January/February 2021

COVID-19’s Effect on Kidney Health
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 14 No. 1 P. 22

This common complication in hospitalized COVID-19 patients can be deadly.

As the COVID-19 pandemic progresses, it’s clear that the disease affects not only the lungs but also other organs, including the kidneys. Several recent studies indicate that acute kidney injury (AKI), a serious and life-threatening condition characterized by a rapid loss of kidney function over a few hours to several days, is a common complication in patients hospitalized with severe COVID-19. These patients frequently require dialysis and are at much greater risk of in-hospital death.

With prompt identification and treatment, kidney damage can often be reversed; however, for a large number of patients, kidney function fails to return to normal by the time of discharge from the hospital. And while the long-term consequences of AKI in these patients is not yet fully understood, there’s great concern that those patients who survive may be at risk of chronic kidney disease, including the need for lifelong dialysis and possible kidney transplant.

Human Coronaviruses
Severe acute respiratory coronavirus 2 (SARS-CoV-2) is the official name of the novel coronavirus that causes COVID-19. The first human coronavirus was identified in the mid-1960s; to date seven have been identified as affecting humans.1 Four of these (229E, NL63, OC 43, and HKU1) cause mild upper respiratory symptoms and are responsible for about 15% of the cases of the common cold.2

SARS-CoV-2, MERS-CoV, which is responsible for Middle Eastern respiratory syndrome, and SARS-CoV, which is responsible for severe acute respiratory syndrome, can cause severe pneumonia with acute respiratory distress syndrome, multiorgan failure, and death.

Spike Proteins
Coronaviruses are named as such due to a “corona,” or crown, of glycoproteins resembling spikes that can be seen through electron microscopes. Researchers from around the world are working to better understand both the structure of the coronavirus and the role of these “spike” proteins.

It’s known that the coronavirus uses its spike proteins to form strong bonds with angiotensin-converting enzyme 2 (ACE2) receptors that are found abundantly throughout the human body, including the kidneys. SARS-CoV-2 has been found to be 10 to 20 times more likely to bind to ACE2 receptors than is the SARS-CoV from 2002 and may be responsible for the highly contagious nature of SARS-CoV-2.3 Once attached to ACE2 receptors, the virus invades and makes copies of itself, which leads to various immune responses that are implicated in COVID-19, causing damage to several organs.

Researchers from the United Kingdom reported that in using an imaging technique known as electron cryo-microscopy to study the molecular structure of SARS-CoV-2, they had unexpectedly found a small “pocket” with linoleic acid (LA) molecules buried inside of the spike proteins.4 They described these LA molecules as being critical to the immune functions that go haywire in COVID-19; according to their data, the coronavirus attaches to LA—basically disarming many of the body’s defenses. They also noted that the rhinoviruses that cause the common cold have a similar pocket.

Drugs that fit into the pocket by mimicking fatty acids such as LA have lessened symptoms in human clinical trials. This suggests that drugs developed to target the pocket on the coronavirus spike protein might help eliminate COVID-19.

Possible Mechanisms of COVID-19–Related AKI
It’s likely that several different mechanisms lead to AKI seen with COVID-19. Some of these include possible direct infection in the kidney, acute tubular necrosis, inflammatory responses, blood clots, and hypoxia.

Direct Infection
Data are conflicting as to whether direct infection of the kidney by SARS-CoV-2 is responsible for AKI; however it’s possible that SAR-CoV-2 binds to ACE2 protein receptors in the kidney, resulting in damage to the kidney directly. Similar damage has been found in the heart, lungs, and brain. Supporting this is an autopsy finding, using light and electron microscopy to examine renal tissue for evidence of SARS-CoV-2 within renal cells, that found the presence of viral particles morphologically identical to SARS-CoV-2.5 And while SARS-CoV-2 was initially not believed to be present in the urine, a newer study describes its successful isolation from the urine of a COVID-19 patient.6

Acute Tubular Necrosis (ATN)
Researchers and doctors from Northwell Heath and the Feinstein Institutes for Medical Research reported that ATN appears to be the most common cause of COVID-19-related severe AKI.7 Their findings were based on clinical and histopathologic findings for 10 hospitalized patients with COVID-19 and AKI who underwent kidney biopsy.

Characteristics of the patients include a mean age of 65 years, and one-half of the patients were female. Of the 10 patients, five patients were Black, three were Hispanic, and two were white. Most of the patients had a history of diabetes mellitus, hypertension, or both. All 10 patients had varying degrees of proteinuria, six had hematuria, and eight required dialysis. Kidney biopsy samples showed varying degrees of acute tubular necrosis in all patients, and one patient also had associated myoglobin cast nephropathy.

Inflammatory Response
Many severe cases and deaths from COVID-19 appear to occur due to an exaggerated inflammatory response that occurs as a result of the body’s own immune system.8 As part of a normal immune response, cells release small proteins called cytokines as part of an inflammatory response and communicate to the immune system the need to fight infection.

For some patients, a cytokine storm can occur, and what begins as a normal immune response to provide protection by destroying the virus ultimately becomes out of control, with healthy kidney tissue being damaged in the process.

Blood Clots
Hypercoagulability leading to blood clots has also been implicated in COVID-19 and is associated with negative outcomes.9 Abnormal clotting can occur and has been seen in large blood vessel clots, including deep vein thrombosis (DVT) in the legs and pulmonary emboli (PE) in the lung; clots in the arteries, causing strokes; and small clots in blood vessels in organs throughout the body.

Early autopsy results are showing widely scattered clots in multiple organs. 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.

Hypoxia
As a result of pneumonia, often resulting in the need for ventilator use in patients with severe COVID-19, too little oxygen reaching the kidney likely plays a role in kidney malfunction and AKI.

Studies Describing AKI Related to COVID-19

Northwell Health Hospitals
A study conducted at 13 Northwell Health hospitals in metropolitan New York describes the presentation, risk factors, and outcomes of hospitalized COVID-19 patients with AKI.10 The study found that AKI occurs frequently among patients with COVID-19 and is associated with a poor prognosis. The researchers noted that AKI occurred early and in temporal association with respiratory failure requiring mechanical ventilation.

A total of 6,447 patients were admitted with COVID-19 between March 1, 2020, and April 5, 2020. Patients younger than 18 and those with end-stage renal disease or with kidney transplant were excluded from the study’s findings. For the study cohort, investigators reviewed the health records of 5,449 patients. Of the patients hospitalized with COVID-19, 1,993 (36.6%) developed AKI, with 46.5% of patients having stage 1 AKI, 22.4% stage 2, and 31.1% stage 3 (increase in stages indicates more severe AKI). Furthermore, 89.7% of patients on mechanical ventilation developed AKI compared with 21.7% of nonventilated patients. Two hundred seventy-six of 285 (96.8%) patients requiring renal replacement therapy were on ventilators.

Of patients who required ventilation and developed AKI, 52.2% had onset of AKI within 24 hours of intubation. Risk factors for AKI included older age, diabetes mellitus, cardiovascular disease, Black race, hypertension, and need for ventilation and vasopressor medications. Among patients with AKI, 694 (35%) died, 519 (26%) were discharged, and 780 (39%) were still hospitalized at the end of the study.

In a second study, researchers examined the outcomes of 9,657 adult COVID-19 patients hospitalized at Northwell Health in New Hyde Park, New York, between March 1, 2020, and April 27, 2020.11 The study’s primary outcome measure was in-hospital death rate for patients hospitalized with COVID-19 and AKI, while secondary outcome measures included patients with COVID-19 and AKI requiring dialysis at discharge and recovery of kidney function.

The study found that about 40% of hospitalized COVID-19 patients older than 18 experienced AKI. The overall incidence rate of AKI was found to be 38.4 per 1,000 patient-days. The in-hospital death rate for COVID-19 patients without AKI was 10.8 per 1,000 patient days compared with 31.1 in those patients with AKI without the need for dialysis and 37.5 for patients who required dialysis. When the researchers adjusted for demographics, comorbidities, and illness severity, the risk of death still remained higher among patients with acute kidney injury.

Among patients with AKI who did not need dialysis, 74% recovered kidney function by the time they were discharged. Among AKI patients who required dialysis, 30.6% still required the therapy after discharge. Chronic kidney disease was the only independent risk factor associated with needing dialysis upon discharge, researchers found.

Montefiore Health System Comparison Study
In a retrospective observational study, researchers evaluated AKI incidence, risk factors, and outcomes for 3,345 adults with COVID-19 and 1,265 without COVID-19 who were hospitalized in one of three tertiary care hospitals (Moses, Wakefield, Weiler) in the Montefiore Health System. The researchers compared those patients with a historical cohort of 9,859 individuals hospitalized a year earlier in the same health system.12 A model to identify predictors of stage 2 or 3 AKI in COVID-19 patients was also developed.

The incidence of AKI was found to be higher among patients with COVID-19 (56.9%) compared with the historical cohort (25.1%). Patients with AKI and COVID-19 were more likely than those without COVID-19 to require renal replacement therapy and were also less likely to recover kidney function. The development of AKI was significantly associated with male sex, Black race, and older age (>50 years). Male sex and being older than age 50 years was associated with a greater need for renal replacement therapy or increased mortality, regardless of COVID-19 status.

Factors that were predictive of stage 2 or 3 AKI included initial respiratory rate, white blood cell count, ratio of neutrophils to lymphocytes, and lactate dehydrogenase level. The authors wrote that vital signs at admission and laboratory data may be useful for risk stratification to predict severe AKI.

Soluble Urokinase Receptor Study
A new study published September 22, 2020, online in the Journal of the American Society of Nephrology found that patients with COVID-19 experience elevated levels of soluble urokinase receptor (suPAR), an immune-derived pathogenic protein that’s strongly predictive of kidney injury. suPAR plays an important role as a regulator of inflammation, immunity, and coagulation. suPAR is produced by cleavage of membrane-bound uPAR in response to inflammatory stimuli such as viruses, as well as in persons with cardiovascular risk factors such as smoking and diabetes mellitus.13

RNA viruses such as HIV and SARS-Cov-2 elicit suPAR response of the innate immune system, leading to a rise in blood suPAR levels and a hyperinflammatory response that may damage kidney cells.

The research team tested suPAR levels of 352 study participants when they were admitted to the hospital for COVID-19 infection. One-quarter of the participants developed AKI while hospitalized, and their median suPAR levels were more than 60% higher than those found in the other participants. The risk of needing dialysis was increased 20-fold in patients with the highest suPAR levels. Overall, median suPAR levels for these study participants hospitalized with severe COVID-19 were almost three times higher than levels seen in healthy people. The researchers found that COVID-19 infected patients who had a suPAR level below 4.6 ng/mL never required dialysis.

This knowledge may provide hospitals an important risk stratification to identify patients at higher risk of severe COVID-19. Furthermore, anti-suPAR mAb (monoclonal antibodies) in experimental models has been able to abrogate the adverse effects of suPAR in the kidneys, and their use is a promising therapeutic target to mitigate AKI.

Possible Kidney Disease Epidemic
The high incidence of AKI and increased mortality rates with COVID-19 is alarming. As a result, steps may be needed to increase public awareness. According to a National Kidney Foundation–Harris Poll Survey on COVID-19 and kidney health, only about 17% of Americans are aware of the risk of developing AKI, as well as the long-term effects of kidney damage, as a result of COVID-19.14 There have also been reports during the current pandemic that there have been inadequate dialysis supplies as well as an insufficient number of health care workers appropriately trained in kidney disease in some areas of the country.

Of additional importance is that while the long-term effects associated with severe COVID-19 are not completely understood, some experts have voiced concern that there may be a new epidemic of patients with chronic kidney disease emerging as a result of COVID-19. Patients who have recovered from AKI related to COVID-19 should be followed by a nephrologist due to their increased risk for chronic kidney disease. Furthermore, it’s important for COVID-19 patients who had blood and/or protein in their urine without AKI to be monitored, as they may also be at an increased risk of developing chronic kidney disease.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Human coronavirus types. Centers for Disease Control and Prevention website. https://www.cdc.gov/coronavirus/types.html. Updated February 15, 2020.

2. Pelczar MJ Jr, Chan ECS, Krieg NR. Microbiology: An Application Based Approach. New Delhi, India: Tata McGraw Hill; 2010:656.

3. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260-1263.

4. Toelzer C, Gupta K, Yadav SKN, et al. Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science. 2020;370(6517):725-730.

5. Farkash EA, Wilson AM, Jentzen JM. Ultrastructural evidence for direct renal infection with SARS-CoV-2. J Am Soc Nephrol. 2020;31(8):1683-1687.

6. Sun J, Zhu A, Li H, et al. Isolation of infectious SARS-CoV-2 from urine of a COVID-19 patient. Emerg Microbes Infect. 2020;9(1):991-993.

7. Sharma P, Uppal NN, Wanchoo R, et al. COVID-19-associated kidney injury: a case series of kidney biopsy findings. J Am Soc Nephrol. 2020;31(9):1948-1958.

8. Adapa S, Chenna A, Balla M, et al. COVID-19 pandemic causing acute kidney injury and impact on patients with chronic kidney disease and renal transplantation. J Clin Med Res. 2020;12(6):352-361.

9. Willyard C. Coronavirus blood-clot mystery intensifies. Nature. 2020;581(7808):250.

10. Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney Int. 2020;98(1):209-218.

11. Ng JH, Hirsch JS, Hazzan A, et al. Outcomes among patients hospitalized with COVID-19 and acute kidney injury [published online September 19, 2020]. Am J Kidney Dis. doi: 10.1053/j.ajkd.2020.09.002.

12. Fisher M, Neugarten J, Bellin E, et al. AKI in hospitalized patients with and without COVID-19: a comparison study. J Am Soc Nephrol. 2020;31(9):2145-2157.

13. Azam TU, Shadid HR, Blakely P, et al. Soluble urokinase receptor (SuPAR) in COVID-19-related AKI. J Am Soc Nephrol. 2020;31(11):2725-2735.

14. COVID-19 patients are becoming kidney patients but most Americans unaware. National Kidney Foundation website. https://www.kidney.org/news/covid-19-patients-are-becoming-kidney-patients-most-americans-unaware. Published May 14, 2020.