Clinical manifestations and diagnosis of acute renal allograft rejection
- W James Chon, MD, FACP
W James Chon, MD, FACP
- Associate Professor
- Division of Nephrology & Hypertension, Department of Medicine
- University of Arkansas for Medical Sciences (UAMS)
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Medical Director and Co-Director of the Comprehensive Transplant Center, Department of Internal Medicine, Division of Nephrology
- Johns Hopkins Medical School
Acute renal allograft rejection is a major cause of allograft dysfunction. Some kidneys do not regain function even with maximal antirejection therapy. (See "Acute renal allograft rejection: Treatment".)
Even among patients who recover, acute rejection episodes can have a negative impact on long-term graft survival. Acute rejection is a major predictor of interstitial fibrosis/tubular atrophy (IF/TA), formerly called chronic allograft nephropathy, which is responsible for most death-censored graft loss after the first year posttransplant. (See "Chronic renal allograft nephropathy", section on 'Importance of acute rejection'.)
There has been a dramatic reduction in the incidence of acute rejection due to the introduction of potent immunosuppressive drugs in the past three decades. However, optimizing immunosuppression to both prevent allograft rejection and minimize drug toxicity, infection, and malignancy remains challenging.
A discussion of the clinical manifestations and diagnosis of acute renal allograft rejection is presented in this topic review. The treatment of acute rejection is presented separately. (See "Acute renal allograft rejection: Treatment".)
Acute renal allograft rejection is defined as an acute deterioration in allograft function associated with specific pathologic changes in the graft. There are two principal histologic forms of acute rejection:
- Rush DN, Henry SF, Jeffery JR, et al. Histological findings in early routine biopsies of stable renal allograft recipients. Transplantation 1994; 57:208.
- Shapiro R, Jordan ML, Scantlebury VP, et al. Renal allograft rejection with normal renal function in simultaneous kidney/pancreas recipients: does dissynchronous rejection really exist? Transplantation 2000; 69:440.
- Roberts IS, Reddy S, Russell C, et al. Subclinical rejection and borderline changes in early protocol biopsy specimens after renal transplantation. Transplantation 2004; 77:1194.
- Kee TY, Chapman JR, O'Connell PJ, et al. Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants. Transplantation 2006; 82:36.
- Nankivell BJ, Chapman JR. The significance of subclinical rejection and the value of protocol biopsies. Am J Transplant 2006; 6:2006.
- Scholten EM, Rowshani AT, Cremers S, et al. Untreated rejection in 6-month protocol biopsies is not associated with fibrosis in serial biopsies or with loss of graft function. J Am Soc Nephrol 2006; 17:2622.
- Serón D, Moreso F. Protocol biopsies in renal transplantation: prognostic value of structural monitoring. Kidney Int 2007; 72:690.
- Thaunat O, Legendre C, Morelon E, et al. To biopsy or not to biopsy? Should we screen the histology of stable renal grafts? Transplantation 2007; 84:671.
- Mengel M, Bogers J, Bosmans JL, et al. Incidence of C4d stain in protocol biopsies from renal allografts: results from a multicenter trial. Am J Transplant 2005; 5:1050.
- http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx (Accessed on May 17, 2013).
- Cecka, JM, Terasaki, PI. Early rejection episodes. In: Clinical Transplants, Terasaki, PI (Eds), UCLA Tissue Typing Laboratory, Los Angeles 1989. p.425.
- Opelz G, Döhler B, Collaborative Transplant Study Report. Influence of time of rejection on long-term graft survival in renal transplantation. Transplantation 2008; 85:661.
- Madden RL, Mulhern JG, Benedetto BJ, et al. Completely reversed acute rejection is not a significant risk factor for the development of chronic rejection in renal allograft recipients. Transpl Int 2000; 13:344.
- Vereerstraeten P, Abramowicz D, de Pauw L, Kinnaert P. Absence of deleterious effect on long-term kidney graft survival of rejection episodes with complete functional recovery. Transplantation 1997; 63:1739.
- Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4:378.
- Rush D, Arlen D, Boucher A, et al. Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study. Am J Transplant 2007; 7:2538.
- Rush D, Nickerson P, Gough J, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998; 9:2129.
- Nankivell BJ, Borrows RJ, Fung CL, et al. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation 2004; 78:242.
- Mengel M, Gwinner W, Schwarz A, et al. Infiltrates in protocol biopsies from renal allografts. Am J Transplant 2007; 7:356.
- Moreso F, Ibernon M, Gomà M, et al. Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss. Am J Transplant 2006; 6:747.
- Cosio FG, Grande JP, Wadei H, et al. Predicting subsequent decline in kidney allograft function from early surveillance biopsies. Am J Transplant 2005; 5:2464.
- Shishido S, Asanuma H, Nakai H, et al. The impact of repeated subclinical acute rejection on the progression of chronic allograft nephropathy. J Am Soc Nephrol 2003; 14:1046.
- Choi BS, Shin MJ, Shin SJ, et al. Clinical significance of an early protocol biopsy in living-donor renal transplantation: ten-year experience at a single center. Am J Transplant 2005; 5:1354.
- Solez K, Colvin RB, Racusen LC, et al. Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant 2007; 7:518.
- Pham, PTT, Nast, et al. Diagnosis and therapy of graft dysfunction. In: Chronic kidney disease, dialysis and transplantation, 2, Periera, BJG, Sayegh, MH, Blake, P (Eds), Elsevier Saunders, Philadelphia 2005. p.641.
- Schaub S, Rush D, Wilkins J, et al. Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol 2004; 15:219.
- Desvaux D, Schwarzinger M, Pastural M, et al. Molecular diagnosis of renal-allograft rejection: correlation with histopathologic evaluation and antirejection-therapy resistance. Transplantation 2004; 78:647.
- Amend, WJ, Vincenti, et al. The first three postansplant months. In: Handbook of Kidney Transplantation, 4th ed, Danovitch GM (Ed), Lippincott Williams & Wilkins, Philadelphia, PA 2005.
- Furness PN, Philpott CM, Chorbadjian MT, et al. Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates. Transplantation 2003; 76:969.
- Fereira LC, Karras A, Martinez F, et al. Complications of protocol renal biopsy. Transplantation 2004; 77:1475.
- Schwarz A, Gwinner W, Hiss M, et al. Safety and adequacy of renal transplant protocol biopsies. Am J Transplant 2005; 5:1992.
- Sorof JM, Vartanian RK, Olson JL, et al. Histopathological concordance of paired renal allograft biopsy cores. Effect on the diagnosis and management of acute rejection. Transplantation 1995; 60:1215.
- Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection: the Banff working classification of kidney transplant pathology. Kidney Int 1993; 44:411.
- Mauiyyedi S, Crespo M, Collins AB, et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol 2002; 13:779.
- Desvaux D, Le Gouvello S, Pastural M, et al. Acute renal allograft rejections with major interstitial oedema and plasma cell-rich infiltrates: high gamma-interferon expression and poor clinical outcome. Nephrol Dial Transplant 2004; 19:933.
- Meehan SM, Domer P, Josephson M, et al. The clinical and pathologic implications of plasmacytic infiltrates in percutaneous renal allograft biopsies. Hum Pathol 2001; 32:205.
- Aiello FB, Calabrese F, Rigotti P, et al. Acute rejection and graft survival in renal transplanted patients with viral diseases. Mod Pathol 2004; 17:189.
- Poduval RD, Kadambi PV, Josephson MA, et al. Implications of immunohistochemical detection of C4d along peritubular capillaries in late acute renal allograft rejection. Transplantation 2005; 79:228.
- Moll S, Pascual M. Humoral rejection of organ allografts. Am J Transplant 2005; 5:2611.
- Furness PN, Taub N, Convergence of European Renal Transplant Pathology Assessment Procedures (CERTPAP) Project. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project. Kidney Int 2001; 60:1998.
- Colvin RB, Cohen AH, Saiontz C, et al. Evaluation of pathologic criteria for acute renal allograft rejection: reproducibility, sensitivity, and clinical correlation. J Am Soc Nephrol 1997; 8:1930.
- Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713.
- Mueller A, Schnuelle P, Waldherr R, van der Woude FJ. Impact of the Banff '97 classification for histological diagnosis of rejection on clinical outcome and renal function parameters after kidney transplantation. Transplantation 2000; 69:1123.
- Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3:708.
- Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008; 8:753.
- Mengel M, Sis B, Haas M, et al. Banff 2011 Meeting report: new concepts in antibody-mediated rejection. Am J Transplant 2012; 12:563.
- Reinke P, Fietze E, Ode-Hakim S, et al. Late-acute renal allograft rejection and symptomless cytomegalovirus infection. Lancet 1994; 344:1737.
- McGilvray ID, Lajoie G, Humar A, Cattral MS. Polyomavirus infection and acute vascular rejection in a kidney allograft: coincidence or mimicry? Am J Transplant 2003; 3:501.
- EPIDEMIOLOGY AND OUTCOMES
- Acute rejection
- Subclinical rejection
- CLINICAL FEATURES
- Clinical manifestations
- Laboratory manifestations
- Radiographic manifestations
- MONITORING FOR ACUTE REJECTION
- Laboratory monitoring
- Protocol (surveillance) biopsies
- Selection of patients for biopsy
- Histopathologic diagnosis
- DIFFERENTIAL DIAGNOSIS
- Clinical symptoms
- Elevated serum creatinine
- Histologic findings
- SUMMARY AND RECOMMENDATIONS