Can we predict outcome by noninvasive assessment of renal haemodynamics in hypertension? The role of renal resistive index

Early abnormalities in renal haemodynamics, namely an increased afferent arteriolar resistance, have been traditionally regarded as a marker of more severe hypertension status and subclinical target organ damage. Although a large body of evidence has been accumulated over the years on this topic in the experimental animal setting, data in humans have been more difficult to be collected because of the relatively cumbersome and invasive techniques used to assess renal haemodynamics in clinical studies. More recently, the possibility to obtain functional and structural information on the renal vasculature by means of noninvasive ultrasonographic Doppler assessment has spurred a growing interest in this area. In particular, blood flow abnormalities detected by analysis of intraparenchymal arterial Doppler waveform, that is the so-called renal resistive index (RRI), have been associated with the occurrence of cardiovascular and renal events [1,2]. The RRI can easily be calculated by the ratio of the difference between maximum and minimum (end-diastolic) flow velocity to maximum flow velocity: RRI = (maximum velocity − minimum velocity)/maximum velocity and may theoretically range from 0 to 1. Three to five reproducible waveforms have to be obtained at interlobar or arcuate arteries in three different renal sites, and RRI values from these waveforms are averaged to compute the mean RRI for each kidney [1,2]. In healthy patients, RRI have been shown to vary from 0.58 ± 0.05 (mean ± SD) to 0.64 ± 0.04, and a value lower than 0.7 has been traditionally taken to indicate normal impedance to renal blood flow, although a considerable heterogeneity has been reported [3]. As a matter of fact, the physiological mechanisms and clinical determinants of RRI are yet to be fully elucidated. Although RRI was initially proposed as an indicator of renal vascular resistance to blood flow, more recent studies suggest that vascular compliance plays a key role in shaping its values [1,2]. Using an electrical model simulating changes in vascular resistance, inductance, and compliance, a recent study helped us to clarify that intrarenal impedance to blood flow, and the RRI vary in response to changes in distal resistance with the same directionality. In contrast, impedance changed in the opposite direction to the RRI when the distal compliance, proximal compliance, or proximal resistance was modified. The stiffening of systemic vasculature triggers an increase in pulse pressure which, in turn, may lead to high RRI values. Additionally, heart rate can affect RRI because of changes in diastolic duration that affect end-diastolic velocity [2]. Besides vascular and haemodynamic factors, other variables such as ureteral obstruction and interstitial renal parenchymal damage may lead to an increase in RRI. As a matter of fact, clinical–pathological correlation studies in patients with chronic kidney disease and renal transplants have reported somewhat contrasting results [1,2]. Arteriolosclerosis and tubulo-interstitial nephropathies seem to be correlated to RRI, whereas glomerular lesions show a minor although significant role in affecting the RRI. These data have led to propose a novel biomarker which, by integrating ultrasonography-derived renal volume assessment and RRI, may prove a better indicator of intrarenal atherosclerosis as compared with RRI alone [4,5]. The renal volume to RRI ratio has proved to be a predictor of new onset diabetes in hypertensive patients, a finding that supports the well known pathogenetic link between renal dysfunction and insulin resistance [6]. The RRI has also been found to be increased in normotensive children with two hypertensive parents as compared with children with only one or no hypertensive parent. This feature has been taken to signal abnormal modulation of the renal vasculature in response to dietary induced variations in renin–angiotensin–aldosterone system activity and suggests that variation of RRI can develop very early in the history of pathophysiological renal adaptation. Accordingly, RRI was shown to decrease after adrenalectomy in patients with primary aldosteronism, and the initial RRI values were significantly associated with long-term postoperative blood pressures. More recently, Bruno and coworkers [7] showed that acutely induced modification in RRI, conceivably representing an index of renal vasodilating capacity, is already altered in newly diagnosed, untreated hypertensive patients and in type 2 diabetes mellitus patients without renal damage, and it represents a predictor of future microalbuminuria onset. Thus, RRI could indicate not only irreversible renal lesions such as arteriosclerosis and/or fibrosis of the tubular-interstitium but also reversible functional changes of the renal circulation. It is likely that both functional (sympathetic activation, autoregulation, and nitric oxide) and structural (arteriolosclerosis and tubulointerstitial damage) changes in renal arterial resistance can modulate RRI. Furthermore, the dependence on systemic vascular parameters justifies the incomplete correlation with renal histology but at the same time may account for the well known power of RRI as a predictor of clinical outcomes (Fig. 1).FIGURE 1: Schematic drawing illustrating the possible determinants of an increased renal resistive index and relationships with cardiovascular and renal events.Increased RRI values have been reported to be associated with early signs of subclinical target organ damage in primary hypertension, both at renal and extrarenal level. At the renal level, an increased RRI may signal a slight reduction in the glomerular filtration rate and/or the presence of microalbuminuria [8]. Moreover, an increased RRI has been found to be inversely related to renal volume, possibly a marker of hypertensive renal damage, in patients with high blood pressure values and normal renal function. At systemic level, high impedance to renal blood flow has been shown to cluster with the presence and severity of left ventricular hypertrophy and with early atherosclerotic carotid changes [4,9], and it has been shown to correlate with the presence of blood pressure load and vascular stiffness, namely higher ambulatory arterial stiffness index values [5]. The finding of increased RRI can therefore be taken as a sign of hypertensive and atherosclerotic involvement at the small vessel level, and unsurprisingly it has recently been shown to carry unfavourable prognostic value. The relationship between early abnormalities in renal haemodynamics and its clinical determinants, however, may be far from being completely elucidated as indicated by the elegant study by Buus and coworkers, appearing on the present issue of the Journal [10]. Building on previous findings that abnormally high renal resistance in off-spring of parents with hypertension may signal a long-term higher risk of hypertension development, the authors set out to assess whether 1-year treatment with a renin–angiotensin–aldosterone inhibitor prevents long-term increase in blood pressure values over a 10-year follow-up period. Although they found that transient reduction in blood pressure and afferent arteriolar resistance by angiotensin II receptor blockade did not prevent blood pressure values from increasing during a 10-year follow-up period, a clear relationship between increased renal vascular resistance and higher blood pressure values was confirmed both at baseline and follow-up, irrespective of drug treatment. Several studies on a variety of different chronic renal diseases have reported an independent prognostic value of an increased RRI. Thus, in a group of 137 patients with proteinuric chronic renal disease, Radermacher et al.[11] found that RRI values greater than 0.80 entailed a worse renal prognosis over a 5-year median follow-up period, independently of traditional renal risk factors such as baseline glomerular filtration rate and the degree of proteinuria. Similar findings have also been reported in patients with type 2 diabetes. Very recently, however, the systematic evaluation of RRI was found to be related to the risk of developing end stage renal disease over a 4-year follow-up in a cohort of 403 stage 2–4 chronic kidney disease patients, but its predictive power did not outperform that of a validated risk equation based on traditional renal risk factors [12]. Many, although not all, studies have reported that RRI is a predictor of future function worsening in transplanted kidneys. Although this biomarker is not useful to identify specific causes of transplant dysfunction, it may generally indicate vascular complications and the need for further investigation. Accordingly, a recent single-centre study showed that increased RRI was related to recipient age and central haemodynamic factors rather than to specific histophatologic changes, and it was also related to recipient survival rather than to graft survival [13]. In a study cohort of more than 800 elderly Americans from the Cardiovascular Health Study, Pearce et al.[14] found that abnormalities in renal parenchymal Doppler-derived parameters indicating increased intrarenal stiffness and impedance to blood flow were significantly related to increased cardiovascular morbidity and mortality over a median follow-up of 7 years, even after adjustment for several confounders such as renal function, hypertension, diabetes, and history of cardiovascular events. Furthermore, in a 3-year follow-up study on 426 patients with primary hypertension, Doi et al.[15] found that increased RRI was an independent predictor of worse cardiovascular and renal outcomes, especially when combined with reduced glomerular filtration rate. More recently, in a large prospective cohort of stage 3–4 chronic kidney patients without renal artery stenosis, Toledo et al.[16] reported that RRI of at least 0.70 is associated with higher mortality. Finally, an increased RRI may have important therapeutic implications in clinical practice. In fact, preliminary studies suggest that variations in RRI may go in parallel to those in urine albumin excretion under antihypertensive drug treatment. In fact, an increase in RRI may signal the presence of intrarenal stiffness and suggests caution in titrating renin–angiotensin–aldosterone system inhibitors, especially when added to diuretics, pending the risk of renal function worsening [1]. Despite its relatively low specificity in terms of clinical–pathological correlations and the still poorly understood pathogenesis, RRI has proved to be useful to gain diagnostic and prognostic insights into a variety of clinical conditions from renal vascular disease to chronic kidney and renal transplant and may be a complement to other variables in the stratification of global risk in clinical practice. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.