An Analysis of Long-term Survival from the OPTN/UNOS Pancreas Transplant Registry

Transcription

1 9 CHAPTER 2 An Analysis of Longterm Survival from the OPTN/UNOS Pancreas Transplant Registry Kayo Waki a,b and Takashi Kadowaki b a Terasaki Foundation Laboratory, Los Angeles, California, b University of Tokyo Hospital, Department of Diabetes and Metabolic Diseases, Tokyo, Japan Improvements in surgical techniques and immunosuppressive regimens have significantly improved the results of pancreas transplantation (1, 2). When technically successful, the procedure has demonstrated efficacy in controlling the diabetic glycemic state and improving the quality of life of people with diabetes (3, 4). The American Diabetes Association now recommends pancreas transplantation as an acceptable therapeutic alternative to continued insulin therapy in diabetic patients with imminent or established endstage renal disease who have had or plan to have a kidney transplant (5). Reductions in technical failure rates and early acute rejection rates have efficiently decreased early graft loss (2, 6); however, significant beneficial effects of these improvements on longterm graft survival have not been documented. In this chapter, we illustrated the etiology of early and late causes of graft loss as well as the changes in longterm pancreas transplant outcomes over time. Number of transplants PATIENTS AND METHODS We used the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) database to estimate the primary deceased donor pancreas transplant allograft and patient survival rates according to KaplanMeier methods. More than 2,667 pancreas transplants were reported to UNOS from October 1987 to November 27, including 14,894 simultaneous pancreas kidney () transplants (72.1%), 3,395 pancreas after kidney (PAK) (16.4%), 2,115 pancreas transplants alone () (1.2%) and 263 pancreas transplants combined with at least one organ other than the kidney (PWK) (1.3%). Patient death with a functioning graft was counted as graft failure. In order to calculate longterm graft survival rates, while minimizing the effects of technical failure which occurred usually within the first year, some analyses were limited to transplants that survived more than one year. Days RESULTS The vertical bars in Figure 1 show that the annual number of pancreas transplants increased until 22, then leveled off or decreased slightly. The average number of days patients waited for a pancreas transplant increased with the number of pancreas transplants. OPTN/UNOS PANCREAS REGISTRY LONGTERM SURVIVAL Figure 1. Annual numbers of pancreas transplants and mean wait times (198727). Clinical Transplants 27, Terasaki Foundation Laboratory, Los Angeles, California

2 1 WAKI AND KADOWAKI Percentage The percentage of pancreas transplants that went to patients with a previous pancreas graft increased annually until 21, but it has remained around 81% over the past 56 years. Number of transplants Figure 2. Annual percentage of repeat pancreas transplants (198727) PAK PWK Although most pancreas transplants have been performed together with a kidney (simultaneous pancreaskidney ()) the number of transplants has not increased since In contrast the number of pancreas transplants alone () has increased slowly over time. The number of pancreas after kidney transplants (PAK) increased yearly until 24, but has since declined. Figure 3. The annual numbers of pancreas transplants from 1987 to 27 for the major pancreas transplant categories. Overall Pancreas Transplant Outcomes By Era Recipients in 2527 were more likely to be older and male, and were less likely to be white when compared with the recipients during other eras. The number of donorrecipient HLA mismatches was higher among recipients of transplants between 25 and 27 than among those between 1987 and 24. The donor age was younger in recent transplants than in the previous eras. Table 1. Patient, donor and transplant demographics (n = 641) (n = 3,75) (n = 5,197) 224 (n = 6,217) 2527 (n = 3,387) Recipient age (years) 34.8 ± ± ± ± ± 8.6 Recipient race (white %) Recipient sex (male %) Donor age (year) 27.3 ± ± ± ± ± 1. Transplant type No. of HLA mismatches 4.1 ± ± ± ± ± 1.2 Waiting days on the list 88 ± ± ± ± ± 38

3 yr 72 % 76 % 83 % 84 % 84 % 9 2 yr 67 % 72 % 78 % 79 % 78 % 55 % 62 % 67 % 66 % 1 yr 43 % 45 % 48 % (n = 625) (n = 3,49) (n = 5,146) 224 (n = 6,145) 2527 (n = 3,126) p < Figure 4. Primary deceased donor pancreas graft survival of all transplants. Others Isletitis Hyperacute rejection Chronic rejection Acute rejction Percentage Technical failures (thrombosis, infection, pancreatitis and anastamotic leak or bleeding) were the leading cause of graft failure in all eras. The proportion of grafts lost to hyperacute rejection significantly decreased after Acute and chronic rejections remain as major causes of graft failure. Primary nonfunction Technical failure Figure 5. Causes of pancreas graft failure among recipients of deceased donor transplants. Graft losses due to acute rejection occurred earlier than the graft losses due to technical failure among transplant recipients between 1987 and However, after 199, technical failures oc curred significantly earlier after transplantation than acute rejection failures. Chronic rejection occurred later than technical failure or acute rejection. Table 2. Mean occurrence time for major causes of pancreas graft failure. Mean days after tx ± s.d Technical failure 534 ± 1, ± 1,75 36 ± ± ± 87 Acute rejection 334 ± ± 1,213 1,7 ±1,5 66 ± ± 178 Chronic rejection 2,656 ± 1,786 2,82 ± 1,421 1,447 ± ± ± 182 OPTN/UNOS PANCREAS REGISTRY LONGTERM SURVIVAL Pancreas graft survival improved significantly between 1987 and 1995, but has remained stable since The pancreas graft survival rates were similarly high among the pancreas recipient transplanted in the eras 1995 to 1999, 2 to 24 and 25 to 27; the oneyear pancreas graft survival rates were 83%, 84% and 84%, respectively. The 5year pancreas graft survival rates in the eras 1995 to 1999 and 2 to 24 were 67% and 66%, respectively.

4 12 WAKI AND KADOWAKI % 94 % 95 % 94 % 92 % 76 % 81 % 81 % 79 % 1 yr 6 % 59 % 59 % 2 yr (n = 449) (n = 2,315) (n = 4,197) 224 (n = 5,1) 2527 (n = 1,159) p < When the analyses were limited to transplants that survived more than one year, the 5year graft survival rates were comparable in all eras. The 5year graft survival rates in the eras 1987 to 1989, 199 to 1994, 1995 to 1999, 2 to 24 were 76%, 81%, 81%, and 79%, respectively. The 1year pancreas graft survival rates for transplants performed in the eras 1987 to 1989, 199 to 1994, 1995 to 1999 were 6%, 59% and 59%, respectively. 1 Figure 6. Longterm pancreas graft survival of pancreas grafts that survived more than one year. 1 Isletitis 8 Chronic rejection 4 Acute rejection 2 Primary non function Technical failure Hyperacute rejection Others B A Causes of graft failure Causes of graft failure Figure 7. Causes of pancreas graft failure during the first year (A) and after one year (B). Technical failures accounted for more than half of graft failures during the first posttransplant year in all eras. Chronic rejection was the major cause of Graft survival PAK 1 1 yr 9 8 graft failure among the transplants which survived more then one year. 78 % 74 % 83 % 54 % 45 % 69 % 1 yr 28 % 24 % 51 % 1 9% 13 % 33 % (n = 14,273) (n = 1,345) PAK (n = 2,473) Figure 8. Deceased donor pancreas graft survival by transplant type. 15 The overall pancreas graft survival rate was significantly higher among recipients of than PAK or transplants. The oneyear graft survival rates were over 74% for all recipients, however, the survival differences among, PAK and recipients became larger with longer followup. The 1year pancreas survival rate for recipients was 51% compared with 28% for PAK and 24% for recipients.

5 13 Technical failures, acute rejection and chronic rejection were the 3 main causes of pancreas graft loss among, PAK and recipients. Technical failures were most common in transplants (44%) and were least common in transplants (31%). grafts had higher acute and chronic rejection rates (17% and 34%, respectively) than (12% and 25%) or PAK (15% and 27%) grafts. Others 1 Isletitis 8 Hyperacute rejection 6 Chronic rejection 4 Acute rejection 2 Primary nonfunction PAK Technical failure Pancreas transplant type A 1 Others 8 Isletitis Hyperacute rejection 6 Chronic rejection 4 Acute rejection rejcetion 2 Primary nonfunction PAK B Technical failure 1 C PAK Transplant type PAK Pancreas transplant type Figure 1. Causes of pancreas graft failure during the first posttransplant year (A), between 11 years (B) and after 1 years (C). Technical failures were the leading cause of graft loss for pancreas grafts during the first year, regardless of transplant type. Between 11 years more than half of all failures were attributed to chronic rejection. After 1 years, 53%, 58% and 54% of PAK, and failures, respectively were due to chronic rejection. Interestingly, up to 15% of graft failures after 1 years were reported as technical failures. OPTN/UNOS PANCREAS REGISTRY LONGTERM SURVIVAL Figure 9. Causes of graft failure of the pancreas graft by transplant type.

6 14 WAKI AND KADOWAKI (n = 1,621) (n = 857) PAK (n = 1,652) Graft survival PAK 1 yr 1 69 % 36 % 11 % 61 % 32 % 18 % 83 % 62 % 4 % When firstyear graft losses were excluded from the analysis, the 1 and 15 year survival rates were 62% and 4%, respectively, for recipients. PAK and grafts that survived the first year were lost more rapidly over time, such that fewer than 2% were still functioning after 15 years Figure 11. Longterm pancreas graft survival for grafts that survived more than one year by transplant type. Patient survival PAK 1 1 yr 95 % 96 % 94 % 84 % 86 % 84 % 9 1 yr 64 % 66 % 69 % % 53 % 54 % (n = 14,41) (n = 1,364) PAK (n = 2,514) p <.1 Patient survival rates were comparable among recipients of, PAK and pancreas grafts through the first 5 posttranplant years, when the survival of PAK recipients began to decline more rapidly. Fifteen year patient survival rates for and grafts were 54% and 53%, respectively, whereas only 36% of PAK recipients survived 15 years Figure 12. Patient survival by transplant type (n = 1,621) (n = 857) PAK (n = 1,652) Patient survival PAK 1 yr 1 89 % 68 % 4 % 89 % 69 % 55 % 91 % 76 % 59 % When the graft survived the first posttransplant year, subsequent patient survival rates were similar among pancreas recipients through 5 years when survival rates for and for PAK and recipients began to diverge. After 15 years, the patient survival rates for,, and PAK recipients were 59%, 55% and 4%, respectively Figure 13. Patient survival among pancreas transplant recipients whose graft survived more than one year.

7 15 About 15% of PAK and recipients whose graft failed during the first year after transplant also died after their pancreas graft failed. Twentyseven percent of recipients whose pancreas graft failed died during the first year following graft loss. Even when recipients survived the first posttransplant year after their pancreas graft failed, they were more likely to die within the next five years than recipients whose pancreas functioned for at least one year. Between the first and fifth posttransplant year, 9% of recipients with a functioning pancreas at one year died (Figure 13) compared with 17% of recipients whose pancreas graft failed in the first year. Subsequent patient survival was comparable in the 2 groups. Among recipients, nearly twice as many pancreas grafts failed during the first posttransplant year as kidney grafts, but late kidney failures brought the survival curves together at 1 years. The pancreas and kidney graft survival rates at 1 and 15 years after transplantion were 51% and 51%, and 33% and 32%, respectively. When first year graft failures were excluded, pancreas and kidney survival rates were comparable during the next 5 years (pancreas 84%, kidney 83%), however, the longterm graft survival rate was slightly better for the pancreas than the kidney. The pancreas survival rates were 63% at 1 years and 41% at 15 years compared to kidney survival rates of 59% at 1 years and 38% at 15 years (n = 1,336) (n = 184) PAK (n = 323) Patient survival PAK 1 yr 1 78 % 56 % 89 % 89 % 77 % 54 % 35 % Figure 14. Patient survival among pancreas transplant recipients whose graft failed during the first year kidney (n = 14,242 ) pancreas (n = 14,242 ) kidney (n = 1,391 ) pancreas (n = 1,391 ) Graft survival pancreas kidney 1 yr 1 yr 1 83 % 69 % 51 % 33 % 9 % 74 % 51 % 32 % Figure 15. Pancreas and kidney graft survival in transplant recipients. 1 yr 1 pancreas kidney 84 % 83 % 63 % 59 % 41 % 38 % OPTN/UNOS PANCREAS REGISTRY LONGTERM SURVIVAL Figure 16. Pancreas and kidney graft survival in transplants which survived more than one year.

8 16 WAKI AND KADOWAKI DISCUSSION Pancreas transplantation has improved over time with continued advances in surgical procedures and immunosuppressive therapy. At 5years, about 66% of all pancreas transplants performed in 222 were still functioning compared with only 55% of those transplanted during Most of the improvements since the OPTN/UNOS Registry began collecting these data have been in reducing the graft failures during the first posttransplant year. When first year failures were excluded, the longterm graft survival rates were strikingly similar during the different eras. Early graft losses were mainly due to technical failures and acute rejection episodes, which occurred mostly within the first year. It is interesting to note that the incidence of reported hyperacute rejection failures and losses due to isletitis have declined to negligible levels, but the proportions of technical failures and losses to acute and chronic rejection have remained relatively unchanged except among recent transplant recipients where longterm followup is lacking. The continued high incidence of technical failures in the first posttransplant year suggests that pancreas transplantation is indeed a technically challenging procedure, but the lack of progress in reducing technical failures may also reflect the expansion of pancreas transplantation to many smaller, less experienced centers in recent years and changing recipient and donor characteristics that may influence the technical success of these transplants (2). After the first year, acute and chronic rejection accounted for about 6% of graft failures and beyond 1 years, 5% of failures were attributed to chronic rejection. Thus, as with most solid organ transplants, there is a need for means to identify early markers of chronic dysfunction and to develop therapeutic interventions to improve longterm survival of grafts. Nearly 8% of pancreas transplants were transplants, which had substantially better outcomes than either pancreas transplants alone or pancreas transplants into recipients with a functioning kidney graft. More than half of the deceased donor transplants survived 1 years and a third were still functioning at 15 years. Only about 25% of and PAK transplants survived 1 years and only about 1% were functioning at 15 years. Although and PAK transplants were more likely to fail over time than transplants, the distribution of causes of graft loss were similar for each type of pancreas transplant. Among recipients, more than 1% of pancreas grafts never functioned and another 7% failed within the first posttransplant year, while only 1% of the kidney grafts failed. However, when both grafts functioned for at least one year, the longterm graft survival rates for both kidney and pancreas were comparable (or perhaps slightly better for the pancreas). Patients whose pancreas graft failed during the first posttransplant year were at higher risk for death than patients whose pancreas graft functioned for more than one year. Attrition was high within the first year 15% of PAK and patients and 27% of recipients died but even among the survivors, deaths were more common during the next 4 years for recipients of and PAK grafts that failed early. Thus, early pancreas graft failure increased the risk of patient death for a prolonged period compared with those whose graft functioned more than one year. SUMMARY Based upon data reported to the OPTN/ UNOS Pancreas Transplant Registry from October 1987 November 27, overall deceased donor pancreas graft survival rates at 1 years improved from 43% for transplants prior to 199 to 48% for transplants between Overall graft survival rates have not improved substantially since 2. The major causes of pancreas graft failure were technical (4%) and acute rejection (15%) during the early posttransplant period, and chronic rejection (25%) of grafts that survived more than 6 months. Pancreas graft survival rates were better for recipients of grafts (83%, 69%, 51% and 33% at one, 5 1 and 15 years, respectively) than for recipients (74%, 45%, 24% and 13% at the same intervals) or PAK recipients (78%, 54%, 28% and 9% at one, 5, 1 and 15 years, respectively).

9 17 1. Sutherland DE, Gruessner AC. LongTerm Results After Pancreas Transplantation. Transplantation Proceedings 27; 39: REFERENCES 4. Meloche RM. Transplantation for the treatment of type 1 diabetes. World J Gastroenterol. 27; 13 (47): Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and nonus cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 24. Clin Transplant. 25; 19 (4): Larsen JL. Pancreas transplantation: indications and consequences. Endocr Rev. 24; 25 (6): Robertson RP, Davis C, Larsen J, Stratta R, Sutherland DE. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care 26; 29 (4): Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non=us cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of May 23, 24. OPTN/UNOS PANCREAS REGISTRY LONGTERM SURVIVAL

10