Markers of Kidney Injury: Proenkephalin A and Uromodulin, but Not Dickkopf-3, Are Elevated in Patients After Hematopoietic Stem Cell Transplantation

Abstract

Kidney injury encompasses a broad spectrum of structural and functional abnormalities, directly associated with stem cell transplantation. Acute kidney injury and chronic kidney disease represent perilous complications of hematopoietic stem cell transplantation (HSCT), with an elevated risk of mortality and progression to end-stage renal disease. The early detection of these complications is, therefore, paramount, and research is increasingly focused on the identification of novel biomarkers of kidney damage. Recently, proenkephalin (PENK), a monomeric peptide that is freely filtered by the glomerulus and thus reflects glomerular filtration very well, has been shown to be an additional useful predictor of the occurrence of acute kidney injury and heart failure. Dickkopf-3 (DKK3) is a glycoprotein secreted by the renal tubular epithelium in response to stress and has been implicated in the development of interstitial fibrosis. It has therefore been evaluated primarily as a marker of fibrosis in chronic kidney disease (CKD), but may also help predict the development of acute kiney injury. Uromodulin is regarded as a renal marker. Previous studies have examined the potential of PENK, DKK-3 and uromodulin as a biomarker in individuals with preserved renal function. However, the urinary levels of PENK, DKK-3 and uromodulin in patients following HSCT have not yet been established. The objective of the present study was to assess urinary PENK, DKK-3, and uromodulin concentrations in patients who had been under ambulatory care of the Hematology, Transplantation and Internal Medicine Department for a minimum of three months following HSCT, and to investigate their correlations with kidney function, as reflected by serum creatinine and eGFR. The study population comprised 80 patients who had undergone allogeneic HSCT for various reasons, primarily hematological malignancies such as acute leukemias and lymphomas. In addition, 32 healthy volunteers were included in order to establish normal ranges for the biomarkers of interest. Urine concentrations of proenkephalin, DKK-3, and uromodulin were evaluated using a commercially available sandwich ELISA immunoassay. Demographic and clinical data were retrieved from the patients' records. Statistical analyses were conducted using XLSLAT 2022 (Lumivero, Denver, CO, USA) and STATISTICAv13.0 (StatSoft, Tulsa, OH, USA). The results showed that PENK and DKK-3 levels were significantly higher in patients after HSCT compared to healthy volunteers. Furthermore, when patients were divided according to kidney function (below and over 60 mL/min/1.72 m²), it was found that the concentration of PENK and DKK-3 were significantly higher in 23 patients with CKD stage 3 relative to patients with eGFR over 60 mL min 1.72 m². In univariate correlations, PENK demonstrated an inverse relationship with eGFR (r: -0.21, p < 0.05), while DKK-3 exhibited no significant correlation with creatinine or eGFR.Patients following allogeneic HSCT, despite having normal or near-normal kidney function, exhibited evidence of kidney injury. However, further research is necessary to ascertain the clinical utility of the novel biomarker.

Keywords: acute kidney injury; biomarkers; chronic kidney disease; hematopoietic stem cell transplantation.

Figure 1

Proenkephalin A—PENK A in the control group and patients after HSCT—hematopoietic stem cell transplantation. Data given are means ± SD. *** p < 0.001.

Figure 2

Dickkopf-3 (DKK-3) in the control group and patients after HSCT—hematopoietic stem cell transplantation. Data given are means ± SD. * p < 0.05.

Figure 3

Uromodulin in the control group and patients after HSCT—hematopoietic stem cell transplantation. Data given are means ± SD. * p < 0.05.

Figure 4

Correlation between PENK A (proenkephalin A) and estimated glomerular filtration rate—eGFR patients after HSCT—hematopoietic stem cell transplantation (shown with blue circles, solid line—mean, dashed lines—coefficient interval).