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Is There a Link Between COVID-19 and AKI? CME / ABIM

MOC / CE
News Author: Nancy A. Melville; CME Author: Laurie Barclay, MD

Posted: 8/5/2020
Note: This is the forty-fourth of a series of clinical briefs on the coronavirus outbreak. The information on this
subject is continually evolving. The content within this activity serves as a historical reference to the information
that was available at the time of this publication. We continue to add to the collection of activities on this subject
as new information becomes available.

Clinical Context
In the early phases of the COVID-19 pandemic, patients in China and Italy had reported rates of AKI ranging
widely from 0.5% to 29%, although most estimates were in the lower end of this range. In contrast, the rate of
COVID-19--associated AKI among critically ill patients in the intensive care unit in a Seattle hospital was 19%,
as varying definitions of AKI and differences in the populations may partly explain observed differences in rates
of AKI.

Among patients hospitalized with COVID-19, the rate of associated AKI and its course, urine findings,
relationship to respiratory failure, renal replacement therapy (RRT) requirements, risk factors, and outcomes
are still unclear. The goal of this multicenter record review by Hirsch and colleagues was to assess the
presentation, risk factors, and outcomes of AKI in patients hospitalized with COVID-19 between March 1 and
April 5 at 13 academic and community hospitals in metropolitan New York.

Study Synopsis and Perspective

The largest study to date focusing on AKI finds high rates in persons hospitalized with COVID-19, with poor
outcomes. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) scientists call for more
research to better understand the phenomenon.

As a new report shows that more than a third of US patients hospitalized with COVID-19 developed AKI and
nearly 15% of these needed dialysis, experts in the field are calling for more robust research into multiple
aspects of this increasingly important issue.

Among 5449 patients admitted to 13 Northwell Health New York-based hospitals between March and April,
36.6% (1993) of them developed AKI.
Acute kidney injury was strongly linked to the occurrence of respiratory failure and was rarely a severe disease
among patients who did not require ventilation: The rate of kidney injury was 89.7% among ventilated patients
compared with 21.7% among other patients.

Acute kidney injury in COVID-19 was also linked to poor prognosis: 35% of persons who developed AKI had
died by time of publication.

The study represents the largest defined cohort of hospitalized patients with COVID-19 to date with a focus on
AKI, said Jamie S. Hirsch, MD, of the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell,
Great Neck, New York, and colleagues in their article published in the July issue of Kidney International.[1]

The findings track with those of a study of New York hospitals published in the June 6 issue of The Lancet,[2] as
reported by Medscape Medical News. In that dataset, just under a third (31%) of critically ill patients developed
severe kidney damage and needed dialysis.

Both of these studies help solidify the experiences of clinicians on the ground, with many US hospitals in the
early phases of the pandemic underestimating the problem of AKI and having to scramble around to find
enough dialysis machines and dialysate solution to treat the most severely affected patients.

"We hope to learn more about the COVID-19 related AKI in the coming weeks, and that by sharing what we
have learned from our patients, other doctors and their patients can benefit," said senior author of the new
study, Kenar D. Jhaveri, MD. Jhaveri is associated chief of nephrology at the Donald and Barbara Zucker
School of Medicine at Hofstra/Northwell.

The new report also comes as scientists from the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) highlight the importance of AKI as a sequelae of COVID-19 in an editorial in the July issue
of Diabetes Care.[3]

They, too, said it is vitally important to better understand what is happening, as more and more hospitals will
face patients with COVID-19 with this complication.

"The natural history and heterogeneity of the kidney disease caused by COVID-19 needs to be unraveled," one
of the authors, Robert A. Star, MD, director of the division of kidney, urologic, and hematologic diseases,
NIDDK, told Medscape Medical News.

Such research is key because "low kidney function is an exclusion criterion in current studies" examining
antiviral medications in COVID-19, he said.

"Clinical trials are needed to test therapeutic interventions to prevent or treat COVID-19-induced AKI," he
added.

Extremely Ill Patients Develop AKI as Their Condition Deteriorates

Identifying risk factors for the development of AKI in COVID-19 will be critical in helping to shed more light on
diagnostic and predictive biomarkers, Star said.

Hirsch and colleagues said that extremely ill patients often develop kidney failure as their conditions
deteriorate, and this happens quickly.
Indeed, the clearest risk factors for the development of AKI were "the need for ventilator support or
vasopressor drug treatment."

Other independent predictors of AKI were older age, black race, diabetes, hypertension, and cardiovascular
disease (CVD).

Of those patients on mechanical ventilation overall in the study that comprised more than 5000 patients, almost
a quarter (23.2%) developed AKI and needed RRT, which consisted of either intermittent or continuous
hemodialysis.

Star and his fellow editorialists said these numbers are important because of the knock-on effects.

"Hemodialysis in critically ill infected patients is associated with significant clotting complications and mortality
as well as increased infection risk to staff," they pointed out.

Star told Medscape Medical News, "The incidence rate of AKI reported in this study is higher than what had
been previously reported by others in the US and China and may reflect differences in population
demographics, severity of illness, prevalence of comorbidities, socioeconomic factors, patient volume
overwhelming hospital capacity, or other factors not yet determined.

"It may be caused by dehydration (volume depletion), heart failure, the inflammatory response to the virus
(cytokine storm), respiratory failure, clotting of blood vessels (hypercoagulation), muscle tissue breakdown
(rhabdomyolysis), and/or a direct viral infection of the kidney," he said.

Renal Biopsies From Patients With AKI May Help Shed Some Light

The editorialists added that findings from kidney biopsies of patients with COVID-19 with AKI may help shed
some light on this condition.

"While difficult to perform, kidney biopsies from patients with early AKI could help us understand the underlying
pathophysiologies at the cellular and molecular level and begin to target specific treatments to specific
subgroups of patients," they wrote.

The authors noted that, as part of funding opportunities provided by the National Institutes of Health for COVID-
19 research, the NIDDK has published a Notice of Special Interest (NOSI)[4] outlining the most urgent areas in
need of research, with one of the focuses being on the kidney.

"As the research community emerges from the crisis situation, there should be renewed efforts for
multidisciplinary research to conduct integrated basic, translational, and clinical studies aimed at greatly
increasing the knowledge base to understand how both the current COVID-19 threat and future health threats
affect both healthy people and people with chronic diseases and conditions," the editorials noted.

The authors of the Diabetes Care editorial have reported no relevant financial relationships. Jhaveri has
reported being a consultant for Astex Pharmaceuticals.

Study Highlights
 Investigators reviewed health records for all patients hospitalized with COVID-19 between March 1 and
April 5 at 13 academic and community hospitals in metropolitan New York; they excluded children and
adolescents age < 18 years, with end-stage renal disease or with a kidney transplant.
 Of 5449 such patients, 1993 (36.6%) developed AKI defined by Kidney Disease: Improving Global
Incomes (KDIGO) criteria.
 Peak stages of AKI were stage 1 in 46.5%, stage 2 in 22.4%, and stage 3 in 31.1%.
 At the time of AKI development, median urine-specific gravity was high and most patients had urinary
sodium < 35 mEq/L.
 14.3% required RRT; of these, 96.8% were on ventilators.
 AKI occurred mostly in patients with respiratory failure, developing in 89.7% of patients on mechanical
ventilation but in only 21.7% of nonventilated patients.
 Among patients who needed ventilation and developed AKI, 52.2% had AKI onset within 24 hours of
intubation.
 In addition to need for ventilation, risk factors for AKI included older age, male sex, diabetes mellitus,
CVD, black race, hypertension, and use of vasopressor medications, but there was less of an
association with body mass index (BMI).
 Use of blockers of the renin--angiotensin-aldosterone system (RAAS) at hospital admission was not
associated with greater AKI risk.
 Outcomes in patients with AKI were death in 35%, discharge in 26%, and continued hospitalization in
39%.
 Among patients on dialysis, the prognosis was even worse: Of 285 patients, 157 died; 9 were
discharged from the hospital at the time of analysis; and 119 were still hospitalized, of whom 108 were
still receiving RRT.
 According to their findings, the investigators concluded that AKI is common in patients with COVID-19,
occurring early and concurrently with respiratory failure, and that it is associated with poor prognosis.
 The investigators recommended additional research to clarify the causes of COVID-19--associated AKI
and patient outcomes.
 In this large cohort of hospitalized patients at tertiary care and community hospitals, AKI rates were
higher than previously reported in the literature from the United States and China, which may result
from different population demographics, illness severity, comorbidities, socioeconomic factors, hospital
resources, or other undetermined factors.
 In addition, severe (stages 2 and 3) AKI occurred in more ventilated than nonventilated patients
(65.5% vs 6.7%).
 The findings strongly suggest that AKI, particularly when severe, occurs among patients with COVID-
19 who also have respiratory failure.
 The cause of AKI in COVID-19 is still unclear, but the close temporal relationship with respiratory
failure may suggest ischemic acute tubular necrosis, which often accompanies systemic collapse.
 Other possible mechanisms underlying the association include prothrombotic state; high urine-specific
gravity and low urinary sodium, reflecting prerenal states, glomerulonephritis, or acute tubular
necrosis; effects of cytokine storm; volume depletion, heart failure, rhabdomyolysis, and/or direct viral
infection of the kidney.
 Study limitations include observational design precluding causal inferences; potential unmeasured
confounding; reliance on electronic health record systems; inability to generalize the findings to
outpatient settings; and lack of data on baseline chronic kidney disease status.
 An editorial by experts from NIDDK noted the importance of AKI as a complication of COVID-19 and
called for additional research into the natural history of and variation in COVID-19-related renal
disease.
  As renal impairment is typically an exclusion criterion in current trials of antiviral agents in COVID-19,
clinical trials are needed to examine interventions to prevent or treat COVID-19-related AKI.
 The need for RRT in many patients is cause for concern, as this treatment in critically ill patients
infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause significant
thrombotic complications and death and put healthcare workers (HCW) at increased risk for infection.
 Renal biopsies of patients with COVID-19 and AKI may help elucidate the underlying mechanisms and
develop specific treatments targeting specific patient subgroups.
 Multidisciplinary research on COVID-19 should include integrated basic, translational, and clinical
studies to determine how COVID-19 and future pandemics affect healthy people as well as those with
medical comorbidities.

Clinical Implications

 Acute kidney injury is common in patients with COVID-19, occurring early and concurrently with
respiratory failure and associated with poor prognosis, according to a multicenter record review by
Hirsch and colleagues of patients with COVID-19 hospitalized in New York.
 As renal impairment is typically an exclusion criterion in current trials of antiviral agents in COVID-19,
clinical trials are needed to examine interventions to prevent or treat COVID-19--related AKI.
 Implications for the Healthcare Team: The need for RRT in many patients is cause for concern, as this
treatment in critically ill patients infected with SARS-CoV-2 may cause significant thrombotic
complications and death and put HCW at increased risk for infection.

Earn Credit

References

1. Hirsch JS, Ng JH, Ross DW, et al. Acute kidney injury in patients hospitalized with COVID-19. Kidney
Int. 2020;98:209-218. https://www.kidney-international.org/article/S0085-2538(20)30532-9/fulltext.
Accessed May 20, 2020. Article full text.
2. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically
ill adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395:1763-1770.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31189-2/fulltext. Accessed May
20, 2020. Article full text.
3. Cefalu WT, James SP, Star RA. Opportunities for Research for COVID-19 in the Mission of
NIDDK. Diabetes Care. 2020;43:1435-1437.
https://care.diabetesjournals.org/content/early/2020/05/13/dci20-0025.full-text.pdf. Accessed May 20,
2020. Editorial full text.
4. National Institutes of Health (NIH). Notice of Special Interest (NOSI): Limited competition for
emergency competitive revisions for community-engaged research on COVID-19 testing among
underserved and/or vulnerable populations. https://grants.nih.gov/grants/guide/notice-files/not-od-20-
121.html. Released June 12, 2020. Accessed May 29, 2020.