It’s a scientific fact that the presence of IDDM1 and ESKD are strongly related to accelerated development of atherosclerosis, and further development of PAD [2, 8, 17]. Patients with PAD have a significantly higher risk of cardiovascular and cerebrovascular events, resulting in significant decrease of quality of life and functional worsening [15, 38, 39]. However, data are limited regarding the prevalence and clinical effects of PAD, specifically on the basis of pre-transplantation ABI testing, on the long-term outcomes in SPKT recipients.
The detection of arteriosclerosis at early stages through adequate and non-invasive preoperative screening and the consequent initiation of optimal preventive medical treatment may help decrease perioperative cardiovascular mortality before transplantation [40]. In this context, the clinical assessment of resting ABI is an accurate, simple and non-invasive diagnostic test to assess the arterial vessel system of the lower extremities, and is additionally a reliable predictor of the presence of lower extremity PAD [12, 19].
The ABI is also an indicator of atherosclerosis at other vascular sites, and it can serve as a prognostic marker of cardiovascular events and functional impairment even in the absence of PAD symptoms [7, 9, 13].
However, the conditions and comorbidities associated with media calcification and vessel stiffness, such as IDDM, ESKD and advanced age, can lead to falsely elevated or normal pressures [2, 28, 40]. Under these circumstances, the measurement of TBI is useful, because the toe vessels are relatively less susceptible to vessel stiffness, and TBI can help provide a more accurate determination of vascular disease in this setting than ABI alone [29].
In our pre-transplantation screening algorithms, the vascular PAD diagnostic consisted of structured arterial physiologic testing, including Doppler-derived ABI or alternatively TBI testing, ultrasonography, patient history and clinical examination.
TBI testing is performed for diagnostic assurance in patients with elevated ABIs and expected vessel stiffness due to relevant comorbidities [41].
In cases of functional symptoms, further noninvasive and invasive physiologic examinations were performed, including pulse wave, Doppler wave and computed/magnetic resonance angiography and walking tests on a treadmill. In this current study, we sought to address the value of ABI testing in a large population of SPKT recipients.
In the pre-transplantation evaluation examinations of SPKT recipients, we found that PAD was identified by a structured lower arterial extremity physiologic evaluation in almost one-fifth of our patients over a study period of approximately 20 years. This finding is consistent with the few previous studies that have found an increased prevalence of PAD in patients with diabetes with ERSD waiting for kidney and/or pancreas transplantation, as compared with patients without these risk factors [25, 42, 43].
Furthermore, we observed that PAD defined by a low ABI was an independent and significant predictor of postoperative patient death, pancreatic graft failure and postoperative cardio- and cerebrovascular events (MI, stroke or peripheral vascular complications) in SPKT recipients. This result was independent of other cardiovascular comorbidities and the number of years of dialysis. Our findings support the use of ABI or accurate preoperative PAD testing for predicting mortality and graft failure in individuals with PAD, independently of other known cardiovascular risk factors.
Recent reports have demonstrated that a successful SPKT that leads to euglycemia can slow the progress of macrovesicular disease, as described in PAD [42–44].
In contrast, according to previous studies from renal transplant recipients, the presence of PAD is associated with an increased risk of allograft failure, as was also seen in our study [6, 26]. However, the pathophysiology underlying the increased risk of graft failure in patients with PAD is not well understood, although factors such as the presence of toxins, arteriosclerotic disease and the inflammatory state of PAD may also play roles [2]. Nevertheless, one explanation may be that the transplantation itself and the use of immunosuppressive medicaments exacerbates the pre-existing risk factors that lead to atherosclerosis or the development of new cardiovascular risk factors [2].
However, despite recent excellent advances in treatment, patients with SPKT, IDDM and ESKD-related conditions tend to have high rates of cardio- and cerebrovascular complications, and CVD remains the leading cause of mortality in SPKT recipients with functioning grafts, as also seen in the current study [23, 24, 45].
Despite of the immanent perioperative cardiovascular risk, successful SPKT offers the best known protection against the progression of CVD and future cardiovascular events [23, 46–48]. Previous studies on kidney–pancreas transplantation have demonstrated the importance of low-risk but highly sensitive screening strategies for major adverse cardiovascular events [22, 24, 49]. Despite these findings, an optimal strategy for cardiovascular risk and postoperative graft outcome assessment in these patients remains lacking. To date, published approaches vary from evaluating patients with different risk scores to screening all patients being considered for SPKT [49–51].
Nevertheless, coronary angiography, an invasive and cost-intensive technique, should be applied only in high-risk patients with a long history of diabetes, severe peripheral or coronary vascular disease or a history of acute myocardial infarction [52, 53].
Therefore, the preoperative assessment of all patients undergoing SPKT by coronary angiography does not appear to be feasible; however, because transplantation in cardiovascular high-risk patients is increasing, a non-invasive but sufficiently sensitive stratification strategy is needed to assess perioperative cardiovascular risk as well as transplant outcomes.
However, a consensus is lacking regarding the best assessment and optimization strategy for cardiovascular risk and transplant outcomes.
In the current study, we therefore aimed to verify the value of screening for PAD through pre-transplantation ABI testing to identify cardiovascular high-risk patients who were eligible for further invasive assessment, as well as specifically modified preoperative risk factors and perioperative protective strategies.
We found that ABI testing is an inexpensive and easily applicable assessment tool during preoperative screening of patients eligible for SPKT.
4.1 Limitations
First, this study was limited by its retrospective nature and small sample size, particularly in the ABI subcategories (‘low-ABI’ and ‘high-ABI’ patients) in both the pre-transplantation and post-transplantation ABI results; the sample size was too small for further analysis or drawing conclusions.
Second, in few SPKT recipients (n = 6; 5.9%), vascular exams were performed quite some time before the transplantation (specifically during pre-transplantation screening examinations for placement on the wait list), and these patients were subsequently categorized as normal controls. However, if peripheral vascular disease and arteriosclerosis might have progressed while the patient was on the waiting list without additional documentation this might have created a small bias. In other words, this bias may have led to an underestimation of PAD at the time of transplant and consecutive outcome analyses. Ideally, all patients should have their vascular diagnostics performed within a year after transplantation.
Third, the results of ABI testing in our patient cohort with IDDM and ESKD must be interpreted carefully, because both comorbidities could lead to increased vascular calcification, thus resulting in vessel stiffness and/or non-compressible vessels [2, 28]. The incompressibility of the vessels could lead to elevated ABIs > 1.4 or falsely normal ABIs. In this setting, the use of an additional TBI testing, toe pressure measurement or Doppler waveform data, which were conducted in our analysis in these patients, would have helped further characterize the patients with an ABI > 1.4, because toe vessels are relatively less affected by calcification [11, 29].
Fourth, the natural history of PAD involves a decrease in ABI over time. However, why the ABI would increase in some patients and decrease in others after transplantation is not well understood. The reason for these findings remains unclear, and the principal patterns of causation should be further evaluated in future prospective studies.
4.2 Conclusions
In conclusion, we demonstrated that ABI evaluation combined with TBI testing in unclear cases is a valuable, inexpensive and feasible assessment tool for accurate examination of perioperative cardiovascular risk in patients undergoing SPKT. We showed that PAD associated with low and high ABIs predicted higher mortality, pancreatic graft failure and poorer cardiovascular outcomes. With the information gained from preoperative ABI testing, patients at high-risk for perioperative cardiovascular complications and simultaneous graft failure can be identified so that further invasive examination and, if possible, reduction of preexisting risk factors can be initiated.
Further research, ideally in large randomized and controlled multicenter trials, are needed to evaluate the use of ABI testing in pre-operative PAD screening in high-risk patient populations. Moreover, future research should focus on the evaluation of functional capacity or walking distance as a comparative tool for ABI testing, to establish the role of ABI in further perioperative risk assessment in high-risk cardiovascular patients and to identify different ABI subcategories for optimized risk stratification.