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EditorialEditorial

The “Renocentric Theory” of Renal Resistive Index: Is It Time for a Copernican Revolution?

GIULIO GERACI, ALESSANDRA SORCE and GIUSEPPE MULÈ
The Journal of Rheumatology April 2020, 47 (4) 486-489; DOI: https://doi.org/10.3899/jrheum.190930
GIULIO GERACI
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Unit of Nephrology and Hypertension, European Society of Hypertension Excellence Centre, University of Palermo, Palermo, Italy.
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  • For correspondence: giulio.geraci@unipa.it
ALESSANDRA SORCE
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Unit of Nephrology and Hypertension, European Society of Hypertension Excellence Centre, University of Palermo, Palermo, Italy.
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GIUSEPPE MULÈ
Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Unit of Nephrology and Hypertension, European Society of Hypertension Excellence Centre, University of Palermo, Palermo, Italy.
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Ultrasound (US) with duplex Doppler scanning has spread to the capillary level, becoming an irreplaceable tool in daily clinical practice thanks to its characteristics: low cost, repeatability, and noninvasiveness. Moreover, US has become over time more sensitive and accurate; it can be considered an extension of the clinician’s hand. For this reason, it currently represents the ideal tool for first-level diagnostic use in several fields, and is the simplest and most flexible instrument for obtaining morphological and functional information on different organs, including the kidneys.

In this issue of The Journal, Gigante, et al1 propose to assess renal involvement in patients with systemic sclerosis (SSc) through the evaluation of both structural and hemodynamic US measurements, paying particular attention to the Doppler-measured renal resistive index (RRI) and its clinical significance.

This index has a relatively recent history and an unfortunate name: resistance index (or resistive index). It was initially proposed by Gosling and King2 and Pourcelot3 in 1974 to identify the renal vascular diseases through the noninvasive measurement of intrarenal hemodynamics indirectly related to changes in arteriolar resistance. For a long time, the role of RRI has remained confined to renal damage, and it has been used as an important marker to predict the progression of renal function in patients with chronic kidney disease (CKD), diabetes mellitus, or hypertension (HTN). Its prognostic value has been studied only in the context of purely kidney diseases, with inconsistent results4.

Over the years many authors have tried to find a correct interpretation of the RRI, and several studies have shown that it was minimally affected by intrarenal resistance: unexpectedly, the correlation between RRI values and changes in renal vascular impedance proved to be weak. Through in vitro studies, Tublin, et al observed that the RRI was dependent on vascular compliance rather than on intrarenal vascular resistance. It became less and less dependent on resistance as compliance decreased, and it was completely independent of vascular resistance when compliance was zero5. The same authors subsequently tried to assess the effect of acute changes in both renal vascular resistance (RVR) and pulse pressure on RRI measured by Doppler US in rabbit kidneys. Interestingly, when RVR increased 5-fold because of phenylephrine hydrochloride, the RRI changed only slightly, whereas the latter showed a stronger relationship with pulse pressure5. Unlike the common opinion based on theoretic considerations, the RRI was not effectively influenced by changes in intrarenal vascular impedance, and this revealed the need to reconsider the real role of RRI and to clarify the possible mechanisms underlying its modifications.

Based on this pioneering demonstration that the RRI is influenced by upstream factors rather than by merely intrarenal conditions, particular attention was subsequently paid by many authors to the possible relationship between RRI and markers of systemic vascular damage regardless of renal function or kidney impairment. Moreover, the growing interest of the scientific community in new potential markers associated with cardiovascular (CV) risk has put the RRI in a new role, similar to that assumed by other markers that are traditionally useful tools for CV risk stratification such as pulse wave velocity (PWV), carotid intima-media thickness, or albuminuria. This point of view is clear from the provocative way that Heine, et al entitled their article (2007): “Do Ultrasound Renal Resistance Indices Reflect Systemic Rather Than Renal Vascular Damage in Chronic Kidney Disease?”6.

Several studies demonstrated a close link between RRI and PWV, a well-known risk factor strongly associated with CV morbidity and mortality and which represents a measure of arterial stiffness as well as an indirect expression of the elastic properties of the aorta. In 264 hypertensive patients with or without CKD, our research group demonstrated a significant positive relationship between the RRI and PWV regardless of renal function, and this close association remained statistically significant even after correction for various potentially confounding factors including glomerular filtration rate (GFR) and albuminuria7.

This link can be easily understood if we consider the pathophysiology of hemodynamics and the physical factors that regulate it. The combined heart-arteries system can be compared to the “Windkessel model,” according to which hemodynamic changes are caused by modifications of peripheral resistance or arterial distensibility: when peripheral resistance increases, the average pressure as well as both systolic and diastolic pressure increase, whereas the average pressure remains substantially unchanged when the arterial distensibility is reduced, despite an increase of pulsatile component with subsequent effect on pressure oscillations and pulsatory pressure. Increased arterial stiffness might therefore predispose the renal circulation to a greater hemodynamic burden (pulse more than mean arterial pressure), leading to higher RRI, itself an expression of renal pulsatile flow7. As suggested by Hashimoto and Ito, the connection between aortic stiffening and coexisting alterations in renal hemodynamics could be mainly imputed to the increase in aortic pulse pressure8. Moreover, it would be the pulsatile component of the pressure wave rather than the “static” one to stimulate the myogenic response of the glomerular afferent arterioles, thus causing an increase in renal vascular resistance7.

Similarly, other markers of subclinical vascular damage also proved to be correlated with RRI, in particular carotid IMT, which represents an expression of atherosclerotic carotid disease and has already shown a close connection to systemic atherosclerosis and CV events. Many authors showed that carotid IMT was associated with renal hemodynamics in different populations9,10, and our group demonstrated a strong association between RRI and severity of carotid atherosclerosis in subjects with or without CKD11,12, thus strengthening the concept that RRI can be considered a marker of systemic vascular damage regardless of renal impairment. Moreover, increased RRI might reflect in situ structural damage of intrarenal vessels, conceivably mirroring systemic structural vascular changes. According to this hypothesis, histological studies conducted by Ikee, et al13 showed that patients with higher RRI had hyaline changes, intimal thickening, and increased intima/media ratio of renal small arteries regardless of renal function, and other authors obtained similar results. Ikee, et al in their above-mentioned studies also reported a positive correlation between renal histopathologic findings of inflammation and RRI modification in patients with CKD13: the inflammatory state might determine endothelial dysfunction and it could promote development of atherosclerotic lesions and changes in endothelium-related regulation of intrarenal vessel motility. Similarly, the link between RRI and oxidative stress14, an essential protagonist in the pathogenesis of atherosclerosis as well as in rheumatologic and CV diseases, could help to explain the association between renal hemodynamics and albuminuria, even in subjects with normal function. This correlation between micro- and macrovascular damage suggests the presence of a mechanism of dynamic integration between large arterial vessels and renal function, of which RRI is an important crossroads15.

The transplanted kidney represents an excellent “human model” with which to understand the overall role of RRI as an expression of extrarenal vascular damage. In renal allograft recipients, Heine, et al16 demonstrated that elevated resistance indices were associated with CV risk factors and with markers of systemic atherosclerotic disease in the recipient, but they were not independently associated with donor transplant function. Moreover, pathological characteristics (rejection) of the transplanted kidney did not always correlate with changes in RRI. Extrarenal upstream factors seemed to have a major effect on determining RRI, and the same authors suggested that RRI should not be considered specific markers of renal damage in transplant patients16.

In line with these findings, the RRI proved to correlate with CV and overall mortality and to have a powerful prognostic value not only in patients with CKD or transplants17, but also in subjects with normal renal function regardless of the CV risk category of the study population. In 426 essential hypertensive subjects, Doi, et al demonstrated that increased RRI was associated with an enhanced risk of CV and renal outcomes regardless of kidney function, and the combination of high RRI and low GFR exponentially and independently increased the risk of unfavorable events18. Other authors obtained similar results in different study populations, coming to overlapping conclusions19,20.

Although most of these studies have been conducted mainly on populations with a traditionally recognized CV risk (HTN, diabetes, CKD, coronary artery disease), some authors have examined the role of RRI in different rheumatological diseases, stressing its role as a marker of renal damage and as a prognostic predictor of renal dysfunction. In 121 patients with SSc, Rosato, et al21 observed an inverse association between GFR and RRI. Higher RRI values were found by Aikimbaev, et al22 in progressive SSc patients with renal involvement compared to those without renal manifestations. Similarly, in patients with lupus nephritis, RRI was correlated with renal cortical fibrosis and other renal histologic findings23. However, systemic vascular damage was not evaluated in any of the above-mentioned studies, and it is well known that subclinical vascular changes are greater and more frequent in patients with renal impairment than in subjects with normal renal function. Moreover, renal damage can be an expression of systemic disease activity of rheumatological diseases, which often recognize an inflammatory pathogenesis and are associated per se with widespread vascular damage and increased CV risk. In line with this, several studies demonstrated that patients with SSc had early structural and functional changes of atherosclerosis24 as well as increased arterial stiffness25, even in the absence of kidney damage. Similarly, it is widely known that patients with systemic lupus erythematosus (SLE) have more extensive vascular damage than healthy subjects26.

It is therefore conceivable that increased RRI could be due to the vascular changes associated with systemic inflammation or with renal dysfunction rather than to the renal involvement per se. According to this hypothesis, in patients with SLE our group demonstrated that RRI was independently associated with IMT and aortic PWV also after adjustment for GFR, whereas SLE patients with normal IMT and PWV had RRI similar to healthy subjects27. Moreover, the evidence that RRI increased with progression of capillaroscopic damage and with presence of digital ulcers in subjects with SSc could represent further evidence of the systemic role of RRI21.

As with other pathologic conditions, the “renocentric theory” of the RRI should therefore be dismissed when approaching rheumatologic disease, and it is desirable that RRI finds a broader use in clinical practice as an expression of systemic damage as well as a potential predictor of CV and overall mortality.

Footnotes

  • See SSc renal parenchymal thickness, page 567

REFERENCES

  1. 1.↵
    1. Gigante A,
    2. Barbano B,
    3. Gasperini ML,
    4. Zingaretti V,
    5. Cianci R,
    6. Rosato E
    . Renal parenchymal thickness in scleroderma patients is related to intrarenal haemodynamic parameters and Raynaud’s renal phenomenon. J Rheumatol 2020;47:567–71.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Gosling RG,
    2. King DH
    . Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med 1974;67(6 Pt 1):447–9.
    OpenUrlPubMed
  3. 3.↵
    1. Pourcelot L
    . [Clinical applications of transcutaneous Doppler examination]. [Article in French] Les Colloques de l’Institut National de la Sante et de la Recherche Medicine, vol. 34. Paris: INSERM; 1974:213–40.
  4. 4.↵
    1. Mule G,
    2. Geraci G,
    3. Geraci C,
    4. Morreale M,
    5. Cottone S
    . The renal resistive index: is it a misnomer? Intern Emerg Med 2015;10:889–91.
    OpenUrl
  5. 5.↵
    1. Tublin ME,
    2. Bude RO,
    3. Platt JF
    . Review. The resistive index in renal Doppler sonography: where do we stand? AJR Am J Roentgenol 2003;180:885–92.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Heine GH,
    2. Reichart B,
    3. Ulrich C,
    4. Köhler H,
    5. Girndt M
    . Do ultrasound renal resistance indices reflect systemic rather than renal vascular damage in chronic kidney disease? Nephrol Dial Transplant 2007;22:163–70.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Geraci G,
    2. Mule G,
    3. Geraci C,
    4. Mogavero M,
    5. D’Ignoto F,
    6. Morreale M,
    7. et al.
    Association of renal resistive index with aortic pulse wave velocity in hypertensive patients. Eur J Prev Cardiol 2015;22:415–22.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Hashimoto J,
    2. Ito S
    . Central pulse pressure and aortic stiffness determine renal hemodynamics: pathophysiological implication for micro-albuminuria in hypertension. Hypertension 2011;58:839–46.
    OpenUrlCrossRef
  9. 9.↵
    1. Kawai T,
    2. Kamide K,
    3. Onishi M,
    4. Yamamoto-Hanasaki H,
    5. Baba Y,
    6. Hongyo K,
    7. et al.
    Usefulness of the resistive index in renal Doppler ultrasonography as an indicator of vascular damage in patients with risks of atherosclerosis. Nephrol Dial Transplant 2011;26:3256–62.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Geraci G,
    2. Mulè G,
    3. Paladino G,
    4. Zammuto MM,
    5. Castiglia A,
    6. Scaduto E,
    7. et al.
    Relationship between kidney findings and systemic vascular damage in elderly hypertensive patients without overt cardiovascular disease. J Clin Hypertens 2017;19:1339–47.
    OpenUrl
  11. 11.↵
    1. Geraci G,
    2. Mule G,
    3. Mogavero M,
    4. Geraci C,
    5. D’Ignoti D,
    6. Guglielmo C,
    7. et al.
    Renal haemodynamics and severity of carotid atherosclerosis in hypertensive patients with and without impaired renal function. Nutr Metab Cardiovasc Dis 2015;25:160–6.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Geraci G,
    2. Mule G,
    3. Costanza G,
    4. Mogavero M,
    5. Geraci C,
    6. Cottone S
    . Relationship between carotid atherosclerosis and pulse pressure with renal hemodynamics in hypertensive patients. Am J Hypertens 2016;29:519–27.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Ikee R,
    2. Kobayashi S,
    3. Hemmi N,
    4. Imakiire T,
    5. Kikuchi Y,
    6. Moriya H,
    7. et al.
    Correlation between the resistive index by Doppler ultrasound and kidney function and histology. Am J Kidney Dis 2005;46:603–9.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Raff U,
    2. Schwarz TK,
    3. Schmidt BM,
    4. Schneider MP,
    5. Schmieder RE
    . Renal resistive index—a valid tool to assess renal endothelial function in humans? Nephrol Dial Transplant 2010;25:1869–74.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Safar ME,
    2. Rizzoni D,
    3. Blacher J,
    4. Muiesan ML,
    5. Agabiti-Rosei E
    . Macro and microvasculature in hypertension: therapeutic aspects. J Hum Hypertens 2008;22:590–5.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Heine GH,
    2. Gerhart MK,
    3. Ulrich C,
    4. Köhler H,
    5. Girndt M
    . Renal Doppler resistance indices are associated with systemic atherosclerosis in kidney transplant recipients. Kidney Int 2005;68:878–85.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Toledo C,
    2. Thomas G,
    3. Schold JD,
    4. Arrigain S,
    5. Gornik HL,
    6. Nally JV,
    7. et al.
    Renal resistive index and mortality in chronic kidney disease. Hypertension 2015;66:382–8.
    OpenUrl
  18. 18.↵
    1. Doi Y,
    2. Iwashima Y,
    3. Yoshihara F,
    4. Kamide K,
    5. Hayashi S,
    6. Kubota Y,
    7. et al.
    Renal resistive index and cardiovascular and renal outcomes in essential hypertension. Hypertension 2012;60:770–7.
    OpenUrlCrossRef
  19. 19.↵
    1. Ennezat PV,
    2. Maréchaux S,
    3. Six-Carpentier M,
    4. Pinçon C,
    5. Sediri I,
    6. Delsart P,
    7. et al.
    Renal resistance index and its prognostic significance in patients with heart failure with preserved ejection fraction. Nephrol Dial Transplant 2011;26:3908–13.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Pearce JD,
    2. Craven TE,
    3. Edwards MS,
    4. Corriere MA,
    5. Crutchley TA,
    6. Fleming SH,
    7. et al.
    Associations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study. Am J Kidney Dis 2010;55:281–90.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Rosato E,
    2. Gigante A,
    3. Barbano B,
    4. Gasperini ML,
    5. Cianci R,
    6. Muscaritoli M
    . Prognostic factors of renal involvement in systemic sclerosis. Kidney Blood Press Res 2018;43:682–9.
    OpenUrl
  22. 22.↵
    1. Aikimbaev KS,
    2. Canataroğlu A,
    3. Ozbek S,
    4. Usal A
    . Renal vascular resistance in progressive systemic sclerosis: evaluation with duplex Doppler ultrasound. Angiology 2001;52:697–701.
    OpenUrlPubMed
  23. 23.↵
    1. Gao J,
    2. Chevalier J,
    3. Auh YH,
    4. Rubin JM,
    5. Wang H,
    6. Sun LN,
    7. et al.
    Correlation between Doppler parameters and renal cortical fibrosis in lupus nephritis: a preliminary observation. Ultrasound Med Biol 2013;39:275–82.
    OpenUrl
  24. 24.↵
    1. Meiszterics Z,
    2. Tímár O,
    3. Gaszner B,
    4. Faludi R,
    5. Kehl D,
    6. Czirják L,
    7. et al.
    Early morphologic and functional changes of atherosclerosis in systemic sclerosis-a systematic review and meta-analysis. Rheumatology 2016;55:2119–30.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Timár O,
    2. Soltesz P,
    3. Szamosi S,
    4. Dér H,
    5. Szántó S,
    6. Szekanecz Z,
    7. et al.
    Increased arterial stiffness as the marker of vascular involvement in systemic sclerosis. J Rheumatol 2008;35:1329–33.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Cacciapaglia F,
    2. Zardi EM,
    3. Coppolino G,
    4. Buzzulini F,
    5. Margiotta D,
    6. Arcarese L,
    7. et al.
    Stiffness parameters, intima-media thickness and early atherosclerosis in systemic lupus erythematosus patients. Lupus 2009;18:249–56.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Morreale M,
    2. Mulè G,
    3. Ferrante A,
    4. D’ignoto F,
    5. Cottone S
    . Association of renal resistive index with markers of extrarenal vascular changes in patients with systemic lupus erythematosus. Ultrasound Med Biol 2016;42:1103–10.
    OpenUrl
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The “Renocentric Theory” of Renal Resistive Index: Is It Time for a Copernican Revolution?
GIULIO GERACI, ALESSANDRA SORCE, GIUSEPPE MULÈ
The Journal of Rheumatology Apr 2020, 47 (4) 486-489; DOI: 10.3899/jrheum.190930

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The “Renocentric Theory” of Renal Resistive Index: Is It Time for a Copernican Revolution?
GIULIO GERACI, ALESSANDRA SORCE, GIUSEPPE MULÈ
The Journal of Rheumatology Apr 2020, 47 (4) 486-489; DOI: 10.3899/jrheum.190930
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