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Saturday 12th December, 2003

 
 
 

Study finds that chronic allograft nephropathy has become the dominant cause of kidney-transplant failure.

 
 

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With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure.

Early rejection is associated with activation of the body's immune system by the transplanted tissue (allograft). T lymphocytes are the the principal immune cells involved and have a direct specificity against donor antigens.  With improved immunosuppression early rejection has become a less common cause of transplant failure.

The failure of transplanted kidneys after several years of adequate function is said to be due to "chronic rejection." In such kidneys, the development of nephrosclerosis (hardening of the renal vessels), with proliferation of the vascular intima of renal vessels, and intimal fibrosis, with marked decrease in the lumen of the vessels, takes place. The result is renal ischemia, hypertension, tubular atrophy, interstitial fibrosis, and glomerular atrophy with eventual renal failure. In addition to the established influence of HLA incompatibility, the age, number of nephrons, and ischemic history of a donor kidney may contribute to ultimate progressive renal failure in transplanted patients. Calcineurin inhibitors (cyclosporine or tacrolimus) may cause deterioration in renal function in a manner similar to a rejection episode. In fact, rejection processes tend to be more indolent with these inhibitors, and the only way to make a diagnosis may be by renal biopsy.

Most late renal allograft loss, other than that associated with the death of the patient, has been attributed to progressive renal dysfunction, termed "chronic allograft nephropathy" (or CAN), a confusing term that lacks a proper definition. It represents an incremental damage to the nephrons from time-dependent immunologic and nonimmunologic causes. It is characterized by progressive renal dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes, and glomerulosclerosis.

When renal function has been good initially, a rise in the serum creatinine level is the most sensitive and reliable indicator of possible rejection and may be the only sign. Arteriography and radioactive iodohippurate sodium renograms of the transplanted kidney may be useful in ascertaining changes in the renal vasculature and in renal blood flow, even in the absence of urinary flow.

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Unfortunately, not much more was known about chronic allograft nephropathy. Recently, the results of a study was designed to investigate the natural history of chronic allograft nephropathy was published in the New England Journal of Medicine. The study which was conducted on a 120 diabetes type 1 patients who received a kidney?pancreas transplant, collected kidney-transplant biopsies regularly for up to 10 years after transplantation. Sequential biopsy specimens were used to pinpoint the onset and evolution of histologic features of chronic allograft nephropathy and their relation to potential risk factors. Patients were treated with triple-therapy immunosuppression that incorporated cyclosporine or tacrolimus. Prednisolone was also given with either azathioprine or mycophenolate mofetil.

Several types of histological reactions were observed. Acute vascular rejection type which results in immediate and extensive immune mediated histologic damage. And secondly, an acute cellular rejection, which, unless severe, caused minimal direct damage or it lead to initiation of persistent subclinical rejection. Subclinical rejection was common early after transplantation and was followed by chronic interstitial fibrosis, tubular atrophy, and nephron loss, contributing to chronic allograft nephropathy especially between 3 and 12 months after transplantation. Persistent graft inflammation led to evidence of chronic tubulointerstitial damage on subsequent biopsy specimens in this and other studies. Because subclinical rejection and tubulitis are patchy processes, the uninvolved nephrons can maintain stable serum creatinine levels by means of compensatory hyperfiltration; consequently, the immunologic injury is clinically silent.

The study demonstrated that long-term calcineurin-inhibitor nephrotoxicity is common and characterized by increasing arteriolar hyalinosis, small-vessel narrowing, and progressive ischemic glomerulosclerosis.  The study goes on to suggest that a two-stage treatment may be preferable, optimizing therapy according to the individual risks during each period after transplantation. An initial stage of powerful therapy incorporating a calcineurin inhibitor might minimize early immunologic injury and its attendant nephron loss. Once subclinical rejection is controlled and possibly verified by biopsy, a second stage of therapy incorporating long-term non-nephrotoxic immunosuppression might be undertaken.

References

Brian J. Nankivell, M.D., Ph.D., Richard J. Borrows, M.B., B.Chir., Caroline L.-S. Fung, M.B., B.S., F.R.C.P.A., Philip J. O'Connell, M.B., B.S., Ph.D., Richard D.M. Allen, F.R.A.C.S., and Jeremy R. Chapman, M.D., Ch.B. The Natural History of Chronic Allograft Nephropathy. NEJM 2003; 349:2326-2333.

 

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