Urinary sediment miRNA levels in adult nephrotic syndrome
Highlights
► Urinary miRNA expression pattern is related to the cause of nephrotic syndrome. ► For each pathology, urinary miRNA levels correlated with kidney damage. ► Urinary miRNA may be valuable biomarkers in adult nephrotic syndrome.
Introduction
Nephrotic syndrome is a common clinical problem characterized by heavy proteinuria, hypoalbuminemia, and edema. In adults, nephrotic syndrome could be caused by a variety of glomerular diseases, including minimal change nephropathy (MCN), focal glomerular sclerosis (FGS), membranous glomerulonephritis (MGN), and diabetic glomerulosclerosis (DGS), and it is important to determine the underlying histological diagnosis to guide the choice of specific treatment [1]. In this respect, each specific cause of nephrotic syndrome has its own distinct pathogenesis. For example, injury to glomerular epithelial cells (podocytes) by circulating factors is generally believed to be the cause of MCN and FGS [2], while circulating and deposited antibodies against the M-type receptor for secretory phospholipase A2 is the major cause of adult idiopathic MGN [3]. In contrast, DGS is the result of multiple problems related to chronic hyperglycemia, including abnormal intra-glomerular hemodynamics, altered glomerular filtration barrier, and tubulointerstitial changes [4]. Traditionally, renal biopsy is the gold standard for the establishment of pathological diagnosis for adult patients presenting with nephrotic syndrome. However, renal biopsy is an invasive method that has potential risk of severe complications, and it is often not feasible to have serial renal biopsy for monitoring of disease progression. Reliable non-invasive biomarkers that can discriminate renal histological lesions and reflect disease severity are urgently needed [5].
MicroRNA (miRNA) is a group of non-coding, single-stranded RNA molecules of about 22 nucleotides in length. They are involved in the regulation of gene expression through post-transcriptional degradation of messenger RNA or translational inhibition of protein synthesis [6]. It is now recognized that miRNAs play important roles in the functioning of eukaryotic cells, and dysregulation of miRNAs has been associated with many human diseases [6], [7]. Recent studies showed that a number of miRNAs species are regulated in renal cells under various pathological conditions and may participate in the pathogenesis of kidney diseases [8], [9], [10], [11], [12], [13], [14].
Our previous studies demonstrated that miRNA could be reliably quantified in urinary sediment, and urinary miRNA levels are altered in chronic glomerular diseases [15], [16]. In this study, we investigated the urinary levels of a panel of miRNA targets in adult nephrotic patients. We aim to explore the role of urinary miRNA level as non-invasive biomarkers for the diagnosis of adult nephrotic patients.
Section snippets
Patient selection
We studied 64 consecutive patients with renal biopsy performed for clinical nephrotic syndrome in our hospital. Patients with dual or other coexisting renal pathology were excluded. On the day of renal biopsy, each patient had a whole-stream early morning urine specimen collected for urinary miRNA study. Clinical data including serum creatinine and 24-h urine protein excretion were recorded. Glomerular filtration rate (GFR) was estimated by a standard equation [17]. We also studied the urine
Results
The demographic and baseline clinical and histological data of the patients were summarized in Table 1. There are 20 patients with DGS, 21 with MCN/FGS, and 23 with MGN. Histological studies showed that the degree of glomerulosclerosis and tubulointerstitial scarring were 15.7 ± 18.6% and 19.9 ± 21.9%, respectively.
Discussion
Although proteinuria and serum creatinine level are commonly used as markers of disease severity in nephrotic syndrome, these parameters do discriminate the underlying pathological diagnosis. Quantification of urinary miRNA has several advantages for the development as non-invasive biomarkers. Many miRNA targets have been found to play important roles in the pathogenesis and progression of kidney diseases [22]. Moreover, miRNA is stable and present in considerable quantity in urinary sediment
Acknowledgements
This study was supported in part by the CUHK research account 6901031. All authors declare no conflict of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format.
References (33)
- et al.
Management of patients with nephrotic syndrome
Swiss Med Wkly
(2009) Minimal change nephropathy and focal segmental glomerulosclerosis
Semin Immunopathol
(2007)- et al.
Pathogenesis of membranous nephropathy: recent advances and future challenges
Nat Rev Nephrol
(2012) - et al.
Mechanisms involved in the genesis of diabetic nephropathy
Curr Diabetes Rev
(2010) Urine proteomic profiling to identify biomarkers of steroid resistance in pediatric nephrotic syndrome
Expert Rev Proteomics
(2008)Non-coding RNAs in human disease
Nat Rev Genet
(2011)- et al.
miR2Disease: a manually curated database for microRNA deregulation in human disease
Nucleic Acids Res
(2009) - et al.
The miR-200 family regulates TGF-beta1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression
Am J Physiol Renal Physiol
(2012) - et al.
Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy
J Am Soc Nephrol
(2012) - et al.
Smad3-mediated upregulation of miR-21 promotes renal fibrosis
J Am Soc Nephrol
(2011)
Suppression of microRNA-29 expression by TGF-beta1 promotes collagen expression and renal fibrosis
J Am Soc Nephrol
Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis
Nephrology (Carlton)
Renal Mir-150 as potential biomarker of chronicity in lupus nephritis
Arthritis Rheum
MicroRNAs and their role in progressive kidney diseases
Clin J Am Soc Nephrol
Expression of microRNAs in the urinary sediment of patients with IgA nephropathy
Dis Markers
Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis
Am J Hypertens
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