Abstract
Objective. To investigate the characteristics of patients with Takayasu arteritis (TA)-related renal artery stenosis and identify the predictors of medium-term adverse outcomes.
Methods. Data for 567 patients registered in the East China Takayasu arteritis cohort, a large prospective observational cohort, up to April 30, 2019, were retrospectively analyzed.
Results. Renal artery stenosis was confirmed in 172/567 (30.34%) patients, with left renal artery involvement seen in 73/172 (42.44%) patients. Renal insufficiency at presentation (HR 2.37, 95% CI 1.76–15.83, P = 0.03), bilateral renal artery involvement (HR 6.95, 95% CI 1.18–21.55, P = 0.01), and severe stenosis (> 75%; HR 4.75, 95% CI 1.08–11.33, P = 0.05) were predictors of adverse outcomes. A matrix model constructed using 3 variables (renal function, stenosis severity, and bilateral renal artery involvement) could identify 3 risk groups. Revascularization was performed for 46 out of 172 (26.74%) patients. Patients without preoperative treatment had higher rate of restenosis (41.46% vs 16.67%, P < 0.01) and worsening hypertension (25.93% vs. 10.53%, P < 0.01) after the procedure. Nonreceipt of preoperative treatment (HR 6.5, 95% CI 1.77–32.98, P = 0.04) and active disease at revascularization (HR 4.21, 95% CI 2.01–21.44, P = 0.04) were independent predictors of adverse outcomes after revascularization.
Conclusion. Patients with TA-associated renal artery stenosis and uncontrolled or worsening hypertension or/and renal function may benefit from revascularization. Those who have received preoperative treatment may have more favorable revascularization outcomes. Prognosis appears to be poorer for patients with renal insufficiency at presentation, bilateral artery involvement, and severe stenosis.
Takayasu arteritis (TA) is a chronic, large vessel vasculitis that primarily affects the aorta and its main branches1,2,3. The incidence of renal artery stenosis in TA is 20–60%, according to previous reports4,5,6. In patients under the age of 40 years, TA is responsible for 60.5% of cases of renal artery stenosis7 and, among Asian patients with TA, almost half have renal artery involvement8. Renal artery stenosis can cause refractory hypertension, renal function disturbance, and premature death8,9,10. Early recognition and treatment of TA-related renal artery stenosis could help in preventing long-term adverse outcomes.
Treatment for TA-related renal artery stenosis includes pharmacotherapy and revascularization procedures. Glucocorticoids, immunosuppressants, and biological agents are used to control systemic and vascular inflammation, and prevent disease progression and organ damage11,12, whereas antihypertensive drugs are used to control blood pressure and prevent ischemic symptoms. Revascularization procedures may be needed to treat severe stenosis, malignant hypertension, or persistent refractory hypertension13,14. The results of vascular interventions for TA have not been consistent in previous studies, with some authors reporting a high rate of restenosis and others demonstrating good long-term arterial patency after treatment15,16,17. A major limitation of these earlier studies was that they did not evaluate how pharmacotherapy influenced the long-term outcomes of vascular interventions15,16,17.
The specific characteristics of patients with TA-related renal artery stenosis, the effect of revascularization procedures on prognosis, and the risk factors for adverse outcomes after the vascular intervention have not been fully investigated in Chinese populations. This study was designed to investigate (1) the characteristics of Chinese patients with TA-related renal artery stenosis, (2) the predictors of medium-term adverse outcomes in these patients, and (3) the predictors of adverse outcomes in the subgroup undergoing revascularization procedures.
MATERIALS AND METHODS
Patients. This study was based on the East China Takayasu arteritis (ECTA) cohort, a prospectively maintained observational cohort. The ECTA (NCT03893136) was established in 2010 in our center, Zhongshan Hospital, which is a tertiary care hospital affiliated to Fudan University, Shanghai, China. For this retrospective study, we included all 567 patients registered in the ECTA up to April 30, 2019. All patients had been diagnosed with TA by rheumatologists using the 1990 American College of Rheumatology criteria18. The diagnoses were confirmed by whole-body enhanced magnetic resonance angiography (MRA), computed tomographic angiography (CTA), or vascular ultrasound (if angiography could not be performed because of allergy to iodine or other contraindications).
This study was performed in accordance with the tenets of the Helsinki Declaration and its amendments. The study protocol was approved by the Ethics Review Board of Zhongshan Hospital (B2013-115). Written informed consent was obtained from all patients.
Medications. At our center, medical therapy for TA has 2 phases: an induction phase and a maintenance phase. In the induction phase, oral prednisone is started at a dose of 0.8–1.0 mg/kg/day; after 4 weeks, the dose is tapered gradually over 5 months to a maintenance dose of 0.1–0.2 mg/kg/day. Along with prednisolone (PSL), an immunosuppressant [cyclophosphamide (CYC), methotrexate (MTX), azathioprine (AZA), leflunomide (LEF), or mycophenolate mofetil (MMF)] or a biological agent is also administered; the choice of immunosuppressant versus biological agent is at the physician’s discretion. The dosages used are as follows: CYC, 0.5–0.75 g/m2 (usually 0.8 g) intravenously every 4 weeks; MTX, 10–15 mg/week orally; AZA, 50–100 mg/day orally; LEF, 10–20 mg/day orally; and MMF, 1–2 g/day orally. Induction treatment lasts for 6 months. If active disease is still present at the end of 6 months, the PSL dose is adjusted and a change of the immunosuppressant drug is considered. Maintenance therapy is with MTX (10–15 mg/week orally), AZA (25–50 mg/day, orally), LEF (10–20 mg/day, orally), or MMF (1–1.5 g/day, orally).
Antihypertensive drugs are used to control blood pressure, with combinations of 2 or more drugs used when necessary. The drugs include calcium channel antagonists, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, α-blockers, diuretics, and others (e.g., clonidine).
Disease activity assessment and follow-up. Data recorded up to April 30, 2019, were collected for analysis. Demographic factors, clinical characteristics, laboratory findings, imaging features, and follow-up data were noted. Estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration equation19. Follow-up was conducted once a month during the induction period, and once every 3 months during the maintenance period. MRA or CTA was performed every 6 months to assess disease progression. Radioisotope renography was performed to evaluate renal dysfunction if necessary.
Disease activity was assessed using Kerr criteria20, which include the following: (1) systemic symptoms (not due to other causes such as infection, tumor and so on); (2) erythrocyte sedimentation rate; (3) vascular ischemic symptoms or signs (e.g., weak pulse or pulselessness, vascular bruits, or asymmetric blood pressure); and (4) positive imaging results. Appearance of new symptoms or worsening of 2 or more criteria indicates active disease.
Definition of adverse outcomes. Renal insufficiency was defined as serum creatinine ≥ 130 μmol/L or eGFR ≤ 60 mL/min. Hypertension was defined as blood pressure ≥ 140/90 mmHg. Refractory hypertension was defined as blood pressure ≥ 160/90 mmHg despite maximal doses of 3 antihypertensive drugs.
Severity of renal artery stenosis was categorized as < 50%, 50–75%, or > 75% on MRA or CTA, as described in a previous study21.
Adverse outcomes for patients with TA-related renal artery stenosis included (1) persistent renal insufficiency at 6 months after diagnosis, or deterioration of renal function (≥ 20% increase in creatinine concentrations or ≥ 20% decrease in eGFR); (2) persistent refractory hypertension at 6 months or malignant hypertension; (3) congestive heart failure; and (4) TA-related death (e.g., death caused by severe arterial stenosis or aortic dissection). Adverse outcomes after renal artery revascularization procedures included (1) restenosis, (2) ≥ 20% increase in blood pressure after the procedure, (3) ≥ 20% deterioration of renal function after the procedure, and (4) TA-related death.
Statistical analysis. Categorical variables were summarized as counts and percentages and compared between groups using the chi-square test. Continuous variables were summarized as means ± SD or as medians with IQR, depending on the normality of the distribution, and compared using the t test, Wilcoxon test, or Mann-Whitney test. Univariate logistic regression analysis was performed to examine the association of baseline factors with outcomes. Factors significantly associated (at P < 0.10) with poor outcome were entered into a Cox proportional hazards regression model to identify the independent predictors of adverse outcomes, and the HR and 95% CI were calculated. Using these results, a risk-prediction matrix was built that could be used to stratify patients according to risk of adverse outcomes. The ability of the model to predict adverse outcomes was assessed using receiver-operating characteristic (ROC) curve analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Statistical analysis was performed using SPSS 22.0 (IBM Corp.). Two-sided P < 0.05 indicated statistical significance.
RESULTS
Patient characteristics. A total of 567 TA patients were included in this study. Table 1 presents the characteristics of the patients. Median age at disease onset was 29 (22–38) years, and median age at diagnosis was 31 (22–38) years. The majority of patients were female (455/567, 80.25%). According to the 1996 Numano classification system22, the most common type was type V (234/567, 41.79%), followed by type II (147/567, 25.93%), type I (74/567, 13.05%), and type IV (63/567, 11.11%).
Comparison of clinical characteristics between Takayasu arteritis patients with and without renal artery stenosis.
Comparison of disease features between patients with and without renal artery involvement. Renal artery involvement was confirmed in 172/567 (30.34%) patients. Bilateral renal artery involvement was observed in 55/172 (31.98%) patients. While 12/172 (6.98%) patients had only renal artery involvement, the rest also had involvement of other arteries, including left carotid artery (56/172, 32.56%), left subclavian artery (57/172, 33.14%), and abdominal aorta (51/172, 29.65%).
The group with renal artery involvement had a significantly lower proportion of female patients (P = 0.04) and a significantly lower prevalence of systemic symptoms (P = 0.03). The group had a significantly higher prevalence of hypertension (P = 0.02), especially refractory hypertension (P < 0.01), and a significantly higher prevalence of renal insufficiency (P = 0.03; Table 1).
Risk factors for medium-term adverse outcomes in TA-related renal artery stenosis. The median follow-up period of patients with renal artery stenosis was 45 (3–78) months. During the follow-up, 46/172 (26.74%) patients suffered adverse outcomes: 17 patients had persistent refractory hypertension, 6 patients had malignant hypertension, 7 patients had persistent renal insufficiency, 4 patients had renal function deterioration, 7 patients had congestive heart failure, and 5 patients died due to TA-related causes (2 congestive heart failure, 1 malignant arrhythmia, 1 aortic dissection, and 1 acute myocardial infarction).
Patients with renal artery stenosis could be separated into 3 groups according to the severity of renal artery stenosis: < 50% stenosis (n = 47), 50–75% stenosis (n = 51), and > 75% stenosis (n = 52). Table 2 presents a comparison of the characteristics of these 3 groups.
Comparisons of clinical characteristics between patients with different degrees of renal artery stenosis.
Supplementary Table 1 (available with the online version of this article) presents the results of logistic regression analysis of baseline factors. Cox proportional hazards regression analysis showed that renal insufficiency at presentation (HR 2.37, 95% CI 1.76–15.83, P = 0.03), bilateral renal artery involvement (HR 6.95, 95% CI 1.18–21.55, P = 0.01), and severe (> 75%) stenosis (HR 4.75, 95% CI 1.08–11.33, P = 0.05) were independent predictors of adverse outcomes (data not shown).
Using these variables (i.e., baseline renal function, severity of renal artery stenosis, and presence of bilateral renal artery involvement), we built a risk-prediction matrix that could be used to stratify patients into different risk groups (Figure 1A). ROC analysis showed satisfactory performance of the model: 89% sensitivity, 71% specificity, 82% PPV, and 88% NPV for predicting risk of adverse outcomes.
(A) Matrix model for predicting risk of adverse outcomes in TA patients with renal artery stenosis. Based on baseline renal function, renal artery stenosis severity, and presence of bilateral involvement, patients could be separated into 3 risk groups: high risk (red, > 50%), moderate risk (green, between 30–50%), and low risk (yellow, < 30%). (B) Matrix model for predicting risk of adverse outcomes after vascular intervention. Based on renal artery stenosis severity, receipt of preoperative treatment, and disease activity at time of intervention, patients could be separated into 3 risk groups: high risk (red, > 25%), moderate risk (green, between 10–25%), and low risk (yellow, < 10%). TA: Takayasu arteritis; NA: not applicable.
Comparisons of characteristics of patients with and without revascularization. A total of 46/172 (26.74%) patients underwent revascularization procedures. Table 3 presents data for patients with and without revascularization. The revascularization group had significantly higher proportions of patients with renal insufficiency (P = 0.03), hypertension (P = 0.04), especially refractory hypertension (P < 0.01), and severe stenosis (P < 0.01).
Comparisons of disease features between patients with and without revascularization.
Effect of preoperative therapy on outcomes of renal artery revascularization. A total of 65 renal artery revascularization procedures were performed in 46 patients (1.41 per person, range: 1–4). The procedures included percutaneous transluminal angioplasty (PTA; 40/65, 61.54%), stent implantation (16/65, 24.62%), autotransplantation (2/65, 3.08%), bypass surgery (3/65, 4.62%), and nephrectomy (4/65, 6.16%). The median follow-up after revascularization was for 34 (3–52) months.
According to whether or not glucocorticoids and immunosuppressant drugs were used, the patients undergoing revascularization procedures could be separated into 2 groups: the preoperative therapy group (n = 24) and the nonpreoperative therapy group (n = 41). In the preoperative therapy group, median duration of preoperative therapy was for 9 (IQR 1–15) months. In the nonpreoperative therapy group, all 41 patients underwent revascularization procedures before definite diagnosis of TA; the procedures were performed to control blood pressure or manage acute ischemic events. In both groups, blood pressure decreased immediately after revascularization. However, at 6 months after the procedure, the nonpreoperative therapy group showed a significant increase in blood pressure (Figures 2C,D). A similar pattern was observed in the changes in renal function in the 2 groups (Figures 2A,B). Restenosis rate was significantly higher in the nonpreoperative therapy group (41.46% vs 16.67%, P < 0.01) during the first 2 years after revascularization (Figure 3A; HR 2.37, 95% CI 1.76–15.83, P = 0.03).
(A–B) Change in renal function (serum creatinine level and eGFR) in patients with and without preoperative treatment before vascular intervention. (C–D) Change in blood pressure of patients with and without preoperative treatment before vascular intervention. eGFR: estimated glomerular filtration rate.
Risk factors for adverse outcomes after renal artery revascularization. The risk factors for adverse outcomes after renal artery revascularization included renal insufficiency at presentation (OR 1.87, 95% CI 1.12–21.34, P = 0.04), refractory hypertension at presentation (OR 2.06, 95% CI 1.07–19.44, P = 0.03), active disease at the time of surgery (OR 4.06, 95% CI 1.42–21.78, P = 0.03), and nonreceipt of preoperative therapy (OR 7.4, 95% CI 2.05–47.31, P = 0.03).
In Cox proportional hazards regression analysis, the independent predictors of adverse outcome after revascularization were nonreceipt of preoperative therapy (HR 6.5, 95% CI 1.77–32.98, P = 0.04; Figure 3B), active disease at the time of surgery (HR 4.21, 95% CI 2.01–21.44, P = 0.04), and severe stenosis (HR 1.98, 95% CI 1.18–17.32).
(A) Cumulative incidence of renal artery restenosis in patients with and without preoperative treatment before vascular intervention. (B) Kaplan-Meier curves of survival without adverse outcome in patients with and without preoperative treatment before vascular intervention.
Using these variables (i.e., nonreceipt of preoperative treatment, presence of active disease at the time of surgery, and severity of stenosis), we built a risk-prediction matrix that could be used to stratify patients into different risk groups (Figure 1B). ROC analysis showed satisfactory performance of the model: 87% sensitivity, 69% specificity, 78% PPV, and 84% NPV for predicting risk of adverse outcomes after revascularization.
DISCUSSION
This study was performed to determine the characteristics of Chinese patients with TA with renal artery involvement and to identify the predictors of medium-term adverse outcomes. To our knowledge, this is the largest cohort of patients with TA-related renal artery stenosis.
In this study, renal artery involvement was seen in 30.34% patients, which is notably lower than the 48.92% reported in another Chinese study8. Consistent with the earlier study, we found hypertension, especially refractory hypertension, and renal insufficiency to be significantly more common in patients with renal artery involvement. In our sample, systemic symptoms were uncommon in patients with renal artery involvement; this is an important finding since it suggests that diagnosis of TA may sometimes be delayed or missed. Thus, in patients with hypertension, especially in those younger than 40 years, an etiological diagnosis is essential, and TA-related renal artery stenosis should be ruled out.
Medium-term outcomes in patients with TA-related renal artery stenosis have been previously described in Korean10 and white23 populations. In the Korean study, bilateral lesions and renal functional impairment at presentation were significant adverse prognostic factors; this result is concordant with our findings. However, in the white population, medium-term nonrenal and renal outcomes were favorable; no patient experienced endstage renal disease or died. The different results in the latter study may be related to the relatively small sample size and short follow-up period, in addition to the ethnicity of the enrolled patients.
PTA was the most commonly used revascularization procedure (61.54%) in our sample; this is consistent with earlier reports24,25,26. Nonreceipt of preoperative treatments and active disease at the time of vascular surgery were the most important risk factors for long-term adverse outcomes after revascularization. TA-related renal artery stenosis is a kind of inflammatory vasculitis, and previous studies have shown that active vascular inflammation may be associated with a higher rate of complications and restenosis after revascularization27,28. There are still no guidelines on how to select the best time for revascularization in TA-related stenosis. While effective preoperative medication may improve outcomes, the optimal preoperative treatment duration remains to be determined.
We found that hypertension caused by TA-related renal artery stenosis might be controlled with the combination of renal artery revascularization and medication. Three patients in our cohort stopped antihypertensive drugs after the renal artery revascularization (Supplementary Table 2, available with the online version of this article); their blood pressure was normal for 6–24 months after the procedure. Randomized controlled trials are needed to confirm the long-term effects and safety of the combination of medication and revascularization.
Our study has several strengths. First, the sample size is much larger than that of previous studies. Second, in addition to reporting the outcomes of patients with TA-related renal artery stenosis, we also identify the risk factors for adverse outcomes. The matrix model that we propose (Figure 1A) can be conveniently applied in clinical practice to identify high-risk patients. We also analyze the outcomes and risk of adverse outcomes for the subgroup of patients undergoing revascularization procedures.
We recognize several limitations in our research. First, the follow-up duration was short. Second, there is a possibility that some patients in this study may have had fibromuscular dysplasia (FMD). FMD is a noninflammatory and nonatherosclerotic vascular disease that mainly involves the renal and carotid arteries. The typical imaging characteristic of FMD is the string-of-beads sign on digital subtraction angiography, CTA, or MRA. A few cases with atypical imaging features may have been misdiagnosed.
In conclusion, our study demonstrated renal artery involvement in 30% of Chinese patients with TA. Patients with uncontrolled or worsening hypertension or/and renal function may benefit from revascularization. Preoperative treatment appears to improve revascularization outcomes, though prognosis may be poorer for patients with renal insufficiency at presentation, bilateral artery involvement, and severe stenosis.
Footnotes
This study was sponsored by the National Natural Science Foundation of China (NSFC 81601398; NSFC 81771730).
- Accepted for publication April 21, 2020.
REFERENCES
ONLINE SUPPLEMENT
Supplementary material accompanies the online version of this article.
