Transplant renal artery stenosis is an increasingly recognized vascular complication after renal transplant. It can result in posttransplant hypertension and graft dysfunction and eventually in graft loss. Timely diagnosis and appropriate intervention for clinically significant transplant renal artery stenosis can potentially halt or reverse these adverse effects, leading to better outcomes. Duplex ultrasonography is the imaging modality of choice to screen suspected cases. Some patients with transplant renal artery stenosis will require invasive treatment with endovascular intervention or surgery, whereas others can be safely treated with blood pressure control and follow-up. In this review, we aimed to discuss the epidemiology, clinical presentation, pathogenesis, diagnosis, and management of this common posttransplant complication.
Key words : Angioplasty, Renal transplant, Surgery, Vascular complications of kidney transplant
Transplant renal artery stenosis (TRAS) is the most common vascular complication following renal transplant. It has a reported incidence of 1% to 23%. This wide range has been attributed to variable definitions and imaging techniques used for its diagnosis.1-4 At present, the condition appears to be more commonly diagnosed, probably as a result of more cases being discovered during surveillance ultrasonographic scans of transplanted kidneys. Transplant renal artery stenosis has been identified as a cause of posttransplant hypertension, graft dysfunction, and graft loss.5 Contemporary use of advanced immunosuppression and protocol-driven management after kidney transplant has led to nonimmunological causes emerging as a leading cause of graft loss.2 Among these causes, TRAS is a potentially curable entity; thus, early recognition and appropriate treatment are vital. This review presents an overview of the current diagnostic and therapeutic strategies available for the management of this condition.
Transplant renal artery stenosis is considered the most common vascular complication after renal transplantation.1,4,6 Hurst and colleagues, who analyzed the US Renal Data System registry, reported its incidence as 8.3 cases per 1000 patient-years.7 In a case series involving 2594 kidney transplants, TRAS was diagnosed in 0.6% of the recipients.8 After analysis of 1367 renal transplants, Dimitroulis and colleagues noted TRAS in 1.4%.1 Another study that used duplex as a surveillance tool in 793 renal transplant recipients reported an incidence of 0.9%.3 Wong and colleagues reported a 2.4% incidence of TRAS in the era before duplex ultrasonography. This increased to 12.4% once duplex ultrasonography was introduced to their practice.9
The common time frame for the diagnosis of TRAS is between 3 months and 2 years after transplant surgery, but early or late presentations are possible.1 Symptoms of TRAS have been reported as early as 1 week after transplant.3 The usual mode of presentation is with worsening or treatment-resistant hypertension and edema with or without graft dysfunction. Rejection, obstructive uropathy, and infection should be excluded before graft dysfunction is attributed to TRAS.2 Sudden, unexplained episodes of pulmonary edema in the absence of left ventricular dysfunction, also known as flash pulmonary edema or Pickering syndrome, is an uncommon presentation of TRAS.2,10 The introduction of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensinogen receptor blockers (ARBs) in some patients with TRAS can precipitate acute graft dysfunction.2 Asymptomatic cases may be discovered during routine surveillance duplex ultrasonography.11 The presence of a bruit over the renal allograft can be associated with TRAS, but this physical sign is nonspecific. Turbulent flow due to hyperdynamic flow at the renal artery anastomosis or stenosis of the iliac artery proximal to the anastomosis can result in such bruits over the iliac fossa. The presence of iatrogenic arteriovenous fistulas secondary to needle biopsy of the renal allograft is another differential diagnosis for a bruit over the transplanted kidney. Transplant renal artery stenosis may also exist without a bruit.2
Etiology and Risk Factors
Depending on the location and the pattern of the arterial narrowing, several morphologies of TRAS have been described: (1) at the site of the anastomosis, (2) proximal to the anastomosis, (3) distal to the anastomosis, (4) multiple stenoses at different locations, and (5) diffuse stenosis of the whole renal artery.2 Stenosis at the anastomosis site can be the result of faulty surgical techniques. Wide suture bites, extra stitches placed for hemostasis, and mechanical tucking of the artery have been identified as potential technical errors that can precipitate anastomotic stenosis. In contrast, techniques that allow a wide anastomosis under direct vision may lower the risk of TRAS.12 End-to-end anastomosis of the donor renal artery to the recipient’s inflow vessel has been reported as a risk factor for suture line stenosis, especially when there is a size mismatch between the 2 vessels.13 In their case series, Sankari and colleagues did not note a difference in TRAS between end-to-end versus end-to-side anastomosis, but all patients who had an end-to-end anastomosis and TRAS were noted to have stenosis at the suture line.14 According to Sutherland and colleagues, the incidence of TRAS was not different between patients who had an end-to-side renal artery anastomosis to the common or external lilac arteries versus those who had end-to-end anastomosis to the internal iliac artery. However, they identified endarterectomy of the internal iliac artery at the time of implantation as a significant risk factor for the late development of suture line stenosis. Intimal damage during endar-terectomy or progression of atherosclerosis explains this phenomenon.15 Another possible mechanism of stenosis at the anastomosis is endothelial damage and intimal flaps created during the donor organ procurement or backbench perfusion.2 Pre- or postanastomotic stenosis can be caused by progressive atherosclerosis of the donor’s renal artery and recipient’s inflow vessel.2 Hurst and colleagues postulated that the increased incidence of TRAS noted in older donors and recipients was probably a consequence of ongoing atherosclerosis.7 Transplant renal artery stenosis due to atherosclerosis tends to present relatively late in the posttransplant course.2 Clamp injury to the recipient’s iliac artery or the donor’s renal artery is another mechanism for loca-lized stenosis proximal or distal to the anastomosis.13 Diffuse stenosis of the allograft renal artery has been attributed to immune-mediated injury.10 The histology of renal arteries affected by TRAS and acute rejection share some similarities.13 As per the findings of Macia and colleagues, episodes of acute rejection were a critical predisposing factor for TRAS. They concluded that TRAS may be a vascular manifestation of acute rejection.16 According to another study by Audard and colleagues, those with TRAS had more acute rejection episodes than those without TRAS, but this difference was not statistically significant.17 Willicombe and colleagues have reported an association between postanastomotic diffuse TRAS and the presence of de novo donor-specific antibodies.18 (Table 1) summarizes the predisposing factors for TRAS depending on the location of the stenosis. Delayed graft function (DGF) has been recognized as a significant risk factor for TRAS by several authors.7,19 Kidneys from extended criteria donors have a higher chance of developing TRAS, which is probably secondary to the higher incidence of DGF associated with such transplants. Increased expression of vascular endothelial growth factor by kidneys that show DGF may cause intimal hyperplasia of the donor renal artery, which can progress to stenosis.7 The relationship between prolonged cold ischemia times and TRAS is controversial.7,17,19 Cytomegalovirus (CMV) infection has been identified as a risk factor for TRAS. In the study from Pouria and colleagues, TRAS was significantly more common in patients with definitive evidence of CMV infection.20 Audard and colleagues have also reported CMV infection as a significant and independent risk factor for the development of TRAS.17 A case report by Ardalan and colleagues illustrated a case of TRAS associated with acute CMV infection. Antiviral therapy for the CMV disease led to spontaneous resolution of the stenosis of the renal artery.21 The mitogenic effects of CMV gene products on the vascular smooth muscle may explain the association between CMV infection and the development of TRAS.18,21 Kinking or mechanical compression of the renal artery can mimic TRAS. Kinking of a redundant renal artery is possible in a right kidney transplant from a deceased donor where the donor renal artery tends to be longer than the renal vein.2 External compression on the transplant renal artery by a polycystic kidney and an anastomotic pseudoaneurysm have been reported as TRAS mimics.10,22
Stenosis of the renal artery reduces the perfusion of the transplanted kidney. Renal ischemia activates the renin-angiotensin pathway and upregulates angio-tensin II production. Angiotensin II in itself is a potent vasoconstrictor and enhances sympathetic nervous system-mediated vasoconstriction. It stimulates the production of aldosterone, which in turn expands the circulatory volume by promoting sodium and water retention. Hypertension in TRAS is a result of this vasoconstriction and volume expansion.2 According to animal studies, stenosis above 70% affecting a single renal artery is sufficient to provoke a rise in systemic blood pressure.23
Calcineurin inhibitor toxicity can present as hypertension and graft dysfunction. Atherosclerotic narrowing of the recipient iliac arteries can be a mimicker of TRAS. This entity is termed “pseudo TRAS,” and affected individuals are likely to have concomitant ischemic symptoms of the ipsilateral lower limb such as claudication, rest pain, and tissue loss. Hypertension in renal transplant recipients may be mediated by the contracted native kidneys or segmental infractions of the transplanted kidney due to thrombosis of polar arteries.2
Duplex ultrasonography is the first-line imaging modality used in suspected TRAS as it is readily available, noninvasive, and avoids nephrotoxic contrast or radiation exposure. Operator depen-dability is its main disadvantage. Compared with digital subtraction angiography (DSA), duplex has a sensitivity of 87% to 94% and a specificity of 86% to 100% for the diagnosis of this condition.2 In addition to diagnosis, duplex ultrasonography is the preferred option for following up patients with TRAS.24 The typical duplex wave from distal to a hemodynamically significant narrowing in the transplanted renal artery will show a “tardus parvus” pattern, with a slow systolic upstroke and a diminished amplitude of the entire waveform (Figure 1). Additional extrarenal and intrarenal duplex indices have been described that can be used to suspect, diagnose, and assess the severity of TRAS. Peak systolic velocity (PSV) of the renal artery (Figure 2) and the ratio of PSV in the renal artery to the PSV in the external iliac artery are “extrarenal” duplex measurements that can be used to confirm TRAS. Acceleration time (AT) in intrarenal arteries and intrarenal resistive index (RI) are helpful “intrarenal” indices.25,26 As reported by de Morais and colleagues, a PSV of 200 cm/s in the renal artery was 90% sensitive and 87.5% specific for the diagnosis of >50% stenosis. When the PSV cutoff was increased to 250 cm/s, the specificity increased to 96.8% but the sensitivity dropped to 70%. According to the same authors, when the PSV ratio between the renal artery and external iliac artery was >2, it showed 80% sensitivity and 100% specificity for detection of significant (>50%) TRAS.25 Baxter and colleagues have reported that a PSV of >250 cm/s had 100% sensitivity and 95% specificity to indicate >50% narrowing of the transplanted renal artery.27 As reported by de Morais and colleagues, an AT of >0.09 seconds in the intrarenal arteries was the best single duplex criterion for the diagnosis of >50% stenosis.25 Another study by Saarinen and colleagues, who used RI cutoff of ?0.6 for the diagnosis of 50% or more stenosis of the transplant renal artery, reported a specificity of 100% and a sensitivity of 67%.28 Gottlieb and colleagues have reported an AT of >0.1 second or the subjective interpretation of a dampened waveform in intrarenal arteries as more accurate indicators compared with elevated PSV.29 The accuracy of the PSV measurements can be affected by the Doppler angle and the tortuosity of the renal artery. Currently, there is no consensus on the use of duplex parameters such as AT and RI for the diagnosis of TRAS.27,30 As described by Fananapazir and colleagues, the use of multiple duplex parameters in combination can increase the sensitivity and specificity of Doppler ultrasonography.31 In the presence of Doppler ultrasonography showing features suspicious for TRAS, the diagnosis should be always confirmed by a more objective imaging modality, especially if the clinical circumstances dictate that TRAS should be confidently excluded.
Contrast-enhanced ultrasonography (CEUS) has been explored as an imaging option for the detection of TRAS. It involves intravenous injection of microbubbles, which act as the ultrasonography contrast agent. The nonnephrotoxic nature of such contrast material is an advantage. During CEUS, a longer time for contrast inflow indicates stenosis, and it is possible to directly identify such lesions on enhanced images. According to Pan and colleagues, who compared CEUS against standard duplex in patients with TRAS, CEUS emerged as the more superior imaging technique.30 However, more experience in imaging with CEUS is required before it can be recommended as a preferred imaging option for TRAS.
Computed tomography angiography
Computed tomography angiography (CTA) is noninvasive but requires intravenous iodinated contrast, which has nephrotoxic properties. Hence, it is not a favored imaging modality in patients suspected of TRAS. Additionally, computed tomog-raphy exposes the patient to ionizing radiation. Despite these disadvantages, CTA can provide excellent images of the allograft vasculature, especially after 3-dimensional (3D) reconstruction.32 According to a study published by Sun and colleagues, 3D CTA had comparable sensitivity to DSA for the detection of TRAS.33
Magnetic resonance angiography
Magnetic resonance angiography (MRA) is nonin-vasive and does not involve ionizing radiation. Gadolinium can be used as a contrast agent, but in those with poor renal function, gadolinium can precipitate nephrogenic systemic fibrosis. Noncontrast-enhanced magnetic resonance imaging has also been reported to generate excellent images of transplanted renal arteries with an accurate depiction of stenoses.34 Claustrophobia and incompatible metallic implants can preclude MRA in certain individuals. Magnetic resonance imaging has a reported sensitivity and specificity for the diagnosis of TRAS that ranges from 67% to 100% and 75% to 100%, respectively.2 Combination of 3D contrast-enhanced MRA and 3D phase-contrast MRA can increase the specificity and accuracy of detecting TRAS. The presence of metallic clips close to the transplant artery is a common cause for false positive diagnoses or overestimation of the stenosis with MRA.35
Because of its poor sensitivity and specificity, renal scintigraphy is no longer recommended as an imaging modality to diagnose renal artery stenosis.36
Digital subtraction angiography
Digital subtraction angiography is considered the gold standard of imaging in TRAS. It is invasive, and arterial puncture can result in complications such as hematoma, pseudoaneurysm, dissection, and throm-boembolism. Patients undergoing DSA are exposed to iodinated contrast material and ionizing radiation. Because of these drawbacks, DSA is generally not used as a first-line diagnostic tool, but it has a place when information gained from noninvasive imaging techniques tends to be nonspecific. In addition to confirming the diagnosis, DSA allows simultaneous treatment of the identified lesion by balloon angioplasty with or without stenting. Carbon dioxide, which is a nonnephrotoxic contrast medium, can be used as an alternative to reduce the volume of iodinated contrast required during diagnostic and therapeutic angiography.37 Fractional flow reserve (FFR) is a technique utilized during coronary angiography to identify hemodynamically significant stenosis that warrants treatment. This involves intra-arterial instillation of papaverine to induce vasodilatation and end-organ hyperemia. During peak hyperemia, the ratio of mean distal and proximal pressures to the stenosis is used to calculate the FFR.38 According to De Bruyne and colleagues, a distal-to-proximal pressure ratio of <0.9 across a renal artery stenosis was associated with the upregulation of renin production.39 Gomes Junior and colleagues used FFR in patients who underwent endovascular revascularization for TRAS and reported that it had a good correlation with other hemodynamic parameters such as the translesional pressure gradient.38 (Table 2) summarizes the advantages and disad-vantages of different imaging modalities used for the diagnosis of TRAS.
Those with stable renal functions and imaging parameters suggestive of <50% stenosis of the renal artery can be managed conservatively with antihypertensives. The preferred first-line antihyper-tensive agents are ACEIs or ARBs.2 These drugs should be introduced with careful monitoring of the renal function, and any deterioration should prompt immediate drug withdrawal. In addition to controlling blood pressure, ACEI or ARB therapy limits cardiac mortality and morbidity in patients with renal artery stenosis. These effects are explained by their ability to mitigate the adverse cardiac effects of elevated angiotensin II and aldosterone.40 Although solid evidence for the use of antiplate-lets and statins in patients with TRAS is unavailable, experts agree that these drugs should be given to patients affected with the condition, as well as for patients with atherosclerosis-related narrowing of the native renal arteries.2 Patients with adequate blood pressure control while on antihypertensive drugs, stable serum creatinine, and nonprogressive lesions on imaging can be continued on conservative management. Invasive treatment is indicated when there is resistant hypertension, graft dysfunction, or evidence of progressive disease.2
Endovascular intervention is the preferred first-line treatment option for patients with TRAS with an indication for invasive intervention (Figure 3). A technical success rate of >90% has been reported.41 Balloon angioplasty has a restenosis rate of 5% to 30% at 6 to 8 months.42 Stenting reduces the incidence of restenosis.43 According to Ngo and colleagues, the overall patency rates for angioplasty alone versus angioplasty combined with stenting for TRAS were 73% and 90.4%, respectively.41 These findings were replicated by Biederman and colleagues, who noted better patency rates for stented lesions compared with nonstented lesions after angioplasty.44 Drug-eluting stents appear superior to bare metal stents in preventing in-stent restenosis, especially for small-diameter renal arteries and postanastomotic TRAS.44,45 Percutaneous intervention for TRAS has a 10% risk of complications. Major complications such as arterial dissection, rupture, or thrombosis occur in <4% of patients.2 Endovascular treatment for TRAS leads to better control of blood pressure and long-lasting impro-vement of renal function.46 According to the findings of Beecroft and colleagues, at the end of 1 month after percutaneous intervention for TRAS, patients had significant improvement of their systolic and diastolic blood pressures with a reduction in the number of antihypertensive agents required to achieve target blood pressure values. Furthermore, they noted a significant drop in serum creatinine after successful revascularization.47 A different study by Gunawardena and colleagues noted significantly better serum creatinine values and diminished antihypertensive drug requirements at the end of 4-year follow-up in patients who had endovascular treatment for clinically significant TRAS.46 Halimi and colleagues reported good long-term outcomes following balloon angioplasty for TRAS, with sustained improvements in blood pressure and renal function. According to their study, at the end of 8 years, patients with TRAS who were treated had patient and graft survival rates similar to those shown in patients without TRAS.19 Patel and colleagues followed up 41 patients with TRAS who underwent angioplasty with or without stenting for 21 years and compared them against a matched sample of renal allograft recipients without TRAS; their results showed that long-term patient and graft survival rates were not different between the 2 groups. According to their findings, successful intervention for TRAS was associated with a 12% improvement in systolic blood pressure, a 7.4% improvement in diastolic blood pressure, and a 27% improvement in serum creatinine values.48
Surgery is indicated for TRAS when percutaneous intervention fails or when there are lesions that are not amenable to angioplasty. Surgical options include revision of the anastomosis, bypass of the stenosis using the saphenous vein graft, patch angioplasty, and endarterectomy.49 Shames and colleagues reported excellent outcomes with the use of ABO blood group-matched deceased donor iliac artery grafts.50 The success after surgical therapy ranges from 67% to 92%. However, morbidity and mortality are much higher compared with that shown with angioplasty, with a 20% risk of graft loss and a 5% risk of death.2
Surgery versus angioplasty for transplant renal artery stenosis
A publication by Benoit and colleagues describes the comparative outcomes between surgery and angioplasty for TRAS. According to their results, the immediate and long-term success for surgery was 92.1% and 82.5%. The corresponding figures for angioplasty were 69% and 40.8%. The angioplasty group had a higher procedure-related morbidity (28% vs 7.6% for surgery).51 These findings are of historical interest only, as advances in technology and operator skills have drastically improved the outcomes of percutaneous interventions.
Comparison of conservative vs interventional therapy for transplant renal artery stenosis
Invasive management of TRAS has been compared against medical therapy in a few studies. The case-control study by Zupunski and colleagues is an example. They studied and compared patients with >50% TRAS who received medical therapy versus those who had some form of invasive treatment, either percutaneous or surgical. The indication for intervention was an increase in serum creatine of 20% or more from baseline. They did not note a significant difference in blood pressure, serum creatinine, and the number of antihypertensive agents between the 2 groups. Among patients, 21% of those who had been conservatively managed had a spontaneous improvement in the severity of stenosis to <50%. The authors concluded that, on long-term follow-up, TRAS seemed to be nonprog-ressive and stable in the majority, irrespective of intervention.52 Another study by Geddes and colleagues com-pared long-term outcomes of those with TRAS who either received percutaneous intervention or medical therapy. The majority of the study population had >50% stenosis affecting the transplant renal artery. Angioplasty with or without stenting was indicated for patients with severe renal impairment, rapid deterioration of their graft function, or treatment-resistant hypertension. At the end of follow-up, there was no significant difference in terms of blood pressure, serum creatinine, or the number of antihypertensives required between the 2 groups. The authors concluded that conservative mana-gement is a reasonable option in patients with TRAS who have stable renal functions and adequate blood pressure control.53
Transplant renal artery stenosis is a treatable cause of graft dysfunction and posttransplant hypertension. Medical treatment with blood pressure control, antiplatelet drugs, and statins can be attempted when the graft function is stable and the stenosis is <50%. Transplant renal artery stenosis associated with resistant hypertension, graft dysfunction, or progression of the severity of stenosis on imaging requires revascularization. At present, endovascular techniques are preferred to open surgery. New evidence indicates that selected patients with >50% TRAS can be managed conservatively with outcomes similar to those who undergo invasive treatment. Further studies with larger patient numbers and randomization will be required to identify patients who are candidates for such conservative treatment.
Volume : 20
Issue : 12
Pages : 1049 - 1057
DOI : 10.6002/ect.2022.0334
From Department of Renal Transplant, Royal Liverpool University Hospital, Liverpool, United Kingdom
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Thilina Gunawardena, Department of Renal Transplant, Royal Liverpool University Hospital, Liverpool, UK
Phone: +44 61420703018
Table 1. Risk Factors for Transplant Renal Artery Stenosis Depending on the Location of the Stenosis
Figure 1. “Tardus Parvus” Wave Pattern on the Duplex Ultrasonograph in a Patient with Transplant Renal Artery Stenosis
Figure 2. Elevated Peak Systolic Velocity
Table 2. Comparison of Imaging Modalities Used for Diagnosis of Transplant Renal Artery Stenosis
Figure 3. Digital Subtraction Angiography Images