Dataset Information

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

ABSTRACT: In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.

SUBMITTER: Nakagawa S

PROVIDER: S-EPMC4552842 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

Nakagawa Shunsaku S Nishihara Kumiko K Miyata Hitomi H Shinke Haruka H Tomita Eri E Kajiwara Moto M Matsubara Takeshi T Iehara Noriyuki N Igarashi Yoshinobu Y Yamada Hiroshi H Fukatsu Atsushi A Yanagita Motoko M Matsubara Kazuo K Masuda Satohiro S

PloS one 20150828 8

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The ...[more]

PMID: 26317775

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Project description:Under specific conditions non-steroidal anti-inflammatory drugs (NSAIDs) may be used to lower therapy-resistant proteinuria. The potentially beneficial anti-proteinuric, tubulo-protective, and anti-inflammatory effects of NSAIDs may be offset by an increased risk of (renal) side effects. We investigated the effect of indomethacin on urinary markers of glomerular and tubular damage and renal inflammation. We performed a post-hoc analysis of a prospective open-label crossover study in chronic kidney disease patients (n = 12) with mild renal function impairment and stable residual proteinuria of 4.7±4.1 g/d. After a wash-out period of six wks without any RAAS blocking agents or other therapy to lower proteinuria (untreated proteinuria (UP)), patients subsequently received indomethacin 75 mg BID for 4 wks (NSAID). Healthy subjects (n = 10) screened for kidney donation served as controls. Urine and plasma levels of total IgG, IgG4, KIM-1, beta-2-microglobulin, H-FABP, MCP-1 and NGAL were determined using ELISA. Following NSAID treatment, 24 h -urinary excretion of glomerular and proximal tubular damage markers was reduced in comparison with the period without anti-proteinuric treatment (total IgG: UP 131[38-513] vs NSAID 38[17-218] mg/24 h, p<0.01; IgG4: 50[16-68] vs 10[1-38] mg/24 h, p<0.001; beta-2-microglobulin: 200[55-404] vs 50[28-110] ug/24 h, p = 0.03; KIM-1: 9[5]-[14] vs 5[2]-[9] ug/24 h, p = 0.01). Fractional excretions of these damage markers were also reduced by NSAID. The distal tubular marker H-FABP showed a trend to reduction following NSAID treatment. Surprisingly, NSAID treatment did not reduce urinary excretion of the inflammation markers MCP-1 and NGAL, but did reduce plasma MCP-1 levels, resulting in an increased fractional MCP-1 excretion. In conclusion, the anti-proteinuric effect of indomethacin is associated with reduced urinary excretion of glomerular and tubular damage markers, but not with reduced excretion of renal inflammation markers. Future studies should address whether the short term glomerulo- and tubulo-protective effects as observed outweigh the possible side-effects of NSAID treatment on the long term.

Project description:In Brazil, the incidence and prevalence of CKD are increasing, the prognosis remains poor and the costs of treating the disease are very high. Added to this is the increase in the main risk factors for the development and progression of CKD, such as greater aging of the population, high prevalence of AH, DM, overweight, smoking and others, which suggests the continuation of CKD as a serious problem of public health. This situation requires prevention actions, early diagnosis of the disease and agile action in the face of the functional changes evidenced. Furthermore, there is a need to find ways to prevent the progression of the disease. A disturbing issue in nephrology practice is the observation that a significant number of CKD patients lose renal function asymptomatically. One of the reasons is late diagnosis and referral to dialysis. The main causes are: the fact that CKD is often asymptomatic, difficulty in diagnosis, tendency of doctors not to refer patients adequately, selection of patients with less morbidities to start dialysis, resistance of patients to treatment, deficient structure of the health system and lack of access to treatment. The consequences of late referral are reflected in greater morbidity, mortality, costs and worse quality of life. In this sense, it is important to search for new markers of the disease that allow early diagnosis, monitoring of progression and, eventually, improving response to treatment. Analyzing mechanisms underlying renal failure and identifying unique biomarkers (such as metabolite ratios) have the potential to increase our understanding of CKD and improve disease diagnosis and treatment algorithms. In this sense, this project can represent important progress in CKD proteomics research, based on complex information obtained from proteomics associated with basic medical information. New biomarkers are needed as non-invasive tools to aid the accurate diagnosis of kidney diseases with similar clinical characteristics but different prognosis. This project aims to investigate the proteomics of saliva from chronic kidney disease patients in the search for molecular markers that can be used in both the diagnosis and prognosis of the disease. So, for this, it was necessary to select healthy individuals and chronic kidney disease patients, and collect sociodemographic, behavioral, food consumption, clinical and anthropometric data from these individuals. Next, the mass spectrometry proteomics technique was performed on saliva samples and investigated molecules that could be used as markers of CKD and other associated comorbidities, in addition to evaluating whether any molecule could be indicative of the progression of CKD.

Dataset Information

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

Publications

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

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