Correspondence

Chronic Allograft Nephropathy

N Engl J Med 2004; 350:1254-1256March 18, 2004

Article

To the Editor:

Nankivell et al. (Dec. 11 issue)1 report that serial renal biopsies in recipients of kidney and pancreas transplants who were given calcineurin inhibitors showed that chronic rejection was rare but that, over time, these drugs led to irreversible lesions. The authors conclude that calcineurin inhibitors are unsuitable for long-term immunosuppression.

The authors should be congratulated for their informative contribution, but their conclusions may be challenged. With a regimen based on calcineurin inhibitors, Nankivell et al. report that the survival rate for kidney grafts, with data censored for patients who died, was 95.2 percent at 10 years. I wonder whether immunosuppressive regimens without calcineurin inhibitors would have prevented chronic rejection, which represented by far the most common cause of late graft failure before the introduction of calcineurin inhibitors. On the other hand, the nephrotoxicity of calcineurin inhibitors does not necessarily lead to the failure of kidney grafts over time. On the basis of our own cumulative experience with cyclosporine, my colleagues and I reported a graft half-life, with data censored for patients who died, of 31 years.2 Caution should be recommended before calcineurin inhibitors are abandoned.

Claudio Ponticelli, M.D.
Via Ampere 126, 20131 Milan, Italy

2 References

1. 1

   Nankivell BJ, Borrows RJ, Fung CL-S, O'Connell PJ, Allen RDM, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-2333
   Full Text | Medline

2. 2

   Ponticelli C, Villa M, Cesana B, Montagnino G, Tarantino A. Risk factors for late kidney allograft failure. Kidney Int 2002;62:1848-1854
   Web of Science | Medline

To the Editor:

Nankivell et al. analyzed the deleterious effect of ischemia on graft outcome at one year. They found an increased incidence of chronic allograft nephropathy among patients with acute tubular necrosis, predominantly with a new onset of tubulointerstitial damage. We recently assessed the distinct contributions of alloreactivity and cold ischemia to the progression of chronic allograft nephropathy.1 Our findings suggest that although immune activation plays the most critical role, ischemia added to the allogeneic background turns into a strong inflammatory insult that accelerates the involved cellular mechanisms, leading to severe tubulointerstitial damage. The usual immunosuppressive schedule used in this well-established model of chronic allograft nephropathy could not control the early immune inflammatory response. These findings suggest that the introduction of new drugs to interfere with these initial mechanisms might be an exciting strategy to explore. In fact, there is some evidence of a promising beneficial effect of antiinflammatory or immunomodulatory strategies on long-term graft outcome.2,3 We think it is time to consider the treatment of post-transplantation inflammatory T-cell–mediated cellular changes associated with renal ischemic injury to prevent chronic allograft nephropathy most effectively.

Juan Torras, M.D.
Immaculada Herrero-Fresneda, M.D.
Josep M. Grinyo, M.D.
Hospital Universitario de Bellvitge, 08907 Barcelona, Spain
15268jta@comb.es

3 References

1. 1

   Herrero-Fresneda I, Torras J, Cruzado JM, et al. Do alloreactivity and prolonged cold ischemia cause different elementary lesions in chronic allograft nephropathy? Am J Pathol 2003;162:127-137
   CrossRef | Web of Science | Medline

2. 2

   Reutzel-Selke A, Zschockelt T, Denecke C, et al. Short-term immunosuppressive treatment of the donor ameliorates consequences of ischemia/reperfusion injury and long-term graft function in renal allografts from older donors. Transplantation 2003;75:1786-1792
   CrossRef | Web of Science | Medline

3. 3

   Kusaka M, Zandi-Nejad K, Kato S, et al. Exploitation of the continuum between early ischemia/reperfusion injury and host alloresponsiveness: indefinite kidney allograft survival by treatment with a soluble P-selectin ligand and low-dose cyclosporine in combination. Transplantation 1999;67:1255-1261
   CrossRef | Web of Science | Medline

To the Editor:

Chronic allograft nephropathy has previously been suggested to cause graft loss in 30 to 40 percent of cases in which the allograft failed more than one year after transplantation.1 However, calcineurin-inhibitor toxicity was implicated in less than 10 percent of cases. In contrast, Nankivell et al. report that 10 years after transplantation, 100 percent of patients had calcineurin-inhibitor nephrotoxicity, and the authors therefore suggest calcineurin-inhibitor–free immunosuppression for long-term treatment. In view of the major implications for the treatment of chronic allograft nephropathy, the sensitivity and specificity of the histopathological diagnosis of calcineurin-inhibitor nephrotoxicity, as well as interobserver variation, should be provided. Previous studies have already shown a very high rate of interobserver variation in the interpretation of findings on renal-transplant biopsy, especially with respect to chronic allograft nephropathy.2 Furthermore, since whole-blood concentrations of calcineurin inhibitors, and presumably also the type of calcineurin inhibitor used, affect nephrotoxicity, trough levels of cyclosporine and tacrolimus should be presented.3,4

Miriam Pietrzyk, M.D.
Ute Hoffmann, M.D.
Bernhard K. Krämer, M.D.
Klinikum der Universität Regensburg, D-93042 Regensburg, Germany
bernhard.kraemer@klinik.uni-regensburg.de

4 References

1. 1

   Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-590
   Full Text | Web of Science | Medline

2. 2

   Furness PN, Taub N. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project. Kidney Int 2001;60:1998-2012[Erratum, Kidney Int 2001;60:2429.]
   CrossRef | Web of Science | Medline

3. 3

   Mayer AD. Chronic rejection and graft half-life: five-year follow-up of the European Tacrolimus Multicenter Renal Study. Transplant Proc 2002;34:1491-1492
   CrossRef | Web of Science | Medline

4. 4

   Jurewicz WA. Tacrolimus versus cyclosporin immunosuppression: long-term outcome in renal transplantation. Nephrol Dial Transplant 2003;18:Suppl 1:i7-i11
   CrossRef | Web of Science | Medline

Author/Editor Response

We do not propose the complete abandonment of calcineurin inhibitors in the absence of alternative approaches to immunosuppression that have been proved effective. As noted by Dr. Ponticelli, our excellent 10-year rate of graft survival, with data censored for patients who died, was facilitated by the use of calcineurin inhibitors, agents that probably alter the histologic pattern of transplanted kidneys. However, any projected improvement in graft half-life must be contrasted with actual graft-survival curves, which still show a progressive and inexorable attrition, despite more potent therapies.1 Whether calcineurin inhibitors can be administered at an effective and safe dose is problematic. Our data indicated that a dose of 5 mg of cyclosporine per kilogram of body weight per day or a higher dose led to progressive arteriolar hyalinosis in pairs of specimens from sequential biopsies, suggesting a threshold dose for cyclosporine nephrotoxicity in this population (but not necessarily in individual patients). This dose is remarkably similar to the widely cited optimal cyclosporine dose that has been suggested to prevent chronic immunologic graft failure,2 indicating an overlap of the nephrotoxic and therapeutic ranges. Hence, we reaffirm our conviction that cyclosporine is unsuitable for long-term therapy in a broad population of kidney-transplant recipients.

We agree with Dr. Pietrzyk and colleagues that interobserver variation occurs in the assessment of renal-transplant biopsy specimens, particularly with acute rejection, which, with the use of the Banff schema, hinges on the finding of relatively scarce tubulitis. In contrast, the changes of chronic allograft nephropathy are relatively easy to recognize and there is correspondingly better agreement between pathologists on these changes. Our interobserver kappa statistics for chronic allograft nephropathy, calcineurin nephrotoxicity, and subclinical rejection were 0.61, 0.48, and 0.76, respectively, and the intraobserver kappa statistics were 0.93, 0.83, and 0.80, respectively. Variation was easily compensated for by the large numbers of biopsies. The specificity and sensitivity for the diagnosis of chronic allograft nephropathy were not calculated, since histologic examination itself is the gold standard. The mean (±SD) cyclosporine dose and trough levels at 1, 5, and 10 years were 5.1±1.5, 4.7±1.5, and 4.1±1.0 mg per kilogram per day and 221±115, 178±102, and 121±51 ng per milliliter, respectively. The one-year tacrolimus dose and trough levels were 0.12±0.06 mg per kilogram per day and 12.4±4.6 ng per milliliter, respectively. Substantial calcineurin-inhibitor nephrotoxicity still occurred with conventional doses and trough levels.

Our study showed an independent effect of both ischemic injury and acute rejection in contributing to tubular damage, results that were similar to the experimental histologic findings of Dr. Torras and colleagues, but we cannot discriminate between an additive and a synergistic mode of action. The greatest burden of tubulointerstitial damage occurred within three months after transplantation and was reduced by tacrolimus and mycophenolate therapy. Hence, controlling early immune-mediated injury and ischemia–reperfusion damage remains the best strategy for preserving functional nephrons.

Brian J. Nankivell, M.D., Ph.D.
Jeremy R. Chapman, M.D.
Westmead Hospital, Westmead 2145, NSW, Australia
Brian_Nankivell@wsahs.nsw.gov.au

2 References

1. 1

   Cecka JM. The UNOS renal transplant registry. In: Cecka JM, Terasaki PI, eds. Clinical transplants 2002. Los Angeles: UCLA Immunogenetics Center, 2003:1-20.
   

2. 2

   Helderman JH, Van Buren DH, Amend WJJ, Pirsch JD. Chronic immunosuppression of the renal transplant patient. J Am Soc Nephrol 1994;4:Suppl:S2-S9
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Waichi Wong, Jean-Pierre Venetz, Nina Tolkoff-Rubin, Manuel Pascual. (2005) 2005 Immunosuppressive Strategies in Kidney Transplantation: Which Role for the Calcineurin Inhibitors?. Transplantation 80:3, 289-296
   CrossRef