Significance of Early Biopsy in Pediatric Kidney Transplantation

Abstract

Long-term renal allograft survival is limited mainly by the progressive process termed chronic allograft nephropathy (CAN) or chronic rejection. A pathological feature of CAN is characterized by progressive interstitial fibrosis. Transforming growth factor (TGF)-β₁ plays an important role in fibrogenesis. We investigated whether the degree of TGF-β₁ expression in early biopsy specimens routinely obtained from stable allografts at 100 days could predict fibrosis and graft dysfunction in the late phase by immunohistochemistry. Patients were children with a graft from related donors. We immunohistochemically determined intracellular and extracellular expression of TGF-β₁ in the graft at 100 days using LC antibody (LC) for intracellular TGF-β₁ and CC antibody (CC) for extracellular TGF-β₁. We used the change in creatinine clearance between 100 days and 3 years after transplantation (ΔCcr) as an index of long-term graft function. Image analysis was used to calculate the relative area involved by interstitial fibrosis in trichrome-stained sections of graft biopsy specimens at 100 days and 3 years, designating the change as ΔFI. ΔCcr was - 4.2 ± 9.4 mL/min in subjects with minimal early immunoreactivity for CC and - 20.5 ± 5.9 mL/min in subjects with strong reactivity (p < 0.05). ΔCcr was - 14.5 ± 18.6 mL/min in subjects with minimal early immunoreactivity for LC and - 11.7 ± 12.8 mL/min in those with strong reactivity. ΔFI in subjects with minimal CC reactivity (1.28 ± 4.11 %) tended to be lower than in subjects with strong reactivity (8.45 ± 15.47 %). Neither fibrosis at 100 days nor ΔFI differed between subjects with minimal and strong LC reactivity. Thus, extracellular TGF-β₁ expression in grafts at 100 days after transplantation has an influence on long-term graft function and tends to be associated with increased graft fibrosis at 3 years.

Key words

Chronic allograft nephropathy - renal function - fibrosis - kidney transplantation

References

• 1 Kahan B D. Cyclosporine.  N Engl J Med. 1989;  321 1725
• 2 Burke J F, Pirsch J D, Ramos E L, Salomon D R, Srabkein D M, Buren D H van, West J C. Long-term efficacy and safety of cyclosporine in renal transplant recipients.  N Engl J Med. 1994;  331 358
• 3 Carpenter C B. Long-term failure of renal transplants; adding insult to injury.  Kidney Int. 1995;  48 (suppl 50) S40
• 4 Paul L C. Chronic renal transplant loss.  Kidney Int. 1995;  47 1491
• 5 The Canadian Multicenter Transplant Study Group . A randomized trial of cyclosporine in cadavaric renal transplantation.  N Engl J Med. 1983;  309 809
• 6 Bia M J. Nonimmunologic causes of late renal graft loss.  Kidney Int. 1995;  47 1470
• 7 Racusen L C, Solez K, Colvin R B, Bonsib S M, Castro M C, Cavallo T, Crocker B P, Demetris A J, Dranchenberg C E, Fogo A B, Furness P, Gaber L W, Gibson I W, Glotz D, Goldberg J C, Grande J, Halloran P P, Hansen H E, Hartley B, Hayry P J, Hill C M, Hoffman E O, Hunsicker L G, Linbrand A S, Marcussen N, Mihatsch M J, Nadasdy T, Nickerson P, Olsen T S, Paradimitriou J C, Randhawa P S, Rayner D C, Roberts I, Rose S, Rush D, Salinas-Madrigal L, Salomon D R, Sund S, Taskinen E, Trpkov K, Yamaguchi Y. The Banff 97 working classification of renal allograft pathology.  Kidney Int. 1999;  55 713
• 8 Kasiske B L, Kalil R S, Lee H S, Rao K Y. Histopathologic findings associated with a chronic progressive decline in renal allograft function.  Kidney Int. 1991;  40 514
• 9 Bruijn J A, Hogendorn P CW, Hoedemaeker P J, Fleuren G J. The extracellular matrix in pathology.  J Lab Clin Med. 1988;  111 140
• 10 Border W A, Noble N A. Transforming growth factor β in tissue fibrosis.  N Engl J Med. 1994;  331 1286
• 11 Border W A, Rupslahti E. Transforming growth factor-β in disease: The dark side of tissue repair.  L Clin Invest. 1992;  90 1
• 12 Laszlo Z H, Helmut F, Martin S, Bettina B, Judith D, Leslie I G, Murray K, Markus W B. Altered expression of transforming growth factor-βs in chronic renal rejection.  Kidney Int. 1996;  50 489
• 13 Fuad S S, Amie M T, Yuanlin S, Maria I W. Expression of TGF-β and matrix protein is elevated in rats with chronic rejection.  Kidney Int. 1996;  50 1904
• 14 Vijay K S, Roxana M B, Guo-Ping X, Baogui L, Janet M, John W, David S, Venkateswara R, Manikkam S. Intragraft TGF-β₁ mRNA: A correlate of interstitial fibrosis and chronic allograft nephropathy.  Kidney Int. 1996;  49 1297
• 15 Bulent C, Mysore S AK, Roy D B, Bruce P, Gail H, David A L, Moona A, Carolyn G, Kathy C, Lavjay B, Benjamin C S, Oleh G P. Transforming growth factor-β levels in human allograft chronic fibrosis correlate wirb rate of decline in renal function.  Transplantation. 1999;  68 785
• 16 Roberts A B, Sporn M B. The transforming factor-βs. In: Peptide growth factors and their receptors: Handbook of Experimental Pharmacology, Sporn MB, Roberts AB (eds.). Heidelberg: Springer 1990 95: pp 419-pp419
• 17 Derynck R, Lindquist P B, Lee A, Wen D, Tamm J, Graycar J L, Rhee L, Mason A J, Miller D A, Coffey R J, Moses H L, Chen E Y. A new type of transforming growth factor β, TGF-β₃.  EMBO J. 1987;  6 1633
• 18 Nakamura T, Miller D, Ruosrahti E, Border W A. Production of extracellular matrix by glomerular epithelial cell is regulated by transforming growth factor-β₁.  Kidney Int. 1991;  41 1213
• 19 Okuda S, Languino L R, Ruoslahti E, Border W A. Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis.  J Clin Invest. 1990;  86 453
• 20 Ignotz R A, Massague J. Transforming growth factor beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix.  J Biol Chem. 1986;  261 4337
• 21 Kehrl J H. Transforming growth factor-β: An important mediator of immunoregulation.  Int J Cell Cloning. 1991;  9 438
• 22 Rush D N, Henry S F, Jeffery J R, Schroeder T J, Gough J. Histological findings in early routine biopsies of stable renal allograft recipients.  Transplantation. 1994;  57 208
• 23 Isoniemi H M, Krogerus L, Willebrand E von, Taskinen E, Ahonen J, Hayry P. Histopathological findings in well-functioning, long-term renal allografts.  Kidney Int. 1992;  41 155
• 24 Rush D N, Jeffery J R, Gough J. Sequential protocol biopsies in renal transplant patients.  Transplantation. 1995;  59 511
• 25 Fujisawa M, Ono H, Isotani S, Higuchi A, Iijima K, Yoshiya K, Aarakawa S, Matumoto O, Nakamura H, Kamidono S, Yoshikawa N. Significance of chronic transplant nephropathy on early protocol biopsies for graft outcome in pediatric renal transplantation.  Transplant Proc. 1999;  31 1678
• 26 Thompson N L, Flanders K C, Smith J M, Ellingworth L R, Roberts A B, Sporn M B. Expression of transforming growth faxtor-β, in specific cell and tissues of adult and neonatal mice.  J Cell Biol. 1989;  108 661
• 27 Flanders K C, Roberts A B, Ling N, Fleurdelys B E, Sporn M B. Antibodies to peptide determinants in transforming growth factor-β and their application.  Biochemistry. 1988;  27 739