Original article
Apoptosis of tubulointerstitial chronic inflammatory cells in progressive renal fibrosis after cancer therapies

https://doi.org/10.1016/j.trsl.2007.01.006Get rights and content

Progressive renal fibrosis is an unwanted and limiting side effect of cancer treatments, whether they are systemic (for example, chemotherapy), local (for example, radiotherapy), or total body irradiation for allogenic bone marrow transplants. The relative roles of macrophages, myofibroblasts, and lymphocytes and the apoptotic deletion of renal functional or inflammatory cell populations in the pathogenesis of renal fibrosis are yet unclear. In this study, rat models of 2 renal cancer treatments: cis-platinum-(II)-diammine dichloride (cisplatin, 6-mg/kg body weight) and radiation (single dose of 20Gy) were used. Kidneys were analyzed 4 days to 3 months after treatment. The extent of renal fibrosis was compared with number and localization of chronic inflammatory cell populations, cell death (apoptosis and necrosis), and expression and localization of profibrotic growth factors transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-alpha (TNF-α). The models provided contrasting rates of fibrogenesis: After cisplatin, development of fibrosis was rapid and extensive (up to 50% fibrosis at 3 months); in comparison, radiation-induced fibrosis was slowly progressive (approximately 10% fibrosis at 3 months). The extent of fibrosis was associated spatially and temporally with increasing numbers of myofibroblasts with TGF-β1 or macrophages with TNF-α. Tubular epithelial apoptosis was highest with high TNF-α (P < 0.05). A significant inverse correlation existed between extent of tubulointerstitial fibrosis and interstitial cell apoptosis for cisplatin and a similar nonsignificant result for radiation (r2 = 0.8671 for cisplatin, P < 0.05; r2 = 0.2935 for radiation, NS). The latter result suggests a role for inflammatory cell apoptosis in minimizing development of renal fibrosis.

Section snippets

Animals and treatments

Sprague–Dawley rats (male, 200 ± 20g; n = 4 per treated or sham-treated group) were housed at 21°C, 12 h/12 h light/dark, and allowed free access to food and water. All experiments followed guidelines set down by the National Health and Medical Research Council of Australia (AEEC Number Path/050/03).

Functional analysis: BUN and plasma creatinine

BUN and plasma creatinine were used as indicators of renal function. Results for cisplatin and radiation treatments are presented in Fig. 1. A significant increase occurred in BUN and serum creatinine at 4 days post-treatment for cisplatin, when the animals were in acute renal failure, and again at 2 and 3 months, perhaps indicative of chronic renal disease. The BUN and creatinine in radiation treatment remained within normal limits, reflecting the limited development of fibrosis in this model.

Cell death and fibrosis in the renal tubulointerstitium

Discussion

Progressive renal fibrosis that may develop as a side effect of otherwise successful cancer treatments limits treatment options for cancer patients. Although significant progress has been made in understanding the pathomolecular pathways for fibrogenesis, new therapeutic approaches that apply such knowledge have rarely progressed beyond cell culture and animal experiments in controlling the fibrosis.26, 27 For control of fibrosis after its benefit to acute healing, and for progressive renal

References (40)

  • A.A. Eddy

    Progression in chronic kidney disease

    Adv Chronic Kidney Dis

    (2005)
  • B. Young et al.

    Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity

    Kidney Int

    (1995)
  • T. Hewitson et al.

    Interstitial myofibroblasts in experimental renal infection and scarring

    Am J Nephrol

    (1999)
  • M. Ide et al.

    Immunohistochemical analysis of macrophages and myofibroblasts appearing in hepatic and renal fibrosis of dogs

    J Comp Pathol

    (2001)
  • J. Yamate et al.

    Participation of different macrophage populations and myofibroblast cells in chronically developed interstitial fibrosis after cisplatin-induced renal injury in rats

    Vet Pathol

    (2002)
  • A. Lane et al.

    Myofibroblast apoptosis and growth factors in development and progression of renal tubulo-interstitial fibrosis in the rat

    Growth Factors

    (2002)
  • F.Y. Chow et al.

    Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis

    Nephrol Dial Transplant

    (2004)
  • D. Goumenos et al.

    Transforming growth factor-β1 and myofibroblasts: a potential pathway towards renal scarring in human glomerular disease

    Nephron

    (2001)
  • W. Qi et al.

    Transforming growth factor-beta1 differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells

    Am J Physiol Renal Physiol

    (2006)
  • D. Vesey et al.

    Interleukin-1β induces human proximal tubule injury, α-smooth muscle actin expression and fibronectin production

    Kidney Int

    (2002)
  • G. Gobe et al.

    The role of apoptosis in the development of renal cortical tubular atrophy associated with healed experimental renal papillary necrosis

    Pathology

    (1991)
  • W. Lieberthal et al.

    Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis

    Am J Physiol

    (1996)
  • G.L. Thomas et al.

    Cellular apoptosis and proliferation in experimental renal fibrosis

    Nephrol Dial Transplant

    (1998)
  • J. Schrama et al.

    Toxicity of the high dose chemotherapy CTC regimen (cyclophosphamide, thiotepa, carboplatin)The Netherlands Cancer Institute experience

    Br J Cancer

    (2003)
  • J. Hartmann et al.

    Platinum organ toxicity and possible prevention in patients with testicular cancer

    Int J Cancer

    (1999)
  • M. Robbins et al.

    The role of the tubulointerstitium in radiation-induced fibrosis

    Radiat Res

    (2001)
  • M. Robbins et al.

    Radiation-induced kidney injury: a role for chronic oxidative stress

    Micron

    (2002)
  • C. Lawton et al.

    Late renal dysfunction in survivors of bone marrow transplantation

    Cancer

    (1991)
  • Y. Oyama et al.

    Late onset bone marrow transplant nephropathy

    Intern Med

    (1996)
  • E.P. Cohen et al.

    End stage renal disease after bone marrow transplantation: poor survival compared with other causes of ESRD

    Nephron

    (1998)

    • Cited by (0)

    View full text
    Copyright © 2007 Mosby, Inc. All rights reserved.