Peripheral Vascular Disease Involving Transplant Renal Artery

Background. Transplant renal artery stenosis (TRAS) can afflict up-to one-fifth of patients with a transplanted kidney. It is associated with uncontrolled hypertension, loss of precious transplanted organs, and mortality. Pathophysiology, diagnosis, and treatment of TRAS is distinct from vascular diseases of the native kidney. The value of preservation of a transplanted kidney is unique, considering the emotional and surgical stakes involved. This field lacks large randomized trials, and ethically it may never be possible to randomize patients with a solitary transplanted kidney. Therefore, vascular interventionalists have to rely on treating factors that can cause graft malfunction like uncontrolled hypertension and renal ischemia, considering that sufficiently large, prospective, randomized data indicating that treating these factors make a difference may never emerge.

J INVASIVE CARDIOL 2021;33(10):E798-E804. Epub 2021 September 8.

Key words: percutaneous renal interventions, renal transplantation, transplant renal artery stenosis, TRAS

Renal transplantation is an established modality of renal replacement therapy, and patients usually prefer renal transplant over dialysis. Renal transplant reduces mortality and is cost effective as compared with dialysis.^1,2 It has been shown that renal transplantation is economical, and survival advantage persists despite comorbidities and advancing age of the patients.² As per the United Network for Organ Sharing (UNOS), a total of 23,401 renal transplants were performed in the United States in 2019. Per organ procurement and transplant network data annual report from 2017, the cumulative number of recipients living with a functioning kidney transplant was 220,000. Since 1996, the probabilities of graft survival and patient survival have steadily improved among recipients of both living and deceased donor kidney transplants. Immune-mediated graft loss has progressively declined with the introduction of effective immunosuppression, which has brought other causes of graft failure to the forefront.³ Graft failure due to drug toxicities, recurrence of the previous disease, and vascular issues is assuming greater importance.⁴ The prevalence of transplant renal artery stenosis (TRAS) has been estimated at 1%-23% in different series.³ The use of different diagnostic modalities and different criteria for diagnosis in these patient series might explain such a vast range. More cases are being diagnosed with increasing use and availability of non-invasive investigative tools, such as Doppler ultrasonography and magnetic resonance angiography (MRA).⁴ TRAS has been associated with graft failure, and the adjusted hazard ratio for death and graft loss is 2.84 (95% confidence interval, 1.70-4.72) in transplant recipients with TRAS.⁵ The kidney is a highly vascular organ. Native kidney needs only 10% of perfusion to remain viable.⁶ Glomerular filtration rate starts dropping after renal blood flow falls below 40% in native kidney.⁶ A very high degree of stenosis, therefore, is needed to cause cellular damage. On the other hand, chronic hypoperfusion of the kidney stimulates activation of the renin-angiotensin system, which in turn increases expression of the TGF-ẞgene, resulting in deposition of extracellular matrix and collagen, which leads to renal damage and fibrosis.⁷ A similar mechanism may play a role in transplanted kidneys afflicted with TRAS and cause graft failure. Physiologically, it seems intuitive that timely restoration of good antegrade blood flow should help with graft survival by halting ischemic nephropathy progression; however, there is no randomized controlled trial addressing this question. Historically, surgical revascularization has been the standard approach, but the transplanted organ site’s re-exploration is technically challenging given extensive fibrotic changes in the surgical field. Percutaneous techniques for treatment of TRAS are increasingly considered the first line of treatment because percutaneous techniques are effective and are less invasive.⁸ A recent study has demonstrated that long-term graft and patient survival after endovascular correction of TRAS is similar to those without TRAS, and most patients were able to avoid returning to dialysis.⁹

Etiology and pathogenesis. Lesion location in TRAS can be in the donor renal artery, feeding native artery, or at the site of the suture line. It usually presents 3 months to 2 years post transplant, with the greatest frequency in the first 6 months.⁵ Surgical issues like a vascular clamp, kinking, or angulation of the artery can also be the possible reasons for flow limitation. Angulation of the renal artery is more likely to occur if there is a discrepancy between the length of the harvested renal artery and the ultimate distance to the planned anastomosis site. Suture-line stenosis is more likely to occur in end-to-end anastomoses. In contrast, end-to-side anastomoses may cause turbulent flow and vessel trauma, which could lead to the development of stenosis.¹⁰

However, there are studies that found no differences in the incidence of transplant renal artery stenosis when comparing end-to-end vs end-to-side anastomosis.^11,12 It has also been shown in a small retrospective study that cytomegalovirus (CMV) infection and delayed graft function have been associated with the development of TRAS.¹³ In patients with cellular rejection, inflammation of smaller intrarenal arteries is seen, and it has been hypothesized that the immune-mediated process might also involve a bigger extrarenal artery and thus result in TRAS. Few studies have indeed found a higher incidence of acute cellular rejection in TRAS; however, it was not statistically significant and could not be established as a causal factor.^13,14 A recent retrospective study done on nearly 42,000 Medicare patients showed that TRAS was more likely to occur in older, CMV positive, diabetic, and hypertensive patients.⁵ The donor type had no statistically significant relationship with TRAS.⁵ Some of the predictors mentioned above are risk factors for atherosclerotic vascular disease, and thus it might seem that vascular dysfunction due to endothelial injury may contribute to the occurrence of TRAS, especially if it is occurring late after renal transplantation, but this is unclear. In a study comprising 1110 cadaveric-donor kidney transplants, 3.4% required endarterectomy of the external iliac artery and use of a donor patch onto the external iliac artery at the time of transplantation using end-to-side anastomosis.¹⁵ The authors of the study mentioned above further showed that patients who needed endarterectomy had lower graft survival, underlining the importance of the pre-existing atherosclerotic disease, vessel trauma associated with surgery, and immunological damage, which may lead to intimal hyperplasia.

Patients with TRAS probably behave physiologically similar to patients with bilateral renal artery stenosis leading to ischemic nephropathy, which ultimately leads to chronic graft malfunctioning.⁶

Clinical features and diagnosis. TRAS is suspected if the patient has difficult-to-control hypertension, episodes of flash pulmonary edema, and graft failure not consistent with immune-mediated rejection.¹⁶ Hypertension has been reported in up to 93%, and in 44% of patients it is combined with the deterioration of graft function.¹⁷ The index of suspicion must be high to diagnose this entity unless routine imaging is performed as a part of the post-transplant protocol. It is important to keep in mind other causes of above-mentioned clinical features because hypertension can also be due to immunosuppressive medications, recurrence of intrinsic renal disease, and chronic rejection. Similarly, kidney allograft dysfunction can be due to volume changes, medication toxicities, and recurrence of the primary disease or chronic allograft rejection.⁵ An abdominal bruit can be present in a large number of patients immediately post transplant due to anatomical and postoperative issues such as anemia, but its persistence after 2 months should prompt evaluation.¹⁸ The majority of patients will present within 6 months to 1 year post transplant.^5,19

Non-invasive investigation modalities. Duplex sonography is the initial screening test.²⁰ Acceleration time in the transplant renal and intrarenal arteries of >0.1 seconds, peak systolic velocity in the renal transplant artery >200 cm/s, and a ratio of peak systolic velocity in the transplant renal artery and external iliac arteries >1.8 are used to diagnose TRAS.²¹ High resistive index (RI) on Doppler signifies postglomerular vasoconstriction due to poor blood flow. A renal arterial resistance index of ≥0.80 measured at least 3 months after transplantation is associated with allograft failure and death. RI, however, becomes abnormal in higher grades of stenosis.⁴ Contrast-enhanced ultrasound can complement traditional ultrasound, and it has been shown that the rate of contrast-enhanced inflow strongly correlates with the severity of stenosis assessed based on computed tomography angiography (CTA)/MRA examination.²² Sometimes, the flow limitation is secondary to inflow obstruction due to stenosis in the iliac artery. Therefore, the iliac artery should be interrogated in patients with clinical symptoms and findings of peripheral arterial disease and the presence of pulsus parvus-et-tardus even if the Doppler is negative for stenosis in the transplanted artery. Doppler evaluation of the stenosed iliac artery will show an increase in peak velocity >200 cm/s, peak systolic velocity (PSV) ratio (stenotic PSV divided by prestenotic or poststenotic PSV) of ≥2.8 within the stenosis, and loss of the triphasic waveform distal to the stenosis.²³ Good-quality Doppler is dependent on operator experience, and patient characteristics such as bowel gas and large body habitus may limit the use of this modality. Where it is not possible to adequately image with Doppler, MRA or CTA can be useful. MRA tends to overestimate the severity of stenosis, but the negative predictive value is high.^24,25 If MRA is considered, the risk of nephrogenic systemic sclerosis should be kept in mind. Isotope renogram is another diagnostic modality, but its use is limited by moderate sensitivity and low specificity of the test.²⁶

Invasive diagnostic modalities. Digital subtraction angiography (DSA) is considered the test of choice for final confirmation of the diagnosis, because it needs less contrast as compared with traditional angiography.²⁷ Iso-osmolar contrast media, which are considered less nephrotoxic and better tolerated by the patient, should be preferred.²⁸ Another method to limit the amount of nephrotoxic contrast is to use carbon dioxide (CO₂) as a contrast agent. CO₂ angiography allows the operator to take several pictures in varying projections; thus, when confirmatory images are performed with iodinated contrast in the most favorable projection, the overall volume of the contrast material is reduced²⁹ (Table 1). DSA is used with CO₂, and because the lungs excrete it, CO₂ can be used in patients with impaired renal function.³⁰ The arteries feeding the renal transplants are anteriorly located, which is an ideal location to image using CO₂ because it rises anteriorly due to it being a gas.²⁹ To prevent air trapping, one should wait for 30-60 seconds before reinjecting. A sufficient volume of blood should be displaced by CO₂ to provide representative images; therefore, sufficient quantity has to be injected to avoid underestimating the diameter of the vessel, but the amount to be injected into subdiaphragmatic arterial vessels should be limited to <300 mL.^3,30 Gadolinium, which is used as a contrast agent for magnetic resonance imaging, can also be used for transplant renal angiograms in an effort to avoid nephrotoxicity.³¹ Due to lower concentration usually used for renal angiograms, the images obtained with gadolinium have lower image quality and may need additional injections of iodinated contrast to achieve diagnostic quality images.^32,33 Due to occasional non-diagnostic images and the danger of nephrogenic systemic fibrosis (NSF), it is better to avoid gadolinium.^32,34

Variable cut-offs have been described for the angiographic diagnosis of TRAS, ranging from 50%-90%.³⁵ Clinical data should be considered before embarking upon any invasive therapeutic option. Measurement of the pressure gradient across the lesion or using fractional flow reserve (FFR) may help assist in the diagnosis and assess the lesion’s hemodynamic significance. Extrapolating from native renal arteries, a peak systolic gradient of 20 mm Hg or a mean pressure gradient of 10 mm Hg can be used to identify hemodynamically significant lesions.³⁶

Hemodynamic assessment using renal hyperemic agents provides a better estimate of the hemodynamic significance of renal artery stenosis as compared with angiography alone.³⁷ Hyperemic systolic gradient of ≥21 mm Hg has high sensitivity, specificity, and accuracy in predicting hypertension improvement after stenting in renal artery stenosis.³⁸ FFR values of <0.80 have been suggested as a cut-off to determine the need for intervention.³⁹ Recently, FFR has been shown to be a useful and reproducible tool during percutaneous intervention for TRAS. In patients with transplant renal artery stenosis, papaverine is the agent of choice for inducing maximal renal hyperemia for FFR because adenosine can cause constriction of afferent arterioles, reducing glomerular filtration rate.^40,41 A 6 Fr guiding catheter is used, and a pressure wire is placed proximal to the lesion where normalization is performed. Thereafter, the pressure wire is advanced across the lesion, and 30 mg of intrarenal papaverine is injected. It is good practice to disengage the guiding catheter both during normalization and actual FFR/hyperemic systolic gradient measurement. If papaverine is not available, 50 µg/kg of intrarenal dopamine can be used.⁴²

Management. There has been debate about the utility of revascularization in native kidneys after large prospective randomized trials failed to show any benefit, but it is essential to realize that renal transplant recipients were excluded from such trials.⁴³ Treatment of transplant renal artery stenosis is considered when there is a history of resistant hypertension, recurrent flash pulmonary edema, fluid retention, or declining graft function.⁴⁴ Before any invasive intervention, graft biopsy is performed to rule out chronic allograft rejection or another form of intrinsic renal disease as the cause of declining allograft function.⁴⁵ When renal function is stable, and Doppler evaluation suggests peak systolic velocity of <180 cm/s and resistive index <0.50, no invasive intervention is needed. Medical management should be tried initially for hypertension. If declining graft function is thought to be due to intrinsic renal pathology, it should be treated as guided by the results of the renal biopsy. In cases where TRAS is believed to be the cause of clinical deterioration, a vascular intervention is indicated. Surgical and percutaneous options are available and need to be considered.

Role of percutaneous transluminal angioplasty. Percutaneous transluminal angioplasty (PTA) is a safe, less-invasive, and generally effective treatment for TRAS. In general, PTA works best for lesions that are short, linear, and relatively distal from the anastomosis. PTA is known to yield poor results if the lesion is at the anastomotic site.⁴⁶ Surgery is useful in cases of kinking and proximal TRAS.⁸ Surgical techniques include revising the anastomosis, saphenous vein bypass grafting, and endarterectomy of the renal artery or iliac artery. PTA and/or stent placement is considered the initial treatment of choice if it is feasible,  considering that surgical therapy has high rates of graft loss approaching 20% and restenosis rates approaching 7%-12%.^47,48 Technical success rates (defined as residual stenosis of <30%) of up to 94% have been reported with PTA.⁴⁹ Percutaneous revascularization has been associated with good clinical success (defined as either improvement in blood pressure control or stabilization or improvement in renal function) approaching 67%-82%.^50,49 However, other studies failed to show a clinical benefit with PTA.⁵¹

Complication rates are generally low, with the rate of graft loss lower for PTA than for surgery. PTA is associated with a complication rate of about 10%, including hematoma at the femoral artery puncture site, arterial rupture, dissection, and thrombosis.¹⁶ Restenosis can occur in up to 20% of patients after PTA.⁵²

Role of stenting. Primary renal artery stenting is considered the preferred revascularization strategy for native atherosclerotic renal artery stenosis due to higher procedural success and lower stenosis rates.⁵³ Stenting is also commonly used for TRAS. Stents have been used more frequently in ostial lesions, and they are helpful if there is residual stenosis or dissection after angioplasty alone.⁵⁴ The technical success rate is significantly higher after stent placement vs after renal PTA alone (98% and 77%, respectively). Restenosis rates are significantly lower after stent placement than after renal PTA alone (17% and 26%, respectively).⁵⁴ In one study, the 5-year actuarial survival rate was similar in patients with TRAS treated with PTA and stenting vs patients with transplanted kidneys who did not have TRAS.⁵⁵ Balloon-expandable stents are used for TRAS. The role of self-expanding stents is limited because of the unavailability of suitably sized stents and difficulties in precise positioning.

The safety of drug-eluting stents has been demonstrated in TRAS.¹⁹ There is no study comparing bare-metal stents with drug-eluting stents; however, drug-eluting stents are usually used where higher restenosis rates are expected, for example, if stenting is done in a vessel with a small diameter. In one study where drug-eluting stents were used in arteries <5 mm, the procedural success was reported at 100%, and excellent patency rates were reported.¹⁹

Lastly, aortoiliac occlusive disease (AIOD) can cause poor inflow, leading to ischemia of the transplanted kidney. AIOD is found in approximately 1.5% of all renal allografts.⁵⁶ AIOD in posttransplant patients is commonly due to atherosclerotic disease, but the use of vascular clamps during transplantation may cause vessel trauma, which can result in stenosis.⁵⁷ If this condition is diagnosed, stenting is usually preferred if technically feasible because PTA alone can be associated with higher restenosis rates.⁵⁶ Embolic protection devices are usually not used for renovascular interventions, but may be utilized to prevent atheroembolism to the transplanted renal artery.⁵⁸

Our approach.  At Rush University Medical Center, approximately 100 renal transplantation surgeries are performed every year, and a total of 5000 patients with a renal transplant are on follow-up. Transplant nephrologists have a low threshold for ordering imaging studies to look for TRAS in patients with uncontrolled hypertension and renal dysfunction, but do not interrogate transplanted patients routinely for TRAS following their surgeries. On average, 12 patients are sent for invasive assessment annually based on non-invasive imaging results suggestive of TRAS. This suggests an incidence of TRAS of approximately 10% per year.

Our invasive evaluation protocol is as follows: CO₂ is insufflated into the dedicated bag of the flush kit with a 3-way on stopcock (ICU Medical) using precautions to prevent any contamination with room air. This is achieved by deflating the bag entirely after each cycle of insufflation with CO₂ and repeating this cycle of insufflation and deflation 4 times before locking the CO₂ in the dedicated bag after the fifth insufflation. Once the CO₂ injection system (Figure 1) is ready, arterial access using a micropuncture (Cook) technique is obtained in the ipsilateral (to the transplanted site) femoral artery, making certain that the wire does not access the renal vasculature. An 11 cm-long, 6 Fr sheath is placed in the common femoral artery. A 30 mL syringe is used for injecting CO₂ into the side port of the arterial sheath. Beginning with a shallow right anterior oblique projection, several pictures are recorded on a dedicated protocol of DSA for CO₂ in varying projections until the potential stenotic lesion is profiled correctly. On average, it takes 5-8 pictures to find the best projection. An ~90° lateral projection is not an uncommon view, given the anterior anastomosis of the renal artery onto the external iliac artery. A final image using a diluted contrast medium is generally recorded for added quality of imaging. Of note, specific attention is paid to diagnose any arteriovenous fistula in the renal vasculature. Given the frequent biopsies that these patients undergo following their transplantation, it is not uncommon to find an iatrogenic fistula as the cause of their hypertension.

If indicated, percutaneous intervention is performed using either the arterial sheath alone as the access port or using a 60 cm-long guide catheter of suitable shape to engage the renal artery. A predilation with an undersized peripheral balloon is always performed before stenting the vessel with a balloon-expandable stent of appropriate size and length. Auscultation for renal bruit and a repeat Doppler study are conducted systematically the next day to establish a new baseline for follow-up visits.