DKK3 as a potential novel biomarker in patients with autosomal polycystic kidney disease.

Autor: Arjune S; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany., Späth MR; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany., Oehm S; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Todorova P; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Schunk SJ; Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg/Saar, Germany., Lettenmeier K; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Chon SH; Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany.; Department of Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany., Bartram MP; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Antczak P; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany., Grundmann F; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Fliser D; Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg/Saar, Germany., Müller RU; Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
Jazyk: angličtina
Zdroj: Clinical kidney journal [Clin Kidney J] 2023 Oct 13; Vol. 17 (1), pp. sfad262. Date of Electronic Publication: 2023 Oct 13 (Print Publication: 2024).
DOI: 10.1093/ckj/sfad262
Abstrakt: Backgound: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging-based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future.
Methods: In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction.
Results: ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients ( PKD1 : 2304 ± 5119; PKD2 : 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R 2 of all models examined (∼0.5).
Conclusion: uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractive candidate to improve outcome prediction of ADPKD in the future.
Competing Interests: R.-U.M. was supported by the Ministry of Science North Rhine-Westphalia (Nachwuchsgruppen.NRW 2015-2021), the Marga and Walter Boll Foundation, the PKD Foundation and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy—CECAD, EXC 2030–390 661 388 as well as DFG MU 3629/6-1, DFG DI 1501/9. R.-U.M. is a member of the Scientific Advisory Board of Santa Barbara Nutrients and Chair of the Working Group “Genes & Kidney” (European Renal Association). F.G. was supported by the Köln Fortune Program/Faculty of Medicine, University of Cologne, and the German Research Foundation (GR 3932/2-2). S.A. was supported by the Köln Fortune Program/Faculty of Medicine, University of Cologne, the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and the Fritz-Scheler-Stipendium/KfH Stiftung Präventivmedizin. M.R.S. was supported by the Cologne Clinician Scientist Program (CCSP), Faculty of Medicine, University of Cologne (funded by the German Research Foundation (DFG, FI 773/15-1), Faculty of Medicine, University of Cologne), the Köln Fortune Program, Faculty of Medicine, University of Cologne and the Dr Werner Jackstädt-Stiftung. D.F. is associated with DiaRen UG. We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 491 454 339). The Dept 2 of Internal Medicine received research funding from Otsuka Pharmaceuticals and Thermo Fisher Scientific.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
Databáze: MEDLINE
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