Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies

Abrass, Christine K.; Berfield, Anne K.; Stehman‐Breen, Catherine; Alpers, Charles E.; Davis, Connie L.

doi:10.1016/s0272-6386(99)70252-0

Cited by 55 publications

(26 citation statements)

References 24 publications

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“…Our results are at variance with a report by Abrass et al (13), which suggested that a pattern of new expression of those molecules at the proximal TBM was specific for CR. In that study, CsAT resulted in the interstitial deposition of collagen I and III.…”

Section: Discussioncontrasting

confidence: 99%

“…We chose to study the molecules collagen I, III, and IV, because they are known to accumulate in the renal cortical interstitium during native kidney disease (5,14). The laminin ␤2 and collagen IV ␣3 chains were investigated because an earlier report suggested that de novo expression of these molecules at the proximal TBM could differentiate CR from chronic CsAT (13).…”

Section: Discussionmentioning

confidence: 99%

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Early Interstitial Accumulation of Collagen Type I Discriminates Chronic Rejection from Chronic Cyclosporine Nephrotoxicity

Bakker¹,

Koop²,

Sijpkens³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. Little is known regarding the composition of the interstitial extracellular matrix of kidney allografts with deteriorating function. Collagen I, III, and IV, the collagen IV α3 chain, and the laminin β2 chain were investigated in biopsies of allografted kidneys with chronic cyclosporine A nephrotoxicity (CsAT) (n = 17), chronic rejection (CR) (n = 12), or chronic allograft nephropathy (CAN) (n = 19). α-Smooth muscle actin expression was also examined. Normal native kidneys were used as control samples (n = 11). Biopsy samples were studied with routine light microscopy and immunostaining. The mean interstitial fibrosis scores were significantly higher for the CR and CAN groups, compared with the chronic CsAT group. The cortical tubulointerstitial areas of the CR and CAN groups, but not the chronic CsAT group, contained more collagen I than did normal control samples. Differences were noted even in biopsies with mild fibrosis. Accumulation of collagen III, IV, and IV α3 was increased in all patient groups. Collagen III accumulation was greater in the CR and CAN groups than in the chronic CsAT group. Receiver-operating characteristic curve analysis demonstrated that collagen I staining had the best discriminatory value in differentiating CR from chronic CsAT, with a sensitivity of 63% and a specificity of 94% at a cutoff value of 19%. Laminin β2 staining did not differentiate CR from CsAT. Increased α-smooth muscle actin staining did not differ among the three groups. It was concluded that, during chronic CsAT, collagen III and IV were preferentially accumulated in the tubulointerstitium. Early increases in the deposition of collagen I, with collagen III and IV, were more specific for CR. CR seems to elicit a more pronounced fibrotic response than does chronic CsAT. E-mail: RNR@euronet.nl

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early Interstitial Accumulation of Collagen Type I Discriminates Chronic Rejection from Chronic Cyclosporine Nephrotoxicity

Bakker¹,

Koop²,

Sijpkens³

et al. 2003

Journal of the American Society of Nephrology

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“…We previously reported a similar change in focal capillaries around proximal tubules in individuals with transplant rejection. 42 The functional significance of new expression of LN␤2 in this location is unknown, although similar transitions have been reported in other capillaries during active angiogenesis and microvessel maturation. 7,43 The expression of LN␣2 and LN␣5 in the face of altered peripheral migration of MCs and poor pericyte investment of other microvessels argues that these LN subunits cannot substitute for LN␣4 in mediating these functions.…”

Section: Abrass Et Almentioning

confidence: 60%

Laminin α4-Null Mutant Mice Develop Chronic Kidney Disease with Persistent Overexpression of Platelet-Derived Growth Factor

Abrass

Hansen

Patton

2010

The American Journal of Pathology

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Each extracellular matrix compartment in the kidney has a unique composition, with regional specificity in the expression of various laminin isoforms. Although null mutations in the majority of laminin chains lead to specific developmental abnormalities in the kidney, Lama4؊/؊ mice have progressive glomerular and tubulointerstitial fibrosis. These mice have a significant increase in expression of platelet-derived growth factor (PDGF)-BB, PDGF-DD, and PDGF receptor ␤ in association with immature glomerular and peritubular capillaries. In addition, mesangial cell exposure to ␣4-containing laminins, but not other isoforms, results in down-regulation of PDGF receptor mRNA and protein, suggesting a direct effect of LN411/LN421 on vessel maturation. Given the known role of overexpression of PDGF-BB and PDGF-DD on glomerular and tubulointerstitial fibrosis , these data suggest that failure of laminin ␣4-mediated down-regulation of PDGF activity contributes to the progressive renal lesions in this animal model. Given the recent demonstration that individuals with laminin ␣4 mutations develop cardiomyopathy , these findings may be relevant to kidney disease in humans.

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“…Glomerulosclerosis and tubulointerstitial fibrosis in 4M and 12M DSS rats aging (17,23,37). Recent studies have shown that in addition to excessive synthesis of the ECM, the presence of amorphous ECM deposits in progressive renal disease are due to decreased activity of the ECM degradative pathway (38,39).…”

Section: Discussionmentioning

confidence: 99%

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

Maric¹,

Sandberg²,

Hinojosa‐Laborde³

2004

Journal of the American Society of Nephrology

191

136

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Abstract. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17␤-estradiol (E 2 ) replacement (OVXϩE 2 ) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-␤ (TGF-␤), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 Ϯ 0.09 versus 12M, 1.43 Ϯ 0.17; P Ͻ 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 Ϯ 4.9; P Ͻ 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 Ϯ 0.34; CTIFI, 74.4 Ϯ 9.2; P Ͻ 0.01 versus Intact at 12M) and attenuated with E 2 replacement ([GSI], 1.09 Ϯ 0.09; CTIFI, 49.2 Ϯ 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 Ϯ 6.7; OVX, 277.4 Ϯ 9.6 AU; P Ͻ 0.01), increased expression of TGF-␤ (Intact, 85.0 Ϯ 23.0; OVX, 178.0 Ϯ 20.5 AU; P Ͻ 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 Ϯ 0.8; OVX, 2.4 Ϯ 0.6 AUC; P Ͻ 0.01). E 2 replacement opposed these effects (laminin, 229.9 Ϯ 6.2 AU; TGF-␤, 101.3 Ϯ 25.2 AU; MMP-9, 5.2 Ϯ 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 Ϯ 0.01; OVX, 0.22 Ϯ 0.01; OVXϩE 2 , 0.28 Ϯ 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 Ϯ 2.1; OVX, 32.6 Ϯ 5.1; OVXϩE 2 , 24.3 Ϯ 2.4 mg/dl). The authors conclude that E 2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.The rate of progression of cardiovascular and renal disease and hypertension increases with age and is lower in premenopausal women compared with age-matched men (1-3). Interestingly, a re-evaluation of the Modification of Diet in Renal Disease (MDRD) study showed that the differences in the rate of decline of renal function between men and women is reduced after age 52 yr (their dividing point) (4), suggesting that menopause may affect the progression of renal disease in women; however, no studies to date have clearly demonstrated this point, suggesting that our understanding of the contribution of ovarian hormones to the development of age-related disease processes remains unclear. The Women's Health Initiative (WHI) reported that hormone replacement therapy with the estrogen-progesterone combination Prempro (conjugated equine estrogen and progestin) causes a slight increase in the risk of cardiovascular disease in a large population of postmenopausal women (5,6). However, numerous studies indicate that estrogen alone has cardiovascular protective effects. Estrogen improves serum lipid levels, increases end...

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Unique changes in interstitial extracellular matrix composition are associated with rejection and cyclosporine toxicity in human renal allograft biopsies

Cited by 55 publications

References 24 publications

Early Interstitial Accumulation of Collagen Type I Discriminates Chronic Rejection from Chronic Cyclosporine Nephrotoxicity

Early Interstitial Accumulation of Collagen Type I Discriminates Chronic Rejection from Chronic Cyclosporine Nephrotoxicity

Laminin α4-Null Mutant Mice Develop Chronic Kidney Disease with Persistent Overexpression of Platelet-Derived Growth Factor

Glomerulosclerosis and Tubulointerstitial Fibrosis are Attenuated with 17β-Estradiol in the Aging Dahl Salt Sensitive Rat

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