Connective Tissue Growth Factor and Susceptibility to Renal and Vascular Disease Risk in Type 1 Diabetes

Jaffa, Ayad A.; Usinger, William R.; McHenry, M. Brent; Jaffa, Miran A.; Lipstiz, Stuart R.; Lackland, Daniel T.; Lopes‐Virella, Maria F.; Luttrell, Louis M.; Wilson, Peter W.F.

doi:10.1210/jc.2007-2544

Cited by 54 publications

(52 citation statements)

References 23 publications

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“…Plasma CTGF levels were elevated in our patients, consistent with a previously observed increase of plasma CTGF levels in patients with diabetic nephropathy (11,12,37). Because CTGF can be expressed by vascular smooth muscle cells and endothelial cells of atherosclerotic lesions (38), and also by injured myocardium (39), circulating CTGF might also reflect fibrotic activity outside the kidney as a biomarker.…”

Section: Discussionsupporting

confidence: 90%

“…In addition elevated circulating CTGF might generate a systemic profibrotic environment and contribute to the pathogenesis of e.g., cardiovascular complications (13,14). Consistently, plasma CTGF was found to independently predict intima-media thickness, end-stage renal disease, and overall mortality in diabetic CKD patients (11,12).…”

Section: Discussionmentioning

confidence: 76%

“…Likewise, in human diabetic nephropathy, CTGF overexpression in renal biopsies is associated with tubulointerstitial fibrosis, proteinuria, and renal function impairment (7,8), and urinary CTGF levels correlate with albuminuria and renal function impairment (9,10). Plasma CTGF levels independently predict end-stage renal disease, intima-media thickness, and mortality in diabetic nephropathy (11,12), supporting a role in intrarenal as well as extrarenal fibrotic processes (13,14). This is underscored by efficacy of CTGF inhibition in experimental models (15).…”

Section: Introductionmentioning

confidence: 96%

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Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Slagman

Nguyen

Waanders

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Connective Tissue Growth Factor (CTGF/CCN-2) is a key player in fibrosis. Plasma CTGF levels predict end-stage renal disease and mortality in diabetic chronic kidney disease (CKD), supporting roles in intra-and extrarenal fibrosis. Few data are available on CTGF in nondiabetic CKD. We investigated CTGF levels and effects of antiproteinuric interventions in nondiabetic proteinuric CKD. Design, setting, participants, & measurementsIn a crossover randomized controlled trial, 33 nondiabetic CKD patients (3.2 [2.5 to 4.0] g/24 h proteinuria) were treated during 6-week periods with placebo, ARB (100 mg/d losartan), and ARB plus diuretics (100 mg/d losartan plus 25 mg/d hydrochlorothiazide) combined with consecutively regular and low sodium diets (193 Ϯ 62 versus 93 Ϯ 52 mmol Na ϩ /d). Conclusions Urinary and plasma CTGF are elevated in nondiabetic CKD. Only urinary CTGF is normalized by antiproteinuric intervention, consistent with amelioration of tubular dysfunction. The lack of effect on plasma CTGF suggests that its driving force might be independent of proteinuria and that short-term antiproteinuric interventions are not sufficient to correct the systemic profibrotic state in CKD. Results

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 96%

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Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Slagman

Nguyen

Waanders

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…In type 1 diabetes, plasma and urine CTGF levels correlate with the level of albuminuria and the stage of progressive renal insufficiency (31)(32)(33)(34), and the plasma CTGF level is an independent predictor of vascular disease as assessed by intimal medial thickness (35) and of mortality and progression to ESRD (36). In renal biopsy specimens from patients with diabetes, elevated levels of CTGF mRNA are associated with chronic tubulointerstitial damage, albuminuria, and progression of renal insufficiency (37)(38)(39).…”

mentioning

confidence: 99%

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Adler¹,

Schwartz²,

Williams³

et al. 2010

Clinical Journal of the American Society of Nephrology

186

103

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Background and objectives: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins.Design, setting, participants, and measurements: Microalbuminuric subjects (n ‫؍‬ 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively.Results: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P ‫؍‬ 0.027) without evidence for a dose-response relationship.Conclusions: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.

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“…They are useful as biomarkers in basic science studies exploring mechanisms of retinal damage and protection, and as a surrogate end-point [235,245]. Whilst there are some (positive) human diabetes studies (in the DCCT-EDIC cohort) linking CTGF genotype and urinary levels, they relate to nephropathy and surrogate end-points of cardiovascular disease [246,247] rather than retinopathy. Studies analyzing these markers in relation to retinopathy would be of interest.…”

Section: Angiogenesis-related Biomarkersmentioning

confidence: 99%

Biomarkers in Diabetic Retinopathy

et al. 2015

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■ AbstractThere is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

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Connective Tissue Growth Factor and Susceptibility to Renal and Vascular Disease Risk in Type 1 Diabetes

Abstract: These findings demonstrate that plasma CTGF is a risk marker of diabetic renal and vascular disease.

Cited by 54 publications

References 23 publications

Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Effects of Antiproteinuric Intervention on Elevated Connective Tissue Growth Factor (CTGF/CCN-2) Plasma and Urine Levels in Nondiabetic Nephropathy

Phase 1 Study of Anti-CTGF Monoclonal Antibody in Patients with Diabetes and Microalbuminuria

Biomarkers in Diabetic Retinopathy

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