A Plant-Based Diet Prevents and Treats Chronic Kidney Disease

Interest in the dietary treatment of chronic kidney disease has been growing as its incidence has been increasing. Chronic Kidney Disease (CKD) is now the 8th leading cause of death in the United States and its treatment consumes substantial amounts of medical resources and money. Several lines of epidemiological research have shown a lower risk of chronic kidney disease among vegetarians. It also shows a substantially increased risk among omnivores, especially those who eat red and processed meats. Although the practice started long ago, research on the use of a low-protein plant-based diet to treat chronic kidney disease diet has intensified in recent years. This research has shown that a low-protein vegetarian diet is safe and efficacious at both treating and slowing the progression of chronic kidney disease. Treatment with a low-protein vegetarian diet, often supplemented with keto analogues, has been shown to reduce acidosis, phosphotemia, uremia, proteinuria and to slow progression. Research shows that this treatment does not result in malnutrition. Research has also shown that larger amounts of plant protein than animal protein can be consumed, without deleterious effects. Treatment with a low protein vegetarian diet also has the advantage of preventing and treating common comorbidities such as type 2 diabetes and coronary artery disease.
Chronic kidney disease is a major health care problem and slowing its progression to end-stage renal disease (ESRD) has obvious clinical and economic benefits. [1-3] Diet is the largest risk factor for CKD patients for death and disability [4,5]. A low-protein diet (LPD) as a therapeutic measure in chronic kidney disease (CKD) was suggested by Beale as early as 1869, [6] and the first attempt to experimentally evaluate an LPD in humans was done by Smith in 1926 [7].
For at least a century, chronic uraemia has been considered an example of “protein intoxication.” Thus, in the history of renal medicine, low protein diets have been attempted as a way to correct the metabolic alterations caused by kidney failure as much as possible [8,9]. Indeed, the first systematic studies on low-protein diets in uraemia patients started with the observation that a protein-restricted diet was effective in reducing the symptoms of “uraemic toxicity” and that it was
even able to prolong life [10-13]. In the mid-1960s, Giordano and Giovannetti were the first to show that a low-protein diet was able to reduce almost all uraemic signs and symptoms [14].
By lowering blood urea and other nitrogenous waste products, a low-protein diet has favorable effects on secondary hyperparathyroidism [15], peripheral resistance to insulin, [16] hyperlipidaemia, [17] hypertension and acid-base disorders [18]. Four meta-analyses of studies on the effects of a low-protein diet on CKD progression in diabetic and non-diabetic patients, have been performed since the early 1990s, all showing a beneficial effect [13,19-22].
Today, the main nutrition-related goals for people with chronic kidney disease involve the slowing of kidney failure progression rate, minimizing uremic toxicity and metabolic disorders of kidney failure, diminishing proteinuria, maintaining good nutritional status, and lowering the risk of complications including cardiovascular disease, bone disease, and disturbed
blood pressure control [23]. A low-protein plant-based diet
has been shown to help accomplish all of these treatment
goals. Plant-based diets lend themselves well to low-protein
diets suitable for CKD patients. They are a safe and efficacious
treatment and still supply adequate protein while helping to
prevent and treat common comorbidities [24,25].
Several epidemiological studies consistently show that
vegans (those who follow a plant-based diet) have a decidedly
lower risk of chronic kidney disease than those who consume
animal derived foods. These studies also indicate that as a
group those following a plant-based diet have better renal
function than those following an omnivorous diet. Furthermore,
epidemiological studies show that vegans also have much lower
levels of risk factors for chronic kidney disease such as type 2
diabetes and hypertension.
Epidemiological studies have been able to show which foods
raise and which foods lower the risk of chronic kidney disease.
These studies show that while eating red meat and other
sources of saturated fat raise the risk of chronic kidney disease,
consuming tree nuts, legumes, fruits and vegetables lowers it.
Studies comparing those who consume animal protein with
those who consume equal amounts of plant protein show that
those who consume plant protein have a lower risk of chronic
kidney disease, indicating a significant advantage for those
following a plant-based diet. The vegan diet is associated with
glomerular and systemic hemodynamic changes which may be
beneficial in the prevention of glomerular sclerotic changes in
health and disease. Details of these studies are provided below:
One study showed that vegans had a lower glomerular
filtration rate (GFR). Early elevation of the GFR plays a central
role in the pathogenesis and progression of renal disease [26].
Since those following a plant-based diet have a lower GFR they
are at reduced risk of incipient or early stage kidney disease.
In this study omnivores were found to have a GFR of 113 ml/
min/1.73 m2, the vegetarians 105 ml/min/1.73 m2 and the
vegans 100 ml/min/1.73 m2 [27]. Omnivores also had a
significantly higher mean urinary albumin excretion rate than
vegans, and higher mean diastolic blood pressure than both
vegans and lactovegetarians.
Vegans have been found to have a 75% decreased risk of
hypertension and a 78% reduced risk of type II diabetes [28].
Since type 2 diabetes and hypertension are both risk factors
for CKD, [29,30] these contribute to their lower risk of CKD. An
uncontrolled diabetic and/or hypertensive patient can easily
and quickly progress to an end-stage kidney disease patient [30].
A study was designed to investigate the effect of protein intake
on glomerular filtration rate, and to demonstrate and evaluate
the functional reserve of the kidney. Normal subjects ingesting
a meat-centered diet had a significantly higher creatinine
clearance than a comparable group of normal subjects ingesting
a vegetarian diet [31].
An epidemiological study with a 23-year follow up period
showed that diets with different dietary protein sources have
different risks of incident CKD: red and processed meat are
adversely associated with CKD risk, while nuts and legumes are
protective against the development of CKD. Red and processed
meat increased the risk of CKD by 23% (Q5:Q1) whereas a
higher dietary intake (Q5:Q1) of nuts and legumes resulted in
a 19% and 17% decreased risk respectively [32]. In a study
of adults aged 45-74 years old, red meat intake was strongly
associated with an increased risk of the eventual development
of End Stage Renal Disease (ESRD) in previously healthy people
in a dose-dependent manner, with the highest quartile having
a 40% increased risk over the lowest. In substitution analysis,
replacing one serving of red meat with other food sources of
protein was associated with a maximum relative risk reduction
of 62.4%. This study shows that red meat intake may increase
the risk of ESRD in the general population, and that substituting
alternative sources of protein may reduce the incidence of ESRD
[33].
Female participants in the Nurses’ Health Study who had
followed a western dietary pattern (higher intake of red and
processed meats, saturated fats, and sweets) had 2.17 times
the risk of microalbuminuria, and a 77% greater risk of rapid
estimated Glomerular Filtration Rate (eGFR) decline, compared
with those following a prudent diet high in fruits, vegetables,
legumes and whole grains [34]. The Western-style diet is high
in animal fat with high levels of saturated fats. A cross-sectional
study (Reasons for Geographic and Racial Differences in Stroke
Study; REGARDS), including more than 19,000 adults over 45
years of age, found a significant association between saturated
fat intake and hyperalbuminuria [35,36]. Several studies showed
that the use of animal proteins compared to plant proteins
induced a worsening of hard outcomes such as mortality and CKD
progression [37,38]. In a meta-study that included six studies,
healthy dietary patterns high in fruits, vegetables, legumes and
whole grains were consistently associated with lower mortality
or ESRD among adults with CKD, with a risk reduction of 30%.
(39) Substituting soy and other legumes for red meat resulted in
a reduced risk for ESRD by about 50%-62% [39].
Looking at soy protein specifically, one study showed
that independent of the quantity of protein, soy protein has
significantly different renal effects from animal protein in
normal humans, which could be partly explained by differences
in glucagon and renal vasodilatory prostaglandin secretion [40].
This study also showed that among normal healthy subjects,
the GFR, RPF (Renal Plasma Flow) and fractional clearance of
albumin and IgG were significantly higher when following the
animal protein diet, compared to the soy protein diet, even
though the quantity of protein were the same in both groups
[40].
Mounting evidence indicates that dietary intervention with
plant-based, alkali-inducing diets is kidney protective. The
National Kidney Foundation recommends a vegetarian diet as
being beneficial to CKD patients [25]. Dietary intervention was
the mainstay approach for kidney failure in the first half of the
20th century, and diet manipulation was tried in its last decades
[41,42]. Different dietary protein regimens have been proposed:
conventional low-protein diets (LPDs; 0.6 g/kg per day), very
low-protein diets (VLPDs; 0.3-0.4 g/kg per day), and practically
vegetarian diets supplemented with either essential amino
acids or a mixture of essential amino acids and nitrogen-free
ketoanalogues (keto diet or KD) [41-43].
Dietary proteins are the source of nitrogen, phosphate, and
acid load. A reduction in protein consumption has been shown
to result in better control of blood pressure and a decrease in
proteinuria, which are major determinants of the progression
of CKD [44]. Moreover, certain complications of advanced CKD,
such as mineral metabolism disorders, acidosis, and oxidative
stress, also involved in accelerating its progression, [45] were
favorably influenced by low-protein diets [4,45]. In a meta-study
of low-protein diets, reducing protein intake in patients with
chronic kidney disease reduces the occurrence of renal death
by 32% as compared with higher or unrestricted protein intake
[21].
Research data indicates that the underlying renal disease
and the type of diet used considerably influence the rate of
progression of chronic renal failure. In relative terms, the course
of the renal disease is mostly changed in patients suffering
from glomerulonephritis, while in absolute terms patients
suffering from polycystic kidney disease exhibit the slowest
rate of progression. The comparison suggests that a low-protein
diet purely based on vegetarian food might considerably slow
down the overall rate of progression of chronic renal failure
[46]. Diets in developed societies are largely acid producing, in
part because of the proportionately greater amount of animalsourced
proteins (which are acid producing) than plant-sourced
proteins (which are largely base producing) [4]. The two changes
in dietary protein quality therefore receiving the most attention
currently is substituting plant-sourced for animal-sourced
protein and substituting non-nitrogen ketoanalogue proteins in
place of animal proteins.
Studies show that the introduction of plant-derived protein
in place of animal-derived protein improves metabolic acidosis,
reduces kidney injury, and slows nephropathy progression,
[4,18,47] and that plant-based diets can delay the progression
of chronic kidney disease, provide endothelial protection, help
control hypertension, and decrease proteinuria, phosphotemia,
acidosis, uremia, FGF 23 and hyperparathyroidism [40,48-54].
Fruits and vegetables can be used to treat CKD without
producing hyperkalemia. A one-year study of fruits and
vegetables in the diet in individuals with stage 4 CKD was
associated with lower than baseline urine indices of kidney
injury. The results indicate that fruits and vegetables improve
metabolic acidosis and reduce kidney injury in stage 4 CKD
without producing hyperkalemia [37]. Higher initial glomerular
filtration rates (GFRs), associated with higher risk of CKD, have
been demonstrated in patients without CKD on an animalprotein
diet, in comparison to persons on a vegetable-based
diet [55,56]. A study of patients without CKD on a high protein
diet (1g/kg/day) of either soy, animal protein, or animal protein
diet supplemented with fiber, revealed significantly higher
renal plasma flow, GFR, and proteinuria in those on the animal
protein diet compared to individuals on the soy diet [40]. The
transition from mixed animal-vegetable diet (1.0 to 1.3 g/kg/
day) to a plant-based diet (0.7g/kg/day) was demonstrated to
be associated with a significant decrease in GFR and proteinuria
in patients with non-diabetic nephrosis [57].
In another study, a diet supplying only foods of plant origin
in definite proportions was used to give an essential amino acid
supply satisfying the recommended dietary allowance. This was
possible using an appropriate cereal legume mixture. Additional
positive features of this special plant-based diet were the high
ratio of unsaturated to saturated fatty acids, the absence of
cholesterol, and the lower net acid production in comparison
with a mixed diet. Improvements were noted in several clinical
variables [57]. A study investigated the impact of a vegetarian
diet on the nutritional status of hemodialysis (HD) patients. This
study revealed that HD patients on vegetarian diets might have
a smaller BMI, but subjective global assessment and function
of daily activities were similar to those of the non-vegetarians.
The haematocrit of vegetarians can be maintained with a higher
erythropoietin dose [58]. A predominantly vegetarian diet may
also have important beneficial effects on diabetic nephropathy
without the need for a heavily restricted total protein intake
[59]. This is because plant protein does not create a lower GFR
the way that meat protein does. In addition, a plant-based diet
can lower glycated hemoglobin even more than metformin
[60]. Studies on animal models suggest that a vegetarian diet
is suitable and nutritionally adequate in CKD [61-63]. Human
studies confirm this [64]. Barsotti et al. [57] showed that a vegan
diet is fully sufficient for a low-protein diet for CKD patients.
In one study by Garneata et al. [24] patients receiving a
vegetarian, ketoanalogue-supplemented diet experienced
an improvement of metabolic abnormalities. The authors
concluded that a vegetarian ketoanalogue-supplemented
diet is nutritionally safe and may defer dialysis initiation in
patients with eGFR<20 ml/min by ameliorating CKD-associated
metabolic disturbances. This study brings forth useful insights
into strategies using low-protein diets that can be aimed at
slowing nephropathy progression [4].
A CKD study by Aparicio et al. demonstrated that in regularly
and carefully monitored CKD patients, vegetarian diets with
low or even a very low-protein content supplemented with
keto-analogues, provided a satisfactory nutritional status.
Improvements in the albumin excretion rate were noted [68].
In another study, twenty steroid-resistant, nephrotic patients
were treated with a vegan, low-protein diet, supplemented with
essential amino acids and ketoanalogues (supplemented vegan
diet), for almost 5 months. Before the study, these patients
followed an unrestricted protein, low sodium diet. Proteinuria,
daily urea nitrogen excretion and creatinine clearance decreased
significantly on the ketoanalogue-supplemented vegan diet
without inducing clinical or laboratory signs of malnutrition
[69].
A very low-protein, ketoanalogue-supplemented, vegetarian
diet was also demonstrated to be safe for predialysis patients,
since it exerted no detrimental effect on the short- and long-term
outcomes of patients, even those already on renal replacement
therapy [70]. A prospective, randomized, controlled trial of the
safety and efficacy of a ketoanalogue-supplemented, vegetarian,
very low-protein diet (KD; 0.3g/kg vegetable proteins and 1
cps/5 kg ketoanalogues per day) revealed the correction of
metabolic abnormalities, no changes in nutritional parameters,
and no adverse reactions in non-diabetic adults with stable eGFR
<30 mL/min per 1.73 m2 [70]. The largest study addressing
CKD, the Modification of Diet in Renal Disease (MDRD) Study,
provided minimal results [71]. However, in this long-term
study, compliance and therefore protein intake was problematic
[72]. Follow up protein measurements were not taken, greatly
reducing confidence in the outcome.
Interventional studies show that a low protein vegetarian
diet can slow the progression of chronic kidney disease in Type
1 diabetics and improve their clinical laboratory test results.
According to a meta-analysis of five studies including a total of
108 patients, dietary protein restriction slowed the progression
of diabetic nephropathy in patients with type 1 diabetes. [19]
More recently, a 4-year randomized controlled trial with 82
patients, who had type 1 diabetes with progressive diabetic
nephropathy, showed that a moderately low-protein diet (0.9 g/
kg/ day) reduced the risk of end-stage renal disease or death by
76%, although no effect on GFR decline was observed [73]. The
mechanisms by which a low-protein diet may reduce progression
of diabetic nephropathy are still unknown but might be related
to improved lipid profile and/or glomerular hemodynamics.
Another study specifically looked at the effect of a vegetarian
low-protein, low phosphorous diet on patients with diabetic
nephropathy secondary to type I diabetes. The diet used
provided 0.3gm/Kg/day protein, no more than 3.5mg/Kg/day
phosphorus, and 60% of the calories were from carbohydrate.
The sodium and potassium contents were 0.3 and 1.1 mmol/Kg/
day respectively. The diet was also supplemented with a mixture
of keto amino acid analogues and essential amino acids 126mg/
Kg/day, CaCO3 3-6gm/day, and a multivitamin with iron [74].
This study showed that a supplemented vegetarian diet in type
I diabetes patients with overt nephropathy resulted in a slowing
or even arrest of the progression of renal failure. Despite the
increased carbohydrate, there was no need to increase the dose
of insulin and in some patients the dose was decreased. The diet
also reduced proteinuria and serum urea [74].
Using the most recent classification system, 3% of women of
childbearing age are affected by CKD [75,76]. For these women,
the risk of an adverse pregnancy rises very significantly, even
in stage 1 [77]. Despite vast improvements in fetal outcomes,
pregnancy in women with CKD is fraught with hazards; worsening
renal function and complications such as preeclampsia and
premature delivery are common [78]. During the pregnancy of
a patient with CKD, the amount of protein in the diet must be
balanced between the goal of diminishing hyperfiltration and
increasing metabolic needs of pregnancy [25] Due to the fact
that pregnancy induces hyperfiltration, diets with restricted
amount of protein should be beneficial in this group of patients
[79,80]. Vegan or vegetarian supplemented low-protein diets
in pregnant women with stages 3-5 CKD reduce the risk of
small-for-gestational-age babies, without detrimental effects on
kidney function or proteinuria in the mother [81].
CKD during pregnancy presents a clinical challenge,
especially considering the paucity of therapeutic tools available
in pregnant women. One study investigated the feasibility of
supplemented vegetarian low-protein diets in pregnancy, as a
“rescue treatment” for severe CKD and or proteinuria [79] None
of the 11 patients needed renal replacement therapy within the
6 months before delivery. No patient complained of side effects,
nor developed hyperkalemia or hypercalcaemia. All babies
were well at 1-month post-delivery, and 7.5 years later [79]. A
supplemented vegetarian low-protein diet (0.6-0.7 g/kg per day)
turned out to be sufficient for the maintenance of satisfactory
nutritional status during the pregnancy and after delivery, even
in breast-feeding women [48].
For pregnant women with focal segmental
glomerulosclerosis, a study showed that a moderately protein
restricted, keto analogue supplemented, plant-based diet helped
control proteinuria [82]. Another study reviewed the results
obtained over 15 years of treating pregnant women with CKD on
moderately restricted plant-based low-protein diets. It confirms
that such a diet is a safe option in the management of pregnant
CKD patients [83] A trend towards better preserved fetal growth
was observed. These results indicate that the treatment of
pregnant CKD women on moderately restricted plant-based lowprotein
diet is a safe option in the management of pregnant CKD.
Metabolic acidosis is a common complication of chronic
kidney disease. The frequency of metabolic acidosis increases
along with the decrease of renal function, especially when
the glomerular filtration rate falls below 30-40 mL/min/1.73
m2 [84-86]. The most common negative consequences are as
follows: bone demineralization, [87] tubulointerstitial fibrosis,
[88,89] inflammation, [90] the stimulation of the reninangiotensin
system [91] and adrenocortiocotrophic hormone
[92]. According to studies, metabolic acidosis is also associated
with increased cardiovascular risk [93-97].
Mechanisms by which metabolic acidosis may stimulate
nephropathy progression in CKD involve sustained, high
levels of mediators of increased distal nephron acidification in
response to GFR reduction, such as endothelin and aldosterone
[98] In CKD patients, low bicarbonate reflects primary metabolic
acidosis, [99] and it is considered to be a risk factor for mortality
and CKD progression [100-103]. Growing evidence suggests that
the source of protein (plant or animal) may be more important
than the quantity of protein consumed. Meat produces more
of a dietary acid load (DAL) than plant foods. A typical diet in
industrialized countries produces acid of about 1 mEq/kg/day.
However, it is reduced by more than one third among vegetarians
and is close to neutrality among vegans [104]. Another study
showed that higher levels of DAL were associated with 3.04
times higher risk of ESRD in the highest versus lowest tertial
[105].
The fact that the acid load linked to animal proteins is
higher than that linked to plant proteins is already known in
the scientific community [105,106,38]. Moe et al. showed that
the use of only plant proteins, compared to animal proteins, was
able to reduce daily serum and urinary phosphate levels in eight
subjects, the load of sodium, calcium and phosphorus being
equal [14,49]. One reason for this is the tendency for excess meat
intake to disrupt the acid base balance, since protein derived
from animal sources contains acid-forming substances such as
sulfur-containing amino acids and phosphorus, in addition to
the excessive protein load. Sulfur-containing amino acids, when
oxidized, generate sulphate, a non-metabolizable anion that
contributes to total body acid load [37,97,107]. Protein from
plant sources contains higher levels of glutamate, an anionic
amino acid that upon metabolism consumes hydrogen ions to
remain neutral, thereby reducing acidity levels [107,97,37].
Plant foods are also generally higher in anionic potassium salts,
which also result in the consumption of hydrogen ions upon
metabolism and thus reducing acid load [37,97,107].
In response to an increase in acid load, the kidney adapts
by increasing ammonium ion excretion in order to expel excess
hydrogen ions, therefore increasing the demand for ammonia
production [108]. This stimulates the breakdown of glutamine
and other amino acids, promoting protein catabolism and muscle
wasting [109] while also leading to renal hypertrophy [110].
Metabolic acidosis also promotes protein muscle wasting via the
activation of the ATP-dependent ubiquitin proteasome system
[111]. In response to a high acid load, the kidney also undergoes
functional changes, including promotion of glomerular
hyperfiltration and renal vasodilation, features typical of early
diabetic kidney disease [37,97,107].
Current guidelines recommend treatment with alkali
when bicarbonate levels are lower than 22 mMol/L, [84] to
prevent complications, such as insulin resistance, [112-114]
cardiovascular diseases and progression of CKD, among others
[96,114]. The Kidney Disease Outcomes Quality Initiative
(KDOQI) recommends Na+ citrate or NaHCO3 in the treatment of
metabolic acidosis in CKD [115]. However, Na+, Na+ citrate and
NaHCO3 may aggravate volume retention and/or hypertension
in CKD [107].
A correction of metabolic acidosis can also be achieved
with a diet rich in fruit and vegetables, [4,37,47,116-122]. as
well as with a very low-protein vegetarian diet [107]. A plantbased
diet was shown to influence survival through its effect
on metabolic acidosis [118]. Results from the Chronic Renal
Insufficiency Cohort Study suggest that consumption of a
greater proportion of protein from plant sources is associated
with higher bicarbonate levels, as well as an improved
phosphorous balance in patients with CKD [123]. A case-control
study by Di Iorio et al. [107] clearly demonstrated that a very
low-protein diet (VLPD) containing a high quantity of fruit and
vegetables, with a very low amount of protein, supplemented
with essential amino acids and ketoanalogs of non-essential
amino acids, reduced net endogenous acid production (NEAP)
by 53% after six months and 67% after 12 months, and potential
renal acid load (PRAL) by 120% after six months and 138%
after 12 months. Also, the correction of hyperpotassemia, as a
consequence of a physiological correction of metabolic acidosis,
was observed after 12 months on the VLPD diet [107]. A study by
Bellasi et al. [93] indicated the relationship between metabolic
acidosis and insulin resistance in diabetic patients with chronic
kidney disease. They also showed that oral sodium bicarbonate
administration or a low-protein vegetarian diet rich in fruit and
vegetables, prescribed to avoid or correct metabolic acidosis,
improved insulin sensitivity in the CKD plus diabetes mellitus
(DM) population [93].
A study of stage 3 CKD patients showed an increase of
bicarbonate levels by increasing the amount fruits and vegetables
in their diet [47]. A one-year study of either added fruits and
vegetables or sodium bicarbonate in individuals with stage 4
CKD, yielded an equal eGFR (estimated glomerular filtration
rate) in both cases. It was associated with higher-than-baseline
plasma total, and lower-than-baseline urine indices of kidney
injury. The data indicated that fruits and vegetables improved
metabolic acidosis and reduced kidney injury in stage 4 CKD
without producing hyperkalemia [37].
Recent studies suggest additional potential benefits of
healthy eating on CKD progression. Individuals consuming too
much saturated fat are more likely to progress to CKD [124].
Growing evidence suggests the potential benefit of dietary fat
modification strategies in CKD patients, including increasing
the amount of linoleic acid (n-6 PUFA) from vegetable oils and
thus reducing the amount of saturated fat ingested. [125,126].
The best way to do this is to reduce the consumption of animal
products which are high in saturated fat, and to increase the
number of nuts and seeds which are rich in linoleic acid. No
studies have yet shown a benefit from increasing Omega-3 fatty
acids for CKD patients.
The impact of environmental chemicals on public health and
clinical well-being has long been recognized, with a historical
focus on heavy metals and molecules that are produced in
the work place. Increasing data have, however, indicated that
the general public is exposed to a wide range of chemicals as
a consequence of normal consumer activities. These activities
include dietary intake of food [127,128]. Numerous reports
have documented toxicity that occurs in response to graded
exposure to a wide range of environmental chemicals. Persistent
organic pollutants (POPs) are synthetic organic chemicals
such as dioxins, furans, polychlorinated biphenyls (PCBs),
and organochlorine pesticides -chemicals mainly created by
industrial and agrichemical activities either intentionally or
as by-products - that have an intrinsic resistance to natural
degradation processes and are therefore environmentally
persistent and bio-accumulate through the food chain, increasing
greatly in concentration at each subsequent trophic level [129].
POPs accumulate in adipose tissue of animals as well as humans.
Thus, the majority of human exposure to persistent organic
pollutants occurs as a result of eating foods containing meat,
milk, eggs and fish due to accumulation of POPs in animal fat
[130,131].
Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans
(PCDFs), and polychlorinated biphenyls (PCBs) are lipophilic
and can persist in the body for years [132]. An individual’s body
burden is a product of multiple years of exposure and a lifetime
of varying elimination rates. Different congeners of PCDDs,
PCDFs, and PCBs each have different levels of persistence in the
human body, reflected in their different reported half-lives. In
human adipose tissue, they may represent a pool of toxicants
with diverse health effects including carcinogenesis and renal
damage [133].
The kidney, because of its high rate of perfusion, active
transport capabilities, and concentrating functions, is often
exposed to much higher concentrations of chemicals than are
other organs. These high concentrations may cause toxic effects
to the kidney [134]. Emerging data suggest that the kidney is
an important site of injury after chemical exposure with POPs
[130,131]. Prolonged cumulative lifetime exposure to certain
POPs, in conjunction with age-associated decline in kidney
function and other comorbid conditions, may accelerate the
rate of deterioration in kidney function and progression to CKD
[130,131]. Exposure to persistent organic pollutants are a very
strong risk factor for type 2 diabetes [60]. Since the kidneys
function to remove waste products from the blood, diabetic
nephropathy could partly be either the cause or the consequence
(or both) of exposure to dioxins, furans and dioxin-like PCBs
[131]. One study examined the association of agricultural
persistent organic pollutants including six organochlorine
pesticides and pesticide metabolites in human blood. When
p,p’-DDT and heptachlor epoxide were both elevated, the odds
ratio for diabetic nephropathy was 2.76 times the average. When
six of six organochlorine pesticides and pesticide metabolites,
were elevated, the odds ratio for diabetic nephropathy was 3.00
[134,135].
Another study assessed the association of persistent
organic pollutants from industrial processes including 6
chlorinated dibenzo-p-dioxins, 9 chlorinated dibenzofurans
and 8 polychlorinated biphenyls (PCBs) in blood with diabetic
nephropathy (defined as urinary albumin to creatinine ratio
>30 mg/g) in diabetics as defined by a glycated hemoglobin of
>6.5%. When 4 or more of the 23 chemicals were elevated the
risk for diabetic nephropathy was 7 times higher than otherwise
[131]. PCDDs and PCDFs are readily absorbed through the
digestive tract, which is enhanced through the ingestion of fatty
foods. The lipophilic characteristics of PCDDs and PCDFs allows
for slow excretion in bile and urine, [131,136]. Thus, prolonging
the exposure of kidney and colon cells to these toxins.
PCB metabolism primarily occurs in the liver, where it must
first be hydroxylated to increase the polarity of the molecule,
before it is excreted in the bile [137]. The rate of metabolism
varies depending on the degree of chlorination of the congener
[138]. Metabolism of PCBs can also produce toxicologically active
agents, such as arene oxides that must be enzymatically detoxified
and excreted, and/or can form toxic adducts which can damage
the kidney cells’ DNA [139]. Dioxins metabolism also takes place
in the liver. Metabolites are excreted through the biliary fecal
route. The half-life of dioxins can be up to several decades, due to enterohepatic recirculation. The effects of dioxins are chiefly
mediated by the aryl hydrocarbon receptor (AHR), a ligandactivated
transcription factor that regulates gene expression
[136]. Studies have shown that those exposed to the greatest
amount of toxins have reduced renal function. Compared to the
lowest quartile, the highest quartile of toxin exposure resulted in
a 14.8 ml/min/1.73 m2 and a 21.5 ml/min/1.73 m2 reduction in
estimated GFR in men and women, respectively [131,136]. This
decrease in GFR must be distinguished from the lower GFRs that
healthy vegans have, that are a consequence of healthy kidneys.
The risk of hyperuricemia was higher for higher serum
concentrations of organochlorine pesticides, PCDDs, and
dioxin-like substances raising the risk of uremia by 1.4, 1.3,
and 2.4 respectively [131,136,140]. Even adults with only lowlevel
exposure to dioxins are also still at heightened risk of
hyperuricaemia. The increase in risk of hyperuricemia ranged
from 2.3 to 3.0, depending upon the specific dioxin congener
exposure [131,136,140].
Uremic retention molecules (URMs), contributing to the
syndrome of uremia, may be classified according to their site of
origin, that is, endogenous metabolism, microbial metabolism,
or exogenous intake. It is increasingly recognized that bacterial
metabolites, such as phenols, indoles, and amines, may
contribute to uremic toxicity. In vitro studies have implicated
bacterial URMs in CKD progression, cardiovascular disease, and
bone and mineral disorders. Furthermore, several observational
studies have demonstrated a link between serum levels of
bacterial URMs and clinical outcomes. Bacterial metabolism
may therefore be an important therapeutic target in CKD. There
is evidence that reduced renal clearance, increased colonic
generation and absorption explain the high levels of bacterial
URMs in CKD [141].
The microbial metabolism of protein also produces a
number of metabolites that may negatively affect the kidneys
[142,143]. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are
uremic toxins derived solely from colonic bacterial fermentation
of protein. [142-144]. Circulating indoxyl sulphate can increase
oxidative stress in the renal tubular cells and the glomeruli
[145,143]. Also, in-vitro indoxyl sulphate has been observed to
activate inflammatory pathways resulting in an increase in the
expression of monocyte chemoattractant protein-1 (MCP-1)
and intracellular adhesion molecule-1 (ICAM-1) [146]. P-cresyl
sulfate has similarly been linked to CKD and CVD mortality,
although the mechanism is not yet as well defined [147,148].
Interestingly, it has been noted that vegetarians have
lower levels of these nephrotoxic compounds compared with
omnivores, in both healthy [149] and CKD populations [150]
Vegetarians tend to have higher fiber intakes, [147] which could
be metabolized by the colonic microbiota instead of amino acids,
leading to a reduction in indoxyl sulphate and p-cresyl sulfate.
This provides another mechanism to explain why vegetarian
protein sources appear less detrimental than animal protein
sources. Furthermore, carnitine and lecithin present in red meat
are metabolized by the microbiota to form trimethylamine-Noxide,
[151] which has been linked to cardiovascular events. The
interaction between animal sources of protein and gut bacteria
in CKD warrants further investigation.
Determining an optimum protein to fiber ratio could
allow for appropriate protein intake to prevent protein energy
wasting, without adverse effects on renal outcomes [143]. Not
only do vegetarian proteins carry an advantage, but vegetarians
themselves produce less sulphate and p-cresyl sulfate. In one
study comparing healthy vegetarian to non-vegetarians, the
average PCS excretion was 62% lower and average IS excretion
was 58% lower in vegetarians, compared to participants
consuming an unrestricted diet [150]. In the same study
vegetarian patients undergoing hemodiafiltration also had
lower levels of Indoxyl sulfate and p-cresyl sulfate [150].
Treatment of ESRD is now focused on removing uremic
solutes by dialysis. In theory, treatments that reduce solute
production could also reduce solute levels and ameliorate uremic
illness [149]. Over the long term, vegetarian and unrestricted
diets may influence PCS and IS production by altering the colon
microbial flora, or microbiome, as well as by providing different
nutrients to colon microbes on a day-to-day basis. [149]. Dietary
fiber was considered as a treatment for chronic renal failure
more than 30 years ago, where it was found to reduce plasma
urea [152]. Interventions that have focused on increasing total
dietary fiber intake in patients with pre-dialysis CKD have
reported reductions in serum creatinine levels [153] and plasma
p-cresol [154]. A four-week study in which patients with chronic
renal failure consumed 50 grams per day of acacia gum, a highly
fermentable fiber, led to a mean reduction in plasma urea of
12% [155]. In another study, supplementation with acacia gum
for three months led to decreases in serum urea, creatinine and
phosphate by 31%, 10% and 22%, respectively [156].
Recently, several short-term studies have been undertaken
using non-digestible carbohydrates in patients receiving
dialysis. A four-week Belgian study in haemodialysis patients
showed that plasma p-cresyl sulfate decreased by 20% when
supplemented with oligofructose-enriched inulin [157]. This
result has been echoed in a similar study that combined galactooligosaccharides
with probiotics [158] While neither of these
studies showed a reduction in indoxyl sulphate, a recent sixweek
dietary intervention with resistant starch in haemodialysis
patients led to a mean reduction of plasma indoxyl sulphate and
p-cresyl sulfate by 29% and 28%, respectively [159].
Some guidelines for the management of CKD make no
mention to the role of non-digestible carbohydrates, which some
researchers feel should be rectified on the basis of emerging
evidence [160]. Dietary fiber intake is about 20%-30% lower in haemodialysis patients compared to control subjects, [161,162]
with dialysis patients consuming approximately 11 g/day
dietary fiber, significantly less than the recommendation of 25 g/
day [163]. These data suggest that non-digestible carbohydrates
are effective at improving biochemical markers in haemodialysis
patients, and that dietary interventions involving these
compounds may be particularly relevant given the low intakes
seen in this population. The use of dietary fiber supplementation
is a simple, non-invasive option that does not negatively impact
patients’ quality of life [25,143,164].
In patients with chronic kidney disease, high dietary
phosphorus burden may worsen hyperparathyroidism and
renal osteodystrophy, promote vascular calcification and
cardiovascular events, and increase mortality. In addition to the
absolute amount of dietary phosphorus, its type (organic versus
inorganic), source (animal- versus plant-derived), and ratio to
dietary protein may be important. Organic phosphorous in plant
foods such as seeds and legumes are less bioavailable because of
limited gastrointestinal absorption [165].
Disturbances in mineral metabolism are common
complications of chronic kidney disease (CKD), beginning at
approximately CKD stage 3 and 4. Patients with advanced chronic
kidney disease maintain a positive phosphorus balance through
phosphaturia. The damaged kidney is unable to fully excrete
a phosphorus load, which leads to compensatory secondary
hyperparathyroidism and elevations in fibroblast growth factor
23 (FGF23) in an attempt to increase urinary phosphorus
excretion to maintain phosphorus balance. [165,166]. This
provides the rationale for recommendations to restrict dietary
phosphate intake to 800 mg/d. Protein-rich foods such as
legumes, meat, poultry, fish, eggs and dairy products are the
main sources of organic phosphate. A strong positive correlation
between dietary protein from animals and phosphorous intake
is responsible for the frequent association of high protein intake
in the diet with excessive ingestion of phosphorous, and the
resulting hyperphosphatemia in people with CKD [65, 152].
However, the protein source of the phosphate is important,
as a high protein (and high phosphorus) diet does not always
translate to increased serum phosphate levels [167-171]. The
bioavailability of organic phosphate varies depending on the
food source (Table 1).
The difference in phosphorus bioavailability between meat
and plant protein sources may partially explain the benefits of
consuming a greater proportion of protein from plants sources,
as described above. Phosphate absorption is linearly related
to phosphate intake, with bioavailability being the major
determining factor in phosphate uptake from the diet [172].
Thus, for organic phosphate, food choices can make a significant
difference in the amount of phosphate that is absorbed from the
diet. Inorganic phosphorous may be added to foods in the form
of additives, which are typically used to improve taste, texture,
shelf life or processing time [173]. These additives are primarily
inorganic phosphate salts that require no enzymatic digestion
and dissociate rapidly in the low pH environment of the stomach.
The phosphoric acid in cola drinks has a bioavailability of 100%
[158]. These foods should therefore be avoided. In one inpatient
study, the results indicated that 1 week on a vegetarian diet led
to lower serum phosphorus levels and decreased FGF23 levels
[166].
A meta study of 12 CKD studies showed that dietary
soy resulted in a significant decrease in serum creatinine,
phosphorous, CRP and proteinuria in predialytic patients. The
study also found that soy protein intake could maintain the
nutritional status in dialysis patients, though no significant
change in CRP, BUN, and serum phosphorus was detected [175].
Another study found that a diet with a higher proportion of
protein from plant sources, primarily soy, is associated with
lower mortality in those with eGFR < 60 mL/min/1.73 m2 of 23%
Therefore, at a given total protein intake, a higher proportion
of dietary protein from plant sources such as soy is associated
with lower mortality risk in chronic kidney disease [176]. These
studies show that soy, a popular and readily available source
of plant-based protein, is an effective choice for treating CKD
patients.
Cardiovascular disease remains a major cause of morbidity
and mortality in patients with chronic kidney disease (CKD),
accounting for approximately 50% of all deaths in patients on
dialysis and in recipients of renal transplants [177]. Recent studies
have demonstrated that modification of the dietary pattern by reducing animal protein intake and increasing consumption of
plant-based foods could influence cardiovascular risk profile
and mortality rate. Moreover, phosphate bioavailability from
plant proteins is reduced. These effects lead to some benefits for
chronic kidney disease (CKD) patients [178].
The vegan diet, known for its better lipoprotein profile
and antioxidant content, can protect against CVD. One study
compared patients with advanced chronic kidney disease on
a conventional low-protein diet with those on a ketoanalogue
supplemented vegan diet. Patients on a vegan diet showed
increased HDL cholesterol levels with a reduction of LDL
cholesterol and an increase of apoA1/apoB ratio. A significant
reduction of total homocysteine, Lp(a) and CRP levels were also
observed in vegan patients [179]. Dialysis patients have both
traditional and nontraditional risk factors for cardiovascular
disease, including the retention of advanced glycation end
products (AGE). In one study, skin auto fluorescence (SAF),
a marker of tissue AGE deposition, was reduced in vegetarian
hemodialysis patients compared to patients on a conventional
chronic kidney disease diet. This study showed that a vegetarian
diet may reduce exposure to preformed dietary AGE thus
reducing their risk of CVD [180].
A study comparing a vegan diet to the more conventional low
and very low-protein diet found that vitamin K1, fiber content,
and the alkalizing potential were all better on a vegan diet than
the other diets. The net endogenous acid production decreased
the most, and the same finding occurred for the potential renal
acid load (PRAL). These features may have favorable effects on
Vitamin K1 status, intestinal microbiota and acid-base balance.
Thus, the vegan diet also has beneficial effects on vascular
calcification and bone disease, on protein metabolism, on colonic
environment and circulating levels of microbial derived uremic
toxins [181]. The low-protein and phosphorus intake has a crucial
role for reducing proteinuria and preventing and reversing
hyperphosphatemia and secondary hyperparathyroidism, which
are major causes of the vascular calcifications, cardiac damage,
and mortality risk of uremic patients.
The reduction of nitrogenous waste products and lowering
of serum PTH levels may also help ameliorate insulin sensitivity
and metabolic control in diabetic patients, as well as increase
the responsiveness to erythropoietin therapy, thus allowing
greater control of anemia. Vegetarian diets may have also antiinflammatory
and antioxidant properties. Proper nutritional
treatment early in the course of renal disease may be useful
to reduce the cardiovascular risk in the renal patient [182]. In
one study patients were examined for triglycerides (TG), total
cholesterol, HDL and LDL cholesterol, and apolipoproteins Apo
A1, Apo B, and Lp(a). Lipid peroxidation (LP) has recently been
suggested to trigger the atherosclerotic process as well as to
worsen the progression of renal disease. Autoantibodies against
oxidized low-density lipoproteins (Ox-LDLAb) were considered
to provide a sensitive marker to detect LDL oxidation in vivo.
This study shows that the vegan diet, by reducing LP, total
cholesterol, TG, and Lp(a), decreases the risk of cardiovascular
disease and is worth being considered as an alternative effective
therapeutic tool in patients with advanced CKD [183].
In another study of CKD patients, Lp(a) concentrations
increased with the progression of renal failure, and a significant
correlation was observed with serum creatinine (sCr). Despite
the elevated sCr levels, patients on a keto analogue supplemented
vegetarian diet had an almost normal Lp(a) concentration
while only 15% of the reference group had [184]. Elevated
blood pressure (BP) is one of the most frequent complications
of chronic kidney disease [185]. Its correction is an important
intervention because uncontrolled hypertension is a recognized
determinant of progression of renal damage [186-189]. It
also represents a major cause for the elevated cardiovascular
morbidity and mortality detected in these patients [190-193].
Accordingly, current clinical practice guidelines strongly suggest
reducing BP to less than 130/80 mmHg [194]. One study of
stage 4 and 5 patients on a very low-protein ketoanalogue
supplemented diet, where the protein was mostly plant protein,
showed an average decrease in blood pressure from 143/84
to 128/78. The benefit of the mostly vegetable protein diet
was observed, even in patients who started with inadequate
BP control at baseline in spite of multidrug antihypertensive
therapy [195]. Other studies have shown that vegetarian diets
are associated with lower blood pressure [196-199]. A recent
study showed that a vegan diet was associated with lower blood
pressure in asymptomatic participants with proteinuria [200].
This diet could be a nonpharmacologic method to reduce blood
pressure and help prevent chronic kidney disease.
Several studies have determined the nutritional safety
of plant-based diets in CKD patients, despite dietary protein
restriction. Plant- based diets are associated with a reduced risk
of all-cause mortality in CKD patients. Studies confirm a kidney
protective effect of plant-based diets in the primary prevention
of CKD and the secondary prevention of CKD progression [201].
Dietary therapy has to be deeply analyzed, and nutritional
prescription has to be focused not only on reduction of protein
content but also on proteins’ quality [4,37,38,105-107].
Adherence to diet, fluids and dialysis are the cornerstone of renal
failure treatment [202]. Extensive changes to food and lifestyle
are required for patients with CKD. Many diet components must
be monitored such as calories, protein, sodium, potassium,
calcium, phosphorus, and fluid [203]. No single educational or
clinical strategy has been shown to be consistently effective
across CKD populations. Highest adherence has been observed
when both diet and education efforts are individualized to each
patient and adapted over time to changing lifestyle and CKD
variables [204]. Factors such as taste, convenience and the
impact of the diet on social eating occasions are also important
in enhancing dietary adherence [205].
The education focus may be more effective by addressing
one opportunity at a time, rather than a broad long-term diet
planning strategy [204]. Social support is especially important
for both hemodialysis and peritoneal dialysis patients in terms of
greater satisfaction and quality of life and fewer hospitalizations.
Intervention studies to possibly improve these outcomes are
warranted [206]. A regimen with 0.6 g/kg/day of proteins
is often difficult for a patient to maintain unless a vegan diet
(usually supplemented with keto acids) has been recommended.
To take the protein level even lower, ‘non-proteic’ (commercially
available) carbohydrates can be added. The combination of
both approaches allows protein intakes as low as 0.3g/kg/day
[3]. In a 4-year study by Piccoli, implementation was aimed
at testing a simplified approach to a plant-based low-protein
diet (protein intake of 0.6 g/kg/day) in patients with severe or
progressive CKD, who had been referred to a new nephrology
unit. In this study, flexibility started from the prescription, as the
diet was simply based on allowed and forbidden foods, without
the need to weigh all foods. Occasional free choice meals were
allowed to reduce the psychological burden [3]. This method
achieved positive results, while providing a simpler regimen
for patients. Supplementation of a VLPD with ketoanalogues
seems to have some advantages above and beyond the protein
restriction. If enough energy is provided, ketoanalogues could
be converted to essential amino acids by urea recycling, allowing
for a nutritionally safe, more severe reduction in protein intake
[41,43]. Furthermore, the calcium content of ketoanalogue
preparations and their phosphate binder capabilities allow
for even better correction of mineral metabolic abnormalities
[41,44].
It is noteworthy that educational level (often associated
with higher compliance), diabetes, overall comorbidity (often
associated with poor dietary compliance) and old age (frequently
considered to impair efficient modulation of the diet) were not
confirmed as strong relevant factors in attaining the medium
term follow up goals of this diet [3].
In this study, the diet was initially prescribed as a one-month
trial and was prescribed and managed by the nephrologist in
the context of the routine clinical follow up. Interestingly, in
stable patients with at least 6 months of follow up, compliance
was impressive, with a median protein intake of 0.5 g/kg/day.
This supports the hypothesis that subtle personal preferences,
as well as clear motivations, are fundamental in the relationship
with food and diet. Therefore, the authors conclude, this diet
should be proposed to all patients without preclusion [3]. The
CKD patient often presents with other chronic diseases such as
hypercholesterolemia, [207] coronary artery disease, [208,209]
and type 2 diabetes [60]. The plant-based diet is useful for
treating these comorbid diseases as well. Clinical parameters
should be monitored, and medications adjusted as the treatment
effect becomes evident.
The overall prevalence of chronic kidney disease in the
general population is approximately 14 percent. Medicare
spending for patients with CKD ages 65 and older exceeded
$50 billion in 2013 and represented 20 percent of all Medicare
spending in this age group. Given that the plant-based diet
reduces the risk of chronic kidney disease in the first place, it
would seem to be a very valuable prophylaxis. At least three main
reasons suggest that the time is ripe for a systematic integration
of a vegetarian diet into the clinical treatment of CKD: the cost of
dialysis, the clinical advantages and the failure of early dialysis
to prolong survival [3]. CKD is a challenging disease to treat for
both patient and physician. There are many clinical variables
to be simultaneously managed. Complicating treatment even
further is that treatment often needs to be modified as the
disease progresses. The plant-based diet can treat phosphotemia,
uremia, acidosis, proteinuria, acidosis and intestinal dysbiosis,
and can help prevent chronic kidney disease from advancing
to end stage renal disease. Almost half of individuals with CKD
also have diabetes and/or self-reported cardiovascular disease.
CKD often occurs in the context of multiple comorbidities and
has been termed a “disease multiplier” [210]. The plant-based
diet helps prevent type 2 diabetes, as well as treat it even more
effectively than the leading medication, Metformin. It can also
help prevent and treat coronary artery disease, the leading
cause of mortality in chronic kidney disease. The plant-based
diet has no contraindications or adverse reactions. It reduces
health care costs for both the patient and society. Low-protein
plant-based diets do not result in malnutrition or hyperkalemia
and are even safe in pregnancy. It may also be possible to raise
the amount of protein in the diet, if the protein is plant-derived.
Supplementation with ketoanalogues make the treatment more
efficacious. Plant-based diets are no longer very unusual as they
have become more popular in the general population in recent
years. Given all of the benefits, the plant-based diet deserves a
place among the physician’s treatment options for CKD.