Renal resistive index for renovascular hypertension: In the quest of the Holy Grail

Arterial hypertension represents a major public health problem that affects more than 1 billion individuals worldwide, and the number significantly increased with the new more aggressive definition (systolic blood pressure [BP] >130 mm Hg) by the American Heart Association.1 A specific cause of BP elevation cannot be identified in the majority of patients (essential hypertension), while secondary causes can be identified in 5% to 15%, forming the group of secondary hypertension. Until now, more than 50 causes of secondary hypertension have been reported with various incidence. The combination of the increased prevalence of arterial hypertension in the general population and the subsequent huge absolute number of patients along with the large number of secondary causes from a variety of systems and organs renders ideal screening tests as the “Holy Grail” of appropriate management of patients with arterial hypertension.

Renovascular hypertension has been traditionally considered the most common cause of secondary hypertension. The advent of renal artery angioplasty for the successful opening of the occluded renal artery made renovascular hypertension a popular research topic during the last 2 to 3 decades of the 20th century. However, two factors have dampened scientific enthusiasm: (1) the failure of renal artery angioplasty to prove its superiority over drug therapy in several randomized controlled clinical trials,2, 3, 4, 5 and (2) the lack of a screening test that would accurately discriminate renovascular hypertension from anatomical renal artery stenosis and predict the BP response to angioplasty.

However, several significant aspects are emerging with a closer look at the abovementioned data. In the DRASTIC (Dutch Renal Artery Stenosis Intervention Cooperative) study,2 22 of 50 participants in a pharmacotherapy subgroup underwent renal artery angioplasty, and eight occlusion events of affected artery were identified in the same group compared with none in the angioplasty group. In the STAR (Stent Placement for Atherosclerotic Renal Artery Stenosis and Impaired Renal Function) trial,3 renal artery stenosis (RAS) was initially evaluated with Doppler, thus the level of stenosis was overestimated. Indeed, it was observed that patients with a stenosis of <50% (1 of 3 participants had a stenosis of 50%–70%) were included in the intervention group, and consequently did not undergo angioplasty, but they were included in the analysis (intention‐to‐treat design). In the ASTRAL (Angioplasty and Stent for Renal Artery Lesions) trial,4 investigators could exclude a candidate from the pharmacotherapy subgroup if they believed that angioplasty could lead to greater benefits, featuring a potent selection bias. In total, 40% of patients had a RAS <70% and 25% an estimated glomerular filtration rate ≥50 mL/min per 1.73 m². On the other hand, the small kidney size (6 cm) of some participants suggests an advanced and irreversible renal injury that questions whether any therapeutic approach could have resulted in clinically significant benefits. Similarly, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study5 included individuals with unilateral RAS and in some cases a renal size of 7 cm. Inclusion criteria and the diagnostic procedure were changed during the study. Altogether, significant concerns about the design and population selection of the aforementioned studies have been expressed, magnifying the necessity of an appropriate selection of the diagnostic procedure to identify the presence, localization, and magnitude of RAS. Therefore, despite the negative findings of randomized controlled trials, pitfalls in study design cannot exclude benefits with angioplasty in a carefully selected group of patients. The American Heart Association recommends the consideration of angioplasty in patients with refractory hypertension, worsening renal function, and intractable heart failure, for whom medical management has failed.1

Despite the uncertainty in the angioplasty reclamation of RAS, the early detection of the disease and implementation of an appropriate therapy are of paramount clinical importance. RAS could range from an isolated anatomical abnormality to more significant hemodynamic, structural, and functional consequences such as renovascular hypertension and ischemic nephropathy.6, 7 Both atherosclerotic renovascular disease and renal fibromuscular dysplasia are associated with increased risk of atherosclerotic disease, resistant hypertension, renal impairment, and end‐stage renal disease, as well flash pulmonary edema.1, 8, 9, 10, 11, 12, 13 Atherosclerotic RAS, which presents the most common cause of renal artery narrowing (approximately 90%), becomes more prevalent with aging and cardiovascular comorbidities, and a wide cluster of pathogenetic mechanisms are responsible for the high BP levels seen with this deterioration.9

Currently, there are several examinations in the physician's armamentarium to detect RAS among patients with clinical suspicion of this disorder, including peripheral renin and B‐type natriuretic peptide levels, renal vein renin sampling, Doppler ultrasonography, magnetic resonance angiography (MRA), helical computed tomographic angiography, renal scintigraphy (captopril scan), and invasive renal angiography, with the latter considered the “gold standard.”8, 9 However, the diagnostic procedure needs to be well structured to address the following aspects: (1) patient comorbidities, (2) localization of stenosis, (3) proportion of narrowing of the affected artery, (4) detection of hemodynamic and anatomic severity, (5) functional and cellular consequences, (6) detection of viable renal tissue, (7) consideration of the progression of RAS over the time, and (8) selection of the optimal therapeutic strategy. The use of plasma renin levels, renal vein renin sampling, and captopril scan is restricted because of the low sensitivity and specificity of such examinations (even if a suppressed plasma renin activity <1 ngAI/mL per h suggests a low probability of RAS).7, 8, 9 Computed tomographic angiography and MRA are noninvasive methods that provide information about renal vasculature and aorta, allowing the assessment of multiple vessels, renal size, and anatomic properties. Nevertheless, these methods are unable to provide functional information and evaluate pressure and renal flow distally to RAS. Doppler ultrasound is an inexpensive, widely feasible method that unveils significant data on hemodynamic and structural alterations. This method does not provide an accurate assessment of renal function and is highly operator dependent, but is characterized by high specificity when conducted by expert radiologists. Intra‐renal digital subtraction angiography aims to confirm the diagnosis of RAS, evaluate the extent of disease, and distinguish aneurysmal or occlusive disease. It offers the highest probability of anatomically visualizing main and/or branch arterial stenosis. Importantly, hemodynamic significance can be directly measured and simultaneously treated with this method. However, similar to conventional catheter angiography, this method carries the risk of an invasive procedure, while it is expensive and inconvenient for patients.

Given the significant disparities between the diagnostic methods of RAS detection, Eklöf and colleagues14 conducted a prospective comparison of Doppler ultrasound, captopril scan, MRA, and computed tomographic angiography in the diagnosis of RAS among 58 patients with hypertension who had clinical suspicion of the disease. RAS observed in 45 participants, as well sensitivity and specificity of captopril scan, Duplex ultrasonography, MRA, and computed tomographic angiography on identifying kidneys with RAS was 52/63%, 73/71%, 93/91%, and 94/62%, respectively. It was concluded that Doppler ultrasound is better than renal scintigraphy in the diagnosis of hemodynamic significant RAS (P = .013), but both methods are inferior to MRA and computed tomographic angiography (P < .001).

In the current issue of the Journal, Grupp and colleagues15 conducted a prospective study of 205 consecutive patients who were referred for secondary hypertension screening to evaluate the diagnostic utility of the difference between the resistive indices (RIs) assessed in renal and splenic arteries in RAS detection. In total, 181 participants free of RAS and 24 patients (47 kidneys) with the disease underwent Duplex ultrasonography (patients with RAS were further assessed angiographically). In 181 patients without RAS, both kidney and spleen RI featured an age‐dependent pattern, but remained parallel in the whole age spectrum for both organs, thus suggesting that the between‐organ difference in RI (ΔRI_k−s) should be independent of age. In addition, the RI of the kidney was consistently higher than the spleen, and the median ΔRI_k−s was 0.055 among participants free of RAS. In the RAS subgroup of patients, a significantly lower ΔRI_k−s was noted in the affected kidney (median: −0.05; P < .002) compared with nonstenotic renal arteries (median: 0.068); the latter did not significantly differ from ΔRI_k−s in the group of patients without RAS. Of great importance, the receiver operating characteristic curve of ΔRI_k−s revealed values ≤0.03 as indicative of RAS, resulting in sensitivity/specificity of 93.3/81.2% and a positive and negative predictive value of 70% and 96.2%, respectively.

Grupp and colleagues15 conducted a clinically important and meaningful study, evaluating an innovative hypothesis. The outcomes suggest that ΔRI_k−s adds a greater diagnostic accuracy in Doppler ultrasonography for the detection of RAS. More specific, the addition of splenic RI that is easily calculated via ultrasound leads to a more accurate predictive value in detecting RAS compared with the traditionally used indexes (difference in RI between both kidneys, peak systolic velocity), as well as in identifying bilateral RAS and RAS in some cases in which a kidney is not sonographically well assessed. These findings, if confirmed in larger groups of patients, could strengthen the role of Doppler ultrasound in the evaluation of RAS and offer a feasible diagnostic method with wide application in everyday clinical practice. The outcomes are limited by the small study sample of participants (especially for bilateral RAS). However, the well‐designed and ‐conducted Doppler ultrasound protocol, the confirmation of RAS using intra‐renal digital subtraction angiography, and the punctilious exclusion of causes that affect both renal and splenic RI are significant strengths of the trial.

Renovascular hypertension is a major cause of secondary hypertension. Thus far, data in this field has remained inconclusive and presents significant limitations. The amelioration of a diagnostic procedure, the calculation of RAS severity, and the recognition of certain subgroups in which renal angioplasty could lead to greater benefits such as patients with adequate viable renal tissue,16, 17 bilateral RAS, or RAS >75% are crucial aspects that need to be addressed in future, large, randomized controlled trials.

CONFLICT OF INTEREST

The authors report no specific funding in relation to this research and have no conflicts of interest to disclose.

Stavropoulos K, Imprialos KP, Athyros VG, Doumas M. Renal resistive index for renovascular hypertension: in the quest of the Holy Grail. J Clin Hypertens. 2018;20:589–591. 10.1111/jch.13221