Current Opinion in Organ Transplantation:
PANCREAS TRANSPLANTATION: Edited by Walter mark
Follow-up of secondary diabetic complications after pancreas transplantation
Boggi, Ugoa; Rosati, Carlo Mariaa; Marchetti, Pierob
aDivision of General and Transplant Surgery
bDivision of Endocrinology and Metabolism of Organ Transplantation, University of Pisa, Pisa, Italy
Correspondence to Ugo Boggi, Associate Professor of Surgery, University of Pisa, Director Division of General and Transplant Surgery, Azienda Ospedaliero-Universitaria Pisana, Via Paradisa 2, 56124 Pisa, Italy. Tel: +39 050996926; fax: +39 050996800; e-mail: email@example.com
Purpose of review: Successful pancreas transplantation restores physiologic glycemic and metabolic control. Its effects on overall patient survival (especially for simultaneous pancreas–kidney transplantation) are clear-cut. We herein review the available literature to define the impact of pancreas transplantation on chronic complications of diabetes mellitus.
Recent findings: With longer-term follow-up, wider patient populations, and more accurate investigational tools (clinical and functional tests, noninvasive imaging, histology, and molecular biology), growing data show that successful pancreas transplantation may slow the progression, stabilize, and even favor the regression of secondary complications of diabetes, both microvascular and macrovascular, in a relevant proportion of recipients.
Summary: Patients who are referred for pancreas transplantation usually suffer from advanced chronic complications of diabetes, which have classically been deemed irreversible. A successful pancreas transplantation is often able to slow the progression, stabilize, and even reverse many microvascular and macrovascular complications of diabetes. Growing clinical evidence shows that the expected natural history of long-term diabetic complications can be significantly modified by successful pancreas transplantation.
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).
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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.
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Internal and Emergency MedicineMetabolic and cardiovascular effects of beta cell replacement in type 1 diabetesInternal and Emergency Medicine
chronic complications of diabetes; diabetes mellitus; macrovascular complications; microvascular complications; pancreas transplantation
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