Glomerular mRNAs in human type 1 diabetes: Biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy

Adler, Sharon G.; Kang, Shin Wook; Feld, Stella; Ryong, Dae; Barba, Lilly; Striker, Liliane J.; Striker, Gary E.; Riser, Bruce L.; LaPage, Janine; Nast, Cynthia C.

doi:10.1046/j.1523-1755.2001.00073.x

Cited by 59 publications

(45 citation statements)

References 18 publications

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“…The apparent discrepancy with the similarly elevated kidney mRNA levels in all five microalbuminuric patients and six patients with DN reported by Adler et al (23) might indicate that plasma CTGF level is not solely determined by renal CTGF expression. Moreover, microalbuminuric patients are heterogeneous with respect to progression.…”

Section: Elevated Plasma Ctgf In Diabetic Nephropathycontrasting

confidence: 79%

“…Adler et al (23) found equally elevated CTGF mRNA levels in glomeruli of microalbuminuric (n ϭ 5) and DN (n ϭ 6) diabetic patients. We now add to this notion that CTGF-N levels are elevated in plasma of almost all type 1 diabetic patients with DN and also in about one-third of microalbuminuric patients, but only in a small minority of normoalbuminuric patients.…”

Section: Plasma Ctgf-n Level Correlates With Hba 1cmentioning

confidence: 96%

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Connective Tissue Growth Factor Is Increased in Plasma of Type 1 Diabetic Patients With Nephropathy

et al. 2004

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OBJECTIVE -Connective tissue growth factor (CTGF) is strongly upregulated in fibrotic disorders and has been hypothesized to play a role in the development and progression of diabetes complications. The aim of the present study was to investigate the possible association of plasma CTGF levels in type 1 diabetic patients with markers relevant to development of diabetes complications.RESEARCH DESIGN AND METHODS -Plasma CTGF levels (full-length and NH 2 -terminal fragments) were determined in 62 well-characterized patients with type 1 diabetes and in 21 healthy control subjects. Correlations of these plasma CTGF levels with markers of glycemic control, platelet activation, endothelial activation, nephropathy, and retinopathy were investigated.RESULTS -Elevated plasma NH 2 -terminal fragment of CTGF (CTGF-N) levels were detected in a subpopulation of type 1 diabetic patients and were associated with diabetic nephropathy. Stepwise regression analysis revealed contribution of albuminuria, creatinine clearance, and duration of diabetes as predictors of plasma CTGF-N level. Elevation of plasma CTGF-N levels in patients with retinopathy was probably due to renal comorbidity.CONCLUSIONS -Plasma CTGF-N levels are elevated in type 1 diabetic patients with nephropathy and appear to be correlated with proteinuria and creatinine clearance. Further studies will be needed to determine the relevance of plasma CTGF as a clinical marker and/or pathogenic factor in diabetic nephropathy.

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Section: Elevated Plasma Ctgf In Diabetic Nephropathycontrasting

confidence: 79%

Section: Plasma Ctgf-n Level Correlates With Hba 1cmentioning

confidence: 96%

Connective Tissue Growth Factor Is Increased in Plasma of Type 1 Diabetic Patients With Nephropathy

et al. 2004

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“…Elevated CTGF levels in glomeruli of NOD mice appear to correlate with the duration of diabetes (89). Elevated CTGF expression was also detected in human DN (89, 162,163). In vitro studies have shown that CTGF is induced in renal cells by both high glucose and AGE (87,89,160), as well as ROS (164), which they generate.…”

Section: Growth Factors and Hormones Affecting Matrix Protein Expressmentioning

confidence: 99%

Extracellular Matrix Metabolism in Diabetic Nephropathy

Mason

Wahab

2003

Journal of the American Society of Nephrology

578

495

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Abstract. Diabetic nephropathy is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane of the glomerulus and in the renal tubulointerstitium. This review summarizes the main changes in protein composition of the glomerular mesangium and basement membrane and the evidence that, in the mesangium, these are initiated by changes in glucose metabolism and the formation of advanced glycation end products. Both processes generate reactive oxygen species (ROS). The review includes discussion of how ROS may activate intracellular signaling pathways leading to the activation of redox-sensitive transcription factors. This in turn leads to change in the expression of genes encoding extracellular matrix proteins and the protease systems responsible for their turnover.

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“…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

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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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Glomerular mRNAs in human type 1 diabetes: Biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy

Cited by 59 publications

References 18 publications

Connective Tissue Growth Factor Is Increased in Plasma of Type 1 Diabetic Patients With Nephropathy

Connective Tissue Growth Factor Is Increased in Plasma of Type 1 Diabetic Patients With Nephropathy

Extracellular Matrix Metabolism in Diabetic Nephropathy

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

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