Transplantation in type 1 diabetes

In the clinical course, type 1 diabetic patients suffer from several micro- and macrovascular complications and usually have progressive renal impairment. For these patients, several transplant strategies are available. These include kidney transplantation, pancreas transplantation and clinical islet transplantation, either alone, in a combined procedure or in a sequential approach [1,2]. Herein we give a short overview on transplantation strategies in type 1 diabetes. We focus on new aspects in simultaneous pancreas–kidney transplantation and the effects of normoglycaemia (achieved by a functioning pancreas allograft) on diabetic complications as well as patient and kidney graft survival. In the USA, 78% of all pancreas transplants are simultaneous pancreas–kidney transplants, 16% are pancreas after kidney transplants and 7% are pancreas transplants alone. Outside the USA, a clear majority of pancreas transplants are performed as combined transplants (91%) as compared to pancreas after kidney transplantation and pancreas transplantation alone (4% each) (International Pancreas Transplant Registry; IPTR; http://www.iptr.umn.edu; [2]). In 2004, 1-, 3- and 5-year renal allograft survival rate after simultaneous pancreas–kidney transplantation was 92%, 85% and 77%, respectively. The 1-, 3- and 5-year pancreas allograft survival rate after simultaneous pancreas–kidney transplantation was 86%, 79% and 71%, and patient survival was 95%, 91% and 86%, respectively (IPTR; http://www.iptr.umn.edu; [2]). Pancreas after kidney transplantation and pancreas transplantation alone represent <10% of the pancreas transplants performed in Europe (IPTR; http://www.iptr.umn.edu; [2]). Especially in pancreas transplantation alone, one has to consider that the benefit of this procedure (normoglycaemia without exogenous insulin) is outweighed by the need of immunosuppressive medication. In contrast, pancreas after kidney transplantation might be an alternative for the type 1 diabetic patient who has already received a kidney transplant and has good renal allograft function. Allograft survival in pancreas after kidney transplantation, however, is much lower than that in simultaneous pancreas–kidney transplantation (IPTR; http://www.iptr.umn.edu; [2]). This might be the consequence of an increased rate of immunological graft loss in pancreas after kidney transplantation. Clinical islet transplantation was long considered an experimental procedure until the so-called Edmonton protocol was published, showing excellent outcome with all seven patients being free of insulin 1 year after the procedure [3]. Unfortunately, the results were not confirmed by a multicentre study where only 53% of patients were free of insulin for 1 year (another 19% received a reduced insulin dose; www.immunetolerance.org). A recent report showed the negative effects of clinical islet transplantation in type 1 diabetic patients who otherwise would not require immunosuppression [4]. The positive effects of normoglycaemia in those patients were outweighed by the negative effects of immunosuppression with accelerated loss of kidney function and an increased excretion of albumin. Several studies impressively illustrated that intensified glycaemic control in diabetic patients (without a renal allograft) can retard the progression of diabetic lesions of different organ systems [5,6]. It had been shown in the Steno studies that multifactorial intervention, e.g. tight glucose control in combination with the use of renin–angiotensin system blockers, aspirin and lipid-lowering agents, reduces cardiovascular deaths, the progression to end-stage renal disease as well as microvascular lesions in type 2 diabetic patients with microalbuminuria [7,8]. There is also evidence that the transplantation of a vascularized pancreas can halt the progression of diabetic micro- and macrovascular lesions in patients with type 1 diabetes (Table 1). However, it takes a long period of normoglycaemia until positive effects become visible, which is impressively illustrated by the work of Fioretto et al. [9,10]. In 13 patients with diabetic nephropathy (of native kidneys), they found no regression of diabetic kidney lesions 5 years after pancreas transplantation [10]. After 10 years, 8 of the initial 13 patients were studied again. They showed a significant improvement of renal pathology with either regression or the complete absence of diabetic lesions [9]. In patients with simultaneous pancreas–kidney transplantation or pancreas after kidney transplantation, the development of diabetic kidney lesions can even be prevented [11]. Impact of glycaemic control on diabetic lesions (modified after [1]) SPK, simultaneous pancreas–kidney transplantation; PAK, pancreas after kidney transplantation; PTA, pancreas transplantation alone. Impact of glycaemic control on diabetic lesions (modified after [1]) SPK, simultaneous pancreas–kidney transplantation; PAK, pancreas after kidney transplantation; PTA, pancreas transplantation alone. Simultaneous pancreas–kidney transplantation is considered to be the treatment of choice for patients with type 1 diabetes and chronic kidney disease stage 4 or 5. After successful simultaneous pancreas–kidney transplantation, a majority of patients have normal or near-normal fasting blood glucose and normal glycosylated haemoglobin levels as well as good kidney function. This is accompanied by a substantial improvement in the quality of life. However, there is still a lack of evidence to support the superiority of simultaneous pancreas–kidney transplantation compared to kidney transplantation alone (either from a living or a deceased donor) in type 1 diabetic patients with chronic kidney disease. There is indeed a survival benefit (with regard to graft and patient survival) for patients who received a combined transplant in contrast to those patients who received a single kidney transplant. However, much of this benefit is attributable to the selection of the allograft recipient as well as the donor organ. Patients who underwent a combined procedure were often younger and in better physical shape. They often had a shorter waiting time and also a shorter time on dialysis. Furthermore, donor organs in simultaneous pancreas–kidney transplantation are usually of better quality. The donors are younger and the cold ischaemia time is short (compared to recipients of deceased donor kidneys). Several studies on this issue with varying results have been published in the past (Table 2). In a recent analysis, Waki and Terasaki studied type 1 diabetic patients who received either a simultaneous pancreas–kidney transplant or the contralateral kidney (kidney transplant alone) from the same deceased donor [12]. By this approach, the authors eliminated donor effects, which might contribute to an improved outcome in recipients of simultaneous pancreas–kidney transplants. In this study, there was no significant difference in the outcome of patients with a combined procedure compared to patients who received a kidney transplant alone with a maximum follow-up of 9 years. In contrast, other authors could prove a superior patient and allograft survival in simultaneous pancreas–kidney transplantation compared to deceased donor renal transplantation, but not living donor transplantation (Table 2). Most of these studies have a median follow-up of <5 years. Taking into account that it takes >5–10 years to halt or reverse diabetic lesions (as demonstrated by the work of Fioretto et al. mentioned earlier), it becomes clear that a comparison of simultaneous pancreas–kidney transplantation and kidney transplantation alone should be performed with >5 years of follow-up. Using the Collaborative Transplant Study (CTS) registry, a recent analysis investigated graft and patient survival in type 1 diabetic patients who received a simultaneous pancreas–kidney transplant or a renal allograft (either from a living or a deceased donor) with a follow-up of 10 and 18 years, for the periods from 1984 to 1990 and 1991 to 2000, respectively [13]. A clear survival benefit for simultaneous pancreas–kidney transplantation and living donor kidney transplantation compared to recipients of a deceased donor allograft was visible. After 10 years, patient survival in simultaneous pancreas–kidney transplantation was even better than that in recipients of a living donor kidney (HR = 0.55; P < 0.005). In parallel, there was a lower rate of cardiovascular deaths in recipients of a combined organ transplant (37%) compared to living donor (49%) and deceased donor (46%) kidney transplantation [13]. This effect was mainly attributable to improved glycaemic control in patients who received a simultaneous pancreas–kidney transplant as compared to those patients with kidney transplantation alone. It is a limitation of this registry analysis, however, that no information is available on glycaemic control in patients who received kidney transplantation alone. One might speculate that with intensified treatment, i.e. by the use of insulin pumps, the latter group (kidney transplantation alone) would have done better. Impact of glycaemic control on renal allograft and patient survival (modified after [1]) SPK, simultaneous pancreas–kidney transplantation; LDK, living donor kidney transplantation; DDK, deceased donor kidney transplantation; n.a., not applicable. Impact of glycaemic control on renal allograft and patient survival (modified after [1]) SPK, simultaneous pancreas–kidney transplantation; LDK, living donor kidney transplantation; DDK, deceased donor kidney transplantation; n.a., not applicable. Simultaneous pancreas–kidney transplantation is now a routine procedure in transplantation. Surgical complication rates are low, and with potent immunosuppressive medication, long-term allograft and patient survival are excellent. From data that were also derived from pancreas transplantation alone, we know that longstanding normoglycaemia can halt or even reverse diabetic lesions in various organs, i.e. heart or kidney. However, data on long-term allograft and patient survival in type 1 diabetics who received a combined transplant in contrast to patients who received a kidney transplant alone (either from a living or a deceased donor) are still scarce. Recent evidence suggests that simultaneous pancreas–kidney transplantation is highly superior to kidney transplantation alone from a deceased donor with respect to allograft and patient survival, and this survival benefit is already visible after only 5 years of follow-up [13]. After 10 years of posttransplant follow-up, patient survival in simultaneous pancreas–kidney transplantation is even superior to that in type 1 diabetic patients who received a kidney transplant (alone) from a living donor. These data clearly argue in favour of simultaneous pancreas–kidney transplantation in type 1 diabetic patients with kidney failure. Therefore, every type 1 diabetic patient with chronic kidney disease stage 4 or 5 should be evaluated for a combined transplant, and this procedure should ideally be performed in a pre-emptive fashion before the patient goes to dialysis. One might speculate that intensified glycaemic control, i.e. targeting a glycosylated haemoglobin value below 6.5% by the use of insulin, might have comparable positive effects in patients who received a kidney transplant alone in type 1 diabetes and this may also apply to patients with type 2 diabetes or posttransplantation diabetes mellitus after kidney transplantation. However, it is often difficult to reach those target levels and adverse events such as hypoglycaemia and even an increased rate of deaths have been reported [14,15]. Conflict of interest statement. None declared.