Received: 17 April 2022 | Revised: 27 July 2022 | Accepted: 30 August 2022

DOI: 10.1002/efd2.33

REVIEW ARTICLE

Therapeutic potential of cranberry for kidney health and diseases

Ruhul Amin1 | Chandrashekar Thalluri1 | Anca Oana Docea2 | Javad Sharifi‐Rad3 |

4
Daniela Calina

1
Faculty of Pharmaceutical Science, Assam
Down Town University, Guwahati, Assam,
India
2 (CRF) is linked to inflammation, oxidative stress, cellular aging, and gut
Department of Toxicology, University of
Medicine and Pharmacy of Craiova, Craiova,
Romania
3
Facultad de Medicina, Universidad del Azuay,
Cuenca, Ecuador
4
Department of Clinical Pharmacy, University
of Medicine and Pharmacy of Craiova,
Craiova, Romania
Correspondence
Javad Sharifi‐Rad, Facultad de Medicina,
Universidad del Azuay, Cuenca, Ecuador.
Email: javad.sharifirad@gmail.com
Daniela Calina, Department of Clinical
Pharmacy, University of Medicine and
Pharmacy of Craiova, Craiova, Romania.
Email: calinadaniela@gmail.com
Funding information
None
Abstract
A higher risk of cardiovascular mortality in persons with chronic renal failure
dysbiosis, to name a few contributing factors. According to a growing body of
evidence, some dietary choices may reduce the severity of certain adverse
effects. Specialized databases such as PubMed/Medline, Embase, Google Scholar,
and UpToDate were searched to find published studies that focus on the
pharmacological effects and mechanisms of cranberries’ bioactive compounds on
CRF and human health. Cranberry supplementation has been demonstrated in
clinical research to offer health advantages for humans, such as reducing urinary
tract infections. Recently, it has been reported that cranberry polyphenols possess
anti‐inflammatory and antioxidant effects and are also known to have the
capacity to affect gut flora. Scientific studies on the beneficial pharmacological
effects of cranberries on human health may provide an understanding of
traditional cranberry therapy in chronic kidney disease and other chronic
conditions. However, translational studies are needed to determine the exact dose
that can be administered to humans as well as the validation of nutritional
supplements that contain cranberry extract.
KEYWORDS
catechin, chronic renal failure, cranberries, human health, procianidins

1 | INTRODUCTION Uttara et al., 2009). Increased gut barrier permeability,

Chronic renal failure (CRF) related to kidney dys-
function has been identified as a major public health
issue worldwide (Agarwal & Srivastava, 2009; Levey
et al., 2007). If you have severe kidney disease, you are
more prone to have symptoms such as hunger and
edema, as well as constipation and a high degree of
stress (physical, psychological, or pharmacological)
(Stenvinkel, 2010). Due to an imbalance between reactive
species oxygen (ROS) and the body's natural antioxidant
defense systems, oxidative stress and inflammation are
widespread in this group of patients (Surai et al., 2019;
along with oxidative stress and inflammation in the gut
microbiota, is associated with chronic kidney disease.
These prevalent findings are important because they can
highlight the progression of kidney disease and chronic
cardiovascular disease, which are responsible for most of
the early mortality related to chronic kidney fail-
ure (Levey et al., 2007; Peev et al., 2014). Foods such
as vegetables and fruits include bioactive compounds
that have anti‐inflammatory and antioxidant properties,
which may help minimize the proinflammatory effects of
a uremic environment. More studies on berries are
necessary (Borges et al., 2018; Esgalhado et al., 2017;

Abbreviations: AOPP, advanced oxidation protein products; CRF, chronic renal failure; FRAP, ferric‐reducing antioxidant power; GPx, glutathione peroxidase;
HOMA‐IR, Homeostatic Model Assessment of Insulin Resistance; LPS, lipopolysaccharides; MDA, malondialdehyde; NAFLD, nonalcoholic fatty liver disease; NF‐κB,
nuclear factor‐κB; oxLDL, oxidized low‐density lipoprotein; PAC, proanthocyanidins; PGC‐1α, peroxisome proliferator‐activated receptor gamma coactivator 1α; SOD,
superoxide dismutase; TLR‐4, Toll‐like receptor 4; TNF‐α, tumor necrosis factor‐α; VUR, vesicoureteral reflux.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2022 The Authors. eFood published by John Wiley & Sons Australia, Ltd on behalf of International Association of Dietetic Nutrition and Safety.

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https://doi.org/10.1002/efd2.33

2 of 14 | THERAPEUTIC POTENTIAL OF CRANBERRY ON KIDNEY
Kowalska et al., 2017; Rysz et al., 2017). Procyanidins,
which are present in American cranberries (Vaccinium
macrocarpon Ait.), have been demonstrated to be
effective against infectious illnesses, oxidative stress,
and inflammation (Feghali et al., 2012; A. Howell,
2008; Mckay & Blumberg, 2007). Studies conducted in
recent decades have shown that bioactive compounds
from cranberries have anti‐infective and anti‐
inflammatory effects on the urinary tract (Mafra et al.,
2019, 2021; Teixeira et al., 2022). Cranberries are foods
rich in bioactive compounds, such as anthocyanins (fruit
coloring pigments), flavonols (yellow pigments), and
proanthocyanidins (PAC) (which are responsible for the
astringent effect of the fruit) (Gudžinskaitė et al., 2020).
They are an important source of vitamin C, vitamin A,
and vitamin B complex, and potassium (Pellerin et al.,
2021). The main source of carbohydrates is sugars, such
as sucrose, glucose, and fructose (Urbstaite et al.,
2022), and the rest is made up of insoluble fibers, such
as pectin, cellulose, and hemicellulose. They also contain
soluble fibers, which is why excessive consumption can
cause diarrhea (Zhao et al., 2020). Cranberries also
contain bioactive compounds and antioxidants, espe-
cially flavonoids (Colletti et al., 2021). Most of these are
concentrated in the peel and are reduced by the
preparation of cranberry juice. Cranberries contain
quercetin, myricetin, peonidine, ursolic acid, and PACs
type‐A (Nemzer et al., 2022). Anthocyanins and other
flavonoids can reduce lipid oxidation and protein
glycosylation; thus, cranberry juice could help reduce
the side effects of diabetes and improve the quality of life
of people with this condition (Bendokas et al., 2020). The
objective of the current updated review is to investigate
the potential mechanisms of action of cranberries'
bioactive compounds in the prevention of CRF.
2 | METHO DOL OGY
For this review, several PubMed/Medline, Embase,
Google Scholar, and UpToDate electronic databases
were searched using the following MeSH terms:
“Animals,” “Phytochemicals/chemistry,” “Phytochem-
icals/metabolism,” “Phytochemicals/pharmacology,”
“Phytotherapy,” “Gastrointestinal Microbiome,”
“Humans,” “Renal Insufficiency, Chronic/diet ther-
apy,” “Renal Insufficiency, Chronic/metabolism,”
“Renal Insufficiency, Chronic/microbiology,” “Vacci-
nium macrocarpon/chemistry,” and “Vaccinium macro-
carpon/metabolism,” The reference lists of the articles
included in this review were searched manually without
limitations of publication type or language restrictions.
The inclusion criteria were as follows:
(i) preclinical in vivo studies that reported the pharma-
cological effects of cranberry extract on kidney and
other diseases,
26663066, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/efd2.33 by Cochrane Malaysia, Wiley Online Library on [10/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
(ii) in vivo experimental studies with a well‐defined
dose, and
(iii) clinical studies on human subjects with various
diseases that were treated with cranberry extract and
with the final results included.
The exclusion criteria were as follows:
(i) studies that did not report the pharmacological
molecular mechanisms of cranberry,
(ii) studies that used cranberry associated with conven-
tional drugs or their metabolites, and homeopathic
products, and
(iii) incomplete articles and duplicate studies.
The scientific name of the plants has been validated
according to PlantList (Heinrich et al., 2020).
3 | CRANBERRY: A BRIEF
OVERVIEW
Traditional medicine and dietary supplements including
the American cranberry (V. macrocarpon Ait.) have long
been used to treat renal failure in animals, and it has
recently been found to be useful in this regard. The
Ericaceae family's American cranberry (V. macrocarpon
Ait.) has long been used as the oldest traditional
medicine and recently it has been reported to be
beneficial in the treatment of renal failure in animals
when used as a dietary supplement (de Almeida
Alvarenga et al., 2019; Noreen et al., 2021). Cranberry
is one of the few fruits that has a low content of natural
carbohydrates relative to its high polyphenolic chemical
content, which includes flavonoids, anthocyanins, PACs,
phenolic acids, and terpenoids; all of these contribute to
the fruit's significant antioxidant abilities (Figure 1). The
active ingredients with beneficial effects on kidney
disease are extracted from cranberry fruits, which have
a dark red color. They contain significant amounts of
vitamin C, salicylic acid, and antioxidants called
anthocyanins and proanthocyanins (Nemzer et al., 2022).
Cranberry is also one of the few fruits that has a high
polyphenolic chemical content relative to its low
carbohydrate content (Blumberg et al., 2013; Ferlemi &
Lamari, 2016; Pappas & Schaich, 2009; Wu et al., 2020).
According to new research, cranberries contain
phytochemicals that distinguish them from other fruits
and may explain some of their health benefits. The
polymerization of flavan‐3‐ol units into PACs, which are
characterized by epicatechin tetra‐ and pentamers, results
in the synthesis of anthocyanins in the phenylpropanol
metabolism. Type A interflavonoid binding PACs
account for more than 95% of the PACs found in
cranberries (PAC type A) (Neto, 2007). PACs have the
potential to defend against bacterial infection by
preventing pathogens, such as Escherichia coli, from

AMIN ET AL.
FIGURE 1 Chemical structures of the most important bioactive compounds of cranberries
sticking to urinary epithelial cells (González de Llano
et al., 2020a; A.B. Howell, 2007).
Many years have passed since cranberry juice was
first used to prevent the symptoms of and avoid
recurrence of urinary tract infections (UTIs) by prevent-
ing microbes from attaching to the bladder walls.
Cranberry juice is less beneficial in the prevention of
infections in the urinary tract than was previously
believed, according to research (UTI)(Alfaro‐Viquez
et al., 2018; A. Howell, 2008). These studies compare
the effectiveness of cranberry juice with other non‐
antibiotic pharmacological approaches for the preven-
tion of UTI (Ghouri et al., 2018; Wawrysiuk et al., 2019).
Dental caries, periodontal diseases, cardiovascular
diseases and gastric ulcers caused by Helicobacter pylori
can be prevented by consuming cranberries that have a
high content of polyphenols (PACs) (Feliciano et al., 2015).
McKay et al. (2015) were the first to discover
bioactive substances of cranberry, called PAC‐A2, in
urine and plasma 24h in 10 healthy older people with no
history of cardiovascular disease after they consumed a
cocktail containing cranberry juice with a low amount of
calories (54% juice). Following consumption of cran-
berry juice, Feliciano et al. discovered that hippuric
acid, catechol‐O‐sulfate, hydroxy hippuric acid,
4‐methylcatechol‐O‐sulfate, phenylacetic acid, ferulic
acid 4‐O‐sulfate, benzoic acid, 4‐hydroxyphenyl‐acetic
acid, dihydro caffeine, and isoferulic acid were the most
abundant plasma metabolites in healthy young men
(787mg polyphenols) (Feliciano et al., 2016; Feliciano
et al., 2017). Another study reported that consumption of
cranberry drinks caused a linear increase in plasma
metabolites; however, there were a lot of individual
variances. Catechol‐O‐sulfate, 3‐(4‐hydroxyphenyl)
propionic acid and hippuric acid proved to be the
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| 3 of 14
most important plasma compounds and their plasma
concentration is variable depending on the intestinal
microbiota.
3.1 | Cranberry and chronic renal diseases
Studies on the beneficial effects of cranberry in prevent-
ing chronic and recurrent UTIs have also shown
beneficial effects through the following mechanisms
(Xia et al., 2021):
i. It limits the risk factors and the recurrence of
manifestations produced by them in the bladder,
urethra, ureters, and kidneys (Fu et al., 2017),
ii. It blocks the connection between specific receptors on
the mucous membranes of the lower and upper
urinary tract and the fimbriae (FimH and FimP)
filamentous formations on the surface of the disrupt-
ing factors with which they attach to the mucous
membranes (González De Llano et al., 2020b),
iii. It maintains a low urinary pH (acidifies urine): it
supports the conversion of quinic acid into hippuric
acid (Liu et al., 2020).
In persons with CRF, premature aging is related to high
mortality of cardiovascular risk factors like systemic
inflammation and oxidative stress (Cachofeiro et al., 2008;
Kooman et al., 2014). Chronic uremic inflammation has
been related to redox‐sensitive signaling pathways. Even
though the biological function occurs at the molecular or
cellular level, processes that induce increased inflammation
in CRF are difficult to understand (Small et al., 2012). Early
on in chronic kidney disease, dysregulation of the body's
redox balance may be detected and it worsens as the disease

4 of 14 | THERAPEUTIC POTENTIAL OF CRANBERRY ON KIDNEY
progresses. When the body's antioxidant capacity does not
increase in response to oxidative stress, a redox status
imbalance arises (Chen et al., 2017; Daenen et al., 2019).
Inflammatory cytokines are produced by transcriptional
activation of antioxidant genes by Nrf2 (nuclear factor
erythroid‐related factor 2). It transforms into nuclear factor‐
κB (NF‐κB), a transcriptional factor with a role in gene
transcription involved in the appearance of inflammatory
cytokines. Increased oxidative stress and systemic inflamma-
tion in CRF occur as a result of Nrf2 and NF‐κB
dysfunction (Mao et al., 2010; Yerra et al., 2013).
Inflammation and oxidative stress may play many roles in
the development of CRF and its effects, such as cardiovas-
cular disease. CRF‐related variables such as uremia,
pharmaceutical treatments, and dietary limitations are linked
to gut dysbiosis and increased gut barrier permeability
(Graboski & Redinbo, 2020; Rysz et al., 2021). In a study, it
was reported that nephrectomy, which resulted in colonic
inflammation and impaired gastrointestinal motility, altered
the gut flora and caused constipation in mice (Nishiyama
et al., 2019).
In individuals with CRF, altered gut flora produces
uremic toxins such as indoxyl sulfate (IS), p‐cresyl
sulfate, trimethylamine N‐oxide, and indole‐3‐acetic
acid, which increase and contribute to oxidative stress
and inflammation (Mafra et al., 2018; Wojtaszek et al.,
2021). Furthermore, these toxic substances stimulate the
production of ROS, activate NADPH oxidase, and
promote the production of inflammatory cytokines, all
of which contribute to the development of autoimmune
disorders (Li et al., 2013; Stockler‐Pinto et al., 2016).
According to a recent study, uremic toxins are linked to
increased NF‐kB expression and reduced Nrf2 in hemo-
dialysis patients (Sun et al., 2020). Uremic toxins have been
linked to cardiovascular illness in people with CRF and have
a wide range of harmful effects, including endothelial
dysfunction (Ito & Yoshida, 2014; Moradi et al., 2013).
Lipopolysaccharides, a primary component of Gram‐
negative bacteria's outer membrane, are transferred into
the host's internal environment when the intestinal barrier is
disrupted, causing inflammation (Chandler & Ernst, 2017).
According to the findings of this study, intestinal inflamma-
tion was shown to be more in nephrectomized rats as
compared to the control or standard group, and elevated
iNOS seemed to play a critical role in the development of
inflammation (Finch et al., 2012). An additional study
discovered that proteins containing epithelial narrow junc-
tions were missing in the guts of nephrectomized rats and
that Nrf2 and its targets (SOD, NQO1, and catalase) were
significantly reduced; also, NF‐kB was activated in the guts
of nephrectomized rats and increased the expression of
inflammatory markers (MCP‐1, COX‐2, gp91phox, and
iNOS)(Aminzadeh et al., 2013; H. J. Kim & Vaziri, 2010).
With the identification of cellular senescence as a
crucial element in the aging process and age‐related
illnesses, it has been demonstrated to be a mechanism
26663066, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/efd2.33 by Cochrane Malaysia, Wiley Online Library on [10/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
that induces irreversible cell death in response to a
variety of stimuli (Sifaki et al., 2020). Individuals with
renal illness show systemic aging characteristics as well as
localized pathology, which is related to low levels of
chronic inflammation, organelle malfunction, senescence,
and macromolecules (Ebert et al., 2021).
In human uremic arteries (Smith, 2016), for example, a
proliferation in the number of senescence‐associated‐gal‐
positive cells was linked to an increase in the degree of
calcification, which is an early indicator of cardiovascular
aging (Baker et al., 2011; Stenvinkel et al., 2017). The
results of preclinical in vivo studies performed on rats
showed that serotherapy alleviated the degenerative phys-
iopathological changes related to age (S.‐H. Lee et al., 2019;
Roos et al., 2016). As a result, blocking cellular senescence
might be a useful method for delaying, lowering, or even
reversing the progression of chronic kidney disease
and its senescence‐related complications (Kirkland &
Tchkonia, 2017).
Dietary changes, pharmaceutical treatment, and dialysis
optimization may all help to lower the risk of CRF, but
there has been no evidence of a significant increase in the life
expectancy of patients in this high‐risk category (Bauer et al.,
2013). A high‐salt, high‐animal‐protein Western diet has
been related to an elevated risk of chronic renal disease
(CRF) (Kramer, 2017). Dietary treatment may be an
alternative to bioactive molecule therapies for lowering the
uremic risk factor profile. Because these substances can
reduce inflammation, oxidative stress, and gut dysbiosis,
they can help people with CRF lead a better lifestyle. Fruits
with a rich red color, such as berries, are known to have
beneficial bioactive compounds, among others (de Almeida
Alvarenga et al., 2018; Mafra et al., 2021), and many studies
have shown that the levels of creatinine and urea in the
blood were reduced by intake of cranberry (Galal et al.,
2019) (Figure 2).
For decades, cranberry has been used to prevent and
reduce the symptoms of UTIs (González de Llano et al.,
2020b). There are two theories in the literature to explain
the effectiveness of cranberry extract in the prevention of
CRF (Molina et al., 2021). The first theory is based on the
acidic character of cranberries, due to the presence of
vitamin C, salicylic acid, and oxalic acid. According to this
theory, cranberry extract acidifies the urine, making it
difficult to develop E. coli colonies, the main cause of this
type of disease (Molina et al., 2021). E. coli is a type of
bacterium that is normally found in the human gut and also
in other warm‐blooded animals. Another theory is that
antioxidants such as anthocyanins and proanthocya-
nins may have the ability to reduce the tendency of bacteria
to adhere to the bladder wall and urethra (Molina et al.,
2021). According to this theory, cranberry is rather effective
prophylactically (in prevention) and less in the acute phase
of the disease. Salicylic acid acts as an anti‐inflammatory
agent and as an antiseptic (Adamczak et al., 2019; Molina
et al., 2021).

AMIN ET AL.
F I G U R E 2 Illustrative scheme of the potential effects of bioactive compounds on CKD and other human diseases. ↑, increased; ↓, decreased;
APO‐A1, apolipoprotein A1; APO‐B, apolipoprotein B; CKD, chronic kidney diseases; HDL, high‐density lipoprotein; LDL, low‐density
lipoprotein; NF‐κB, nuclear factor κ‐light‐chain‐enhancer of activated B cells; Nrf2, nuclear factor erythroid 2‐related factor 2; ROS, reactive oxygen
species; TLR4, Toll‐like receptor 4; and TNF‐α, tumor necrosis factor‐α.
4 | OTHER POTENTIAL
BENEFITS OF CRANBERRY FOR
HUMAN HEALTH
4.1 | Antioxidant effects
Inflammation and oxidative stress are known character-
istics of age‐related chronic disorders, which are
caused by poor lifestyle choices, and increase the risk
of cardiovascular disease (J. Sharifi‐Rad, Rodrigues,
Sharopov, et al., 2020; M. Sharifi‐Rad, Kumar,
et al., 2020). Flavonoid and non‐flavonoid polyphenols
from cranberries have antioxidant and anti‐
inflammatory properties. Polyphenols in cranberries are
regarded as potent antioxidants, and this has been the
focus of the majority of studies (Pappas & Schaich,
2009). Polyphenols may neutralize ROS and disrupt cell
signaling pathways; however, the mechanisms by which
they do so remain unclear (Duthie et al., 2006; Metcalfe
& Alonso‐Alvarez, 2010; Valentová et al., 2007).
Polyphenols influence stress‐related gene expression,
increasing the body's natural antioxidant capacity
(Safari et al., 2020). Both antioxidant and inflammatory
properties of cranberries have been reported in animal
research, in in vitro studies, and even in clinical trials in
patients with chronic diseases who did not have chronic
kidney disease (Table 1).
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| 5 of 14
4.2 | Potential role in the intestinal flora
Intestinal bacteria live within the human body. They play
a critical physiological role, regulating the host's metab-
olism and other activities, as well as maintaining overall
health (J. Sharifi‐Rad, Rodrigues, Stojanovic‐Radic,
et al., 2020). It is necessary to further explore the benefits
of cranberries, as well as how these polyphenols change
the makeup of the gut composed microbiota, considering
their antibacterial action in the urinary system, as
reported by researchers (Requena et al., 2010). Phyto-
chemicals such as the polyphenols present in cranberries
can have a positive impact on the homeostasis of the
intestinal microbiota, acting as effective prebiotics.
(Rodríguez‐Daza et al., 2021). They may also help to
decrease inflammation while also improving the design
and intestinal homeostasis of the mucosal layer (Anhê
et al., 2015) (Figure 2). Studies have shown that in rats
given enteral nutrition with cranberry derivatives, recov-
ery was promoted and there was an increase in the
number of goblet cells as well as an increase in the
amount of 2‐mucin, interleukin‐4, and interleukin‐13,
resulting in an improvement in the function of the
intestinal mucus layer (Pierre et al., 2013). Goblet cells
(specialized intestinal epithelial cells) secrete mucins,
which are necessary for preserving the reliability of the
intestinal mucosal wall. Goblet cells travel across the villi
 26663066, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/efd2.33 by Cochrane Malaysia, Wiley Online Library on [10/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 14 | THERAPEUTIC POTENTIAL OF CRANBERRY ON KIDNEY

TABLE 1 Beneficial effects on and potential pharmacological mechanisms of cranberry in terms of human health
Type of study Model/doses Effects/potential mechanisms of action Ref.
In vivo Rabbits antioxidant Han et al. (2007)
VUR‐induced oxidative renal damage protect the kidneys from infection‐induced oxidative renal
Dose = 1 g of cranberry powder/kg damage
BW, daily ↓ mononuclear cell infiltration
3 weeks ↓interstitial fibrosis

Obese diabetic mice antioxidant M. J. Kim et al. (2013)

Dose = 2600 mg anthocyanins – ↓illnesses caused by oxidative stress
freeze‐dried cranberries/daily ↑ insulin's ability to regulate blood sugar level
6 weeks ↓ CRP, ↓ IL‐1, ↓ IL‐6 l

Mice
Gr‐ A: PAC 8 mg up to 5 days
Gr‐ B: 50 mg PAC daily/5 days
Gr‐ C: 100 mg PAC daily/5 days
Groups A and B: IL‐13 rises
Group C: IL‐4 and IL‐13 rise
PACs restore the mucous layer of the gut and its activities Pierre et al. (2013)
↑ growth of GC structures
↑ IL‐ 4, ↑ IL‐ 13
↑MUC2

Rats for maintaining the pH at a lower level, the Fe 3–TPTZ M. J. Kim et al. (2014)
Cranberry—anthocyanins complex undergoes reduction and forms ferrous
(120 g/100 g) tri‐pyridyl triazine Fe2 TPTZ
PACs dose = 2600 mg/daily ↓ catalase, ↓ SOD
LPS dose = 100 g/daily
6 weeks

Mice antiobesity, antidiabetes Anhê et al. (2015)

Dose = 200 mg/kg/day cranberry ↑ insulin sensitivity, ↑ insulin tolerance
extract, 8 weeks ↓ weight, ↓ TG

Rats antiobesity Peixoto et al. (2018)

Dose = 200 mg/kg/day (CE) antioxidant, ↓ HFD‐induced obesity
cranberry extract

Overweight rats hepatoprotective Glisan et al. (2016)

Dose = 0.5–7 g cranberry ↓ expression of genes related to the nucleotide, ↓ leucine,
polyphenol‐rich extract/daily, ↓pyrin 3
10 weeks ↓ALT, ↓ severity of NAFLD

Rats losartan and cranberry extract act synergistically to prevent Galal et al. (2019)
Dose = 100 mg/kg BW, cranberry hepatorenal injury and cardiotoxicity produced by AlCl3
extract ↓ urea, ↓ ALT, ↓ AST, ↓ cholesterol, ↓ TG, ↓ creatinine
28 days

Clinical studies Noncontrolled study no significant change in the proinflammatory cytokines Simão et al. (2013)
56 subjects with metabolic TNF‐α, IL‐1, IL‐ 6, ↓ lipid peroxidation,
syndrome ↓ oxidation of proteins,
↑ folic acid, ↑ adiponectin, ↑ homocysteine, ↓ LDL

Randomized‐controlled study ↓ oxidation of lipids Basu et al. (2011)

31 subjects with metabolic ↑ plasma antioxidants, ↓ LDL
syndrome
Dose = 700 ml cranberry juice/
daily, 8 weeks
Dose = 480 ml CJ/daily, 8 weeks

21 healthy men ↑ plasma antioxidants Ruel et al. (2005)

Dose = 7 ml CJ/kg BW/daily, ↓ LDL levels
2 weeks

Randomized‐controlled study protect human vascular endothelial Duthie et al. (2006)

20 healthy female participants protect cell cultures against DNA breakage
Dose = 750 ml CJ/daily, 2 weeks ↓ oxidative cell membrane damage
↓ growth of colon cancer cell lines
↑ vitamin C plasmatic level

78 subjects overweight men and antioxidant Chew et al. (2019)

women ↓ CVD risk factors

AMIN ET AL.
TABLE 1 (Continued)
Type of study Model/doses
Dose = 450 ml CJ/daily
8 weeks
65 healthy women
Dose = 400 mg DCJ or 1200 mg
cranberry beverage
8 weeks
30 subjects with T2D and oral
hypoglycemic medication
Dose = 500 mg cranberries extract
encapsulated/daily, 12 weeks
Double‐blind, randomized,
placebo‐controlled study, 12
normal adults
Dose = 475 ml cranberry extract,
8 weeks
Double‐blind
placebo‐controlled study, 56
healthy persons
Dose = 240 ml bottles of low‐calorie
cranberry juice/daily, 8 weeks
25 adults with T2D
Dose = 40 g cranberries dried
extract/daily, 12 weeks
Double‐blind study, 16 subjects
Dose = 200 mg CE/daily, 6 weeks
Abbreviations: ↑, increased; ↓, decreased; ALT, alanine transaminase; AST, aspartate aminotransferase; CE, cranberry extract; CJ, cranberry juice; COX2,
cyclooxygenase‐2; CVD, cardiovascular diseases; DCJ, dried encapsulated cranberry; GPx, glutathione peroxidase; HDL, high‐density lipoprotein; IFN‐α, interferon‐α;
IL, interleukin; LDL, low‐density lipoprotein; NAFLD, nonalcoholic fatty liver disease; NO, nitric oxide; PGE2, prostaglandin E2; SOD, superoxide dismutase;
TG, triglycerides; TNF‐α, tumor necrosis factor‐α.
and develop from the crypt of stem cells, and they replace
the layer of epithelium cells every 3–5 days, as does the
epithelial layer (Monk et al., 2016). Mucin synthesis is
triggered by cholinergic stimulation, which is controlled
by the T‐helper 2 cytokines IL‐4 and IL‐13, which are
produced by the lamina or intraepithelial lymphocytes
and are released into the environment (Grondin et al.,
2020). A study by Anhê et al. (2015) found that cranberry
treatment increased the sensitivity of insulin and
decreased triglyceride levels; then, decreased inflamma-
tion occurred in the intestinal area, along with oxidative
stress, in mice fed with a diet high in fat and sugar for
12 weeks. The researchers also speculated that cranberry
would boost the development of Akkermansia sp., an
astringent of Gram‐negative‐type anaerobe and mucin‐
degrading bacterium that has been associated with the
intestinal barrier shield in a previous study.
4.3 | Cardioprotective effects
Although the evidence is ambiguous, cranberries appear to
have a cardioprotective effect. It is possible to gain this
advantage via several mechanisms, including antioxidant
effects (such as a reduction in peroxidation of lipids and
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| 7 of 14
Effects/potential mechanisms of action Ref.
↓ glucose, ↑ insulin levels, ↓ inflammatory biomarkers, ↑
HDL, ↓ endothelin‐1, ↓ CRP
preventing oxidative stress in populations at risk, such as those Valentová
with metabolic syndrome and dialysis patients, ↓ oxidized et al. (2007)
glutathione ratio, ↑ interferon, ↑ NO, ↑ HDL
↓risk of atherosclerosis, ↓ total cholesterol I. Lee et al. (2008)
↓ LDL, ↑ HDL
anti‐inflammatory, antioxidant Mathison et al. (2014)
↓ urinary bacterial adhesion
↑ GPx, ↑ glutathione, ↑ SOD, ↓ IL‐4
↓blood pressure, ↓ CRP Novotny et al. (2015)
↓TG, ↓ glucose
↓ipid peroxidation, ↓ postprandial glucose Schell et al. (2017)
↓IL‐18, ↓IFN‐α, ↓glucose levels
anti‐inflammatory Skarpańska‐Stejnborn
↓TNF‐α, ↓IL‐6, ↓PGE2, ↓COX2 et al. (2017)
oxidation involving protein), but also through other actions
such as reducing the levels of homocysteine and altering the
lipid content of protein profiles such as an increase in the
levels of HDL‐c, APO‐A1, and paraoxonase‐1, and a
decrease in oxidized LDL and APO‐B levels (Chew et al.,
2019; Glisan et al., 2016) (Figure 2).
4.4 | Blood pressure regulation
According to studies, cranberry consumption may reduce
endothelial progenitor cells (EPCs), in turn reducing
epithelial dysfunction (Dohadwala et al., 2011). EPCs
play a role in tissue calcification and inadequate healing,
resulting in vascular damage that persists. Four hours
after administration, cranberry juice with a concentra-
tion of 1238 mg total polyphenols was the most effective
on vascular function in healthy men (Rodriguez‐Mateos
et al., 2016). According to researchers, polyphenol
indicators in the plasma are linked to increases in flow‐
mediated dilation. Administration of cranberry juice
with a concentration of 835 mg polyphenols in patients
with cardiovascular disease showed vasodilation with
increased blood flow (Dohadwala et al., 2011). Despite
this, there was no long‐term influence on endothelial

8 of 14 | THERAPEUTIC POTENTIAL OF CRANBERRY ON KIDNEY
vasodilator function, which is consistent with the results
of Flammer et al. (2013) showing that cranberry juice
had no long‐term effect on vascular function (2× 230 ml
daily for 4 months, with a total phenolic content of
1740 g/ml) (Flammer et al., 2013).
4.5 | Hepatoprotective effects
Some studies recently demonstrated that bioactive
compounds contained in cranberries reduced hepatic
steatosis by decreasing the production of fatty acids,
TNF‐α, Toll‐like receptor 4 (TLR‐4) and NF‐κB
(de Almeida Alvarenga et al., 2019; Glisan et al., 2016;
Jia et al., 2020; Peixoto et al., 2018; Rodriguez‐Mateos
et al., 2016). Galal et al. (2019) discovered that cranberry
extract (when combined with losartan) decreased hepa-
totoxicity and cardiotoxicity in rats (Figure 2).
4.6 | Anti‐diabetic effects
Bioactive compounds from cranberries are also effective
in the management of diabetes and patients with
metabolic syndrome (Kowalska & Olejnik, 2016). In
addition, cranberry powder administered to obese
patients and type 2 DM lowers the postprandial plasma
glucose level (Schell et al., 2017) (Figure 2).
5 | THERAPEUTIC
PERSPECTIVES AND
CLINICAL GAPS
Cranberries are phytonutrients rich in flavonoids that can
protect against and prevent many diseases. Flavonoids
have a number of beneficial properties, the most impor-
tant of which is their antioxidant effect (Xiao, 2022). They
can protect the body, first of all, from intense harmful
reactions and free radicals. Flavonoids can enhance the
physiological effects of other dietary antioxidants, such as
vitamins E and C, as they synergize with them, promoting
their regeneration (Zhong et al., 2022). Studies carried out
with other natural products that contain flavonoids,
polyphenols, and cranberry have reported a reduction in
the incidence of recurrent UTIs. As a result, a modern
nutritional approach to the treatment of these kidney
diseases could decrease the use of antibiotics and in turn
decrease the resistance of bacteria to antibiotics in UTIs
(Cao et al., 2022; González de Llano et al., 2020b;
Xiao, 2022)
Researchers are interested in studying the impact
of flavonoids and nonflavonoids on senescent cells
and their related secretory phenotypes. Sirtuin has
emerged as a major player in the control of age‐
related processes such as telomere attrition and DNA
damage repair, although its exact involvement in
26663066, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/efd2.33 by Cochrane Malaysia, Wiley Online Library on [10/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
these processes is unknown (S.‐H. Lee et al., 2019).
According to Rahnasto‐Rilla et al. (2018), many
flavonoid classes may either block or trigger the in
vitro deacetylation activity of SIRT6, with anthocya-
nidins, bioactive molecules found in abundance in
cranberries, being the most significant enhancer of
deacetylation SIRT6 among all the categories of
flavonoids. Quercetin, a natural flavonoid that in-
hibits AMPK via an mTOR‐dependent mechanism,
may help to slow down the aging process (Hwang
et al., 2009; Stenvinkel et al., 2016). Along with their
research on mTOR pathway inhibitors, Feresin et al.
(2016) found that polyphenol extracts obtained from
all typical fruit categories, such as blackberry and
raspberry, can reduce ROS, p21,p53, β‐galactosidase
and Nox1. Even though the polyphenols in this
research were not sourced from cranberries, the fact
that they have a polyphenol profile comparable to
these cranberries implies that cranberry polyphenols
may have a similar effect on cellular senescence. Other
natural flavonols, such as quercetin, which was one of
the first antiapoptotic medicines, have been proven to
be useful in the treatment of age‐related disorders
(Zhu et al., 2015). The use of dasatinib in combina-
tion with other drugs has been shown to minimize
physical impairment and increase late‐life survival in
rats (Xu et al., 2018). After ultraviolet A exposure to
caffeic and ferulic acids from cranberries, which are
nonflavonoid extracts from the fruit, antioxidant
enzyme activity was increased and matrix‐
metalloproteinase‐1 production was reduced in
immortalized human keratinocytes (de Almeida
Alvarenga et al., 2019; Pluemsamran et al., 2012)
One of the therapeutic limitations is the lack of studies
on the bioavailability of PACs. In vitro investigations
have revealed that the release of acid molecules into the
stomach destroys PACs. According to a clinical study, the
small intestine appears to be a safe site for PACs action,
and this may be because the bolus reduces exposure of
PACs to the acidic environment by neutralizing gastro-
intestinal acid secretion (Bouchoucha et al., 1997;
Feliciano et al., 2015; Spencer et al., 2000). Because of
their polymeric nature and large molecular weight, PACs
are poorly absorbed in the small intestine, resulting in high
levels in the colon. Bacteria in the colon may break down
PACs into phenolic acids and valerolactones via enzymes
such as esterase, glycosidase, demethylation, dihydroxyla-
tion, and decarboxylation (Sallam et al., 2021), which
contain antioxidant and anti‐inflammatory properties and
are absorbed via the gut mucosa. Polyphenols and their
metabolites have been shown to have an impact on gut
ecology and microbiota (Aravind et al., 2021).
Due to their acidity, cranberries can be quite difficult
to administer to some people. More than half of the
people who participated in the studies showed some of the
following side effects: gastroesophageal reflux, epigastric
pain, nausea, and diarrhea.

AMIN ET AL.
Another therapeutic limitation is that cranberry juice
is rich in mineral salts such as oxalates, which can
crystallize and result in the formation of kidney stones.
As a result, people at high risk for kidney stones should
avoid cranberry consumption.
Clinical pitfalls result from cranberry interactions with
some drugs that should be avoided at the same time. Among
the food supplement–drug pharmacodynamic interactions,
the most important are those with effects on blood clotting.
Thus, warfarin can interfere with cranberry polyphenols and
can cause severe bleeding. In addition, cranberry may
stimulate increased vitamin B12 absorption in patients being
treated with proton pump inhibitors, stimulating the rapid
metabolism of alkaline drugs (e.g., antidepressants or
opioids) and reducing their therapeutic efficacy (Redmond
et al., 2019).
6 | LIMITATIONS O F T HE
EVIDENCE
The evidence provided by meta‐analyses is generally
limited by the small number of participants and studies
analyzed, the involvement of manufacturers, and the
limited clinical significance of relevant results of the
pharmacotherapeutic effect of cranberries.
Other clinical limitations may result from the
following:
i. cranberries contain, in addition to polyphenols with a
beneficial effect proven in CKD, other bioactive
compounds such as monounsaturated fatty acids,
minerals, vitamin C, and fibers, and as a result,
identifying the therapeutic effects of only polyphenols
is quite difficult when studying some groups of food;
ii. the content of cranberry polyphenols is variable
depending on the species, soil, sun exposure, and
soil type;
iii. intestinal absorption of bioactive compounds
(including polyphenols) from cranberries is variable
depending on each individual;
iv. preclinical experimental pharmacological studies
that include cranberry bioactivities do not take into
account their preparation and cooking processes, as
a result of which polyphenols can transform into
pharmacologically inactive molecules or are lost; and
v. there is a lack of translational studies to determine
pharmacologically active doses in humans, and there
is often a large discrepancy between in vitro and in
vivo doses.
7 | OVERAL L CONC LUS I ON
Inflammation and downregulation of Nrf2 are seen in
chronic kidney disease as well as other chronic diseases
that are largely the result of lifestyle factors, such as
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| 9 of 14
obesity associated with metabolic syndrome and diabe-
tes, nervousness/depression, osteoporosis and coronary
heart disease. Gut dysbiosis, which is widespread in
people with the condition, is another complicated key
factor for the growth of CRF and increased cardiovas-
cular risk. The prooxidant and proinflammatory milieu
in the body is exacerbated by gut dysbiosis. It makes
sense to treat inflammation, oxidative stress, and gut
dysbiosis in CRF patients, according to these data.
Dietary changes may help to alleviate some of these
problems. Given the abundance of PACs, the main
bioactive element in cranberries, it is fair to believe that
cranberry supplementation might lower oxidative stress,
inflammation, and intestinal dysbiosis. From a pharma-
cotherapeutic point of view, cranberries are considered as
adjuvant and complementary therapies to the current
treatment of patients. There are sufficient data to justify
conducting clinical studies to explore if cranberry
supplements can benefit persons with CRF (Anhê
et al., 2015). Although the advantages of cranberry
supplementation in kidney disease patients have not been
examined, cranberries may have favorable metabolic
effects on renal disease patients, according to the
research presented in this review, such as lowering
inflammation, oxidative stress, and gut dysbiosis. Cran-
berry supplementation studies in patients associated with
CRF may help researchers in better understanding the
long‐term functions and pharmacological actions of
cranberry supplementation in individuals, which may
lead to improved clinical research approaches in the
future.
AUTHOR CONTRI BUTI ONS
Ruhul Amin: Conceptualization; data curation; investiga-
tion; methodology of this study; project administration;
resources; visualization; writing of the manuscript –
original draft; writing of the manuscript – review and
editing. Chandrashekar Thalluri: Conceptualization; data
curation; formal analysis; investigation; methodology of
this study; project administration; resources; software;
validation; visualization; writing of the manuscript –
original draft; writing of the manuscript – review and
editing. Anca Oana Docea: Investigation; methodology;
resources; validation; visualization; writing of the manu-
script – original draft; writing of the manuscript – review
and editing. Javad Sharifi‐Rad: Conceptualization; data
curation; formal analysis; funding acquisition; investiga-
tion; methodology of the study; project administration;
resources; supervision; validation; visualization; writing
of the manuscript – original draft; writing of the
manuscript – review and editing. Daniela Calina: Con-
ceptualization of the study; data curation; funding
acquisition; investigation; project administration; super-
vision; validation; visualization; writing of the manu-
script – original draft; writing of the manuscript – review
and editing. All authors listed have made a substantial,
direct, and intellectual contribution to the review.

10 of 14 | THERAPEUTIC POTENTIAL OF CRANBERRY ON KIDNEY
CONFLI CT OF I NTE RES T
The authors declare no conflicts of interest.
ET HI CS ST ATE MENT
None declared.
ORCID
Javad Sharifi‐Rad http://orcid.org/0000-0002-
7301-8151
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