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Renal artery stenosis after kidney transplantation: Diagnostic and therapeutic approach
Kidney International, Vol. 54, Suppl. 68 (1998), pp. S-99 –S-106
Renal artery stenosis after kidney transplantation: Diagnostic and therapeutic approach MANUEL RENGEL, GIL GOMES-DA-SILVA, LUIS INCH´AUSTEGUI, JOS´E L. LAMPREAVE, RICARDO ROBLEDO, ANTONIO ECHENAGUSIA, JOS´E L. VALLEJO, and FERNANDO VALDERR´ABANO Nephrology Department, Nuclear Medicine Department, Vascular Radiology Section, Echography Section, and Cardiovascular Surgery Department. Hospital General Universitario Gregorio Maran ˜o ´n, Universidad Complutense de Madrid, Madrid, Spain
Renal artery stenosis after kidney transplantation: Diagnostic and therapeutic approach. Transplant renal artery stenosis (TRAS) is a common complication after transplantation and an important cause of graft dysfunction. Many factors have been implicated as possible causes of TRAS, such as damage from trauma and atherosclerosis. We reviewed all 286 patients transplanted in our unit from January 1990 to July 1997 to study the prevalence, clinical features, and diagnostic and therapeutic approach. Thirteen patients with TRAS were identified, and their mean age was 40 6 15 years. The detected incidence was 4.5%. They were treated with triple therapy (prednisone, azathioprine and cyclosporine A). The mean age of the donors was 28 6 27 years. TRAS was diagnosed within nine months after transplant. All patients were studied with Doppler ultrasound, renography with captopril and angiography. The preferred initial therapy was percutaneous transluminal balloon renal angioplasty. Angioplasty was performed in four patients with good results. Two patients underwent surgery because angioplasty was not possible. Blood pressure control could be achieved with less antihypertensive medication after angioplasty. Transplantectomy was performed in one patient because of surgical complications. In conclusion, most patients with TRAS can be treated successfully with percutaneous transluminal angioplasty as the initial interventional treatment of choice for high-grade renal artery stenosis, and surgical revascularization is indicated when percutaneous transluminal angioplasty cannot be done or is unsuccessful.
Hypertension is a recognized complication following renal transplantation, occurring in approximately 60% of recipients with long-term functioning grafts [1]. Post-transplant hypertension correlates negatively with graft survival, and is a major risk factor for accelerated cardiovascular disease and mortality after renal transplantation [2]. The etiology of hypertension after transplantation is multiple and includes many conditions, such as acute and chronic rejection, steroid therapy, cyclosporine therapy, diseased native kidneys, recurrence of original renal disease, essential
Key words: transplant renal artery stenosis, blood pressure, graft dysfunction, atherosclerosis, blood pressure, angioplasty.
© 1998 by the International Society of Nephrology
hypertension and transplant renal artery stenosis (TRAS) [3]. Of these conditions, renal artery stenosis represents a potentially curable cause of post-transplant hypertension. Renal artery stenosis is a well-known cause of posttransplant hypertension that can result in renal allograft dysfunction [4, 5]. The reported incidence of post-transplant RAS in different series ranged from 1 to 12% depending on the definition of the degree of significant stenosis and on indications for arteriography [1]. In relation to the arterial anastomotic site, the stenosis can be proximal due to recipient atherosclerotic arterial disease, anastomotic or distal in the donor renal artery [1]. Anastomotic stenosis is usually regarded as of technical origin due to a faulty surgical technique and/or to postoperative fibrosis [1]. The etiology of distal stenosis is less clear, but it may be related to mechanical or immunological damage [1]. An early diagnosis of TRAS is important, in order to reduce associated morbidity and mortality. Although arteriography is the definitive diagnostic method, new noninvasive procedures such as Doppler ultrasonography and scintigraphy with captopril seem to be useful for the screening of this pathology [6]. Three different treatment modalities are currently available for patients with transplant RAS. (1) Medical management may be effective in controlling hypertension, but its effect on kidney function is not known. (2) Percutaneous transluminal balloon angioplasty has received considerable attention as a noninvasive treatment approach [1], but the long-term effects on blood pressure control and renal function have not been well studied. (3) Surgical revascularization may be successful in treating TRAS, but this is a major operation with associated morbidity [1]. We have reviewed our experience with TRAS to assess the long-term outcome of different treatment modalities on blood pressure control and kidney function. METHODS In a series of 286 consecutive heterotopical cadaveric kidney transplants, performed in our service between January 1990 and July 1997, a total of 13 (4.5%) episodes of
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Fig. 1. Renal artery stenosis. Doppler spectrum showing focal elevated peak systolic velocity (faster than 200 cm/second) with mild spectral broadening at the anastomosis.
RAS occurred. The mean age of the recipients was 40 6 15 years, and all of them were males. They were treated with triple therapy (prednisone, azathioprine and cyclosporine A). The mean age of the donors was 28 6 27 years; 46% of them were younger than 10 years and 39% were older than 50 years. Anastomosis of the allograft renal artery to the host artery was performed by an end-to-side technique to the external iliac artery. Renal artery stenosis was suspected in patients with new or worsening hypertension. Four patients with severe transplant renal artery stenosis showed recurrent episodes of acute pulmonary edema. Color flow Doppler ultrasound and captopril renography were performed in all patients according to an established diagnostic protocol. Color flow Doppler was performed right before captopril renography to search for turbulences and increased systolic velocities in the renal artery and intrarenal vessels. The scintigraphic procedure was performed by administering an oral dose of captopril 50 mg one hour before injecting approximately 111 MBq of 99m Tc-MAG3. Blood pressure was then monitored and oral hydration was performed. Furosemide 20 mg were administered intravenously at the time of the radiotracer injection
to prevent possible false positive results secondary to tracer retention in the renal pelvis. A baseline scintigraphy was performed in order to compare with the captopril renography. Renal artery stenosis was assessed by angiography and, if a significant lesion was found, interventional treatment was performed (angioplasty and/or surgery). Medically uncontrolled hypertension was required to treat TRAS. The average length of follow-up from graft to diagnosis of TRAS was nine months. RESULTS Doppler ultrasound showed the presence of a focal stenosis in the graft artery in all 13 cases with suspected renal artery stenosis (Fig. 1). In four of these cases, renography with captopril was negative, and the remaining nine patients showed changes in the scintigraphy (Figs. 2 and 3). Arteriography was performed in all patients. Stenosis was at the anastomotic site in nine patients, whereas a post-anastomotic stenosis was seen in the other four patients (Fig. 4). The grade of the stenosis was greater than 50% in seven patients (54%). Antihypertensive medication
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Fig. 2. Baseline scintigraphy in a kidney transplanted patient with renovascular hypertension.
required to maintain blood pressure under control increased with time (Fig. 5). Evolution of graft function is shown in Figure 6. Four patients were treated with percutaneous transluminal angioplasty; in three of these patients the stenosis was resolved, while the remaining one showed no change after the treatment. In the three patients in which stenosis was resolved, blood pressure control improved. Primary surgical treatment was indicated in two patients because angioplasty was not possible. Two patients underwent surgical revascularization for renal artery stenosis with postoperative improvement of hypertension in one and a failure in the other due to surgical complications, and finally the graft was nephrectomized. The renal artery stenosis was higher in cadaveric donor kidneys from pediatric and elderly donors (46% and 38%; Fig. 7). Seven patients underwent primary medical treatment for renal artery stenosis because stenosis was smaller than 50%, with a successful result to date. Renal function improved, since serum creatinine was
2.4 6 0.2 mg/dl before treatment and 1.3 6 0.3 mg/dl after treatment. DISCUSSION Renal artery stenosis is a relatively common cause of refractory hypertension and allograft dysfunction in renal transplant patients, and it is potentially curable. Its incidence rate ranges from 1% to 23% [7–11]. The incidence of TRAS in our center was 4.5%, and in recent reports has ranged from 1.5% to 7%, a typical number being 5.5% [12], but it is likely that it is not functionally active in all cases. The use of color Doppler ultrasonography is useful for early detection of TRAS [13]. The most common presentation is severe hypertension with or without allograft dysfunction that becomes apparent from three months to two years after renal transplantation [7, 14]. If angiotensin-converting (ACE) inhibitors are used, they may cause impaired renal function, severe hypotension, or even acute renal failure [15]. The presence
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Fig. 3. Post-captopril scintigraphy in a kidney transplanted patient with renovascular hypertension. Note the massive changes in the scintigraphy curve after Captopril administration, both in the uptake and excretory phases.
of a bruit may be of little diagnostic value [14, 16], since a significant TRAS can also occur in the absence of an audible bruit [7]. Color flow Doppler ultrasound is the screening procedure of choice, and it can have a high sensitivity and specificity, but an experienced operator is required. A positive screening test or severe hypertension are indications for angiography. Transplant renal artery stenosis greater than 50% is functionally active in some, but not all, cases. However, the success rate is variable, with significant improvement as judged by angiography usually in 60% to 80% of patients, but with relapse in up to 30% [14, 17]. Relapse can be treated by repeat angioplasty with or without stent implantation. Following angioplasty, color Doppler is a useful technique for follow-up. Severe TRAS has been reported as a cause of recurrent pulmonary edema in transplant patients with normal cardiac function [18]. Stenosis of the anastomosis may be secondary to the suture technique and has been more commonly observed after end-to-end arterial anastomosis [19 –21]. This complication is rare when a Carrel patch of the donor aorta is used for end-to-side anastomosis to the external iliac artery [14,
20, 22]. However, no differences have been found in the incidence of transplant renal artery stenosis when comparing end-to-end versus end-to-side anastomosis [10, 11, 23]. Support for an immunologic cause has come from both experimental and human studies [7, 24 –26]. In grafts from HLA-identical living related donors a similar incidence of TRAS as in cadaveric donor grafts has also been found, arguing against immunological factors as a major etiologic determinant [10, 12, 17]. Finally, cyclosporine A has been implicated in the TRAS, with resolution after cyclosporine withdrawal [27]. Plasma renin levels must be interpreted carefully in TRAS [7, 28], since specificity is low [29], and selective measurement of plasma renin levels has several disadvantages [30]. Finally, renin hypersecretion from the kidney transplant can be found in rejection without renal artery stenosis [31]. Duplex and color-flow Doppler ultrasound are highly sensitive, with a high specificity and a positive predictive value, but angiographic confirmation is still required [32] and the assessment of TRAS by Doppler depends highly on the operator skills. Isotopic scintigraphy performed before and after a dose
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Fig. 4. A stenosis of the renal artery after endto-side anastomosis of the renal artery to the external iliac artery.
of Captopril has a reported sensitivity of 75% but a specificity of 67% [33]. However, Shamlou et al reported Captopril renography to be highly predictive for physiologically significant renal artery stenosis [30]. The gold standard for diagnosing TRAS is selective graft arteriography, but unfortunately this is associated with contrast-induced renal failure and hypersensitive reactions [33, 34]. In transplant patients there are no reports of contrast-induced acute renal failure [25, 33, 35]. Spiral computed tomography can provide satisfactory three-dimensional reconstruction of vessels, avoids arterial puncture and requires less intravenous contrast than conventional angiography [36]. Magnetic resonance angiography is less reliable [37]. Carbon dioxide angiography can be successfully used to visualize the stenosis as a preferred imaging technique, as it avoids nephrotoxicity and hypersensitivity reactions [38]. Magnetic resonance imaging is a useful diagnostic test, as is spiral computed tomography [39], but both these investigations are expensive and not universally available. Although spontaneous regression of TRAS has been reported [26, 38, 40], most patients experience poorly controlled hypertension and worsening allograft function
[23, 41]. The preferred initial mode of therapy is percutaneous transluminal balloon renal angioplasty (PTRA) [10, 17, 28, 42]. The procedure achieves either a cure or an improvement in 76% of cases [10, 42] associated with discontinuation of a least two antihypertensive medications, and some patients who had been on dialysis recovered renal transplant function [11, 43, 44]. Lower success rates have been reported, and may be related to center experience or the type of lesion [9, 43, 44]. Despite the efficacy and safety of PTRA, complications may occur in up to 10% of cases, including hematoma at the femoral artery puncture site, intimal flaps, arterial rupture, arterial dissection, and thrombosis [26, 43], graft loss or mortality [9]. It is recommended to have a surgeon available during the procedure who is prepared to operate immediately should a surgical emergency occur. PTRA is usually recommended as the procedure of choice for TRAS that are short, linear, and relatively distal from the anastomosis [26]. For stenoses at the anastomosis line (usually end-to-end renal artery to internal iliac artery), this procedure has a lower rate of success [44] and carries a high risk of complication [21]. It has been recommended that these patients should be
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Fig. 5. The number of antihypertensive drugs increased with time evolution of transplant renal artery stenosis (TRAS). Symbols are: (f) 1 medication; (M) 2 medications; (u) 3 medications.
Fig. 6. Serum creatinine improved after TRAS treatment. Symbols are: (f) functioning graft; gray line, creatinine level.
treated surgically [9, 21]. However, this experience is not universal [10, 42]. Recurrent renal artery stenosis does occur, with rates between 10% and 33% [10, 17, 26, 42, 43]. However, PTRA can be repeated, and a repair procedure can maintain long-term improvement. Metallic stents have been recently used to treat recurrent TRAS, but the experience is limited, and their use was not without complications [45]. Indeed, for many years surgical correction was the only treatment option for TRAS. Patients who have unsuccess-
ful angioplasty, or stenoses that are very severe or inaccessible to PTRA, may require surgical intervention [14]. Surgery carries a significant risk of graft loss, ureteral injury, reoperation and mortality [10 –12, 19, 43]. In general, however, surgery has been successful, and correction rates ranging from 63% to 92% have been reported [7, 9, 19, 23, 26, 46]. Surgery is indicated as the primary treatment in cases of kinking and proximal stenosis, while PTRA is preferred when TRAS is recent, linear, and relatively distal to the
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Fig. 7. Donor age distribution. Young and elderly donors predominate.
anastomosis. Even with successful surgery, TRAS may reoccur at a rate of approximately 12% [25, 26]. Occasionally, retransplantation may represent a simpler and safer alternative to repeat surgery in these patients [5, 14]. In conclusion, these data suggest that Doppler ultrasound and captopril scintigraphy are accurate and reliable tools for the diagnosis and follow-up of TRAS in kidney transplanted patients, showing a high correlation with the physiological changes present in the clinical course of this disease. Patients with TRAS can be treated successfully with percutaneous transluminal angioplasty, which is the initial interventional procedure of choice for high grade renal artery stenosis, while surgical revascularization is indicated if percutaneous transluminal angioplasty cannot be done or is unsuccessful. ACKNOWLEDGMENTS This work was supported in part by a grant of the Fundacio ´n Renal ´In ´ lvarez de Toledo. We are grateful to all members of the Nephrol˜igo A ogy Service staff for their help in the care of the transplanted patients. Reprint requests to Manuel Rengel, M.D.,Ph.D., Hospital General Universitario Gregorio Maran ˜o ´n, Servicio de Nefrologı´a, Dr Esquerdo, 46, 28007 Madrid, Spain. E-mail: [email protected]
REFERENCES 1. SANKARI BR, GEISINGER M, ZELCH M, BROUHARD B, CUNNINGHAM R, NOVICK AC: Post-transplant renal artery stenosis: Impact of therapy on long-term kidney function and blood pressure control. J Urol 155:1860 –1864, 1996 2. WASHER GF, SHRO ¨ TER GP, STARZL TE, WEIL R: Causes of death after kidney transplantation. JAMA 250:49 –54, 1983 3. WALTZER WC, TURNER S, FROHNERT P, RAPAPORT FT: Etiology and pathogenesis of hypertension following renal transplantation. Nephron 42:102–109, 1986 4. LUKE RG, CURTIS J: Biology and treatment of transplant hypertension, in Hypertension Pathophysiology, Diagnosis and Management, edited by LARAGH JH, BRENNER BM, New York, Raven Press, 1995, pp 2471–2483 5. TALBOT-WRIGHT R, ALCARAZ A, PUYOL M, UMBERT B, SERRANOJ, ANDREU J, CARRETERO P: Complicaciones vasculares del trasplante renal. Estenosis de la arteria renal. Actas Urol Esp 14:352–355, 1990
6. MAZUECOS A, NUN ˜ EZ V, G´ OMEZ B, MANRIQUE A, ANDRES A, HIDALGO E, FERNA ´ NDEZ G, HERNA ´ NDEZ E, MORALES JM: Usefulness of isotopic renography with Captopril in the diagnosis of transplant renal artery stenosis. Transplant Proc 27:2242–2243, 1995 7. LACOMBE M: Arterial stenosis complicating renal allotransplantation in man. Ann Surg 181:283–289, 1975 8. MARGULES RM, BELZER FO, KOUNTZ SL: Surgical correction of renovascular hypertension following renal allotransplantation. Arch Surg 106:13–16, 1973 9. ROBERTS JP, ASHER NL, FRYD DS, HUNTER DW, DUNN DL, PAYNE WD, SUTHERLAND DER, CASTAVEDA-ZUNIGA W, NAJARIAN JS: Transplant renal artery stenosis. Transplantation 48:580 –583, 1989 10. GREENSTEIN S, VERSTANDING A, MCLEAN G, DAFOE DC, BURKE DR, MERANZE SG, NAJI A, GROSSMAN RA, PERLOFF LJ, BARKER CF: Percutaneous transluminal angioplasty. Transplantation 43:29 –32, 1987 11. GROSSMAN RA, DAFOE DC, SHOENFELD RB, RING EJ, MCLEAN GK, OLEAGA JA, FREIMAN DB, NAJI A, PERLOFF LJ, BARKER CF: Percutaneous transluminal angioplasty treatment of renal transplant artery stenosis. Transplantation 34:339 –343, 1982 12. MERKUS JWS, HUYMANS FTM, HOITSMA AJ, BUSKENS FGM, SKOTNICKI SH, KOENE RAP: Renal allograft artery stenosis: Results of medical treatment and interventions: A retrospective analysis. Transplant Int 6:111–115, 1993 13. WONG W, FYNN SP, HIGGINS RM, WALTERS H, EVANS S, DEANE C, GROSS D, BEWICK M, SNOWDEN SA, SCOBLE JE, HENDRY BM: Transplant renal artery stenosis in 77 patients— does it have an immunological cause? Transplantation 61:215–219, 1996 14. GRAY DWR: Graft renal artery stenosis in the transplanted kidney. Transplant Rev 8:15–21, 1994 15. CURTIS JJ, LUKE RG, WHELCHE JD, DIETHELM AG, JONES P, DUSTAN HP: Inhibition of angiotensin converting enzyme in renal-transplant recipients with hypertension. N Engl J Med 308:377–381, 1983 16. ALFREY EJ, SMYTHE R, FRIEDMAN A, MERANZE S, GROSSMAN RA, PERLOFF LJ, NAJI A, BARKER CF, DAFOE DC: Two masqueraders of transplant renal artery stenosis (TRAS). Clin Transplant 7:183–187, 1993 17. FAUCHALD P, VATNE K, PAULSEN D, BRODAHL U, SODAL G, HOLDAAS H, BERG KJ, FLATMARK A: Long term clinical results of percutaneous transluminal angioplasty in transplant renal artery stenosis. Nephrol Dial Transplant 7:256 –259, 1992 18. LYE WC, LEONG SO, LEE EJ: Transplant renal artery stenosis presenting with recurrent acute pulmonary edema. Nephron 72:302– 304, 1996 19. SMITH RB, COSIMI AB, LORDON R, THOMPSON AL, EHRLICH RM: Diagnosis and management of arterial stenosis causing hypertension after successful renal transplantation. J Urol 115:639 – 642, 1976 20. FUNG LC, MCLORIE GA, KHOURY AE, CHURCHILL BM: Donor aortic
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cuff reduces the rate of anstomotic arterial stenosis in pediatric renal transplantation. J Urol 154:909 –913, 1995 SUTHERLAND RS, SPEES IK, JONES JW, FINK DW: Renal artery stenosis after renal transplantation: The impact of the hypogastric artery anastomosis. J Urol 149:980 –985, 1993 LINDER R, BILLING H, TIBELL A, TYDEN G, GROTH CG: Fibromuscular dysplasia in donor kidneys: Experiences with three cases. Transplant Int 2:228 –231, 1989 MORRIS PJ, YADAV RVS, KINCAID-SMITH P, ANDERTON J, HARE WSC, JOHNSON N, JOHNSON W, MARSHALL VC: Renal artery stenosis in renal transplantation. Med J Aust 1:1255–1257, 1971 O’CONNELL TX, MOWBRAY JF: Arterial intimal thickenning produced by alloantibody and xenoantibody. Transplantation 15:262–263, 1973 BENOIT G, HIESSE C, ICARD P, BENSADOUN H, BELLAMY J, CHARPENTIER B, JARDIN A, FRIES D: Treatment of renal artery stenosis after renal transplantation. Transplant Proc 19:3600 –3601, 1987 BENOIT G, MOUKARZEL M, HIESSE C, VERDELLI G, CHARPENTIER B, FRIES D: Transplant renal artery stenosis: Experience and comparative results between surgery and angioplasty. Transplant Int 3:137–140, 1990 SAWAYA B, PROVENZANO R, KUPLIN WL, VENKAT KK: Cyclosporine induced renal macroangiopathy. Am J Kidney Dis 12:534 –537, 1988 SNIDERMAN KW, SPRAYREGEN S, SOS TA, SADDEKNI S, HILTON S, MOLLENKOPF F, SOBERMAN R, CHEIGH JS, TAPIS L, STUBENBORD W JR, TELLIS V, VEITH FJ: Percutaneous transluminal dilatation in renal transplant artery stenosis. Tranplantation 30:440 – 444, 1980 THIBONNIER M, JOSEPH A, SASSANO P, GUYENNE TT, CORVOL P, RAYNAUD A, SEUROT M, GAUX JC: Improved diagnosis of unilateral renal artery lesion after Captopril administration. JAMA 251:56 – 60, 1984 SHAMLOU KK, DRANE WE, HAWKINS IF, FENNELL RS: Captopril renogram and the hypertensive renal transplantation patient: A predictive test of therapeutic outcome. Radiology 190:153–159, 1994 SREEPADA TK, GUPKA SK, BUTT KM, KOUNTZ SL, FRIEDMAN EA: Relationship of renal transplantation to hypertension in end-stage renal failure. Arch Intern Med 138:1236 –1241, 1978 ERLEY CM, DUDA SH, WAKAT JP, SOKLER M, REULAND P, MULLERSCHAUENBURG W, SCHARECK M, LAUCHART W, RISLER T: Noninvasive procedures for diagnosis of renovascular hypertension in renal transplant recipients: A prospective analysis. Transplantation 54:863– 867, 1992
33. HALL KA, WONG RW, HUNTER GC, CAMAZINE BM, RAPPAPORT WA, SMYTH SH, BULL DA, MCINTYRE KE, BERNHARD VM, MISIORWSKI RL: Contrast-induced nephrotoxicity: The effects of vasodilator therapy. J Surg Res 53:317–320, 1992 34. MARTIN-PAREDERO V, DIXON SM, BAKER JD, TAKIFF H, GOMES AS, BUSUTTIL RW, MOORE WS: Risk of renal failure after major arteriography. Arch Surg 118:1417–1420, 1983 35. HESSEL SJ, ADAMS DF, ABRAMS HL: Complications of angiography. Radiology 138:273–281, 1981 36. RUBIN GD, DAKE MD, NAPEL SA, MCDONNELL CH, JEFFREY RB JR: Three-dimensional spiral CT angiography of the abdomen. Initial clinical experience. Radiology 186:147–152, 1993 37. LEWIN JS, LAUB G, HAUSMANN R: Three-dimensional time-of-fight MR angiography: Applications in the abdomen and thorax. Radiology 179:261–264, 1991 38. KUO PC, PETERSEN J, SEMBA C, ALFREY EJ, DAFOE DC: CO2 angiography: A technique for vascular imaging in renal allograft dysfunction. Transplantation 61:652– 654, 1996 39. MELL MW, ALFREY EJ, RUBIN GD, SCANDLING JD, JEFFREY RB, DAFOE DC: Use of spiral computed tomography in the diagnosis of transplant renal artery stenosis. Transplantation 57:746 –748, 1994 40. FONTAINE E, BEURTON D, BARTHELEMY Y, QUENTEL P, CUKIER J, BROYER M: Renal artery stenosis following pediatric renal transplantation. Transplant Proc 26:293–294, 1994 41. SMELLIE WA, VINIK M, HUME DM: Angiographic investigation of hypertension complicating human renal transplantation. Surg Gynecol Obstet 128:963–968, 1969 42. RAYNAUD A, BEDROSSIAN J, REMY P, BRISSER JM, ANGEL CY, GAUX JC: Percutaneous transluminal angioplasty of renal transplant renal arterial stenosis. Am J Roentgenol 146:853– 857, 1986 43. CLEMENTS R, EVANS C, SALAMAN JR: Percutaneous transluminal angioplasty of renal transplant artery stenosis. Clin Radiol 38:235–237, 1987 44. CHANDRASOMA P, ABERLE AM: Anastomotic line renal artery stenosis after transplantation. J Urol 135:1159 –1162, 1986 45. NEWMAN-SANDERS APG, GEDROYC WG, AL-KUTOUBY MA, KOO C, TAUBE D: The use of expandable metal stents in transplant renal artery stenosis. Clin Radiol 50:245–250, 1995 46. HOHNKE C, ABENDROTH D, SCHLEIBNER S, LAND W: Vascular complications in 1200 kidney transplantations. Transplant Proc 19:3691– 3692, 1987
Renal artery stenosis after kidney transplantation: Diagnostic and therapeutic approach MANUEL RENGEL, GIL GOMES-DA-SILVA, LUIS INCH´AUSTEGUI, JOS´E L. LAMPREAVE, RICARDO ROBLEDO, ANTONIO ECHENAGUSIA, JOS´E L. VALLEJO, and FERNANDO VALDERR´ABANO Nephrology Department, Nuclear Medicine Department, Vascular Radiology Section, Echography Section, and Cardiovascular Surgery Department. Hospital General Universitario Gregorio Maran ˜o ´n, Universidad Complutense de Madrid, Madrid, Spain
Renal artery stenosis after kidney transplantation: Diagnostic and therapeutic approach. Transplant renal artery stenosis (TRAS) is a common complication after transplantation and an important cause of graft dysfunction. Many factors have been implicated as possible causes of TRAS, such as damage from trauma and atherosclerosis. We reviewed all 286 patients transplanted in our unit from January 1990 to July 1997 to study the prevalence, clinical features, and diagnostic and therapeutic approach. Thirteen patients with TRAS were identified, and their mean age was 40 6 15 years. The detected incidence was 4.5%. They were treated with triple therapy (prednisone, azathioprine and cyclosporine A). The mean age of the donors was 28 6 27 years. TRAS was diagnosed within nine months after transplant. All patients were studied with Doppler ultrasound, renography with captopril and angiography. The preferred initial therapy was percutaneous transluminal balloon renal angioplasty. Angioplasty was performed in four patients with good results. Two patients underwent surgery because angioplasty was not possible. Blood pressure control could be achieved with less antihypertensive medication after angioplasty. Transplantectomy was performed in one patient because of surgical complications. In conclusion, most patients with TRAS can be treated successfully with percutaneous transluminal angioplasty as the initial interventional treatment of choice for high-grade renal artery stenosis, and surgical revascularization is indicated when percutaneous transluminal angioplasty cannot be done or is unsuccessful.
Hypertension is a recognized complication following renal transplantation, occurring in approximately 60% of recipients with long-term functioning grafts [1]. Post-transplant hypertension correlates negatively with graft survival, and is a major risk factor for accelerated cardiovascular disease and mortality after renal transplantation [2]. The etiology of hypertension after transplantation is multiple and includes many conditions, such as acute and chronic rejection, steroid therapy, cyclosporine therapy, diseased native kidneys, recurrence of original renal disease, essential
Key words: transplant renal artery stenosis, blood pressure, graft dysfunction, atherosclerosis, blood pressure, angioplasty.
© 1998 by the International Society of Nephrology
hypertension and transplant renal artery stenosis (TRAS) [3]. Of these conditions, renal artery stenosis represents a potentially curable cause of post-transplant hypertension. Renal artery stenosis is a well-known cause of posttransplant hypertension that can result in renal allograft dysfunction [4, 5]. The reported incidence of post-transplant RAS in different series ranged from 1 to 12% depending on the definition of the degree of significant stenosis and on indications for arteriography [1]. In relation to the arterial anastomotic site, the stenosis can be proximal due to recipient atherosclerotic arterial disease, anastomotic or distal in the donor renal artery [1]. Anastomotic stenosis is usually regarded as of technical origin due to a faulty surgical technique and/or to postoperative fibrosis [1]. The etiology of distal stenosis is less clear, but it may be related to mechanical or immunological damage [1]. An early diagnosis of TRAS is important, in order to reduce associated morbidity and mortality. Although arteriography is the definitive diagnostic method, new noninvasive procedures such as Doppler ultrasonography and scintigraphy with captopril seem to be useful for the screening of this pathology [6]. Three different treatment modalities are currently available for patients with transplant RAS. (1) Medical management may be effective in controlling hypertension, but its effect on kidney function is not known. (2) Percutaneous transluminal balloon angioplasty has received considerable attention as a noninvasive treatment approach [1], but the long-term effects on blood pressure control and renal function have not been well studied. (3) Surgical revascularization may be successful in treating TRAS, but this is a major operation with associated morbidity [1]. We have reviewed our experience with TRAS to assess the long-term outcome of different treatment modalities on blood pressure control and kidney function. METHODS In a series of 286 consecutive heterotopical cadaveric kidney transplants, performed in our service between January 1990 and July 1997, a total of 13 (4.5%) episodes of
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Fig. 1. Renal artery stenosis. Doppler spectrum showing focal elevated peak systolic velocity (faster than 200 cm/second) with mild spectral broadening at the anastomosis.
RAS occurred. The mean age of the recipients was 40 6 15 years, and all of them were males. They were treated with triple therapy (prednisone, azathioprine and cyclosporine A). The mean age of the donors was 28 6 27 years; 46% of them were younger than 10 years and 39% were older than 50 years. Anastomosis of the allograft renal artery to the host artery was performed by an end-to-side technique to the external iliac artery. Renal artery stenosis was suspected in patients with new or worsening hypertension. Four patients with severe transplant renal artery stenosis showed recurrent episodes of acute pulmonary edema. Color flow Doppler ultrasound and captopril renography were performed in all patients according to an established diagnostic protocol. Color flow Doppler was performed right before captopril renography to search for turbulences and increased systolic velocities in the renal artery and intrarenal vessels. The scintigraphic procedure was performed by administering an oral dose of captopril 50 mg one hour before injecting approximately 111 MBq of 99m Tc-MAG3. Blood pressure was then monitored and oral hydration was performed. Furosemide 20 mg were administered intravenously at the time of the radiotracer injection
to prevent possible false positive results secondary to tracer retention in the renal pelvis. A baseline scintigraphy was performed in order to compare with the captopril renography. Renal artery stenosis was assessed by angiography and, if a significant lesion was found, interventional treatment was performed (angioplasty and/or surgery). Medically uncontrolled hypertension was required to treat TRAS. The average length of follow-up from graft to diagnosis of TRAS was nine months. RESULTS Doppler ultrasound showed the presence of a focal stenosis in the graft artery in all 13 cases with suspected renal artery stenosis (Fig. 1). In four of these cases, renography with captopril was negative, and the remaining nine patients showed changes in the scintigraphy (Figs. 2 and 3). Arteriography was performed in all patients. Stenosis was at the anastomotic site in nine patients, whereas a post-anastomotic stenosis was seen in the other four patients (Fig. 4). The grade of the stenosis was greater than 50% in seven patients (54%). Antihypertensive medication
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Fig. 2. Baseline scintigraphy in a kidney transplanted patient with renovascular hypertension.
required to maintain blood pressure under control increased with time (Fig. 5). Evolution of graft function is shown in Figure 6. Four patients were treated with percutaneous transluminal angioplasty; in three of these patients the stenosis was resolved, while the remaining one showed no change after the treatment. In the three patients in which stenosis was resolved, blood pressure control improved. Primary surgical treatment was indicated in two patients because angioplasty was not possible. Two patients underwent surgical revascularization for renal artery stenosis with postoperative improvement of hypertension in one and a failure in the other due to surgical complications, and finally the graft was nephrectomized. The renal artery stenosis was higher in cadaveric donor kidneys from pediatric and elderly donors (46% and 38%; Fig. 7). Seven patients underwent primary medical treatment for renal artery stenosis because stenosis was smaller than 50%, with a successful result to date. Renal function improved, since serum creatinine was
2.4 6 0.2 mg/dl before treatment and 1.3 6 0.3 mg/dl after treatment. DISCUSSION Renal artery stenosis is a relatively common cause of refractory hypertension and allograft dysfunction in renal transplant patients, and it is potentially curable. Its incidence rate ranges from 1% to 23% [7–11]. The incidence of TRAS in our center was 4.5%, and in recent reports has ranged from 1.5% to 7%, a typical number being 5.5% [12], but it is likely that it is not functionally active in all cases. The use of color Doppler ultrasonography is useful for early detection of TRAS [13]. The most common presentation is severe hypertension with or without allograft dysfunction that becomes apparent from three months to two years after renal transplantation [7, 14]. If angiotensin-converting (ACE) inhibitors are used, they may cause impaired renal function, severe hypotension, or even acute renal failure [15]. The presence
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Fig. 3. Post-captopril scintigraphy in a kidney transplanted patient with renovascular hypertension. Note the massive changes in the scintigraphy curve after Captopril administration, both in the uptake and excretory phases.
of a bruit may be of little diagnostic value [14, 16], since a significant TRAS can also occur in the absence of an audible bruit [7]. Color flow Doppler ultrasound is the screening procedure of choice, and it can have a high sensitivity and specificity, but an experienced operator is required. A positive screening test or severe hypertension are indications for angiography. Transplant renal artery stenosis greater than 50% is functionally active in some, but not all, cases. However, the success rate is variable, with significant improvement as judged by angiography usually in 60% to 80% of patients, but with relapse in up to 30% [14, 17]. Relapse can be treated by repeat angioplasty with or without stent implantation. Following angioplasty, color Doppler is a useful technique for follow-up. Severe TRAS has been reported as a cause of recurrent pulmonary edema in transplant patients with normal cardiac function [18]. Stenosis of the anastomosis may be secondary to the suture technique and has been more commonly observed after end-to-end arterial anastomosis [19 –21]. This complication is rare when a Carrel patch of the donor aorta is used for end-to-side anastomosis to the external iliac artery [14,
20, 22]. However, no differences have been found in the incidence of transplant renal artery stenosis when comparing end-to-end versus end-to-side anastomosis [10, 11, 23]. Support for an immunologic cause has come from both experimental and human studies [7, 24 –26]. In grafts from HLA-identical living related donors a similar incidence of TRAS as in cadaveric donor grafts has also been found, arguing against immunological factors as a major etiologic determinant [10, 12, 17]. Finally, cyclosporine A has been implicated in the TRAS, with resolution after cyclosporine withdrawal [27]. Plasma renin levels must be interpreted carefully in TRAS [7, 28], since specificity is low [29], and selective measurement of plasma renin levels has several disadvantages [30]. Finally, renin hypersecretion from the kidney transplant can be found in rejection without renal artery stenosis [31]. Duplex and color-flow Doppler ultrasound are highly sensitive, with a high specificity and a positive predictive value, but angiographic confirmation is still required [32] and the assessment of TRAS by Doppler depends highly on the operator skills. Isotopic scintigraphy performed before and after a dose
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Fig. 4. A stenosis of the renal artery after endto-side anastomosis of the renal artery to the external iliac artery.
of Captopril has a reported sensitivity of 75% but a specificity of 67% [33]. However, Shamlou et al reported Captopril renography to be highly predictive for physiologically significant renal artery stenosis [30]. The gold standard for diagnosing TRAS is selective graft arteriography, but unfortunately this is associated with contrast-induced renal failure and hypersensitive reactions [33, 34]. In transplant patients there are no reports of contrast-induced acute renal failure [25, 33, 35]. Spiral computed tomography can provide satisfactory three-dimensional reconstruction of vessels, avoids arterial puncture and requires less intravenous contrast than conventional angiography [36]. Magnetic resonance angiography is less reliable [37]. Carbon dioxide angiography can be successfully used to visualize the stenosis as a preferred imaging technique, as it avoids nephrotoxicity and hypersensitivity reactions [38]. Magnetic resonance imaging is a useful diagnostic test, as is spiral computed tomography [39], but both these investigations are expensive and not universally available. Although spontaneous regression of TRAS has been reported [26, 38, 40], most patients experience poorly controlled hypertension and worsening allograft function
[23, 41]. The preferred initial mode of therapy is percutaneous transluminal balloon renal angioplasty (PTRA) [10, 17, 28, 42]. The procedure achieves either a cure or an improvement in 76% of cases [10, 42] associated with discontinuation of a least two antihypertensive medications, and some patients who had been on dialysis recovered renal transplant function [11, 43, 44]. Lower success rates have been reported, and may be related to center experience or the type of lesion [9, 43, 44]. Despite the efficacy and safety of PTRA, complications may occur in up to 10% of cases, including hematoma at the femoral artery puncture site, intimal flaps, arterial rupture, arterial dissection, and thrombosis [26, 43], graft loss or mortality [9]. It is recommended to have a surgeon available during the procedure who is prepared to operate immediately should a surgical emergency occur. PTRA is usually recommended as the procedure of choice for TRAS that are short, linear, and relatively distal from the anastomosis [26]. For stenoses at the anastomosis line (usually end-to-end renal artery to internal iliac artery), this procedure has a lower rate of success [44] and carries a high risk of complication [21]. It has been recommended that these patients should be
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Fig. 5. The number of antihypertensive drugs increased with time evolution of transplant renal artery stenosis (TRAS). Symbols are: (f) 1 medication; (M) 2 medications; (u) 3 medications.
Fig. 6. Serum creatinine improved after TRAS treatment. Symbols are: (f) functioning graft; gray line, creatinine level.
treated surgically [9, 21]. However, this experience is not universal [10, 42]. Recurrent renal artery stenosis does occur, with rates between 10% and 33% [10, 17, 26, 42, 43]. However, PTRA can be repeated, and a repair procedure can maintain long-term improvement. Metallic stents have been recently used to treat recurrent TRAS, but the experience is limited, and their use was not without complications [45]. Indeed, for many years surgical correction was the only treatment option for TRAS. Patients who have unsuccess-
ful angioplasty, or stenoses that are very severe or inaccessible to PTRA, may require surgical intervention [14]. Surgery carries a significant risk of graft loss, ureteral injury, reoperation and mortality [10 –12, 19, 43]. In general, however, surgery has been successful, and correction rates ranging from 63% to 92% have been reported [7, 9, 19, 23, 26, 46]. Surgery is indicated as the primary treatment in cases of kinking and proximal stenosis, while PTRA is preferred when TRAS is recent, linear, and relatively distal to the
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Fig. 7. Donor age distribution. Young and elderly donors predominate.
anastomosis. Even with successful surgery, TRAS may reoccur at a rate of approximately 12% [25, 26]. Occasionally, retransplantation may represent a simpler and safer alternative to repeat surgery in these patients [5, 14]. In conclusion, these data suggest that Doppler ultrasound and captopril scintigraphy are accurate and reliable tools for the diagnosis and follow-up of TRAS in kidney transplanted patients, showing a high correlation with the physiological changes present in the clinical course of this disease. Patients with TRAS can be treated successfully with percutaneous transluminal angioplasty, which is the initial interventional procedure of choice for high grade renal artery stenosis, while surgical revascularization is indicated if percutaneous transluminal angioplasty cannot be done or is unsuccessful. ACKNOWLEDGMENTS This work was supported in part by a grant of the Fundacio ´n Renal ´In ´ lvarez de Toledo. We are grateful to all members of the Nephrol˜igo A ogy Service staff for their help in the care of the transplanted patients. Reprint requests to Manuel Rengel, M.D.,Ph.D., Hospital General Universitario Gregorio Maran ˜o ´n, Servicio de Nefrologı´a, Dr Esquerdo, 46, 28007 Madrid, Spain. E-mail: [email protected]
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