Biomarkers as Predictors of Adverse Kidney Outcomes in COVID-19

Acute kidney injury (AKI), defined using Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria, occurs in 30% to 50% of patients hospitalized with COVID-19. Of the patients with AKI, nearly 20% require dialysis. There are associations between development of clinical AKI during hospital admission and increased need for admission to the intensive care unit, worse short-term mortality, and adverse long-term outcomes. In addition, compared with AKI due to other causes, there may be an association between COVID-19-related AKI and greater long-term decline in kidney function.

Older age, male sex, diabetes mellitus, hypertension, obesity, and heart failure have all been associated with increased risk among patients with COVID-19. Even after adjustment for those risk factors, patients with COVID-19 have a more than 40% higher risk of AKI compared with patients without COVID-19.

In previous studies in other clinical settings of AKI, Steven Menez, MD, MHS, and colleagues identified 26 candidate plasma biomarkers representing different biological pathways of injury, inflammation, and repair. In a recent study, the researchers sought to examine the association of plasma biomarkers with major adverse kidney events (MAKE) and assess the predictive capability of top biomarkers.

The prospective cohort study was designed to test the hypothesis that there would be a strong association between plasma biomarkers and MAKE in the setting of COVID-19, and that the biomarkers would have clinically significant predictive potential. Results of the study were reported in the American Journal of Kidney Diseases [2023;82(3):322-332].

The outcome of interest was MAKE, defined as KDIGO stage 3 AKI, AKI requiring dialysis, or mortality up to 60 days. The study exposure was 26 plasma biomarkers of injury, inflammation, and repair from first available blood samples collected during hospitalization.

The researchers utilized Cox proportional hazards regression to associate biomarker level with MAKE. They also applied the least absolute shrinkage and selection operator (LASSO) and random forest regression for prediction modeling and used time-varying Cox index to estimate model discrimination.

Following application of inclusion and exclusion criteria, the study included samples from 576 patients during hospitalization for COVID-19. On admission, mean patient age was 60.3 years and 42% (n=243) were female. Mean baseline serum creatinine was 0.87 mg/dL and mean admission serum creatinine was 1.23 mg/dL.

Thirty-five percent of the patients (n=203) had diabetes mellitus, 51% (n=293) had hypertension, and 29% (n=168) had obesity, with a body mass index ≥30 kg/m². Thirty-percent of patients (n=52) had baseline chronic kidney disease, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Median length of hospitalization for COVID-19 was 9 days.

Sixteen percent of patients (n=95) experienced MAKE. Of those, 60% (n=57) developed stage 3 AKI, 33% (n=31) required dialysis, and 73% (n=69) died within 60 days. Prior to biomarker measurement, 22% of patients (n=125) were treated with remdesivir, and 24% (n=140) received steroids. Sixty-seven percent of the biosamples were collected within 72 hours of hospital admission; a smaller percentage were collected between 4 and 7 days and later.

There were significant associations between 15 of the 26 candidate biomarkers and MAKE: 11 were associated with increased risk and four with decreased risk. After adjustment for clinical covariates, there was a significant association between each 1-SD increase in log₂-transformed angiopoietin 1, interleukin 13, vascular endothelial growth factor A (VEGFA), and VEGFC and a lower risk of MAKE.

Of the 11 biomarkers associated with increased risk of MAKE, each 1-SD increase in either soluble tumor necrosis factor receptor 1 (sTNFR1) or sTNFR2 was associated with a greater than two-fold higher risk of 60-day MAKE (adjusted hazard ratios, 2.30; 95% CI, 1.86-2.85 and 2.26; 95% CI, 1.73-2.95, respectively).

Results were similar in subgroup analyses in a subgroup of 499 patients whose biosample collection occurred within the first week of admission, with 73 events observed. In a subset of patients who did not receive steroids prior to collection of biosample (n=436), there were 73 events. The strongest associations with MAKE were with sTNFR1 and sTNFR2.

In analyses that limited the outcome to stage 3 AKI or dialysis, the associations between sTNFR1, sTNFR2, and neutrophil gelatinase-associated lipocalin remained the most robust. Similar trends were seen for other biomarkers based on time to MAKE. In an analysis among participants with more than one plasma biomarker measurement prior to the onset of stage 3 AKI (n=70), both sTNFR1 and sTNFR2 increased in those who subsequently developed MAKE compared with those who did not develop MAKE.

The C index of sTNFR1 alone was 0.80 (95% CI, 0.78-0.84) and the C index of sTNFR2 was 0.81 (95% CI, 0.77-0.84). Using all biomarkers, LASSO and random forest regression modeling yielded C indexes of 0.86 (95% CI, 0.83-0.89) and 0.84 (95% CI, 0.78-0.91), respectively.

The researchers cited some limitations to the study, including the lack of a control group of hospitalized patients without COVID-19, and the inability to include other biomarkers such as soluble urokinase plasminogen activator receptor and cystatin-C in the analysis.

In summary, the authors said, “Increased plasma concentrations of sTNFR1 and sTNFR2 are each independently and strongly associated with MAKE in patients hospitalized with COVID-19. In particular, combining clinical variables with either sTNFR1 or sTNFR2 has very strong discrimination for predicting MAKE, and further studies should confirm these findings in COVID-19 and other hospitalized clinical settings to identify high-risk patients. These results support that those with severe disease need postdischarge care, and longer follow-up studies in a larger population are necessary to understand the full spectrum of health consequences from COVID-19.”

Takeaway Points

1. Patients hospitalized with COVID-19 are at increased risk for long-term adverse outcomes, including major adverse kidney events (MAKE).
2. Researchers examined the association between 26 candidate biomarkers with MAKE in hospitalized patients with acute kidney injury related to COVID-19 to examine the predictive value of the biomarkers.
3. There were strong independent associations between both soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 and MAKE in this patient population. Both biomarkers can serve as predictors of adverse kidney outcomes.

Source: American Journal of Kidney Diseases