1 Unità Operativa Nefrologia e Dialisi, Policlinico Monteluce and 2 Istituto Radiologia Università di Perugia, Italy
Correspondence and offprint requests to: Attilio Losito, via dei Mille 5, San Mariano, 06070 Perugia, Italy. Email: atlosito{at}tin.it
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Abstract |
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Methods. ARVD was demonstrated angiographically in 195 patients who were consecutively enrolled into a follow-up study. Patient age was 65.6±11.2 years, serum creatinine was 1.74±1.22 mg/dl and renal artery lumen narrowing was 73.5±17.5%. A revascularization was performed in 136 patients, whereas 54 subjects having comparable characteristics were maintained on a medical treatment throughout the study; five patients were lost during follow-up.
Results. The main follow-up was 54.4±40.4 months. The assessment of cardiovascular survival and renal survival at the end of follow-up revealed 46 cardiovascular deaths, 20 patients with end-stage renal disease (ESRD) and 41 patients with an increase in serum creatinine of over one-third. The multivariate analysis showed that renal revascularization did not affect mortality or renal survival compared with medical treatment. Revascularization produced slightly lower increases in serum creatinine and a better control of blood pressure. A longer survival was associated with the use of angiotensin-converting enzyme inhibitors (ACEIs) (P = 0.002) in both revascularized and medically treated patients. The only significant predictor of ESRD was an abnormal baseline serum creatinine.
Conclusions. On long-term follow-up, ARVD was associated with a poor prognosis due to a high cardiovascular mortality and a high rate of ESRD. In our non-randomized study, revascularization was not a major advantage over medical treatment in terms of mortality or renal survival. The use of ACEIs was associated with improved survival.
Keywords: angiotensin-converting enzyme inhibitors; end-stage renal failure; renovascular disease; revascularization; survival
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Introduction |
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Patients and methods |
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Renal artery stenosis assessment
Angiographs of all patients were reviewed by two of our team (A.L. and R.E.) and were subsequently assessed for renal size and classified according to lumen narrowing. Grades of stenosis were 5060, 6075,7590 and >90%. Sites of stenosis were right or left artery, ostial, proximal or distal; monolateral or bilateral.
The average renal artery stenosis on the whole cohort of patients was 73.5±17.5%. In 50 subjects, the stenosis was bilateral with an average lumen narrowing of 75.8±20.1% on the main side and of 66.3±13.5% on the secondary side. Serum creatinine was 1.62±1.08 mg/dl in monolateral and 2.06±1.50 mg/dl in bilateral disease.
The stenosis was proximal in 79.2%, ostial in 6.3% and distal in 14.6% of cases. Vascular disease in other areas was present in 139 patients. Revascularization was perfomed up to and including 1992 only by angioplasty, and by endovascular stent only from 1998. Both simple angioplasty and stents were used in the interval years.
Statistical analysis
Data are shown as means±SD. Continuous variables were compared with analysis of variance (ANOVA) and t-tests. Non-parametric tests were used on discrete variables with non-normal distribution. For the follow-up study, primary end-points chosen for statistical analysis were cardiovascular death and starting of dialysis for ESRD. As a secondary end-point, we analysed increases in serum creatinine more than one-third of the basal value. Cox regression was employed for univariate and multivariate analysis.
Putative predictors of the chosen end-points were first analysed separately, and then all predictors with a statistical significance of P<0.1 were simultaneously entered in a joint model (backward stepwise procedure). Differences in survival, obtained with the KaplanMeier method, were compared with the log-rank test.
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Results |
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In 41 patients, serum creatinine increased by more than one-third from baseline, and regular dialysis was started for ESRD in 20 patients. Mean dialysis-free survival was 154.1±20.9 months.
Results of different treatments
There were 136 cases of patients treated invasively, and 54 subjects that were maintained on a medical treatment. The clinical characteristics of the two groups were comparable, although the number of patients on statins was higher in the medical group (Table 2).
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Mean dialysis-free survival was comparable for the two groups: 123.4±4.5 in the revascularization group and 185.1±35.7 in the medically treated group (log rank test = 0.02, P = 0.896, NS).
Survival analysis
To assess the risk factors for mortality, we applied the Cox regression analysis with the following variables: age, sex, smoking habit, diabetes, presence of vascular co-morbidity, total and low-density lipoprotein (LDL) cholesterol, baseline creatinine, hypertension, type and degree of stenosis (monolateral or bilateral, >75 or <75%), type of treatment (medical or invasive) and use of statins or ACEIs. We also analysed changes in serum creatinine and blood pressure as covariates varying over time. Antihypertensive drugs other than ACEIs were also analysed, but they showed no effect either singly or in combination.
The variables were first entered into the univariate regression analysis and those selected (P<0.1) were analysed with multivariate analysis. This model produced two significant factors, which were the use of ACEIs and the change in serum creatinine. ACEI treatment induced a hazard ratio of 0.24 [95% confidence interval (CI) 0.080.71, P = 0.0098], and the change in serum creatinine produced a ratio of 1.62 (95% CI 1.041.28). Vascular co-morbidity was significantly associated in the univariate model (P = 0.054) but not in the multivariate model.
The KaplanMeier survival for patients treated or not treated with ACEIs produced a significant log rank test: 9.07, P = 0.0026 (Figure 1). The multivariate analysis with the same factors was repeated separately for patients treated medically (30.1% on ACEIs) or invasively (38.8% on ACEIs). The regression analysis confirmed a positive effect of ACEI treatment on survival. The effect was more significant in patients treated medically (P = 0.015) than in those treated invasively (P = 0.05). The survival over 50 months in survivors was 128.4±4.3 months in the invasive group, 159.4±28 in the medical group (NS), 211.7±34.5 in patients on ACEIs, and 123.5±4.5 in patients not on ACEIs (NS).
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Impairment of renal function (increase of serum creatinine of more than one-third)
The multivariate analysis revealed two factors. The first, an abnormal baseline serum creatinine (1.6 mg/dl), was a significant predictor of impairment with a hazard ratio of 1.42 (95% CI 1.031.95, P = 0.028). The second, the use of ACEIs, was associated with a reduced risk with a hazard ratio of 0.29 (95% CI 0.090.92, P = 0.036). The KaplanMeier analysis of survival time, free of confounding by serum creatinine, revealed a significant difference between subjects treated with ACEis and those not treated (log rank test = 6.75, P = 0.009) (Figure 2).
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Discussion |
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We are fully aware that the unbalanced number of patients in the two groups (revascularization and medical treatment) is a weak point of this study. However, the similarity in clinical characteristics in the two groups and length of the follow-up strengthen our conclusions. In addition, our results support a recently published analysis that confirms the general benefits of renal revascularization [8]. Chabova et al. [13] conducted an observational study in medically treated patients with ARVD that was comparable in size with ours. In their patients, which had the same age range, a high cardiovascular risk and a modest deterioration in renal function were observed. We extended the observation period over 5 years, and in the follow-up there was no substantial difference between revascularization and medical treatments on the major end-points such as mortality or ESRD. The only exception, in terms of ESRD, was the impending occlusive bilateral disease. In this case, as was shown previously, revascularization can totally revert a poor renal prognosis [14]. We also confirmed that there is a lack of correlation between the degree of renal artery stenosis and baseline renal function or functional outcome [10].
The benefit on survival provided by ACEIs was demonstrated previously in a smaller group of patients with ARVD [15]. In the present study, which was longer and with a larger group, we confirmed this effect in both patients treated only medically and those who underwent revascularization. Furthermore, we extended these observations to renal function.
With respect to renal survival, we found less renal function impairment associated with the use of ACEIs.
Unfortunately, we were not able to ascertain the number of patients who received this type of drug before ARVD diagnosis, nor for how long they received treatment. It is possible that some patients used drugs with protecting properties on renal function, which could explain why some patients evolved inexorably towards ESRD whereas others did not.
In patients who did not proceed to ESRD, we found that the change in serum creatinine during the observation was very modest, and that the benefits of revascularization over medical treatment at the end of the long follow-up were unimpressive.
This finding suggests that certain patients with ARVD are more prone to evolve to ESRD, and this is independent of therapeutic approach and obvious clinical characteristics of the patients. Renal size is a well known predictor of progression. It has already been demonstrated that prognosis is worse with reduced renal size [16]. In addition, the presence of already established renal parenchymal damage renders revascularization useless [17]. It is well known that at many levels there are major gaps in our understanding of the mechanisms and progression of ARVD [18].
We also observed an evolution towards ESRD in patients with normal renal size. Thus, these patients could be identified early in the course of their disease by using other criteria. We have already reported that carriers of the D allele of the ACE gene polymorphism had a higher mortality during ARVD [19]. Thus, an association of genetic factors with other clinical characteristics may cause this irreparable course of the disease.
The therapeutic arm of our study deals with ACE inhibition. We found that the use of ACEIs improved prognosis in both patient groups. This finding is of importance since this class of drugs is thought to increase the risk of serious worsening in renal function in ARVD, and there is great resistance to their use in these patients [20]. The administration of ACEIs in renovascular hypertension was wisely suggested years ago, because of their ability to control blood pressure and reduce vascular damage induced by hypertension [21]. Our present findings support and extend these indications. Given the extremely high cardiovascular mortality in ARVD, limiting the use of a drug known to protect the cardiovascular system deprives these patients with cardiovascular co-morbidities of a powerful therapeutic tool. The same applies to renal disease. The damage to renal parenchymal tissue associated with atherosclerotic renal artery stenosis is a target for ACEIs, and this mechanism may explain the minor changes in serum creatinine that were observed during ACEI use during both medical and invasive treatments.
Clearly, these drugs cannot be prescribed without due consideration, and there are risks associated with their use. Nonetheless, a close monitoring of ARVD patients, especially after revascularization, could reduce potential side effects of this drug. In addition, tighter control of all the factors negatively affecting prognosis, blood pressure, blood lipids and sodium state could completely change outcomes [22].
In conclusion, the present follow-up study based on a multiyear observation of patients with ARVD given revascularization or medical treatment showed that the prognosis of these patients was serious. No single therapeutic tool provided a superior overall beneficial effect. Although the invasive treatment alone did not significantly affect the outcome, combination with a tailored medical treatment, including ACEIs, may also improve the prognosis after revascularization.
Conflict of interest statement. None declared.
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References |
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