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Magnetic Resonance Materials in Physics, Biology and Medicine
https://doi.org/10.1007/s10334-023-01126-7
REVIEW
Physiological confounders ofrenal blood flow measurement
BashairAlhummiany1 · KanishkaSharma2· DavidL.Buckley1· KyweKyweSoe2· StevenP.Sourbron2
Received: 9 May 2023 / Revised: 26 September 2023 / Accepted: 12 October 2023
© The Author(s) 2023
Abstract
Objectives Renal blood flow (RBF) is controlled by a number of physiological factors that can contribute to the variability
of its measurement. The purpose of this review is to assess the changes in RBF in response to a wide range of physiological
confounders and derive practical recommendations on patient preparation and interpretation of RBF measurements with MRI.
Methods A comprehensive search was conducted to include articles reporting on physiological variations of renal perfusion,
blood and/or plasma flow in healthy humans.
Results A total of 24 potential confounders were identified from the literature search and categorized into non-modifiable
and modifiable factors. The non-modifiable factors include variables related to the demographics of a population (e.g. age,
sex, and race) which cannot be manipulated but should be considered when interpreting RBF values between subjects. The
modifiable factors include different activities (e.g. food/fluid intake, exercise training and medication use) that can be stand-
ardized in the study design. For each of the modifiable factors, evidence-based recommendations are provided to control for
them in an RBF-measurement.
Conclusion Future studies aiming to measure RBF are encouraged to follow a rigorous study design, that takes into account
these recommendations for controlling the factors that can influence RBF results.
Keywords Renal blood flow· Kidney· Perfusion· Within-subject variation· Between-subject variation
Introduction
Renal blood flow (RBF) has an important role in provid-
ing high capillary pressure to drive glomerular filtration and
maintain oxygen supply to meet the demands of renal metab-
olism. A well-recognized feature of the renal circulation is
its ability to maintain RBF at a relatively constant level as
a result of autoregulation [1]. This mechanism is essential
for preserving body fluid balance and protecting the glo-
merular capillaries from an increase in blood pressure. Renal
autoregulation does not imply that RBF is unchangeable, as
RBF is known to change remarkably with daily activities [2,
3]. This is because the kidney actively participates in blood
pressure regulation [4] through baroreceptor reflex and the
release of vasoactive agents [5] which ultimately modulate
renal haemodynamics.
Alterations in renal microcirculation play a critical role
in the pathophysiological mechanisms of renal disease [6].
Measurement of RBF is therefore considered an important
biomarker in the evaluation of renal function. However, a
significant problem in the interpretation of RBF is the large
heterogeneity of normal reported values due to combination
of measurement error and inherent physiological changes of
RBF [7]. While it is difficult to distinguish between the two
effects, understanding and quantifying potential physiologi-
cal factors can promote standardization and reduce variabil-
ity in RBF measurements. Such standardization is essential
to ensure that disease-related changes are not confounded by
physiological events.
Recently, a consensus-based project has outlined a num-
ber of technical recommendations to improve the stand-
ardization of renal biomarkers such as RBF, perfusion and
blood oxygen level dependent (BOLD) magnetic resonance
imaging (MRI) [8–10]. The results highlighted a lack of
* Bashair Alhummiany
ml16baba@leeds.ac.uk
* Steven P. Sourbron
s.sourbron@sheffield.ac.uk
1 Department ofBiomedical Imaging Sciences, University
ofLeeds, LeedsLS29NL, UK
2 Department ofImaging, Infection, Immunity
andCardiovascular Disease, The University ofSheffield,
Sheffield, UK
Magnetic Resonance Materials in Physics, Biology and Medicine
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consensus among experts concerning aspects of patient
preparation due to incomplete understanding of the impact
of physiological variability.
The aim of this review is to develop a practical reference
for the preparation and interpretation of RBF values. For
this purpose, a literature review was conducted to identify
and assess a wide range of factors that can contribute to
the variability in RBF in heathy humans. Based on brief
discussion of the variability in the applied techniques and
a comprehensive analysis of the physiological variability
in the literature, evidence-based recommendations will be
formulated for future studies aiming to achieve a more stand-
ardized approach for RBF quantification.
Materials andmethods
Scope
Different biomarkers quantify the amount of blood delivered
to the kidney. Renal blood flow (RBF, expressed in mL/
min) measures the delivery of blood at the macrovascular
level, whereas tissue perfusion (expressed in mL/min/100
mL) measures delivery to the capillaries at the microvascu-
lar level. Measurements of RBF are often indexed to body
surface area (BSA) and presented per 1.73 m2, thereby pro-
viding comparable estimates between different populations.
Different methods are available to measure RBF [Clear-
ance technique, Radionuclide scintigraphy, Doppler ultra-
sound (US), and Phase contrast MRI (PC)], or perfusion
[Positron emission tomography (PET), Dynamic contrast
enhanced (DCE) and Arterial spin labelling (ASL)]. Ref-
erence values tend to be dependent on the measurement
methodology used and are summarized in Table1. All these
methods are considered in this review, assuming that rela-
tive changes under influence of confounders are comparable
even if absolute values are not. Analysis of this review was
based on RBF (mL/min) with renal perfusion studies only
interpreted in the results section.
Literature search andselection
An initial exploratory search was performed using Pubmed,
Ovid MEDLINE and Web of Science databases with the
terms physiological, biological, variability and ‘renal circu-
lation’. Articles obtained from this search were used to deter-
mine a list of physiological factors that cause changes in
RBF. The identified factors focussed both on normal physio-
logical changes that cause within- or between-subject varia-
tion in RBF. Each identified factor was searched individually
to include studies up to June 2021. The search terms used for
each influencing factor are provided in Table2. Reference
lists from acquired articles were also searched for inclusion
of relevant studies. English, full-text articles reporting perfu-
sion, blood and/or plasma flow in adult human subjects were
included in this review.
Table 1 Typical renal hemodynamic measurements obtained using available techniques in humans with normal kidney function
a Conversion between RBF units was performed using body surface area provided in the paper
Technique References N (F/M) Age Renal blood flow (RBF)aRemarks
mL/min/1.73 m2mL/min
Clearance technique Goldring etal. [178] 43 (0/43) 39 ± 12 1189 ± 242 1205 ± 245 Diodrast (continuous infusion)
Bolomey etal. [179] 18 (5/13) 41 ± 10 1052 ± 236 1014 ± 228 PAH (continuous infusion)
Radionuclide scintigraphy Esteves etal. [180] 106 (62/44) 40 ± 10.8 321 ± 69 356 ± 76 99mTc-MAG3 (camera clearance)
Doppler ultrasound Greene etal. [181] 16 (6/10) 28 ± 8 790 ± 125 800 ± 127 Average velocity profile
Phase contrast MRI Bax etal. [19] 20 29 ± 5 –1133 ± 268 Cine (2D) imaging
Eckerbrom etal. [25] 28 (15/13) 24 ± 5.3 963 ± 160 1013 ± 169 2D imaging with cardiac gating
Renal perfusion (mL/min/100
mL)
Cortex Medulla
Positron emission tomography Nitzsch etal. [182] 20 (4/16) 29 ± 9 470 ± 28 –15O-water
Normand etal. [183] 10 (0/10) 22 ± 3.7 329 ± 65 –15O-water
Dynamic contrast enhanced
MRI
Wu etal. [184] 19 (7/12) 41 ± 15 272 ± 60 122 ± 30 Magnevist contrast agent
Eikeord etal. [185] 20 (16/4) 25 ± 4.5 345 ± 84 – Dotarem contrast agent
Arterial spin labelling (ASL) Wu etal. [184] 19 (7/12) 41 ± 15 227 ± 30 101 ± 21 Pseudo-continuous ASL
Eckerbrom etal. [25] 28 (15/13) 24 ± 5.3 290 ± 63 91 ± 14 Pulsed ASL
Magnetic Resonance Materials in Physics, Biology and Medicine
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Table 2 Search terms for the
potential factors influencing
renal blood flow
* Truncation command to search for the root of the free-text word with any alternative ending
RBF terms Influencing factor Search terms Number of
articles
‘Renal blood flow’ AND Age Age 1190
‘Renal plasma flow’ Lifespan
‘Renal circulation’ Elderly
‘Renal perfusion’ Gender Gender 142
Sex
Dimorphism
Race Race 57
Ethnicity
BMI ‘Body mass index’ 151
Lean
Overweight
Obese
Circadian rhythm ‘Circadian rhythm’ 27
‘Circadian cycle’
‘Biological clock’
Pregnancy Pregnan* 279
Gestation
Matern*
Menstrual cycle ‘Menstrual cycle’ 18
‘Follicular phase’
‘Luteal phase’
Food intake Food 203
Meal
Ingest*
Eat*
Fluid intake Water 1142
Hydrat*
Fluid
Smoking Nicotine 35
Smok*
Cigarette*
Caffeine Caffeine 62
Coffee
‘Energy drink*’
‘Soft drink*’
Alcohol Alcohol 233
Drink*
Beer
Altitude Altitude 20
Climb*
Exercise Exercise 273
‘Physical activity’
Training
Mental stress ‘Mental stress’ 94
Anxiety
Depression
Thermal stress ‘Heat stress’ 80
*Thermia
Medication Medication* 2985
Drug*
Treatment*
Combined with OR Combined with OR
Magnetic Resonance Materials in Physics, Biology and Medicine
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Data synthesis
The magnitude of change was determined for each factor as
the absolute (mL/min) and relative (%) difference of baseline
RBF values. Results are presented as mean (and range) of
absolute and relative change in RBF across studies. Since
renal dysfunction can modulate the renal response to some
physiological factors, only studies reporting on subjects with
normal kidney function were included in the analysis. When
RPF was reported, a conversion to RBF was made assuming
a haematocrit value of 42% known from the literature [11],
except where haematocrit was reported in the original study.
Results
The search terms yielded a total of 6987 articles, after
removing duplicates. Following abstract and title screen-
ing and assessing for eligibility, 215 full-text articles were
reviewed. A total of 162 original studies were summarized
and included in this review; of which 110 studies reported
quantitative measurement for the absolute and/or relative
change. These studies investigated the effect of 24 potential
factors on renal circulation.
The factors were divided into non-modifiable and modi-
fiable. Non-modifiable factors essentially compromise the
demographic characteristics of a population, such as age,
sex, and race. While these factors cannot be manipulated
in an experiment, acknowledging their impact on the meas-
ured RBF means that researchers can account for those in
the study design or data analysis. The modifiable factors
include a range of activities which can be controlled for in
an experiment. Figure1 shows the absolute change in RBF
obtained from each study for all identified factors. The esti-
mated absolute and relative change in RBF average across
studies were summarized in Table3 and presented in Fig.2.
Non‑modifiable factors
Age
The kidney undergoes multiple changes with advanced
age, including reduced renal function [12], decreased kid-
ney size, and alterations in blood flow. Changes in RBF
with normal ageing are well-documented and have been
reported using different methods. Davies and Shock [13]
were one of the first to report the decline in resting RBF in
adults after the age of 40. In this study, baseline measure-
ments using clearance methods were compared in male
subjects aged between 20 and 90years old. Differences in
RBF were observed between age groups for each decade
with the largest reduction (53%) between the youngest and
the oldest groups from a mean of 1170 to 433mL/min.
This observation has consistently been reported by other
Fig. 1 The absolute change
in renal blood flow for all
physiological confounders. Each
point refers to measurement
reported by one empirical study
and coded according to the
applied method
Magnetic Resonance Materials in Physics, Biology and Medicine
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investigators using PAH clearance [14–17], 99mTc-MAG3
scintigraphy [18] and similarly using PC-MRI [19, 20].
Renal cortical perfusion estimated with ASL and DCE
showed lower values in the older adults and negative asso-
ciation with advanced age [20–22]. Collectively, RBF was
found to decrease after the age of 40 by − 10% each decade
with an average decline of − 85 mL/min per decade (range
from − 49 to − 106 mL/min) between different studies [13,
16, 19]. The effect of age is important and should therefore
be considered when interpreting RBF between subjects of
different age groups.
Table 3 Summary of all physiological confounders of renal blood flow and possible ways to control
↑ Increase RBF; ↓ Decrease RBF; ↕ Both increase and decrease have been reported; = No change in RBF; ? a potential factor (not sufficiently
studied)
Influencing factor RBF response Change in RBF % (and absolute) How to control
Before/during measurement
Acute meal (High fat) [59]↑ + 23% Provide standard meal/use questionnaire to
record last meal
Acute meal (Carbohydrate) [60, 61] = =
Acute meal (High protein) [62–68]↑ + 30% (260 mL/min)
Fluid intake (Hydration) [83] ↕ Normal hydration protocol
Nicotine (acute smokers) [89] = = No restriction
Caffeine (Acute) [93, 94] = =
Alcohol (Acute) [92] = =
Exercise (High intensity) [96–100]↓− 40% (− 450mL/min) Avoid heavy physical exercise on the day
High altitude (Short stay) [115, 116]↓− 17% (− 177mL/min) Use questionnaire to record recent exposure to
high altitude
Circadian cycle (Mid-day) [3, 54–56]↑ + 35% (283 mL/min) Schedule repeat scans at fixed time of the day
Pregnancy (Early weeks) [44–47]↑ + 60% (514 mL/min) Use questionnaire to record menstrual health
and history
Menstrual cycle (Luteal phase) [48–51]↑ + 8% (77 mL/min)
Mental activity (During stress) [121, 122]↓− 19% (− 135mL/min) Ensure patient feels comfortable. Record feel-
ings of anxiety
Temperature (High) [97, 128]↓− 31% (− 383mL/min) Measure body temperature
NSAID (Acute oral intake) [137–139]↓− 12% (122mL/min) Record regular use of treatments. Withdraw
acute use of medication when possible
OCP (Regular use) [153, 154]↓− 10% (102mL/min)
RAS inhibitors (Acute oral intake) [148, 158,
160, 162, 163, 186]
↑ + 15% (282mL/min)
Calcium antagonists (Acute oral intake)
[159]
↑ + 23%
Beta blockers (Acute oral intake) [158, 167]↓− 11% (− 128mL/min)
Diuretics (Acute oral intake) [169]↓− 20% (− 187mL/min)
Interpreting the measurement
Age (> 40 years) [13, 16, 17, 19]↓− 10% (− 85mL/min) per decade Include in statistical analysis model
Sex (Female) [16, 19, 23]↓− 20% (− 243 mL/min)
BMI (Overweight) [39, 40]↑ + 20% (105 mL/min)
Additional information
Race [30] ? For between-subjects comparison. Use ques-
tionnaire to record individual habits
Diet habits (low salt) [75–77]↓− 10% (− 100mL/min)
Diet habits (low protein) [71, 72]↓− 10% (− 94 mL/min)
Diet habits (Plant-based) [69]↓− 12% (− 132mL/min)
Smoking habits (chronic smokers) [90]↓− 23%
Drinking habits ?
Exercise habits (fit) [107] ?
High altitude (natives) [118]↓− 28% (− 288mL/min)
Depression/anxiety ?
Magnetic Resonance Materials in Physics, Biology and Medicine
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Sex
The total RBF in women was found to be − 20% (range − 16
to − 23%) lower than men by an average of − 243 mL/min
(range − 187 to − 385 mL/min) [16, 19, 23–25]. The effect
of gender on the renal haemodynamics appears to be driven
by the protective action of oestrogen in women during repro-
ductive age [26]. As a result, an interaction between age and
gender was demonstrated, where gender-related differences
were found to disappear after the age of 60 [16, 19]. The
gender effect on RBF can also be secondary to the difference
in body size and kidney volume between men and women
[27]. The findings reported by Berg [23] suggest no differ-
ences when the measurement was indexed to 1.73 m2 BSA.
While it remains unclear whether there is a truly physiologi-
cal difference, the gender effect appears to be important and
should be considered.
Race
Race has long been considered a critical variable in the
estimation of glomerular filtration rate (eGFR). The mis-
use of race in the assessment of renal function is subject
to an ongoing debate [28], and a replacement of current
eGFR equations is under evaluation [29]. However, stud-
ies investigating racial differences for RBF are limited.
Using PAH clearance, RPF of African Americans was
found to be 16% lower than age-matched Caucasians
when participants followed a high-salt diet [30]. The dif-
ference in RPF between the two groups disappeared when
switching to a low-salt diet in a subsequent study [31].
These data suggest an underlying physiological difference
between the two ethnic groups, which involve a blunted
renal response to angiotensin-II receptor antagonist in the
kidneys of African Americans [32]. There is also some
evidence pointing towards the involvement of genetic fac-
tors, whereby specific gene variants appear to be associ-
ated with RPF variations in individuals of African descent
[33]. Future studies on sufficiently large population and
including other racial groups are necessary to better under-
stand how race, social and genetic factors interact to affect
kidney function.
Body mass index
The effect of body mass index (BMI) on renal haemo-
dynamics is not specific to obesity or being overweight
as it appears across wide BMI ranges. Comparing lean
(BMI: 18–25 kg/m2) and overweight subjects (BMI: 25–35
kg/m2), with normal kidney function, showed a marked
positive correlation with renal circulation [25, 34], and
an increase in RBF on average by 20% (range 13–31%)
with higher BMI [34–36]. The relation between BMI and
RBF persists even when adjusted for age and sex [37, 38].
A reduction in RBF with weight loss following bariatric
surgery has also been reported [39, 40]. However, renal
perfusion measured using 15O-H2O PET in both cortex and
medulla was not affected by changes in weight between
normal and obese [40]. Of note, correcting RBF for body
dimensions (expressed per 1.73 m2 BSA) was found to
be negatively associated with BMI [37, 38, 41]. Indexing
for height has been suggested as an alternative approach
[42], in which the association with RBF was found to be
eradicated and therefore, make the measurement more
Fig. 2 The relative change in
renal blood flow (%) averaged
across studies. Only factors with
consistent impact reported in
the literature are presented
Magnetic Resonance Materials in Physics, Biology and Medicine
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comparable between individuals. However, this alternative
way of indexing was not widely adopted as it would lead
to the same error as BSA in populations of variable height
measurements. Overall, the effect of BMI is apparent and
should be considered when comparing RBF between sub-
jects with variable body dimensions.
Pregnancy andmenses
Major changes in RBF were noted during pregnancy, which
can occur as early as the sixth gestational week [43]. Serial
studies using PAH clearance performed on pregnant women
showed substantial increase in RBF during the first trimes-
ter by an average of 514mL/min (range 434–625mL/min)
[44–47] reaching maximal level at ~ 12 gestational week
[43]. Although a marked reduction in RBF is expected
during the third trimester − 308mL/min (range − 631 to
− 117mL/min), the value remains to be 30% (range 14–61%)
higher than the measurement obtained from non-pregnant
women [44–47]. Women investigated before pregnancy and
after delivery showed no difference between measurements
[45], indicating a return to normal values after childbirth
[47].
Similar changes in RBF, but at smaller effect 8% (range
7–10%), were noted during the menstrual cycle [48]. In the
luteal phase of the menstrual cycle, RBF measured using
PAH clearance was found to increase on average by 77mL/
min (range 58–95mL/min) [49]. This small variation in
RBF was not detected in some studies using the same clear-
ance method [50, 51].
Taken together, changes in RBF during normal pregnancy
are substantial and if not considered can be confounded
with hyperaemia. The impact of the menstrual cycle on
RBF appears to be relatively small but controlling for this
effect can inform a rigorous study design. In any case, query-
ing information regarding menstrual health and history for
female participants should be considered.
Modifiable factors
Circadian cycle
A typical circadian cycle of renal haemodynamics exhibits
a sinusoidal course [52], with peak and trough observed at
late daytime wakefulness and night-time sleep, respectively
[53]. Using the clearance technique, the average amplitude
of change in RPF with day-night cycle was found to be 35%
(range 25–52%) [52, 54–56]. A similar pattern was observed
in global renal perfusion values, measured with ASL, which
is more pronounced in the cortex than medulla [56]. In one
study, no change in RPF was found when subjects were
maintained at bed rest throughout the experiment [57],
suggesting that circadian fluctuation of the renal circulation
can be driven by behavioural stimulant such as changes in
activity, food and fluid consumption during the day [58].
Nevertheless, the effect of circadian rhythms has been found
to be persistent when identical meals were taken at regular
intervals throughout the 24h [3]. In line with these data,
acquiring RBF measurement during a fixed time of the day
should be considered to minimize the influences of daily
cycle.
Food intake
Food intake is accompanied by profound cardiovascu-
lar changes in which hormonal and nervous systems are
engaged to promote the digestion, absorption, and storage
of nutrients in the body. Postprandial change in renal circu-
lation is evident and depends on the size and macronutrient
content of the meal.
The intake of high-energy fatty meal (142 g fat) was asso-
ciated with a modest but sustained increase in RBF meas-
ured with PC-MRI of 23% after 20 min [59]. No change in
RBF was observed after ingestion of mixed meal high in
carbohydrate (> 90 g) in 1 h [60] or 4 h duration [61] using
ultrasound.
After the ingestion of high protein meal, RBF measured
with PAH clearance was found to increase by an average
of 260mL/min (range 150–390mL/min) with peak values
achieved 60–120min postprandially [62–67]. The test meal
used in these trials contained 80–90 g (1.2g/kg) of differ-
ent types of animal protein (including lean meat or dairy
products) [64, 67]. Reducing the amount of protein (0.55g/
kg) appears to be associated with smaller renal response
[68]. Two studies looked at RBF changes using PAH clear-
ance in response to vegetarian protein, but the results are not
aligned. One study showed no acute changes in RPF after
consuming 80 g soy protein meal compared to meat meal in
healthy subjects [69]. Another showed 14% increase in RPF
values 90min after intake of 77g soy protein [70]. Given
the small number of participants in both studies (n ≤ 10),
it is difficult to conclude whether or not plant-based pro-
tein will elicit short-term changes in renal haemodynam-
ics. The inconsistency between findings could be attributed
to differences in the follow-up duration between studies, or
heterogeneity in the soy protein supplement and the amino
acid composition.
Studies investigating the chronic response of protein diet
showed similar results to single-meal protein experiments.
High protein diet (2.0g/kg/day) was found to increase RPF
compared to low protein diet (0.5g/kg/day) when consumed
for period of 6 days [71] or 3 weeks [72] in the adult kidney,
but not in the elderly [73]. Switching from animal to vegeta-
ble-based protein diet for a period of 3 weeks was associated
with lower resting RPF in healthy subjects [69, 74].
Magnetic Resonance Materials in Physics, Biology and Medicine
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A trend towards higher RBF in individuals following high
sodium diet (> 200 mmol/day or 11.7 g/day) compared to
low sodium diet (50–70 mmol/day or 3–4 g/day) for period
of 5–7 days was described in some [75–77], but not all stud-
ies [78, 79]. While PAH clearance was applied in all studies,
the discrepancy might be explained by the amount of water
intake which is known to enhance renal sodium excretion
and hence modify the RAS-activity expected from a low
sodium diet [80].
Since meal consumption is often associated with RBF
changes, fasting before the study is commonly used. Low
baseline RBF value was observed in some studies [63, 81,
82] in which the authors have attributed to overnight fasting,
but no empirical study has yet sufficiently addressed this
point. While awaiting further insight from future studies on
the matter, a preliminary conclusion can be reached from the
literature synthesis as to stress the importance of controlling
food intake prior to RBF measurement.
Fluid intake/hydration
Water loading (20mL/kg) induced a 10% increase in total
RBF measured using PC-MRI [83], but no changes were
observed in perfusion values of the cortex and medulla esti-
mated using ASL [84]. In both studies, the renal response
was evaluated relative to fasting conditions (i.e. fluid restric-
tion). Comparing different hydration levels (high: 24mL/
kg vs. low: 3mL/kg) using PAH clearance showed contra-
dictory results. One study reported no change in RPF with
different degree of water loading [85], while another found
lower RPF (− 13%) in the higher hydration regimen [81].
Sampling error associated with the use of different methods
for urine collection (spontaneous voiding [85] versus blad-
der catheterization [81]) imply that these findings should be
interpreted with caution. A study conducted using 131I-hip-
puran scintigraphy showed that hydration did not affect the
measurement of RBF, despite large inter-individual differ-
ences in RBF response [86]. The authors concluded that
hydration can be advantageous as it aids rapid transport of
radioactivity, and therefore peak activity can be achieved at
an earlier time.
While the magnitude and direction of change in response
to hydration status remains elusive, it can be inferred that
acute physiological changes in RBF may appear in cases of
sub-optimal or excessive hydration. There is no evidence
against the regular intake of water which is in line with the
recent consensus recommendation for PC-MRI [9].
Smoking, caffeine, andalcoholic consumption
Cigarette smoking has a profound systemic vasoconstric-
tion effect associated with increased sympathetic stimula-
tion and these responses are specific to nicotine component
of the cigarettes. Chewing nicotine gum (4mg) was asso-
ciated with acute reduction (− 15%) in RPF in non-smok-
ers [87, 88]. Habitual smokers, however, showed impaired
renal response following active smoking (2–3 mg nicotine)
[89], suggesting the development of nicotine tolerance in
these individuals compared to non-smokers [87]. Compar-
ing chronic smokers and non-smokers showed a lower RPF
(− 23%) in the smoking group [90], and steeper decline in
RPF with age in smoking male subjects [91].
Few studies have looked at the effect of caffeine and
alcohol consumption, despite their well-known diuretic
effect. One study using PAH clearance found no change in
RPF after consuming beer (666mL) or water containing
2.7% alcohol [92]. Similarly, caffeine intake had no acute
effect on PAH clearance when consumed in doses less than
400mg [93, 94]. There were no reports concerning the
impact of regular (chronic) consumption of alcohol, caf-
feine, or other recreational drugs on RBF in humans.
At present, the limited data on the potential effect on
RBF, preclude restricting the acute use of nicotine, alco-
hol, or caffeine substances. Future studies are required to
confirm these findings. Nevertheless, querying the habitual
use of these substances should be considered to support
the interpretation of RBF results [90].
Exercise
The renovascular adjustments to exercise training occur
in response to the increased sympathetic neural out-
flow, resulting in blood flow being directed away from
the kidneys [95]. Using PAH clearance, a substantial
decline − 40% (range − 26 to − 58%) in RBF − 450 mL/
min (− 279 to − 759 mL/min) was reported immediately
following dynamic exercise [96–100]. Similar response
was observed in renal perfusion of the cortex [101–103]
and medulla [103], measured using PET [101, 102] and
MRI [103], following static handgrip exercise. A return to
near pre-exercise RBF value can appear 30–60 min after
completion of the dynamic exercise bouts [2, 104], with
full-recovery reported at 2-h post-activity [105]. In older
adults, changes in RBF during exercise is lower [106, 107]
and recover at slower rate [106, 108]. Studies investigat-
ing the effect of variable level of exercise training showed
minimal RBF response with low exercise intensity [99,
100, 109, 110]. The degree of RBF reduction can also be
related to other factors such as exercise duration [100],
Magnetic Resonance Materials in Physics, Biology and Medicine
1 3
ambient temperature [97, 99, 107], and hydration level
[111].
Difference in resting RBF measurements between sed-
entary and well-trained young individuals was noted in
a cross-sectional study [107]. Nevertheless, no effect on
RBF was found when subjects underwent a sustained exer-
cise training program for 4weeks [107] or 6months [112].
The transient change in RBF post-exercise might be
confounded with reduced renal function. Hence, heavy
physical activity should be restricted on the day of RBF
measurement.
High altitudes
Exposure to high altitude is associated with an elevation
in haemoglobin concentration and a redistribution of RBF
which serve to restore normal blood oxygenation as a
consequence of acute hypoxia. RBF measured with PAH
clearance [113–115] or Doppler ultrasound [116] showed
a reduction of − 17% (range − 10 to − 23%) in response
to short-term (1–7 days) exposure to high altitude (range
3500–6500 m). The reduction in RBF is maintained dur-
ing prolonged stay (> 60 days) [115] but was not detected
with shorter exposure time (6 h) using Doppler US [117].
Natives living at high altitude have also been found to
have − 28% lower RBF values when compared with sea
level residents [118, 119]. While the impact of altitude
adaptation might be less relevant in single-centre studies,
it should be considered when comparing data that involve
individuals residing at high-altitude environment.
Mental activity
The renal response to acute mental stress is character-
ized by a rapid and transient vasoconstriction stimulated
by sympathoadrenal excitation. Cortical [120] and total
RBF [121–123] was found to decrease − 19% (range − 6
to − 33%) in response to solving stressful mental arith-
metic [123] or the Stroop colour-word tests [120–122].
Alterations in RBF were observed at 2 min of mental
stress [120] which would gradually return to baseline at
1 h [122]. The reduction in RBF can be negatively associ-
ated with the increment in systolic blood pressure during
mental stress [123]. In the elderly, mental stress results on
more pronounced and prolonged reduction in RBF [124].
Similar changes were noted in renal circulation following
emotional stress induced by the discussion of sensitive
personal topics [125]. In addition, individuals annoyed
by environmental noise were found to have 10% lower
RBF compared to non-noise-annoyed individuals [126].
These data support that anxiety, tenseness, and annoy-
ance are factors that should be considered (and possibly
controlled) when measuring RBF. Ensuring the partici-
pant feels comfortable before and during the scan can
be achieved by thorough explanation of the procedure.
Since the MRI scanner environment can be an obvious
source of apprehension to some participants (i.e. claus-
trophobia), it is advised to record for such effects which
would aid the interpretation of results. In addition, captur-
ing information on individual’s feelings (i.e. anxiety and
depression) should provide additional comparative data
between subjects.
Thermal stress
Exposure to thermal stress causes a redistribution of RBF
where the kidney acts to maintain internal body tempera-
ture by activating the sympathetic outflow. Reduced RBF
measured with PAH clearance − 31% (range − 26 to − 38%)
was reported in response to increased body temperature + 0.5
to + 2°C following exposure to hot environment (50°C dry
bulb) [97], or passive heating induced with water-perfused
suits [127–129]. RBF reduction was only minimal when
subjects were exposed at a milder air temperature (36°C)
[99], or internal body temperature rose by 0.4°C [99, 130].
Sustained heat exposure (i.e. heat acclimation) at 30°C for
period of 4days had no measurable effect on baseline RBF
[131]. The cooling effect provoke similar renal response.
One study using ASL reported reduced renal perfusion in the
cortex but not in the medulla when participant’s feet were
covered with ice packs at 1°C for 2min [132]. This effect
has similarly been observed on ultrasound measured renal
blood velocity and resistance index [133–135]. The pattern
that emerges from these studies is that changes in body tem-
perature is associated with large RBF fluctuation. Measure-
ment of body temperature should therefore be obtained, and
the study can be delayed in case of fever.
Medication use
Extensive research has been performed to investigate the
alterations of renal circulation in response to a wide range
of pharmacological treatments. In this section, an emphasis
will be given to the use of commonly prescribed medications
that have been studied in normal human subjects.
Nonsteroidal anti-inflammatory drugs (NSAID) can
inhibit prostaglandin synthesis, thereby causing important
alterations in renal function. Studies on normal subjects
have reported variable RBF response of selective and non-
selective NSAIDs.
The oral administration of indomethacin (50 mg) was
found to acutely reduce RPF − 16% (range − 10 to − 23%)
measured using PAH clearance in young normotensive sub-
jects who were maintained on sodium balance [136–138].
Magnetic Resonance Materials in Physics, Biology and Medicine
1 3
However, the short-term intake of indomethacin for period
of 3–7days resulted on preserved RPF both in young
[139–141] and elderly subjects [142].
Under conditions of severe salt depletion, single oral
dose of celecoxib (400mg) resulted on a transient drop in
RPF measured with PAH clearance within 1 h [143], but no
changes were observed in the same study when a lower dose
(200mg) was used. This reduction in RPF with the higher
dose of celecoxib (400mg) was not observed in a separate
study performed on subjects with minimal salt depletion
[144].
A daily dose of diclofenac (50 mg) used for period of
2–3days had no alteration in RPF measured using standard
PAH clearance both in young [145] and older patients with-
out impaired renal function [146]. Similarly, using ASL no
changes in renal perfusion were detected after single oral
dose (50 mg) or short-term tropical application (3days) of
diclofenac [147]. However, a significant reduction in renal
perfusion was reported, in the same study, in sub-group of
subjects with high plasma diclofenac level after oral intake
only.
Previous studies that have investigated the effect of ibu-
profen (400–800mg) on renal circulations reported no sig-
nificant changes in RPF after acute [137, 148], short-term
(3days) [141] or sustained (14days) [149] administration in
salt-replete subjects. Similarly, therapeutic doses of etodolac
(300 mg) [149], paracetamol (500 mg) [140], Aspirin
(975mg) [137, 150], diflunisal (500 mg) [137], naproxen
(500mg) [143] or ketoprofen (50mg) [139] for short-term
did not affect RPF in healthy young subjects.
These data indicate that various NSAIDs have different
effects on RBF in normal individuals. It can also be inferred
that the changes in RBF are more pronounced during acute
oral use, rather than the repeated use of NSAIDs, possi-
bly due to counterregulatory mechanism operating in the
human kidney. In addition, the specific effect of NSAIDs
can be confounded by the state of sodium intake, with more
pronounced effect expected during sodium-restriction [151].
Taken together, participants can be advised to avoid NSAIDs
before RBF measurement, and recent use of NSAIDs should
be documented.
The use of oral contraceptive pills (OCP) is known to
be associated with increased RAS activity, but their impact
on renal hemodynamic has been controversial. An earlier
study reported reduction in renal perfusion by an average
of − 25%, estimated from the disappearance curve of radi-
oactive xenon, in normotensive women using a variety of
combined oestrogen-progestogen drugs for long-term (> 6
months) [152]. Similar, though minor, differences were
observed when comparing baseline RBF between OCP users
(30 ± 5 µg ethynyl-oestradiol) and non-users in some [153,
154], but not all studies [155, 156] using PAH clearance.
The progestational and androgenic activity in the OCP has
been found to be associated with enhanced angiotensin-
dependent control of the renal circulation [157]. The discon-
tinuation of OCP for period of 6 months had no measurable
effect on baseline RBF [155]. These data suggest that the
regular use of OCP should be documented when measuring
RBF in women.
Renin-angiotensin system (RAS) inhibitors, reduce the
formation of angiotensin-II, which results on reduced sys-
temic and renal vascular resistance and favourable renal vas-
odilator effect. Different classes of RAS inhibitors have been
studied previously namely, angiotensin converting enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARB) and
direct renin inhibitors. In spite of differences in their mecha-
nism of actions, the acute administration of these agents has
been found to increase RBF to variable degree.
In healthy subjects, the acute administration of Captopril
(25 mg) caused marked rise in RPF (range 14–24%) [148,
158] with peak values reported at 3–4 h [158]. Two ascend-
ing doses of Ramipril (2.5 mg and 10 mg) administrated
on separate days resulted on similar increase in RBF, with
an estimated change of 18% reported with the highest dose
during 3.75–4.75 h period [159]. Treatment with Enalapril
(20 mg) caused modest increase in RPF (range 10–13%) at
2–4 h [160, 161], but maximal vasodilation was noted 6h
after drug intake [160].
Studies using drugs of the ARB class showed similar
renal hemodynamic effect to those using ACE inhibitor
[162]. In healthy, salt depleted subjects, single oral dose
of Eprosartan (200mg) increased baseline RPF by 20% at
3.75h post-administration [163]. In the same study, the low-
est Eprosartan dose sufficient to cause significant renal vaso-
dilation was determined to be < 10mg, whereas the near-
maximal vasodilator response was achieved with a dose of
100mg. In similar laboratory sittings, escalating doses of
Candesartan caused progressive increase in RPF with peak
response (24%) achieved with a dose of 16mg during 4h
after administration [164]. Studies using Valsartan (80mg)
[160] or Losartan (50mg) [165] on healthy subjects showed
relatively small increase in RBF (range 8–11%) during 3–4
h after acute administration.
One study looked at the effect of direct renin inhibitor,
Aliskiren, and found marked dose-related renal vasodila-
tion [166]. Under conditions of salt-depletion, a change from
baseline RPF values of 16%, 22% and 30% were reported in
repones to acute aliskiren doses of 75 mg, 150 mg, and 300
mg, respectively. In addition, baseline RPF remained sig-
nificantly increased after each aliskiren dose when repeated
measurements were performed 48 h post-drug intake [166].
Calcium channel blockers represent another class of
drugs that have been associated with a preferential vasodi-
lation effect on afferent arterioles. Normal subjects receiving
two separate doses of felodipine (5mg and 20mg) showed
major changes in RBF acutely, with maximum estimated
Magnetic Resonance Materials in Physics, Biology and Medicine
1 3
change of 40% reported with the higher dose [159]. On the
other hand, the acute use of Nifedipine (10mg) caused mini-
mal vasodilation in baseline RPF value [158]. This consid-
erable variability in the renal hemodynamic effects among
calcium antagonists, might be related to differences in the
intrinsic actions of the agents studied.
Beta blockers suppress cardiac output and inhibit medi-
ated vasodilation, both effects could result in reduced RBF.
However, previous studies reported conflicting results which
make the effect of beta blockers difficult to interpret. One
study using PAH clearance showed the anticipated reduc-
tion in RBF (-11%) in the first hour following oral intake of
metoprolol (100 mg) or pindolol (10 mg) in hypertensive
patients with normal kidney function [167]. An opposite
trend was reported in response to the same dose of metopro-
lol in a separate study performed on healthy volunteers. No
changes in baseline RBF were reported following 10days
treatment with metoprolol (200mg) compared to placebo
[168].
In general, anti-hypertensive medications represent potent
modulators of RBF. Patients with prescribed anti-hyperten-
sive treatments (RAS inhibitors, calcium channel blockers,
beta blockers) can be advised to withdraw acute use of drugs
before RBF measurement where possible.
Diuretics can affect renal haemodynamics through their
actions as an inhibitor of sodium-reabsorption in the ascend-
ing loop of Henle. One study, using PAH clearance, com-
pared the effect of oral intake of four different loop diuretics
on healthy volunteers and reported no alteration in RPF in
response to piretanide (6mg) or bumetanide (1mg), whereas
ethacrynic acid (100mg) and furosemide (40mg) induced
reduction in RPF by − 23% and − 7%, respectively [169].
Variable effects have been found in response to the acute
parenteral administration of furosemide in healthy volun-
teers. Two studies, using PAH clearance, reported transient
increase in RPF in the first 20min after furosemide (20mg)
injection [141, 170]. Other studies applying PAH clearance
[171] or PC-MRI [103] reported no alteration in RBF post-
furosemide injection. Regional perfusion in the cortex and
medulla, estimated using ASL, have been found to decrease
post-furosemide injection [172].
While the inconsistency between findings makes the net
effect of loop diuretics difficult to conclude, omitting diu-
retic drugs in the morning before RBF measurement should
be considered where possible.
Discussion
This review has evaluated the magnitude and direction of
change of several influencing factors on RBF with the goal
to formulate evidence-based recommendations. The results
obtained from the literature support the need for a rigorous
study design to enable more efficient quantification of RBF.
Despite some large variability in the reported magnitude of
change, the direction of change was mostly aligned between
studies. It must be noted that measurement error is inevitable
and constitute an additional source of variability, even if a
gold-standard method was used.
Standardization is a pivotal initial phase in biomarker
validation. Ongoing efforts for standardisation of renal
MRI seek to establish consistent and reliable measurement
protocols [8–10]. The work presented in this review paper
supplement existing recommendations with additional evi-
dence-based information and could promote an alignment
of opinions in future revisions of the consensus. A wide
range of influencing factors was found to cause changes in
RBF. In the recently published technical recommendations
for PC-MRI, the panel has advised against restricted diet
and hydration (i.e. fasting), instead scans are recommended
to be performed in the normal hydration state while avoid-
ing salty- and protein rich meals [9]. Although there is a
dispute on the acute effect of water loading, hydration is
undeniably a standard procedure used in clearance studies to
maintain urine flow at constant rate. At present, the provided
evidence supports the relevance of normal hydration before
RBF measurements. With respect to food intake, our recom-
mendation is less clear-cut, and calls for future research in
this matter.
Depending on the influencing factor, RBF can decrease
by a mean of 130mL/min or increase by 250 mL/min.
Differences of this magnitude have an important clinical
implication and can be confounded with disease character-
istics. For instance, patients with benign hypertension show
reduced RBF compared to controls subjects [173]. An effect
of similar magnitude and direction can be observed post
exercise or in response to heat exposure. By contrast, newly
diagnosed diabetes is characterized by higher RBF than in
normal subjects [174, 175]. An effect of similar pattern can
be observed in response to protein meal in healthy subjects
[67].
Considering the data presented in this review, we propose
evidence-based recommendations to provide future research-
ers a means to interpret and possibly correct for the influenc-
ing factors. While the review primarily aimed at assessing
RBF and perfusion, the proposed recommendation might
also apply to other techniques such as renal BOLD MRI.
The specific recommendations are summarized in Table3,
and include all factors, even those only minimally contribut-
ing to the variability. The physiological confounders were
arranged into three separate categories in relation to the
stage where they should be considered. Since it may not
be feasible to control for all modifiable in clinical practice,
it can be advised to acquire information using question-
naire. For instance, providing a standardized meal before
conducting the exam can ensure reducing the influence of
Magnetic Resonance Materials in Physics, Biology and Medicine
1 3
certain type of food on RBF, but may also cause financial
and practical constrains. An alternative option would be to
ask participants to keep a record of their last meal, which
can be referred to in case of unusual measurement. While
current evidence in the literature showed preserved RBF
in response to acute use of caffeine, nicotine and alcoholic
products, more studies would be helpful to support this con-
clusion. Our recommendation to withdraw acute medications
was based on current preparation worked in a clinical trial
[176]. However, whether this acute cessation of treatment
has an impact on renal haemodynamics was not studied
before. Similarly, little is known about the acute use of some
novel medications, notably sodium–glucose cotransporter
2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-
1) receptor agonists. These medications have been found
to contribute to improved renal outcomes [177], and more
comprehensive investigation into their acute influence on
RBF is needed to understand their potential implications.
As a general rule, obtaining additional information regard-
ing individual habits, and/or prescribed medications can be
considered for a rigorous study design. These factors can
then be used as covariates in the statistical analysis model to
enable better interpretation of RBF measurement.
Limitations
One limitation of this review arises from the inclusion of
studies using various techniques to measure RBF in response
to each influencing factor. The unit of RBF was inconsist-
ently reported in the literature, where normalization to BSA
was used in some but not all studies. For the analysis of this
review, RBF was assessed in absolute units (i.e. mL/min) as
correcting to BSA is a potential confounder and therefore
can obscure some of the variation between individuals of
different body dimensions. It must therefore be emphasized
that the magnitude of change in absolute units presented in
this review should not be used to correct for such effects but
rather as an estimation of the effect size. A detailed discus-
sion of the underlying physiological mechanism affecting
an individual confounding factor would enable better under-
standing of the reported results, but this was not the main
objective of the current review.
Conclusions
The variability in RBF in response to physiological factors
is an important consideration in the development of an effi-
cient study design to assess the renal hemodynamic. In this
review, the effect of several influencing factors was assessed
in order to provide an evidence-based recommendation.
Future studies aiming to measure RBF are encouraged to
follow a rigorous study design, which takes into account
the factors that can influence RBF results. In addition, some
gaps in the scientific literature were highlighted that repre-
sent exciting opportunities for future exploration to expand
our understanding of kidney physiology and more impor-
tantly, promote well-controlled quantitative assessment.
Acknowledgements BA is funded by Taibah University, Saudi Arabia.
KS, KKS and SPS are supported by the BEAT-DKD project funded
by the Innovative Medicines Initiative 2 Joint Undertaking under grant
agreement No 115974. This Joint Undertaking receives support from
the European Union’s Horizon 2020 research and innovation pro-
gramme and EFPIA with JDRF.
Author contributions BA performed the literature search, analysis,
and writing the first draft of the manuscript. KS, DLB, KKS, and SPS
commented on later versions of the manuscript. All authors read and
approved the final manuscript.
Data availability Data sharing is not applicable to this review article
as no new data were created or analyzed in this study.
Declarations
Conflict of interest The authors declare that they have no conflict of
interest.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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