The use of combined biomarkers targeting three main pathophysiologic mechanisms of sickle cell disease (SCD) significantly improved the accuracy of detection of early-stage chronic kidney disease (CKD) compared with the use of a single biomarker, according to data published as a letter in Blood Advances.
CKD is the most common complication of SCD and is largely unrecognized and undetected, according to study researcher Marina Jerebtsova, PhD, of Howard University in Washington, DC. A new panel using combined biomarkers “could potentially improve kidney disease outcomes in [patients with SCD] by early CKD detection and expedited treatment,” Dr. Jerebtsova said.
Kidney diseases are complex and as diverse as cancers. Despite that, clinical assessment of kidney disease relies largely on the testing of serum creatinine and urine albumin levels.
“These non-specific and indirect biomarkers delay detection of kidney injury,” Dr. Jerebtsova said. “Because kidney disease is detected too late in the progression of injury, an effective treatment is challenging to implement.”
Among patients with SCD, CKD results in poor outcomes and a high prevalence of end-stage renal disease.
“Low blood creatinine levels, elevated glomerular filtration rates, and urine concentration defect in [patients with SCD], collectively, make the universal biomarkers unreliable,” Dr. Jerebtsova said. Because of that, specific biomarkers for the detection of early-stage renal disease are needed.
In their study, Dr. Jerebtsova and colleagues tested whether the use of a combination of urinary biomarkers for basic pathologic mechanisms of sickle cell anemia (SCA) improved the accuracy of early detection of CKD among 45 patients with SCA from the University of Illinois at Chicago.
They tested iron homeostasis (ceruloplasmin [CP]), inflammation (orosomucoid [ORM]), and hemoglobin (Hb), individually and in various combinations. These were measured by ELISA and normalized to urinary creatinine. CKD was defined using the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines.
The first analysis looked at each individual biomarker in patients with stage 1 CKD or without CKD, but each had limited utility for CKD detection alone. In contrast, the combination of all three biomarkers significantly improved the Youden indexes from 69.6% (with Hb alone) to 78.1% and significantly increased the area under the curve (AUC; p=0.018). This combination had a sensitivity of 95.5%, a specificity of 82.6%, and a positive predictive value of 79.2%.
Different two-biomarker combinations were then compared against Hb alone or the combination of all three. Hb plus CP and CP plus ORM did not improve Youden indexes but showed trends of improvement for AUC, compared with Hb alone. Hb plus ORM improved the Youden index and AUC. Although not statistically significant, all of the two-biomarker combinations improved the accuracy of stage 1 CKD detection.
When discussing the clinical application of this panel of biomarkers, Dr. Jerebtsova said the development of a simple panel test that includes these biomarkers could facilitate the routine use of multiple biomarkers in clinical settings.
“Identification of specific pathways altered in patients may help to administer specific treatment at the early stages of kidney injury and improve the disease outcome,” Dr. Jerebtsova said. “A multiple biomarker panel might be used as a diagnostic, prognostic, and predictive test for outcome of intervention. The panel of more sensitive and disease-specific biomarkers might decrease the required sample size for trial enrollment, increase statistical power, and reduce trial costs for the development of novel therapeutics.”
The researchers acknowledged several limitations of the study including its small sample size, cross-sectional nature, and the limited number of tested biomarkers. Dr. Jerebtsova said, “Future validation will require a longitudinal study in a larger cohort and a careful comparison with the universal biomarkers of kidney disease.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Sesquen YC, Saraf SL, Gordeuk VR, Nekhai S, Jerebtsova M. Use of multiple urinary biomarkers for the early detection of chronic kidney disease in sickle cell anemia [published online, 2023 Jan 12]. Blood Adv. doi: 10.1182/bloodadvances.2022008006.