Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy

Rossini, Michele; Naito, Takashi; Yang, Haichun; Freeman, Michael L.; Donnert, Ellen; Ma, Lijun; Dunn, Stephen; Sharma, Kumar; Fogo, Agnes B.

doi:10.1093/ndt/gfp724

Cited by 31 publications

(21 citation statements)

References 32 publications

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“…In addition to the likely involvement of TGFβ and PAI1, Ang II is certainly the principal mediator of this process. The results of this study showed that sulodexide (15 mg/kg/day by subcutaneous injection, 6 days/week for 4, 8 and 12 weeks) is effective in reducing the early, but not late, indicators of radiation nephropathy and has no influence on renal damage, despite sulodexide considerably diminishing TGFβ activation (61).…”

Section: Physical Models -Radiation Nephropathymentioning

confidence: 73%

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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Abstract. Chronic kidney disease (CKD) is a long-term condition in which theChronic kidney disease (CKD) represents a serious hazard to human health, and has a high prevalence. In developed countries, it is estimated that more than 10% of adults present some degree of CKD (1). Despite a varied initial evolution, which is related to the diversity of its aetiologies -namely genetics, autoimmune-related infections, environmental factors, diet, and drugs -progressive renal disease frequently results in renal fibrosis and finally in renal failure. The mechanisms implicated in renal fibrosis are still poorly understood, and existing therapies are ineffective or only slightly successful, hence it is essential to understand the pathophysiological mechanisms underlying the usual development of CKD, and to discover and better understand new strategies for treating this disease. In order to study the biopathology of this disease and to evaluate new treatments, animal models are required. The perfect animal model for renal disease research should have human-like renal anatomy, haemodynamics and physiology, as well as enabling the determination of relevant renal, biochemical and haemodynamic parameters. In all probability, no species can consistently meet all these requirements, and the experimental plan and other constraints often determine the choice of animal models for particular research applications. With this in mind, this review aims to describe and analyze animal models of renal fibrosis and suggest new areas of research. Renal Fibrosis: Aetiology and PathophysiologyDiabetes and hypertension are currently the two principal causes of CKD (2), among other causes such as infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations, autoimmune diseases (1) and drugs (3, 4). In general, diabetes causes glomerular hypertension by reducing the afferent arteriolar resistance while stimulating the efferent arterioles (2). Thus, elevated glomerular capillary pressure is one of the major factors in progressive renal sclerosis (5). Diabetes and hypertension gradually lead to glomerular expansion, which causes endothelial dysfunction and haemodynamic changes: loss of the glomerular basement membrane electric charge and its thickening, a decreased number of podocytes, foot-process effacement and mesangial distension have been shown to 1

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Section: Physical Models -Radiation Nephropathymentioning

confidence: 73%

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

2017

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“…In rats with radiation nephropathy, sulodexide did not change renal function, but lowered proteinuria; and in diabetic mice, sulodexide had no effect on proteinuria. 118 In rats with adriamycin nephropathy, sulodexide markedly decreased albuminuria and reverted from diffuse to segmental foot process involvement. It also reduced levels of a molecule known to degrade the proteoglycan layer of endothelium (heparanase messenger RNA), a cytoskeleton stabilizer (desmin), and a slit diaphragm component (CD2AP).…”

Section: Novel Agents In Diabetic Nephropathymentioning

confidence: 99%

Off the Beaten Renin–Angiotensin–Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy

Gordon

Kopp²

2011

Advances in Chronic Kidney Disease

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CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin–angiotensin–aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin–angiotensin–aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria.

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“…Recent experimental models suggest that sulodexide may ameliorate early but not late kidney disease. 33 As discussed previously, 32 potential confounding factors must be mentioned. First, although previous pharmacokinetic studies demonstrated oral absorption of sulodexide from the gastrointestinal tract, this was at levels that did not alter hemostasis.…”

Section: Discussionmentioning

confidence: 99%

Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy

Packham

Wolfe

Reutens

et al. 2012

Journal of the American Society of Nephrology

161

137

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Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (.900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine $6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

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Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy

Cited by 31 publications

References 32 publications

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies

Off the Beaten Renin–Angiotensin–Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy

Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy

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