Academic Edi o : Ramón C. He mida
Recei ed: 31 Decembe 2024
Re ised: 19 Janua y 2025
Accep ed: 24 Janua y 2025
Published: 28 Janua y 2025
Ci a ion: Ca ollo, C.; Vadalà, M.;
So ce, A.; Sina a, N.; O lando, E.;
Ci a ici, E.; Bennici, M.; Polosa, R.;
Bon iglio, V.M.E.; Mulè, G.; e al.
Rela ionship Be ween Renal Resis i e
Index and Re inal Vascula Densi y in
Indi iduals wi h Hype ension.
Biomedicines 2025,13, 312. h ps://
doi.o g/10.3390/biomedicines
13020312
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Licensee MDPI, Basel, Swi ze land.
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A icle
Rela ionship Be ween Renal Resis i e Index and Re inal
Vascula Densi y in Indi iduals wi h Hype ension
Ca e ina Ca ollo 1,* , Ma ia Vadalà2, Alessand a So ce 1, Nicola Sina a 3, Emanuele O lando 4,
Emanuele Ci a ici 1, Mi iam Bennici 1, Ricca do Polosa 5, Vincenza Ma ia Elena Bon iglio 2, Giuseppe Mulè1
and Giulio Ge aci 5
1
Uni o Neph ology and Dialysis, Hype ension Excellence Cen e, Depa men o Heal h P omo ion, Mo he
and Child Ca e, In e nal Medicine and Medical Special ies (PROMISE), Uni e si y o Pale mo, 90133 Pale mo,
I aly; emanuele.ci a ici@communi y.unipa.i (E.C.); [email p o ec ed] (G.M.)
2Biomedicine, Neu oscience and Ad ance Diagnos ic (BIND) Depa men , Uni e si y o Pale mo,
90133 Pale mo, I aly; [email p o ec ed] (M.V.)
3UOSD Ne ologia e Dialisi, Ospedale Paolo Bo sellino, 91025 Ma sala, I aly; sina a.nicola@libe o.i
4Depa men o Heal h P omo ion, Mo he and Child Ca e, In e nal Medicine and Medical
Special ies (PROMISE), Uni e si y o Pale mo, 90133 Pale mo, I aly; [email p o ec ed]
5Depa men o Medicine and Su ge y, “Ko e” Uni e si y o Enna, 94100 Enna, I aly;
[email p o ec ed] (G.G.)
*Co espondence: ca e ina.ca [email p o ec ed]
Abs ac : Backg ound/Objec i es: Conside ing he physiological analogies be ween he
eye and he kidney, his s udy aimed o in es iga e he po en ial ela ionship be ween e i-
nal ascula densi y, assessed using Op ical Cohe ence Tomog aphy Angiog aphy (OCT-A),
and he enal esis i e index (RRI) in pa ien s wi h a e ial hype ension. Me hods: A o al
o 82 hype ensi e pa ien s (mean age 48
±
13) we e en olled in he s udy. Pa icipan s
unde wen ou ine biochemical e alua ions, o ice-based blood p essu e measu emen ,
24 h ambula o y blood p essu e moni o ing, OCT-A imaging, and enal Dopple ul a-
sound examina ions. Resul s: The mean RRI in he s udy popula ion was 0.616
±
0.06.
Pa icipan s we e di ided in o wo g oups based on he 75 h pe cen ile h eshold o he
RRI dis ibu ion (0.66, 95% CI 0.64–0.68). The g oup wi h RRI > 75 h pe cen ile, which
appea ed o ha e a highe numbe o smoke s, exhibi ed signi ican ly highe mean iglyc-
e ide and u ina y albumin exc e ion (UAE) le els and a signi ican ly educed es ima ed
glome ula il a ion a e (eGFR) as compa ed o he g oup wi h RRI < 75 h pe cen ile.
Among he hemodynamic pa ame e s, 24 h pulse p essu e (PP), day ime and nigh ime
PP, and nigh ime sys olic blood p essu e (SBP) we e signi ican ly highe in he g oup
wi h RRI > 75 h pe cen ile. Rega ding e inal ascula densi y indices, he only signi ican
di e ence was obse ed in he deep o eal ascula plexus, which displayed a educed
densi y in he g oup wi h RRI > 75 h pe cen ile. Logis ic eg ession analysis e ealed ha
RRI > 75 h pe cen ile was independen ly associa ed wi h inc eased nigh ime mean pulse
p essu e (OR = 1.13,
95% CI
: 1.049–1.221, p= 0.0014) and educed deep o eal ascula
densi y (OR =
−
0.5026, 95% CI: 1.0493–1.2211, p= 0.0044). Conclusions: Ou indings
demons a e ha ocula mic o ascula al e a ions a e associa ed wi h RRI, a ma ke wi h a
well-es ablished p ognos ic alue o enal disease p og ession and sys emic mac o ascula
dys unc ion. These esul s u he subs an ia e he close ela ionship be ween enal and
ocula mic oci cula ion.
Keywo ds: hype ension; mic oci cula ion; angio-OCT; enal esis i e index
Biomedicines 2025,13, 312 h ps://doi.o g/10.3390/biomedicines13020312
Biomedicines 2025,13, 312 2 o 13
1. In oduc ion
Sys emic hype ension signi ican ly impac s bo h he s uc u e and unc ion o he
mic o ascula sys em [
1
]. The de elopmen o mic o ascula damage, pa icula ly mi-
c o ascula a e ac ion, is belie ed o be a c ucial pa hological ea u e o hype ension.
Changes in he s uc u e and unc ion o he mic o ascula u e, in addi ion o being
linked o he de elopmen o hype ension by in luencing low esis ance and issue pe u-
sion, unde lie much o he o gan damage associa ed wi h a e ial hype ension and appea
o be c ucial o i s pa hogenesis and p og ession [2,3].
Since he eye and kidney sha e common de elopmen al, s uc u al, and pa hogenic
pa hways, changes in eye mic oci cula ion could he e o e be co ela ed wi h in a enal
hemodynamic damage, which has been associa ed wi h endo helial dys unc ion, subclinical
o gan damage, and ad e se ca dio ascula ou comes, and appea s o be a good indica o
o sys emic mo pho unc ional a e ial impai men , pa icula ly in hype ensi e indi iduals
wi h o wi hou no mal enal unc ion [2,4–7].
The ocula mic oci cula o y sys em is eadily accessible o clinical and mo phological
assessmen , allowing o epea ed and non-in asi e examina ion [
8
,
9
]. This p o ides a
unique oppo uni y o obse e he ascula ne wo k when impac ed by sys emic condi ions
like hype ension, diabe es melli us, and ch onic kidney disease (CKD). The in eg a ion o
op ical cohe ence omog aphy angiog aphy (OCTA) in o clinical p ac ice has in oduced a
dependable me hod o examining e inal and cho oidal ci cula ion om a mo phologi-
cal pe spec i e.
The e is a subs an ial body o e idence ha he a e ial s i ness p edic s u u e ca -
dio ascula and o al mo ali y isk in a ious pa ien popula ions, and clinical s udies
ha e associa ed i s ele a ion wi h he de elopmen o mac o ascula and mic o ascula
damage [10–12].
The enal esis i e index (RRI) is a sonog aphic measu e o he in a enal a e ies,
calcula ed as (peak sys olic eloci y—end-dias olic eloci y)/peak sys olic eloci y. RRI
measu emen is ela i ely simple, and Dopple ul asonog aphy is a non-in asi e, cos -
e ec i e, and apid imaging echnique ha p o ides eal- ime isualiza ion o blood low
wi hin he enal essels.
The RRI is a well-es ablished p ognos ic ma ke o bo h enal disease p og ession
and sys emic mac o ascula al e a ions [
13
–
15
]. Despi e he e idence o s ong p ognos ic
po en ial, he e is no uni e sal op imal cu -o alue o he RRI. Mos o he dedica ed
s udies epo a ange be ween 0.5 and 0.7 [16,17].
Since bo h enal and ocula mic oci cula ion a e in luenced by simila mechanisms o
hemodynamic and endo helial dys unc ion, we aimed o in es iga e whe he changes in
he enal esis i e index could be co ela ed wi h al e a ions in ocula mic oci cula ion.
Such a ela ionship could p o ide aluable insigh s in o he sys emic na u e o as-
cula diseases, whe e bo h he kidney and he eye may e lec sha ed pa hophysiological
mechanisms, o e ing po en ial o he ea ly diagnosis and moni o ing o ca dio ascula
and enal condi ions.
2. Ma e ials and Me hods
The popula ion o his s udy was selec ed om hype ensi e pa ien s a ending he
ESH Hype ension Excellence Cen e Ou pa ien clinic o ou Neph ology and Hype en-
sion Uni . En olmen was conduc ed in acco dance wi h he ollowing exclusion c i e ia:
•Age < 20 yea s o >70 yea s;
•Known diabe es o as ing glucose le els > 126 mg/dL;
•P egnancy;
Biomedicines 2025,13, 312 3 o 13
•
Sys emic o ocula diseases (e.g., glaucoma, u ei is, high myopia, macula degene a-
ion) o a his o y o ocula su ge ies po en ially causing e inal o cho oidal damage;
•
Neph opa enchymal, eno ascula , malignan , o endoc ine hype ension, o obs uc-
i e sleep apnea synd ome;
•
He edi a y o non-he edi a y kidney diseases, neph i ic synd ome, o o e p o ein-
u ia/hema u ia;
•
Es ima ed glome ula il a ion a e (eGFR) < 15 mL/min/1.73 m
2
o enal eplacemen
he apy ( ansplan o dialysis);
•
Rapid decline in enal unc ion, de ined as a >25% educ ion in eGFR o a >1.5- old
inc ease in se um c ea inine le els om baseline [18];
•
Poo -quali y ul asound imaging o abno mal enal mo phology, as p e iously de-
sc ibed [6];
•
His o y o clinical e idence o hea ailu e (NYHA class II–IV), co ona y a e y disease,
o ce eb o ascula disease;
•
Majo non-ca dio ascula condi ions (e.g., li e ci hosis, ch onic obs uc i e pul-
mona y disease, o a his o y o malignancies);
•
Condi ions in e e ing wi h eliable blood p essu e (BP) measu emen s using he oscil-
lome ic echnique, such as a ial ib illa ion, equen ec opic bea s, o second/ hi d-
deg ee a io en icula blocks.
Pa ien s wi h an a m ci cum e ence exceeding 32 cm we e no excluded. Ins ead,
app op ia ely sized cu s we e used o ensu e accu a e BP measu emen s.
The s udy p o ocol adhe ed o he p inciples o he Decla a ion o Helsinki, and w i en
in o med consen was ob ained om all pa icipan s.
2.1. S udy Design
A o al o 82 pa ien s wi h a e ial hype ension (mean age 48.78
±
12.61 yea s; 79%
male) we e en olled and unde wen he ollowing assessmen s:
•Rou ine biochemical e alua ions;
•
24 h ambula o y b achial blood p essu e moni o ing (ABPM) using an oscillome ic
BP Lab Vaso ens de ice;
•Op ical Cohe ence Tomog aphy Angiog aphy (OCT-A);
•Renal Dopple ul asound.
2.1.1. Blood P essu e Measu emen
O ice-based blood p essu e (BP) was de e mined as he a e age o h ee consecu-
i e measu emen s aken a wo-minu e in e als using an elec onic oscillome ic de ice
(Wa chBP O ice, Mic oli e AG, Widnau, Swi ze land) a e i e minu es o sea ed es .
Fo he 24 h ambula o y blood p essu e moni o ing (ABPM), an oscillome ic de ice (BP
Lab Vaso ens) was used, adhe ing o cu en Eu opean Socie y o Hype ension (ESH)
guidelines o p ope eco ding [
19
]. Measu emen s we e au oma ically aken a 15 min
in e als du ing he day ime and a 20 min in e als du ing nigh ime. The cu was placed
a ound he non-dominan a m, and pa ien s we e ins uc ed o keep he a m s ill and a oid
any mo emen du ing he eadings. Oscilla ions wi hin he cu we e eco ded du ing
g adual de la ion o measu e he BP.
The 24 h pulse p essu e (24 h PP) is de ined as he di e ence be ween 24 h sys olic
blood p essu e (SBP) and 24 h dias olic blood p essu e (DBP). Day ime and nigh ime pulse
p essu e a e calcula ed using he same me hod wi hin hei espec i e ime pe iods.
Biomedicines 2025,13, 312 4 o 13
2.1.2. Biochemical Pa ame e s
Rou ine biochemical pa ame e s we e de e mined using he s anda d echniques
wi h an au oma ed analyze (Boeh inge Mannheim o Hi achi sys em 911, Mannheim,
Ge many). Glome ula il a ion a e (GFR) was es ima ed using he CKD-EPI equa ion.
2.1.3. Oph halmological E alua ion
A comp ehensi e oph halmological examina ion was pe o med on all he pa ien s,
including co ec ed isual acui y measu emen using he Ea ly T ea men Diabe ic Re inopa-
hy S udy (ETDRS) cha s [
20
]. In aocula p essu e (IOP) was assessed wi h a Goldmann
applana ion onome e . An e io and pos e io segmen e alua ions we e conduc ed using
a sli lamp unde pha macologically induced myd iasis wi h 1% phenyleph ine d ops. Re i-
nal imaging was pe o med using a swep -sou ce op ical cohe ence omog aphy (SS-OCT)
de ice (T i on; Topcon Inc., I abashi, Japan).
All scans we e conduc ed by a single ope a o be ween 10:00 A.M. and 12:00 P.M. The
igh eye was examined i s , ollowed by a s anda dized scanning p o ocol. Poo -quali y
scans we e epea ed o disca ded. Since no signi ican di e ences we e obse ed be ween
he wo eyes, only one eye pe subjec was selec ed o analysis using a andom numbe
gene a o . I he selec ed eye’s scan quali y was deemed insu icien , he con ala e al eye
was analyzed.
2.1.4. Re inal Imaging P o ocols
The ollowing OCT scan p o ocols we e used o each eye:
•3D 7 ×7H Scan;
•Macula Radial 6.0 Scan;
•Angio-OCT 4.5 Scan,
Re inal hickness ( om he in e nal limi ing memb ane o he inne su ace o he
e inal pigmen epi helium) and cho oidal hickness ( om he ou e su ace o he e inal
pigmen epi helium o he scle a) we e au oma ically calcula ed using he OCT mapping
so wa e. Measu emen s we e p esen ed as mean
±
s anda d de ia ion ac oss he nine
egions de ined by he ETDRS s udy g id.
The ETDRS g id di ides he macula and cho oid in o nine ields. The g id, cen e ed
on he o ea, consis s o h ee concen ic ings wi h diame e s o 1 mm, 3 mm, and 6 mm.
The inne mos and ou e mos ings a e u he di ided in o empo al, nasal, in e io , and
supe io quad an s, enabling de ailed opog aphic analysis.
2.1.5. Quan i a i e Analysis
OCT angiog ams cen e ed on he o ea (4.5
×
4.5 mm; 320
×
320 pixels) we e analyzed
o e alua e he supe icial ascula plexus and he deep ascula plexus. The supe icial
ascula plexus is loca ed wi hin he ganglion cell laye , while he in e media e and deep
ascula plexuses a e posi ioned abo e and below he inne nuclea laye , collec i ely
e e ed o as he deep capilla y complex. The pe ime e o he o eal a ascula zone (FAZ)
was manually delinea ed by a single ope a o on all he images o he supe icial plexus.
Using he OCT so wa e (DRI T i on e sion 1.04E—1.36.2, Topcon Inc., Tokyo, Japan), he
FAZ a ea was au oma ically calcula ed.
To minimize he s a is ical e o s associa ed wi h subjec i e measu emen s, he inal
da a used in he s udy we e de i ed om he a e age o wo independen measu emen s.
Image p ocessing and measu emen s o e inal ascula densi y we e pe o med using
Image J so wa e, e sion 1.49 (Na ional Ins i u es o Heal h, Be hesda, MD, USA). Re inal
ascula ne wo k images we e gene a ed using an au oma ic h esholding algo i hm.
Biomedicines 2025,13, 312 5 o 13
Vascula densi y was de ined as he pe cen age o he a ea occupied by blood essels, wi h
essels iden i ied as pixels exceeding he de ined h eshold alue.
The calcula ions we e pe o med on he ollowing wo egions o in e es (ROIs):
he o eal and pa a o eal egions. The o eal ROI was de ined as a cen al ci cle wi h
a diame e o 120 pixels (1.2 mm), while he pa a o eal ROI was de ined as an annulus
91 pixels wide su ounding he o eal egion.
2.1.6. Ul asound E alua ion
In a enal duplex ul asonog aphy was pe o med on all pa ien s by a single ained
ope a o blinded o he clinical da a. The measu emen s we e ob ained using a GE Logiq
P5-PRO de ice wi h a 4 MHz ansduce and a Dopple equency o 2.5 MHz. Pa ien s
we e in a supine posi ion, and he Dopple signal was ob ained om he in e loba a e ies
by posi ioning he sample olume a he co ico-medulla y junc ion.
The Renal Resis i e Index (RRI) was calcula ed using he ollowing o mula:
RRI = Peak Sys olic Veloci y −End-Dias olic Veloci y/Peak Sys olic Veloci y
Values we e a e aged om six measu emen s ( h ee pe kidney) a e conduc ing
hypo hesis es ing and inding no s a is ically signi ican di e ence in he RRI alues
be ween he wo kidneys. Dopple angles we e main ained a <60
◦
, ensu ing no enal
comp ession o Valsal a maneu e , which could a i icially ele a e RRI.
2.1.7. Renal Func ion Pa ame e s
In pa ien s wi h u inalysis showing p o einu ia, e en in ace amoun s, o mic oalbu-
minu ia de ec ed ia semiquan i a i e dips ick e alua ion, a 24 h u ina y albumin exc e ion
assay was eques ed.
Albuminu ia was measu ed using a u bidime ic me hod and exp essed in mg/day.
Se um c ea inine le els we e de e mined using a s anda dized enzyma ic me hod (C ea i-
nine Plus, Roche Diagnos ics). The glome ula il a ion a e (GFR) was es ima ed using
he CKD-EPI (Ch onic Kidney Disease Epidemiology Collabo a ion) equa ion.
The s udy popula ion was s a i ied in o wo g oups based on he in a enal pa enchy-
mal enal esis i e index (RRI) alues abo e and below he 75 h pe cen ile o he RRI
dis ibu ion; he h eshold alue was se a 0.66.
2.2. S a is ical Analysis
S a is ical analysis was conduc ed using Medcalc e sion 15 and IBM-SPSS e sion 26
so wa e packages. The dis ibu ion o con inuous a iables was e alua ed o no mali y
using he Kolmogo o –Smi no es , which e ealed a no mal dis ibu ion o all a iables
excep u ina y albumin exc e ion and iglyce ide le els, which exhibi ed a posi i ely
skewed dis ibu ion. These non-no mally dis ibu ed a iables we e epo ed as medians
and in e qua ile anges and we e log- ans o med p io o u he s a is ical analysis. No -
mally dis ibu ed con inuous a iables we e p esen ed as means and s anda d de ia ions.
Ca ego ical a iables we e exp essed as pe cen ages.
Di e ences be ween g oups we e assessed using he independen - es o con inuous
a iables and he chi-squa ed es o , when app op ia e, Fishe ’s exac es o ca ego ical
a iables. Po en ial con ounde s we e adjus ed using he analysis o co a iance (ANCOVA).
To examine he ela ionship be ween e inal ascula densi ies and he o he a iables,
simple linea eg ession analysis and Pea son’s co ela ion coe icien s we e employed. To
assess he independen con ibu ion o e inal ascula densi ies, mul iple linea eg ession
models we e buil , wi h each e inal ascula densi y a iable as he dependen a iable and
Biomedicines 2025,13, 312 6 o 13
he pa ame e s ha demons a ed signi ican associa ions wi h bo h he enal esis i e index
(RRI) and he e inal ascula densi ies in uni a ia e analyses as independen a iables.
Addi ionally, s epwise logis ic eg ession analysis was conduc ed, using RRI> o < he
75 h pe cen ile as he dependen a iable, wi h he e inal ascula densi ies, he blood
p essu e alues, and he o he clinical pa ame e s as explana o y a iables.
The null hypo hesis was ejec ed o all wo- ailed es s wi h p- alues < 0.05.
3. Resul s
The mean RRI in he en i e s udy popula ion was 0.616 ±0.06.
Table 1p esen s he main demog aphic, an h opome ic, and clinical cha ac e is ics o
bo h he en i e s udy popula ion and he wo g oups in which he pa ien s we e ca ego ized
based on hem being abo e o below he 75 h pe cen ile o he dis ibu ion o RRI (0.66,
95% CI 0.64–0.68).
Table 1. Main demog aphic, an h opome ic, clinical, and biochemical cha ac e is ics o he s udy popula ion.
To al
(n= 92) RRI < 75 pc RRI > 75 pc p
Age, y 48 ±13 48 ±12 52 ±14 0.24
Male sex, n(%) 65 (79) 47 (78) 18 (83) 0.85
BMI (kg/m2)28 ±4.6 27.5 ±4.6 29.4 ±4.5 0.10
Wais ci cum e ence (cm) 96 ±13 96 ±13 99 ±12 0.10
Cu en smoke s, n(%) 20 (22.2) 11 (17.4) 9 (38.9) 0.054
eGFR (mL/min/1.73 m2)87 ±20 90 ±19 76 ±24 0.018
U ina y albumin exc e ion (mg/day) 76 (31–252) 36 (30–86) 387 (126–646) 0.009
Hemoglobin (g/dL) 14.6 ±1.4 14.7 ±1.3 14.2 ±1.6 0.12
To al Choles e ol (mg/dL) 194 ±29 196 ±29 186 ±26 0.14
HDL-Choles e ol (mg/dL) 48 ±12 49 ±12 45 ±9 0.11
T yglice ides (mg/dL) 118 (75–154) 106 (89–131) 122 (80–165) 0.02
Fas ing Blood glucose (mg/dL) 96 ±17 96 ±18 97 ±14 0.80
Table 2illus a es he dis ibu ion o pha macologically ea ed pa ien s, including he
a ious an ihype ensi e d ugs and o he medica ions a ge ing he ca dio ascula sys em.
Table 2. Pe cen age o Pha macologically T ea ed Pa ien s.
To al RRI < 75 pc RRI > 75 pc p
Pha macologically ea ed
hype ensi e subjec s 67.1 69.4 58.8 0.60
An ihype ensi e d ugs
Angio ensin-con e ing enzyme
(ACE) inhibi o s, % 29.1 27.4 35.3 0.57
Sa ans, % 37.9 40.3 29.4 0.46
Calcium channel blocke s, % 35.4 38.7 23.5 0.28
Alpha-2 Ad ene gic Recep o
Agonis s, % 7.6 3.2 23.5 0.005
A-Blocke s, % 27.8 29 23.6 0.57
α β-blocke s, % 12.7 12.9 11.8 0.58
β-blocke s, % 12.7 14.5 5.8 0.63
Diu e ics % 35.4 33.9 41.2 0.71
O he ca dio ascula agen s
S a ins, % 11.4 9.7 17.6 0.71
An ipla ele agen s, % 25.3 29 11.8 0.57
Allopu inol, % 6.3 4.8 11.8 0.83
Biomedicines 2025,13, 312 7 o 13
While he pe cen age o subjec s ea ed o hype ension did no di e signi ican ly
be ween he wo g oups, a highe p e alence o pa ien s ecei ing cen ally ac ing an i-
ad ene gic agen s was obse ed in he g oup wi h RRI > 75 h pe cen ile.
Among he hemodynamic pa ame e s, 24 h pulse p essu e and day ime and nigh ime
pulse p essu e we e signi ican ly highe in he g oup wi h RRI > 75 h pe cen ile (Table 3).
Table 3. Hemodynamic pa ame e s o whole popula ion and wo subg oups.
To al RRI < 75 pc RRI > 75 pc p
O ice-based SBP (mmHg) 137 ±12 137 ±13 136 ±11 0.94
O ice-based DBP (mmHg) 86 ±9 87 ±9 85 ±9 0.83
O ice-based PP (mmHg) 51 ±9 50 ±9 52 ±12 0.83
Hea Ra e (bpm) 73 ±11 74 ±12 72 ±11 0.87
Mean 24-h SBP (mmHg) 130 ±13 133 ±13 138 ±13 0.71
Mean 24-h DBP (mmHg) 82 ±9 83 ±9 82 ±9 0.92
24-h PP (mmHg) 47 ±10 45 ±10 52 ±9 0.013
Day ime SBP (mmHg) 134 ±13 129 ±13 134 ±13 0.70
Day ime DBP (mmHg) 85 ±9 86 ±10 85 ±9 0.92
Day ime PP (mmHg) 48 ±11 47 ±11 54 ±9 0.038
Nigh ime SBP (mmHg) 119 ±14 117 ±13 126 ±15 0.03
Nigh ime DBP (mmHg) 75 ±10 75 ±10 75 ±10 1
Nigh ime PP (mmHg) 44 ±10 43 ±9 51 ±10 0.001
Abb e ia ions—SBP: sys olic blood p essu e; DBP: dias olic blood p essu e; PP: pulse p essu e.
Rega ding he e inal ascula densi y pa ame e s, he only signi ican di e ence
be ween he wo g oups was obse ed a he le el o he deep o eal ascula plexus, which
showed lowe densi y in he g oup wi h he highe RRI (Table 4).
Table 4. Re inal ascula densi y pa ame e s o whole popula ion and wo subg oups.
To al RRI < 75 pc RRI > 75 pc p p *
Pa a o eal Vascula Plexus
Densi y (%)—Supe icial Laye 37.3 ±0.87 37.4 ±0.84 36.9 ±0.89 0.053 0.052
Pa a o eal Vascula Plexus
Densi y (%)—Deep Laye 38.3 ±1.08 38.3 ±1.06 38.3 ±1.19 0.956 0.876
Fo eal Vascula Densi y (%)
–Supe icial Laye 34.5 ±1.88 34.7 ±1.69 33.7 ±2.34 0.147 0.110
Fo eal Vascula Densi y (%)
–Deep Laye 32.9 ±1.95 33.26 ±1.72 31.47 ±2.11 0.01 0.001
p* a e ANCOVA co ec ion o eGFR, log- ans o med iglyce ides, mean noc u nal pulse p essu e, and smoking).
This di e ence emained s a is ically signi ican e en a e co ec ion h ough he anal-
ysis o co a iance (ANCOVA) o eGFR, mean nigh ime pulse p essu e, iglyce idemia,
and smoking (p= 0.01 and p< 0.001, espec i ely).
Table 5p esen s he s a is ically signi ican co ela ions be ween RRI and he a ious
pa ame e s, including demog aphic ac o s, ma ke s o enal damage, glome ula il a ion
a e, nigh ime pulse p essu e, and deep o eal ascula densi y.
Biomedicines 2025,13, 312 8 o 13
Table 5. Co ela ions be ween RRI and o he pa ame e s.
Age eGFR
Nigh ime
PP UAE
Deep Fo eal Plexus
Vascula Densi y
(RRI)
= 0.235 −0.288 0.3027 0.555 * −0.524
p= 0.0336 0.0087 0.0057 <0.001 <0.001
* The da a ela ed o UAE* e e o he pa ien s who es ed posi i e in he semi-quan i a i e e alua ion o his
pa ame e and subsequen ly unde wen quan i ica ion h ough a 24-h u ine collec ion.
The in e se ela ionship be ween he RRI and he deep o eal densi y appea ed
pa icula ly s ong (Figu e 1).
Biomedicines 2025, 13, x FOR PEER REVIEW 8 o 14
Table 5. Co ela ions be ween RRI and o he pa ame e s.
Age eGFR Nigh ime PP UAE Deep Fo eal Plexus Vascu-
la Densi y
(RRI) = 0.235 −0.288 0.3027 0.555 * −0.524
p= 0.0336 0.0087 0.0057 <0.001 <0.001
* The da a ela ed o UAE* e e o he pa ien s who es ed posi i e in he semi-quan i a i e e alua-
ion o his pa ame e and subsequen ly unde wen quan i ica ion h ough a 24-hou u ine collec-
ion.
The in e se ela ionship be ween he RRI and he deep o eal densi y appea ed pa -
icula ly s ong (Figu e 1).
Figu e 1. Co ela ion be ween RRI and Deep Fo eal Vascula Densi y. (Blue Line ep esen s he
linea eg ession endline, showing he nega i e co ela ion be ween he wo a iables. The slope
indica es he s eng h and di ec ion o he ela ionship; do ed lines ep esen s he con idence in-
e als o he eg ession line; o ange do s ep esen s e indi idual da a poin s.
In he g oup o pa ien s in which he semiquan i a i e analysis o mic oalbuminu ia
was posi i e, comp ising 18 subjec s, a signi ican in e se co ela ion was obse ed be-
ween he loga i hm o u ina y albumin exc e ion and he supe icial pa a o eal ascula
densi y ( = −0.555; p < 0.001). The small size o his subg oup does no allow us o pe o m
s a is ical co ec ions o assess whe he his ela ionship is independen o po en ial con-
ounding ac o s.
The associa ion be ween enal esis i e index and deep o eal ascula densi y was
es ed in mul i a ia e models whe e, al e na ely, RRI and deep o eal ascula densi y
we e conside ed as dependen a iables (see Tables 6 and 7). In bo h cases, he ela ion-
ships be ween hese wo a iables emained la gely signi ican .
0.4
0.5
0.6
0.7
0.8
0.9
24 26 28 30 32 34 36 38 40
Fo eal Vascula Densi y –Deep Laye (%)
RRI
= − 0.524
P < 0.0001
N = 82
Figu e 1. Co ela ion be ween RRI and Deep Fo eal Vascula Densi y. (Blue Line ep esen s he linea
eg ession endline, showing he nega i e co ela ion be ween he wo a iables. The slope indica es
he s eng h and di ec ion o he ela ionship; do ed lines ep esen s he con idence in e als o he
eg ession line; o ange do s ep esen s e indi idual da a poin s.
In he g oup o pa ien s in which he semiquan i a i e analysis o mic oalbuminu ia
was posi i e, comp ising 18 subjec s, a signi ican in e se co ela ion was obse ed be-
ween he loga i hm o u ina y albumin exc e ion and he supe icial pa a o eal ascula
densi y (
=−0.555
;p< 0.001). The small size o his subg oup does no allow us o pe -
o m s a is ical co ec ions o assess whe he his ela ionship is independen o po en ial
con ounding ac o s.
The associa ion be ween enal esis i e index and deep o eal ascula densi y was
es ed in mul i a ia e models whe e, al e na ely, RRI and deep o eal ascula densi y we e
conside ed as dependen a iables (see Tables 6and 7). In bo h cases, he ela ionships
be ween hese wo a iables emained la gely signi ican .
Biomedicines 2025,13, 312 9 o 13
Table 6. Mul iple linea eg ession analysis.
Dependen Va iable:
RRI B * SE R Pa ial p
Fo eal Vascula Densi y (%)
–Deep Laye −0.0158 0.0029 −0.549 <0.0001
Mean nigh ime PP (mmHg) 0.0020 0.0006 0.3063 0.0007
Cons an 1.0468
* B uns anda dized eg ession coe icien . SE s anda d e o ; R co ela ion coe icien . O he a iables ha did no
each s a is ical signi icance include eGFR, LogT, smoking, cen ally ac ing an i-ad ene gic d ugs.
Table 7. Mul iple linea eg ession analysis.
Dependen Va iable:
Fo eal Vascula Densi y (%)
–Deep Laye
B * SE R Pa ial p
RRI −18.98 3.43 −0.549 <0.0001
Mean nigh ime PP (mmHg) 0.048 0.0027 0.2615 0.025
Cons an 42.38
* B uns anda dized eg ession coe icien . SE s anda d e o ; R co ela ion coe icien . O he a iables ha did no
each s a is ical signi icance include eGFR, LogT, smoking, cen ally ac ing an i-ad ene gic d ugs.
Mo eo e , in mul iple logis ic eg ession analysis, an inc ease in mean nigh ime pulse
p essu e (OR = 1.1319, CI 1.049–1.221) and a educ ion in deep o eal ascula densi y
(
OR = 0.5026
) (Table 8) a e independen ly associa ed wi h a highe likelihood o an RRI
abo e he 75 h pe cen ile.
Table 8. Mul iple logis ic eg ession analysis.
Dependen Va iable:
RRI> o <75 pc Odds Ra io 95% CI p
Co a ia es
Fo eal Vascula Densi y (%)
–DeepLaye −0.5026 0.3129–0.8073 0.0044
Mean nigh ime PP (mmHg) 1.1319 1.0493–1.2211 0.0014
Cons an 15.3587
O he a iables ha did no each s a is ical signi icance include eGFR, LogT, smoking, cen ally ac ing an i-
ad ene gic d ugs.
4. Discussion
I is widely ecognized ha damage o small essels exe s a compa able e ec on
mo bidi y and mo ali y, pa icula ly due o he impai men o ce eb al and enal mic oci -
cula ions, which a e especially ulne able o luc ua ions in sys emic pulsa ile blood low.
In his con ex , albuminu ia, al hough no uni e sally associa ed wi h mic o ascula dam-
age, is ega ded as a bioma ke o mic o ascula dys unc ion and se es as an independen
p edic o o bo h mo bidi y and mo ali y [21].
The assessmen o mac o ascula and mic o ascula ci cula ion is essen ial o he
imely and accu a e diagnosis o ascula abno mali ies, playing a c i ical ole in he
p ima y and seconda y p e en ion o ca dio ascula diseases, as well as in de e mining he
mos e ec i e he apeu ic s a egies, pa icula ly in pa ien s wi h hype ension o ch onic
kidney disease.
In he con ex o ca dio ascula isk, an inc eased RRI, as an indica o o enhanced
mic o ascula one, is associa ed wi h he deg ee o enal impai men caused by ele a ed
