Skip to main content

Advertisement

SpringerLink
Log in

Chronic allograft nephropathy in paediatric renal transplantation

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Chronic allograft nephropathy (CAN) is now the leading cause of renal transplant loss in paediatric transplant recipients. Despite improvements in immunosuppression, which have significantly reduced the incidence of acute rejection, the rates of chronic kidney loss have remained unchanged in paediatric transplant patients over the last 20 years. Chronic allograft nephropathy is a pathological diagnosis of which the key features are tubular atrophy and interstitial fibrosis. More consistent definitions and grading of these through the Banff classification have allowed more rigorous study of the development of chronic allograft nephropathy along with further identification of specific lesions associated with the underlying aetiologies. While initially thought to be primarily due to immune injury, it is now evident that CAN is the end result of a variety of immune and non-immune injuries including ischaemia reperfusion injury, calcineurin inhibitor (CNI) toxicity and infections. Protocol biopsy studies have demonstrated rates of CAN development in children similar to those in adults with comparable underlying pathological processes. This review outlines the current knowledge of CAN within the context of paediatric renal transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

CAN:

Chronic allograft nephropathy

SCR:

Subclinical rejection

CNI:

Calcineurin inhibitors

CADI:

Chronic Allograft Damage Index

CCTT:

Cooperative Clinical Trials in Transplantation

PAS:

Periodic Acid Schiff

ACR:

Acute cellular rejection

TGF-β:

Tissue Growth Factor - β

HLA:

Human Leucocyte Antigen

BK:

BK Polyoma virus

CMV:

Cytomegalovirus

EBV:

Epstein Barr virus

UNOS:

United Network of Organ Sharing

N/A:

not applicable

References

  1. Birk PE, Stannard KM, Konrad HB, Blydt-Hansen TD, Ogborn MR, Cheang MS, Gartner JG, Gibson IW (2004) Surveillance biopsies are superior to functional studies for the diagnosis of acute and chronic renal allograft pathology in children. Pediatr Transplant 8:29–38

    PubMed  Google Scholar 

  2. Grimm P (2004) The protocol renal allograft biopsy: has its time come? Pediatr Transplant 8:3–5

    PubMed  Google Scholar 

  3. Kasiske BL, Gaston RS, Gourishankar S, Halloran PF, Matas AJ, Jeffery J, Rush D (2005) Long-term deterioration of kidney allograft function. Am J Transplant 5:1405–1414

    PubMed  Google Scholar 

  4. Isoniemi H, Taskinen E, Hayry P (1994) Histological chronic allograft damage index accurately predicts chronic renal allograft rejection. Transplantation 58:1195–1198

    CAS  PubMed  Google Scholar 

  5. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindbald AS, Marcussen N, Mihatsch MJ, Nadasdy T, Nickerson P, Olsen TS, Papadimitriou JC, Randhawa PS, Rayner DC, Roberts I, Rose S, Rush D, Salinas-Madrigal L, Salomon DR, Sund S, Taskinen E, Trpkov K, Yamaguchi Y (1999) The Banff 97 working classification of renal allograft pathology. Kidney Int 55:713–723

    CAS  PubMed  Google Scholar 

  6. Solez K, Axelsen RA, Benediktsson H, Burdick JF, Cohen AH, Colvin RB, Croker BP, Droz D, Dunnill MS, Halloran PF, Hayry P, Jennette JC, Keown PA, Marcussen N, Mihatsch MJ, Morozumi K, Myers BD, Nast CC, Olsen S, Racusen LC, Ramos EL, Rosen S, Sachs DH, Salomon DR, Sanfilippo F, Verani R, Vonwillebrand E, Yamaguchi Y (1993) International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 44:411–422

    CAS  PubMed  Google Scholar 

  7. Feucht HE, Felber E, Gokel MJ, Hillebrand G, Nattermann U, Brockmeyer C, Held E, Riethmuller G, Land W, Albert E (1991) Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 86:464–470

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Colvin RB (2003) Chronic allograft nephropathy. N Engl J Med 349:2288–2290

    CAS  PubMed  Google Scholar 

  9. Nankivell BJ, Chapman JR (2006) Chronic allograft nephropathy: current concepts and future directions. Transplantation 81:643–654

    PubMed  Google Scholar 

  10. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR (2003) The natural history of chronic allograft nephropathy. N Engl J Med 349:2326–2333

    CAS  PubMed  Google Scholar 

  11. Jain S, Furness PN, Nicholson ML (2000) The role of transforming growth factor beta in chronic renal allograft nephropathy. Transplantation 69:1759–1766

    CAS  PubMed  Google Scholar 

  12. Pilmore HL, Eris JM, Painter DM, Bishop GA, McCaughan GW (1999) Vascular endothelial growth factor expression in human chronic renal allograft rejection. Transplantation 67:929–933

    CAS  PubMed  Google Scholar 

  13. Melk A, Schmidt BM, Vongwiwatana A, Rayner DC, Halloran PF (2005) Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney. Am J Transplant 5:1375–1382

    CAS  PubMed  Google Scholar 

  14. Vongwiwatana A, Tasanarong A, Rayner DC, Melk A, Halloran PF (2005) Epithelial to mesenchymal transition during late deterioration of human kidney transplants: the role of tubular cells in fibrogenesis. Am J Transplant 5:1367–1374

    CAS  PubMed  Google Scholar 

  15. Chapman JR, O’Connell PJ, Nankivell BJ (2005) Chronic renal allograft dysfunction. J Am Soc Nephrol 16:3015–3026

    PubMed  Google Scholar 

  16. Bunchman TE, Fryd DS, Sibley RK, Mauer SM (1990) Manifestations of renal allograft rejection in small children receiving adult kidneys. Pediatr Nephrol 4:255–258

    CAS  PubMed  Google Scholar 

  17. Singh A, Cortes L, Tejani A (1995) Pediatric renal transplantation. Curr Opin Nephrol Hypertens 4:478–481

    CAS  PubMed  Google Scholar 

  18. Qvist E, Krogerus L, Laine J, Jalanko H, Ronnholm K, Salmela K, Sairanen H, Leijala M, Holmberg C (1998) Long-term follow up of renal function and histology after renal allograft transplantation in early childhood. Transpl Int 11 (Suppl 1):S39–S41

    PubMed  Google Scholar 

  19. Birk PE, Chavers BM (1997) Does cytomegalovirus cause glomerular injury in renal allograft recipients? J Am Soc Nephrol 8:1801–1808

    CAS  PubMed  Google Scholar 

  20. Birk PE, Matas AJ, Gillingham KJ, Mauer SM, Najarian JS, Chavers BM (1997) Risk factors for chronic rejection in pediatric renal transplant recipients-a single-center experience. Pediatr Nephrol 11:395–398

    CAS  PubMed  Google Scholar 

  21. Tejani A, Cortes L, Stablein D (1996) Clinical correlates of chronic rejection in pediatric renal transplantation. A report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 61:1054–1058

    CAS  PubMed  Google Scholar 

  22. Mihatsch MJ, Ryffel B, Gudat F (1995) The differential diagnosis between rejection and cyclosporine toxicity. Kidney Int Suppl 52:S63–S69

    CAS  PubMed  Google Scholar 

  23. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Chapman JR, Allen RD (2004) Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 78:557–565

    CAS  PubMed  Google Scholar 

  24. Pascual M, Swinford RD, Ingelfinger JR, Williams WW, Cosimi AB, Tolkoff-Rubin N (1998) Chronic rejection and chronic cyclosporin toxicity in renal allografts. Immunol Today 19:514–519

    CAS  PubMed  Google Scholar 

  25. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ (2002) Risk of renal allograft loss from recurrent glomerulonephritis. N Engl J Med 347:103–109

    PubMed  Google Scholar 

  26. Chadban S (2001) Glomerulonephritis recurrence in the renal graft. J Am Soc Nephrol 12:394–402

    CAS  PubMed  Google Scholar 

  27. Gallagher MP, Hall B, Craig J, Berry G, Tiller DJ, Eris J (2004) A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients: 15-year results. Transplantation 78:1653–1660

    CAS  PubMed  Google Scholar 

  28. Rush DN, Jeffery JR, Gough J (1995) Sequential protocol biopsies in renal transplant patients. Clinico-pathological correlations using the Banff schema. Transplantation 59:511–514

    CAS  PubMed  Google Scholar 

  29. Beveridge T, Calne RY (1995) Cyclosporine (Sandimmun) in cadaveric renal transplantation. Ten-year follow-up of a multicenter trial. European Multicentre Trial Group. Transplantation 59:1568–1570

    CAS  PubMed  Google Scholar 

  30. Flechner SM, Kurian SM, Solez K, Cook DJ, Burke JT, Rollin H, Hammond J, Whisenant T, Lanigan C, Head S, Salomon D (2004) De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant 4:1776–1785

    CAS  PubMed  Google Scholar 

  31. Fujisawa M, Ono H, Isotani S, Higuchi A, Iijima K, Yoshiya K, Arakawa S, Matsumoto O, Nakamura H, Kamidono S, Yoshikawa N (1999) Significance of chronic transplant nephropathy on early protocol biopsies for graft outcome in pediatric renal transplantation. Transplant Proc 31:1687–1690

    CAS  PubMed  Google Scholar 

  32. Filler G, Womiloju T, Feber J, Lepage N, Christians U (2005) Adding sirolimus to tacrolimus-based immunosuppression in pediatric renal transplant recipients reduces tacrolimus exposure. Am J Transplant 5:2005–2010

    CAS  PubMed  Google Scholar 

  33. Schachter AD, Meyers KE, Spaneas LD, Palmer JA, Salmanullah M, Baluarte J, Brayman KL, Harmon WE (2004) Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol. Pediatr Transplant 8:171–177

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Dharnidharka VR, Stablein DM, Harmon WE (2004) Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant 4:384–389

    PubMed  Google Scholar 

  35. Srivastava T, Zwick DL, Rothberg PG, Warady BA (1999) Posttransplant lymphoproliferative disorder in pediatric renal transplantation. Pediatr Nephrol 13:748–754

    CAS  PubMed  Google Scholar 

  36. Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K, Vimalachandra D, Craig JC (2005) Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 365:2105–2115

    CAS  PubMed  Google Scholar 

  37. Ginevri F, De Santis R, Comoli P, Pastorino N, Rossi C, Botti G, Fontana I, Nocera A, Cardillo M, Ciardi MR, Locatelli F, Maccario R, Perfumo F, Azzi A (2003) Polyomavirus BK infection in pediatric kidney-allograft recipients: a single-center analysis of incidence, risk factors, and novel therapeutic approaches. Transplantation 75:1266–1270

    CAS  PubMed  Google Scholar 

  38. Oertel SH, Anagnostopoulos I, Bechstein WO, Liehr H, Riess HB (2000) Treatment of posttransplant lymphoproliferative disorder with the anti-CD20 monoclonal antibody rituximab alone in an adult after liver transplantation: a new drug in therapy of patients with posttransplant lymphoproliferative disorder after solid organ transplantation? Transplantation 69:430–432

    CAS  PubMed  Google Scholar 

  39. Mannon RB (2004) Polyomavirus nephropathy: what have we learned? Transplantation 77:1313–1318

    PubMed  Google Scholar 

  40. Nevins TE, Matas AJ (2004) Medication noncompliance: another iceberg’s tip. Transplantation 77:776–778

    PubMed  Google Scholar 

  41. Nevins TE (2002) Non-compliance and its management in teenagers. Pediatr Transplant 6:475–479

    PubMed  Google Scholar 

  42. Nevins TE, Kruse L, Skeans MA, Thomas W (2001) The natural history of azathioprine compliance after renal transplantation. Kidney Int 60:1565–1570

    CAS  PubMed  Google Scholar 

  43. Cecka JM, Gjertson DW, Terasaki PI (1997) Pediatric renal transplantation: a review of the UNOS data. United Network for Organ Sharing. Pediatr Transplant 1:55–64

    CAS  PubMed  Google Scholar 

  44. Smith JM, Ho PL, McDonald RA (2002) Renal transplant outcomes in adolescents: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 6:493–499

    PubMed  Google Scholar 

  45. Smith JM, McDonald RA (2005) Renal transplantation in adolescents. Adolesc Med Clin 16:201–214

    PubMed  Google Scholar 

  46. Rush DN, Henry SF, Jeffery JR, Schroeder TJ, Gough J (1994) Histological findings in early routine biopsies of stable renal allograft recipients. Transplantation 57:208–211

    CAS  PubMed  Google Scholar 

  47. Sarwal MM, Cecka JM, Millan MT, Salvatierra O Jr (2000) Adult-size kidneys without acute tubular necrosis provide exceedingly superior long-term graft outcomes for infants and small children: a single center and UNOS analysis. United Network for Organ Sharing. Transplantation 70:1728–1736

    CAS  PubMed  Google Scholar 

  48. Qvist E, Krogerus L, Ronnholm K, Laine J, Jalanko H, Holmberg C (2000) Course of renal allograft histopathology after transplantation in early childhood. Transplantation 70:480–487

    CAS  PubMed  Google Scholar 

  49. Rush D, Nickerson P, Gough J, McKenna R, Grimm P, Cheang M, Trpkov K, Solez K, Jeffery J (1998) Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 9:2129–2134

    CAS  PubMed  Google Scholar 

  50. Shishido S, Asanuma H, Nakai H, Mori Y, Satoh H, Kamimaki I, Hataya H, Ideda M, Honda M, Hasegawa A (2003) The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy. J Am Soc Nephrol 14:1046–1052

    PubMed  Google Scholar 

  51. Kamimaki I, Shishido S, Ikeda M, Honda M (2002) Histopathological findings of 10-year protocol biopsy in pediatric kidney transplant recipients. Transplant Proc 34:3130–3131

    CAS  PubMed  Google Scholar 

  52. Benamenyo JP, Droz D, Niaudet P (2001) One-year routine renal transplant biopsies in children. Pediatr Nephrol 16:971–977

    CAS  PubMed  Google Scholar 

  53. Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, Salvatierra O Jr (2003) Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 349:125–138

    CAS  PubMed  Google Scholar 

  54. Schaub S, Rush D, Wilkins J, Gibson IW, Weiler T, Sangster K, Nicolle L, Karpinski M, Jeffery J, Nickerson P (2004) Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol 15:219–227

    CAS  PubMed  Google Scholar 

  55. Sarwal M (2006) Steroid elimination is coming of age. Pediatr Nephrol 21:2–4

    PubMed  Google Scholar 

  56. Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC (2004) Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation 77:166–176

    CAS  PubMed  Google Scholar 

  57. Kreis H, Oberbauer R, Campistol JM, Mathew T, Daloze P, Schena FP, Burke JT, Brault Y, Gioud-Paquet M, Scarola JA, Neylan JF, Rapamune Maintenance Regimen Trial (2004) Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol 15:809–817

    CAS  PubMed  Google Scholar 

  58. Ibanez JP, Monteverde ML, Goldberg J, Diaz MA, Turconi A (2005) Sirolimus in pediatric renal transplantation. Transplant Proc 37:682–684

    CAS  PubMed  Google Scholar 

  59. Butani L (2004) Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 78:1362–1366

    PubMed  Google Scholar 

  60. Mulay AV, Hussain N, Fergusson D, Knoll GA (2005) Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials. Am J Transplant 5:1748–1756

    CAS  PubMed  Google Scholar 

  61. Russ G, Segoloni G, Oberbauer R, Legendre C, Mota A, Eris J, Grinyo JM, Friend P, Lawen J, Hartmann A, Schena FP, Lelong M, Burke JT, Neylan JF, for the Rapamune Maintenance Regimen Study Group (2005) Superior outcomes in renal transplantation after early cyclosporine withdrawal and sirolimus maintenance therapy, regardless of baseline renal function. Transplantation 80:1204–1211

    CAS  PubMed  Google Scholar 

  62. Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmaz S, Hayry P, Neylan JF, Ramamune Maintenance Regimen Trial (2004) Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant 4:953–961

    CAS  PubMed  Google Scholar 

  63. Hoyer PF, Ettenger R, Kovarik JM, Webb NJ, Lemire J, Mentser M, Mahan J, Loirat C, Niaudet P, VanDamme-Lombaerts R, Offner G, Wehr S, Moeller V, Mayer H, Everolimus Pediatric Study Group (2003) Everolimus in pediatric de nova renal transplant patients. Transplantation 75:2082–2085

    PubMed  Google Scholar 

  64. Krieger NR, Emre S (2004) Novel immunosuppressants. Pediatr Transplant 8:594–599

    CAS  PubMed  Google Scholar 

  65. Bartosh SM, Knechtle SJ, Sollinger HW (2005) Campath-1H use in pediatric renal transplantation. Am J Transplant 5:1569–1573

    CAS  PubMed  Google Scholar 

  66. Elster EA, Hale DA, Mannon RB, Cendales LC, Swanson SJ, Kirk AD (2004) The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials. Transpl Immunol 13:87–99

    CAS  PubMed  Google Scholar 

  67. Cosimi AB, Sachs DH (2004) Mixed chimerism and transplantation tolerance. Transplantation 77:943–946

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Kidney Research, Children’s Hospital at Westmead, Westmead, NSW, 2145, Australia

    Stephen I. Alexander & Jeffrey T. Fletcher

  2. Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, 2145, Australia

    Brian Nankivell

Authors
  1. Stephen I. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey T. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian Nankivell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen I. Alexander.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alexander, S.I., Fletcher, J.T. & Nankivell, B. Chronic allograft nephropathy in paediatric renal transplantation. Pediatr Nephrol 22, 17–23 (2007). https://doi.org/10.1007/s00467-006-0219-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-006-0219-y

Keywords

Search

Navigation