Effect of Addition of Silymarin to Renin-Angiotensin System Inhibitors on Proteinuria in Type 2 Diabetic Patients With Overt Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial

Fallahzadeh, Mohammad Kazem; Dormanesh, Banafshe; Sagheb, Mohammad Mahdi; Roozbeh, Jamshid; Vessal, Ghazal; Pakfetrat, Maryam; Daneshbod, Yahya; Kamali-Sarvestani, Eskandar; Lankarani, Kamran Bagheri

doi:10.1053/j.ajkd.2012.06.005

Cited by 120 publications

(128 citation statements)

References 36 publications

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“…43 The importance of proteinuria in CKD and the role it plays in the subsequent development of ESRD has identified proteinuria as a potential surrogate outcome in clinical trials 5 ; indeed, proteinuria change as a surrogate for ESRD has been used in many small-scale, earlier-phase trials. [44][45][46] However, proteinuria is currently not accepted as a surrogate outcome in broader large-scale, multicenter trials. 5 Accumulating data from post hoc analyses of RCTs, particularly in BP-lowering trials, do, however, suggest that further assessment of the surrogacy of proteinuria is warranted.…”

Section: Discussionmentioning

confidence: 99%

Assessing the Validity of Surrogate Outcomes for ESRD

Jun

Turin

Woodward

et al. 2015

Journal of the American Society of Nephrology

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Validation of current and promising surrogate outcomes for ESRD in randomized controlled trials (RCTs) has been limited. We conducted a systematic review and meta-analysis of RCTs to further inform the ability of surrogate outcomes for ESRD to predict the efficacy of various interventions on ESRD. MEDLINE, EMBASE, and CENTRAL (from inception through September 2013) were searched. All RCTs in adults with proteinuria, diabetes, or CKD stages 1-4 or renal transplant recipients reporting $10 ESRD events and a surrogate outcome (change in proteinuria or doubling of serum creatinine [DSCR]) for ESRD during a $1-year follow-up were included. Two reviewers abstracted trial characteristics and outcome data independently. To assess the correlation between the surrogate outcomes and ESRD, we determined the treatment effect ratio (TER), defined as the ratio of the treatment effects on ESRD and the effects on the change in surrogate outcomes. TERs close to 1 indicate greater agreement between ESRD and the surrogate, and these ratios were pooled across interventions. We identified 27 trials (97,458 participants; 4187 participants with ESRD). Seven trials reported the effects on change in proteinuria and showed consistent effects for proteinuria and ESRD (TER, 0.82; 95% confidence interval, 0.59 to 1.16), with minimal heterogeneity. Twenty trials reported on DSCR. Treatment effects on DSCR were consistent with the effects on ESRD (TER, 0.98; 95% confidence interval, 0.85 to 1.14), with moderate heterogeneity. In conclusion, DSCR is generally a good surrogate for ESRD, whereas data on proteinuria were limited. Further assessment of the surrogacy of proteinuria using prospective RCTs is warranted. CKD is commonly defined as a GFR,60 ml/min per 1.73 m 2 or the presence of markers of kidney damage, including proteinuria. 1 The global burden of CKD is increasing, with a prevalence of 10%-16% worldwide. 2 The clinical management of people with CKD has been difficult, particularly for those with irreversible kidney failure or ESRD. Preserving kidney function and slowing the progression of kidney disease is thus important. In measuring the efficacy of interventions in clinical trials focusing on this strategy, ESRD (defined as long-term dialysis or kidney transplantation) is the most definitive outcome in kidney disease. However, kidney disease often progresses slowly over many years. This presents logistic challenges in the conduct of randomized controlled trials (RCTs) because long follow-up and extensive resources are required. These considerations 4 There is considerable interest in using proteinuria or smaller changes in serum creatinine or eGFR as surrogate outcomes. 5-7 However, rigorous validation of a surrogate outcome is needed before it can be implemented in large-scale trials. We therefore conducted a systematic review and meta-analysis of RCTs, irrespective of intervention or comparator, in adults with proteinuria, diabetes, CKD stages 1-4, or renal transplant recipients to further inform the ability of surrogate...

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Section: Discussionmentioning

confidence: 99%

Assessing the Validity of Surrogate Outcomes for ESRD

Jun

Turin

Woodward

et al. 2015

Journal of the American Society of Nephrology

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“…The patients were on maximum doses of angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least 6 months. A dose of 140 mg of silimarin three times a day led to a 50% reduction in urinary albumin excretion, urinary TNFα levels, and urinary and serum MDA levels in almost half of the patients in the treatment group [30].…”

Section: Human Studiesmentioning

confidence: 93%

“…A randomized, controlled study consisted of a sample of 60 patients with type 2 diabetes who presented at baseline with diabetic macroalbuminuria (urinary albumin excretion > 300 mg/24h in two occasions), estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73 m², HbA1c < 10%, and blood pressure < 160 / 100 mmHg [30]. The patients were on maximum doses of angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for at least 6 months.…”

Section: Human Studiesmentioning

confidence: 99%

The Therapeutic Potential of Milk Thistle in Diabetes

Kazazis¹,

Evangelopoulos²,

Kollas³

et al. 2014

Rev Diabet Stud

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■ AbstractMilk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed.

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“…According to these studies antioxidant supplementation such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. However, some studies that used combined antioxidants therapy or antioxidant with anti-inflammatory agent showed that improvement of albuminuria, HbA1C and MDA in diabetic patients (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%