Effects of simultaneous pancreas-kidney transplantation and kidney transplantation alone on the outcome of peripheral vascular diseases

Simultaneous transplantation of the pancreas and kidney (SPKT) still represents the gold standard surgical treatment for patients with insulin dependent diabetes mellitus type-1 (IDDM1) and end stage renal disease (ESRD) [1]. Diabetes mellitus is one of the main risk factors for the development and progression of peripheral vascular disease (PVD), which together with other macrovascular syndromes such as stroke and myocardial infarction represent one of the major causes of death in SPKT patients with functioning grafts [2]. However, successful pancreas transplantation leads to euglycemia, which could slow the progression of diabetic micro- and macrovascular complications [3].

In this context, it has been reported that long-term normoglycemia following successful SPKT sustains significant improvement of diabetic retinopathy and glomerulosclerosis, and that the human kidney even has the potential to substantially restore glomerular and tubular structures that have been previously injured by long term diabetes [3‐8].

In contrast, data on the potential reversal or progression of macroangiopathic lesions by SPKT are far from clear. On one hand several studies report a significant higher incidence of PVD and worse vascular outcomes in patients with a SPKT when compared to those receiving a kidney transplant alone (KTA) [9]. A recent long-term study on incidence and risk factors in SPKT patients also reported a higher incidence of amputation after SPKT (up to 8.64%) when compared to KTA [10].

On the other hand, there is a big amount of data implying that progression of macrovascular disease is reduced in patients with IDDM1 after more than 5 years of successful combined pancreas-kidney transplantation when compared to kidney transplantation alone [11, 12]. A plethora of conflicting reports lead to the conclusion that the effects of SPKT on macrovascular disease are far from clear and warrant additional study and more target focus.

Therefore, the aim of this study was to determine the impact of SPKT and KTA on the progression of PAD and the development of lower-extremity ischemia, in a group of patients with diabetic vasculopathy and to some extent preexisting peripheral arterial disease (PAD). Additionally, the vascular risk factors and metabolic parameters after SPKT and KTA were evaluated.

Our study highlights some important findings. Peripheral vascular disease is a serious affection in patients qualifying for kidney and/or combined pancreas kidney transplantation. From a demographic perspective, patients evaluated for KTA were significantly older and had a higher number of cardiovascular risk factors including higher BMI, high blood pressure and presence of cardiovascular disease making a direct comparison with younger and leaner IDDM1 patients not feasible. Risk factor adjusted multivariate subgroup analysis, however, revealed that patients undergoing KTA are more likely to have progression of PVD leading to increased rates of PVC. A functioning pancreas and kidney allograft in SPKT patients with its accompanying metabolic benefits seems to significantly reduce progression of PVD and led to decreased rates of PVC in IDDM1 patients. Mean follow up of 8.4 years (101 ± 34 month) revealed a significant increase of perivascular complications in KTA patients. This increase was paralleled by a significant raise of parameters relating to the patients’ metabolic risk profile like HbA1c and Triglycerides. In contrast, our diabetic patients even displayed a decrease in their metabolic risk profile after SPKT.

In terms of vascular protective effects our data are in line with recently published work which demonstrated a regression of coronary atherosclerosis in IDDM1 patients after successful SPKT [18]. Our data also confirm recent evidence of improved long term survival for SPKT predominantly 5 years after transplantation [19].

Patients with end stage renal disease (ESRD) have an increased risk for arteriosclerosis and PVD [20, 21]. This risk is even higher in IDDM1 patients with ESRD most probably due to the larger amount of concomitant metabolic disorders.

In this context, age, prior cardiovascular events and state of aortic calcification have been shown to be good markers for the identification of patients with higher risks for mortality [22]. Our data additionally show that an altered serologic metabolic risk profile such as high HbA1c and triglyceride levels significantly contribute to increased perivascular complications and amputations.

Peripheral arterial disease affects 3–12% of the global population [23]. The prevalence in individuals with ESRD, IDDM1 who are on hemodialysis (HD) is even higher, ranging from 17 to 48%. The annual incidence of PAD-related amputation within this group has been reported to be 0.012 to 0.05% [24]. The risk of amputation in SPKT patients with PAD ranges from 9.5 to 23% [25]. In our study we investigated amputations in SPKT and KTA patients after a minimum of 5 years follow up and found an incidence rate of 13 and 31% respectively. Similar results were reported by Biesenbach et al. who also found a significant lower incidence of amputations in IDDM1 patients undergoing SPKT compared to KTA (16 and 31%, respectively) [11].

Additional studies have investigated the amputation rate in SPKT and KTA patients, however, data are inconsistent with those reported previously, and the effects of a functioning pancreas allograft on secondary macrovascular complications of diabetes mellitus remain uncertain.

Morissey et al. found that despite excellent transplant outcomes and lower risk factors for PAD, SPKT recipients had a greater incidence of PAD related complications more than 4 years after transplantation [9]. Recent long-term data by MacCraith et al. indicate that also after a 10 year follow up, patients are at significant greater risk of amputation after SPKT compared to KTA [10]. Increased risks of PAD in SPKT recipients might in part depend on the technique of pancreas transplantation. Systemic portal drainage generates a state of ?A3B2 show $132#?>peripheral hyperinsulinemia which has been shown to contribute to arteriosclerosis by stimulating vascular smooth-muscle growth and arterial wall lipid deposition [26]. Portal vascular drainage of the pancreas allograft would lessen the degree of hyperinsulinemia after transplantation, however the effect of this change on the progression of arteriosclerosis and its complications is unknown [27].

Understanding the pathophysiology of diabetes mellitus and its vascular complications is crucial for the development of new treatment strategies to prevent vascular problems. An abnormal metabolic state is commonly linked to long-term immunosuppression. Immunosuppression adversely affects different components of the vasculature leading to inflammation and hypercoagulation, both contributing to neointima proliferation and atherosclerosis [28]. In this context, impaired nitric oxide homeostasis plays a major role in limiting vascular inflammation. We have recently shown that a complex interplay of redox related inflammatory processes have a major impact on smooth muscle cell proliferation and atherosclerosis development in an experimental model of murine aortic transplantation [29].

Modern immunosuppressive agents like tacrolimus and rapamycin have been associated with a reduction in vascular narrowing a central feature for both chronic rejection and atherosclerosis [30]. The immunosuppressive therapy in our SPKT and KTA groups were different. All SPKT recipients received an induction therapy consisting of anti-thymocyte globulin or an IL-2 receptor antagonist followed by a standard triple therapy of cyclosporine or tacrolimus, MMF and tapered steroids. KTA recipients were less likely to receive induction therapy and in case only IL-2 receptor antagonists were applied. Maintenance therapy consisted of cyclosporine, tacrolimus or rapamycin, MMF and tapered steroids. However, the hypothesis that different immunosuppressive regimens in SPKT and KTA patients could be held responsible for the difference in PVD after transplantation is statistically not supported by our data.

Our study has several limitations. The comparison of SPKT with KTA hangs loose, due to the fact that SPKT recipients are younger and more robust. In spite of lack of statically significance in PVD between our SPKT and KTA recipients, by nature the vascular system of our young SPKT recipients has not suffered for the same amount of time from detrimental metabolic conditions when compared to patients in the KTA group. Therefore, the conclusion that superior outcomes for SPKT are related to the pancreas transplant alone or the type of patient receiving the graft must be conceived with caution [19].

In subgroup analysis, we could demonstrate that at 8.4 years of functioning pancreas graft the progression of macrovascular diseases is significantly reduced in diabetic patients with SPKT when compared to recipients of KTA. This vascular protective effect after SPKT could be explained by a better vascular risk profile of SPKT recipients compared to KTA recipients. Furthermore, our study demonstrates that SPKT and KTA can be performed safely in diabetic patients with ERSD even in (a) symptomatic patients with PAD, without deterioration of lower extremity ischemia. Further studies are surely required, in lager series, to investigate the natural history and course of PVD before and after SPKT compared to KTA in diabetic patients.