Urinary Epidermal Growth Factor: A Promising “Next Generation” Biomarker in Kidney Disease

Kidney Diseases 

Lupus Nephritis 

Lupus nephritis (LN) affects 40–60% of those with systemic lupus erythematosus (SLE). Late LN diagnosis is linked to an increased risk of kidney failure, with 10–15% of nephritis patients advancing to ESKD. There is an unmet need for a simple, non-invasive, accurate, and low-cost biomarker to help in the early identification and pre-diction of LN patients' prognosis.

A proteomic-based method identified the uEGF/Cr ratio as a potentially relevant biomarker in an LN discovery cohort. LN patients' urinary peptides matched the precursor proEGF protein. In two large multiethnic LN cohorts, active LN patients had significantly lower uEGF than patients with active nonrenal SLE, patients with active SLE, and kidney donors (Table 3). The histologic equivalents of chronic renal damage, such as interstitial fibrosis, tubular atrophy, and glomerular sclerosis, as well as the total of these components, known as the histologic chronicity index, were all linked with uEGF (r = −0.67, p-value 0.001). A multivariate survival study revealed that uEGF was related to the time it took for serum creatinine to double, a sign of potential ESKD. Low uEGF/Cr at the start and/or overtime was linked to progressive loss of kidney function, showing a greater risk of poor renal outcomes in people with LN. All patients who advanced to ESKD were identified by an uEGF/Cr threshold of 5.3 ng/ mg. When paired with other indicators of kidney function during a flare, such as proteinuria, eGFR, and histo logic chronicity index, uEGF/Cr levels at LN flare were independently linked with progressive loss of kidney function and improved the predictive value of these variables [19].

Table 3. Relationship between uEGF and kidney function in patients with kidney disease

Table 3 (continued)

In another small study of 58 SLE patients and 30 healthy controls, uEGF values were considerably lower in the patient group. However, the urine protein/creatinine ratio (PCR) did not correlate with the uEGF levels [42]. This could be due to a faster shift in uEGF than in PCR, which is a glomerular disease activity measure. The reduced uEGF was connected to the histological findings on the renal biopsy. The mean uEGF concentration was higher in classes I, II, and III than in classes IV and V. There was a significant difference in uEGFR between classes II and III, which grew as the interclass comparison was widened (e.g., classes II and IV). At a cut-off value of 40.6, a receiver operating characteristic (ROC) analysis of uEGF as a predictor of LN revealed a sensitivity of 90.4% and a specificity of 83.3%.

NEW HERBAL FORMULATION FOR CHRONIC DAMAGE

A TaqMan low-density array examination of biomarkerers in 54 archival formalin-fixed, paraffin-embedded renal biopsy tissues of patients with LN found an inverse association between mRNA EGF level and the severity of chronic damage and also renal function at the time of biopsy (unadjusted p < 0.01). EGF's trophic and anti-apoptotic properties may block the activity of transforming growth factor-β (TGF-β), another major mediator of kidney injury in LN [52]. A common clinical dilemma is deciding whether to continue immunotherapy to avoid CKD or to discontinue immunotherapy and focus only on conservative therapies. Serum creatinine, for instance, has not always shown the best association with (decline in) renal function in LN patients [53]. 

The course of uEGF/Cr after LN treatment predicts the evolution of kidney failure in the future. This supports the role of uEGF/Cr as a tool for CKD, adding to the existing list of biomarkers. In the absence of any acute alterations that may occur during active disease, uEGF/Cr can be assessed during an LN flare and then following LN resolution to establish a baseline level. The EGF/Cr level during a flare and its behavior following a flare may help identify people who are likely to regain kidney function, which may impact therapy choice, intensity, and persistence in patients with LN flare and acute renal damage. Before serum creatinine rises and eGFR declines, uEGF/Cr may be able to detect patients with CKD. After even one episode of aggressive LN, patients in remission often have persistent kidney damage that is not obvious from serum creatinine or eGFR. Serial uEGF/Cr monitoring in quiescent LN may provide a means of tracking silent histologic damage, alerting clinicians that such patients may require closer monitoring after exposure to nephrotoxic medications or may require dose adjustments of drugs excreted by the kidneys [19].

Diabetic Kidney Disease 

Type 1 DM Albuminuria is the characteristic first indication of DN, followed by a loss of kidney function and, eventually, ESKD [54]. Even though microalbuminuria is usually used to predict DN, only 30% of people advance to overt proteinuria. Some people who do not have microalbuminuria have severe renal pathology, indicating that microalbuminuria may not be the greatest early indicator of DKD [55]. To detect diabetic kidney deterioration early, more sensitive and specific indicators than mimicroalbuminuria are necessary. Renal tubulointerstitial alterations, in addition to glomerular damage, are a common characteristic of DN and a strong predictor of renal failure [53]. Lower uEGF levels in children with type 1 DM (T1DM) may indicate a decreased kidney regenerative capacity, making uEGF a possible biomarker of early DN. Unlike microalbuminuria, which is a symptom of glomerular disease, a decrease in renal EGF production indicates tubulointerstitial kidney injury and increasing kidney injury. EGF/Cr was considerably lower in T1DM when compared to age-matched healthy controls in a case-control study. Children with T1DM who had a de-creased eGFR had significantly lower uEGF/Cr corrected for age. Only uEGF remained an independently linked parameter with renal function in a multivariate analysis [37].

Glomerular hyperfiltration precedes and even causes early tubulointerstitial kidney damage, and a combination of low microalbuminuria and low uEGF may indicate early renal function decrease due to tubulointerstitial fibrosis superimposed on the glomerular injury. The screening potential of uEGF/Cr for DN in T1DM should be further explored in a long-term follow-up study [37]. Adding uEGF/creatinine to the standard of care regimen in T1DM patients will almost certainly result in a financial advantage. The earlier DN is identified, the sooner preventative medication can begin to halt the course of CKD. VEGF is a possible "new generation" biomarker linked to early DN symptoms in children and adolescents, and it deserves to be examined further in long-term follow-up research as a single biomarker or as part of a multi-biomarker panel for DN [37].

Type 2 DM

DKD is also a significant complication of T2DM, with up to 40% of the patients having renal failure [56]. In many cases, DKD does not follow the glomerular hyperfiltration pattern of microalbuminuria, resulting in rising levels of overt albuminuria and a decrease in eGFR [57]. The balance of protective growth factors and pro-inflammatory cytokines in DKD is thought to affect the extent of renal tissue damage and disease progression [46]. Predicting renal outcomes in diabetic individuals with normoalbuminuria is extremely difficult at the time. 642 participants from the Edinburgh Type 2 Diabetes Study, which was normoalbuminuric at baseline, were studied to see if uEGF could be used as a biomarker of the progressive decline of renal function. At the outset of the study, there was a weakly positive correlation between eGFR and uEGF/Cr (r = 0.11; p < 0.01), and a higher proportion of patients in the highest tertile of uEGF/Cr had an uACR >0.5 mg/mmol. During the follow-up period, patients in the tertile with the lowest uEGF concentration had a substantially greater chance (p = 0.003) of developing an eGFR <60 mL/min/1.73 m2, even though uACR was not a meaningful prognostic factor. The unadjusted log (uEGF/Cr) odds ratios for incident eGFR of <60 mL/ min/1.73 m2, fast worsening in renal function, or a combination of both end goals were 0.49 (95% confidence interval [CI]: 0.30–0.80)], 0.54 (95% CI: 0.35–0.84), and 0.45 (95% CI: 0.30–0.68), respectively. These correlations remained significant after correcting for baseline variables. So, regardless of other risk factors, a low uEGF/Cr ratio is linked to a rapid deterioration in renal function and the onset of CKD. The validity of employing uEGF as a biomarker for risk classification in diabetic individuals with normoalbuminuria should be tested in different populations [43].

In two Chinese population-based studies (the Cohort Research of Chronic Kidney Disease [C-STRIDE] and the Incident, Development, and Prognosis of DKD [INDEED] study), the relationships of uEGF with kidney involvement were studied in individuals at early and advanced stages of DKD. In the cross-sectional study of the INDEED cohort (early stage DKD), uEGF/Cr and uEGF/ monocyte chemotactic peptide-1 (MCP-1) were found to have a negative correlation with the development of DKD. In the C-STRIDE cohort's longitudinal investigation, uEGF/Cr, uMCP-1/Cr, and uEGF/MCP-1 were independently related with the composite outcome after controlling for relevant covariates. uMCP-1/Cr was found to be strongly linked to albuminuria, whilst uEGF/ Cr was found to be more closely tied to eGFR. In advanced-stage DKD patients, uECF/Cr could be used as a predictive marker for kidney disease progression. When uMCP-1 levels were standardized and expressed as the uEGF: MCP-1 ratio, it not only remained significantly associated with the occurrence of DKD, but it also improved the ability to differentiate patients with kidney involvement from those with T2DM using clinical indicators such as eGFR and uACR. When compared to uEGF/Cr or uMCP-1/Cr alone, uEGF/MCP-1 exhibited a superior predictor of the renal composite outcome [44]. In terms of MCP-1's underlying involvement in DKD pathogenesis, it may contribute to the course of the illness by re-cruiting and activating monocytes/macrophages and worsening tubulointerstitial inflammatory lesions [58]. As a result, it's possible that the uEGF: MCP-1 ratio has such a significant relationship to kidney involvement in both the early and late phases of DKD because it is a better predictor of tubulointerstitial damage [44].

The pace of renal function decline varies widely across diabetic individuals [59–61], allowing researchers to look for indicators that predict the rate of decline and identify patients at risk many years before ESKD develops. Many criteria have been used to diagnose such decreases, but they all rely on serially recorded serum creatinine and an analysis of the trajectory of creatinine-based eGFR over time. The 2nd Joslin Kidney Study included 1,032 people with normal renal function who were assessed for factors of early progressive renal impairment in T2DM. Early renal deterioration was defined using eGFR slopes calculated from serial serum creatinine values throughout a 5- to 12-year period of follow-up. More specifically, the result was defined as a decrease in eGFR of more than 30% from baseline over 5 years. EGF/Cr and uEGF/ MCP-1 were substantially linked with the probability of early renal deterioration in univariate analysis (area under the curve (AUC) = 0.58, p = 0.003 and AUC = 0.75, p < 0.001). When the impacts of tumor necrosis factor receptor 1, kidney injury molecule-1, systolic blood pressure, uACR, and uEGF/MCP-1 ratio were combined, the latter had the most influence. When these indicators were merged into a multimarker prognosis test, the discriminatory performance of early renal deterioration risk pre-diction increased dramatically when compared to uACR and systolic blood pressure alone. However, the study only looked at T2DM individuals with mostly European ancestry, and the positive predictive value in albuminuric patients was only 50%. The suggested multimarker prognosis test represents a novel way of developing a prognostic test based on the findings of etiological research. The test has a low predictive value, and it cannot be recommended for clinical use at this time due to a lack of relevant indicators. To develop a better predictive test for such decline that may be employed in a clinical context, new and more informative makers are required [45].

In a small prospective cohort study [46] of T2DM with DKD at high risk for renal insufficiency development, the effectiveness of uEGF, uMCP-1, or their ratio in predictinging fast decline of GFR was investigated. Patients with an annual eGFR reduction of >25% exhibited significantly higher baseline levels of uMCP-1 and uACR, as well as lower uEGF and uEGF/MCP-1 ratios. With ROC analysis, uMCP-1, uEGF, uEGF/MCP-1, and uACR all predicted primary outcomes. eGFR, uACR, uMCP-1, uEGF, uEGF/ MCP-1, and blood pressure were all linked to rapid GFR reduction in univariate analysis. After multivariate analysis with conventional components, uMCP-1, and the uEGF/MCP-1 ratio exhibited considerable predictive potential. The uMCP-1 or uEGF/MCP-1 ratio was connected to rapid renal development in DKD, regardless of established risk factors. Previous research has indicated that MCP-1 expression in the kidneys is elevated in DKD. uMCP-1 levels have been connected to the degree of tubulointerstitial leukocyte infiltration [58, 62], but its significance in predicting renal prognosis in DKD remains uncertain. MCP-1-mediated macrophage accumulation and activation are critical processes in DN [63, 64]. High uMCP-1 levels were predictive of rapid renal function loss over a wide range of kidney functions in Asian patients with stage 1–5 DKD, regardless of traditional variables. Low uEGF was a consistent predictor of quick renal deterioration over a wide range of GFR and albuminuria, including a subset of people with low albuminuria. In the context of more advanced DKD or noticeable proteinuria, the value of VEGF as a biomarker of rapid advancement over established markers may be lessened. Although a high uEGF/MCP-1 ratio was independent of fast GFR loss in DKD, the ratio's overall performance was equal to that of uMCP-1 alone. As a result, given the higher expenditure, this research did not demonstrate the value of routine uEGF monitoring in addition to MCP-1. EGF or uEGF/MCP-1 may be useful in the DKD subgroup with normal- or low-grade albuminuria and decreased eGFR. Larger studies are needed to determine the cost-benefit of uEGF testing in predicting adverse renal outcomes in this population [46].