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      Transforming Growth Factor-β 1 SNPs: Genetic and Phenotypic Correlations in Progressive Kidney Insufficiency

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          Abstract

          Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. TGF-β<sub>1</sub> plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubulointerstitial fibrosis. In this study, single nucleotide polymorphisms (SNPs) in the TGFβ1 gene were investigated as possible markers for the progression of chronic kidney failure (CKF). 145 Caucasian patients with CKF were screened for four TGFβ1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CKF patients and controls in allele frequencies of two of the SNPs, Leu10Pro (p = 0.038) and C-509T (p = 0.02) and in haplotype distributions (p = 0.0175), indicating an association with susceptibility to CKF. We also observed a significant association between progression of CKF and homozygosity for Arg25 (odds ratio 3.77, 95% confidence interval 1.57–9.04, p = 0.002). Homozygosity for Arg25 was also associated with severity of proteinuria at diagnosis (p = 0.038), plasma TGF-β<sub>1</sub> protein levels (p = 0.01), and severity of glomerulosclerosis (p = 0.04). Homozygosity for -509T was associated with severity of proteinuria at diagnosis (p = 0.0017), level of renal tubular TGF-β<sub>1</sub> immunostaining (p = 0.0006) and with severity of renal interstitial inflammatory cellular infiltration (p = 0.01). Tubular TGF-β<sub>1</sub> immunostaining was significantly higher in biopsies with inflammatory cellular infiltration compared those without inflammation (p = 0.0048). There was a significant difference in haplotype distributions between CKF patients with progressive, as opposed to non-progressive disease (p = 0.0484). TGFβ1 SNPs may be useful prognostic indicators for the progression of CKF.

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          Most cited references 25

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          Pathophysiology of progressive nephropathies.

           T Bertani,  G. Remuzzi (1998)
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            Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

            Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.
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              The role of proteinuria in the progression of chronic renal failure.

              The cause of the relentless progression of chronic renal failure of diverse origins remains unknown and is likely to be multifactorial. Numerous studies have now demonstrated a correlation between the degree of proteinuria and the rate progression of renal failure, which has led to the hypothesis that proteinuria may be an independent mediator of progression rather than simply being a marker of glomerular dysfunction. This article reviews the evidence underlying this hypothesis and the mechanisms by which particular proteins may cause renal pathology. The abnormal filtration of proteins across the glomerular basement membrane will bring them into contact with the mesangium and with the tubular cells. There is evidence to support a role of lipoproteins on mesangial cell function, which ultimately could contribute to glomerular sclerosis. The proximal tubular cells reabsorb proteins from the tubular fluid, which leaves them particularly vulnerable to any adverse effects proteins may have. It has been postulated that the sheer amount of protein to be metabolized by these cells may overwhelm the lysosomes and result in leakage of cytotoxic enzymes into the cells. In addition, the increased metabolism of proteins may result in production of ammonia, which can mediate inflammation through activation of complement. Specific proteins that have been shown to be cytotoxic are transferrin/iron, low-density lipoprotein, and complement components, all of which appear in the urine in proteinuric states. Other specific proteins have been shown to stimulate production of cytokines, chemoattractants, and matrix proteins by tubular cells and thus may stimulate interstitial inflammation and scarring. The mechanisms by which the presence of proteins in the tubular fluid alters tubular cell biology is yet to be determined.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2005
                October 2005
                08 June 2005
                : 101
                : 2
                : e31-e41
                Affiliations
                aBiomedical Science Research Centre, Sheffield Hallam University, Sheffield, bSheffield Kidney Institute, Northern General Hospital, Sheffield, and cSection of Medical Genetics, Faculty of Medicine, Imperial College London, London, UK
                Article
                86227 Nephron Exp Nephrol 2005;101:e31–e41
                10.1159/000086227
                15942255
                © 2005 S. Karger AG, Basel

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                Page count
                Tables: 7, References: 39, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86227
                Categories
                Original Paper

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