Overview of factors contributing to the pathophysiology of progressive renal disease

Renal Division, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Kidney International (Impact Factor: 8.52). 10/2008; 74(7):860-6. DOI: 10.1038/ki.2008.351
Source: PubMed

ABSTRACT Some basic premises must be considered when validating hypothesis about progression of renal disease. In an accompanying series of five articles, specific aspects of progression will be reviewed by experts in the field: mechanisms of tissue and matrix remodelling; interstitial fibrosis; the contribution of ischemia and hypoxia; the role and type of the inflammatory infiltrate; and, finally, glomerular sclerosis.

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    • "As frequently demonstrated, most obese and diabetic individuals tend to show the same pattern of glomerular hemodynamics as compared to patients and animals with reduced renal mass (preglomerular vasodilation, increased glomerular filtration rate, and filtration fraction). Glomerular filtration rate (GFR) has been shown to be higher in obese individuals, while proteinuria and secondary glomerulosclerosis are now recognized as specific complications of severe obesity [3]. Huge progress has been recently achieved in the study of the endocrine features of adipose tissue, which is able to produce several hormone-like peptides named grouped adipokines. "
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    ABSTRACT: Chronic kidney disease is a major public health problem and characterized by a progressive loss in renal function over a period of months or years as defined by structural or functional abnormalities of the kidney. Several elements contribute to determine a progression of the kidney injury, inducing a worsening of renal damage and accelerating the decline of renal function: obesity and hypertension are two known factors of kidney progression. Remarkable improvements have been recently achieved in the study of the endocrine features of the adipose tissue and have been able to produce hormone-like peptides named adipokines or adipocytokines. Among these adipocytokines, which represent a link between obesity, hypertension, and chronic nephropathy, leptins and adiponectin appear to play an important role. Leptin not only is a prohypertension element (renal progression factor) through the activation sympathetic nervous, but also is able to induce prosclerotic effects directly on the kidney. In contrast, a decline of adiponectin levels has been shown to be related to a picture of hypertension: an endothelial dysfunction has been described as the main pathogenic mechanism responsible for this phenomenon.
    12/2012; 2012:943605. DOI:10.1155/2012/943605
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    ABSTRACT: At present, there are no specific cures for most of the acquired chronic kidney diseases, and renal transplantation is limited by organ shortage, therefore present efforts are concentrated on the prevention of progression of renal diseases. There is robust experimental and clinical evidence that progression of chronic nephropathies is multifactorial; however, intraglomerular haemodynamic changes and proteinuria play a key role in this process. With a focus on renoprotection, we first examine more established therapies--such as those that modulate the renin-angiotensin-aldosterone system--that can be used for the treatment of proteinuric renal diseases. We then discuss examples of novel drugs and biologics that might be used to target the inflammatory and profibrotic process, and glomerular injury, highlighting results from recent clinical trials.
    dressNature Reviews Drug Discovery 11/2008; 7(11):936-53. DOI:10.1038/nrd2685 · 37.23 Impact Factor
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    ABSTRACT: The acute phase response is traditionally characterized by hepatic synthesis of proteins as an inflammatory response to injury, with interleukin-6 (IL-6) being the key mediator. In contrast, microarray studies in human renal transplant implantation biopsies indicate a strong acute phase response in the deceased donor kidney, associated with a significant upregulation of oncostatin M receptor beta (OSMR). The aim of this study was to determine whether the kidney can generate a strong acute phase response, mediated by the OSM/OSMR gateway. Genes associated with the IL-6 cytokine family and acute phase reactants were analyzed by real-time RT-PCR in four groups of human biopsies spanning a spectrum of renal injury. OSM, OSMR, and fibrinogen beta (FGB) were progressively more highly expressed from prenephrectomy, living donor, deceased donor, to discarded donor kidneys, suggesting correlation with severity of injury and local renal synthesis. Acute phase response gene expression was analyzed in human proximal tubular cells in culture in response to OSM. OSM induced a significant increase in expression of FGB, OSMR, serpin peptidase inhibitor A1, IL-6, and lipopolysaccharide binding protein, and a decrease in IL-6R. These changes were largely attenuated by coincubation with an OSMR blocking antibody, indicating the OSM effect was mediated through OSMR. OSM also resulted in a significantly altered expression of acute phase genes compared with IL-6 or leukemia inhibitory factor, suggesting that OSM is the predominant cytokine mediating the renal tubular acute phase response. In conclusion, the renal parenchyma is capable of generating a strong acute phase response, likely mediated via OSM/OSMR.
    American journal of physiology. Renal physiology 02/2009; 296(4):F875-83. DOI:10.1152/ajprenal.90633.2008 · 3.30 Impact Factor
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