Potential Renal Damage Biomarkers in Alport Syndrome—A Review of the Literature

Abstract

Alport syndrome (AS) is the second most common cause of inherited chronic kidney disease. This disorder is caused by genetic variants on COL4A3, COL4A4 and COL4A5 genes. These genes encode the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). The heterodimer COL4A3A4A5 constitutes the majority of the GBM, and it is essential for the normal function of the glomerular filtration barrier (GFB). Alterations in any of collagen type IV constituents cause disruption of the GMB structure, allowing leakage of red blood cells and albumin into the urine, and compromise the architecture of the GFB, inducing inflammation and fibrosis, thus resulting in kidney damage and loss of renal function. The advances in DNA sequencing technologies, such as next-generation sequencing, allow an accurate diagnose of AS. Due to the important risk of the development of progressive kidney disease in AS patients, which can be delayed or possibly prevented by timely initiation of therapy, an early diagnosis of this condition is mandatory. Conventional biomarkers such as albuminuria and serum creatinine increase relatively late in AS. A panel of biomarkers that might detect early renal damage, monitor therapy, and reflect the prognosis would have special interest in clinical practice. The aim of this systematic review is to summarize the biomarkers of renal damage in AS as described in the literature. We found that urinary Podocin and Vascular Endothelial Growth Factor A are important markers of podocyte injury. Urinary Epidermal Growth Factor has been related to tubular damage, interstitial fibrosis and rapid progression of the disease. Inflammatory markers such as Transforming Growth Factor Beta 1, High Motility Group Box 1 and Urinary Monocyte Chemoattractant Protein- 1 are also increased in AS and indicate a higher risk of kidney disease progression. Studies suggest that miRNA-21 is elevated when renal damage occurs. Novel techniques, such as proteomics and microRNAs, are promising.

Ameliorative effects of glycine on cobalt chloride‐induced hepato‐renal toxicity in rats

“…Therefore, the observed decrease in the expression of podocin in renal tissues of rats treated with glycine in this study suggests a preservation of the structural integrity of renal tissues and therefore indicates that glycine is a potent renoprotective agent against renal toxicities associated with CoCl 2 exposures. Recent experimental studies also confirmed high expression of podocin as a novel biomarker of renal damage during acute kidney injury [49][50][51]. In conclusion, the results of this study clearly demonstrate the protective effects of glycine against tissue injuries and derangement of normal physiological functioning of the hepatic and renal systems in rats.…”

“…Therefore, the observed decrease in the expression of podocin in renal tissues of rats treated with glycine in this study suggests a preservation of the structural integrity of renal tissues and therefore indicates that glycine is a potent renoprotective agent against renal toxicities associated with CoCl 2 exposures. Recent experimental studies also confirmed high expression of podocin as a novel biomarker of renal damage during acute kidney injury 49–51 …”

“…Recent experimental studies also confirmed high expression of podocin as a novel biomarker of renal damage during acute kidney injury. 49 , 50 , 51 …”

Deletion of the endothelial glycocalyx component endomucin leads to impaired glomerular structure and function

“…Podocin colocalizes to tight junctions between foot processes and serves as scaffolding tethering tight junction proteins to the cytoskeleton 97 . Its reduction is a biomarker for early podocyte injury and dysfunction 98,99 .…”

Ramipril therapy in integrin α1‐null, autosomal recessive Alport mice triples lifespan: mechanistic clues from RNA‐seq analysis

“…As is evident in Figure 5E, loss of podocyte pedicle structure progressively worsened as a function of disease progression. In a recent relevant study, it was found that podocin in the urine of Alport patients may serve as an early biomarker [57], suggesting active breakdown of the slit diaphragm molecular architecture.…”