| Abstract|| |
The dramatic improvement observed in the short term of graft survival following the introduction of cyclosporine A, led many transplant doctors to think that long term patient and graft survival will also show similar improvement. This has not been the case and after the first year, the survival curves run parallel to those observed during the earlier years. In an analysis of 446 patients whose grafts functioned for more than 1 year, chronic rejection alone accounted for more than 80% cases of graft loss among the 53 cases with progressive graft failure. Previous acute rejection was found to be an important predisposing factor to chronic rejection in these cases. Since chronic rejection is still an untreatable condition, all efforts should be made to prevent acute rejection in the hope that this may lessen the likelihood of late graft failure.
Keywords: Renal transplantation, Chronic rejection, Acute rejection, Cyclosporine A, Renal allograft loss.
|How to cite this article:|
Briggs J D. Incidence and Causes of Long-term Renal Allograft Loss. Saudi J Kidney Dis Transpl 1994;5:159-62
After a moderate rate of improvement in the 1970s, short-term graft survival improved to a greater degree during the 1980s. For example, the one year survival of cadaveric grafts in the Western Infirmary Unit in Glasgow, rose from around 60% in the early 1980s to more than 85% in the late 1980s. Some, although not all, of this improvement was due to the introduction of cyclosporine and many transplant doctors had the impression during the mid-1980s that this improve ment in short-term graft survival would lead to a substantial improvement in long-term patient and graft survival as well. However, this has not taken place and if one examines the survival curves from the early and late 1980S; one can gee that they run in parallel after the first year showing that most of the improvement in graft survival has been during the first year rather than later This short-term improvement has been mainly, although not entirely, due to a reduced incidence of graft loss from acute rejection. With the aim of further investigating the incidence and pattern of long-term graft loss, a group of 446 patients, whose cadaveric grafts functioned for longer than one year, were examined. Four patterns of function were seen, as follows:
- Stable good function: serum creatinine consistently is less than 200 µmol/L.
- Stable poor function: serum creatinine stable but greater than 200 µmol/L.
- Progressive dysfunction: slow but inexorable rise in serum creatinine over a period of months or years.
- Acute graft loss: sudden development of a rapid rise in serum creatinine after a period of stable renal function.
[Table 1] shows the incidence of these four patterns of function. Progressive graft dysfunction occurred in 14% of patients and if one adds to this acute graft loss, the total cumulative loss of grafts at five years amounts to around 20% of those patients who had functioning kidneys at one year after transplantation. Follow-up of patients beyond five years shows a continuing loss of grafts due mainly to progressive graft dysfunction but with a few cases of acute graft loss as well.
A breakdown of the causes of long-term graft loss is shown in [Table 2]. As with the earlier analysis, these were all kidneys which had functioned for at least one year. One can see that the overwhelming cause is chronic rejection with all the others combined amounting to less than 20%. All of these varieties of graft loss are irreversible and therefore the emphasis clearly must be on prevention rather than treatment therefore, to improve long-term graft survival, we have to concentrate on preventing chronic rejection. Before we are able to do this, we must know more about its etiology.
A large number of analyses have been carried out in an effort to determine the factors associated with chronic rejection. The most consistent association shown has been between the occurrence of one or more acute rejection episodes and the subsequent development of chronic rejection. In common with a number of other investigators, we have found a highly significant relationship between acute rejection and subsequent chronic rejection. Also there was no correlation between chronic rejection and other factors such as recipient age and sex, the degree of HLA match or the HLA sensitization status of the recipient. In our own analysis, we found that the cumulative risk at five years of progressive graft dysfunction was 25% in patients with one or more previous acute rejection episodes but only 10% in those with no previous acute rejection.
Various other aspects of this relationship between acute and chronic rejection have been looked at in a number of separate studies. One of these is the association between the time, during the post transplant period, of the occurrence of acute rejection and the development of chronic rejection. Basadonna et al, found an incidence of chronic rejection of 63% when acute rejection occurred more than two months post-transplant in contrast to 34% when acute rejection took place within the first two months  . Also in their analysis, of the 109 patients who did not have acute rejection at any time, none developed chronic rejection. Another interesting observation was reported by Van Sasse et al  . They showed a negligible difference in five year graft survival between patients with no acute rejection in the first three months (74%) and those with a previous acute rejection shown by renal biopsy to be cellular in type (72%). By contrast, patients with changes of vascular rejection on a previous biopsy had a five year graft survival of only 36%. The final analysis I wish to mention is that of Troppmann et al  . They showed that patients with delayed onset of renal function and subsequent acute rejection had a much lower graft survival at six years, namely 22%, than those with immediate function and subsequent acute rejection (59%) and immediate function and no acute rejection (79%). Thus, acute rejection would appear to be an important predisposing factor to chronic rejection, particularly when associated with ischemic damage or vascular changes on renal biopsy and when it either occurs late or more than once. The most important initiative to reduce the incidence of chronic rejection is probably therefore to reduce the incidence of acute rejection and our efforts should be directed along these lines.
While causes of long-term graft loss other than chronic rejection are important, they are all much less common. Recurrence of native kidney disease in renal allografts is well recognized but accounts for only a few percent of graft failures. In the long-term, the largest number of graft losses due to recurrence of original disease will probably be in patients with IgA nephropathy due to the fact that this is a common cause of renal failure as well as one of the diseases more liable to recur. .Other diseases with a high incidence of recurrence are focal segmental glomerulosclerosis, type II mesangiocapillary glomerulonephritis and the hemolytic uremic syndrome but as none of these entities are common causes of renal failure, the overall incidence of graft loss due to recurrence is small. The only condition in which renal transplantation is followed by a very high incidence of recurrence leading to graft failure is primary hyperoxaluria and the treatment of choice now for this entity is combined hepatic and renal transplantation which has been shown to produce good results  . In the much longer-term, diabetic nephropathy will recur but, at such a late stage that transplantation is still very worthwhile. The subject of recurrence of diseases is comprehensively reviewed by Matthew  . One point of importance is that the recognition of recurrent disease may be difficult as the renal allograft is often damaged by ischemia or rejection and the features of the recurrent disease are therefore not as clear cut as in the native kidneys. In this context, fluorescence microscopy is essential for the diagnosis of recurrent disease.
An uncommon cause of long-term dysfunction but rarely of graft loss is ureteric obstruction occurring as a result of fibrosis at the ureterovesical junction. This condition is often asymptomatic until associated with a severe degree of hydronephrosis, but is easily diagnosed at an early stage by renal ultrasound. There is therefore a good case for routine ultrasound examination of the graft at approximately annual intervals following transplantation. Another equally uncommon cause of dysfunction is transplant renal artery stenosis. This condition is frequently associated with hypertension but many renal allograft recipients are hypertensive without the presence of renal artery stenosis. Doppler examination is both a sensitive and specific screening test and an abnormal result is an indication for arteriography  .
The final and probably the most difficult cause of chronic dysfunction to diagnose, is cyclosporin nephrotoxicity. The histological features in this condition are basically those of ischemia with often no specific diagnostic features. A vasculopathy is sometimes seen but this can be difficult to distinguish from the vascular changes of chronic rejection. There are widely varying views both regarding the diagnosis of cyclosporin nephrotoxicity and the optimum cyclosporin dose to avoid rejection without causing nephrotoxicity. The high maintenance dose of more than 6.0 mg/kg/day used in the first few years after the introduction of cyclosporin were followed by downward revision to doses between 3.0 and 5.0 mg/kg/day. Increasing experience of long term cyclosporin use is now beginning to suggest that progressive nephrotoxicity is an uncommon problem and a number of studies have shown stable serum creatinine levels over periods of up to eight years in cyclosporin treated patients  . With the lessening in degree of concern about progressive cyclosporin nephrotoxicity and with the clear evidence that chronic rejection is by far the most important cause of long-term graft loss, we are probably now moving into a phase when long-term cyclosporin doses may even begin to rise slightly  . Many authorities now believe that the optimum long-term cyclosporin dose probably lies between 4.0 and 5.0 mg/kg/day and some analysis have suggested a dose of more than 5.0 mg/kg/day  . However, in considering high cyclosporin doses, one has to bear in mind not only the risk of nephrotoxicity but also of other side-effects of heavy immunosuppressive therapy, particularly that of neoplasia.
In summary, the main area of progress in renal transplantation during the 1980s has been the marked decrease in graft loss from acute rejection. As a consequence, chronic rejection has now emerged as the most important cause of graft failure. There is evidence from a number of sources that previous acute rejection is an important predisposing factor to chronic rejection and our efforts should therefore be directed at preventing acute rejection in the hope that this, in turn, will lower the incidence of chronic rejection.
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J D Briggs
Consultant Physician, Renal Unit, Western Infirmary, Glasgow, Gl 1 6NT
Source of Support: None, Conflict of Interest: None
[Table 1]SaudiJKidneyDisTranspl_1994_5_2_159_41342_1.jpg, [Table 2]SaudiJKidneyDisTranspl_1994_5_2_159_41342_2.jpg