Predictive value of biomarkers for tubulointerstitial and glomerular interactions in diabetic nephropathy

Abstract

This article comments on Varatharajan et al recent article, highlighting the role of tubulointerstitial damage mechanisms in diabetic nephropathy progression. Evidence suggests a bidirectional interaction between the interstitium, tubular cells, and glomeruli. Renal tubules are highly susceptible to proteinuria, metabolic disorders, and toxins. Since diabetic nephropathy persistently activates inflammatory and fibrotic pathways, epithelial-to-mesenchymal transition mechanisms present promising targets for risk assessment. Periostin, a cellular matrix protein, plays a key role in modulating extracellular interactions. Increased periostin expression in tissue, serum, and urine correlates with type 2 diabetes, making it a valuable biomarker alongside neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. While periostin and neutrophil gelatinase-associated lipocalin reflect distal tubular damage, kidney injury molecule-1 serves as a marker for proximal tubular injury. Combining these biomarkers enhances diagnostic precision.

Key Words: Tubular biomarkers; Tubulointerstitium; Diabetic nephropathy; Proteinuria; Renal fibrosis

Core Tip: Diabetic kidney disease is characterized by albuminuria and progressive deterioration of renal function; however, traditional markers may fail to categorize a substantial proportion of patients who do not exhibit albuminuria. Tubulointerstitial biomarkers have been proven to be particularly valuable in predicting the onset of albuminuria and the progression of kidney injury in patients with type 2 diabetes. The standardization of biomarker measurements, including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and periostin, can potentially enhance prognostic indicators for diabetic kidney disease.

INTRODUCTION

Diabetic kidney disease is a leading cause of chronic kidney disease (CKD). Traditional markers such as albuminuria and estimated glomerular filtration rate (eGFR) primarily assess glomerular damage but may fail to detect early tubulointerstitial injury. Studies indicate that up to 47% of patients with type 2 diabetes (T2D) reach CKD stage 3 without albuminuria, potentially leading to undertreatment[1]. Several biomarkers have been investigated in various types of kidney disease, including acute kidney injury, CKD, and glomerulopathies. The sensitivity and specificity of these biomarkers are variable, and many have severe limitations that prevent their widespread use in daily clinical practice. Although albuminuria and the eGFR are easily accessible markers that can be used to evaluate disease progression, they are relatively nonspecific for assessing the degree of injury to any renal compartment except for the glomeruli[2-4]. However, many patients may have impaired renal function even without albuminuria.

TUBULOINTERSTITIAL DISEASE AND DISEASE PROGRESSION

Biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), periostin, and monocyte chemoattractant protein-1 offer a more precise evaluation of renal injury. The predictive power of these biomarkers is adequate, even after adjusting for conventional risk factors such as systolic blood pressure, anemia, serum creatinine, albuminuria, and body mass index[5]. Tubulointerstitial damage often correlates more strongly with eGFR decline than glomerular injury[6,7]. The activation of pathways like Wnt/β-catenin, nuclear factor (erythroid-derived 2)-like factor 2/antioxidant responsive element, and signal transducer and activator of transcription 3/nuclear factor kappa B accelerates renal fibrosis. Experimental models confirm that interventions targeting inflammatory pathways can mitigate fibrosis and CKD progression[8].

PROTEINURIA, INFLAMMATION AND TUBULOINTERSTITIAL DAMAGE

Proteinuria exacerbates tubulointerstitial injury by impairing proximal tubule receptor-mediated endocytosis, leading to oxidative stress and mitochondrial dysfunction[9,10]. This cascade activates fibroblasts and pro-inflammatory cytokines, driving progressive renal fibrosis. KIM-1, a biomarker of proximal tubular injury, further perpetuates this cycle (Figure 1). Inflammation may favor the initiation of harmful mechanisms in tubular cells and the interstitium. Considerable albumin reabsorption by the proximal tubule activates the RAS-related C3 botulinum toxin substrate 1-induced nicotinamide adenine dinucleotide phosphate oxidase pathway. Nicotinamide adenine dinucleotide phosphate oxidase causes mitochondrial dysfunction, increases the production and release of cytochrome C, and triggers cell apoptosis pathways[11-13].

Figure 1 Proteinuria (particularly significant albuminuria) can alter the receptor-mediated endocytosis mechanism, thus favoring reactive oxygen species production, which induces mitochondrial dysfunction and activates the nicotinamide adenine dinucleotide phosphate oxidase pathway, thereby producing cytochrome C. This figure was created in BioRender (Supplementary material). Cytochrome C can activate fibroblasts that release proinflammatory cytokines and profibrotic molecules such as transforming growth factor β1. The common final pathways include tubular atrophy and interstitial fibrosis, which cause progressive deterioration of kidney function. KIM-1: Kidney injury molecule-1; NGAL: Neutrophil gelatinase-associated lipocalin; TGF-β1: Transforming growth factor-β1.

BIOMARKERS FOR EARLY DIAGNOSIS NGAL AND KIM-1

NGAL, a widely studied marker of acute kidney injury, also correlates with CKD progression in diabetes[14]. Elevated urinary NGAL levels predict eGFR decline and albuminuria onset. In a study that included 952 patients with T2D without albuminuria or hypertension, the area under the receiver operating characteristic curve value for the NGAL/Creatinine ratio was 0.51 for the early detection of CKD, thus indicating a direct correlation with the log eGFR (r = 0.28, P < 0.001)[15]. A meta-analysis demonstrated NGAL’s sensitivity (0.79) and specificity (0.87) in detecting diabetic kidney disease[16]. KIM-1 is undetectable in healthy kidneys but is highly expressed in injured proximal tubules[17]. Nephroprotective medications, such as renin-angiotensin-aldosterone system inhibitors, can reduce urine KIM-1 excretion[18]. Its levels correlate with worsening renal function and albuminuria severity[19]. Nephroprotective therapies such as renin-angiotensin-aldosterone system inhibitors have been shown to reduce KIM-1 excretion. Periostin (POSTN) is a 90 kDa cellular matrix protein that was initially described in osteoblasts. It is also known as osteoblast-stimulating factor 2[20]. POSTN modulates the interaction between cells and the extracellular matrix; thus, it plays an essential role in regeneration, remodeling, and fibrosis[21]. Studies reveal increased urinary POSTN levels in T2D patients, independent of albuminuria. Its diagnostic accuracy is high, with an area under the receiver operating characteristic curve value of 0.78-0.99 for distinguishing different diabetic nephropathy stages; the cutoff levels for urine POSTN/Creatinine that showed the best performance were 1.39 ng/mg to distinguish normoalbuminuric T2D patients from healthy controls[22].

CLINICAL IMPLICATIONS

Current risk stratification for diabetic nephropathy relies on albuminuria and eGFR. However, tubulointerstitial biomarkers could enable earlier intervention, particularly in normoalbuminuric patients. Standardizing biomarker measurements may enhance prognostic capabilities and guide individualized treatment strategies.

CONCLUSION

NGAL, KIM-1, and POSTN are promising biomarkers for diabetic nephropathy risk assessment. While currently used for research purposes, they hold potential for early disease stratification and therapeutic guidance.