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BACKGROUNDWhile urinary biomarkers show promise in predicting diabetic kidney disease (DKD) progression, distal tubular markers remain understudied. We investigated the association of distal tubule markers, epidermal growth factor (EGF) and uromodulin (UMOD), with DKD progression in the Veterans Affairs Diabetes in Nephropathy (VA NEPHRON-D) clinical trial. We used Cox regression models to evaluate the association between each biomarker and DKD progression and the relationship between change over time in biomarker and DKD progression. We used mixed models to investigate biomarker levels at baseline, 12 months, and over time and their relationships with longitudinal eGFR change. Participants (n = 1,116) had type 2 diabetes, urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g, and eGFR 30-89.9 mL/min/1.73 m2. Mean age was 65 years, mean eGFR was 56 (SD 19) mL/min/1.73 m2, and median UACR was 840 (IQR 424-1,780) mg/g. One hundred forty-four participants (13%) had DKD progression over a median follow-up of 2.2 (1.3-3.1) years. Higher baseline EGF and UMOD were independently associated with a lower risk of DKD progression (adjusted HR 0.68, 95% CI 0.47, 0.99 and 0.85, [0.75, 0.98] per 2-fold higher concentration of EGF and UMOD, respectively). Serial biomarker measurements were performed at baseline and 12 months, and a slower decline in biomarkers was associated with a lower risk of DKD progression when adjusted for baseline biomarker levels. Urinary EGF and UMOD may serve as valuable prognostic biomarkers in DKD. gov NCT00555217. NIH U01DK102730, U01DK103225, K23 DK118198, R01DK137087, U01DK103225, R37DK039773, U01DK114866, U01DK106962, U01DK129984, and R01DK093770; National Institute of Diabetes and Digestive and Kidney Diseases contract U01DK106965.

Epidermal growth factor (EGF) stimulates cell proliferation and differentiation after binding to its receptor. Next to its role in magnesium homeostasis, EGF disturbances have been described in oncology, diabetes and autism spectrum disorders. The aim of this study was to determine EGF serum and urine values for both healthy children and adults. Next, we investigated the relation between several variables and urinary and serum EGF concentrations. Both healthy adults (n = 50) and children (n = 78) were included. Serum and urinary EGF concentrations were measured with ELISA technology. Serum EGF was inversely correlated with age (r = -0.873; p<0.001) and positively correlated with serum magnesium (r = 0.597; p<0.001). The urinary EGF was also inversely correlated with age (r = -0.855; p<0.001). In adults and children older than 13 years of age, the urinary EGF significantly differed between sexes (p = 0.001). Urinary EGF was positively correlated with serum magnesium (r = 0.583; p<0.001) and creatinine clearance (r = 0.524; p<0.001) and negatively correlated with the fractional excretion of magnesium (r = 0.248; p = 0.014). In a multivariate model, age and serum magnesium remained independently related to serum EGF while age, serum EGF and serum magnesium remained independently related to urinary EGF. This study provides valuable insights in urinary and serum EGF patterns in healthy subjects. By systematically correcting EGF for body surface, significant correlations with age, gender and magnesium were observed.

Approximately one in five patients undergoing coronary artery bypass graft (CABG) surgery will develop post-operative acute kidney injury (AKI). We sought to determine whether biomarkers of kidney tubule dysfunction and injury are associated with long-term risk of acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery. We performed a cohort study using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS), a national, population-based, longitudinal cohort study of 30,239 U.S. adults aged ≥45 years. Of 760 REGARDS participants who underwent CABG surgery after their REGARDS baseline visit, we excluded those with a history of dialysis or kidney transplant, missing laboratory data or with illegible or erroneous records, leaving 394 in the analysis. Exposures included urinary biomarkers of kidney tubule dysfunction (urine alpha-1 microglobulin [A1M], uromodulin [UMOD] and epidermal growth factor [EGF]) and injury (kidney injury molecule-1 [KIM-1]), measured at an average of 5.5 years before CABG surgery. The primary outcome was AKI development following CABG surgery, defined as an increase in serum creatinine ≥0.3 mg/dL from 48 hours prior to CABG surgery to end of hospitalization. Of 394 participants, 176 (45%) experienced post-CABG surgery AKI. Higher baseline urine A1M was associated with higher odds of AKI (adjusted OR 1.34 per 2-fold higher A1M, 95% Confidence Interval (CI): 1.00-1.80). Higher urine UMOD was associated with lower odds of AKI (adjusted OR 0.77 per 2-fold higher UMOD, 95% CI 0.62-0.95). Higher EGF showed a tendency towards lower odds of AKI (adjusted OR 0.79 per 2-fold higher EGF, 95% CI 0.59-1.05). KIM-1 was not associated with AKI (adjusted OR 0.92 per 2-fold higher KIM-1, 95% CI 0.77-1.10). Select biomarkers of kidney tubule dysfunction, but not injury, are associated with future risk of AKI after CABG surgery. Biomarkers measured years before surgery may predict post-CABG surgery AKI.

Background Increased monocyte chemoattractant protein-1 (MCP-1) and decreased epidermal growth factor (EGF) are promising biomarkers to predict progressive decline in kidney function in non-diabetic kidney diseases. We aimed to evaluate the performance of urinary EGF, MCP-1 or their ratio in predicting rapid decline of GFR in a cohort of Type 2 diabetic patients (T2DM) with diabetic kidney disease (DKD). Methods T2DM patients ( n  = 83) with DKD at high risk for renal progression were followed up prospectively. The baseline urine values of MCP-1 to creatinine ratio (UMCP-1), EGF to creatinine ratio (UEGF), EGF to MCP-1 ratio (UEGF/MCP-1) and albumin to creatinine ratio (UACR) were measured. The primary outcome was a decline in estimated glomerular filtration rate (GFR) of ≥25% yearly from baseline. Results During follow-up time of 23 months, patients with rapid decline in estimated GFR of ≥25% yearly from baseline had significantly higher baseline levels of UMCP-1, and UACR and lower UEGF and UEGF/MCP-1 ratio. All renal biomarkers predicted primary outcomes with ROC (95%CI) for UMCP-1=0.73 (0.62-0.84), UEGF=0.68 (0.57-0.80), UEGF/MCP-1=0.74 (0.63-0.85), and UACR =0.84 (0.75-0.93). By univariate analysis, blood pressure, GFR, UACR, UMCP-1, UEGF, and UEGF/MCP-1 were associated with rapid decline GFR. By multivariate analysis, UACR, systolic blood pressure, and UMCP-1 or UEGF/MCP-1 were independently associated with rapid GFR decline. Conclusions UMCP-1 or UEGF/MCP-1 ratio were associated with rapid renal progression independent from conventional risk factors in DKD.

Improved biomarkers are needed to enhance prognostication in kidney transplantation. We evaluated urinary Epidermal Growth Factor (uEGF) as a predictor of long-term allograft loss. We conducted a prospective, single-center cohort study of 290 adult kidney transplant recipients with uEGF measured 3 months post-transplant. The primary outcome was allograft loss, defined as return to dialysis or pre-emptive re-transplantation. Multivariable cause-specific Cox models assessed the independent association between uEGF and allograft loss. Model performance was compared to an existing prediction model using 7-year time-dependent AUC and Akaike Information Criterion (AIC), with internal validation via bootstrap resampling. Temporal validation was performed in an independent cohort of 203 patients. uEGF correlated with markers of chronic injury, including eGFR, donor age, and interstitial fibrosis. After a median 8.8- year follow-up, lower uEGF was independently associated with allograft loss (adjusted HR 0.19; 95% CI, 0.11−0.32). Adding uEGF to the existing prediction model improved discrimination (AUC 0.72 vs. 0.63) and reduced AIC (383 vs. 394). While results were robust to internal validation, temporal validation did not show an independent association of uEGF with allograft loss. These findings suggest uEGF may provide independent prognostic value, but further studies in larger and more diverse cohorts are needed to confirm its clinical utility.

Urinary epidermal growth factor (uEGF) and clusterin (uCLU) are emerging biomarkers in chronic kidney disease (CKD), but rigorous analytical validation is required before clinical implementation. We evaluated intra-individual variability and long-term storage stability of uEGF and uCLU in CKD. In the prospective, multicenter UVALID study, 60 adults with CKD stages 2–4 underwent urine sampling at three visits over 8 weeks. First-morning and 24-h urine samples were collected to assess intra-individual variability over 24 h, 3 days and 8 weeks. Biomarkers were measured in duplicate by ELISA and normalized to urinary creatinine (/Cr). Inter-laboratory performance was assessed using quality control samples. Stability after 12 and 15 months of storage at −20 °C and −80 °C and the influence of pH were evaluated. Over 24 h, 3 days, and 8 weeks, uEGF/Cr demonstrated low variability and remained stable after long-term storage at both temperatures. In contrast, uCLU/Cr showed greater variability and pronounced instability at −20 °C, whereas stability was preserved at −80 °C. Samples with pH > 6 partially preserved uCLU stability at −20 °C. Inter-laboratory reproducibility was acceptable for uEGF but suboptimal for uCLU at low concentrations. Thus, uEGF showed robust analytical performance, supporting its potential clinical applicability in CKD, whereas uCLU exhibited important analytical and pre-analytical limitations, warranting further assay optimization. These findings underscore the need for rigorous validation to facilitate biomarker implementation in clinical practice.

IntroductionThe current study aimed to investigate the association between urinary epidermal growth factor (uEGF) and renal disease severity and outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).MethodsIntrarenal EGFmRNA expression was extracted from transcriptomic data of microdissected tubulointerstitial compartments of kidney biopsies of patients with AAV. uEGF was measured in 173 patients with AAV in active stage and 143 in remission, and normalised to urine creatinine excretion (uEGF/Cr). The association between uEGF/Cr (or EGFmRNA) and clinical–pathological parameters was tested using linear regression analysis. The ability of uEGF/Cr to predict renal outcomes was analysed using Cox’s regression analysis.ResultsIn patients with AAV, intrarenal EGFmRNA expression was significantly associated with estimated glomerular filtration rate (eGFR)(log2) at time of biopsy (β=0.63, p<0.001). The level of uEGF/Cr was significantly higher in patients in remission than in patients with active disease, both when looking at patients with sequential measurements (2.75±1.03vs 2.08±0.98, p<0.001) and in cross-sectional comparison. uEGF/Cr level was positively associated with eGFR(log2) at time of sampling in both active and remission stage (β=0.60, p<0.001; β=0.74, p<0.001, respectively). Patients with resistant renal disease had significantly lower uEGF/Cr levels than responders (1.65±1.22vs 2.16±1.26, p=0.04). Moreover, after adjusting for other potential predictors, uEGF/Cr was independently associated with composite endpoint of end-stage renal disease or 30% reduction of eGFR (HR 0.61, 95% CI 0.45 to 0.83, p=0.001).ConclusionLower uEGF/Cr levels are associated with more severe renal disease, renal resistance to treatment and higher risk of progression to composite outcome in patients with AAV.

Background Previous studies highlighted the utility of individual urinary biomarkers in the prediction of interstitial fibrosis in IgA Nephropathy patients. However, it´s uncertain which biomarker or combination of biomarkers provides a more accurate estimation of renal interstitial fibrosis Surface. Herein, we measured the urinary excretion of a set of seven tubular injury biomarkers in a group of patients with primary IgA Nephropathy and analyzed their utility as non-invasive estimators of interstitial fibrosis area found on kidney biopsy. Methods Two hundred forty-seven adults with primary IgA Nephropathy diagnosed by kidney biopsy and a control group of 50 healthy control were included. The urinary excretion of EGF, MCP-1, NGAL, KIM-1, L-FABP, β2-microglobulin and DKK-3 was measured in urine samples collected at the day of the renal biopsy. Estimated glomerular filtration rate was measured by the CKD-EPI formula. Interstitial fibrosis area was quantified using a quantitative morphometric procedure and graded according to Oxford Classification. Predictive multivariate models were developed to predict the interstitial fibrosis surface. Results Patients with primary IgA Nephropathy showed significantly higher urinary levels of DKK-3, L-FABP and β2-microglobulin, and lower EGF levels than healthy controls. Interstitial fibrosis was negatively correlated with urinary EGF levels and positively with age, proteinuria, eGFR and urinary DKK-3, L-FABP and β2-microglobulin. The best model to predict interstitial fibrosis area accounted for > 60% of its variability and included age, eGFR, proteinuria, DKK-3, EGF, L-FABP and β2-microglobulin. Conclusions Our study provides a model to estimate the IFS in IgA Nephropathy which could be useful to monitor the progression of chronic kidney injury.

There is a need for sensitive and specific biomarkers to predict kidney damage and therapeutic response in lupus nephritis (LN). Monocyte chemoattractant protein-1 (MCP-1) and epidermal growth factor (EGF) are cytokines with divergent roles. EGF or EGF/MCP1 ratio have been shown to correlate with prognosis in primary glomerulonephritis, but there is limited information in lupus nephritis (LN). This study evaluated the roles of MCP-1, EGF or their ratio as biomarkers of histopathology and response to treatment in LN. This was a cross-sectional and observational study. Baseline urine MCP-1 and EGF levels in systemic lupus erythematosus (SLE) patients and controls (total n = 101) were compared, and levels were correlated with clinicopathological findings and subsequent response to treatment. MCP-1 was higher in active LN (n = 69) compared to other SLE groups and controls, whereas EGF was not different. MCP-1 correlated with disease activity (proteinuria, renal SLEDAI, classes III/IV/V, and high activity index.) By contrast, EGF correlated with eGFR, but not with proteinuria, activity index, or class III/IV/V. MCP-1 was higher, and EGF was lower in high chronicity index. EGF/MCP-1 decreased with greater clinicopathological severity. In a subgroup with proliferative LN who completed six months of induction therapy (n = 41), EGF at baseline was lower in non-responders compared to responders, whereas MCP-1 was similar. By multivariable analysis, baseline EGF was independently associated with subsequent treatment response. Area under the curve for EGF to predict response was 0.80 (0.66-0.95). EGF ≥ 65.6 ng/ mgCr demonstrated 85% sensitivity and 71% specificity for response. EGF/MCP-1 did not improve the prediction for response compared to EGF alone. MCP-1 increased with disease activity, whereas EGF decreased with low GFR and chronic damage. Urine EGF may be a promising biomarker to predict therapeutic response in LN. EGF/MCP-1 did not improve the prediction of response.

Several novel urinary kidney damage biomarkers predict the progression of kidney disease. However, the relations of these biomarkers to atherosclerosis, a major consequence of kidney disease, are less studied. Urinary levels of several biomarkers, including kidney injury molecule-1 (KIM-1), osteopontin, epidermal growth factor, and Dickkopf-3, were assessed in participants enrolled in the Swedish CArdioPulmonary BioImage Study. The study included 9,628 individuals with a mean age of 57.5 years, of which 52.4% were women. The presence of coronary artery stenosis and the coronary artery calcium score (CACS) were determined using coronary computed tomography angiography. To analyze the associations between coronary atherosclerosis and urinary biomarker levels, an ordered logistic regression model adusting for confounding factors was employed. KIM-1 was the only biomarker associated with both coronary stenosis and CACS after adjusting for established cardiovascular risk factors (odds ratio [95% confidence intervals], 1.23[1.05–1.44] and 1.25[1.07–1.47]). These results were consistent in sensitivity analyses of individuals without hypertension, diabetes, or known cardiovascular disease and with normal kidney function. Urinary KIM-1, a specific marker of proximal tubular damage, was robustly linked to coronary atherosclerosis even in apparently healthy individuals, which suggests that the detrimental interplay between the kidney and cardiovascular system begins before clinically overt kidney disease. Additional studies are warranted to evaluate the urinary KIM-1 to predict kidney and cardiovascular disease.