Pancreas transplantation can replenish the lost insulin secretion in patients with complicated type 1 diabetes mellitus and in selected patients with type 2 diabetes mellitus [1▪▪,2,3▪,4▪]. However, notwithstanding the improvements of the past decades [5▪▪,6▪,7▪▪,8▪,9], pancreas transplantation remains a major surgical undertaking, associated with sizeable early morbidity and mortality, and with mandatory life-long immunosuppression. The beneficial effects of pancreas transplantation must therefore be carefully balanced against its risks.
Successful pancreas transplantation induces full insulin independence, thus avoiding both acute complications of diabetes mellitus and side-effects of life-long insulin therapy . In addition, evidence is growing to show that combined pancreas and kidney transplantation in type 1 diabetes mellitus is a life-saving procedure [1▪▪,5▪▪,7▪▪,11,12▪▪,13,14]. At the same time, the debate continues if pancreas transplantation can improve the course of chronic diabetic complications [15,16].
Tight glycemic control, as provided by intensive insulin regimens, may in part prevent progression of chronic diabetic complications , and beneficial effects of even a limited period of intensive glycemic control persist in the long term (metabolic legacy) [18–20]. Moreover, the benefit of measurable levels of C-peptide for the vessels has been demonstrated previously .
As pancreas transplantation candidates usually present with a long history of diabetes, most of them have already developed far advanced chronic diabetic complications. Avoidance of acute diabetic complications is a prerequisite for successful pancreas transplantation. On the contrary, the tempo of progression of chronic complications is much more delayed, requiring a longer follow-up to assess a potential effect of pancreas transplantation on them.
In this article we briefly review current evidence on the impact of pancreas transplantation on overall patient survival to then scrutinize the most recent literature regarding the impact of pancreas transplantation on the course of both microvascular and macrovascular complications of diabetes mellitus.
IMPACT ON PATIENT SURVIVAL
Pancreas transplantation can be performed in diabetic patients with or without end-stage renal disease (ESRD). Uremic patients often receive a simultaneous pancreas kidney transplantation (SPK), posturemic patients may receive a pancreas after kidney transplantation (PAK), whereas patients with preserved native renal function may receive a pancreas transplantation alone (PTA). In the latter two categories, pancreas transplantation is referred to as ‘solitary’, because of the lack of a kidney from the same donor.
According to the International Pancreas Transplant Registry, the current unadjusted patient survival rates at 5 years after pancreas transplantation are 87% for SPK, 83% for PAK, and 89% for PTA [5▪▪]. Patient and pancreas graft survival curves achieved at the University of Pisa are reported in Fig. 1[1▪▪].
For the diabetic patient with ESRD there are many therapeutic options [22▪▪], including dialysis, living donor or deceased donor kidney transplantation alone (KTA), with or without a subsequent PAK, and SPK, which in rare occasions has also been performed utilizing a kidney and a segmental pancreas graft from the same living donor [23▪,24▪], or by concurrently transplanting a deceased donor pancreas and a living donor kidney [25,26]. Moreover, each transplant can be performed before or after starting dialysis [27▪].
Notwithstanding its early postoperative risk (2–5% absolute mortality rate in the first year) and some conflicting reports [28,29▪], SPK offers significant long-term survival advantage over both deceased donor and living donor KTA [11,12▪▪,13,14,22▪▪,27▪].
For the patient lucky enough to have a potential living donor kidney, the decision to undergo KTA first with subsequent PAK, or to wait for an upfront SPK is not straightforward, being influenced by the needs of the individual patient and local waiting times for pancreas transplantation. In general, living donor KTA should be considered a valid alternative to SPK for all patients already on dialysis [22▪▪].
The importance of pancreas graft function after pancreas transplantation is highlighted by the fact that the relative risk for patient mortality increases by 3–4-fold after pancreas graft failure in SPK and PAK recipient and by 11-fold in PTA recipients [5▪▪]. Since the survival advantage of an SPK over a living donor KTA is dependent upon the function of the pancreas graft [30–32,33▪], a pancreas donor risk index has been developed to maximize the acceptance of all suitable donors for pancreas transplantation .
Whereas an SPK usually provides more durable pancreas graft function than a PAK, supporting SPK as the ‘ideal’ option, a successful PAK provides a long-term survival advantage, too [30,35–37,38▪,39].
Regarding PTA, whereas a first analysis performed by Venstrom et al. apparently showed an increased relative risk of death for pancreas transplantation recipients as compared to patients remaining in the waiting list, Gruessner et al.[41,42] reanalyzed the same data, correcting for multiple listings and recipient category misclassifications, and did not confirm the higher mortality risk for PTA recipients. However, since there is no clear-cut evidence of a survival advantage for PTA, the rationale of this operation  should stand in its ability to prevent the acute complications of diabetes mellitus, to modify the evolution of the chronic complications and to improve quality of life.
EFFECTS ON CARDIOVASCULAR RISK FACTORS
Pancreas transplantation, in its several forms, has beneficial effects on lipid profile and blood pressure [43–45]. We recently reported our experience with 71 PTA [46▪▪,47▪▪]. After a 5-year follow-up period there was a significant reduction in serum total and low-density lipoprotein-cholesterol levels with no change in high-density lipoprotein-cholesterol and triglyceride levels, despite similar use of statins, and improved SBP and DBP control, without relevant differences in the use of antihypertensive medications.
Of interest, SPK is able to correct hemostatic abnormalities that are present in uremic type 1 diabetic patients more effectively than KTA . Pancreas transplantation is also able to reverse pathologic inflammatory pathways that are evident in skin biopsies of T1D patients using techniques such as proteomics, clinical biochemistry, electron microscopy, and immunohistochemistry .
EFFECTS ON MICROVASCULAR COMPLICATIONS
Retinopathy, nephropathy, and neuropathy are the classical microvascular complications of DM.
Despite early conflicting evidence [50–57], partially compounded by inconsistent classification systems used to grade the disease, it is now clear that pancreas transplantation slows the progression, stabilizes, and even reverses diabetic retinopathy and macular edema (Fig. 2) [58,59]. We compared the evolution of both nonproliferative and proliferative or laser-treated retinopathy in a group of 48 patients who underwent SPK with a control group of 43 nontransplanted type 1 diabetic patients. Diabetic retinopathy and its improvement/deterioration were assessed according to the criteria proposed by the EURODIAB Study . At a median follow-up of 17 months (range 6–60 months), the number of improved/stabilized patients was significantly higher in the transplanted group .
Similarly, we prospectively studied the course of diabetic retinopathy in 33 PTA recipients (follow-up 30 ± 11 months) and in 35 control nontransplanted type 1 diabetic patients (follow-up 28 ± 10 months) and found that the percentage of patients with improved or stabilized diabetic retinopathy was significantly higher in the PTA group . Likewise, our most recent data (71 patients) confirm the positive impact of PTA on ocular complications of diabetes mellitus after 4 years of follow-up [46▪▪]. However, no beneficial effects have instead been reported on other ocular complications, such as cataract and glaucoma [59,61].
Type 1 diabetes mellitus patients are at extremely high risk of developing renal complications. Progression to ESRD in this patient population has grim prognostic implications [62,63] and proves to be resistant to most nephroprotective therapeutic measures [64▪]. Pancreas transplantation prevents the recurrence of diabetic nephropathy in renal allografts and may slow the progression, stabilize, and even reverse the course of the disease in native kidneys. These facts are proven by functional and histologic evidence. In SPK recipients the presence of a functioning pancreas improves renal graft survival as compared to KTA, and this advantage is dependent on pancreas graft function: pancreas graft failure during the first 90 days [31,33▪] or the first year  after the procedure is a strong risk factor for the subsequent loss of the kidney graft, too.
Despite lower pancreas graft survival, as compared to SPK, PAK improves kidney graft survival in the long term [36,37,38▪]. The beneficial impact of PAK on kidney graft function is highly dependent on the time interval between the two transplants, which should be shorter than 1 year [65,66▪].
The effects of PTA on renal function are still a matter of debate. Currently available immunosuppressive drugs are nephrotoxic, and this places pancreas transplantation recipients, like other solid organ recipients , at risk for post-transplant nephropathy [68▪,69]. The renal function of diabetic patients without overt ESRD who are referred for pancreas transplantation must be adequately assessed in order to counsel them about the best transplant alternative (solitary pancreas transplantation vs. preemptive SPK) [70,71]. The ideal management of patients with borderline renal function is still controversial [72▪▪]. Gruessner et al. showed that a serum creatinine level above 1.5 mg/dL and recipient age below 30 years are significantly associated with development of overt renal failure after PTA. However, Chatzizacharias et al.[74▪] reported no significant deterioration of renal function at 1 year after PTA in patients with glomerular filtration rate (GFR) of about 50 ml/min.
We showed no significant change in creatinine concentration and clearance and an improvement in proteinuria at 1 year after PTA , and recently reported our updated findings on 71 PTA recipients 5 years after transplantation [46▪▪,47▪▪]. In this series proteinuria improved significantly, whereas only one patient developed ESRD. In the 51 patients with sustained pancreas graft function, kidney function (serum creatinine and glomerular filtration rate) decreased over time with a slower decline in recipients with pretransplant GFR less than 90 ml/min in comparison to those with pretransplant GFR greater than 90 ml/min (Fig. 3), possibly as a result of correction of hyperfiltration following normalization of glucose metabolism. This finding is in contrast to a previous study by Genzini et al., who found an accelerated decline in renal function after PTA in the patient population with lower pretransplant GFR.
The evolution of diabetic nephropathy has been well characterized both functionally and histologically [77–79]. Fioretto et al.[80,81] performed protocol biopsies in patients who had received a successful PTA and found that, whereas 5 years after transplant the histologic lesions of diabetic nephropathy were unaffected , at 10 years reversal of diabetic glomerular and tubular lesions was evident .
The histologic reversibility of diabetic nephropathy was previously shown in the case of transplantation of human cadaveric kidneys into nondiabetic recipients [82,83] and is supported by the current favorable outcome of deceased diabetic donor kidneys [84▪▪]. Accordingly, using 31P-magnetic resonance spectroscopy to assess high-energy phosphate metabolism in the kidney graft of type 1 diabetes mellitus patients who had undergone KTA or SPK, Fiorina et al. found that a functioning pancreas graft has beneficial effects on metabolism of the kidney graft.
Diabetic neuropathy develops in the majority of patients with a long history of diabetes mellitus, and it exacts a heavy toll in terms of morbidity and mortality [86,87▪]. When referred for pancreas transplantation, diabetic patients usually have far-advanced neuropathy. However, pancreas transplantation has beneficial effects on diabetic neuropathy (sensory, motor, and autonomic), as assessed by clinical scores of symptoms, physical examination (including qualitative sensory testing), nerve conduction studies and other electrophysiological measurements, and autonomic function tests [88–92]. These benefits have been reported for all types of pancreas transplantation. Navarro et al. compared the evolution of diabetic neuropathy in 115 patients with a functioning pancreas transplantation (31 SPK, 31 PAK, 43 PTA without and 10 PTA with subsequent kidney transplantation) and 92 control patients along 10 years of follow-up. Using clinical examination, nerve conduction studies, and autonomic function tests, the authors found significant improvements in the transplanted groups (similar across the different subgroups) . Interestingly, Martinenghi et al. monitored nerve conduction velocities in five patients who underwent SPK, reporting a significant improvement which was strictly dependent on pancreas graft function. In addition, we found a significant improvement in Michigan Neuropathy Screening Instrument scores , vibration perception thresholds, nerve conduction studies, and autonomic function tests in a series of PTA patients with long-term follow-up [46▪▪,47▪▪]. The beneficial effects of pancreas transplantation on cardiac autonomic neuropathy were also reported by Cashion et al. using 24 h heart rate variability monitoring. However, spectral analysis of heart rate variation was performed by Boucek et al., but without significant findings.
Nerve regeneration is defective in diabetic patients . In a case report, Beggs et al. performed sequential sural nerve biopsies after PTA and found histologic evidence of nerve regeneration. Quantification of nerve fiber density in skin biopsies [97–99] or in gastric mucosal biopsies obtained during endoscopy  is an interesting tool to assess diabetic neuropathy. However, Boucek et al.[101,102] did not find any significant improvement in intraepidermal nerve fiber density after pancreas transplantation. In contrast, Mehra et al. used corneal confocal microscopy, a noninvasive and well validated imaging technique [103,104], and were able to find significant small nerve fiber repair within 6 months after pancreas transplantation .
EFFECTS ON MACROVASCULAR COMPLICATIONS
Cardiovascular events represent a primary cause of morbidity and mortality after pancreas transplantation , both in the immediate postoperative period  and in the long term .
It is essential to perform a thorough preoperative cardiac evaluation of pancreas transplantation candidates, and for that goal widely available and applied clinical and instrumental tests (like electrocardiogram, transthoracic echocardiography, and coronary angiography) [109,110], might be integrated or partially replaced by others, such as myocardial perfusion scintigraphy [111▪].
Despite previous conflicting reports [112–115], in (pre)uremic type I diabetic patients, SPK offers clear benefits (strictly dependent on a functioning pancreatic graft ) compared to medical management or even KTA, reflecting reduction in overall mortality and specifically in cardiovascular mortality, reduced incidence of myocardial infarctions [117–119], improvement of left-ventricular function [118–120], improved cardiac metabolism as assessed by 31P magnetic resonance spectroscopy , reduced incidence of cerebrovascular disease , and improvement of carotid atherosclerosis (as evaluated by intima media thickness) [43,122,123] and of peripheral arterial disease (PAD) .
In order to assess the impact of pancreas transplantation on macrovascular complications of diabetes mellitus, a sufficiently long follow-up is necessary. Whereas Biesenbach et al. (mean follow-up 70 months) and Knight et al. (median follow-up 45 months) reported no differences between SPK and KTA in their impact on PAD, and Morrissey et al. (mean follow-up 4 years) reported even worse vascular outcomes for SPK vs. KTA patients, in a different study, Biesenbach et al. found no significant differences at 5-year follow-up, but a significantly better outcome for SPK vs. KTA at 10-year follow-up.
Evidence is growing about the positive impact on macrovascular complications of PTA, too. As we recently reported [46▪▪,47▪▪], in our center, 71 patients underwent PTA with a 5-year follow-up, showing slight but significant improvement in both diastolic and systolic cardiac function.
Pancreas transplantation, if timely performed, is able to slow the progression, stabilize, and even reverse chronic complications of diabetes mellitus (Table 1). In this regard, advantages of SPK are widely accepted. Whereas the role of solitary pancreas transplantation is more debated, growing data are becoming available in its favor.
In order to adequately assess the impact of pancreas transplantation on diabetes mellitus complications, however, it is essential to use validated and accurate diagnostic tools and grading systems. Histologic proof of the potential reversibility of microvascular complications of diabetes mellitus after pancreas transplantation has shed new light on the pathophysiology of this disease and of organs affected. Interesting techniques are emerging as powerful tools for unprecedented monitoring of the evolution of diabetic complications. Noninvasive functional imaging techniques have great potential. Corneal confocal microscopy, for instance, has shown the reversibility of diabetic neuropathy after pancreas transplantation and has been proposed as a sensitive tool for the early diagnosis of this complication in the diabetic population at large [103–105].
Together with improving the surgical and immunological aspects of pancreas transplantation, a thorough understanding of its potential benefits allows to adequately counsel each individual diabetic patient.
Conflicts of interest
Disclosure of funding: none.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 125–126).
1▪▪. Boggi U, Vistoli F, Egidi FM, et al. Transplantation of the pancreas. Curr Diab Rep 2012; 12:568–579.
This study provides a comprehensive review of pancreas transplantation practice and outcomes.
2. American Diabetes Association. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care 2006; 29:935.
3▪. Sampaio MS, Kuo HT, Bunnapradist S. Outcomes of simultaneous pancreas-kidney transplantation in type 2 diabetic recipients. Clin J Am Soc Nephrol 2011; 6:1198–1206.
After adjustment for multiple risk factors, no different outcomes (patient and organ survival) were found between type 1 and type 2 diabetes mellitus recipients of SPK.
4▪. Orlando G, Stratta RJ, Light J. Pancreas transplantation for type 2 diabetes mellitus. Curr Opin Organ Transplant 2011; 16:110–115.
Up to 7% of SPK recipients are classified as having type 2 diabetes mellitus and their outcomes are comparable to type 1 diabetes mellitus recipients.
5▪▪. Gruessner AC. 2011 update on pancreas transplantation: comprehensive trend analysis of 25,000 cases followed up over the course of twenty-four years at the International Pancreas Transplant Registry (IPTR). Rev Diabet Stud 2011; 8:6–16.
The most recent analysis of the data from the International Pancreas Transplant Registry: a must-read text.
6▪. Perosa M, Boggi U, Cantarovich D, Robertson P. Pancreas transplantation outside the USA: an update. Curr Opin Organ Transplant 2011; 16:135–141.
The most accurate report of pancreas transplantation outside the US: a pivotal study, considering the lack of an international registry of pancreas transplantation.
7▪▪. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant 2012; 17:100–105.
An excellent review on the topic.
8▪. Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant 2011; 11:1226–1235.
Long-term graft survival continues to be less than optimal.
9. Waki K, Terasaki PI, Kadowaki T. Long-term pancreas allograft survival in simultaneous pancreas-kidney transplantation by era: UNOS registry analysis. Diabetes Care 2010; 33:1789–1791.
10. Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the ‘dead-in-bed’ syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr Pract 2010; 16:244–248.
11. Sollinger HW, Odorico JS, Becker YT, et al. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg 2009; 250:618–630.
12▪▪. Wai PY, Sollinger HW. Long-term outcomes after simultaneous pancreas-kidney transplant. Curr Opin Organ Transplant 2011; 16:128–134.
The superior outcomes of SPK over KTA: a review of the literature with a special focus on the experience of the University of Wisconsin, USA.
13. Morath C, Zeier M, Dohler B, et al. Metabolic control improves long-term renal allograft and patient survival in type 1 diabetes. J Am Soc Nephrol 2008; 19:1557–1563.
14. Morath C, Zeier M, Döhler B, et al. Transplantation of the type 1 diabetic patient: the long-term benefit of a functioning pancreas allograft. Clin J Am Soc Nephrol 2010; 5:549–552.
15. Gruessner RWG, Sutherland DER. Gruessner RWG, Sutherland DER. Effects of pancreas transplantation on secondary complications of diabetes. Transplantation of the pancreas. New York:Springer-Verlag; 2004. 455–508.
16. Gremizzi C, Vergani A, Paloschi V, Secchi A. Impact of pancreas transplantation on type 1 diabetes-related complications. Curr Opin Organ Transplant 2010; 15:119–123.
17. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986.
18. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643–2653.
19. Pop-Busui R, Low PA, Waberski BH, et al. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Circulation 2009; 119:2886–2893.
20. Chaturvedi N. Metabolic memory in the autonomic neuropathy of diabetes: implications for pathogenesis and patient care. Circulation 2009; 119:2865–2867.No abstract (comment).
21. Nordquist L, Wahren J. C-Peptide: the missing link in diabetic nephropathy? Rev Diabet Stud 2009; 6:203–210.
22▪▪. Wiseman AC. Pancreas transplant options for patients with type 1 diabetes mellitus and chronic kidney disease: simultaneous pancreas kidney or pancreas after kidney? Curr Opin Organ Transplant 2012; 17:80–86.
An elegant and thorough dissection of the pros and cons of the different options for this group of patients: a must-read.
23▪. Boggi U, Amorese G, Marchetti P, Mosca F. Segmental live donor pancreas transplantation: review and critique of rationale, outcomes, and current recommendations. Clin Transplant 2011; 25:4–12.
Critical review on segmental live donor pancreas transplantation.
24▪. Sutherland DE, Radosevich D, Gruessner R, et al. Pushing the envelope: living donor pancreas transplantation. Curr Opin Organ Transplant 2012; 17:106–115.
A review on the topic from the group with the largest experience in the world.
25. Boggi U, Pietrabissa A, Vistoli F, et al. Simultaneous pancreas-kidney transplantation is improved by living kidney donation program. Transplant Proc 2004; 36:1061–1063.
26. Boggi U, Vistoli F, Del Chiaro M, et al. Simultaneous cadaver pancreas-living donor kidney transplantation. Transplant Proc 2004; 36:577–579.
27▪. Huang E, Wiseman A, Okumura S, et al. Outcomes of preemptive kidney with or without subsequent pancreas transplant compared with preemptive simultaneous pancreas/kidney transplantation. Transplantation 2011; 92:1115–1122.
No significant difference in short-term mortality after preemptive living donor KTA in comparison to preemptive SPK. Worst outcome found for deceased donor KTA.
28. Young BY, Gill J, Huang E, et al. Living donor kidney versus simultaneous pancreas-kidney transplant in type I diabetics: an analysis of the OPTN/UNOS database. Clin J Am Soc Nephrol 2009; 4:845–852.
29▪. Ziaja J, Chudek J, Kolonko A, et al. Does simultaneously transplanted pancreas improve long-term outcome of kidney transplantation in type 1 diabetic recipients? Transplant Proc 2011; 43:3097–3101.
No significant benefits of PSK over KTA were reported by these authors from Poland.
30. Salvalaggio PR, Dzebisashvili N, Pinsky B, et al. Incremental value of the pancreas allograft to the survival of simultaneous pancreas-kidney transplant recipients. Diabetes Care 2009; 32:600–602.
31. Hill M, Garcia R, Dunn T, et al. What happens to the kidney in an SPK transplant when the pancreas fails due to a technical complication? Clin Transplant 2008; 22:456–461.
32. Weiss AS, Smits G, Wiseman AC. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol 2009; 4:988–995.
33▪. Norman SP, Kommareddi M, Ojo AO, Luan FL. Early pancreas graft failure is associated with inferior late clinical outcomes after simultaneous kidney-pancreas transplantation. Transplantation 2011; 92:796–801.
Early (<90 days) pancreas graft failure in SPK transplant recipients is associated with an increased risk for subsequent kidney failure and death.
34. Axelrod DA, Sung RS, Meyer KH, et al. Systematic evaluation of pancreas allograft quality, outcomes and geographic variation in utilization. Am J Transplant 2010; 10:837–845.
35. Fridell JA, Mangus RS, Hollinger EF, et al. The case for pancreas after kidney transplantation. Clin Transplant 2009; 23:447–453.
36. Sampaio MS, Poommipanit N, Cho YW, et al. Transplantation with pancreas after living donor kidney vs. living donor kidney alone in type 1 diabetes mellitus recipients. Clin Transplant 2010; 24:812–820.
37. Kleinclauss F, Fauda M, Sutherland DE, et al. Pancreas after living donor kidney transplants in diabetic patients: impact on long-term kidney graft function. Clin Transplant 2009; 23:437–446.
38▪. Browne S, Gill J, Dong J, et al. The impact of pancreas transplantation on kidney allograft function. Am J Transplant 2011; 11:1951–1958.
PAK is associated with improved kidney allograft survival, and pre-PAK GFR 30-39 ml/min should not preclude PAK.
39. Poommipanit N, Sampaio MS, Cho Y, et al. Pancreas after living donor kidney versus simultaneous pancreas-kidney transplant: an analysis of the Organ Procurement Transplant Network/United Network of Organ Sharing database. Transplantation 2010; 89:1496–1503.
40. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. J Am Med Assoc 2003; 290:2817–2823.
41. Gruessner RW, Sutherland DE, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004; 4:2018–2026.
42. Gruessner RW, Sutherland DE, Gruessner AC. Survival after pancreas transplantation. J Am Med Assoc 2005; 293:675–676.
43. Fiorina P, La Rocca E, Venturini M, et al. Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes. Diabetes 2001; 50:496–501.
44. Luan FL, Miles CD, Cibrik DM, Ojo AO. Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus. Transplantation 2007; 84:541–544.
45. Lauria MW, Figueiro 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; 23:199–205.
46▪▪. Boggi U, Vistoli F, Amorese G, et al. Results of pancreas transplantation alone with special attention to native kidney function and proteinuria in type 1 diabetes patients. Rev Diabet Stud 2011; 8:259–267.
Successful PTA improves proteinuria, corrects pretransplant hyperfiltration, and does not accelerate progression of diabetic nephropathy in most patients. Improvements are also noted for cardiovascular risk factors, retinopathy, and neuropathy.
47▪▪. Boggi U, Vistoli F, Amorese G, et al. Long-term (5 years) efficacy and safety of pancreas transplantation alone in type 1 diabetic patients. Transplantation 2012; 93:842–846.
Our single-center experience (71 patients) shows the beneficial effects of PTA on secondary complications of diabetes mellitus.
48. Fiorina P, Folli F, D’Angelo A, et al. Normalization of multiple hemostatic abnormalities in uremic type 1 diabetic patients after kidney-pancreas transplantation. Diabetes 2004; 53:2291–2300.
49. Folli F, Guzzi V, Perego L, et al. Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients’ skin which are normalized by kidney-pancreas transplantation. PLoS One 2010; 5:e9923.
50. Ramsay RC, Goetz FC, Sutherland DE, et al. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1988; 318:208–214.
51. Scheider A, Meyer-Schwickerath E, Nusser J, et al. Diabetic retinopathy and pancreas transplantation: a 3-year follow-up. Diabetologia 1991; 34:S95–96.
52. Zech JC, Trepsat D, Gain-Gueugnon M, et al. Ophthalmological follow-up of type 1 (insulin-dependent) diabetic patients after kidney and pancreas transplantation. Diabetologia 1991; 34:S89–S91.
53. Königsrainer A, Miller K, Steurer W, et al. Does pancreas transplantation influence the course of diabetic retinopathy? Diabetologia 1991; 34:S86–S88.
54. Wang Q, Klein R, Moss SE, et al. The influence of combined kidney-pancreas transplantation on the progression of diabetic retinopathy. A case series. Ophthalmology 1994; 101:1071–1076.
55. Chow VC, Pai RP, Chapman JR, et al. Diabetic retinopathy after combined kidney-pancreas transplantation. Clin Transplant 1999; 13:356–362.
56. Koznarová R, Saudek F, Sosna T, et al. Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy. Cell Transplant 2000; 9:903–908.
57. Pearce IA, Ilango B, Sells RA, Wong D. Stabilisation of diabetic retinopathy following simultaneous pancreas and kidney transplant. Br J Ophthalmol 2000; 84:736–741.
58. Giannarelli R, Coppelli A, Sartini M, et al. Effects of pancreas-kidney transplantation on diabetic retinopathy. Transpl Int 2005; 18:619–622.
59. Giannarelli R, Coppelli A, Sartini MS, et al. Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients. Diabetologia 2006; 49:2977–2982.
60. Aldington SJ, Kohner EM, Meuer S, et al. Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM complications study. Diabetologia 1995; 38:437–444.
61. Pai RP, Mitchell P, Chow VC, et al. Posttransplant cataract: lessons from kidney-pancreas transplantation. Transplantation 2000; 69:1108–1114.
62. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol 1987; 59:750–755.
63. Borch-Johnsen K, Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1987; 294:1651–1654.
64▪. Rosolowsky ET, Skupien J, Smiles AM, et al. Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol 2011; 22:545–553.
Despite the widespread adoption of renoprotective treatment, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD.
65. Pavlakis M, Khwaja K, Mandelbrot D, et al. Renal allograft failure predictors after PAK transplantation: results from the New England Collaborative Association of Pancreas Programs. Transplantation 2010; 89:1347–1353.
66▪. Luan FL, Kommareddi M, Cibrik DM, et al. The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation. Clin Transplant 2012; 26:403–410.
Time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than 3 years may reduce the risk of kidney graft loss.
67. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349:931–940.
68▪. Fioretto P, Najafian B, Sutherland DE, Mauer M. Tacrolimus and cyclosporine nephrotoxicity in native kidneys of pancreas transplant recipients. Clin J Am Soc Nephrol 2011; 6:101–106.
The nephrotoxic potential of tacrolimus and cyclosporine are equivalent.
69. 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; 86:1789–1794.
70. Brennan DC, Stratta RJ, Lowell JA, et al. Cyclosporine challenge in the decision of combined kidney-pancreas versus solitary pancreas transplantation. Transplantation 1994; 57:1606–1611.
71. Lane JT, Ratanasuwan T, Mack-Shipman R, et al. Cyclosporine challenge test revisited: does it predict outcome after solitary pancreas transplantation? Clin Transplant 2001; 15:28–31.
72▪▪. Smail N, Paraskevas S, Tan X, et al. Renal function in recipients of pancreas transplant alone. Curr Opin Organ Transplant 2012; 17:73–79.
The ideal management of candidates for PTA with eGFR less than 60 ml/min/1.73 m2 remains controversial.
73. Gruessner RW, Sutherland DE, Kandaswamy R, et al. Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus. Transplantation 2008; 85:42–47.
74▪. Chatzizacharias NA, Vaidya A, Sinha S, et al. Renal function in type 1 diabetics one year after successful pancreas transplantation. Clin Transplant 2011; 25:E509–515.
Renal function did not deteriorate significantly one year after pancreas transplant (PTA or PAK), even in patients with substantial pre-existing renal dysfunction.
75. Coppelli A, Giannarelli R, Vistoli F, et al. The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care 2005; 28:1366–1370.
76. Genzini T, Marchini GS, Chang AJ, et al. Influence of pancreas transplantation alone on native renal function. Transplant Proc 2006; 38:1939–1940.
77. Fioretto P, Caramori ML, Mauer M. The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007. Diabetologia 2008; 51:1347–1355.
78. Steinke JM. The natural progression of kidney injury in young type 1 diabetic patients. Curr Diab Rep 2009; 9:473–479.
79. Fornoni A. Proteinuria, the podocyte, and insulin resistance. N Engl J Med 2010; 363:2068–2069.
80. Fioretto P, Mauer SM, Bilious RW, et al. Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 1993; 342:1193–1196.
81. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69–75.
82. Abouna GM, Al-Adnani MS, Kremer GD, et al. Reversal of diabetic nephropathy in human cadaveric kidneys after transplantation into nondiabetic recipients. Lancet 1983; 2:1274–1276.
83. Abouna GM, Adnani MS, Kumar MS, Samhan SA. Fate of transplanted kidneys with diabetic nephropathy. Lancet 1986; 1:622–623.
84▪▪. Mohan S, Tanriover B, Ali N, et al. Availability, utilization and outcomes of deceased diabetic donor kidneys: analysis based on the UNOS registry. Am J Transplant 2012; 12:2098–2105.
Both overall and death-censored survival of organs from diabetic standard criteria donors was significantly better than that of organs obtained from nondiabetic extended criteria donors, while inferior to that from nondiabetic standard criteria donors. More recently, many diabetic donor kidneys have been given to diabetic recipients with early graft survival being similar to that among nondiabetic recipients.
85. Fiorina P, Perseghin G, De Cobelli F, et al. Altered kidney graft high-energy phosphate metabolism in kidney-transplanted end-stage renal disease type 1 diabetic patients: a cross-sectional analysis of the effect of kidney alone and kidney-pancreas transplantation. Diabetes Care 2007; 30:597–603.
86. Boucek P. Advanced diabetic neuropathy: a point of no return? Rev Diabet Stud 2006; 3:143–150.
87▪. Shakher J, Stevens MJ. Update on the management of diabetic polyneuropathies. Diabetes Metab Syndr Obes 2011; 4:289–305.
A useful review on the topic.
88. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990; 322:1031–1037.
89. Hathaway DK, Abell T, Cardoso S, et al. Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life. Transplantation 1994; 57:816–822.
90. Allen RD, Al Harbi IS, Morris JG, et al. Diabetic neuropathy after pancreas transplantation: determinants of recovery. Transplantation 1997; 63:830–838.
91. Navarro X, Sutherland DE, Kennedy WR. Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 1997; 42:727–736.
92. Martinenghi S, Comi G, Galardi G, et al. Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas. Diabetologia 1997; 40:1110–1112.
93. Feldman EL, Stevens MJ, Thomas PK, et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17:1281–1289.
94. Cashion AK, Hathaway DK, Milstead EJ, et al. Changes in patterns of 24-hr heart rate variability after kidney and kidney-pancreas transplant. Transplantation 1999; 68:1846–1850.
95. Boucek P, Saudek F, Adamec M, et al. Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation. Transplant Proc 2003; 35:1494–1498.
96. Beggs JL, Johnson PC, Olafsen AG, et al. Signs of nerve regeneration and repair following pancreas transplantation in an insulin-dependent diabetic with neuropathy. Clin Transplant 1990; 4:133–141.
97. Kennedy WR, Wendelschafer-Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology 1996; 47:1042–1048.
98. Beiswenger KK, Calcutt NA, Mizisin AP. Epidermal nerve fiber quantification in the assessment of diabetic neuropathy. Acta Histochem 2008; 110:351–362.
99. Nolano M, Provitera V, Caporaso G, et al. Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. Neurology 2010; 75:1089–1097.
100. Selim MM, Wendelschafer-Crabb G, Redmon JB, et al. Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy? Neurology 2010; 75:973–981.
101. Boucek P, Havrdova T, Voska L, et al. Severe depletion of intraepidermal nerve fibers in skin biopsies of pancreas transplant recipients. Transplant Proc 2005; 37:3574–3575.
102. Boucek P, Havrdova T, Voska L, et al. Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation. Diabetes Care 2008; 31:1611–1612.
103. Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a noninvasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 2003; 46:683–688.
104. Tavakoli M, Hossain P, Malik RA. Clinical applications of corneal confocal microscopy. Clin Ophthalmol 2008; 2:435–445.
105. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care 2007; 30:2608–2612.
106. Sollinger HW, Odorico JS, Becker YT, et al. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg 2009; 250:618–630.
107. Medina-Polo J, Domínguez-Esteban M, Morales JM, et al. Cardiovascular events after simultaneous pancreas-kidney transplantation. Transplant Proc 2010; 42:2981–2983.
108. Näf S, José Ricart M, Recasens M, et al. Macrovascular events after kidney-pancreas transplantation in type 1 diabetic patients. Transplant Proc 2003; 35:2019–2020.
109. Fossati N, Meacci L, Amorese G, et al. Cardiac evaluation for simultaneous pancreas-kidney transplantation and incidence of cardiac perioperative complications: preliminary study. Transplant Proc 2004; 36:582–585.
110. Rondinini L, Mariotti R, Cortese B, et al. Echocardiographic evaluation in type 1 diabetic patients on waiting list for isolated pancreas or kidney-pancreas transplantation. Transplant Proc 2004; 36:457–459.
111▪. Ruparelia N, Bhindi R, Sabharwal N, et al. Myocardial perfusion is a useful screening test for the evaluation of cardiovascular risk in patients undergoing simultaneous pancreas kidney transplantation. Transplant Proc 2011; 43:1797–1800.
Myocardial perfusion scintigraphy may be a useful tool during pretransplant cardiac evaluation.
112. Biesenbach G, Margreiter R, Königsrainer A, et al. Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease. Diabetologia 2000; 43:231–234.
113. Knight RJ, Zela S, Schoenberg L, et al. The effect of pancreas transplantation on peripheral vascular disease complications. Transplant Proc 2004; 36:1069–1071.
114. Morrissey P, Shaffer D, Monaco A, et al. Peripheral vascular disease after kidney-pancreas transplantation in diabetic patients with end-stage renal disease. Arch Surg 1997; 132:358–361.
115. Nankivell BJ, Lau SG, Chapman JR, et al. Progression of macrovascular disease after transplantation. Transplantation 2000; 69:574–581.
116. Jukema J, Smets Y, van der Pijl J, et al. Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end stage renal failure due to type 1 diabetes. Diabetes Care 2002; 25:906–911.
117. La Rocca E, Fiorina P, Astorri E, et al. Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplantation alone in uremic IDDM patients. Cell Transplant 2000; 9:929–932.
118. La Rocca E, Fiorina P, Di Carlo V, et al. Cardiovascular outcomes after kidney-pancreas and kidney alone transplantation. Kidney Int 2001; 60:1964–1971.
119. Biesenbach G, Konigsrainer A, Gross C, Margreiter R. Progression of macrovascular diseases is reduced in type 1 diabetic patients after more than 5 years successful combined pancreas–kidney transplantation in comparison to kidney transplantation alone. Transpl Int 2005; 18:1054–1060.
120. Fiorina P, La Rocca E, Astorri E, et al. Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients. Diabetes Care 2000; 23:1804–1810.
121. Perseghin G, Fiorina P, De Cobelli F, et al. Cross-sectional assessment of the effect of kidney and kidney–pancreas transplantation on resting left ventricular energy metabolism in type 1 diabetic-uremic patients: a phosphorous-31 magnetic resonance spectroscopy study. J Am Coll Cardiol 2005; 46:1085–1092.
122. Larsen JL, Ratanasuwan T, Burkman T, et al. Carotid intima media thickness is decreased after pancreas transplantation. Transplantation 2002; 73:936–940.
123. Larsen JL, Colling CW, Ratanasuwan T, et al. Pancreas transplantation improves vascular disease in patients with type 1 diabetes. Diabetes Care 2004; 27:1706–1711.