Asynchronous Kidney Allograft Loss After Simultaneous Pancreas-Kidney Transplantation: Impact on Pancreas Allograft Outcome at a Single Center

Asynchronous Kidney Allograft Loss After Simultaneous Pancreas-Kidney Transplantation: Impact on Pancreas Allograft Outcome at a Single Center E.B. Rangel, A.M. Gonzalez, M.M. Linhares, W.F. Aguiar, M. Nogueira, S. Ximenes, J.R. Sá, C.S. Melaragno, and J.O. Medina-Pestana ABSTRACT Objective. We analyzed the clinical evolution of pancreas allografts in simultaneous pancreas-kidney transplantation (SPKT) cases after asynchronous kidney allograft loss and kidney retransplantation at a single non-United States center. Patients and Methods. We performed a retrospective analysis of 168 SPKT from December 2000 to June 2007. Results. The 5-year kidney allograft survival rate was 71%. Excluding cases of death with a functioning graft after SPKT (n ⫽ 35; 74.4%), 12 kidney allografts were lost due to acute rejection (n ⫽ 7; 15%) or chronic allograft nephropathy (n ⫽ 5; 10.6%). Delayed graft function contributed to kidney allograft loss. Five of 12 patients underwent kidney retransplantation. Sixty percent of pancreas allografts were lost after this procedure, which was attributed to either the diabetogenic effects of the immunosuppressive regimen or to the perioperative stress. Oral glucose tolerance tests performed before kidney retransplantation identified patients with good pancreas allograft function versus those with intolerance on glucose tests who received reduced glucocorticoid doses. Conclusions. In SPKT, pancreas allograft function was seriously affected by kidney retransplantation. Oral glucose tolerance tests performed before kidney retransplantation were helpful to assess beta-cell function and suggest prescription of lower steroid doses to decrease the pancreas allograft dysfunction. IMULTANEOUS pancreas-kidney transplantation (SPKT) is an effective treatment for patients with insulin-dependent diabetes and chronic kidney failure. Patient, kidney, and pancreas survival rates at 1 year after SPKT have been reported to be 92% to 95%, 88% to 92%, and 78% to 86%, respectively.1–3 The main causes of kidney allograft loss after SPKT include acute rejection, chronic nephropathy, and death with a functioning graft. They have been reported to occur in 5% to 9% of cases during a 5-year follow-up.4 – 6 Additionally, either pancreas or kidney allograft function has a positive impact on patient survival rates.7 Retransplantation of the kidney after asynchronous loss following SPKT may also be associated with pancreas allograft dysfunction,6 which may be attributed to immunological stimuli, immunosuppressive drug toxicity, insulin resistance, or perioperative stress. However, there are few data regarding pancreas allograft dysfunction after kidney allograft loss and retransplantation. The aims of this study

S

were to report the patient and kidney allograft survivals after SPKT and the evolution of pancreas allograft function after asynchronous kidney loss and subsequent kidney retransplantation. PATIENTS AND METHODS Between December 2000 and June 2007, 168 SPKT were performed for patients with a history of insulin dependence and chronic renal failure. In Brazil, pancreas and kidney allocation for SPKT is determined by time on the waiting list. Enteric drainage was performed in 161 patients (7 patients underwent bladder drainage); an iliac vein or caval verious anastomosis was performed From the Department of Nephrology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil. Address reprint requests to Erika B. Rangel, MD, Universidade Federal de São Paulo, Rua Botucatu, 740 Vila Clementino, São Paulo, SP 04021-900, Brazil.

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0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.01.107

Transplantation Proceedings, 41, 1773–1777 (2009)

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1774 in all cases. Belzer and Eurocollins solutions were used for pancreas and kidney preservation, respectively. Only heart-beating donors were selected for organ donation. We excluded individuals ⬎45 years old or with a positive history of diabetes in first-degree relatives. The initial immunosuppressive regimen included tacrolimus (0.15 mg/kg/dose), adjusted according to the period after transplantation: levels of 10 to 15 ng/mL during the first 30 days, 8 to 10 ng/mL between 31 and 90 days, and subsequently 5 to 10 ng/mL. Prednisone (30 mg/d) was reducted by 5 mg each month until reaching a maintenance dose of 5 mg/d by 8 months. Mycophenolate mofetil (2 g/d) or mycophenolate sodium (1.44 g/d) was prescribed in all cases. Induction with mono- or polyclonal antibodies was not routinely employed for SPKT, but only in cases wherein the panel-reactive antibody was ⬎20% or the cold ischemia time exceeded 24 hours. All results are reported as mean values ⫾ SD, unless otherwise indicated. Fisher exact test and one-way analysis of variance (ANOVA) were performed for numerical variables, and Pearson chi-square test for categorical variables. Kaplan-Meier curves were used to analyze patient and graft survival rates. Statistical analyses performed using SPSS 12.0 (Chicago, Ill, United States) were assumed to be significant when P ⬍ .05.

RESULTS

The mean age, diabetes history, and time on dialysis were 34.8 ⫾ 8.1 years (range, 18 –57 years), 21.9 ⫾ 6.2 years (range, 10 – 43 years), and 27.4 ⫾ 18.1 months (range, 0 –108 months), respectively; 52.4% of patients were males and 22% black. Kidney and pancreas cold ischemia times were 14.3 ⫾ 4.6 hours (range, 6 –27 hours) and 14 ⫾ 3.9 hours (range, 6 –29 hours), respectively. Patient, kidney, and pancreas survivals at 1, 3, and 5 years were 82.3%, 76%, and 74.4%; 80.5%, 70.6%, and 65.4%; and 75.5%, 66.4%, and 62%, respectively. Delayed kidney allograft function and acute rejection occurred in 23.2% and 30.4% of cases, respectively. Forty-eight kidney allografts (28.6%) were lost during the 6.5-year follow-up, the main cause being death with a functioning kidney allograft (74.4%). Twelve kidney allografts were lost due to either acute rejection (15%) or chronic allograft nephropathy (10.6%). Delayed kidney graft function occurred among 48.7% of subjects who lost their kidneys compared with 21.7% who had good initial function (P ⬍ .0001). Five of 12 patients underwent kidney retransplantation. There were 2 cases of death with a nonfunctioning kidney allograft during the first year that were attributed to acute kidney rejection: a 32-year-old man underwent allograft nephrectomy due to persistent acute rejection simultaneous with sepsis, and a 20-year-old man, acute kidney rejection and hemorrhagic shock. During kidney retransplantation, 2 of 5 patients received induction with Thymoglobulin or OKT3. The doses of calcineurin inhibitors were the same as those used during SPKT, and mycophenolate was maintained at least 75% of the maximum. Lower doses of steroids were used in 2 patients. Table 1 presents the demographic data of 5 patients who underwent kidney retransplantation. Sixty percent of patients (n ⫽ 3) lost their pancreas allograft following kidney

RANGEL, GONZALEZ, LINHARES ET AL

retransplantation: 2 had chronic pancreas allograft rejection and 1 died with functioning allografts. Patients 1 and 2 underwent drainage conversion from bladder to enteric due to hemorrhagic cystitis and urethral disruption plus reflux pancreatitis after 4 months and 21 days, and 9 months and 14 days, respectively. During cyclosporine treatment, patient 1 showed altered oral glucose tolerance tests (OGTT) with 75 g of glucose at 4 months after preemptive kidney retransplantation (fasting, 98 mg/dL; 2 hour, 153 mg/dL). Unfortunately, at 6 months after the altered OGTT, she was diagnosed with diabetes and started on insulin treatment. Her basal Cpeptide ranged from 3.51 ng/mL (normal range, 1.1–5 ng/mL) in the second month after kidney retransplantation facing to 2.42 ng/mL at 5 months and then to ⬍0.5 ng/mL at 10 months. OGTT was not available for patient 2. Pancreas biopsy was not performed due to the great requirement of insulin associated with low C-peptide values. Patient 3 underwent OGTT before kidney retransplantation: fasting 96 mg/dL and 2-hour 92 mg/dL. Prednisone doses were reduced more quickly, so that 5 mg/d was administered at the end of the third month. She experienced a good evolution of endocrine pancreas allograft function after kidney retransplantation. Patient 4 displayed thrombotic microangiopathy restricted to the kidney allograft before developing acute vascular rejection. She lost her second kidney allograft from a haploidentical donor after 10 months due to acute vascular rejection with negative C4-d staining, even though Thymoglobulin was administrated with tacrolimus, prednisone, and mycophenolate. She underwent a third kidney transplantation from a deceased donor receiving OKT3 monoclonal antibody. She never presented acute kidney rejection during the course of this third kidney allograft retransplantation; prednisone dose was 5 mg/d at the end of the third month. Almost 3 years after the SPKT, her basal C-peptide is 5 ng/mL and OGTT shows values at fasting of 92 mg/dL and at 2 hours of 105 mg/dL. Patient 5 received Thymoglobulin induction experiencing severe sepsis secondary to pneumonia during the first week after retransplantation. Patient 6 presented thrombotic microangiopathy and acute vascular rejection that was unsuccessfully treated with Thymoglobulin and tacrolimus replacement for sirolimus. Subsequently, she developed refractory anemia secondary to the combination of sirolimus and mycophenolate as well as chronic kidney failure, requiring frequent blood transfusions. The sirolimus dose was gradually reduced. Thereafter, she developed serious hemorrhagic shock due to a digestive tract hemorrhage, which was attributed to severe acute pancreas rejection. The pancreas allograft was removed; she has been on the waiting list since then, showing 92% class I panel-reactive antibody. Patients 7, 8, and 11 synchronously lost kidney and pancreas allografts after irreversible acute rejections (Table 2) despite treatment with polyclonal antibody. Both pancreas

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Table 1. Demographic Data and Patient, Pancreas, and Kidney Allograft Outcomes After Kidney Retransplantation Patient 1

Sex/age of recipient (y) Time of kidney loss after SPKT (d) BMI (kg/m2) Cause of kidney loss Time of kidney retransplantation (d) Sex/age of donor (y)/ HLA compatibility during retransplantation

Patient 2

Patient 3

Patient 4

Female/37 917

Male/29 500

Female/37 1017

Female/22 83

Male/20 16

22.7 Chronic nephropathy Preemptive

23.4 Chronic nephropathy 82

20.1 Chronic nephropathy 64

19.6 Acute rejection 155

22.5 Acute rejection 130

Female/56/haploidentical (mother)

Female/41/identical

Male/38/distinct (husband)

2nd: male/45/ haploidentical (father)

Female/25/distinct (aunt)

Immunosuppression after kidney retransplantation

CsA/Pred/MMF

TAC/Pred/MMF

TAC/Pred/MMF

MDRD-creatinine clearance (mL/min/ 1.73 m2); time after kidney retransplantation Pancreas allograft outcome

42; 39 months

50; 33 months

92.7; 9 months

3rd: male/22/ deceased 2nd: TAC/Pred/ MMF plus Thymoglobulin 3rd: TAC/Pred/ MMF plus OKT3 83.9; 11 months

Loss (chronic rejection)

Loss (chronic rejection)

Euglycemic

Euglycemic

HbAlc (%) Patient outcome

Patient 5

6.7 Alive

8.3 Alive

6.3 Alive

5.8 Alive

TAC/Pred/MMF plus Thymoglobulin

—

Death with functioning allografts — Death

SPKT, simultaneous pancreas-kidney transplantation; BMI, body mass index; HLA, human leukocyte antigens; MDRD, Modification of Diet in Renal Disease; HbAlc, glycated hemoglobin (normal range, 4.5%– 6.4%); CsA, cyclosporine; TAC, tacrolimus; Pred, prednisone; MMF, mycophenolate mofetil.

and kidney allografts were removed in patient 8, because she developed abdominal sepsis simultaneous with acute rejection. Patients 9 and 10 lost their kidney allografts due to chronic allograft nephropathy, although they still have good glycemic control. Furthermore, the immunosuppressive regimen was maintained; they are awaiting kidney retransplantation. Patient 9 had the diagnosis of vascular insufficiency, which already required foot amputation, whereas patient 10 showed pneumonia complicated by pleural effusion. DISCUSSION

In the present study, we reported the causes of asynchronous kidney allograft loss after SPKT and the impact on pancreas allograft function after kidney retransplantation at a non-United States center. In the literature, asynchronous kidney allograft loss after SPKT is rare. In our cases, the causes of kidney loss were: secondary to death with a functioning kidney allograft (74.4%) followed by acute rejection (15%) and chronic allograft nephropathy (10.6%). These data are quite different from other studies, which have reported the causes acute rejection (31.3%), chronic rejection (29.3%), and death with a functioning graft (25.3%).5 The greater mortality with a functioning kidney

allograft is being studied at our center. Our data showed that delayed kidney allograft function was independently predictive of both a 1-year and long-term kidney allograft loss.8,9 Kidney retransplantation after asynchronous kidney loss following SPKT has been associated with pancreas allograft loss in almost 30% of cases.6 We believed that perioperative stress and steroid doses, as well as conversion of drainage in 2 of our patients, contributed to pancreas allograft dysfunction after kidney retransplantation. The last 2 subjects also received a steroid regimen that included an initial dose of 30 mg/d with a 5 mg reduction each month for either SPKT or kidney retransplantation. This may explain in part why the rate of pancreas loss in our cases was greater than that reported elsewhere.6 Additionally, it is well known that steroids increase insulin resistance which may or may not be associated with a dose-dependent mechanism.10,11 Another mechanism involved in beta-cell dysfunction includes calcineurin inhibitor toxicity, namely structural damage to beta cells including cytoplasmic swelling, vacuolization, apoptosis, and abnormal insulin immunostaining.12 Toxic tacrolimus levels or steroid pulses have been associated with hyperglycemia after transplantation.10 –13 All of our patients received the same regimen of tacrolimus during both

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Table 2. Demographic Data and Patient and Pancreas Outcomes After Kidney Loss of Patients Awaiting Retransplantation Patient 6

Sex/age of recipient (y) Time of kidney loss after SPKT (d) Cause of kidney loss

Pancreas allograft outcome

Immunosuppressive regimen Pancreas allograft removed Patient outcome

Female/24

Patient 7

Female/55

Patient 8

Female/31

Patient 9

Male/54

Patient 10

Male/35

Patient 11

Female/44

334

222

1162

1640

1931

535

Acute rejection (kidney allograft removed)

Acute rejection (kidney allograft not removed)

Acute rejection (kidney allograft removed)

Loss (acute rejection) synchronous to kidney loss

Loss (acute rejection) synchronous to kidney loss

Chronic allograft nephropathy (kidney allograft not removed) Still functioning

Acute rejection (kidney allograft not removed)

Loss (acute rejection) at 1 year from kidney allograft loss —

Chronic allograft nephropathy (kidney allograft not removed) Still functioning

—

—

TAC/Pred/MMS

CsA/Pred/MMF

Yes

No

Yes

No

No

No

Alive

Alive

Alive

Alive

Alive

Alive

Loss (acute rejection) synchronous to kidney loss —

Patient 12 is not included in Table 2 because his kidney allograft was removed on day 46 due to persistent acute rejection and he died from sepsis on day 58. TAC, tacrolimus; Pred, prednisone; MMS, mycophenolate sodium; CsA, cyclosporine; MMF, mycophenolate mofetil.

transplantations, which certainly increased the damage to the beta cells. In one report, reducing tacrolimus levels by 30% produced increases of 24% in insulin and 36% in basal C-peptide levels,14 particularly during the first month after transplantation. However, one limitation of our study is that we did not perform a pancreas biopsy during glycemic alterations, which may have elucidated the mechanisms involved in pancreas allograft dysfunction, which we believe to be due to toxicity secondary to the immunosuppressive regimen. In patient 1, cyclosporine was prescribed instead of tacrolimus during kidney retransplantation, because she already showed altered fasting glucose values and it had been described that a switch from tacrolimus to cyclosporine improved glucose metabolism.15 However, it has been reported that the difference in insulin secretion between tacrolimus and cyclosporine regimens was only observed during the first 3 weeks posttransplantation; after 6 months, there was no significant change in any parameter of glucose metabolism, indicating that long-term use of calcineurin inhibitors does not produced chronic cumulative pancreatic toxicity.16 In contrast, even calcineurin inhibitor withdrawal with switch to sirolimus may be associated with impaired glucose tolerance and new-onset diabetes.17 Beta-cell function and beta-cell mass after pancreas transplantation are well assessed by fasting plasma glucose, HbA1c, and acute insulin and acute C-peptide responses to intravenous glucose or arginine injection.18 We suggest that if the 2-hour OGTT shows a pattern of impaired glucose tolerance, a regimen with low-dose steroids or even withdrawal or avoidance of steroids should be employed, as well as reduced doses of calcineurin inhibitors during retrans-

plantation. This strategy was employed in patients 3 and 4 of our study. Altered OGTT seemed to more accurately reflect pancreas allograft function than C-peptide values, inasmuch as these values may be within normal ranges even among patients with glucose intolerance and/or impaired fasting glucose values. Another point of great concern is the fact that there is no legislation in Brazil to prioritize SPK patients who had lost their kidney allografts: those subjects are under both dialysis and immunosuppressive treatments, which certainly impacts the pancreas allograft both short and long term, as well as increase infectious and cardiovascular events. In conclusion, asynchronous kidney allograft loss after SPKT is rare. Kidney retransplantation may be associated with a high incidence of pancreas allograft loss. Deterioration of pancreas graft function is probably attributed to perioperative stress and to steroid and calcineurin inhibitor administrations, as well as to previous surgical pancreas complications. OGTT may be helpful to identify patients with an increased risk of pancreas allograft dysfunction. REFERENCES 1. 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 June 2004. Clin Transplant 19:433, 2005 2. Cohen DJ, St Martin L, Christensen LL, et al: Kidney and pancreas transplantation in the United States, 1995–2004. Am J Transplant 6:1153, 2006 3. Sutherland DE, Gruessner RW, Dunn DL, et al: Lessons learned from more than 1000 pancreas transplants at a single institution. Ann Surg 233:463, 2001

ASYNCHRONOUS KIDNEY ALLOGRAFT LOSS AFTER SPKT 4. Tesi RJ, Elkhammas EA, Henry ML, et al: Pattern of graft loss after combined kidney-pancreas transplant. Transplant Proc 26:425, 1994 5. Sollinger HW, Odorico JS, Knechtle SJ, et al: Experience with 500 simultaneous pancreas-kidney transplants. Ann Surg 228:284, 1998 6. Chinnakotla S, Taylor RJ, DeRoover A, et al: Fate of the pancreas after asynchronous kidney loss in patients undergoing simultaneous kidney/pancreas transplantation. Transplant Proc 33:1696, 2001 7. Szmidt J, Grochowiecki T, Galazka Z, et al: Influence of pancreas and kidney function on recipient outcome. Transplant Proc 38:263, 2006 8. McLaren AJ, Jassem W, Gray DW, et al: Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation. Clin Transplant 13:266, 1999 9. Ojo AO, Wolfe RA, Held PJ, et al: Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 63:968, 1997 10. Rangel EB, Melaragno CS, de Sa JR, et al: Risk factors for the development of posttransplantation diabetes mellitus in simultaneous pancreas and kidney recipients. Transplant Proc 36:982, 2004 11. Schiel R, Heinrich S, Steiner T, et al: Post-transplant diabetes mellitus: risk factors, frequency of transplant rejections, and long term prognosis. Clin Exp Nephrol 9:164, 2005

1777 12. Drachenberg CB, Klassen DK, Weir MR, et al: Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396, 1999 13. Maes BD, Kuypers D, Messiaen T, et al: Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors. Transplantation 72:1655, 2001 14. van Hooff JP, Christiaans MH, van Duijnhoven EM: Evaluating mechanisms of post-transplant diabetes mellitus. Nephrol Dial Transplant 19(suppl 6):vi8, 2004 15. Bouchta NB, Ghisdal L, Abramowicz D, et al: Conversion from tacrolimus to cyclosporine is associated with significant improvement of glucose metabolism in patients with new-onset diabetes mellitus after renal transplantation. Transplant Proc 37: 1857, 2005 16. Teutonico A, Schena PF, Di Paolo S: Glucose metabolism in renal transplant patients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 16:3128, 2005 17. van Duijnhoven EM, Christiaans MH, Boots JM, et al: Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression. J Am Soc Nephrol 13:213, 2002 18. Robertson RP: Consequences of ␤-cell function and reserve after long-term pancreas transplantation. Diabetes 53:633, 2004