DKK3: A novel diagnostic tool for improving the management of CKD patients and thus to mitigate the future burden of CKD

The prevalence of chronic kidney disease (CKD) is relatively high, at approximately 10% of the population, but only relatively few patients have endstage renal disease and require renal replacement therapy.

It is not possible at present to stratify patients reliably according to whether or not their kidney disease is progressing (rapidly). A new biomarker, urinary DKK3, identifies CKD patients at risk of kidney disease progression, regardless of the cause of kidney injury. ‘Therefore, it may be a novel diagnostic tool for improving the management of CKD patients and thus to mitigate the future burden of CKD’. 
 
Although the prevalence of chronic kidney disease (CKD) is relatively high, at approximately 10% of the population, many patients live ‘well’ for a long time with stage-1 to stage-3 restriction of kidney function, with some patients even showing no sign of progression. Markers which stratify high-risk patients, i.e. those whose kidney disease is progressing and who are at high risk of needing renal replacement therapy within a few months or years, would be desirable in order to provide targeted therapy. The current assessment of risk based on deteriorating GFR and albuminuria/proteinuria is somewhat simplistic, in that some patients, e.g. patients with interstitial kidney diseases such as ADTKD (autosomal dominant tubulointerstitial kidney disease), do not experience severe albuminuria/proteinuria at all - even on reaching end-stage renal failure [1-3]. 
 
The pathomorphological correlate of progressive kidney damage is tubulointerstitial fibrosis, the mechanisms of which are the subject of intensive research at present. Damaged cells of renal tubules produce various cytokines which control regenerative processes, on the one hand, but which can also lead to the development of tubulointerstitial fibrosis. Regenerative processes may occur in the early stages of activation, via the well-known Wnt signaling pathway (signaling pathway for cell differentiation and proliferation/regeneration), but continuous Wnt activation is detrimental and induces tubulointerstitial fibrosis [4, 5]. Modulators of the signaling chain include Dickkopf-related (DKK) proteins, which interact with the canonical Wnt signaling pathway. Urinary DKK3 can thus be used as a biomarker for tubular stress and progressing tubulointerstitial fibrosis – and therefore potentially as a marker for distinguishing progressing CKD patients from stable patients. At the ERA-EDTA-congress in Copenhagen, Professor Fliser, Homburg/Saar, Germany, presented the results of a prospective cohort study [7] of patients with various CKD etiologies (N=575) and annual follow-up (2.035 patient years), a prospective clinical trial of patients with biopsy-proven IgA nephropathy (STOP-IgAN trial, N=96) and a cross-sectional general population study (N=481). Median urinary DKK3/creatinine concentration was significantly higher in patients with CKD as compared to the general population (33 [126] vs. 431 [1,388] pg/mg; p<0.0001). Besides, urinary DKK3 concentrations were significantly associated with CKD progression in patients with CKD. Urinary DKK3 >1,000 pg/mg creatinine and >4,000 pg/mg creatinine were associated with a mean annual eGFR decline of 2.4% (95% CI: -4.6 to -0.2%; p=0.007) and 7.6% (95% CI: -10.9 to -4.2%; p<0.001) independent of eGFR and albuminuria. 
 
“These findings show that urinary DKK3 identifies CKD patients at risk for kidney disease progression, regardless of the cause of kidney injury. Therefore, urinary DKK3 might represent a novel diagnostic tool to improve the management of CKD patients and thereby to prevent the major burden of CKD,” explains Fliser, co-author of the study.  
 
A newly developed Dkk3-ELISA test provides relatively simple identification: 1 ml of spot urine (frozen at -20°C, or cooled at 4°C if measurement is performed within 24 hrs) are required to determine Dickkopf-related protein 3 (DKK3). 
 
[1] Eckardt KU, Alper SL, Antignac C et al. Kidney Int 2015; 88(4): 676-83 [2] Porrini E, Ruggenenti P, Mogensen CE et al. Lancet Diabetes Endocrinol 2015; 3(5): 382-91 [3] Perkins BA, Ficociello LH, Roshan B et al. Kidney Int 2010; 77(1): 57-64 [4] Zhou D, Tan RJ, Fu H et al. Lab Invest 2016; 96(2): 156-67 [5] Liu BC, Tang TT, Lv LL et al. Kidney Int 2018; 93(3): 568-79 [6] Federico G, Meister M, Mathow D et all JCI Insight 2016; 1(1): e84916 [7] Stephen Zewinger, Thomas Rauen, Michael Rudnicki et al. DKK3 IN URINE IDENTIFIES PATIENTS WITH PROGRESSIVE CHRONIC KIDNEY DISEASE. ERA-EDTA Congress 2018. Publication Number: LB06 
 
About ERA-EDTA With more than 7,500 members, the ERA-EDTA ("European Renal Association – European Dialysis and Transplant Association") is one of the biggest nephrology associations worldwide and one of the most important and prestigious European Medical Associations. It supports basic and clinical research in the fields of clinical nephrology, dialysis, renal transplantation and related subjects. It also supports a number of studies as well as research groups and has founded a special "Fellowship Programme" for young investigators as well as grant programmes. In order to involve young nephrologists in all its activities, ERA-EDTA has created the "Young Nephrologists’ Platform" (YNP), a very active committee whose board includes members who are 40 years old or younger. In addition, it has established various working groups to promote the collaboration of nephrologists with other medical disciplines (e.g. cardiology, immunology). Furthermore, a "European Renal Best Practice" (ERBP) advisory board was established by the ERA-EDTA to draw up and publish guidelines and position statements. Another important goal of the ERA-EDTA is education: The series of CME courses combined with the annual congress offer an attractive scientific programme to cover the need for continuous medical education for doctors working in the fields of nephrology, dialysis and transplantation. The association’s journals, NDT (Nephrology, Dialysis, Transplantation) and CKJ (Clinical Kidney Journal), are currently the leading nephrology journals in Europe; furthermore NDT-Educational is the online educational journal of the society, with free access for all users, as well as being a very important and useful feature of the NDT-Educational “Literature Review”. The ERAEDTA Registry is a large epidemiologic database comparing countries by assessing nephrology practices throughout Europe. ENP, the European Nephrology Portal, is the latest new initiative of ERA-EDTA, where all those interested in the activities of the Society can find everything that is happening, all in one place. Finally, ERA-EDTA is a member of the European Kidney Health Alliance (EKHA), a consortium of patients, nurses and foundations relating to renal issues that actively interacts with the European Parliament.

www.era-edta.org