of this pandemic, a better understanding of the pathophysiology of the virus and the varied imaging findings of COVID-19 in the involved organs is crucial to better manage this complex multi-organ disease and to help improve overall survival. This manuscript provides a comprehensive overview of the pathophysiology of the virus along with a detailed and systematic imaging review of the extra-thoracic manifestation of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and features of MIS-C will be reviewed. In Part II, manifestations of COVID-19 in the musculoskeletal, central nervous and vascular systems will be reviewed.

Keywords: Abdominal imaging, COVID-19, Multisystem inflammatory syndrome

1. Abdominal findings of COVID019 in adults

The coronavirus 2019 disease (COVID-19), which originated in Wuhan, China, has quickly become a global pandemic, bringing normal life to a standstill in almost all countries around the world. The severe acute respiratory syndrome coronavirus (SARS-CoV-2) is a novel virus preceded by two other recent coronavirus infections, the severe acute respiratory syndrome coronavirus (SARS-CoV-1) and the Middle Eastern respiratory syndrome coronavirus (MERS–CoV), but it has more far-reaching and devastating consequences. As of March 2021, the COVID-19 pandemic has resulted in over 29 million cases in the United States and over 121 million cases globally. As of April 2021, it is responsible for the deaths of over half a million people in the United States and more than 2 ½ million worldwide [1]. As the disease has evolved over the past year, so has our understanding of the virus, including its pathophysiology, clinical presentation and imaging manifestations. Although COVID-19 is predominately a pulmonary illness, it is now established to have widespread extra-pulmonary involvement affecting multiple organ systems. The SARS-CoV-2 has a highly virulent spike protein which binds efficiently to the angiotensin converting enzyme 2 (ACE2) receptors which are expressed in many organs, including the airways, lung parenchyma, several organs in the abdomen, particularly the kidneys and GI system, central nervous system and the smooth and skeletal muscles of the body [2]. The virus initially induces a specific adaptive immune response, and when this response is ineffective, it results in uncontrolled inflammation, which ultimately results in tissue injury [2].

This article provides a comprehensive review of the pathophysiology and imaging findings of the extra-thoracic manifestations of COVID-19 with the exception of unique cardiothoracic features associated with multisystem inflammatory syndrome in children (MIS-C). In Part I, extra-thoracic manifestations of COVID-19 in the abdomen in adults and the varying features of multisystem inflammatory syndrome in children will be reviewed, with imaging findings summarized in Table 1Table 2 . In Part II, manifestations of COVID-19 in the musculoskeletal system, the central nervous system and central and peripheral vascular systems will be reviewed.

Table 1

Summary of abdominal imaging findings in COVID-19 in adults.

OrganImaging findings
Liver• Hepatomegaly
• Increased or coarsened echogenicity on US
• Hypoattenuation on non-contrast or contrast enhanced CT
• Periportal edema and heterogeneous enhancement on CT
• Loss of signal on opposed-phase sequences on MRI
• Portal vein thrombus
Pancreas• Features of acute interstitial pancreatitis
Biliary Tree• Biliary ductal dilatation
Kidney• Increased or heterogeneous parenchymal echogenicity on US
• Loss of corticomedullary differentiation on US
• Preserved cortical thickness
• Perinephric fat stranding and thickening of Gerota’s fascia on CT
• Wedge shaped perfusion defects on CT or MRI
• Thrombus in the renal artery or vein
Gallbladder• Distension
• Mural edema
• Sludge
• Acalculous cholecystitis
Urinary Bladder• Bladder wall thickening
• Mural hyperenhancement
• Perivesicular stranding
Bowel• Mural thickening
• Ileus
• Fluid-filled colon
• Pneumatosis intestinalis
• Portal vein gas
• Pneumoperitoneum
• Acute mesenteric ischemia
• Vascular occlusion (superior mesenteric artery, superior mesenteric vein, or portal vein)
• Mesenteric fat stranding, ascites
• Active gastrointestinal bleeding (duodenal or gastric ulcer) on CTA
• Clostridium difficile colitis
• Ischemic colitis
Spleen• Wedge shaped perfusion defects on CT or MRI
• Thrombus in the splenic artery or vein

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Table 2

Summary of imaging findings in Multisystem Inflammatory Syndrome in Children.

RegionImaging findings
Cardiothoracic• Bilateral symmetric diffuse airspace opacities with lower lobe predominance on CXR
• Diffuse ground glass opacity, septal thickening, and mild hilar lymphadenopathy on CT
• Bilateral pleural effusions
• Cardiomegaly
• Pericardial effusion
• Myocarditis pattern on cardiac MRI
Abdominal• Mesenteric lymphadenopathy, most common in right lower quadrant
• Mesenteric edema
• Ascites
• Bowel wall thickening
• Ileus
• Hepatosplenomegaly
• Gallbladder wall thickening

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2. Abdominal findings of COVID-19 in adults

2.1. Hepatobiliary derangement

Varying derangements of the liver, biliary system, gallbladder, portal vein and pancreas may occur in COVID-19 with hepatic parenchymal injury and biliary stasis reported with highest frequency. The mechanism of involvement of these structures appears to be multifactorial. The most direct form of injury results from SARS CoV-2 entry into host cells by binding to ACE2 receptors detected in several locations in the hepatobiliary system, including biliary epithelial cells (cholangiocytes), gallbladder endothelial cells and both pancreatic islet cells and exocrine glands [[3][4][5][6]].

2.1.1. Hepatic injury

Direct SARS CoV-2 entry into cholangiocytes may cause liver damage by disrupting bile acid transportation or by triggering acid accumulation resulting in liver injury [7]. Systemic inflammation, hypoxia inducing hepatitis and adverse drug reactions may incite liver injury [8]. Several drugs commonly used to treat COVID-19 patients, including acetaminophen, lopinavir and ritonavir can be hepatotoxic [9]. One study excluding COVID-19 patients receiving hepatotoxic drugs, still found patients with liver injury. Therefore, liver damage in COVID-19 patients is likely not entirely drug-induced but may also be due to acute infection [8,9]. Furthermore, since patients with chronic liver disease such as cirrhosis, autoimmune liver disease and prior liver transplantation are more susceptible to COVID-19 infection [9], underlying conditions may also contribute to liver injury.

The most frequent hepatic derangement is abnormal liver function tests reported in 16–53% of patients [10,11] and including raised levels of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase with mild elevation of bilirubin. The majority of cases are mild and self-limited, with severe liver damage rare [7]. Liver injury is most prevalent in the second week of COVID-19 infection, and has a higher incidence in those with gastrointestinal symptoms and more severe infection [9]. Based on a meta-analysis of hepatic autopsy findings of deceased COVID-19 patients in 7 countries, hepatic steatosis (55%), hepatic sinus congestion (35%) and vascular thrombosis (29%) were the most common [10]. In a retrospective study of abdominal imaging findings of 37 COVID-19 patients, 27% who underwent ultrasound had increased hepatic echogenicity considered to represent fatty liver with elevated liver enzymes being the most frequent indication for ultrasound [4]. It should be noted that since obesity is a major risk factor for severe COVID-19 infection, it might contribute to the frequency of steatosis identified on imaging. In another retrospective abdominal sonographic study of 30 ICU patients with COVID-19, the most common finding was hepatomegaly (56%), with most cases having increased hepatic echogenicity and elevated liver function tests [12]. In the only retrospective case-control study of 204 COVID-19 patients who underwent non-contrast chest CT scan, steatosis was found in 31.9% of cases and only 7.1% of controls [13]. Steatosis was based on a single ROI measurement in the right lobe with an attenuation value ≤ 40 HU. However, underlying risk factors for steatosis such as diabetes, obesity, hypertension and abnormal lipid profile, were not available to exclude preexisting conditions leading to steatosis. Finally, unlike in the spleen and kidney where infarcts are reported in COVID-19, hepatic infarction is not a distinct feature. This is likely due to the liver’s unique dual blood supply.

On imaging the liver may be enlarged. On ultrasound, the liver of patients with abnormal liver function tests may be coarsened and/or increased in echogenicity (Fig. 1Fig. 2 ). On CT scan, the liver may be hypoattenuated on non-contrast or contrast-enhanced exam due to steatosis (Fig. 3 ). Periportal edema and heterogeneity of hepatic enhancement may be seen on contrast-enhanced CT or MRI due to parenchymal inflammation. On MRI, loss of signal on opposed-phase sequences (Fig. 4 ) may be seen due to steatosis and periportal edema may be conspicuous on T2-weighted images or on contrast-enhanced images [7,8,14]. Periportal lymphadenopathy, typical of chronic liver disease, is not reported in COVID-19 [8]. In patients with severe COVID-19 infection, ancillary manifestations of hepatic inflammation and injury, such as parenchymal attenuation changes and abscesses may be seen (Fig. 5 ).

This Article Presents a Detailed Overview with Imaging. To View the Rest of This Analysis Click Here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223038/

Study examines the effects of COVID-19 on human kidney cells

Date: June 10, 2021Source:American Society of Nephrology

Summary:

The virus that causes COVID-19 can infect and replicate in human kidney cells, but this does not typically lead to cell death. Kidney cells that already have features of injury may be more easily infected and develop additional injury.

Researchers have studied human kidney cells in the lab to examine the effects of COVID-19 on kidney health. The findings appear in an upcoming issue of JASN.

Many individuals who develop COVID-19 also experience kidney damage, but it’s unclear if this is a direct result of viral infection or a consequence of another condition or the body’s response to the infection. To investigate, a team led by Benjamin Dekel, MD, PhD (Sheba Medical Center, in Israel) cultivated human kidney cells in lab dishes and infected them with the virus that causes COVID-19.

The researchers found that although the virus that causes COVID-19 could enter, infect, and replicate in human adult kidney cells, this did not typically lead to cell death. Prior to infection, the cells contained high levels of interferon signaling molecules, and the infection stimulated an inflammatory response that increased these molecules. In contrast, infection of kidney cells deficient in such molecules resulted in cell death, suggesting a protective effect.

The cells in these experiments were grown as a three-dimensional spheroid that imitates the healthy kidney or as a two-dimensional layer that mimics the cells of an acutely injured kidney. Cells that mimicked an acutely injured kidney were more prone to infection and additional injury but not cell death.

“The data indicate that it is unlikely that the virus is a primary cause of acute kidney injury seen in COVID-19 patients. It implies that if such injury takes place in the kidney by any cause, the virus might jump on the wagon to intensify it. Therefore, if we’re able to limit the common scenario of acute kidney injury in the first place, then there might be the possibility to minimize potential damage caused by the virus,” Dr. Dekel explained.

Study co-authors from the Sheba Medical Center and the Israel Institute for Biological Research include Dorit Omer, PhD, Oren Pleniceanu, MD, PhD, Yehudit Gnatek, MSc, Michael Namestnikov, Osnat Cohen-Zontag, PhD, Sanja Goldberg, PhD, Yehudit Eden Friedman, MD, Nehemya Friedman, PhD, Michal Mandelboim, PhD, Einat B. Vitner, PhD, Hagit Achdout, PhD, Roy Avraham, PhD, Eran Zahavy, PhD, Tomer Israely, PhD, and Haim Mayan, MD.

Disclosures: Dr. Dekel is a co-founder and shareholder at KidneyCure Ltd.make a difference: sponsored opportunity


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Materials provided by American Society of NephrologyNote: Content may be edited for style and length.

Another Hidden Covid Risk: Lingering Kidney Problems

September 1, 2021in News

Since the beginning of the pandemic, doctors have found that people who become very ill with Covid-19 often experience kidney problems, not just the lung impairments that are the hallmark of the illness.

Now, a large study suggests that kidney issues can last for months after patients recover from the initial infection, and may lead to a serious lifelong reduction of kidney function in some patients.

The study, published Wednesday in the Journal of the American Society of Nephrology, found that the sicker Covid patients were initially, the more likely they were to experience lingering kidney damage.

But even people with less severe initial infections could be vulnerable.

“You see really, across the board, a higher risk of a bunch of important kidney-associated events,” said Dr. F. Perry Wilson, a nephrologist and associate professor of medicine at Yale, who was not involved in the study. “And what was particularly striking to me was that these persisted.”

Kidneys play a vital role in the body, clearing toxins and excess fluid from the blood, helping maintain a healthy blood pressure, and keeping a balance of electrolytes and other important substances. When the kidneys are not working properly or efficiently, fluids build up, leading to swelling, high blood pressure, weakened bones and other problems.

The heart, lungs, central nervous system and immune system can become impaired. In end-stage kidney disease, dialysis or an organ transplant may become necessary. The condition can be fatal.

The new study, based on records of patients in the Department of Veterans Affairs health system, analyzed data from 89,216 people who tested positive for the coronavirus between March 1, 2020, and March 15, 2021, as well as data from 1,637,467 people who were not Covid patients.

Between one and six months after becoming infected, Covid survivors were about 35 percent more likely than non-Covid patients to have kidney damage or substantial declines in kidney function, said Dr. Ziyad Al-Aly, chief of the research and development service at the V.A. St. Louis Health Care System and senior author of the study.

“People who have survived the first 30 days of Covid are at risk of developing kidney disease,” Dr. Al-Aly, a nephrologist, said.

Because many people with reduced kidney function do not experience pain or other symptoms, “what’s really important is that people realize that the risk is there and that physicians caring for post-Covid patients really pay attention to kidney function and disease,” he said.

The two sets of patients in the study differed, in that members of one group had all been infected with Covid and members of the other group may have had a variety of other health conditions. Experts cautioned that there were limitations to the comparisons.

The researchers tried to minimize the differences with detailed analyses that adjusted for a long list of demographic characteristics, pre-existing health conditions, medication usage and whether people were in nursing homes.

Another limitation is that patients in the V.A. study were largely male and white, with a median age of 68, so it is unclear how generalizable the results are.

One strength of the research, experts said, is that it involves over 1.7 million patients with detailed electronic medical records, making it the largest study so far on Covid-related kidney problems.

While the results most likely would not apply to all Covid patients, they show that for those in the study, “there’s a pretty notable impact on kidney health in survivors of Covid-19 over the long term, particularly those who were very sick during their acute illness,” said Dr. C. John Sperati, a nephrologist and associate professor of medicine at Johns Hopkins, who was not involved in the study.

Other researchers have found similar patterns, “so this is not the only study suggesting that these events are transpiring after Covid-19 infection,” he added.

He and other experts said that if even a small percentage of the millions of Covid survivors in the United States developed lasting kidney problems, the impact on health care would be great.

To assess kidney function, the research team evaluated levels of creatinine, a waste product that kidneys are supposed to clear from the body, as well as a measure of how well the kidneys filter the blood called the estimated glomerular filtration rate.

Healthy adults gradually lose kidney function over time, about 1 percent or less a year, starting in their 30s or 40s, Dr. Wilson said. Serious illnesses and infections can cause more profound or permanent loss of function that may lead to chronic kidney disease or end-stage kidney disease.

The new study found that 4,757 Covid survivors had lost at least 30 percent of kidney function in the year after their infection, Dr. Al-Aly said.

That is equivalent to roughly “30 years of kidney function decline,” Dr. Wilson said.

Covid patients were 25 percent more likely to reach that level of decline than people who had not had the illness, the study found.

Smaller numbers of Covid survivors had steeper declines. But Covid patients were 44 percent more likely than non-Covid patients to lose at least 40 percent of kidney function and 62 percent more likely to lose at least 50 percent.

End-stage kidney disease, which occurs when at least 85 percent of kidney function is lost, was detected in 220 Covid patients, Dr. Al-Aly said. Covid survivors were nearly three times as likely to receive the diagnosis as patients without Covid, the study found.

Dr. Al-Aly and his colleagues also looked at a type of sudden renal failure called acute kidney injury, which other studies have found in up to half of hospitalized Covid patients. The condition can heal without causing long-term loss of kidney function.

But the V.A. study found that months after their infection, 2,812 Covid survivors suffered acute kidney injury, nearly twice the rate in non-Covid patients, Dr. Al-Aly said.

Dr. Wilson said the new data supported results of a study of 1,612 patients that he and colleagues conducted that found that Covid patients with acute kidney injury had significantly worse kidney function in the months after leaving the hospital than people with acute kidney injuries from other medical conditions.

In the new study, researchers did not directly compare Covid survivors with people infected with other viruses, like the flu, making it hard to know “are you really any sicker than if you just had another bad infection,” Dr. Sperati said.

In a previous study by Dr. Al-Aly’s team, however, which looked at many post-Covid health issues, including kidney problems, people hospitalized with Covid-19 were at significantly greater risk of developing long-term health problems in virtually every medical category, including cardiovascular, metabolic and gastrointestinal conditions, than were people hospitalized with the flu.

Every type of kidney impairment measured in the new study was much more common in Covid patients who were sicker initially — those in intensive care or who experienced acute kidney injury in the hospital.

People who were less ill during their Covid hospitalization were less likely to have lingering kidney problems, but still considerably more likely than non-Covid patients.

“People who are at highest risk are the people who really had it bad to start with,” Dr. Al-Aly said. “But really, no one is spared the risk.”

The study also found that even Covid patients who never needed hospitalization had slightly higher risk of kidney trouble than the general V.A. patient population. But the risk seemed so small, Dr. Sperati said, that “I don’t know that I would hang my hat on” those results.

Dr. Wilson noted that some Covid patients who did not need hospitalization were nonetheless quite ill, needing to stay in bed for days. He said it’s possible that those were the ones who developed long-term kidney dysfunction, rather than people at the mildest end of the Covid spectrum.

Doctors are unsure why Covid can cause kidney damage. Kidneys might be especially sensitive to surges of inflammation or immune system activation, or blood-clotting problems often seen in Covid patients may disturb kidney function, experts said.

Dr. Sperati said Covid patients in the hospital seemed to have greater need for dialysis, and more protein and blood in their urine, than patients hospitalized with other severe illnesses.

“Covid is probably a little more of a kidney-toxic virus,” Dr. Wilson said. “I do think that the Covid syndrome has some long-term adverse effects on the kidney.”

The post Another Hidden Covid Risk: Lingering Kidney Problems appeared first on New York Times.

How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes

Authors: By Meredith WadmanJennifer Couzin-FrankelJocelyn KaiserCatherine MatacicApr. 17, 2020 , 6:45 PM

On rounds in a 20-bed intensive care unit one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. “They are all COVID positive.”

As the number of confirmed cases of COVID-19 surges past 2.2 million globally and deaths surpass 150,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, its reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.

“[The disease] can attack almost anything in the body with devastating consequences,” says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. “Its ferocity is breathtaking and humbling.”

Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? What explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? “Taking a systems approach may be beneficial as we start thinking about therapies,” says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP).

What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body, especially in the roughly 5% of patients who become critically ill. Despite the more than 1000 papers now spilling into journals and onto preprint servers every week, a clear picture is elusive, as the virus acts like no pathogen humanity has ever seen. Without larger, prospective controlled studies that are only now being launched, scientists must pull information from small studies and case reports, often published at warp speed and not yet peer reviewed. “We need to keep a very open mind as this phenomenon goes forward,” says Nancy Reau, a liver transplant physician who has been treating COVID-19 patients at Rush University Medical Center. “We are still learning.”

The infection begins

When an infected person expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose, according to a preprint from scientists at the Wellcome Sanger Institute and elsewhere. They found that cells there are rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissues vulnerable to infection, because the virus requires that receptor to enter a cell. Once inside, the virus hijacks the cell’s machinery, making myriad copies of itself and invading new cells.

As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus’ new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system doesn’t beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung’s respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts this healthy oxygen transfer. Front-line white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells—pus—behind. This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration (see graphic). Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome (ARDS). Oxygen levels in their blood plummet and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

For More Information: https://www.sciencemag.org/news/2020/04/how-does-coronavirus-kill-clinicians-trace-ferocious-rampage-through-body-brain-toes