Acute Kidney Injury in COVID-19 Varies, But It Is Deadly

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The incidence of acute kidney injury (AKI) among patients hospitalized for COVID-19 in China was significantly lower than for similar patients in the United States, a new retrospective study from Wuhan indicates.

However, mortality among patients who do develop AKI following COVID-19 infection — especially if they require dialysis — is much higher in both regions than it is for patients who do not sustain kidney damage, this and other studies consistently show.

In an editorial accompanying the Wuhan study, published in the Clinical Journal of the American Society of Nephrology, Edward Siew, MD, Vanderbilt University Medical Center, and Bethany Birkelo, DO, Veterans Affairs, Nashville, Tennessee, say the Chinese researchers should “be commended” for their contribution to the literature. “The extraction and analysis of data under challenging conditions with several clinical and logistical unknowns are laudable,” they write.

Yet, they add, “Although the findings add important data to the existing knowledge on COVID-19–associated AKI, important knowledge gaps remain.”

“Among these are the need to better understand the factors underpinning individual differences in the risk for AKI. The incidence of AKI in this study was one fifth of that observed in more recent studies of hospitalized patients from Western countries,” they comment.

Do Age, Presence of Comorbidities Explain the Differences?

Digging down, it would appear that age and the presence of comorbidities explain a large part of the variance in AKI incidence rates.

In the group of 1392 COVID-19–infected patients admitted to a tertiary teaching hospital in Wuhan between January 18 and February 28, 2020, only 7% developed AKI during their hospital stay. That said, 72% of patients who developed AKI died in hospital. 

In contrast, among hospitalized patients who did not develop AKI, the mortality rate was only 14%, note Yichun Cheng, MD, of Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China, and colleagues in their article published online September 22 in the Clinical Journal of the American Society of Nephrology.

“Acute kidney injury is a common, serious complication in critically ill patients that is associated with increased mortality, longer hospital stay, and higher medical costs,” the Chinese investigators point out.

Meanwhile, US researchers have updated a prior analysis in which the incidence of AKI was 36.6% among approximately 5500 patients admitted to 13 New York hospitals between March 1 and April 5, 2020, as reported by Medscape Medical News.

At the time of publication, 40% of these patients were still in hospital, “so we didn’t know what happened to them,” second author of the new paper, Jamie Hirsch, MD, told Medscape Medical News.

The incidence of AKI of 39.9% in the larger cohort of 9657 hospitalized patients is similar to the earlier figure. The updated analysis was published online September 19 by Jia H. Ng, MD, MSCE, of the Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York City, and colleagues in the American Journal of Kidney Diseases.

Hirsch said: “There are several factors that we are noticing more and more that contribute to differences in incidence rates, not only in AKI, but also for COVID-19.”

The current analysis from Wuhan, for example, was one of the earlier reports on COVID-19 to come out of China and involved much younger patients than those hospitalized in New York, he noted.

These younger patients, therefore, had far fewer comorbidities than people in New York: “less diabetes, less hypertension and less obesity — which [in any case] are a much bigger problem in the US than in China,” observed Hirsch, who is assistant professor of medicine at the Barbara Zucker School of Medicine.

“The severity of the AKI tracks the severity of COVID-19 in general. Ultimately, the risk factors for the development of AKI were less present in [the Wuhan, China] cohort,” he added

Risk Factors for AKI, Prognosis

One of the interesting aspects of the study by Cheng and colleagues is that they analyzed data from both electronic hospitalization and laboratory databases in Tongji Hospital to identify not just the incidence of AKI in their large COVID-19 cohort, but risk factors, along with patients’ prognosis following onset of AKI versus non-AKI controls.

“AKI was defined as an increase in serum creatinine by 0.3 mg/dL within 48 hours or a 50% increase in serum creatinine from baseline within 7 days according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria,” the authors note.

After detection, the physicians staged AKI based on peak serum creatinine levels.

The mean age of the cohort was 63 years, half were men, and on admission, 25% of patients presented with a fever and 41% had severe COVID-19 infection. Half of the Wuhan cohort had comorbidities on presentation, but rates of chronic disease, especially chronic kidney disease and chronic lung disease, were low.

Of the AKI observed in the study cohort, 40% occurred within 1 week of hospital admission.

On multivariate analysis, factors that increased the risk of AKI by roughly twofold or more included severe infection, higher baseline serum creatinine levels, lymphopenia, and elevated D-dimer levels (Table).

Table. Factors Associated With Higher Risk of AKI (Wuhan Cohort)

Risk Factor Odds Ratio 95% CI
Severe infection 2.25 1.37-3.67
Higher baseline serum creatinine 2.19 1.17-4.11
Lymphopenia 1.99 1.12-3.53
Elevated D-dimer levels 2.68 1.07-6.70

 

Patients with AKI were more likely to be in the intensive care unit (ICU), at 75%, compared with only 5% of patients who did not experience AKI, investigators note.

A large proportion of patients who required mechanical ventilation also developed AKI, at 56%, while a higher proportion of patients who received vasopressor therapy, at 76%, developed AKI compared with only 9% of those who did not.

And more patients who developed AKI also required treatment with extracorporeal membrane oxygenation, at 6%, compared with only 0.4% of those who did not develop AKI.

Only 15% of those who developed AKI required dialysis during hospitalization, but of the handful of patients with AKI who survived to discharge, 68% recovered from their kidney injury.

Predictably, in-hospital mortality rates rose as kidney injury became more severe, with 62%, 77%, and 80% of patients with AKI stage 1, stage 2, and stage 3 dying in hospital, respectively.

In contrast, only 23% of patients who developed AKI stage 1 and did not require admission to ICU or mechanical ventilation died in hospital, Cheng and colleagues note.

After adjustment for age, sex, and all other AKI risk factors identified in the study, multivariate analysis showed AKI was associated with an over fivefold greater risk of in-hospital death, at an odds ratio of 5.1.

The authors suggest that, to help prevent poor outcomes in patients with COVID-19, “frequent monitoring of serum creatinine should be encouraged, especially [during] the early period of hospitalization.”

“To our knowledge, this is the first study exploring risk factors for AKI in patients with COVID-19 [and we found] that COVID-19 patients with AKI demonstrated an extremely poor prognosis,” they conclude.

New York Study Conducted at Peak of Pandemic

Hirsch says his new study shows that older age continues to be a very strong risk factor for the development of AKI, as are comorbidities. And these same risk factors are also associated with severity of COVID-19 infection.

Patients needing mechanical ventilation for respiratory failure, for example, develop AKI at much higher rates than those who do not need ventilation. And among patients with AKI who required dialysis, 91% needed both mechanical ventilation and treatment with vasopressors.

“Clearly, patients who have AKI and who require dialysis are the sicker patients,” Hirsch reaffirmed, “and while the kidney injury is being caused by the severity of the illness, having the kidney injury also confers an additional risk [of death],” he noted.

The latest New York data show, even after adjustment for demographics, comorbidities, and illness severity, that the risk of in-hospital mortality was 3.4 times higher, at 46.4%, among patients who developed AKI but who did not require dialysis compared with those who did not develop AKI at all, among whom only 7.3% died in hospital.

When patients with AKI did require dialysis, the adjusted risk of death was 6.4 times higher, at 79.3%, than it was in the non-AKI group, the authors point out.

Patients who developed AKI and needed dialysis had a median length of stay of almost 1 month compared with only about 5 days for patients who did not develop AKI.

And, importantly, among dialyzed patients who survived their AKI episode, 30.6% remained on dialysis following hospital discharge.

But Hirsch emphasized their analysis was a retrospective, observational study conducted in metropolitan New York at the peak of the COVID-19 pandemic.

And even within New York, itself, “mortality rates there are changing over time because now a lot of patients who are being affected by COVID-19 are younger because they are not being careful, while older patients are hunkering down and staying safe,” he pointed out.

At the same time, hospitals — at least in New York — are less overwhelmed than they were earlier this year, and clinicians are better at treating COVID-19, with more widespread use of steroids, different oxygenation strategies, and even the simple act of positioning patients differently, all of which are helping to improve outcomes.  

“If you look at what would happen today, say in…September, we may well see lower hospitalization rates, AKI rates, and mortality rates than we saw in March and April where our data came from,” Hirsch predicted.

“[The data we analyzed] may not be representative of later outcomes due to changes in resource capacity, patient characteristics, treatment protocols, and therapeutic refinements.”

Still Much to Learn

In their editorial, Siew and Birkelo say a clear explanation is still “lacking” for why the development of AKI in COVID-19 has a “strikingly high mortality rate.”

These rates are “higher than even observed in critically ill non-COVID-19 populations,” they note, adding that AKI, in the setting of COVID-19, “may be a marker of a more ominous systemic process.”

In summary, they write, “the last few months have informed us that the effect of COVID-19 on kidney health is significant and varied. With a staggering amount remaining to be learned, taking up this gauntlet will require leveraging the tools developed over the past two decades to refine our phenotyping of AKI in this disease, understand its molecular mechanisms, identify modifiable risk factors and novel treatments, and reduce the long-term implications on kidney health.

“The global effort mobilized to date from clinicians, investigators, and trainees has been remarkable and provides optimism that the nephrology community can meet this challenge and provide valuable insights relevant to both COVID-19–associated AKI and the AKI field as a whole,” they conclude.

The Wuhan, China study was funded by the National Natural Science Foundation of China, among other national research and development programs. No funding source was noted for the New York study. Chinese researchers and Hirsch have reported no relevant financial relationships.

Clin J Am Soc Nephrol. Published online September 22, 2020. Full text, Editorial

Am J Kidney Dis. Published online September 19, 2020. Full text

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