Cardiac parameters assessed pretransplant by Doppler echocardiographic examinations resulted within the normal range as reported for a local control population at the pretransplant evaluation (data not shown). At the end of posttransplant follow-up, left ventricular ejection fraction increased slightly, but significantly, from 54.4±4.3 to 58.1±2.0% (P<0.01), and the E/A velocity ratio (a diastolic parameter obtained by Doppler mitral flow) also improved (from 1.18±0.33 to 1.39±0.49 cm/sec), although not significantly. The other indexes remained stable (data not shown).
Proteinuria and Renal Function
Overall, proteinuria decreased from 1.36±2.72 g per day (pretransplant) to 0.38±0.66 g per day (last control posttransplant) (P<0.02). One patient developed end-stage renal disease; her calculated (Cockroft-Gault formula) pretransplant GFR value was 60.3 mL/min. In all the other patients with long-term functioning pancreas graft, serum creatinine concentrations increased from 0.95±0.28 to 1.13±0.33 mg/dL (P<0.01). GFR decreased of approximately 20% (from 94±39 to 75±22 mL/min) (P<0.01), with an average reduction of 3.8 mL/min/year. The yearly rate of GFR decline was significantly lower in patients with a pretransplant GFR below 90 mL/min (Fig. 2a). The decline of GFR over time after PTA is given in Figure 2b. Duration of diabetes was inversely correlated with GFR posttransplantation, whereas age and insulin dose pretransplant were not (P value from 0.1 to 0.07).
This study describes the efficacy and safety of PTA (single-center experience) in a series of T1D patients followed for 5 years after transplantation. Actual 5-year patient survival and insulin-independence rates (reported at 5 years) are substantially in line with those generally reported with a tendency to somewhat better outcomes (1–3). However, it has to be kept in mind that other centers have reported series larger than ours (1–3, 12). Normalization of plasma glucose concentrations was solid and sustained, as documented by HbA1c levels stability within normal ranges. Moreover, improvement of lipid parameters (total and LDL-cholesterol) previously reported after a shorter follow-up period (20) was maintained after 5 years from transplant. A nonsignificant 14% and 8% decrease of LDL-cholesterol after 1 and 2 years from PTA has been previously reported in a small group (n=11) of patients with systemic venous drainage of endocrine secretion of the graft (21). Whether the portal or the systemic drainage of insulin may affect lipid levels remains uncertain, as discussed in the case of combined pancreas and kidney transplantation (22, 23).
We found a significant decrease in the level of proteinuria after transplantation and a 20% cumulative decrease of GFR over the 5 years of follow-up. Similar rates of loss of GFR after 5 years from PTA have been recently reported, with no major difference between the use of tacrolimus or cyclosporine A as calcineurin inhibitor (17). Interestingly, in this study the loss of renal function was less evident in patients with a pretransplant GFR below 90 mL/min, suggesting that part of the loss of function after transplantation observed in patient with greater GFR (>90 mL/min) may be associated with the correction of hyperfiltration following normalization of glucose metabolism by the PTA. However, one patient developed posttransplant end-stage renal disease, with a pretransplant calculated GFR of approximately 60 mL/min. Immunosuppression (including tacrolimus dose and blood levels) and other clinical characteristics were similar in this patient as in the other subjects. As our institutional policy does not favor protocol biopsies, renal histology was not routinely obtained before or after PTA in the present series. However, light and electron microscopy data on the native pancreas have been previously reported by authors who have addressed the effect of PTA on diabetic nephropathy (24, 25). A report of sequential native kidney biopsies from eight PTA recipients with established nephropathy but without uremia showed that long-term normoglycemia (10 years) led to the reversal of the characteristic glomerular lesions of diabetic nephropathy (24). However, the mean creatinine clearance rate of the eight patients decreased from 108±20 mL/min/1.73 m2 before transplant to 74±14 mL/min/1.73 m2 at 10 years. Subsequent morphometric investigations by the same authors described the reversibility of cortical interstitial expansion and reabsorption of atrophic renal tubules at 10 years after PTA (25). Interestingly, in type 1 diabetic patients on the waiting list for islet transplantation, the annual decrease of kidney function was 5.4 mL/min (26).
The results of our study do not allow conclusions on why there was a reduction of proteinuria after PTA. As previously discussed (15), it is possible that normalization of blood glucose and restored C-peptide secretion may play a role. Reduction of glucose levels is associated with decreased hyperfiltration and diminished albuminuria (27), and C-peptide exerts beneficial actions on the endothelium in the diabetic kidney (28). Notably, recent data show that the risk of end-stage renal disease remains high and unchanged despite almost universal renoprotective treatment, suggesting the need for newer therapies for diabetic patients with overt nephropathy (29).
It is conceivable that the normoglycemic condition and the improvement in other parameters (lipids in particular) may favorably impact on the vascular system. As assessed by ultrasound examination, improvement of ventricular ejection fraction was observed after PTA in this study, which confirms a previous finding made shortly after PTA (20). These cardiovascular parameters were, however, within the normal range before transplantation. At present, therefore, it is not known whether cardiac performance and the rate of cardiac events may be beneficially affected by PTA, as it has been clearly demonstrated after SPK in diabetic and uremic patients (1–3).
Whether and how the several positive events encountered in our patients after PTA could benefit long-term patients' life expectancy is still an unsettled issue. Venstrom et al. (5) reported a survival disadvantage for PTA recipients, with an overall relative risk of mortality (compared with patients awaiting the same procedure) over the 4-year follow-up of 1.57. Shortly after this report, Gruessner et al. (6, 7) performed a similar analysis after excluding patients with multiple listings at different transplant centers, including a more recent patient cohort and extending the follow-up period. These reports showed that the mortality at 4 years for solitary pancreas transplant recipients was equivalent to that of patients on the waiting list. It has to be kept in mind, however, that T1D patients with proteinuria, severe retinopathy, or neuropathy have a well-known increased mortality risk (30, 31).
At the present time, there is no prospective, randomized, controlled clinical trial comparing PTA and some other therapeutical interventions in T1D patients, mainly due to ethical constraints. However, the overall available results (including our data) suggest that PTA is an effective and reasonably safe option in selected T1D patients. Normoglycemia can in fact be achieved long term in many patients (with disappearance of acute diabetes complications), encouraging results in reduction of risk factors for cardiovascular disease can be obtained and positive effects on microvascular complications have been reported. Studies with longer follow-up are of course needed to obtain conclusive results in this regards.
MATERIALS AND METHODS
Altogether, 71 T1D consecutive patients were evaluated. The study was performed with the approval of the Ethics Committee of the University of Pisa. At the time of transplantation, patients showed the following characteristics: age, 38.4±8.5 years; gender, 37 males and 34 females; body mass index, 23.5±3.0 kg/m2; duration of diabetes, 23.7±9.9 years; and daily insulin requirement, 44±14 IU. Nineteen patients (27%) were considered for PTA mainly because of glycemic instability (14 had hypoglycemia unawareness), whereas the remaining also had varying degrees of single or combined chronic diabetes complications (diabetic retinopathy in 53 patients, peripheral neuropathy in 31, and autonomic neuropathy causing gastroparesis in 6). Only patients with a GFR of more than or equal to 50 mL/min were included, according to what was suggested in previous studies (1–3). Pancreas donors showed the following characteristics: age, 26.6 years (range, 5–55); gender, 53 males and 18 females; and body mass index, 23.0±3.2 kg/m2. Cumulative human leukocyte antigen-A and human leukocyte antigen-B mismatching was 2.8 (range 1–4). Mean pancreas cold ischemia time was 11 hr and 36 min (range, 8–18 hr).
A detailed description of the surgical techniques used at our institution for pancreas transplantation was previously reported (32, 33). Briefly, all grafts were placed in the space behind the ascending colon and its mesentery. Enteric exocrine drainage was used in all recipients while venous effluent was created in the portal system (73.2%) or in the systemic circulation (26.8%). All patients received an induction treatment, consisting of either high-dose steroids plus basiliximab (20 mg) (Simulect, Novartis, Basel, Switzerland) in 54 recipients (76%) or a single steroid bolus plus antithymocyte globulin (1 mg/kg/day) (Thymoglobulin, Genzyme Corporation, Cambridge, MA) in the remaining 17 recipients (24%). The first dose of either antibodies was administered before graft reperfusion. Thymoglobulin was given for 7 consecutive days with the daily dose held if the total leukocyte count was less than 2500/mm3 or if the lymphocyte count was less than 100/mm3. The same maintenance therapy, including tacrolimus (Prograf, Astellas Pharma, Tokyo, Japan), mycophenolate mophetil (MMF, CellCept, Roche, Basel, Switzerland) or mycophenolic acid (EC-MPA, Novartis, Basel, Switzerland), and steroids (tapered to 5 mg at 3 months posttransplant), was given to all recipients. The dose of tacrolimus was adjusted to maintain blood through levels of 10 to 15 ng/mL during the first month and of 8 to 12 ng/mL thereafter. MMF and EC-MPA were given at the highest tolerated dose (initial dose of 2 g/day of MMF and 1440 mg/day of EC-MPA) mainly based on hematologic toxicity.
The protocol for CMV prophylaxis consisted in ganciclovir, 250 mg per day intravenously during the first 3 posttransplant days, followed by valganciclovir, 900 mg per day orally up to sixth posttransplant month. As previously described (33, 34), a standard prophylaxis protocol for thrombosis prevention was applied, consisting in 2500 units of intravenous heparin intraoperatively just before clamping the vessels for pancreas implantation. This heparin bolus was followed by a postoperative regimen of a continuous infusion of heparin at 300 units/hr for 24 hr, then 400 units/hr for 24 hr, then 500 units/hr until postoperative day 7, at which time the heparin was stopped. Aspirin (100/mg/day) was begun on day 4 posttransplant, and the patient was placed also on warfarin 1 mg per day on day 5 for 6 months. Moreover, we monitored the grafted pancreas routinely during the first posttransplant week, on daily basis, by ultrasound color Doppler scan, irrespective of any clinical indication, just to detect early initial signs of thrombosis.
The transplanted pancreas was considered functionally competent as long as fasting blood glucose, random blood glucose, and glycated hemoglobin were within the normal range without any pharmacological antidiabetic therapy. For the purpose of this study, the following parameters were assessed and hereby presented before transplantation and at 1 and 5 years afterward: body weight, fasting plasma glucose, glycated hemoglobin A1c (HbA1c), fasting C-peptide, fasting total cholesterol and triglycerides, high-density lipoprotein-cholesterol and LDL cholesterol, and blood pressure (measured three times with a sphygmomanometer after sitting position for at least 10 min; the mean of the last two measurements was recorded). Complete cardiac evaluation and Doppler echocardiographic examinations (with the Sonos 5500 echograph; Agilent Technologies, Andover, MA) were performed, with geometric, systolic, and diastolic parameters computed as described earlier (20). Renal function and proteinuria were evaluated as previously detailed by this group (14, 15).
Data are presented as mean±standard deviation. Comparisons of results were performed by the two-tailed Student's t test for paired or unpaired data, as appropriate.
1. Larsen JL. Pancreas transplantation
: Indications and consequences. Endocr Rev 2004; 25: 919.
2. Gruessner AC, Sutherland DE, Gruessner RW. Pancreas transplantation
in the United States: A review. Curr Opin Organ Transplant 2010; 15: 93.
3. White SA, Shaw JA, Sutherland DER. Pancreas transplantation
. Lancet 2009; 373: 1808.
4. Schenker P, Vonend O, Krüger B, et al.. Long-term results of pancreas transplantation
in patients older than 50 years. Transpl Int 2011; 24: 136.
5. Venstrom JM, McBride MA, Rother KI, et al.. Survival after pancreas transplantation
in patients with diabetes and preserved kidney function. JAMA 2003; 290: 2817.
6. Gruessner RWG, Sutherland DE, Gruessner AC. Survival after pancreas transplantation
. JAMA 2005; 293: 675.
7. Gruessner RWG, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004; 4: 2018.
8. Dean PG, Kudva YC, Stegall MD. Long-term benefits of pancreas transplantation
. Curr Opin Organ Transplant 2008; 13: 85.
9. Gremizzi C, Vergani A, Paloschi V, et al.. Impact of pancreas transplantation
on type 1 diabetes
-related complications. Curr Opin Organ Transplant 2010; 15: 119.
10. American Diabetes Association. Pancreas and islet transplantation in type 1 diabetes
. Diabetes Care 2006; 29: 935.
11. Società Italiana di Diabetologia. Il trapianto di pancreas e di isole pancreatiche. Il Diabete 2002; 14: 113.
12. Gruessner RW, Sutherland DE, Kandaswamy R, et al.. Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus. Transplantation 2008; 85: 42.
13. Sutherland DE, Gruessner AC. Long-term results after pancreas transplantation
. Transplant Proc 2007; 39: 2323.
14. Giannarelli R, Coppelli A, Sartini MS, et al.. Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients. Diabetologia 2006; 49: 2977.
15. Coppelli A, Giannarelli R, Vistoli F, et al.. The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care 2005; 28: 1366.
16. Scalea JR, Butler CC, Munivenkatappa RB, et al.. Pancreas transplant alone as an independent risk factor for the development of renal failure: A retrospective study. Transplantation 2008; 86: 1789.
17. Fioretto P, Najaran B, Sutherland DE, et al.. Tacrolimus and cyclosporine nephrotoxicity in native kidneys of pancreas transplant recipients. Clin J Am Soc Nephrol 2011; 6: 101.
18. Drachenberg CB, Odorico J, Demetris AJ, et al.. Banff schema for grading pancreas allograft rejection: Working proposal by a multi-disciplinary international consensus panel. Am J Transplant 2008; 8: 1237.
19. Gruessner RWG. Immunobiology, diagnosis, and treatment of pancreas graft rejection. In: Gruessner RWG, Sutherland DER, eds Transplantation of the pancreas. New York, Springer-Verlag 2004, pp 349.
20. Coppelli A, Giannarelli R, Mariotti R, et al.. Pancreas transplant alone determines early improvement of cardiovascular risk factors
and cardiac function in type 1 diabetic patients. Transplantation 2003; 76: 974.
21. Lauria MW, Figueiró JM, Machado LJ, et al.. The impact of functioning pancreas-kidney transplantation and pancreas alone transplantation on the lipid metabolism of statin-naïve diabetic patients. Clin Transplant 2009; 23: 199.
22. Martin X, Petruzzo P, Dawahra M, et al.. Effects of portal versus systemic venous drainage in kidney-pancreas recipients. Transpl Int 2000; 13: 64.
23. Petruzzo P, Laville M, Badet L, et al.. Effects of venous drainage on insulin action after simultaneous pancreas-kidney transplantation. Transplantation 2004; 77: 1875.
24. Fioretto P, Steffes MW, Sutherland DE, et al.. Reversal of lesions of diabetic nephropathy after pancreas transplantation
. N Engl J Med 1998; 339: 69.
25. Fioretto P, Sutherland DE, Najafian B, et al.. Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int 2006; 69: 907.
26. Warnock GL, Thompson DM, Meloche RM, et al.. A multi-year analysis of islet transplantation compared with intensive medical therapy on progression of complications in type 1 diabetes
. Transplantation 2008; 86: 1762.
27. Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabetes 2001; 109(suppl 2): S424.
28. Wahren J, Ekberg K, Samnegard B, et al.. C-peptide: A new potential in the treatment of diabetic nephropathy. Curr Diab Rep 2001; 1: 261.
29. Rosolowsky ET, Smiles AM, Skupien J, et al.. The risk of ESRD in patients with type 1 diabetes
and macroalbuminuria remains high despite reno-protective treatment. J Am Soc Nephrol 2011; 22: 545.
30. Soedamah-Muthu S, Chaturvedi N, Witte D, et al.. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: The EURODIAB Prospective Complications Study (PCS). Diabetes Care 2008; 31: 1360.
31. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: A clinical perspective. Diabetes Care 2010, 33:434.
32. Boggi U, Amorese G, Marchetti P. Surgical techniques for pancreas transplantation
. Curr Opin Organ Transplant 2010; 15: 102.
33. Boggi U, Vistoli F, Del Chiaro M, et al.. A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation. Surgery 2004; 135: 629.
Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Pancreas transplantation; Type 1 diabetes; Cardiovascular risk factors