The prognostic value of Dickkopf-3 (Dkk3), TGFB1 and ECM-1 in prostate cancer.

Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-ß signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-ß signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression (p < 0.0001) associated with increased DNA methylation in its promoter region (p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours (p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression (p = 0.082). However, while ECM1 showed no association with tumour stage (p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression (p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (p = 0.0266), progression-free survival (p = 0.047) and disease-free (p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (p = 0.00032) and disease-free survival (p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.

Urinary Dickkopf 3 Is Not an Independent Risk Factor in a Cohort of Kidney Transplant Recipients and Living Donors.

Urinary dickkopf 3 (uDKK3) is a marker released by kidney tubular epithelial cells that is associated with the progression of chronic kidney disease (CKD) and may cause interstitial fibrosis and tubular atrophy. Recent evidence suggests that uDKK3 can also predict the loss of kidney function in CKD patients and kidney transplant recipients, regardless of their current renal function. We conducted a prospective study on 181 kidney transplant (KTx) recipients who underwent allograft biopsy to determine the cause, analyzing the relationship between uDKK3 levels in urine, histological findings, and future allograft function progression. Additionally, we studied 82 living kidney donors before unilateral nephrectomy (Nx), 1-3 days after surgery, and 1 year post-surgery to observe the effects of rapid kidney function loss. In living donors, the uDKK3/creatinine ratio significantly increased 5.3-fold 1-3 days after Nx. However, it decreased significantly to a median level of 620 pg/mg after one year, despite the absence of underlying primary kidney pathology. The estimated glomerular filtration rate (eGFR) decreased by an average of 29.3% to approximately 66.5 (±13.5) mL/min/1.73 m2 after one year, with no further decline in the subsequent years. uDKK3 levels increased in line with eGFR loss after Nx, followed by a decrease as the eGFR partially recovered within the following year. However, uDKK3 did not correlate with the eGFR at the single time points in living donors. In KTx recipients, the uDKK3/creatinine ratio was significantly elevated with a median of 1550 pg/mg compared to healthy individuals or donors after Nx. The mean eGFR in the recipient group was 35.5 mL/min/1.73 m2. The uDKK3/creatinine ratio was statistically associated with the eGFR at biopsy but was not independently associated with the eGFR one year after biopsy or allograft loss. In conclusion, uDKK3 correlates with recent and future kidney function and kidney allograft survival in the renal transplant cohort. Nevertheless, our findings indicate that the uDKK3/creatinine ratio has no prognostic influence on future renal outcome in living donors and kidney recipients beyond the eGFR, independent of the presence of acute renal graft pathology, as correlations are GFR-dependent.

Predictive value of glycoprotein DKK3 for early neurological deterioration after ischemic stroke.

OBJECTIVE: To explore the value of serum Dickkopf-3 (sDKK3) in predicting Early Neurological Deterioration (END) and in-hospital adverse outcomes in acute ischemic stroke (AIS) patients. METHODS: AIS patients (n = 200) were included and assessed by the National Institutes of Health Stroke Rating Scale. Serum Dkk3 levels were assessed by ELISA. END was defined as an increase of ≥ 4 points in NIHSS score within 72h. The biological threshold of sDKK3 level and END occurrence were predicted based on X-tile software. Primary outcomes were END and all-cause death, and the secondary outcome was ICU admission during hospitalization. The logistic regression model and Cox risk regression model were applied to evaluate the relationship between DKK3 level and END incidence, all-cause in-hospital mortality, and in-hospital adverse outcomes (ICU admission). RESULTS: During hospitalization, the incidence of END in patients with AIS was 13.0 %, and the mortality rate within 7 days after END was 11.54 % (3/26). In patients below the serum DKK3 cutoff (93.0 pg/mL), the incidence of END was 43.5 % (20/48). Patients with lower sDKK3 levels were associated with a 1.188-fold increased risk of developing END (OR = 1.188, 95 % CI 1.055‒1.369, p < 0.0001). However, there was no significant association with admission to the ICU. sDKK3 below the threshold (93.0 pg/mL) was a risk factor for death. CONCLUSION: Predictive threshold levels of serum DKK3 based on X-tile software may be a potential predictive biomarker of in-hospital END in patients with AIS, and low levels of DKK3 are independently associated with increased in-hospital mortality.

Prognostic Biomarkers and AKI: Potential to Enhance the Identification of Post-Operative Patients at Risk of Loss of Renal Function.

Acute kidney injury (AKI) is a common complication after surgery and the more complex the surgery, the greater the risk. During surgery, patients are exposed to a combination of factors all of which are associated with the development of AKI. These include hypotension and hypovolaemia, sepsis, systemic inflammation, the use of nephrotoxic agents, tissue injury, the infusion of blood or blood products, ischaemia, oxidative stress and reperfusion injury. Given the risks of AKI, it would seem logical to conclude that early identification of patients at risk of AKI would translate into benefit. The conventional markers of AKI, namely serum creatinine and urine output are the mainstay of defining chronic kidney disease but are less suited to the acute phase. Such concerns are compounded in surgical patients given they often have significantly reduced mobility, suboptimal levels of nutrition and reduced muscle bulk. Many patients may also have misleadingly low serum creatinine and high urine output due to aggressive fluid resuscitation, particularly in intensive care units. Over the last two decades, considerable information has accrued with regard to the performance of what was termed "novel" biomarkers of AKI, and here, we discuss the most examined molecules and performance in surgical settings. We also discuss the application of biomarkers to guide patients' postoperative care.

Kidney damage is common after major surgery with a recent study showing almost 1 in 5 patients suffer kidney damage. The usual tests for measuring kidney function are excellent in the outpatient but not so good in acute scenario's. Therefore, there has been a lot of interest in new markers of kidney damage (so-called novel biomarkers) which perform well acutely and allow earlier detection of damage allowing treatment to be started earlier. This article summarises the currently available biomarkers for use post-operatively and points out the different information that can be achieved by using them routinely.

DKK3 expression is associated with immunosuppression and poor prognosis in glioblastoma, in contrast to lower-grade gliomas.

PURPOSE: We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/ß-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/ß-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. METHODS: We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson's correlation analysis to investigate the relationships between Wnt/ß-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. RESULTS: A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/ß-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/ß-catenin pathway might be different between LGG and GBM. CONCLUSION: According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/ß-catenin pathway, between LGG and GBM.

The role of urinary Dickkopf-3 in the prediction of acute kidney injury: a systematic review meta-analysis.

BACKGROUND: To systematically evaluate the diagnostic efficacy of urinary Dickkopf-Related Protein 3 (DKK-3) in acute kidney injury and to explore the clinical application value of urinary DKK-3. METHOD: English databases (PubMed, Embase, Cochrane, and WOS) and Chinese databases (VIP, WanFang data, and China National Knowledge Internet) were screened for relevant papers published before March 12, 2023. After literature screening and data extraction, quality assessment was performed according to the QUADAS-2 scoring system. Then, the combined diagnostic and predictive parameters were calculated using a bivariate mixed effect meta-analysis model. Deek's funnel plot asymmetry test assessed publication bias, and Fagan's nomogram plot was used to verify its clinical utility. RESULT: A total of 5 studies involving 2787 patients were included in this meta-analysis, of which 4 focused on contrast-induced acute kidney injury (CI-AKI) and 1 focused on AKI associated with cardiac surgery. The analysis showed that urine Dickkopf-3 has high diagnostic accuracy for AKI, with a sensitivity of 0.55 (95% CI [0.41, 0.68]), specificity of 0.80 (95% CI [0.70, 0.87]), positive likelihood ratio (PLR) of 2.7 [1.8, 4.1], negative likelihood ratio (NLR) of 0.56 [0.42, 0.75], diagnostic odds ratio (DOR) of 5 [3, 9], and AUC of 0.74 [0.70-0.77]. We did not perform subgroup analyses for predictive value due to the small number of included studies. CONCLUSION: Urinary DKK3 may have limited predictive ability for acute kidney injury, especially for AKI associated with cardiac surgery. Therefore, urinary DKK3 may serve as a potential predictor for AKI. However, clinical studies with larger samples are still needed for validation.

Urinary Dickkopf-3 (DKK3) Is Associated with Greater eGFR Loss in Patients with Resistant Hypertension.

Patients with resistant hypertension (HTN) demonstrate an increased risk of chronic kidney disease and progression to end-stage renal disease; however, the individual course of progression is hard to predict. Assessing the stress-induced, urinary glycoprotein Dickkopf-3 (uDKK3) may indicate ongoing renal damage and consecutive estimated glomerular filtration rate (eGFR) decline. The present study aimed to determine the association between uDKK3 levels and further eGFR changes in patients with resistant HTN. In total, 31 patients with resistant HTN were included. Blood pressure and renal function were measured at baseline and up to 24 months after (at months 12 and 24). uDKK3 levels were determined exclusively from the first available spot urine sample at baseline or up to a period of 6 months after, using a commercial ELISA kit. Distinctions between different patient groups were analyzed using the unpaired t-test or Mann-Whitney test. Correlation analysis was performed using Spearman's correlation. The median uDKK3 level was 303 (interquartile range (IQR) 150-865) pg/mg creatinine. Patients were divided into those with high and low eGFR loss (≥3 vs. <3 mL/min/1.73 m²/year). Patients with high eGFR loss showed a significantly higher median baseline uDKK3 level (646 (IQR 249-2555) (n = 13) vs. 180 (IQR 123-365) pg/mg creatinine (n = 18), p = 0.0412 (Mann-Whitney U)). Alternatively, patients could be classified into those with high and low uDKK3 levels (≥400 vs. <400 pg/mg creatinine). Patients with high uDKK3 levels showed significantly higher eGFR loss (-6.4 ± 4.7 (n = 11) vs. 0.0 ± 7.6 mL/min/1.73 m2/year (n = 20), p = 0.0172 (2-sided, independent t-test)). Within the entire cohort, there was a significant correlation between the uDKK3 levels and change in eGFR at the latest follow-up (Spearman's r = -0.3714, p = 0.0397). In patients with resistant HTN, high levels of uDKK3 are associated with higher eGFR loss up to 24 months later.

Dickkopf-3: An Update on a Potential Regulator of the Tumor Microenvironment.

Dickkopf-3 (Dkk-3) is a member of the Dickkopf family protein of secreted Wingless-related integration site (Wnt) antagonists that appears to modulate regulators of the host microenvironment. In contrast to the clear anti-tumorigenic effects of Dkk-3-based gene therapies, the role of endogenous Dkk-3 in cancer is context-dependent, with elevated expression associated with tumor promotion and suppression in different settings. The receptors and effectors that mediate the diverse effects of Dkk-3 have not been characterized in detail, contributing to an ongoing mystery of its mechanism of action. This review compares the various functions of Dkk-3 in the tumor microenvironment, where Dkk-3 has been found to be expressed by subpopulations of fibroblasts, endothelial, and immune cells, in addition to epithelial cells. We also discuss how the activation or inhibition of Dkk-3, depending on tumor type and context, might be used to treat different types of cancers.

High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/ß-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/ß-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/ß-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/ß-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM.

Dickkopf­3 and ß­catenin play opposite roles in the Wnt/ß­catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis.

Osteoarthritis (OA) is condition which poses a main concern to the aging population and its severity is expected to increase with the increasing life expectancy. In the future, several possible targets for OA treatment need to be defined. Dickkopf­related protein 3 (DKK3) is an atypical member of the Wnt­antagonistic dickkopf­related protein (DKK) family. The availability of research into the role of DKK3 in the abnormal remodeling of subchondral bone in human knee joints is currently limited. Thus, the aim of the present study was the evaluation of DKK3 expression in the abnormal bone remodeling of subchondral bone in human knee OA in order to clarify the role of DKK3 in subchondral bone remodeling and to acknowledge its potential relevance to ß­catenin. In total, 38 specimens were collected from osteotomies of the medial tibial plateau of the human knee. The patient samples were then divided into the normal, mild, moderate and severe symptom groups, according to the Osteoarthritis Research Society International (OARSI) score. Following hematoxylin and eosin (H&E) and Safranin O­fast green staining for alkaline phosphatase (AZO method), changes in the distribution and number of osteocytes in the subchondral bone and the degree of sclerosis of the subchondral bone were observed. Immunohistochemical staining, immunofluorescence, western blot analysis and reverse­transcription quantitative PCR (RT­qPCR) were used for the detection of DKK3 and ß­catenin expression level changes in osteoblasts in the subchondral bone of the medial tibial plateau. H&E and alkaline phosphatase staining revealed that the total number of osteocytes in the subchondral bone increased with the severity of the disease. The samples were also evaluated using Safranin O­Fast Green staining and were attributed a score according to the OARSI scoring system: The scoring number and cartilage damage increased along with OA severity. Immunohistochemistry and immunofluorescence assays demonstrated that ß­catenin expression in osteocytes increased from mild to moderate, whereas DKK3 expression decreased with the development of arthritis from normal, mild to moderate. According to the results of western blot analysis, ß­catenin expression was higher in moderate OA and then decreased in severe OA. On the other hand, the DKK3 levels decreased along with the progression from normal, mild to moderate OA. The results of RT­qPCR demonstrated that ß­catenin and DKK3 gene expression differed with the degree of OA. On the whole, the present study demonstrates that DKK3 and ß­catenin may play opposite roles in OA subchondral bone remodeling.

lnc­MICAL2­1 sponges miR­25 to regulate DKK3 expression and inhibits activation of the Wnt/ß­catenin signaling pathway in breast cancer.

The Dickkopf 3 (DKK3) protein antagonizes the Wnt receptor complex in the Wnt signaling pathway; however, to date, there have been no relevant studies investigating its upstream regulatory mechanism in breast cancer (BC), to the best of our knowledge. The present study aimed to explore whether long non­coding RNA MICAL2­1 (lnc­MICAL2­1) sponged microRNA (miR)­25 to regulate DKK3 and inhibit activation of the Wnt/ß­catenin signaling pathway. The Atlas of non­coding RNA in Cancer database was used to measure the expression levels of lnc­MICAL2­1 and their correlation with DKK3 expression levels. In addition, cell proliferation, invasion and migration were determined following the silencing or overexpression of lnc­MICAL2­1. The binding between lnc­MICAL2­1 and miR­25, or miR­25 and DKK3 was verified using RNA pull­down and dual­luciferase reporter assays. The effects of overexpression or knockdown of lnc­MICAL2­1 on DKK3 expression and the Wnt signaling pathway were further evaluated in a nude mouse xenograft model. The results revealed that, compared with in adjacent normal tissue, the expression levels of lnc­MICAL2­1 were downregulated in BC tissues, and the expression levels of lnc­MICAL2­1 were found to be positively correlated with DKK3 expression. The overexpression of lnc­MICAL2­1 in BC cells upregulated the mRNA expression levels of DKK3 and inhibited their proliferation. Results from the RNA pull­down and dual luciferase reporter assays validated that lnc­MICAL2­1 could bind to miR­25, which targets DKK3. The in vivo experimental data demonstrated that lnc­MICAL2­1 inhibited tumor growth via regulating the Wnt signaling pathway. In conclusion, the findings of the present study highlighted a novel molecular mechanism through which lnc­MICAL2­1 may regulate the DKK3­mediated Wnt signaling pathway in BC, highlighting potential targets for the treatment of the disease.

Association of Urinary Dickkopf-3 with Residual Renal Function Decline in Patients Undergoing Peritoneal Dialysis.

Background and Objectives: Urinary levels of dickkopf-3 (DKK-3) are associated with poor renal survival in patients with non-dialytic chronic kidney disease. However, it remains unknown whether urinary DKK-3 levels can predict residual renal function (RRF) decline in patients undergoing peritoneal dialysis (PD). Therefore, we investigated the correlation between urinary levels of DKK-3 and the subsequent rate of RRF decline in PD patients. Materials and Methods: This study included 36 PD patients who underwent multiple peritoneal equivalent tests during 2011-2021. The relationship between baseline clinical characteristics and the subsequent annual rate of Kt/V decline was investigated. Results: The annual rate of renal Kt/V decline was 0.29 (range: 0.05-0.48), which correlated with renal Kt/V (r = 0.55, p = 0.0005) and 24 h urinary DKK-3 excretion (r = 0.61, p < 0.0001). Similarly, 24 h urinary DKK-3 excretion (ß = 0.44, p = 0.0015) and renal Kt/V (ß = 0.38, p = 0.0059) were independently associated with the annual rate of renal Kt/V decline in multivariate analyses. Conclusions: Urinary DKK-3 assessment may help identify PD patients at a high risk of RRF decline.

Measurement of urinary Dickkopf-3 uncovered silent progressive kidney injury in patients with chronic obstructive pulmonary disease.

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD.

Urinary Dickkopf-3: a new biomarker for CKD progression and mortality.

BACKGROUND: Kidney fibrosis has been reported to be a prognostic factor in chronic kidney disease (CKD) progression. Previous studies have shown that the assessment of urinary Dickkopf-3 (uDKK3), a stress-induced tubular epithelial-derived profibrotic glycoprotein, might be a potential tubulointerstitial fibrosis biomarker and might identify patients at short-term risk of glomerular filtration rate loss. We aim to evaluate uDKK3 as a potential biomarker for progression of CKD in a cohort with various aetiologies of CKD and subsequently in an overt diabetic nephropathy cohort. METHODS: We prospectively studied two independent cohorts comprising a total of 351 patients with Stages 2 and 3 CKD. Combined primary outcome consisted of a 50% increase in serum creatinine, end-stage kidney disease or death. The Progreser cohort included patients with heterogeneous aetiologies and the Pronedi cohort (101 patients) with overt diabetic nephropathy. The median follow-up time was 36 months [interquartile range (IQR) 30-39] and 36 (16-48), respectively. RESULTS: At baseline, median uDKK3 was 2200 pg/mg (IQR 671-7617) in the Progreser cohort and 3042 pg/mg (IQR 661-9747) in the Pronedi cohort. There were no statistically significant differences in the uDKK3 ratio between both cohorts nor between CKD aetiologies. Baseline uDKK3 was significantly higher in patients who reached the primary outcome. In the Cox proportional hazards model, the highest levels of uDKK3 were found to be an independent factor for renal progression in the Progreser cohort {hazard ratio [HR] 1.91 [95% confidence interval (CI) 1.04-3.52]} and in the Pronedi cohort [HR 3.03 (95% CI 1.03-8.92)]. uDKK3 gradually increased in the following months, especially in patients with higher proteinuria. Treatment with renin-angiotensin-aldosterone system blockers did not modify uDKK3 after 4 or 12 months of treatment. CONCLUSIONS: uDKK3 identifies patients at high risk of CKD progression regardless of the cause of kidney injury. uDKK3 might serve as a useful biomarker for kidney disease progression and therefore could be used by clinicians to optimize staging for renal progression and monitor the response to potential treatments.

Precision medicine in diabetic nephropathy and chronic kidney disease.

Progressive chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, CKD leading to uremia can be seen as a systemic disease with a critical impact on virtually all organ systems. Thus it is of particular importance to identify patients with incipient CKD and ongoing CKD progression, but the individual course of CKD is challenging to predict. Patterns of progression in persons with CKD include linear and nonlinear trajectories of glomerular filtration rate (GFR) loss. Kidney function can also remain stable for years, especially in the elderly. In particular, one-fifth of individuals show a substantial GFR decline in the absence of high albuminuria (nonproteinuric CKD), rendering albuminuria less suitable for predicting the progression in such individuals.

Dickkopf 3-a novel biomarker of the 'kidney injury continuum'.

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/ß-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.

Dickkopf-3 in the prediction of contrast media induced acute kidney injury.

BACKGROUND: Dickkopf-3 (DKK3) has recently been discovered as a urinary biomarker for the prediction of acute kidney injury (AKI) after cardiac surgery. This finding needs to be confirmed for AKI in other clinical settings. The present study investigates whether DKK3 can predict contrast-induced AKI (CI-AKI). METHODS: We performed a prospective study in 490 patients undergoing coronary angiography. Primary endpoint was an increase in serum creatinine concentration ≥ 0.3 mg/dl within 72 h after the procedure. DKK3 was assessed < 24 h before coronary angiography. Predictive accuracy was assessed by receiver operating characteristic (ROC) curves. RESULTS: CI-AKI was observed in 30 (6.1%) patients, of whom 27 corresponded to stage I and 3 to stage II according to the Acute Kidney Injury Network (AKIN) criteria. Subjects who developed CI-AKI had a 3.8-fold higher urinary DKK3/creatinine ratio than those without CI-AKI (7.5 pg/mg [interquartile range [IQR] 1.2-1392.0] vs. 2.0 pg/mg [IQR 0.9-174.0]; p = 0.047). ROC analysis revealed an area under the curve (AUC) of 0.61. Among subjects without clinically overt chronic kidney disease (estimated glomerular filtration rate [eGFR] > 60 ml/min, urinary albumin creatinine ratio < 30 mg/g), the DKK3/creatinine ratio was 5.4-fold higher in those with subsequent CI-AKI (7.5 pg/mg [IQR 0.9-590.1] vs. 1.38 pg/mg [IQR 0.8-51.0]; p = 0.007; AUC 0.62). Coronary angiography was associated with a 43 times increase in the urinary DKK3/creatinine ratio. CONCLUSIONS: Urinary DKK3 is an independent predictor of CI-AKI even in the absence of overt chronic kidney disease (CKD). The study thereby expands the findings on DKK3 in the prediction of postoperative loss of kidney function to other entities of AKI.

Dickkopf-3 in Human Malignant Tumours: A Clinical Viewpoint.

Dickkopf-3 (DKK3), also known as REIC, is a secreted glycoprotein. DKK3 is aberrantly expressed in various types of human malignant tumours. Promoter methylation status, intracellular protein expression, and protein expression in tumour vessels are significantly correlated with clinical prognostic factors, including survival. In malignant cells, DKK3 is involved in the induction of apoptosis, inhibition of invasion, and remodelling of tumour vasculature. These activities are carried out via the regulation of the beta-catenin signalling and c-Jun N-terminal kinase-dependent cellular pathway, both of which are critical for carcinogenesis. This review explores the potential value of DKK3 as a clinical biomarker and a therapeutic candidate in human malignancies.

DKK3 attenuates JNK and AP-1 induced inflammation via Kremen-1 and DVL-1 in mice following intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most devastating stroke subtype, with a poor prognosis and few proven treatments. Neuroinflammation is associated with ICH-induced brain injury and unfavorable outcomes. There is growing evidence that Dickkopf (DKK) 3 plays a key role in the adaptive anti-inflammatory and neuroprotective responses following intracerebral hemorrhage. This study aimed to evaluate the protective effects of DKK3 against brain edema and neuroinflammation in a mice model of ICH. METHODS: Male, adult CD1 mice were subjected to sham or ICH surgery using a collagenase injection model. ICH animals received either recombinant DKK3, Kremen-1 siRNA, or DVL-1 siRNA. The neurobehavioral deficits were evaluated at 24 h, 72 h, and 28 days after ICH induction. Western blot and immunofluorescence were employed to examine the expression and localization of DKK3, Kremen-1, Dishevelled-1 (DVL-1), c-JUN N-terminal kinase (JNK), Activator protein-1 (AP-1), cleaved caspase-1, NF-κB, and IL-1ß in the brain. RESULTS: The expression of endogenous DKK3 and DVL-1 was transiently decreased after ICH compared to that in the sham group. Compared to the mice of ICH, exogenous rDKK3 administration reduced the brain water content and affected the neurological functions in ICH mice. Moreover, DKK3 was colocalized with Kremen-1 in microglia. Using a Kremen-1 or DVL-1 siRNA-induced in vivo knockdown approach, we demonstrated that the effects of DKK3 against ICH were mediated, at least partly, by the Kremen-1 and DVL-1 pathways. CONCLUSIONS: DKK3 improves the neurological outcomes, potentially by decreasing JNK/AP-1-mediated inflammation, thereby ameliorating the short- and long-term sequelae after ICH.