Types of transplants

FIGURE 2 shows the evolution of the different types of renal transplants since 1984. Renal transplants from cadaver donors (RTC) are more frequent in Catalonia. At the beginning of the 1980's, transplant from live donors (RTL) was more frequently used, 45 were done in 1984, but the number of this types of transplant has been decreasing. Multiple transplants from cadaver donors have become more common. The first transplants done were of the kidney and pancreas in diabetic patients, which have increased since 1990 to more than ten transplants every year, and in recent years has been between fifteen and twenty per year. A more recently developed activity, multiple transplant of the kidney and liver, is still less common, with 5 transplants of this type in 1997 and 29 from 1988. Double kidney transplants (dual RT) were performed for the first time in 1997. There has resulted in an attempt to take better advantage of resources, since with this new technique kidneys can be considered viable organs when the transplant of a single kidney would not be considered acceptable.

Since 1984 there have been some changes in the characteristics of the renal transplants done, in the selection criteria of the recipients as well as the technique itself. TABLE 2 shows a summary of the data from the various factors studied, and groups the years into two periods: the former collects the transplants done from 1984 to 1989, and the second from 1990 to 1997.

In summary, it is possible to say that currently in Catalonia transplants are being done in older patients, with more HLA-DR matches, that these patients reach the stage of transplantation less hypersensitive, that more transplants are done with diabetic patients (principally simultaneous kidney and pancreas transplants), that there is a slight increase in the proportion of patients that receive a retransplant and that the number of patients who are not residents of Catalonia has decreased.

FIGURE 2. Evolution of the number of transplants by type. Period 1984-1997

TABLE 2. Comparative data on renal transplant in Catalonia. Periods 1984-1989 and 1990-1997

 

Description of the population in renal replacement therapy

FIGURE 3 shows the age and gender pyramid for patients in RRT, patients with a functioning renal transplant, residents of Catalonia on December of 1997. Compared to the Catalan population, were the distribution is basically inverse, the patient population is older and presents a slightly greater percentage of men. FIGURE 4 shows the age and gender pyramid for all the patients that received a transplant in Catalonia in the period 1990-1997, at the moment of their transplant.

The mean age of patients at the moment of receiving a renal transplant has gone from 34.0 years in 1985 to 47.4 years in 1997 (FIGURE 5).

FIGURE 6 presents the evolution of the distribution of patients in RRT on December 31 according to their type of treatment (dialysis or transplant), and their age group. In 1986, 48.1% of patients under 45 years old had a functioning transplant; in 1997, this proportion was 62.4%. The increased rate in the group from 45 to 64 years old is even more spectacular: from 17.4% in 1986 to 54.3% in 1997. In the group of patients over 64 years, the percentage of patients with a functioning transplant was practically non-existent in 1986, while in 1997 it had grown to 13.8%.

FIGURE 3. Age and gender pyramid of patients in renal replacement therapy and with a functioning renal transplant on December 31, 1997

FIGURE 4. Age and gender pyramid of patients that received a transplant. Transplants 1990-1997

FIGURE 5. Evolution of the percentage of renal transplants in patients over 55 years and the mean age of patients that have received a transplant. Period 1984-1997

FIGURE 6. Distribution of patients on dialysis with a functioning transplant, by age group. Period 1986-1997

 

Primary renal disease

Primary renal diseases (PRD) that present with the most frequency are of unknown etiology in 20.4% of the patients who begin RRT, diabetes in 16.8%, followed by a nephropathy of glomerular origin with 16.7%. The most frequent PRD of patients who have received a renal transplant are of glomerular origin in 20.8% of patients, interstitial nephropathy in 16.8% and of unknown etiology in 16.0% (FIGURE 7).

FIGURE 7. Types of renal replacement therapy by primary renal disease. New cases 1990-1997

 

 

Waiting list

Despite the continuing increase in RRT, the number of patients on the waiting list (including patients pending clinical or histocompatibility studies) is practically stable, which translates to a decrease in the percentage of patients on the waiting list, as has been observed in recent years (FIGURES 8 and 9). Another fact to be pointed out is the spectacular increase in the number of patients excluded from the waiting list for clinical reasons since 1990: in 1989, 222 (6.3% of the total) were excluded for this reason and in 1997, 792 (24.5%) were excluded. This may be a consequence of a change in the notification criteria, since it is in these years that the age limits for receiving a transplant were extended.

The percentage of patients on the waiting list decreases with age: from 75% of children under 15 years old on dialysis to 2.5% of patients over 74 years old. Exclusion for clinical reasons represents around 30% of patients from 45 to 75 years old. There are large differences in the status of the waiting list depending on primary renal disease: more than 57% of glomerular patients on dialysis are waiting to receive a transplant, while only 23% of the diabetic patients are doing so. Furthermore, the group of diabetic patients is where the largest percentage of patients excluded for clinical reasons (41%) are seen.

FIGURE 10 shows the time prior to dialysis for patients who are residents in Catalonia and who received a first RT from a cadaver donor in the period 1984-1997 in Catalonia, expressed with the annual means and their respective 95% confidence intervals. The global mean for the period is 41.5 months, while in 1997 this figure was 32.8 months. Despite these fluctuations, a clear decreasing trend in time on dialysis while awaiting transplant is seen.

The probability of receiving a first transplant in relation to time on RRT is shown in FIGURE 11. The accumulated probability in the second year is 31.6%, 54.9% in the fourth year and 65.1% in the sixth. This probability varies as a function of different factors like age of the recipient and PRD; It decreases with age and diabetic patients have the lowest probability of receiving a transplant, followed by patients with vascular nephropathies and nephropathies of unknown origin.

FIGURE 8. Number of patients in renal replacement therapy and residents in Catalonia in relation to transplant. Period 1987-1997

FIGURE 9. Percentage of patients in renal replacement therapy and residents in Catalonia in relation to transplant. Period 1987-1997

FIGURE 10. Previous time on dialysis of patients that received a first renal transplant from a cadaver donor. Period 1984-1997

FIGURE 11. Cumulative probability of receiving a first transplant for patients on the waiting list. Period 1990-1997.

 

Treatment with immunosuppressors

Immunosuppresant drugs have changed over time, from the early 1980's when the discovery of cyclosporine meant a huge improvement in this field, up until recent years in which new immunosuppressors with less side effects have appeared on the market (mycophenolate, tacrolimus, etc.).

FIGURE 12 shows the types of drugs used in immunosuppressant maintenance treatment for patients with functioning transplants on December 1997. It can be seen that the most frequent used immunosuppressors are corticosteroids and cyclosporine, followed by azathioprine and mycophenolate.

FIGURE 12. Immunosuppressant maintenance therapy for functioning transplants on December 31, 1997

 

Description of donors

The characteristics of organ donors have changed in recent years. During 1995, the RMRC retrospectively collected data about donors, such as age, gender and cause of death, back to 1990.

In 1990, 17.6% of kidney donors were over 50 years of age, while in 1997 that figure was 44.9% (FIGURE 13). Furthermore the number of kidneys from donors 70 years old or older has increased, from 0.8% in 1990 to 8.1% in 1997. As a consequence, the mean age of donors had gone from 31. 4 years in 1990 to 45.6 years in 1997.

When analyzing causes of death, a decrease in organs from donors who died of craneoencephalic trauma (CET) and an increase in those that died from a cerebrovascular accident (CVA) is seen (FIGURE 14).

FIGURE 13. Evolution of the percentage of renal transplants from cadaver donor over 50 years old and the mean age of donors. Period 1990-1997

FIGURE 14. Evolution of the distribution of renal transplants from cadaver donor by cause of death of donor. Period 1990-1997

 

Glomerular filtration

The RMRC does not collect information on glomerular filtration, but it does collect information on the serum creatinine (every December 31) of patients with a functioning transplant. The Cockroft-Gault formula has been used to estimate the depuration of creatinine, which uses serum creatinine, age, weight and gender of the recipient for this calculation. This test is very useful and accepted as an indirect measure of glomerular filtration.

The Cockroft-Gault formula:

FIGURE 15 shows estimated creatinine depuration, obtained using this formula, for patients with a transplant functioning on December 31, 1997, by gender. In general, men have a greater glomerular filtration than women, only 9.3% have insufficient levels (under 30 mL/min), while in women this average is 18.1%.

Glomerular filtration was also analyzed in relation to the age of the donor and the recipient, as shown in FIGURES 16 and 17. The data presented correspond to the first of the updates on December 31 of the same year in which the transplant was done. In both figures it can be seen that, as age increases -for the donor as well as the recipient- the levels of glomerular filtration are worse and the percentage of patient fatalities increases. Also, in both cases the percentage of patients that return to dialysis is practically non-existent.

FIGURE 15. Estimated serum creatinine depuration by gender. Patients with a functioning transplant on December 31, 1997

FIGURE 16. Estimated serum creatinine depuration by recipient age. Update in first year of transplant. Transplants 1990-1997

FIGURE 17. Estimated serum creatinine depuration by age of donor. Update in the first year of transplantation. Transplants 1990-1997

 

Grade of functional autonomy

This variable makes it possible to estimate an aspect of quality of life of patients on RRT and the measurement instrument used is based on the Karnofsky activity scale, adapted by Gutman for patients on dialysis. This scale makes it possible to measure the grade of functional autonomy in five categories.

1 - Normal: Development of normal physical activity.

2 - Almost normal: Development of nearly normal activity most of the time.

3 - Limited: Development of limited physical activity. Can care for self.

4 - Special services: Requires special services the majority of the time. Can not care for self.

5 - Continuous services: Requires hospitalization or continuous services.

Given that the populations in each type of treatment differ in parameters like age or primary renal disease, which influence the level of functional autonomy and the morbidity of the patients, a comparison was made by adjusting the populations by these factors so that they remain more homogenous. For each of the treatment groups (dialysis and transplant), patients over 45 and under 65 years old with a standard PRD (glomerular, interstitial, and hereditary diseases, as well as diseases of unknown etiology) were selected, and, in the case of patients on dialysis, those that were included on the transplant waiting list. The mean ages for these new groups are 55.17 years for patients on dialysis (460 cases) and 54.93 for patients with a functioning transplant (921 cases). Of the patients with a functioning transplant, 91.4% had a normal grade of functional autonomy while among patients on dialysis treatment this percentage is only 68.3% (p<0.00001) (FIGURE 18).

FIGURE 18. Grade of functional autonomy by last treatment type. Patients from 45 to 64 years old with standard primary renal disease and on the waiting list or with a functioning transplant. Cases on December 31, 1997

 

Morbidity

As in the previous section, to facilitate the comparison of associated morbidity by the last treatment, the same study groups have been used. In general terms it can be observed that the mean number of accompanying diseases is similar in both groups, despite the fact that the patients on dialysis still maintain a higher number of diseases. The percentage of patients on dialysis with ischemic heart disease, cardiomyopathies, esophageal, duodenal or stomach disease, and especially arthropathy, is much greater than that of the patients that have received a transplant. The most frequent pathologies among patients with functioning transplants are vascular diseases and chronic liver diseases, and to a lesser extent tumors and diabetes (FIGURE 19).

The most frequent neoplasms found in patients that have received a transplant are skin neoplasms. The probability of developing a skin neoplasm after five years of transplantation is 3.17%, which increases to 6.52% at ten years post-transplantation. In patients treated with dialysis this probability is lower; 0.88% and 2.04% at five and ten years post-transplantation, respectively.

FIGURE 19. Accompanying diseases by last treatment type. Patients from 45 to 64 years old with standard primary renal disease and on the waiting list or with a functioning transplant. Cases on December 31, 1997

 

Graft failure

In the period 1990-1997 there were 2,518 transplants done, of which 425 cases of graft failure were reported, and in 181 cases this resulted in the death of the patient. The distribution of the principle causes of the losses vary in relation to the time since the transplant. These causes have been analyzed in two periods depending on the point in which the graft failure occurred: within the first year after transplant or in later years. Thirty-one percent (31.8%) of cases that lost a graft during the first year of transplantation were caused by chronic transplant nephropaty (chronic or acute rejection), 27.8% for complications, 4.3% for hyperacute rejection and 1.45% for abandonment of immunosuppressant treatment. Only 1.4% of the cases were due to unknown causes.

The principal cause of loss of a graft once the first year after transplant had passed was also chronic transplant nephropathy (57.4%). A recurrence of the PRD took place in 4.7% of the cases and in 2.4% of the cases the loss was produced by abandonment of immunosuppressant treatment. Only in 2.7% of the cases was the cause unknown (FIGURE 20).

When studying the loss of kidneys in the first year after transplant, it is possible to differentiate between two categories: those due to the failure of the graft and those caused by the death of the patient (whether the kidney was functioning or not). In 1984 and 1985 the percentage of lost kidney transplants was about 11% due to the death of the patient and 14% due to graft failure, while in recent years these figures were 5% and 10%, respectively (FIGURE 21).

In the distribution of lost kidney grafts by age, it is seen that as age increases the percentage of loss due to rejection clearly decreases (from 22.8% of transplants in patients under age 15 to 9.0% in patients over 59 years), while failures caused by the death of the patient increase (from 3.5% in patients under age 15 to 14.1% in patients over 59). It is also worth mentioning that in the group of patients from 15 to 54 years old the global percentage of lost kidney transplants is less than in the other categories (22% of all transplants done in the period 1990-1997).

Despite all this data, it is worth putting these figures into context, since this analysis has not taken into account the time that the transplant was functioning (time of exposure) and as mentioned earlier, in recent years transplants in older persons and in diabetic patients have increased considerably, and therefore the time of exposure for these patients is less than in the groups of patients with standard PRD or in patients under 55 years old. It is for this reason that these data should be analyzed together with the data from the survival analysis of patients that have received a transplant and of the grafts, by age and PRD, since this study does take into account the time that the patients have had a functioning transplant.

FIGURE 20. Distribution of causes of graft loss by time since transplant. Trasplants 1990-1997

FIGURE 21. Evolution of the percentage of graft failures and death of patients in the first year of transplant. Trasplants 1984-1996

 

Retransplantation

Of the 4,036 transplants done in Catalonia in the period 1984-1997, 473 (11.7%) have been retransplants. Of these, 450 were second transplants, 21 third transplants and 2 fourth transplants. The gender distribution of the patients that received a transplant is identical to that of the patients who received a first transplant: 64% are men in both cases. In TABLE 3 the principal differences between patients that receive a first transplant and those that received more than one can be seen. In summary, it is possible to say that patients that received more than one transplant are younger, that the proportion of diabetics is lower and that the majority are hypersensitive by the time that they receive a transplant.

The characteristics of the patients that receive a second transplants have also changed over time. In general, transplants are increasingly done in older patients and in patients with more HLA matching (TABLE 4).

As mentioned earlier, the number of patients included on the transplant waiting list has stabilized. When analyzing these patients in more detail, it can be seen that each year there are 900 patients waiting to receive a first transplant, while the number of patients that are awaiting a retransplant has gone from 155 in 1987 to 346 in 1997. The number of patients with a functioning first transplant has increased from 750 in 1987 to 1,988 in 1997 and the number of patients with a functioning retransplant has gone from 64 to 220 (FIGURE 22).

Regarding time on dialysis before receiving a second transplant, there is no clear tendency, unlike the case with time on dialysis before a first transplant. The annual number of retransplants is lower and, therefore, the 95% confidence intervals are wider (FIGURE 23).

TABLE 3. Differences between first transplants and retransplants. Trasplants 1984-1997

TABLE 4. Comparative data on renal transplants in Catalonia. Period 1984-1989 and 1990-1997

FIGURE 22. Situation of patients in renal replacement therapy and residents of Catalonia in relation to transplant and retransplant. Period 1987-1997

FIGURE 23. Previous time on dialysis of patients that have received a second renal transplant from a cadaver donor. Transplants 1984-1997

 

Survival

The actuarial method was used in order to calculate the survival of the graft and the patient and the level of statistical significance between the different curves with the Log-Rank test.

The majority of the data presented in this section pertain to the period 1990-1997 in order to have a more up to date view of these results. FIGURE 24 shows the survival of the 3,694 grafts from cadaver donors transplanted in Catalonia in the period 1984-1997, which is 66.1% at 5 years and 47.8% at 10 years. Once past the first year, the chances of losing a graft are less than 5% annually. The survival of the patients is 90.6% to 5 years and 83.2% to 10 years. Mortality takes place principally during the first year and is less than 2% annually. These results are very satisfactory, especially if it is taken into account that the registry consists entirely of patients, of which a considerable portion received a transplant more than 5 years ago, and that 20% of the recipients are over 54 years old. It is important to keep this in mind when comparing the results with other similar studies. The results in patients that have received a transplant from a live donor are even better (survival of the patients to 5 years is 96.1% and 91.9% to 10 years, survival of the graft is 75.4% and 58.1%, respectively).

TABLE 5 shows the survival of the patient and the graft to one year, three years, and five years, for the different types of transplants and periods. Survival of the patient and the graft in simultaneous transplants of the kidney and liver is only shown to one year given the low number of cases available.

In the study of kidney transplants in the periods 1984-1989 and 1990-1997 there are no differences in the survival of the patient, but there are differences in the survival of the graft. This difference is 4% in the first year and reaches 9% at five years. The survival probability of the patient has been maintained despite the fact that in the second period (1990-1997) there was an increase in the mean age of the recipients and their number of risk factors, as described earlier. The same situation exists with the survival of the graft; in recent years the characteristics of the donors have changed (older and less deaths for craneoencephalic trauma), but despite these factors the survival of the graft in the second period has improved.

The increasing number of patients that have received more than one transplant (286 in the period 1990-1997) means that retransplants need to be considered separately. The differences between the survival of recipients of first and second transplants are not significant. As far as survival of the graft, there are slightly greater differences. At three years the survival of second grafts is 70%, 10% less than that of first grafts (p=0.0001). These figures show a very acceptable survival probability for patients that get a second opportunity.

When analyzing patient survival by age at transplant (TABLE 6), it is seen that patients under 55 show more than 94% survival to five years, which decreases gradually (90% for patients 55-59 years old and 80% for patients over 59, p<0.00001). The survival analysis by PRD shows that the probability of a patient surviving to five years is 92% for those that have a standard PRD, 82% for diabetics, and 88% for those with other PRD (p=0.001) (TABLE 7).

The survival of the graft in relation to HLA-DR antigen matches between the donor and the recipient of cadaver grafts done in Catalonia in the period 1990-1997 is greater in the group of patients with more HLA-DR matches. At 5 years it is 75%, 10% greater than that of patients that received a transplant without any matches (p=0.0009) (TABLE 7).

The fact that recipients have antibodies to HLA antigens before transplantation makes it necessary to find donors that present a panel of antigens against which the antibodies of the recipient will not react. This is currently one of the most important obstacles to finding adequate donations. The survival analysis of grafts by whether or not the recipient has antibodies to a panel of HLA antigens (Panel Reacting Antibodies or PRA), is done by separately taking into account the existence of antibodies immediately prior to transplantation (last-PRA) and the maximum level of antibodies that the patient has presented at any time during treatment (maximum-PRA). For patients without antibodies (maximum-PRA between 0% and 10%) the survival of the grafts is 74% to the fifth year, it is 63% for patients with few antibodies (maximum-PRA between 11% and 50%) while it is 57% for those patients with many antibodies (hypersensitive, maximum-PRA > 50%). This difference is more evident when only the percentage of antibodies at the moment of transplantation is taken into account: the survival of the graft to the fifth year is 73% for recipients without antibodies (last-PRA between 0% and 10%), 61% for sensitive patients (last-PRA between 11% and 50%) and 36% for hypersensitive patients (last-PRA > 50%). These data show that the presence of antibodies (PRA) in the recipient is one of the most important factors in the survival of a renal transplant. Thus, the presence of antibodies at the moment of transplantation, even at low levels, is a factor that should be considered in treatment plans.

FIGURE 25 shows how graft survival declines as donor age increases. This effect is especially important when donors are over 70.

FIGURE 24. Patient and graft survival in transplants from cadaver donor. Transplants 1984-1997

TABLE 5. Survival of patient and graft by type of transplant and period (Actuarial analysis). Years from 1984 to 1997
* Less than 10 patients

TABLE 6. Survival of patients with renal transplant from a cadaver donor, by age of recipient and primary renal disease (Actuarial analysis). Transplants 1990-1997

TABLE 7. Survival of renal graft from cadaver donor by number of HLA-DR matches, and maximum-PRA and last-PRA (Actuarial analysis). Transplants 1990-1997
* Less than 10 patients

FIGURE 25. Graft survival in transplants from cadaver donor by donor age. Transplants 1984-1997

 

Mortality

When studying the causes of death in patients that have received a renal transplant, deaths occurring when the patient has a functioning transplant and those occurring within three months following the failure of a graft have been analyzed. This section compares deaths that occurred in patients on dialysis with those of patients that had received a transplant (FIGURE 26).

Patients that received a renal transplant died most often due to infections, vascular causes, hepatic diseases, unknown causes and other causes (miscellaneous). Within this last group neoplasms should be mentioned, which represent 13.1% of all deaths while for patients on dialysis this percentage is 6.8%.

Mortality in the first year was also analyzed by age groups and compared with the global mortality of patients on RRT and that of the population of Catalonia.

FIGURE 27 shows the global mortality rates of patients that received a renal transplant and that of patients on RRT. The specific rates were calculated for an age interval, from 15 to 74, since there are not enough cases of patients who have received a transplant in the extreme ages. The mortality rates are for the first year of treatment, RRT or transplantation, for patients that began treatment between 1990 and 1997. Mortality rates for patients are much higher than those of the Catalan population in all age intervals. There are also important differences between patients on RRT and those that have received a transplant, mainly in the oldest age group. The only age group in which the mortality rates are greater than in patients that have received a transplant is in the group from 35 to 44 years. This may be due to patients with diabetes mellitus that usually receive a multiple kidney-pancreas transplant at this age and that have a higher mortality than the other patients.

The relationship between mortality rates of patients that have received a transplant and that of patients in RRT expressed by the standard mortality ratio (SMR) is shown in FIGURE 28. The SMR below one indicates that the mortality of patients that have received a transplant is lower than those in RRT. These differences are only significant in the 55-64 year age group, in which the 95% confidence interval is also below one; mortality of patients in RRT in this age group is 1.7 times greater than those that received a transplant.

In summary, the mortality of patients that received a renal transplant is less than the overall mortality for the patients in the Registry.

FIGURE 26. Distribution of causes of death by treatment type. Period 1990-1997

FIGURE 27. Truncated mortality rates (15 to 74 years) of the Catalan population, for new cases on renal replacement therapy and in patients that have received a transplant. Period 1990-1997

FIGURE 28. Standard mortality ratio for first year on renal replacement therapy with respect to first year of transplant (truncated mortality rates between 15 and 74 years). New cases 1990-1997

 

ANNEX

Abbreviations

AHT: arterial hypertension

CET: craneoencephalic trauma

CI: confidence interval

CNS: central nervous system

CVA: cerebrovascular accident

EDTA: European Dialysis and Transplant Association

ESRF: end stage renal failure

HD: hemodialysis

HLA: human leukocyte antigen

HLA - A and B: class I human leukocyte antigen codified by A and B loci

HLA - DR: class II human leukocyte antigen codified by DR locus

PD: peritoneal dialysis

pmp: per million population

PRA: panel reacting antibodies

PRD: primary renal disease

RMRC: Catalan registry of renal patients

RRT: renal replacement therapy

RT: renal transplant

RTC: renal transplant from cadaver donor

RTL: renal transplant from live donor

SMR: standard mortality ratio