Low-protein diets in CKD: How can we achieve them? A narrative, pragmatic review

Abstract

Low-protein diets (LPDs) have encountered various fortunes, and several questions remain open. No single study, including the famous Modification of Diet in Renal Disease, was conclusive and even if systematic reviews are in favour of protein restriction, at least in non-diabetic adults, implementation is lagging. LPDs are considered difficult, malnutrition is a threat and compliance is poor. LPDs have been reappraised in this era of reconsideration of dialysis indications and timing. The definition of a normal-adequate protein diet has shifted in the overall population from 1 to 1.2 to 0.8 g/kg/day. Vegan-vegetarian diets are increasingly widespread, thus setting the groundwork for easier integration of moderate protein restriction in Chronic Kidney Disease. There are four main moderately restricted LPDs (0.6 g/kg/day). Two of them require careful planning of quantity and quality of food: a 'traditional' one, with mixed proteins that works on the quantity and quality of food and a vegan one, which integrates grains and legumes. Two further options may be seen as a way to simplify LPDs while being on the safe side for malnutrition: adding supplements of essential amino and keto acids (various doses) allows an easier shift from omnivorous to vegan diets, while protein-free food intake allows for an increase in calories. Very-low-protein diets (vLPDs: 0.3 g/kg/day) combine both approaches and usually require higher doses of supplements. Moderately restricted LPDs may be adapted to virtually any cuisine and should be tailored to the patients' preferences, while vLPDs usually require trained, compliant patients; a broader offer of diet options may lead to more widespread use of LPDs, without competition among the various schemas.

Full text

Ckj Review
Low-protein diets in CKD: how can we achieve them?
A narrative, pragmatic review
Giorgina Barbara Piccoli1, Federica Neve Vigotti1, Filomena Leone2, Irene Capizzi1, Germana Daidola3,
Gianfranca Cabiddu4and Paolo Avagnina5
1
Nephrology, Clinical and Biological Sciences Department, S. Luigi Gonzaga Hospital, University of Turin, Italy,
2
Dietetics, Surgical
Sciences Department, S. Anna Hospital, University of Torino, Turin, Italy,
3
Nephrology, S. Giovanni Battista Hospital, University of Turin,
Italy,
4
Nephrology, Brotzu hospital, Cagliari, Italy and
5
Clinical Nutrition, Clinical and Biological Sciences Department, S. Luigi Gonzaga
Hospital, University of Turin, Italy
Correspondence to: Giorgina Barbara Piccoli; E-mail: gbpiccoli@yahoo.it
Abstract
Low-protein diets (LPDs) have encountered various fortunes, and several questions remain open.
No single study, including the famous Modification of Diet in Renal Disease, was conclusive and
even if systematic reviews are in favour of protein restriction, at least in non-diabetic adults, im-
plementation is lagging. LPDs are considered difficult, malnutrition is a threat and compliance is
poor. LPDs have been reappraised in this era of reconsideration of dialysis indications and timing.
The definition of a normal-adequate protein diet has shifted in the overall population from 1 to
1.2 to 0.8 g/kg/day. Vegan–vegetarian diets are increasingly widespread, thus setting the ground-
work for easier integration of moderate protein restriction in Chronic Kidney Disease. There are
four main moderately restricted LPDs (0.6 g/kg/day). Two of them require careful planning of
quantity and quality of food: a ‘traditional’one, with mixed proteins that works on the quantity
and quality of food and a vegan one, which integrates grains and legumes. Two further options
may be seen as a way to simplify LPDs while being on the safe side for malnutrition: adding
supplements of essential amino and keto acids (various doses) allows an easier shift from omniv-
orous to vegan diets, while protein-free food intake allows for an increase in calories. Very-low-
protein diets (vLPDs: 0.3 g/kg/day) combine both approaches and usually require higher doses of
supplements. Moderately restricted LPDs may be adapted to virtually any cuisine and should be tai-
lored to the patients’preferences, while vLPDs usually require trained, compliant patients; a broader
offer of diet options may lead to more widespread use of LPDs, without competition among the
various schemas.
Keywords: CKD; compliance; keto acids and amino acids; low-protein diets; very-low-protein diets
Low protein diets: a new garden?
In a wonderful book, ‘Cradle to Cradle, Remaking the
Way We Make Things’, a manifesto of the ‘new industrial
revolution’, a chemist and an architect search for a new
production strategy combining abundance, safety and
efficacy. One of the many anecdotes concerns the mother
of one of the authors, who used to cultivate a wild garden
full of diverse flowers and unusual trees. In 1982, the
woman was fined by the local administration because her
garden was ‘too messy’. The lady continued paying a
yearly fine for about a decade, until she won an award
for creating a habitat for songbirds. The authors con-
cluded that it was not a change in the garden; it was a
change in the prevailing aesthetic. It was a change in the
society [1].
A similar story may be told for low-protein diets (LPDs).
Since the pioneering studies by Thomas Addis, who foresaw
Brenner’stheoryof‘workload’on the remnant nephrons
and systematically used diets in clinical practice, LPDs have
encountered alternate fortunes [2–9]. Strong supporters
and determined adversaries contributed to the controversy,
reflecting changes in the near-world of renal replacement
therapies, and the wider-world of nutrition [10–12].
The conflicting interpretation of the largest randomized
controlled trial on diet in kidney disease, the Modification
of Diet in Renal Disease (MDRD) study, which failed to
demonstrate an advantage in the primary intention-to-
treat analysis, but supported a positive effect in the sec-
ondary per-protocol analyses, further radicalized the
positions in favour of or against LPDs [9,13–17].
The MDRD study highlighted the crucial role of compli-
ance, not yet fully appreciated in chronic diseases, and
added two important tools: the MDRD equation for the as-
sessment of GFR and the only dietary satisfaction ques-
tionnaire validated in kidney patients [18,19].
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.This isan Open Access article distributedunder the terms of the Creative
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Clin Kidney J (2015) 8: 61–70
doi: 10.1093/ckj/sfu125
Advance Access publication 2 December 2014

The issue of the diet was not solved by a Cochrane review
in favour of protein restriction in non-diabetic adults, leaving
the definition of the optimal protein intake in LPDs up for
debate [20,21].
The present cultural drive favours a lower protein intake
in the overall population: several studies have tried to
define a healthy diet, i.e. one that is rich in ‘healthy foods’,
such as vegetables, fruits, nuts, olive oil and grains, and
poor in red or processed meat [22–24]. Globalization con-
fronts the current European and North American diets with
different ones, which are often lower in animal proteins,
and this has also led to an in-depth review of recom-
mended daily allowances [25–27]. Rediscovery of the Medi-
terranean diets, rich in vegetables, legumes and cereals,
and demonstration of their association with longer survival,
call for attention to traditional diets which are more easily
‘transformed’into LPDs [28–30]. Meanwhile, evidence of
the increase in all-cause mortality, cardiovascular diseases
and cancer related to diets that are rich in red and pro-
cessed meat calls for attention to the ‘too much’[31,32].
In counter-tendency to the classical food marketing
strategy that highlighted the presence of ‘valuable’ingredi-
ents, a world-wide campaign is being carried out to regu-
late additives in food [33–35]. Growing attention to the
quality rather than the quantity of what we eat activates
virtuous cycles of ‘zero km’production, with renewed inter-
est in non-preserved, additive-free food.
In this context, vegetarian and vegan diets are becom-
ing increasingly popular, setting the groundwork for easier
integration of vegetarian protein-restricted diets in our pa-
tients who are no longer seen as ‘outliers’in a carnivorous
world [36–38].
Vegan–vegetarian diets usually contain between 0.6
and 0.8 g/kg/day of vegetable proteins and may be less ef-
fective in enhancing renal hyper-filtration, also since vege-
table proteins are less bioavailable than animal proteins
[39–42]. Provided that deficits are controlled and corrected
(in particular, iron, vitamin B12 and vitamin D), these diets
are considered safe by the most eminent associations, in-
cluding the American Dietary Association, in all phases of
life, including growth, pregnancy and lactation [36–38].
This paradigm shift allows ‘our’LPDs to be more easily
integrated in a society in which ‘eating together’is a pivotal
moment, with easier access to vegan menus, available on
intercontinental flights as well as in most international
restaurants.
No alibi: it is possible to reduce protein content and to
follow at least a moderately protein-restricted diet almost
everywhere. As for the wild garden, our society is moving
towards a reappraisal of traditional diets, characterized by
lower animal protein content, better quality of food and
fewer additives [29–31,43–47].
Are we answering the unanswered questions?
Almost 30 years after the provocative paper ‘Dietary
treatment for chronic renal failure, ten unanswered ques-
tions’and its tentative answers, many questions are still
unanswered (Does chronic renal failure always progress?
How should we assess progression, nutritional status or
compliance? Is there a placebo effect in diet trials? When
should a low-protein diet start? What are the risks of a
low-protein diet? What is the cost of a low-protein diet?)
[10,11]. In this narrative review, we will focus on the most
practical one: ‘Which low-protein diet?’as a key for imple-
menting the ‘right diet’with the ‘right patient’.
What is a diet?
On Wikipedia, ‘diet is the sum of food consumed by a
person or other organism’.Wewillemploytheword‘diet’in
this broad meaning, preferring it for the sake of simplicity
to the more elegant, but less practical ‘nutritional ap-
proach’‘nutritional therapy’, however without the restrictive
meaning ‘diet as reduction of …’.
Diet is all that we eat. Implicit in this is the opinion that
for Chronic Kidney Disease (CKD) patients, being on a diet
should consist of changing their habits and not (simply) in
restricting the use of some (many-most) foods.
What is a normal protein diet and what is an LPD?
From attention to under-nutrition to attention to
over-nutrition
If the definition of diet is simple, the definition of normal
protein intake is not. Following the increased availability of
food, in the Western world, a ‘healthy’diet progressively
switched from a diet containing a ‘minimum requirement
to avoid deficits’to one not surpassing an ‘ideal intake’to
avoid over-nutrition [48].
The FDA Reference Daily Intake or Recommended Daily
Intake (that substitutes the older ‘Recommended Daily Allow-
ance’) is the daily intake that suffices to meet the require-
ments of 97–98% of healthy individuals in every demographic
in the USA: this is presently identified as 0.8 g/kg/day of
proteins, lower than the previous 1.0 g/kg/day, considered
the hallmark of ‘normal’protein intake [25–27].
As a consequence, what we used to call moderately re-
stricted ‘LPDs’(0.8 g/kg/day) now have ‘normal protein’
content, while diets at 1.0–1.2 g/kg/day should be consid-
ered ‘high protein’. This is not only semantic: it casts a dif-
ferent light on the classical 0.6 g/kg/day diets, no longer
radically different from ‘normal’diets (Table 1).
A practical nomenclature: vegan–vegetarian diets
The systematic distinction between vegan and vegetarian
diets is relatively new: the term vegan was coined by
Donald Watson in 1944: ‘vegan’from the beginning and
end of vegetarian ‘because veganism starts with vegetar-
ianism and carries it through to its logical conclusion’[49].
The two terms were often used interchangeably in the
past, or, most often, vegetarian diets were subdivided into
‘strict’, corresponding to the current vegan diets, and ‘ovo-
lacto’vegetarian diets [36–38,49].
Vegetarian diets are free from fish, meat and poultry,
i.e. from living sources of food; there is however, a long list
of variants, including ovo-vegetarian (eggs only), lacto-
vegetarian (milk and dairy products) and pescetarian (fish
is allowed). Honey is excluded by some diets, while others
take care in avoiding all animal-derived components which
are common in food processing, for example, sugars whi-
tened with bone char, cheeses that use animal rennet or
gelatin from animal collagen. Watson, who was registered
as ‘a conscientious objector’in World War II, expanded his
philosophy to object to any harm to living creatures. This
latter attitude is extended in the Fruitarianism, based upon
fruit, nuts, seeds and food gathered without ‘harming the
plant’[50].
The cultural roots of vegetarianism are deep: the list of
eminent vegetarians includes Buddha, Leonardo Da Vinci,
62 G.B. Piccoli et al.

Gandhi, Tolstoy, George Bernard Shaw (who foresaw the
participation at his funeral of all the animals he had not de-
voured), Isaac Bashevic Singer (I did not become a vegetar-
ian for my health, I did it for the health of the chickens), but
also music stars, such as Paul McCartney (If slaughter-
houses had glass walls, everyone would be a vegetarian).
Even if the demonstration of the possibility to combine
public success and vegetarian diet is reassuring, the moti-
vations of a ‘vegetarian by choice’, be it for the sake of the
chickens or for the sake of the soul, may be different from
those of a ‘vegetarian for health’, in whom the motivation
is sustaining health, or avoiding dialysis. We need different
strategies, while learning from the ‘vegans–vegetarians’
by choice.
LPDs in CKD: learning from the beginning
Tracking the development of LPDs is fascinating: the first
attempts to counterbalance the hyper-azotaemia of ad-
vanced kidney disease date to the first half of the Twenti-
eth Century [3,51–53]. However, most of the approaches
that proved to be effective in clinical practice were devel-
oped in the 50–60s; our current diets are the result of the
strategies to overcome the difficulties identified in these
early studies.
The first problem was combining LPDs with a sufficient
caloric intake, because a hyper-catabolic state leads to an
increase in blood urea [54–57]. Different sources of cal-
ories were tested, and the cultural differences were high-
lighted: surrogates of pasta and bread were compatible
only with Italian diets, while in Anglo-Saxon countries
mixtures of lipids and carbohydrates were tested, overall
with poor success [54–58].
These first diets were very hard: the effort of having to
keep all foods under control made them exceedingly
complex: this is, for example, a typical dinner published in
the late ‘60s with a low-protein mixed diet: 120 g carrots
(cooked weight); 100 g runner beans; 100 g potatoes (raw
weight); 15 g salt-free butter; 135 g tinned peaches (100 g
peach, 35 g juice); 15 g single cream and 10 g white
bread. The modified Giovannetti diet was no easier: this is
a‘supper’from a 1970 paper: ‘50 g egg; 15 g lettuce; 55 g
tomato; 30 g beetroot (cooked weight); 50 g low-protein
bread; 15 g unsalted butter; 100 g mandarins (tinned) (80
g fruit + 20 g juice); 15 g single cream’[57].
The definition of the protein target was a crucial issue.
The underlying idea was simple: protein intake should be
‘the lowest the best’, provided that hyper-catabolism was
avoided [3,52–62].
Different levels of protein restriction were tested, initially
defined according to total protein content (the 40 g versus
the 20–19–18 g diets [54–57]) and later according to body
weight, finally leading to a pragmatic subdivision into LPDs
at 0.8–0.6–0.3 g of protein per kg/body weight (Tables 1
and 2,Figure 1).
Early studies attempted to assess the minimum protein
intake requirement. ‘Very-low-protein diets’(vLPDs) derive
from data suggesting that 0.3 g/kg/day is the lowest,
safely achievable protein intake, provided supplementa-
tion with essential amino and/or keto acids is included.
Table 1. Characteristics of the main LPDs, defined according to protein content
Diet definition Type of proteins Scheme Advantages—problems
Supplements protein-
free food
Moderate protein restriction: 0.6 g/kg/day
‘Traditional’LPD 0.6 g/kg/day, mixed,
with at least 50% of
animal origin (or
‘high biological
value’)
The diet requires adaptation to the
local habits; 30–35 kcal/kg are
reached by implementing protein-
poor calorie-rich natural food ( for
example, rice, potatoes, tapioca,
fruit, oil and butter)
Advantage: no supplement or special
food needed; limits: skilled dietician is
needed. The caloric intake may be
difficult to reach in particular in ‘small’
patients
None
Vegan LPD 0.6 g/kg/day,
vegetable origin
This diet is strictly vegan; it is based
upon a combination of different
proteins of vegetable origin, mainly
in grains, legumes and soy protein
Advantage: no supplement or special
food are needed; limits: the
combination of legumes and cereals at
each meal is demanding. May not be
suited to patients with diverticulosis or
intestinal problems
None
Vegan
supplemented with
keto and amino
acids
0.6 g/kg/day,
vegetable origin
This diet is strictly vegan; it may be
based upon forbidden (all food of
animal origin) and allowed food (all
food of vegetable origin).
Supplements allow integration
without need for combining grains
and legumes at each meal
Advantage: simplified scheme based
upon allowed and forbidden food; may
be used in patients who do not like or
tolerate legumes. Limits: need for
supplementation of many pills (free of
charge only in a few countries).
Alpha-keto acids and
amino acids, min: 1:10,
max 1:5 kg BW
LPD with protein-
free food
0.6 g/kg/day, mixed
origin
Cereals are all or in part replaced by
protein-free food (mainly pasta and
bread). This allows moderate
quantities of proteins of animal
origin
Advantage: no need to drastically
change food habits. Problems: easily
integrated in Mediterranean diets, less
in Northern diets. Limited availability
(high cost) of protein-free food in
several countries.
Protein-free food
vLPD: 0.3 g/kg/day
vLPD-vegan
supplemented
0.3 g/kg/day,
vegetable origin
This diet is strictly vegan; it may be
based upon forbidden (all food of
animal origin) and allowed food (all
food of vegetable origin). More easily
carried out if bread and pasta are
substituted with protein-free food.
Advantage: probably more effective in
postponing dialysis. Problems: requires
separate cooking, is monotonous and
requires a high number of pills. Limited
availability (high cost) of protein-free
food in several countries.
Alpha-keto acids and
amino acids, 1:5 kg
BW; optional: protein-
free food.
In pregnancy: 0.6–0.8 LPD–vegan vegetarian—supplemented: mainly vegetable proteins; small doses of milk and yogurt allowed. Alpha-keto acids and
amino acids 1:8–10 kg BW in the first trimester, increased to 1:5–8 kg BW in the last.
Low-protein diets in CKD: achievable? 63

Conversely, the other ‘magic number’of 0.6 g/kg/day was
believed to identify the upper level of protein restriction ex-
erting a measurable effect on CKD progression [3,52–62].
The concept of malnutrition came later, when the avail-
ability of dialysis allowed to carry out a long-term analysis
of the diet and of its carry-over effect after the start of renal
replacement therapy [61–64].
Interestingly, these early studies calculated that LPDs
allowed life span to be prolonged by about 1 year (in the
absence of dialysis) and slowed progression when started
earlier [55,61]. These results are remarkably similar to
more recently reported ones, with different, more palatable,
LPDs, in a context of widespread dialysis availability [8,16,
20,21,62–71].
Why is the evidence on LPDs in CKD inconclusive:
personalized medicine, or RCTs?
The controversy over LPDs in CKD is indirect proof of the lack
of conclusive data [7–11,14–16,63,64]. After the MDRD
study, several well-conducted Randomized Controlled Trials
(RCTs) and one Cochrane review on non-diabetic adults
were in favour of protein restriction [14,65–67,71–73].
However, no study is devoid of biases and none represented
a paradigm shift towards a systematic acceptance of LPDs
in CKD.
There are many reasons why studies may be non-
conclusive or biased. Diet, for which compliance is key to
success, is highly intrusive in a patient’s life, as demon-
strated by the attrition bias according to which patients
tend to switch to their preferred diets despite the original
prescriptions [14,74–78].
Personalized, patient-centred medicine is an emerging
clinical model, that is hardly compatible with the rigidity of
RCTs [79–82]. Following the lesson of the complementary
medicines, the focus may shift from the demonstration of
the superiority of a treatment to an observational multidi-
mensional ‘whole system’approach [83].
In fact, to cite a BMJ educational report, ‘when the effect-
iveness of the intervention depends on the subject’s active
participation’,areflection of the patient’s preferences,
‘a randomized trial may be inappropriate because the very
act of random allocation may reduce the effectiveness of
the intervention’[84]. Thus, while RCTs are best for studying
short-term efficacy, observational studies may be more
appropriate for analysing their implementation and high-
lighting the interactions with patients’preferences and
compliance [76,84–86]. RCTs and observational studies
have complementary roles: ‘high quality observational
studies may extend evidence over a wider population and
are likely to be dominant in the identification of harms
and when RCTs would be unethical or impractical’[87].
The methodological drawbacks of studies on diets in
CKD are similar to those of dialysis: randomization of
peritoneal dialysis versus haemodialysis is considered
‘unethical and unpractical’. The endless search for the
best dialysis treatment shows that the main reason for
supporting treatment choice is the demonstration of its
equivalence in terms of hard end points [88]. The diet is
probably as intrusive as dialysis is in daily life. The price of
an appealing randomized study design not involving ‘indif-
ferent’therapies is a low enrolment rate or an important
attrition bias: indeed how many of us would accept being
randomized to a restricted versus an unrestricted diet?
[14,15,65,66,71].
Table 2. Energy, minerals and vitamins in the different LPDs
‘Traditional’LPD LPD with protein-free food
Vegan
LPD
Vegan
supplemented
with keto and amino acids VLPD-vegan supplemented
Calories 30–35 kg body weight: this is the most crucial point to avoid protein malnutrition, in particular in elderly patients with cardiovascular disease (MIA syndrome); this is a basic prescription for all LPD;
the risk of hyper-catabolism may increase in ‘very low’protein diets
Calcium Calcium is usually added Calcium is contained in the supplements; further addition may not be
routinely needed
Phosphate Phosphate content strictly depends upon the quota of
animal proteins. It may be increased if canned,
preserved or frozen foods are employed
Phosphate content is usually low in vegan diets, in particular if only fresh food is used. Bioavailability of vegetable phosphate may be
different. Readily bioavailable phosphate may be remarkably increased if canned or frozen food is routinely consumed (usually frozen
vegetables and canned legumes)
Vit D Supplementation is commonly needed; however the
quota of animal proteins may protect from severe
deficits
Vitamin D is commonly needed; bioavailable vit D is less represented in vegetable-based products
Folate Supplementation may be needed if the patient eats
low quantities of fresh fruits and vegetables
Supplementation usually not needed if fresh food is used
B12 Supplementation may be needed; however, the quota
of animal proteins usually protects from severe
deficits
Supplementation is commonly needed; B12 deficit is particularly prevalent and may lead to severe problems in vegan–vegetarian
pregnancy
Iron Supplementation is commonly needed; however, the
quota of animal proteins may protect from severe
deficits
Supplementation is usually needed; the bioavailability of vegetable iron is usually lower, even if well-designed vegan diets are not
necessarily associated with a deficit in iron
We did not consider in this review the intake of two main nutrients: sodium and potassium, on the account of their dependence from several otherelements, including, for the former the type of disease (interstitial
versus vascular or glomerular nephropathy), the blood pressure level and the anti-hypertensivetherapy, and for the latter the acidosis status, the use of diuretics and the eventual potassium-containing food
additives.
64 G.B. Piccoli et al.

A practical nomenclature: moderate protein
restriction: low-protein ‘0.6-diets’:‘traditional’,
vegan, vegan-supplemented and with
protein-free food
The approaches to ‘moderate protein restriction’which is
synonymous with a diet having a protein intake of 0.6 g/kg/
day encompass various combinations of protein content,
prevalence of vegetable proteins, use of dietary supple-
ments and protein-free food (Tables 1and 2,andFigure 1).
There are four main policies for achieving a balanced
‘0.6 diet’:wewillcallthem‘traditional’, vegan, vegan-
supplemented and with protein-free food.
Although all protein-restricted diets share the risk for
malnutrition, which is obviously enhanced by baseline
malnutrition, severe atherosclerotic disease and inflamma-
tion (the Malnutrition-Inflammation-Atherosclerosis (MIA)
Fig. 1. A diet flowchart and counseling tips.
Low-protein diets in CKD: achievable? 65

syndrome), the risks are low in moderately restricted diets
and may be more frequent in the case of stricter protein
restriction. A ‘hidden’but crucial point in the management
of all types of LPDs is indeed the exclusion of the cases
with baseline malnutrition, long-term steroid therapy,
very advanced age, with or without MIA [89,90]. Differ-
ences in exclusion policy may account for the different
results obtained in various studies, in particular as for the
safety issues.
‘Traditional’0.6-diets
There is substantial agreement that moderate protein re-
striction is feasible without the need for supplements or
protein-free food [12,72,73,75,91].
Achieving this goal may be easier where the traditional
cuisine is mainly based upon vegetable proteins, such as in
India or in Mediterranean countries, and is integrated with
small quantities of animal proteins, but may be difficult in
Anglo-Saxon or Northern European countries [28–32,43–46].
Designing LPDs with mixed protein content may start
from an adaptation of local diets: for example, Mediterra-
nean diets integrate legumes and cereals, and the addition
of a very small amount of dairy products or meat-fish
supplies the essential amino acids that are needed; on the
other side of the world, in the ‘Okinawa diet’,verysmall
amounts of animal protein were added to a diet that is rich in
fruit and vegetables [23,29,30,92]. Adaptation may be more
difficult in other contexts where thebaselinedietislessrich
in vegetables and cereals, however protein content has only
recentlyrisenintheWesternworld,andmosttraditionalcui-
sines have a lower protein intake in ‘everyday food’[28–31].
Vegan 0.6–0.8 diets
As already mentioned, non-restricted vegan diets usually
provide a protein intake of 0.6–0.8 g/kg/day and are nutri-
tionally adequate if carried out with attention to the inte-
gration of essential amino acids [36–38]. As a rule,
legumes and cereals and/or soy should be combined at
every meal, and a high variety of legumes and cereals
ensures integration of essential amino acids. Some inter-
esting schemas are available from different parts of the
world, such as the Italian Barsotti scheme, or the Israel
approach by Soroka. Both Barsotti and Sokora employed
dietary regimens at 0.7–0.8 g/kg/day on the account of
the lower bioavailability of vegetable proteins [40,41,93].
Supplemented, vegan 0.6-diets
Supplementation with amino and keto acids and substitu-
tion with protein-free commercial food represent two
strategies to ‘be on the safe side’as for malnutrition. The
first strategy provides supplementation of essential amino
acids (in the form of amino and keto acids, metabolized
in vitro with an additional urea-sparing effect), the second
one adds calories in the form of protein-free food [89,94].
In the past, various mixtures/combinations of amino
acids and keto acids were used; presently only two of
them, both of which are marketed by the same company,
are available: Alfa Kappa (in Italy) or Ketosteril (all over
the world) [94,95]. Their composition is identical but for
the presence of 23 mg per pill of L-tryptophan in Ketoster-
il. The Italian formula is tryptophan free due to its possible
role as a precursor of pro-fibrotic cytokines and indoles
[96,97]. In the absence of a clear demonstration of any
clinical difference, they are usually considered equivalent
and have been used interchangeably in some studies, also
on account of manufacturing changes that have taken
place over time [69,70].
According to a consensus statement, supplements are
not strictly needed in vegan diets at 0.6 g/kg/day of pro-
teins [89]. However, they may be useful when omnivorous
patients are ‘forced’into a vegan regimen, or when a
patient does not like or cannot tolerate legumes. Supple-
mentation allows a simplified quantitative approach that
excludes animal-derived food, but leaves a free choice of
vegetables, fruits, legumes and cereals [69,70]. On the
basis of our group’s experience, this is also a good strategy
in fragile patients, including diabetics, pregnant women or
patients recovering renal function [69,70,89,98–101].
The dose of supplements with the 0.6 diets is not stan-
dardized; our group indicates 1 pill every 10 kg of body
weight, as a compromise between ‘too many pills’and risk
of malnutrition [69,70,98–101].
0.6-Diets with protein-free food
The issue of protein-free foods is complex [102]. The idea
was born in the era of limited dialysis availability: natural
protein-free foods (tapioca, butter, sugar, fruits and vegeta-
bles) resulted in very monotonous diets. Following the English
example of starch-containing food for coeliac patients,
the first protein-free pasta was produced in 1966, followed
in the late ‘70s by an industrial production of pasta, flour,
biscuits, bread and crispbread. More recently, protein-free
drinks, snacks, and partially cooked foods have become
commercially available [102]. However, to the best of our
knowledge, protein-free food is available free of charge to
CKD patients only in Italy, thus limiting the systematic dif-
fusion of this approach [70].
Replacing the usual cereals with protein-free food allows
the patient to achieve a high caloric intake, thus giving
him/her more freedom to plan the rest of the diet. This is
especially favourable in Mediterranean countries where up
to half of the proteins derive from bread and pasta (12 g of
proteins per 100 g), and replacing them allows the patients
to reach the target protein intake without substantially
changing their dietary habits. Hence, in our experience,
these diets are preferred by elderly patients, while younger
ones tend to prefer vegan supplemented diets [70,71].
Adding calorie-rich food to avoid malnutrition was also
attempted by other supplements ( for example, maltodex-
trin and oil creamer), once more in keeping with the local
dietary habits [103,104].
vLPDs: a combination of vegan, supplemented
diets and protein-free food
A supplemented LPD is not synonymous with a vLPD [89].
However, vLPDs (usually at 0.3 g/kg/day) require integra-
tion to avoid malnutrition [14–16,66–68,71,72,90,104].
The amount of amino and keto acid supplements, conven-
tionally measured in pills per kg/day, is 1 pill/5 kg of body
weight [89].
The combination of a vegan diet, requiring many pills,
possibly together with commercial protein-free food, makes
these ‘artificial diets’extremely complex and an option for
only a small number of patients. The Bucharest group,
which to date has probably achieved the best compliance
with vLPDs, enrolled about 10% of the initially screened pa-
tients into their trial [71,105]. Similar difficulties were
66 G.B. Piccoli et al.

encountered in the Brunori trial [65–67]. Interestingly, in our
observational study, which allowed patients to freely choose
their own diet, the prevalence vLPDs was also about 10%
with respect to all LPDs [70]. Despite the difficulties, vLPDs
are usually considered more effective in postponing dialysis
in compliant patients [71–75]. A ‘missing point’in the litera-
ture is the actual menu of these diets.
In Italy, the availability of protein-free food makes it
easier to reach the ideal caloric intake, however, when
protein-free food is not available, the diet may be even
more demanding [16,66–68,71,72,105].
While this review was focussed on the ‘classical’indica-
tions for CKD; however, it may be worth mentioning that
vLPDs may have a specific indication in the ‘rescue treatment’
of nephrotic syndrome resistant to the therapies specifically
addressed at the pathophysiologic mechanisms [106,107].
Quality matters, but compliance matters more;
different proteins may have different effects,
and what about ‘unrestricted meals’?
The quality of the protein matters: some studies suggest
there is a favourable effect of soy proteins in kidney trans-
plant patients, diabetic patients or experimental animals
[108–111]. However, the evidence is limited and shares
the same methodological drawbacks as trials on LPDs:
compliance is crucial in the long term and it is difficult to
achieve if the diet is too rigid.
Various policies have been employed to improve compli-
ance: one option is to alternate different LPDs in order to
increase the variety of food [112].
The approach followed by our group is a qualitative sim-
plification of the diet, based upon forbidden and allowed
food for the vegan diets, or upon substitution of carbohy-
drates with protein-free food, without otherwise changing
the diet [69,70,98–101]. An occasional unrestricted meal
(one to three times per week) or one day a week off-diet is
another strategy for ensuring compliance. At least two
groups have systematically reported inclusion of free meals,
thus leading to good compliance [69,70,75,98–101,113].
A warning: an LPD is not synonymous
with a healthy diet
A decrease in kidney function is associated with an in-
creased risk in adverse drug reactions. Less is known
about the toxic effect of food additives, preserving agents
or taste enhancers. Recent studies highlighted the import-
ance of added polyphosphates and warned about sodium
and potassium content [114–117]. The list of potentially
toxic additives is long and the effect in the context of
reduced kidney function has not yet been investigated.
While waiting for further studies to be carried out, atten-
tion should be paid to all food components and not only
to the quantity of proteins, and should be a warning to pa-
tients and manufacturers alike.
This review did not consider other important elements,
including sodium and potassium, on account of their
highly complex inter-dependence with other issues, in-
cluding type of disease, blood pressure level and anti-
hypertensive therapy, acidosis balance and food additives.
While each of these issues may be worth a specific review,
reminding them may underline the complexity of a com-
prehensive dietary approach to CKD patients [118,119].
Working conclusions: which diet for which patient?
If we extend the approach that has been developed for
dialysis, i.e. allowing each patient to choose the most ac-
ceptable treatment and encouraging empowerment and
self-care, we may design a multiple choice diet system
with easy access to different options so that each patient
may find the best diet (or at least the least intrusive one).
A stepwise option, starting from moderate protein re-
striction, could be proposed to all patients with progressive
or advanced CKD in an attempt to allocate each patient to
the simplest and most feasible diet option (such as vegan
simplified diets for younger patients, traditional and with
protein-free food for elderly patients), while strict 0.3 diets
will probably play a role in highly motivated, well-trained
patients, or in selected patients for whom postponing dialy-
sis may be of particular relevance (Figure 1).
In such a setting, there may be no competition among
different diets, and the availability of more schemas may
allow a greater number of patients to follow an LPD for a
longer period, with potential benefits for the overall CKD
population.
Conflict of interest statement. G.B.P. belongs to the Ketosteril
advisory board (Fresenus Kabi); F.N.V. received a Fresenus Kabi
research fellowship through a University grant to G.B.P. (University
of Torino). The other authors have no potential conflict of interest.
The results presented in this paper have not been published
previously in whole or part.
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Received for publication: 30.8.14; Accepted in revised form: 1.11.14
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