Renal artery stenosis in China: The state of changes

In the last few decades, China has undergone rapid and large‐scale modernization and can therefore offer us a unique window to predict future events in the developing world. In this regard, the manuscript presented in this current issue of the Journal by Xiong and colleagues1 provides an interesting and valuable addition to the existing literature as it explores the shifts of renal artery stenosis (RAS) diagnoses in a referral center‐based Chinese population. A total of 2905 subjects diagnosed with RAS were enrolled from a highly specialized renal artery disease center in China, the Fuwai Hospital National Center for Cardiovascular Diseases. Of the total study population 82.4% have been classified as atherosclerotic in origin, and subjects with Takayasu arteritis (TA), fibromuscular dysplasia (FMD), and other causes occupied the rest of the study group. Of note, a very similar study by some of the current authors, Peng and colleagues2 was previously published in 2016 with the title “Etiology of renal artery stenosis in 2047 patients,” from a largely overlapping cohort of patients. This latter study focused on the etiology of distribution in renal artery stenosis2 whereas the present study reviews time trends of RAS etiology in different groups of patients at a higher resolution, as a function of enrollment years across genders and age groups.1 Some features of the enrolled cohort can be gleaned only from the paper of Peng and others2 (local catchment vs nationwide referral; interventions performed for RAS).

As interesting the current study might be however, several limitations of the paper are immediately striking. First, the center experienced a logarithmic rise in RAS evaluations during the 18‐year study period of 1999 through 2016. Such a dramatic expansion of evaluations, rising from the 100s to 1500 in a single‐center study, invites major potential bias for selective referrals of enrollees. Second, the current study enrolled inpatients exclusively; however, the definition or criteria for hospitalization may vary tremendously between countries and health care systems and subject to changes over the years. We suspect that the admission criteria in this Chinese institution may have been less rigid than those in the United States – but no concrete data are available to the writers of this review to confirm such presuppositions. Third, there are methodological limitations as regards the interpretation of case definitions in specific categories. The authors state that the diagnosis of atherosclerosis (AS) required at least one risk factor for AS (hypertension, diabetes, hyperlipidemia, age > 40 years, or long‐term smoking); however, hypertension itself was the underlying reason to conduct the study! Moreover, this would further imply that creating the diagnostic category of atherosclerotic RAS under these circumstances had the potential for false categorization that, in turn, would explain the striking differences in subcohort characteritics in Table 1's demographic data. The Method section is also perplexing and confusing as it states that patients were enrolled with a stage II or III hypertension without taking antihypertensive drugs, whereas in demographic Table 1,1 it is stated that the patients were on 2.0‐2.3 antihypertensive drugs. If patients were started thereafter on antihypertensive medications, inpatient or otherwise, this should be clarified by the authors. Fourth, during the nearly 2 decades the study was conducted, we witnessed the remarkable technological migration from renal angiogram to multiscanner CT, which, despite reporting the number of patients scanned with each method, may limit interpretation and comparability across the years. It is worth noting that several valuable specific diagnostic methods to assess functionality of an observed stenosis were not used in the present study. For instance, visceral and renal Doppler ultrasonography3 as well as angiotensin converting enzyme scans4 may both provide insights about the functional nature of a RAS, more so in unilateral lesions. In contrast to previous large‐scale studies that viewed stenosis > 60%‐70% as hemodynamically significant, the present study considers stenosis diagnosis at > 50%. It is unclear whether the authors meant that 50% is the minimal value to diagnose, whereas > 60%‐70% is the value necessitating intervention. Objectively, unifying the diagnostic criteria in this matter is essential.

Last, but not least, in the study of Xiong and coauthors,1 there are no data on subsequent interventions and outcomes of interventions for these patients with RAS. Acknowledging the heterogeneity of the underlying diagnoses, it would be interesting to see outcome data from this cohort, including the intervention pursued and long‐term outcomes in the FMD, TA, and AS subcohorts over the years.

Notwithstanding these limitations, this current paper by Xiong and colleagues1 suggests that the prevalence of atherosclerotic RAS has progressively increased in older Chinese subjects because of the Westernization of their diets as well as the advances of diagnostic and therapeutic modalities and it is now similar to the prevalence in Western countries, 82.4% in Chinese versus 60% to 90% in Western populations.5 Proportionally, the prevalence of FMD is lower in China compared to that of the West.6 As noted by the authors, the indications for hospitalization, angiography, and percutaneous renal angioplasty have changed over time, probably because of the emergence of studies not favoring intervention over medical treatment for this disease. The STAR study7 demonstrated that stent placement with medical treatment had no clear effect on the progression of impaired renal function but led to a small number of significant procedure‐related complications. The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL)8 study showed no difference between endovascular therapy and “best medical therapy’ other than a minor reduction in antihypertensive medications after revascularization. Regarding renal function, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial9 reported no benefit from endovascular therapy over optimal medical therapy. This has led to a probable reverse trend, with a constantly diminishing number of patients being investigated for renovascular hypertension and a subsequent reduction of atherosclerotic RAS rates in recent years. It is worth mentioning that the ASTRAL and CORAL studies were published during the present study period, which may have led to an additional potential confounding factor for this study. Undoubtedly, the shifting paradigm of what constitutes best effective medical therapy–aggressive incorporation of statin therapy, antiplatelet agents and the ever‐expanding armamentarium of antihypertensive drug therapy – has redefined what effective medical therapy means in contrast to the 80s or early 90s. Most recently, the 2017 ESC Guidelines 5 on the Diagnosis and Treatment of Peripheral Arterial Diseases made a recommendation against routine revascularization in RAS secondary to atherosclerosis. Moreover, recent subgroup analyses have shown that neither baseline blood pressure nor lesion gradient can predict improved outcome after stent intervention.10 However, patients with albuminuria have benefitted from stent intervention.10 These findings may still have an impact on remodifying the upcoming guidelines regarding intervention and consequently increase the number of RAS‐diagnosed subjects in the coming years. Another review by Mohan and colleagues11 demonstrates the current evidence supporting intervention for specific patients including those with a RAS value of > 80% with a significant translesional pressure gradient; difficult‐to‐control blood pressure with more than 3 antihypertensives, especially in younger patients; those with truncal rather than ostial stenosis; patients with a rapid deterioration of renal function; flash pulmonary edema; and posttransplant RAS. This variation in results indeed affects clinicians’ decisions and adds more confusion. All of us can testify to clinical scenarios where there was no doubt left regarding the functional significance of RAS and we all witnessed dramatic improvements ofblood pressure, edemas, and renal function after relieving the stenosis.

Looking beyond AS disease, some of the study's findings do seem to reflect well‐established facts, whereas others are more perplexing. In women under age 40, FMD and TA are the predominant causes of RAS. FMD remains very rare over age 40 but has had a remarkable stability over the years, presumably serving as an “internal control” for the process, despite the dramatic escalation of study subjects (~100/y at the start to 1000‐1500/y in the last years). Somewhat hidden in the paper is, however, a remarkable decline of TA diagnoses in women over age 40 (Figure 4C).1 Why TA is declining in subjects > 40 in this cohort so drastically is in fact unknown. Although earlier outpatient diagnoses are most certainly playing a role in the phenomenon, it is tempting to speculate that the penetration of newer disease modifier agents for autoimmune diseases may have the “collateral benefit” to virtually eliminate TA in the referral population.

In summary, even if we acknowledge the bias in referrals and changes in diagnostic criteria, in the last 2 decades the underlying etiology of RAS in China has shifted to a pattern similar to that of Western societies. Lifestyle changes, time, and indications for diagnostic techniques are likely major drivers of these changes. However, at present time, a physician‐based subjective decision remains a grey zone in this area, affecting the number of captured patients and potentially long‐term outcome.

AUTHORS’ CONTRIBUTION

Karim M. Soliman, MD: initial draft of manuscript and literature review. Sohail Abdul Salim, MD: manuscript revision, clinical correlations. Tibor Fülöp, MD, PhD: senior author, manuscript development and revisions, literature review, correspondence.