© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2015: 29: 747–755 DOI: 10.1111/ctr.12574
Clinical Transplantation
Long-term outcomes of transplant recipients referred for angiography for suspected transplant renal artery stenosis Ali A, Mishler D, Taber T, Agarwal D, Yaqub M , Mujtaba M, Goggins W, Sharfuddin A. Long-term outcomes of transplant recipients referred for angiography for suspected transplant renal artery stenosis. Abstract: Our aim was to study the long-term outcomes of all transplant recipients who underwent angiography for suspected TRAS at our institution. The patients were divided into TRAS+ve and TRAS ve groups based upon angiographically confirmed results. TRAS was confirmed in 58.1% of 74 patients with median time of 8.9 months. Primary angioplasty alone was performed in 56% of patients with TRAS, while the remaining had PTA with stent (PTAS). There was reduction in systolic and diastolic BP (165 19–136 15 mmHg and 82 14 mmHg to 68 12 mmHg; p < 0.05) and number of antihypertensive drugs (3.5 0.9–2.7 1.0; p < 0.05). Overall, graft survival and patient survival from time of transplant were similar in both groups. Graft function was similar for the patients with treated TRAS+ve as compared to TRAS ve over time. Graft survival and patient survival when compared to an age- and year of transplant-matched cohort control group were also similar. In conclusion, angiography for suspected TRAS is more likely to yield a confirmatory result early in the transplant course as compared to late. Treatment of TRAS in these patients had sustained long-term graft function. Alternative etiologies of HTN and graft dysfunction should be sought for recipients further out from transplant.
Anum Alia, Dennis Mishlera, Tim Tabera, David Agarwalb, Muhammad Yaquba, Muhammad Mujtabaa, William Gogginsc and Asif Sharfuddina a
Division of Nephrology, Department of Medicine, bDivision of Interventional Radiology, Department of Radiology and c Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA Key words: graft function – graft survival – hypertension – kidney transplant – transplant renal artery stenosis Corresponding author: Asif A. Sharfuddin, Associate Professor of Clinical Medicine, Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 550 North University Blvd, UH 4620, Indianapolis, IN 46202, USA. Tel.: 1 317 944 4370; fax: 1 317 944 5046; e-mail: [email protected] Conflict of interest: The authors of this manuscript have no conflicts of interest to disclose. Portions of this manuscript were presented as an abstract at ASN Annual Meeting 2013. Accepted for publication 2 June 2015
Transplant renal artery stenosis (TRAS) is a known vascular complication in renal allografts. Hemodynamically significant stenosis usually occurs when the area of cross-section of the renal artery decreases by as much as 50% (1–5). TRAS is often the cause for refractory or new-onset hypertension in transplant patients along with allograft dysfunction (6, 7). A variable incidence of TRAS has been reported in literature, with most studies putting the incidence between 1 and 13% (1, 2, 4, 8–12), while some report up to 25%. Differences in diagnostic criteria and modalities used for establishing a diagnosis of TRAS may be responsible for this large variation (8). Doppler US has been considered the
choice of noninvasive screening procedure for TRAS not just for its sensitivity but also for its accessibility and cost-effectiveness. Its major limitation is that its sensitivity is strongly operator dependent. Spiral computed tomography (CT) and magnetic resonance (MR) angiography are more expensive modalities that are not operator dependent, are more consistent, but have limitations due to the associated risks of contrast agents. The management of TRAS includes conservative, noninvasive treatment aimed at controlling blood pressure vs. invasive interventions to categorically restore perfusion. Interventions for restoring perfusion to the transplanted kidney
747
Ali et al.
include percutaneous transluminal angioplasty (PTA) alone, PTA with stenting, or surgery. Both PTA and PTA with stenting have been shown to re-establish perfusion to the kidney, eventually leading to better graft function and improving blood pressure control (3–5, 9, 13, 14). Surgery to treat stenosis and restore perfusion is generally nowadays regarded as a last resort in TRAS patients with either an unsuccessful angioplasty or stent placement or those with a critical stenosis who are not candidates for PTA. The purpose of the study was to (i) study the outcomes of all patients who underwent IADSA for suspected TRAS, and (ii) assess graft function and survival.
Methods Patient selection
A retrospective cohort study of all patients transplanted at Indiana University Hospital who underwent a transplant renal intra-arterial digital subtraction angiogram (IADSA) between January 1999 and August 2012. Study patients included patients with living donor, deceased donor, and multi-organ transplants. En bloc and dual kidney transplants were excluded. All the patients referred for IADSA had clinical features of suspected TRAS. They displayed either graft dysfunction as defined by decrease in GFR from baseline or uncontrolled hypertension as defined by requiring >3 medications with features of volume overload, or both, along with noninvasive imaging, suggesting a hemodynamically significant stenosis of >50% on an indication imaging examination. The final referral to angiography was determined by the primary nephrologist. The presence of hemodynamic significant TRAS on doppler imaging was defined by a narrowing or the arterial lumen diameter by >50% and/or a peak systolic velocity in the transplant renal artery exceeding 200 cm/s with renal to external iliac artery peak velocity ratio exceeding 2, prompted further evaluation with a IADSA. Some patients also underwent IADSA if the imaging tests were inconclusive (unable to assess velocities due to technical body habitus or poor visualization), when the clinical suspicion was highly suggestive of TRAS. All imaging tests were carried out at the hospital radiology unit. All IADSA procedures were performed by the same group of interventional radiologists following the same criteria for TRAS. The patients with a confirmed angiographic diagnosis of TRAS were considered as one group
748
(TRAS+) and the rest were considered the control group (TRAS ). Angiographic TRAS was defined as a >70% reduction in vessel lumen and/or 20 mmHg pressure gradient across the lesion. Balloon expandable stents were placed where indicated and included those manufactured by GenesisTM, AviatorTM, ExpressTM, CookTM, PalmazTM, and MedtronicTM. In addition, N-acetylcysteine and intravenous hydration was used. Patients were maintained on lifelong aspirin, and clopidogrel was prescribed for a minimum of three months. Standard BP checks (two measurements) during clinic follow-up were recorded at routine clinic visits up to last available follow-up. Standard renal function measurements using serum creatinine were used as a marker for graft function. Followup for graft survival was calculated up to graft loss or last available follow-up data on the patient. Graft loss was defined as return to dialysis, retransplantation, or patient death. Patients were followed up until the last available documented hospital or clinic visit or death. For comparison to the general transplant population, an age- and year of transplant-matched control group was selected 15:1 for each TRAS+ve subject. If there were similar age and year group TRAS subjects, the control group for that subject was not duplicated. Surgical transplant operative reports were reviewed for each case and classified as “complex” surgery if there was documentation of vascular reconstruction after primary anastomosis, dissection, intraoperative thrombosis, or the need for re-implantation. The study was approved by the IRB. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” Statistical analysis
All analyses were carried out using SPSS v 20.0. Comparisons of mean and frequencies were calculated using t-tests and chi-square tests. Outcomes of the TRAS group were measured in terms of efficacy and safety of intervention. Graft survival and patient survival following IADSA between two groups were calculated by Kaplan–Meier survival analysis. ANOVA was used to analyze betweengroup allograft function and BP control. p < 0.05 was considered to be significant. Results
A total of 74 patients underwent IADSA, of which 43 patients (58.1%) had clinically significant TRAS
Outcomes in transplant renal artery stenosis (TRAS+ve) as defined in our criteria above. A majority of the patients were male (74.4%). Mean age at transplant was 51.4 13.3 yr. Baseline demographics of TRAS+ve and TRAS ve are shown in Table 1. Mean follow-up post-intervention in the TRAS+ve group was 6.4 yr, and median follow-up was 7.9 yr with maximum follow-up to 14.9 yr. The median follow-up in the TRAS+ group from time of transplant was 9.2 yr. There were baseline differences between the two groups (Table 1), including mean age at IADSA, mean serum creatinine at IADSA, history of diabetes, number of transplants, and delayed graft function [defined as need for dialysis within seven d of transplant and also measured by creatinine reduction ratio (15)]. More notably, TRAS was found more commonly in an earlier post-transplant course. A total of 2,683 adult kidney transplants were carried out during the study period, yielding a prevalence rate of 1.3% for TRAS (including kidney transplants carried out with multi-organ transplants).
had a higher mean peak systolic velocity (PSV) on US: pre-intervention measurements of 4.2 1.6 m/s as compared to the TRAS ve group of 2.1 1.2 m/s.
Radiological evaluation
Blood pressure outcomes
Baseline radiological findings prior to IADSA are shown in Table 2. A significantly larger number of TRAS+ve patients had US performed and they
Due to extreme variability in BP measurements, BP medication changes, and a smaller number of patients in the TRAS ve group and BP
TRAS+ve intervention
PTA alone was performed in 24 patients (55.8%). PTA with stent (PTAS) was performed in 18 patients (41.8%). One patient underwent surgical intervention. There were nine cases (20.9%) of recurrent stenosis. Of these, eight (88.9%) occurred in the PTA alone group and only one occurred in PTAS group. Five of the recurrent stenosis were stented on repeat IADSA. Median duration to restenosis was 6.5 months (range was 1–21 months). Only one patient in the TRAS ve group had a repeat IADSA performed which also did not show any TRAS. At last follow-up in the TRAS+ve intervention group, a total of 22 (52.3%) TRAS+ve patients had a stent placed (Table 3).
Table 1. Baseline demographics of TRAS+ve and TRAS ve patients
Mean age at IADSA (yr) Mean age at transplant (yr) Race Sex Mean time from transplant to IADSA (months) Median time from transplant to IADSA (months) Mean Cr at IADSA (mg/dL) Retransplants (%) Mean duration of dialysis pre-transplant (months) Preemptive transplant (%) Type of transplant Living (%) Deceased (%) Mean PRA (CL1, CL2) (%) Total HLA mismatch Class 1 mismatch Class 2 mismatch Recipients with existing diabetes (%) Recipient with existing peripheral arterial disease Patients with acute rejection pre-IADSA (%) POD 1–2 Cr reduction ratio Need for RRT post-transplant Mean follow-up time from IADSA (months) Median follow-up time from IADSA (months) Mean graft survival time from IADSA (yr) Mean overall graft survival from transplant time (yr)
TRAS+ve (n = 43)
TRAS ve (n = 32)
53.9 11.8 51.40 13.3 35 C/6 AA/2 H 32 M/11 F 30.6 59.5 8.9 2.2 0.9 2.3% 37.8 28.9 9.3
49.5 15.20 42 15.8 25 C/7 AA 24 M/8 F 75.4 88.6 48.3 2.8 1.3 15.6% 42.5 36.5 3.1
9.3 90.7 7.1, 4.2 3.6 1.6 2.6 1.2 1.0 0.7 51.1 11.6
28.1 71.8 12.3, 6.1 3.5 1.4 2.5 1.1 1.0 0.6 25 21.8%
46.5 0.22 11.6% 778 55.3 94.7 6.5 4.6 9.2 6.4
43.7 0.26 6.2% 41.3 48.8 22.7 3.5 4.0 9.7 7.9
p-Value 0.18 0.02 0.59 0.90 0.016 0.02 0.08 0.60
0.03 0.31, 0.67 0.89 0.70 0.72 0.016 0.02 0.88 0.60 0.042 0.002 0.002 0.80
749
Ali et al. Table 2. Surgical and radiological characteristics of TRAS+ve and TRAS ve patients
Mean warm ischemia time (min) Mean cold ischemia time (h) No. of patients with screening US performed (%) No. of patients with screening MRA performed (%) No. of patients with both US and MRA performed (%) Peak systolic velocity on US (m/s) Resistive index on US >1 artery (%) Complex surgery (%) Type of anastomosis (%) Carrell patch End–end End–side Location of stenosis (%) Anastomosis Post-anastomosis Pre-anastomosis
TRAS+ve
TRAS ve
p-Value
44.3 20.9
44.0 17.6
0.95
20.1 11.6
17.1 12.3
0.31
76.7
93.7
0.014
34.8
31.2
0.29
26.1
25
0.52
4.2 1.6
2.1 1.2
Clin Transplant 2015: 29: 747–755 DOI: 10.1111/ctr.12574
Clinical Transplantation
Long-term outcomes of transplant recipients referred for angiography for suspected transplant renal artery stenosis Ali A, Mishler D, Taber T, Agarwal D, Yaqub M , Mujtaba M, Goggins W, Sharfuddin A. Long-term outcomes of transplant recipients referred for angiography for suspected transplant renal artery stenosis. Abstract: Our aim was to study the long-term outcomes of all transplant recipients who underwent angiography for suspected TRAS at our institution. The patients were divided into TRAS+ve and TRAS ve groups based upon angiographically confirmed results. TRAS was confirmed in 58.1% of 74 patients with median time of 8.9 months. Primary angioplasty alone was performed in 56% of patients with TRAS, while the remaining had PTA with stent (PTAS). There was reduction in systolic and diastolic BP (165 19–136 15 mmHg and 82 14 mmHg to 68 12 mmHg; p < 0.05) and number of antihypertensive drugs (3.5 0.9–2.7 1.0; p < 0.05). Overall, graft survival and patient survival from time of transplant were similar in both groups. Graft function was similar for the patients with treated TRAS+ve as compared to TRAS ve over time. Graft survival and patient survival when compared to an age- and year of transplant-matched cohort control group were also similar. In conclusion, angiography for suspected TRAS is more likely to yield a confirmatory result early in the transplant course as compared to late. Treatment of TRAS in these patients had sustained long-term graft function. Alternative etiologies of HTN and graft dysfunction should be sought for recipients further out from transplant.
Anum Alia, Dennis Mishlera, Tim Tabera, David Agarwalb, Muhammad Yaquba, Muhammad Mujtabaa, William Gogginsc and Asif Sharfuddina a
Division of Nephrology, Department of Medicine, bDivision of Interventional Radiology, Department of Radiology and c Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA Key words: graft function – graft survival – hypertension – kidney transplant – transplant renal artery stenosis Corresponding author: Asif A. Sharfuddin, Associate Professor of Clinical Medicine, Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 550 North University Blvd, UH 4620, Indianapolis, IN 46202, USA. Tel.: 1 317 944 4370; fax: 1 317 944 5046; e-mail: [email protected] Conflict of interest: The authors of this manuscript have no conflicts of interest to disclose. Portions of this manuscript were presented as an abstract at ASN Annual Meeting 2013. Accepted for publication 2 June 2015
Transplant renal artery stenosis (TRAS) is a known vascular complication in renal allografts. Hemodynamically significant stenosis usually occurs when the area of cross-section of the renal artery decreases by as much as 50% (1–5). TRAS is often the cause for refractory or new-onset hypertension in transplant patients along with allograft dysfunction (6, 7). A variable incidence of TRAS has been reported in literature, with most studies putting the incidence between 1 and 13% (1, 2, 4, 8–12), while some report up to 25%. Differences in diagnostic criteria and modalities used for establishing a diagnosis of TRAS may be responsible for this large variation (8). Doppler US has been considered the
choice of noninvasive screening procedure for TRAS not just for its sensitivity but also for its accessibility and cost-effectiveness. Its major limitation is that its sensitivity is strongly operator dependent. Spiral computed tomography (CT) and magnetic resonance (MR) angiography are more expensive modalities that are not operator dependent, are more consistent, but have limitations due to the associated risks of contrast agents. The management of TRAS includes conservative, noninvasive treatment aimed at controlling blood pressure vs. invasive interventions to categorically restore perfusion. Interventions for restoring perfusion to the transplanted kidney
747
Ali et al.
include percutaneous transluminal angioplasty (PTA) alone, PTA with stenting, or surgery. Both PTA and PTA with stenting have been shown to re-establish perfusion to the kidney, eventually leading to better graft function and improving blood pressure control (3–5, 9, 13, 14). Surgery to treat stenosis and restore perfusion is generally nowadays regarded as a last resort in TRAS patients with either an unsuccessful angioplasty or stent placement or those with a critical stenosis who are not candidates for PTA. The purpose of the study was to (i) study the outcomes of all patients who underwent IADSA for suspected TRAS, and (ii) assess graft function and survival.
Methods Patient selection
A retrospective cohort study of all patients transplanted at Indiana University Hospital who underwent a transplant renal intra-arterial digital subtraction angiogram (IADSA) between January 1999 and August 2012. Study patients included patients with living donor, deceased donor, and multi-organ transplants. En bloc and dual kidney transplants were excluded. All the patients referred for IADSA had clinical features of suspected TRAS. They displayed either graft dysfunction as defined by decrease in GFR from baseline or uncontrolled hypertension as defined by requiring >3 medications with features of volume overload, or both, along with noninvasive imaging, suggesting a hemodynamically significant stenosis of >50% on an indication imaging examination. The final referral to angiography was determined by the primary nephrologist. The presence of hemodynamic significant TRAS on doppler imaging was defined by a narrowing or the arterial lumen diameter by >50% and/or a peak systolic velocity in the transplant renal artery exceeding 200 cm/s with renal to external iliac artery peak velocity ratio exceeding 2, prompted further evaluation with a IADSA. Some patients also underwent IADSA if the imaging tests were inconclusive (unable to assess velocities due to technical body habitus or poor visualization), when the clinical suspicion was highly suggestive of TRAS. All imaging tests were carried out at the hospital radiology unit. All IADSA procedures were performed by the same group of interventional radiologists following the same criteria for TRAS. The patients with a confirmed angiographic diagnosis of TRAS were considered as one group
748
(TRAS+) and the rest were considered the control group (TRAS ). Angiographic TRAS was defined as a >70% reduction in vessel lumen and/or 20 mmHg pressure gradient across the lesion. Balloon expandable stents were placed where indicated and included those manufactured by GenesisTM, AviatorTM, ExpressTM, CookTM, PalmazTM, and MedtronicTM. In addition, N-acetylcysteine and intravenous hydration was used. Patients were maintained on lifelong aspirin, and clopidogrel was prescribed for a minimum of three months. Standard BP checks (two measurements) during clinic follow-up were recorded at routine clinic visits up to last available follow-up. Standard renal function measurements using serum creatinine were used as a marker for graft function. Followup for graft survival was calculated up to graft loss or last available follow-up data on the patient. Graft loss was defined as return to dialysis, retransplantation, or patient death. Patients were followed up until the last available documented hospital or clinic visit or death. For comparison to the general transplant population, an age- and year of transplant-matched control group was selected 15:1 for each TRAS+ve subject. If there were similar age and year group TRAS subjects, the control group for that subject was not duplicated. Surgical transplant operative reports were reviewed for each case and classified as “complex” surgery if there was documentation of vascular reconstruction after primary anastomosis, dissection, intraoperative thrombosis, or the need for re-implantation. The study was approved by the IRB. The clinical and research activities being reported are consistent with the Principles of the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” Statistical analysis
All analyses were carried out using SPSS v 20.0. Comparisons of mean and frequencies were calculated using t-tests and chi-square tests. Outcomes of the TRAS group were measured in terms of efficacy and safety of intervention. Graft survival and patient survival following IADSA between two groups were calculated by Kaplan–Meier survival analysis. ANOVA was used to analyze betweengroup allograft function and BP control. p < 0.05 was considered to be significant. Results
A total of 74 patients underwent IADSA, of which 43 patients (58.1%) had clinically significant TRAS
Outcomes in transplant renal artery stenosis (TRAS+ve) as defined in our criteria above. A majority of the patients were male (74.4%). Mean age at transplant was 51.4 13.3 yr. Baseline demographics of TRAS+ve and TRAS ve are shown in Table 1. Mean follow-up post-intervention in the TRAS+ve group was 6.4 yr, and median follow-up was 7.9 yr with maximum follow-up to 14.9 yr. The median follow-up in the TRAS+ group from time of transplant was 9.2 yr. There were baseline differences between the two groups (Table 1), including mean age at IADSA, mean serum creatinine at IADSA, history of diabetes, number of transplants, and delayed graft function [defined as need for dialysis within seven d of transplant and also measured by creatinine reduction ratio (15)]. More notably, TRAS was found more commonly in an earlier post-transplant course. A total of 2,683 adult kidney transplants were carried out during the study period, yielding a prevalence rate of 1.3% for TRAS (including kidney transplants carried out with multi-organ transplants).
had a higher mean peak systolic velocity (PSV) on US: pre-intervention measurements of 4.2 1.6 m/s as compared to the TRAS ve group of 2.1 1.2 m/s.
Radiological evaluation
Blood pressure outcomes
Baseline radiological findings prior to IADSA are shown in Table 2. A significantly larger number of TRAS+ve patients had US performed and they
Due to extreme variability in BP measurements, BP medication changes, and a smaller number of patients in the TRAS ve group and BP
TRAS+ve intervention
PTA alone was performed in 24 patients (55.8%). PTA with stent (PTAS) was performed in 18 patients (41.8%). One patient underwent surgical intervention. There were nine cases (20.9%) of recurrent stenosis. Of these, eight (88.9%) occurred in the PTA alone group and only one occurred in PTAS group. Five of the recurrent stenosis were stented on repeat IADSA. Median duration to restenosis was 6.5 months (range was 1–21 months). Only one patient in the TRAS ve group had a repeat IADSA performed which also did not show any TRAS. At last follow-up in the TRAS+ve intervention group, a total of 22 (52.3%) TRAS+ve patients had a stent placed (Table 3).
Table 1. Baseline demographics of TRAS+ve and TRAS ve patients
Mean age at IADSA (yr) Mean age at transplant (yr) Race Sex Mean time from transplant to IADSA (months) Median time from transplant to IADSA (months) Mean Cr at IADSA (mg/dL) Retransplants (%) Mean duration of dialysis pre-transplant (months) Preemptive transplant (%) Type of transplant Living (%) Deceased (%) Mean PRA (CL1, CL2) (%) Total HLA mismatch Class 1 mismatch Class 2 mismatch Recipients with existing diabetes (%) Recipient with existing peripheral arterial disease Patients with acute rejection pre-IADSA (%) POD 1–2 Cr reduction ratio Need for RRT post-transplant Mean follow-up time from IADSA (months) Median follow-up time from IADSA (months) Mean graft survival time from IADSA (yr) Mean overall graft survival from transplant time (yr)
TRAS+ve (n = 43)
TRAS ve (n = 32)
53.9 11.8 51.40 13.3 35 C/6 AA/2 H 32 M/11 F 30.6 59.5 8.9 2.2 0.9 2.3% 37.8 28.9 9.3
49.5 15.20 42 15.8 25 C/7 AA 24 M/8 F 75.4 88.6 48.3 2.8 1.3 15.6% 42.5 36.5 3.1
9.3 90.7 7.1, 4.2 3.6 1.6 2.6 1.2 1.0 0.7 51.1 11.6
28.1 71.8 12.3, 6.1 3.5 1.4 2.5 1.1 1.0 0.6 25 21.8%
46.5 0.22 11.6% 778 55.3 94.7 6.5 4.6 9.2 6.4
43.7 0.26 6.2% 41.3 48.8 22.7 3.5 4.0 9.7 7.9
p-Value 0.18 0.02 0.59 0.90 0.016 0.02 0.08 0.60
0.03 0.31, 0.67 0.89 0.70 0.72 0.016 0.02 0.88 0.60 0.042 0.002 0.002 0.80
749
Ali et al. Table 2. Surgical and radiological characteristics of TRAS+ve and TRAS ve patients
Mean warm ischemia time (min) Mean cold ischemia time (h) No. of patients with screening US performed (%) No. of patients with screening MRA performed (%) No. of patients with both US and MRA performed (%) Peak systolic velocity on US (m/s) Resistive index on US >1 artery (%) Complex surgery (%) Type of anastomosis (%) Carrell patch End–end End–side Location of stenosis (%) Anastomosis Post-anastomosis Pre-anastomosis
TRAS+ve
TRAS ve
p-Value
44.3 20.9
44.0 17.6
0.95
20.1 11.6
17.1 12.3
0.31
76.7
93.7
0.014
34.8
31.2
0.29
26.1
25
0.52
4.2 1.6
2.1 1.2
