Pediatr Nephrol (2014) 29:461–467 DOI 10.1007/s00467-013-2681-7
ORIGINAL ARTICLE
Transplant renal artery stenosis in children: risk factors and outcome after endovascular treatment Giulia Ghirardo & Marco De Franceschi & Enrico Vidal & Alessandro Vidoni & Gaetano Ramondo & Elisa Benetti & Raffaella Motta & Alberto Ferraro & Giovanni Franco Zanon & Diego Miotto & Luisa Murer
Received: 11 June 2013 / Revised: 17 October 2013 / Accepted: 25 October 2013 / Published online: 5 December 2013 # IPNA 2013
Abstract Background Transplant renal artery stenosis (TRAS) is an increasingly recognised cause of post-transplant hypertension. Methods We retrospectively analysed 216 paediatric renal recipients transplanted between 2001 and 2011 to assess TRAS prevalence and percutaneous transluminal angioplasty (PTA) efficacy. To assess risk factors, we compared children with TRAS with a propensity score-matched cohort of recipients without TRAS. Results Of the 216 paediatric patients who were transplanted in the study period, 44 were hypertensive (prevalence 20.3 %) and ten presented with TRAS (prevalence 4.6 %, median age at transplantation 14 years, range 6.78–17.36 years). Hypertensive patients without TRAS were prescribed one to two antihypertensive agents, whereas patients with TRAS required one to five medications. In the TRAS group, one recipient presented with vascular complications during surgery, and in three patients the graft had vascular abnormalities. TRAS was detected by Doppler ultrasonography (US) performed due to hypertension in nine of the patients with TRAS, but in the tenth case the TRAS was clinically silent and detected by routine
Doppler-US screening. TRAS diagnosis was refined using angio-computed tomography or angio-magnetic resonance imaging. All patients underwent PTA without complications. Significant improvement after PTA was observed in the standard deviation scores for blood pressure [3.2±1.4 (pre-PTA) vs. 1.04±0.8 (post-PTA); p =0.0006) and graft function [creatinine clearance: 69±17.08 (pre-PTA) vs. 80.7±21.5 ml/min/ 1.73 m2 (post-PTA); p =0.006] We observed no significant differences between the two cohorts for cold ischaemia time, recipient/donor weight ratio, delayed graft function, cytomegalovirus infections and acute rejection episodes. Conclusions Our study reports a low but significant TRAS prevalence among the paediatric patients who were transplanted at our centre in the study period and confirms that PTA is an effective and safe therapeutic option in paediatric renal transplant recipients. Known risk factors do not appear to be related to the development of TRAS. Keywords Children . Renal artery stenosis . Transplantation . Kidney
Diego Miotto and Luisa Murer contributed equally to this study. G. Ghirardo (*) : E. Vidal : E. Benetti : A. Ferraro : L. Murer Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University Hospital of Padua, Via Giustiniani 2, 35128 Padova, Italy e-mail: [email protected] M. De Franceschi ICU, Cardiovascular Institute, University Hospital of Padua, Padua, Italy A. Vidoni : G. Ramondo : R. Motta : D. Miotto Department of Medical Diagnostic Sciences and Special Therapies, University Hospital of Padua, Padua, Italy G. F. Zanon Pediatric Surgery Unit, Department of Pediatrics, University Hospital of Padua, Padua, Italy
Introduction Transplant renal artery stenosis (TRAS) is an increasingly recognised, potentially curable cause of refractory high blood pressure (BP) and allograft dysfunction. Its incidence varies from 1 to 23 % in adult case series due to a wide variability in both the cutoff designed to define arterial stenosis and the diagnostic techniques used [1–3]. Data on paediatric patients are scarce, with a reported prevalence of 5–9 % [4, 5]. The use of grafts from younger donors who present a minor extent of vascular damage (i.e. atherosclerotic changes) as compared to adults, probably determines the lower prevalence of TRAS in the paediatric population. However, as TRAS accounts for approximately 1–5 % of all post-transplant hypertension cases
462
in adults [6], and as hypertension is a relevant complication also in children (>25 % of children are hypertensive at age 5 years following renal transplantation [7]), there is a need for further investigations of TRAS in the paediatric population. In adults, TRAS accounts for at least 75 % of all posttransplant vascular complications, and it usually becomes apparent between 3 months and 2 years after renal transplantation, but it may appear at any time [6]. It frequently presents with worsening or drug-resistant hypertension and/or graft dysfunction in the absence of rejection, ureteric obstruction or infection. Different sites of renal artery stenosis and timing of disease onset might reflect diverse aetiologies. Prolonged cold ischaemia time causing vascular damage and fibrosis [8] could explain the higher incidence of renal artery stenosis in non-living compared with living-related transplants. Other risk factors which may have the potential to give rise to TRAS that have been suggested in the relevant literature include graft rejection and delayed graft function (DGF) because of endothelial damage subsequent to inflammation or ischaemia/reperfusion injury, trauma to the donor or recipient vessels during surgical manipulation, surgical techniques, atherosclerotic factors and cytomegalovirus (CMV) infection (due to the mitogenic effects of a viral cytomegalic gene product on the intima, triggering smooth-muscle cell proliferation and accumulation) [2, 9]. TRAS treatments comprise conservative therapy with lowdose, short-acting angiotensin-converting enzyme inhibitor [ACEi; in the case of stable renal function and exclusion of haemodynamically significant stenosis by ultrasonography (US)-Doppler imaging]. However, if the BP can no longer be controlled by pharmacological treatment and renal function deteriorates, a diagnostic arteriography is indicated combined with percutaneous transluminal angioplasty (PTA) and stenting. Surgery is indicated for patients with unsuccessful angioplasty or with very severe stenoses that are inaccessible to PTA [3]. The percentage of success of PTA has been reported to range between 70 and 90 % both in adult [3, 22] and paediatric series [5]. Minor complications (i.e. related to the puncture site) are reported in about 10 % of cases; major complications, such as arterial dissection, rupture or thrombosis, are reported in 20 % compared to baseline) underwent US to assess the presence of TRAS [11]. Doppler was also performed as a routine diagnostic procedure, independently of clinical signs, in all patients at 6 months post-renal transplantation. Doppler-US imaging abnormalities were defined as peak systolic velocities of ≥200 cm/s at the main renal artery and/or reduced intraparenchymal peak systolic velocity [11]. Patients with a diagnosis of TRAS based on US findings underwent further radiological assays [computed tomography (CT) or magnetic resonance (MR)] to refine the diagnosis with quantitative and morphological findings [12]. When TRAS was confirmed, selective renal graft angiography with PTA was performed. PTA efficacy was evaluated by analysing the trend in creatinine clearance, calculated using the Schwartz formula [13], and in mean BP standard deviation scores (SDS). These parameters were calculated immediately before and 30– 60 days after the PTA procedure. BP was measured with an oscillometric device using the office-monitoring method [14]; a series of automated measurements was taken for a short period of time (30 min) with the patient sitting alone in a quiet room. As BP in childhood is strongly influenced by gender and age, BP SDS values were calculated according to the Cole and Green LMS method [15]. In order to assess TRAS risk factors, we performed a propensity score matching analysis (PSM) [16] in which we investigated two cohorts of children, i.e. those with and without TRAS, respectively, with similar in baseline characteristics. The following variables were then compared between the TRAS and non-TRAS groups: cold ischaemia time, incidence of DGF, incidence of acute rejection (both cellular and humoral), incidence of CMV reactivation or de novo infection and recipient/donor (R/D) weight ratio. DGF was defined by the need for dialysis during the first 7 days after transplantation [17]. Acute rejection was diagnosed by kidney allograft biopsy according to the Banff 2009 classification [18]. CMV infection was diagnosed in serum samples using the PCR. CMV disease was defined when a positive CMV biological test was associated with the presence of suggestive symptoms such as fever, leucopoenia, pneumonia, gastrointestinal tract disorders or liver abnormalities. In our cohort of patients, all CMV immunoglobulin (IgG)-negative recipients grafted with
Pediatr Nephrol (2014) 29:461–467
IgG-positive donors received 6 months of treatment with oral valganciclovir or aciclovir prophylaxis for the prevention of CMV infection. Statistical analysis Categorical variables were expressed as absolute frequency distribution (percentage). Continuous variables with a normal distribution were expressed as the mean ± standard deviation and those with a non-normal distribution (assessed by the Shapiro–Wilk normality test) were presented as the median and interquartile range (IQR; 25–75 %). The propensity score was calculated using a logistic regression model. Matching was performed using calipers of width 0.2 of the standard deviation of the logit of the propensity score [19]. Variables used for the propensity score matching were: age, sex, primary renal disease (congenital anomalies of kidney and urinary tract, glomerulopathies, hereditary tubulopathies, other diseases), modality of renal replacement therapy (haemodialysis, peritoneal, preemptive), duration of dialysis and use of calcineurin inhibitor (tacrolimus, cyclosporine). Comparisons between the two groups were carried out taking into account the matched nature of the propensity score-matched sample [20]. A paired t test or Wilcoxon signed rank test was used for continuous variables, and a McNemar test was used for binary (dichotomous) variables. Statistical significance was set at p < 0.05. Analyses were performed using STATA software (Release 10.0 for Windows, StataCorp LP, College Station, TX).
Results Between January 2001 and December 2011, 216 paediatric kidney transplants in 210 recipients were performed in our Department. Among these, ten patients developed TRAS, resulting in a prevalence of 4.6 %. In the TRAS case series, median age at time of transplantation was 14 (IQR 6.7–17.3) years, and median body weight was 46 (IQR 21.2–53.2) kg. One of these ten patients had received the graft from a living donor. One recipient with TRAS presented with vascular complications during surgery (perianastomotic bleeding requiring vessel suture), and in three of the patients with TRAS the graft had vascular abnormalities: two patients with double arteries (in one case both arteries were anastomised to the common iliac artery; in the other case the superior polar artery was sutured and the principal artery anastomised to common iliac artery) and one patient with a kinked artery at its origin. In the first of the latter three patients PTA was performed due to severe refractory hypertension; angiography performed before PTA showed a severe stenosis (luminal narrowing of 80–90 %) of the principal renal artery. The second patient underwent PTA because of mild hypertension associated with parenchymal hypoperfusion; angiography showed severe
463
renal artery stenosis (luminal narrowing of >85 %) along with hypoperfused subcapsular areas. Stenosis of the kinked renal artery in the third patient was clinically silent and was detected by routine Doppler-US (pulsus parvus et tardus, parenchymal IR85 %) not involving the vessel’s kinked tract. Median time between kidney transplantation and TRAS diagnosis was 7.5 (IQR 6.6–17.3) months. An audible bruit was detected on clinical examination in four of the ten patients with TRAS. Four TRAS cases involved new onset hypertension while five cases involved a worsening of pre-existing hypertension. One patient showed no clinical evidence of hypertension, and routine Doppler-US screening resulted in the detection of TRAS. Hypertensive recipients without TRAS required one to two anti-hypertensive agents to control BP levels (median 1, IQR 1–1), whereas in the TRAS group eight of nine hypertensive patients required one to five anti-hypertensive drugs (median 2, IQR 0–4; p =0.06); one patient did not require antihypertensive treatment because of prehypertension [10]. Firstchoice antihypertensive agents were calcium channel blockers [extended-release nifedipine 0.5–1 mg/kg/dose twice daily (BID) or amlodipine 0.06–0.5 mg/kg/day] followed by βblockers (atenolol 0.5–1 mg/kg/day) and diuretics [hydrochlorothiazide 0.5–2 mg/kg/day or furosemide 1–2 mg/kg/dose BID or three times daily (TID)]. If this therapy was insufficient in controlling hypertension a central α-agonist (clonidine 1–6 μg/kg/dose BID or TID) or peripheral α-agonist (doxazosin 0.02–0.1 mg/kg/day) was added to the treatment regimen. For patients who required five antihypertensive agents a low-dose ACEi (captopril 0.01 mg/kg/dose TID or ramipril 0.05 mg/kg/day maximum 7.5 mg/day) was added. An anti-hypertensive score (AHT score; Guidi et al. [21]) for the patients with TRAS was calculated, taking into account the BP level, number of anti-hypertensive drugs, dosage of anti-hypertensive drugs: the median AHT score pre-PTA was 3 (IQR 1–7). In all patients, Doppler-US criteria for clinically and haemodynamically relevant stenosis were defined using published criteria [22]. The diagnosis of TRAS was then refined in four of the ten cases using angio-CT imaging and in five cases using angio-MR imaging. Eight patients presented a sub-occlusive (luminal narrowing >85 %) stenosis (5 anastomotic, 1 perianastomotic, 2 distal stenosis 2–3 cm after anastomosis). One patient presented a double stenosis (perianastomotic and distal) on the main renal artery with an estimated luminal narrowing of 50–75 %. Finally, one patient presented with a sub-occlusive ostial stenosis of a small inferior polar artery emerging from the proximal third of the principal renal artery (Table 1). All patients in the TRAS group underwent PTA without complications. In brief, an ipsilateral or contralateral femoral approach was chosen. The stenotic site was traversed with a
464
Pediatr Nephrol (2014) 29:461–467
hydrophilic guidewire; a balloon angioplasty catheter was then exchanged across the stricture via the hydrophilic guidewire. Dilatation of the stenotic lesion was then executed by inflating the balloon (diameter 2.5–5 mm, length 15– 20 mm); this may be repeated as appropriate until a radiologic demonstration of success, defined by a significant (>50 %) reduction in the percentage of stenosis. In three cases a cutting balloon, inflated to achieve a pressure of 15 atmospheres, was used; only in one of three patients was a good luminal dilatation reached. Patients were subsequently observed for 1– 2 days in our transplant clinic. Mean BP SDS significantly decreased after PTA [3.2±1.4 (pre-PTA) vs. 1.04±0.85 (post-PTA); p =0.0006] (Fig. 1a), resulting in a significant reduction in the AHT score post-PTA (median 0, IQR range 0–2; p =0.003). The mean creatinine clearance before angioplasty was found to be 69±17.1 ml/ min/1.73 m2, which is significantly lower than that obtained after angioplasty (80.7±21.5 ml/min/1.73 m2; p =0.006) (Fig. 1b). At the last available follow-up for which data were available for our analysis (median 4.1 years, IQR 1.1–8.5), all patients still had functioning grafts and no complications related to PTA had occurred. To assess TRAS risk factors, patients with TRAS were compared with ten patients without TRAS having similar baseline demographic and clinical characteristics (Table 2). In the control population, 56 of 210 patients were excluded from the analysis due to referral to the adult centre (n = 42 patients), death (9), graft loss within 1 week after transplantation (not due to vascular diseases) (3) and significant comorbidities (2). The 154 remaining patients were then included in the analysis and ten matched pairs were created using PSM. There were no significant differences between children with and without TRAS in terms of mean cold ischaemia time,
incidence of DGF, R/D weight ratio, incidence of CMV infections and episodes of acute rejection (Table 2). In the cohort of children with TRAS, seven of the ten patients received oral valganciclovir or aciclovir prophylaxis for 6 months after being transplanted.
Discussion Published data on TRAS in paediatric kidney transplant recipients are scarce. Consequently, our aim was to analyse the prevalence and risk factors for TRAS in a group of paediatric recipients who had received a kidney transplant at our centre. Among this patient population the prevalence of TRAS was 4.6 %, which is similar to that reported in both adult series [1, 8, 23] and in the only previously published paediatric study [5]. Cold ischaemia time and the occurrence of DGF are considered significant risk factors for TRAS [9, 23]. Acute graft rejection can also play a role in the development of TRAS as it is related to ischaemia/reperfusion injury and subsequent endothelial damage [9]. In our study, we did not find significant differences between the TRAS and non-TRAS groups in terms of mean cold ischaemia time, incidence of DGF or episodes of acute rejection. This can be explained by the significantly lower cold ischaemia time and subsequently lower occurrence of DGF observed in our case series as compared to those reported in other studies [9, 24]. CMV infection is a recognised risk factor for the development of arterial stenosis [8]. The molecular mechanism, although unclear, seems to be related to the mitogenic effects of a viral cytomegalic gene product on the intima which triggers smooth-muscle cell proliferation and accumulation. CMV infection is also likely to impair the nitric oxide pathway and to
Table 1 Angiographic presentation of patients with transplant renal artery stenosis Patients with TRAS
Gender Age at transplantation Angiographic morphology (years)
Luminal narrowing
1 2
Male 1.24 Female 17.48
>85 % >85 %
3 4 5 6 7 8 9
Male Male Male Male Male Male Male
3.60 17.27 11.74 15.88 16.78 9.27 5.83
10
Male
2.76
TRAS, Transplant renal artery stenosis
Subocclusive anular anastomotic stenosis Subocclusive ostial stenosis of inferior polar artery (originated from the proximal third of principal renal artery) Subocclusive distal stenosis (3 cm after anastomosis) “Diaphragm-like” subocclusive perianastomotic stenosis Subocclusive anastomotic stenosis; hypoperfused subcapsular areas Subocclusive anastomotic stenosis Subocclusive anastomotic stenosis Anastomotic kinking and subocclusive anastomotic stenosis; post-stenotic ectasia Moderate perianastomotic stenosis; moderate distal stenosis (2 cm after anastomosis)
>85 % >85 % >85 % >85 % >85 % >85 % Double stenosis, 50–75 % both Distal subocclusive stenosis (2 cm after anastomosis); moderate post-stenotic ectasia >85 %
Pediatr Nephrol (2014) 29:461–467
465
Fig. 1 a Distribution of mean blood pressure standard deviation scores (SDS) pre- and post-percutaneous transluminal angioplasty (PTA), b distribution of creatinine clearance pre- and post-PTA. Horizontal line in box Median, box interquartile range (25–75 %), whiskers standard deviation
induce endothelial dysfunction [9, 25]. In our study, we did not find any relationship between CMV infection and TRAS, but only one case of symptomatic CMV infection was reported. In addition to the known risk factors for TRAS which have been reported in adult populations, an adjunctive risk factor in children might be represented by the diameter of the small vessels. Size mismatch of anastomosed vessels due to disproportional body weight between donor and recipient might indeed result in perianastomotic stenosis. However, in our study, no statistical significant difference in R/D weight ratio between the TRAS and non-TRAS groups was observed even though two patients in the TRAS group received their graft from the same donor with significantly high R/D body weight ratios (3.3 and 4, respectively), suggesting that size mismatch might indeed represent a potential risk factor for TRAS. Our patients presented clinically with new-onset hypertension or worsening of pre-transplant hypertension in almost all cases; the number of anti-hypertensive drugs needed to control BP was higher in patients with TRAS compared to hypertensive transplanted patients without TRAS. In our experience, hypertensive renal transplant recipients requiring two or more drugs to control BP values need to be investigated further to rule out the presence of TRAS. However, TRAS can also be clinically silent; therefore, regular screening of renal transplant patients by Doppler-US imaging (monthly for the first 6 months, then twice a year) should be a fundamental part of the follow-up regimen. In the literature, there is no established consensus about the degree of renal arterial narrowing that justifies percutaneous revascularisation. Lesions causing arterial diameter stenosis of ≤50 %, as evidenced by angiography, are generally considered not to be haemodynamically relevant. Clinical criteria for revascularisation in the presence of significant renal artery
stenosis in native kidneys are well established [22], whereas there are no clear indications in renal transplant recipients. In our cohort, the findings on the kidney graft Doppler-Us were significant in all patients with TRAS (>60 %). This led to angio-CT or angio-MR imaging being performed in nine of the ten patients to refine the diagnosis; one patient underwent angiography and angioplasty without CT or MR because of neurological comorbidities that contraindicated multiple sedations. Even if angiography is the gold standard for TRAS diagnosis, CT and MR imaging procedures are able to accurately detect the extent and the site of arterial stenosis, thus allowing a more precise procedural planning [12, 26]. AngioCT and angio-MR imaging procedures provide the best angiographic projections, thereby guaranteeing a faster visualisation of arterial stenosis, and they also minimise the radiation dose. In our centre we usually perform angio-MR before angiography to refine the TRAS diagnosis; however, as angio-CT is faster than MR, CT is preferred for patients aged 80 % along with clinical success, as measured by the treatment of hypertension and improvement of allograft function [2, 27, 28]. Patel et al. used a 15 % reduction in serum creatinine and a 15 % reduction in diastolic BP with no change in anti-hypertensive medication or a 10 % reduction in diastolic BP with a reduction in anti-hypertensive medication to define clinical success [23]. In our series, we observed a significant improvement in graft function, with a 14 % rise in creatinine clearance at 30–60 days after PTA. Moreover, a significant reduction in mean BP values and anti-hypertensive medication used was observed. Among the ten patients with TRAS, we observed an optimal (>75 %) and a good (>50 %) luminal gain in three and five
466
Pediatr Nephrol (2014) 29:461–467
Table 2 Baseline characteristics of the two groups patients with TRAS and patients without TRAS) before and after propensity score matching and the analysis of TRAS risk factors Baseline characteristics of the study population Before PSM Characteristicsa TRAS group (n =10) Age (years) 11.78±6.00 Male sex 9 (90) Cause of renal disease Malformative uropathies 6 (60) Glomerulonephritis 1 (10) Hereditary tubulopathies 2 (20) Other 1 (10) Type of dialysis Haemodialysis Peritoneal Preemptive Duration of dialysis (months) Calcineurin inhibitor (FK506) Analysis of TRAS risk factors TRAS risk factorsa Cold ischaemia time Delayed graft function Recipient/donor weight ratio Cytomegalovirus infections Acute rejection
5 (50) 4 (40) 1 (10) 18.3±13.9 9 (90)
0.94 0.17
After PSM TRAS group (n =10) 11.78±6.00 9 (90)
No TRAS group (n =10) 12.26±6.27 9 (90)
0.82 1.00
84 (58.3) 32 (22.2) 12 (8.3) 16 (11.1)
0.81 0.63 0.40 0.60
6 (60) 1 (10) 2 (20) 1 (10)
7 (70) 1 (10) 2 (20) 0 (0)
0.60 1.00 1.00 0.30
73 (50.7) 63 (43.7) 8 (5.5) 24.1±29.06 102(70.8)
0.78 0.96 0.88 0.26 0.43
5 (50) 4 (40) 1 (10) 18.3±13.9 9 (90)
5 (50) 3 (30) 2 (20) 20.4±25.2 9 (90)
1.00 0.60 0.50 0.83 1.00
No TRAS group (n =144) 11.95±7.32 91 (63.2)
TRAS group (n = 10) 15.4±5.6 2 (20) 0.84 (0.59-4) 1 (10) 2 (20)
p value
No TRAS group (n = 10) 12.9±3.8 1 (10) 1.06 (0.25-2.27) 0 (0) 3 (30)
p value
p value 0.38 1.00 0.62 1.00 1.00
PSM, Propensity score matching a
Values are presented as the mean ± standard deviation, as the median with the range in parenthesis or as the number of patients with the percentage in parenthesis
patients, respectively, which is a success percentage of 80 %, similar to that reported in other published series [29]. In two out of 10 cases the procedure was considered to be suboptimal (>30 %). However, despite of angiographic features, these two patients showed a significant improvement in graft function, which continues to be stable at 4.7 and 6 years post-PTA, respectively. Moreover, one of these two patients was completely withdrawn from anti-hypertensive treatment. As already reported by other authors [30], high-grade TRAS, even when not completely resolved, can improve and remain stable over time with an excellent long-term graft survival. In our study, post-PTA follow-up was performed using color Doppler flow imaging, as its ultrasonographic sensitivity and specificity range from 58 to 100 % and from 87 to 100 %, respectively [11]. There were no adverse events detected, and all patients showed good and stable graft function with normal Doppler features at the last follow-up.
This study represents a single-centre analysis involving a relatively small number of patients. As such, we clearly acknowledge that our results, although of clinical and statistical significance, will need to be validated in a larger population. We report a low but significant TRAS prevalence in paediatric renal transplant recipients, underlining the importance of checking for TRAS in all patients having hypertension after transplantation, starting with renal echocolour-Doppler imaging. In our series, known risk factors did not seem to be related to the development of TRAS, at least in part because of the prevention strategies used (CMV prophylaxis, shorter cold ischaemia time whenever possible). The effect of donor/recipient weight mismatch, which seems to be an adjunctive risk factor in the paediatric population, needs to be confirmed by investigations in a larger number of patients. Finally, our study confirmed that PTA is also an effective and safe therapeutic option in
Pediatr Nephrol (2014) 29:461–467
paediatric recipients as it ensured excellent medium-term results with regard to graft function and BP values.
Conflict of interest statement None.
References 1. Fervenza FC, Lafayette RA, Alfrey EJ, Petersen J (1998) Renal artery stenosis in kidney transplantation. Am J Kidney Dis 31:142–148 2. Sishir G, Rajapurkar M (2009) Vascular complications following renal transplantation. J Nephrol Ren Transplant 2:122–132 3. Bruno S, Remuzzi G, Ruggenenti P (2004) Transplant renal artery stenosis. J Am Soc Nephrol 15:134–141 4. Seeman T (2009) Hypertension after renal transplantation. Pediatr Nephrol 24:959–972 5. Fontaine E, Barthelemy Y, Gagnadoux MF, Cukier J, Broyer M, Beurton D (1994) A review of 72 renal artery stenoses in a series of 715 kidney transplantations in children. Prog Urol 4:193–205 6. Roberts JP, Ascher NL, Fryd DS, Hunter DW, Dunn DL, Payne WD, Sutherland DE, Castaneda-Zuniga W, Najarian JS (1989) Transplant renal artery stenosis. Transplantation 48:580–583 7. Sinha MD, Kerecuk L, Gilg J, Reid CJ (2012) Systemic arterial hypertension in children following renal transplantation: prevalence and risk factors. Nephrol Dial Transplant 27:3359–3368 8. Rengel M, Gomes-Da-Silva G, Inchaustegui L, Lampreave JL, Robledo R, Echenagusia A, Vallejo JL, Valderrabano F (1998) Renal artery stenosis after kidney transplantation: diagnostic and therapeutic approach. Kidney Int Suppl 68:S99–S106 9. Audard V, Matignon M, Hemery F, Snanoudi R, Desgranges P, Anglade MC, Kobeiter H, Durrbach A, Charpentier B, Lang P, Grimbert P (2006) Risk factors and long-term outcome of transplant artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty. Am J Transplant 6:95–99 10. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114[2 Suppl 4th Report]:555–576 11. O’Neill WC, Baumgarten DA (2002) Ultrasonography in renal transplantation. Am J Kidney Dis 39:663–678 12. Vasbinder GBC, Nelemans PJ, Kessels AG, Kroon AA, de Leeuw PW, van Engelshoven JM (2001) Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: a meta-analysis. Ann Intern Med 135:401–411 13. Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 4:1832–1843 14. Vidal E, Murer L, Matteucci MC (2013) Blood pressure measurement in children: which method? Which is the gold standard? J Nephrol. doi:10.5301/jn.5000244 15. Cole TJ, Green PJ (1992) Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 11:1305–1319 16. D’Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of treatment to a non-randomized control group. Stat Med 17:2265–2281
467 17. Perico N, Cattaneo D, Sayegh MH, Remuzzi G (2004) Delayed graft function in kidney transplantation. Lancet 364:1814–1827 18. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, Einecke G, Gloor J, Glotz D, Kraus E, Legendre C, Liapis H, Mannon RB, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Rodriguez ER, Seron D, Seshan S, Suthanthiran M, Wasowska BA, Zachary A, Zeevi A (2010) Banff ’09 meeting Report: antibody mediated graft deterioration and Implementation of Banff Working Groups. Am J Transplant 10:464–471 19. Austin PC (2011) Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 10:150–161 20. Austin PC (2011) Comparing paired vs non-paired statistical methods of analyses when making inferences about absolute risk reductions in propensity-score matched samples. Stat Med 30:1292–1301 21. Guidi E, Bianchi G, Rivolta E, Ponticelli C, Quarto di Palo F, Minetti L, Polli E (1985) Hypertension in man with a kidney transplant: role of familial versus other factors. Nephron 41:14–21 22. Rundback JH, Sacks D, Kent KC, Cooper C, Jones D, Murphy T, Rosenfield K, White C, Bettmann M, Cortell S, Puschett J, Clair D, Cole P, AHA Councils on Cardiovascular Radiology, High Blood Pressure Research, Kidney in Cardiovascular Disease, CardioThoracic and Vascular Surgery, and Clinical Cardiology, and the Society of Interventional Radiology FDA Device Forum Committee. American Heart Association (2002) Guidelines for the reporting of renal artery revascularization in clinical trials. Circulation 106:1572–1585 23. Patel NH, Jindal RM, Wilkin T, Rose S, Johnson MS, Shah H, Namyslowski J, Moresco KP, Trerotola SO (2001) Renal arterial stenosis in renal allografts: retrospective study of predisposing factors and outcome after percutaneous transluminal angioplasty. Radiology 219:663–667 24. O’Callaghan JM, Knight SR, Morgan RD, Morris PJ (2012) Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. Am J Transplant 12:896–906 25. Pouria S, State OI, Wong W, Hendry BM (1998) CMV infection is associated with transplant renal artery stenosis. QJM 91:185– 189 26. Ismaeel MM, Abdel-Hamid A (2011) Role of high resolution contrast-enhanced magnetic resonance angiography (HR CeMRA) in management of arterial complications of the renal transplant. Eur J Radiol 79:e122–e127 27. Leonardou P, Gioldasi S, Pappas P (2011) Transluminal angioplasty of transplanted renal artery stenosis: a review of the literature for its safety and efficacy. J Transplant 2011:693820 28. Pappas P, Zavos G, Kaza S, Leonardou P, Theodoropoulou E, Bokos J, Boletis J, Kostakis A (2008) Angioplasty and stenting of arterial stenosis affecting renal transplant function. Transplant Proc 40:1391– 1396 29. Marini M, Fernandez-Rivera C, Cao I, Gulias D, Alonso A, LopezMuñiz A, Gómez-Martínez P (2011) Treatment of transplant renal artery stenosis by percutaneous transluminal angioplasty and/or stenting: study in 63 patients in a single institution. Transplant Proc 43:2205–2207 30. Butorović-Ponikvar J, Ponikvar R (2003) High-grade renal transplant artery stenosis after suboptimal angioplasty: favourable long-term outcome. Transplant Proc 35:2891–2893
ORIGINAL ARTICLE
Transplant renal artery stenosis in children: risk factors and outcome after endovascular treatment Giulia Ghirardo & Marco De Franceschi & Enrico Vidal & Alessandro Vidoni & Gaetano Ramondo & Elisa Benetti & Raffaella Motta & Alberto Ferraro & Giovanni Franco Zanon & Diego Miotto & Luisa Murer
Received: 11 June 2013 / Revised: 17 October 2013 / Accepted: 25 October 2013 / Published online: 5 December 2013 # IPNA 2013
Abstract Background Transplant renal artery stenosis (TRAS) is an increasingly recognised cause of post-transplant hypertension. Methods We retrospectively analysed 216 paediatric renal recipients transplanted between 2001 and 2011 to assess TRAS prevalence and percutaneous transluminal angioplasty (PTA) efficacy. To assess risk factors, we compared children with TRAS with a propensity score-matched cohort of recipients without TRAS. Results Of the 216 paediatric patients who were transplanted in the study period, 44 were hypertensive (prevalence 20.3 %) and ten presented with TRAS (prevalence 4.6 %, median age at transplantation 14 years, range 6.78–17.36 years). Hypertensive patients without TRAS were prescribed one to two antihypertensive agents, whereas patients with TRAS required one to five medications. In the TRAS group, one recipient presented with vascular complications during surgery, and in three patients the graft had vascular abnormalities. TRAS was detected by Doppler ultrasonography (US) performed due to hypertension in nine of the patients with TRAS, but in the tenth case the TRAS was clinically silent and detected by routine
Doppler-US screening. TRAS diagnosis was refined using angio-computed tomography or angio-magnetic resonance imaging. All patients underwent PTA without complications. Significant improvement after PTA was observed in the standard deviation scores for blood pressure [3.2±1.4 (pre-PTA) vs. 1.04±0.8 (post-PTA); p =0.0006) and graft function [creatinine clearance: 69±17.08 (pre-PTA) vs. 80.7±21.5 ml/min/ 1.73 m2 (post-PTA); p =0.006] We observed no significant differences between the two cohorts for cold ischaemia time, recipient/donor weight ratio, delayed graft function, cytomegalovirus infections and acute rejection episodes. Conclusions Our study reports a low but significant TRAS prevalence among the paediatric patients who were transplanted at our centre in the study period and confirms that PTA is an effective and safe therapeutic option in paediatric renal transplant recipients. Known risk factors do not appear to be related to the development of TRAS. Keywords Children . Renal artery stenosis . Transplantation . Kidney
Diego Miotto and Luisa Murer contributed equally to this study. G. Ghirardo (*) : E. Vidal : E. Benetti : A. Ferraro : L. Murer Pediatric Nephrology, Dialysis and Transplant Unit, Department of Pediatrics, University Hospital of Padua, Via Giustiniani 2, 35128 Padova, Italy e-mail: [email protected] M. De Franceschi ICU, Cardiovascular Institute, University Hospital of Padua, Padua, Italy A. Vidoni : G. Ramondo : R. Motta : D. Miotto Department of Medical Diagnostic Sciences and Special Therapies, University Hospital of Padua, Padua, Italy G. F. Zanon Pediatric Surgery Unit, Department of Pediatrics, University Hospital of Padua, Padua, Italy
Introduction Transplant renal artery stenosis (TRAS) is an increasingly recognised, potentially curable cause of refractory high blood pressure (BP) and allograft dysfunction. Its incidence varies from 1 to 23 % in adult case series due to a wide variability in both the cutoff designed to define arterial stenosis and the diagnostic techniques used [1–3]. Data on paediatric patients are scarce, with a reported prevalence of 5–9 % [4, 5]. The use of grafts from younger donors who present a minor extent of vascular damage (i.e. atherosclerotic changes) as compared to adults, probably determines the lower prevalence of TRAS in the paediatric population. However, as TRAS accounts for approximately 1–5 % of all post-transplant hypertension cases
462
in adults [6], and as hypertension is a relevant complication also in children (>25 % of children are hypertensive at age 5 years following renal transplantation [7]), there is a need for further investigations of TRAS in the paediatric population. In adults, TRAS accounts for at least 75 % of all posttransplant vascular complications, and it usually becomes apparent between 3 months and 2 years after renal transplantation, but it may appear at any time [6]. It frequently presents with worsening or drug-resistant hypertension and/or graft dysfunction in the absence of rejection, ureteric obstruction or infection. Different sites of renal artery stenosis and timing of disease onset might reflect diverse aetiologies. Prolonged cold ischaemia time causing vascular damage and fibrosis [8] could explain the higher incidence of renal artery stenosis in non-living compared with living-related transplants. Other risk factors which may have the potential to give rise to TRAS that have been suggested in the relevant literature include graft rejection and delayed graft function (DGF) because of endothelial damage subsequent to inflammation or ischaemia/reperfusion injury, trauma to the donor or recipient vessels during surgical manipulation, surgical techniques, atherosclerotic factors and cytomegalovirus (CMV) infection (due to the mitogenic effects of a viral cytomegalic gene product on the intima, triggering smooth-muscle cell proliferation and accumulation) [2, 9]. TRAS treatments comprise conservative therapy with lowdose, short-acting angiotensin-converting enzyme inhibitor [ACEi; in the case of stable renal function and exclusion of haemodynamically significant stenosis by ultrasonography (US)-Doppler imaging]. However, if the BP can no longer be controlled by pharmacological treatment and renal function deteriorates, a diagnostic arteriography is indicated combined with percutaneous transluminal angioplasty (PTA) and stenting. Surgery is indicated for patients with unsuccessful angioplasty or with very severe stenoses that are inaccessible to PTA [3]. The percentage of success of PTA has been reported to range between 70 and 90 % both in adult [3, 22] and paediatric series [5]. Minor complications (i.e. related to the puncture site) are reported in about 10 % of cases; major complications, such as arterial dissection, rupture or thrombosis, are reported in 20 % compared to baseline) underwent US to assess the presence of TRAS [11]. Doppler was also performed as a routine diagnostic procedure, independently of clinical signs, in all patients at 6 months post-renal transplantation. Doppler-US imaging abnormalities were defined as peak systolic velocities of ≥200 cm/s at the main renal artery and/or reduced intraparenchymal peak systolic velocity [11]. Patients with a diagnosis of TRAS based on US findings underwent further radiological assays [computed tomography (CT) or magnetic resonance (MR)] to refine the diagnosis with quantitative and morphological findings [12]. When TRAS was confirmed, selective renal graft angiography with PTA was performed. PTA efficacy was evaluated by analysing the trend in creatinine clearance, calculated using the Schwartz formula [13], and in mean BP standard deviation scores (SDS). These parameters were calculated immediately before and 30– 60 days after the PTA procedure. BP was measured with an oscillometric device using the office-monitoring method [14]; a series of automated measurements was taken for a short period of time (30 min) with the patient sitting alone in a quiet room. As BP in childhood is strongly influenced by gender and age, BP SDS values were calculated according to the Cole and Green LMS method [15]. In order to assess TRAS risk factors, we performed a propensity score matching analysis (PSM) [16] in which we investigated two cohorts of children, i.e. those with and without TRAS, respectively, with similar in baseline characteristics. The following variables were then compared between the TRAS and non-TRAS groups: cold ischaemia time, incidence of DGF, incidence of acute rejection (both cellular and humoral), incidence of CMV reactivation or de novo infection and recipient/donor (R/D) weight ratio. DGF was defined by the need for dialysis during the first 7 days after transplantation [17]. Acute rejection was diagnosed by kidney allograft biopsy according to the Banff 2009 classification [18]. CMV infection was diagnosed in serum samples using the PCR. CMV disease was defined when a positive CMV biological test was associated with the presence of suggestive symptoms such as fever, leucopoenia, pneumonia, gastrointestinal tract disorders or liver abnormalities. In our cohort of patients, all CMV immunoglobulin (IgG)-negative recipients grafted with
Pediatr Nephrol (2014) 29:461–467
IgG-positive donors received 6 months of treatment with oral valganciclovir or aciclovir prophylaxis for the prevention of CMV infection. Statistical analysis Categorical variables were expressed as absolute frequency distribution (percentage). Continuous variables with a normal distribution were expressed as the mean ± standard deviation and those with a non-normal distribution (assessed by the Shapiro–Wilk normality test) were presented as the median and interquartile range (IQR; 25–75 %). The propensity score was calculated using a logistic regression model. Matching was performed using calipers of width 0.2 of the standard deviation of the logit of the propensity score [19]. Variables used for the propensity score matching were: age, sex, primary renal disease (congenital anomalies of kidney and urinary tract, glomerulopathies, hereditary tubulopathies, other diseases), modality of renal replacement therapy (haemodialysis, peritoneal, preemptive), duration of dialysis and use of calcineurin inhibitor (tacrolimus, cyclosporine). Comparisons between the two groups were carried out taking into account the matched nature of the propensity score-matched sample [20]. A paired t test or Wilcoxon signed rank test was used for continuous variables, and a McNemar test was used for binary (dichotomous) variables. Statistical significance was set at p < 0.05. Analyses were performed using STATA software (Release 10.0 for Windows, StataCorp LP, College Station, TX).
Results Between January 2001 and December 2011, 216 paediatric kidney transplants in 210 recipients were performed in our Department. Among these, ten patients developed TRAS, resulting in a prevalence of 4.6 %. In the TRAS case series, median age at time of transplantation was 14 (IQR 6.7–17.3) years, and median body weight was 46 (IQR 21.2–53.2) kg. One of these ten patients had received the graft from a living donor. One recipient with TRAS presented with vascular complications during surgery (perianastomotic bleeding requiring vessel suture), and in three of the patients with TRAS the graft had vascular abnormalities: two patients with double arteries (in one case both arteries were anastomised to the common iliac artery; in the other case the superior polar artery was sutured and the principal artery anastomised to common iliac artery) and one patient with a kinked artery at its origin. In the first of the latter three patients PTA was performed due to severe refractory hypertension; angiography performed before PTA showed a severe stenosis (luminal narrowing of 80–90 %) of the principal renal artery. The second patient underwent PTA because of mild hypertension associated with parenchymal hypoperfusion; angiography showed severe
463
renal artery stenosis (luminal narrowing of >85 %) along with hypoperfused subcapsular areas. Stenosis of the kinked renal artery in the third patient was clinically silent and was detected by routine Doppler-US (pulsus parvus et tardus, parenchymal IR85 %) not involving the vessel’s kinked tract. Median time between kidney transplantation and TRAS diagnosis was 7.5 (IQR 6.6–17.3) months. An audible bruit was detected on clinical examination in four of the ten patients with TRAS. Four TRAS cases involved new onset hypertension while five cases involved a worsening of pre-existing hypertension. One patient showed no clinical evidence of hypertension, and routine Doppler-US screening resulted in the detection of TRAS. Hypertensive recipients without TRAS required one to two anti-hypertensive agents to control BP levels (median 1, IQR 1–1), whereas in the TRAS group eight of nine hypertensive patients required one to five anti-hypertensive drugs (median 2, IQR 0–4; p =0.06); one patient did not require antihypertensive treatment because of prehypertension [10]. Firstchoice antihypertensive agents were calcium channel blockers [extended-release nifedipine 0.5–1 mg/kg/dose twice daily (BID) or amlodipine 0.06–0.5 mg/kg/day] followed by βblockers (atenolol 0.5–1 mg/kg/day) and diuretics [hydrochlorothiazide 0.5–2 mg/kg/day or furosemide 1–2 mg/kg/dose BID or three times daily (TID)]. If this therapy was insufficient in controlling hypertension a central α-agonist (clonidine 1–6 μg/kg/dose BID or TID) or peripheral α-agonist (doxazosin 0.02–0.1 mg/kg/day) was added to the treatment regimen. For patients who required five antihypertensive agents a low-dose ACEi (captopril 0.01 mg/kg/dose TID or ramipril 0.05 mg/kg/day maximum 7.5 mg/day) was added. An anti-hypertensive score (AHT score; Guidi et al. [21]) for the patients with TRAS was calculated, taking into account the BP level, number of anti-hypertensive drugs, dosage of anti-hypertensive drugs: the median AHT score pre-PTA was 3 (IQR 1–7). In all patients, Doppler-US criteria for clinically and haemodynamically relevant stenosis were defined using published criteria [22]. The diagnosis of TRAS was then refined in four of the ten cases using angio-CT imaging and in five cases using angio-MR imaging. Eight patients presented a sub-occlusive (luminal narrowing >85 %) stenosis (5 anastomotic, 1 perianastomotic, 2 distal stenosis 2–3 cm after anastomosis). One patient presented a double stenosis (perianastomotic and distal) on the main renal artery with an estimated luminal narrowing of 50–75 %. Finally, one patient presented with a sub-occlusive ostial stenosis of a small inferior polar artery emerging from the proximal third of the principal renal artery (Table 1). All patients in the TRAS group underwent PTA without complications. In brief, an ipsilateral or contralateral femoral approach was chosen. The stenotic site was traversed with a
464
Pediatr Nephrol (2014) 29:461–467
hydrophilic guidewire; a balloon angioplasty catheter was then exchanged across the stricture via the hydrophilic guidewire. Dilatation of the stenotic lesion was then executed by inflating the balloon (diameter 2.5–5 mm, length 15– 20 mm); this may be repeated as appropriate until a radiologic demonstration of success, defined by a significant (>50 %) reduction in the percentage of stenosis. In three cases a cutting balloon, inflated to achieve a pressure of 15 atmospheres, was used; only in one of three patients was a good luminal dilatation reached. Patients were subsequently observed for 1– 2 days in our transplant clinic. Mean BP SDS significantly decreased after PTA [3.2±1.4 (pre-PTA) vs. 1.04±0.85 (post-PTA); p =0.0006] (Fig. 1a), resulting in a significant reduction in the AHT score post-PTA (median 0, IQR range 0–2; p =0.003). The mean creatinine clearance before angioplasty was found to be 69±17.1 ml/ min/1.73 m2, which is significantly lower than that obtained after angioplasty (80.7±21.5 ml/min/1.73 m2; p =0.006) (Fig. 1b). At the last available follow-up for which data were available for our analysis (median 4.1 years, IQR 1.1–8.5), all patients still had functioning grafts and no complications related to PTA had occurred. To assess TRAS risk factors, patients with TRAS were compared with ten patients without TRAS having similar baseline demographic and clinical characteristics (Table 2). In the control population, 56 of 210 patients were excluded from the analysis due to referral to the adult centre (n = 42 patients), death (9), graft loss within 1 week after transplantation (not due to vascular diseases) (3) and significant comorbidities (2). The 154 remaining patients were then included in the analysis and ten matched pairs were created using PSM. There were no significant differences between children with and without TRAS in terms of mean cold ischaemia time,
incidence of DGF, R/D weight ratio, incidence of CMV infections and episodes of acute rejection (Table 2). In the cohort of children with TRAS, seven of the ten patients received oral valganciclovir or aciclovir prophylaxis for 6 months after being transplanted.
Discussion Published data on TRAS in paediatric kidney transplant recipients are scarce. Consequently, our aim was to analyse the prevalence and risk factors for TRAS in a group of paediatric recipients who had received a kidney transplant at our centre. Among this patient population the prevalence of TRAS was 4.6 %, which is similar to that reported in both adult series [1, 8, 23] and in the only previously published paediatric study [5]. Cold ischaemia time and the occurrence of DGF are considered significant risk factors for TRAS [9, 23]. Acute graft rejection can also play a role in the development of TRAS as it is related to ischaemia/reperfusion injury and subsequent endothelial damage [9]. In our study, we did not find significant differences between the TRAS and non-TRAS groups in terms of mean cold ischaemia time, incidence of DGF or episodes of acute rejection. This can be explained by the significantly lower cold ischaemia time and subsequently lower occurrence of DGF observed in our case series as compared to those reported in other studies [9, 24]. CMV infection is a recognised risk factor for the development of arterial stenosis [8]. The molecular mechanism, although unclear, seems to be related to the mitogenic effects of a viral cytomegalic gene product on the intima which triggers smooth-muscle cell proliferation and accumulation. CMV infection is also likely to impair the nitric oxide pathway and to
Table 1 Angiographic presentation of patients with transplant renal artery stenosis Patients with TRAS
Gender Age at transplantation Angiographic morphology (years)
Luminal narrowing
1 2
Male 1.24 Female 17.48
>85 % >85 %
3 4 5 6 7 8 9
Male Male Male Male Male Male Male
3.60 17.27 11.74 15.88 16.78 9.27 5.83
10
Male
2.76
TRAS, Transplant renal artery stenosis
Subocclusive anular anastomotic stenosis Subocclusive ostial stenosis of inferior polar artery (originated from the proximal third of principal renal artery) Subocclusive distal stenosis (3 cm after anastomosis) “Diaphragm-like” subocclusive perianastomotic stenosis Subocclusive anastomotic stenosis; hypoperfused subcapsular areas Subocclusive anastomotic stenosis Subocclusive anastomotic stenosis Anastomotic kinking and subocclusive anastomotic stenosis; post-stenotic ectasia Moderate perianastomotic stenosis; moderate distal stenosis (2 cm after anastomosis)
>85 % >85 % >85 % >85 % >85 % >85 % Double stenosis, 50–75 % both Distal subocclusive stenosis (2 cm after anastomosis); moderate post-stenotic ectasia >85 %
Pediatr Nephrol (2014) 29:461–467
465
Fig. 1 a Distribution of mean blood pressure standard deviation scores (SDS) pre- and post-percutaneous transluminal angioplasty (PTA), b distribution of creatinine clearance pre- and post-PTA. Horizontal line in box Median, box interquartile range (25–75 %), whiskers standard deviation
induce endothelial dysfunction [9, 25]. In our study, we did not find any relationship between CMV infection and TRAS, but only one case of symptomatic CMV infection was reported. In addition to the known risk factors for TRAS which have been reported in adult populations, an adjunctive risk factor in children might be represented by the diameter of the small vessels. Size mismatch of anastomosed vessels due to disproportional body weight between donor and recipient might indeed result in perianastomotic stenosis. However, in our study, no statistical significant difference in R/D weight ratio between the TRAS and non-TRAS groups was observed even though two patients in the TRAS group received their graft from the same donor with significantly high R/D body weight ratios (3.3 and 4, respectively), suggesting that size mismatch might indeed represent a potential risk factor for TRAS. Our patients presented clinically with new-onset hypertension or worsening of pre-transplant hypertension in almost all cases; the number of anti-hypertensive drugs needed to control BP was higher in patients with TRAS compared to hypertensive transplanted patients without TRAS. In our experience, hypertensive renal transplant recipients requiring two or more drugs to control BP values need to be investigated further to rule out the presence of TRAS. However, TRAS can also be clinically silent; therefore, regular screening of renal transplant patients by Doppler-US imaging (monthly for the first 6 months, then twice a year) should be a fundamental part of the follow-up regimen. In the literature, there is no established consensus about the degree of renal arterial narrowing that justifies percutaneous revascularisation. Lesions causing arterial diameter stenosis of ≤50 %, as evidenced by angiography, are generally considered not to be haemodynamically relevant. Clinical criteria for revascularisation in the presence of significant renal artery
stenosis in native kidneys are well established [22], whereas there are no clear indications in renal transplant recipients. In our cohort, the findings on the kidney graft Doppler-Us were significant in all patients with TRAS (>60 %). This led to angio-CT or angio-MR imaging being performed in nine of the ten patients to refine the diagnosis; one patient underwent angiography and angioplasty without CT or MR because of neurological comorbidities that contraindicated multiple sedations. Even if angiography is the gold standard for TRAS diagnosis, CT and MR imaging procedures are able to accurately detect the extent and the site of arterial stenosis, thus allowing a more precise procedural planning [12, 26]. AngioCT and angio-MR imaging procedures provide the best angiographic projections, thereby guaranteeing a faster visualisation of arterial stenosis, and they also minimise the radiation dose. In our centre we usually perform angio-MR before angiography to refine the TRAS diagnosis; however, as angio-CT is faster than MR, CT is preferred for patients aged 80 % along with clinical success, as measured by the treatment of hypertension and improvement of allograft function [2, 27, 28]. Patel et al. used a 15 % reduction in serum creatinine and a 15 % reduction in diastolic BP with no change in anti-hypertensive medication or a 10 % reduction in diastolic BP with a reduction in anti-hypertensive medication to define clinical success [23]. In our series, we observed a significant improvement in graft function, with a 14 % rise in creatinine clearance at 30–60 days after PTA. Moreover, a significant reduction in mean BP values and anti-hypertensive medication used was observed. Among the ten patients with TRAS, we observed an optimal (>75 %) and a good (>50 %) luminal gain in three and five
466
Pediatr Nephrol (2014) 29:461–467
Table 2 Baseline characteristics of the two groups patients with TRAS and patients without TRAS) before and after propensity score matching and the analysis of TRAS risk factors Baseline characteristics of the study population Before PSM Characteristicsa TRAS group (n =10) Age (years) 11.78±6.00 Male sex 9 (90) Cause of renal disease Malformative uropathies 6 (60) Glomerulonephritis 1 (10) Hereditary tubulopathies 2 (20) Other 1 (10) Type of dialysis Haemodialysis Peritoneal Preemptive Duration of dialysis (months) Calcineurin inhibitor (FK506) Analysis of TRAS risk factors TRAS risk factorsa Cold ischaemia time Delayed graft function Recipient/donor weight ratio Cytomegalovirus infections Acute rejection
5 (50) 4 (40) 1 (10) 18.3±13.9 9 (90)
0.94 0.17
After PSM TRAS group (n =10) 11.78±6.00 9 (90)
No TRAS group (n =10) 12.26±6.27 9 (90)
0.82 1.00
84 (58.3) 32 (22.2) 12 (8.3) 16 (11.1)
0.81 0.63 0.40 0.60
6 (60) 1 (10) 2 (20) 1 (10)
7 (70) 1 (10) 2 (20) 0 (0)
0.60 1.00 1.00 0.30
73 (50.7) 63 (43.7) 8 (5.5) 24.1±29.06 102(70.8)
0.78 0.96 0.88 0.26 0.43
5 (50) 4 (40) 1 (10) 18.3±13.9 9 (90)
5 (50) 3 (30) 2 (20) 20.4±25.2 9 (90)
1.00 0.60 0.50 0.83 1.00
No TRAS group (n =144) 11.95±7.32 91 (63.2)
TRAS group (n = 10) 15.4±5.6 2 (20) 0.84 (0.59-4) 1 (10) 2 (20)
p value
No TRAS group (n = 10) 12.9±3.8 1 (10) 1.06 (0.25-2.27) 0 (0) 3 (30)
p value
p value 0.38 1.00 0.62 1.00 1.00
PSM, Propensity score matching a
Values are presented as the mean ± standard deviation, as the median with the range in parenthesis or as the number of patients with the percentage in parenthesis
patients, respectively, which is a success percentage of 80 %, similar to that reported in other published series [29]. In two out of 10 cases the procedure was considered to be suboptimal (>30 %). However, despite of angiographic features, these two patients showed a significant improvement in graft function, which continues to be stable at 4.7 and 6 years post-PTA, respectively. Moreover, one of these two patients was completely withdrawn from anti-hypertensive treatment. As already reported by other authors [30], high-grade TRAS, even when not completely resolved, can improve and remain stable over time with an excellent long-term graft survival. In our study, post-PTA follow-up was performed using color Doppler flow imaging, as its ultrasonographic sensitivity and specificity range from 58 to 100 % and from 87 to 100 %, respectively [11]. There were no adverse events detected, and all patients showed good and stable graft function with normal Doppler features at the last follow-up.
This study represents a single-centre analysis involving a relatively small number of patients. As such, we clearly acknowledge that our results, although of clinical and statistical significance, will need to be validated in a larger population. We report a low but significant TRAS prevalence in paediatric renal transplant recipients, underlining the importance of checking for TRAS in all patients having hypertension after transplantation, starting with renal echocolour-Doppler imaging. In our series, known risk factors did not seem to be related to the development of TRAS, at least in part because of the prevention strategies used (CMV prophylaxis, shorter cold ischaemia time whenever possible). The effect of donor/recipient weight mismatch, which seems to be an adjunctive risk factor in the paediatric population, needs to be confirmed by investigations in a larger number of patients. Finally, our study confirmed that PTA is also an effective and safe therapeutic option in
Pediatr Nephrol (2014) 29:461–467
paediatric recipients as it ensured excellent medium-term results with regard to graft function and BP values.
Conflict of interest statement None.
References 1. Fervenza FC, Lafayette RA, Alfrey EJ, Petersen J (1998) Renal artery stenosis in kidney transplantation. Am J Kidney Dis 31:142–148 2. Sishir G, Rajapurkar M (2009) Vascular complications following renal transplantation. J Nephrol Ren Transplant 2:122–132 3. Bruno S, Remuzzi G, Ruggenenti P (2004) Transplant renal artery stenosis. J Am Soc Nephrol 15:134–141 4. Seeman T (2009) Hypertension after renal transplantation. Pediatr Nephrol 24:959–972 5. Fontaine E, Barthelemy Y, Gagnadoux MF, Cukier J, Broyer M, Beurton D (1994) A review of 72 renal artery stenoses in a series of 715 kidney transplantations in children. Prog Urol 4:193–205 6. Roberts JP, Ascher NL, Fryd DS, Hunter DW, Dunn DL, Payne WD, Sutherland DE, Castaneda-Zuniga W, Najarian JS (1989) Transplant renal artery stenosis. Transplantation 48:580–583 7. Sinha MD, Kerecuk L, Gilg J, Reid CJ (2012) Systemic arterial hypertension in children following renal transplantation: prevalence and risk factors. Nephrol Dial Transplant 27:3359–3368 8. Rengel M, Gomes-Da-Silva G, Inchaustegui L, Lampreave JL, Robledo R, Echenagusia A, Vallejo JL, Valderrabano F (1998) Renal artery stenosis after kidney transplantation: diagnostic and therapeutic approach. Kidney Int Suppl 68:S99–S106 9. Audard V, Matignon M, Hemery F, Snanoudi R, Desgranges P, Anglade MC, Kobeiter H, Durrbach A, Charpentier B, Lang P, Grimbert P (2006) Risk factors and long-term outcome of transplant artery stenosis in adult recipients after treatment by percutaneous transluminal angioplasty. Am J Transplant 6:95–99 10. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114[2 Suppl 4th Report]:555–576 11. O’Neill WC, Baumgarten DA (2002) Ultrasonography in renal transplantation. Am J Kidney Dis 39:663–678 12. Vasbinder GBC, Nelemans PJ, Kessels AG, Kroon AA, de Leeuw PW, van Engelshoven JM (2001) Diagnostic tests for renal artery stenosis in patients suspected of having renovascular hypertension: a meta-analysis. Ann Intern Med 135:401–411 13. Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 4:1832–1843 14. Vidal E, Murer L, Matteucci MC (2013) Blood pressure measurement in children: which method? Which is the gold standard? J Nephrol. doi:10.5301/jn.5000244 15. Cole TJ, Green PJ (1992) Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 11:1305–1319 16. D’Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of treatment to a non-randomized control group. Stat Med 17:2265–2281
467 17. Perico N, Cattaneo D, Sayegh MH, Remuzzi G (2004) Delayed graft function in kidney transplantation. Lancet 364:1814–1827 18. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, Einecke G, Gloor J, Glotz D, Kraus E, Legendre C, Liapis H, Mannon RB, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Rodriguez ER, Seron D, Seshan S, Suthanthiran M, Wasowska BA, Zachary A, Zeevi A (2010) Banff ’09 meeting Report: antibody mediated graft deterioration and Implementation of Banff Working Groups. Am J Transplant 10:464–471 19. Austin PC (2011) Optimal caliper widths for propensity-score matching when estimating differences in means and differences in proportions in observational studies. Pharm Stat 10:150–161 20. Austin PC (2011) Comparing paired vs non-paired statistical methods of analyses when making inferences about absolute risk reductions in propensity-score matched samples. Stat Med 30:1292–1301 21. Guidi E, Bianchi G, Rivolta E, Ponticelli C, Quarto di Palo F, Minetti L, Polli E (1985) Hypertension in man with a kidney transplant: role of familial versus other factors. Nephron 41:14–21 22. Rundback JH, Sacks D, Kent KC, Cooper C, Jones D, Murphy T, Rosenfield K, White C, Bettmann M, Cortell S, Puschett J, Clair D, Cole P, AHA Councils on Cardiovascular Radiology, High Blood Pressure Research, Kidney in Cardiovascular Disease, CardioThoracic and Vascular Surgery, and Clinical Cardiology, and the Society of Interventional Radiology FDA Device Forum Committee. American Heart Association (2002) Guidelines for the reporting of renal artery revascularization in clinical trials. Circulation 106:1572–1585 23. Patel NH, Jindal RM, Wilkin T, Rose S, Johnson MS, Shah H, Namyslowski J, Moresco KP, Trerotola SO (2001) Renal arterial stenosis in renal allografts: retrospective study of predisposing factors and outcome after percutaneous transluminal angioplasty. Radiology 219:663–667 24. O’Callaghan JM, Knight SR, Morgan RD, Morris PJ (2012) Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. Am J Transplant 12:896–906 25. Pouria S, State OI, Wong W, Hendry BM (1998) CMV infection is associated with transplant renal artery stenosis. QJM 91:185– 189 26. Ismaeel MM, Abdel-Hamid A (2011) Role of high resolution contrast-enhanced magnetic resonance angiography (HR CeMRA) in management of arterial complications of the renal transplant. Eur J Radiol 79:e122–e127 27. Leonardou P, Gioldasi S, Pappas P (2011) Transluminal angioplasty of transplanted renal artery stenosis: a review of the literature for its safety and efficacy. J Transplant 2011:693820 28. Pappas P, Zavos G, Kaza S, Leonardou P, Theodoropoulou E, Bokos J, Boletis J, Kostakis A (2008) Angioplasty and stenting of arterial stenosis affecting renal transplant function. Transplant Proc 40:1391– 1396 29. Marini M, Fernandez-Rivera C, Cao I, Gulias D, Alonso A, LopezMuñiz A, Gómez-Martínez P (2011) Treatment of transplant renal artery stenosis by percutaneous transluminal angioplasty and/or stenting: study in 63 patients in a single institution. Transplant Proc 43:2205–2207 30. Butorović-Ponikvar J, Ponikvar R (2003) High-grade renal transplant artery stenosis after suboptimal angioplasty: favourable long-term outcome. Transplant Proc 35:2891–2893
