Guia 15941

Journal of Endocrinological Investigation
https://doi.org/10.1007/s40618-024-02446-8
CONSENSUS STATEMENT
Nutritional assessment and medical dietary therapy for management

of obesity in patients with non‑dialysis chronic kidney disease:
a practical guide for endocrinologist, nutritionists and nephrologists.
A consensus statement from the Italian society of endocrinology
(SIE), working group of the club nutrition–hormones and metabolism;
the Italian society of nutraceuticals (SINut), club ketodiets
and nutraceuticals “KetoNut‑SINut”; and the Italian society
of nephrology (SIN)
G. Annunziata1,2 · M. Caprio3,4 · L. Verde5 · A. M. Carella1,6 · E. Camajani4 · A. Benvenuto6 · B. Paolini7 ·
L. De Nicola8 · F. Aucella9 · V. Bellizzi10 · S. Barberi11 · D. Grassi12 · F. Fogacci13,14 · A. Colao15,16,17 ·
A. F. G. Cicero13,14 · F. Prodam18,19 · G. Aimaretti18 · G. Muscogiuri15,16,17 · L. Barrea16,20
Received: 8 February 2024 / Accepted: 19 August 2024

© The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE) 2024
Abstract
Purpose Chronic kidney disease (CKD) is a serious health concern with an estimated prevalence of about 13.4% worldwide.
It is cause and consequence of various comorbidities, including cardiovascular diseases. In parallel, common pathological
conditions closely related to ageing and unhealthy dietary habits increase the risk of CKD development and progression,
including type 2 diabetes and obesity. Among these, obesity is either independent risk factor for new onset kidney disease
or accelerates the rate of decline of kidney function by multiple mechanisms. Therefore, the role of diets aimed at attain-
ing weight loss in patients with obesity is clearly essential to prevent CKD as to slow disease progression. Various dietary
approaches have been licensed for the medical dietary therapy in CKD, including low-protein diet and Mediterranean diet.
Interestingly, emerging evidence also support the use of low-carbohydrate/ketogenic diet (LCD/KD) in these patients. More
specifically, LCD/KDs may efficiently promote weight loss, improve metabolic parameters, and reduce inflammation and
oxidative stress, resulting in a dietary strategy that act globally in managing collateral conditions that are directly and indi-
rectly related to the kidney function.
Conclusion This consensus statement from the Italian Society of Endocrinology (SIE), working group of the Club Nutrition
– Hormones and Metabolism; the Italian Society of Nutraceuticals (SINut), Club Ketodiets and Nutraceuticals “KetoNut-
SINut”; and the Italian Society of Nephrology (SIN) is intended to be a guide for Endocrinologist, Nutritionists and Neph-
rologist who deal with the management of patients with obesity with non-dialysis CKD providing a practical guidance on
assessing nutritional status and prescribing the optimal diet in order to best manage obesity to prevent CKD and its progres-
sion to dialysis.
Giuseppe Annunziata, Massimiliano Caprio and Ludovica Verde

equally contributed to this work as co-first.
Giovanna Muscogiuri and Luigi Barrea equally contributed to this

work as co-last.
Extended author information available on the last page of the article
Vol.:(0123456789)
Graphical abstract
Nephrological clinical
evaluation
Assessment of kidney function.
Endocrinological clinical
evaluation
Patients with obesity, non- Assessment of metabolic
diseases associated with Patients with obesity
dialysis chronic kidney disease obesity and chronic kidney and non-dialysis
and obesity-related diseases disease chronic kidney disease
Nutritional clinical evaluation Obesity-related
Assessment of nutritional status kidney disease
MEDITERRANEAN
VLEKT DIET
Keywords Chronic kidney disease · Obesity · Nutritional management · Bioelectrical impedance analysis · Mediterranean
diet · Ketogenic diet · Nutrition · Diet
Abbreviations IR Insulin resistance

AER Albumin excretion rate K Potassium
β-HB β-Hydroxybutyrate KB Ketone body
BC Body composition KD Ketogenic diet
BIA Bioelectrical impedance analysis KeNuT Ketogenic nutritional therapy
BIVA Bioelectrical impedance vector analysis LCD Low-carbohydrate
BMI Body mass index LCKD Low-calorie ketogenic diet
BW Body weight MD Mediterranean Diet
CKD Chronic kidney disease MetS Metabolic syndrome
CRP C-reactive protein Na Sodium
CVD Cardiovascular diseases NKF Normal kidney function
DXA Dual-energy x-ray absorptiometry nPCR Normalised protein catabolic rate
ECW Extracellular water ORG Obesity-related glomerulopathy
eGFR Estimated glomerular filtration rate OxS Oxidative stress
FA Fatty acid P Phosphorus
FM Fat mass PBD Plant-based diet
FSGS Focal and segmental glomerulosclerosis PEW Protein-energy wasting
HGS Handgrip strength PhA Phase angle
ICKD Isocaloric ketogenic diet PUFA Polyunsaturated fatty acids
ICW Intracellular water R Resistance
IL Interleukin RAAS Renin–angiotensin–aldosterone system
REE Resting energy expenditure diets in CKD with obesity [9, 19–24]. These diets have been
SIE Italian Society of Endocrinology reported to be effective in reducing BW [9], inflammation
SIN Italian Society of Nephrology and oxidative stress (OxS) [25] and improving metabolic
SINut Italian Society of Nutraceuticals parameters [26, 27], resulting in a valid approach for the
TBW Total body water management the obesity-related CKD. Nevertheless, a
TCI Total calorie intake potential drawback in patients with obesity and more
T2DM Type 2 diabetes mellitus advanced CKD (estimated glomerular filtration rate -eGFR-
UACR Urinary Albumin-to-Creatinine Ratio less than 45 ml/min/1.73m2) may be the protein intake
VLCKD Very-low-calorie KD relatively higher for the kidney function level [28].
VLEKT Very Low-Energy Ketogenic Therapy To date, there is a lack of clear scientific consensus and
VAT Visceral adipose tissue practical guidelines for the clinical-nutritional management
WC Waist circumference of patients with obesity-related CKD. In detail, the
Xc Reactance nutritional management of these patients is based, to
date, only on the clinical practice guidelines for adults
with chronic renal failure without taking into account the
Introduction “obesity” variable which, in itself, is a determining factor in
the progression of the CKD, whose mechanisms are complex
Chronic kidney disease (CKD) is a global public health and include hemodynamic changes, chronic low-grade
burden, with an estimated prevalence of 13.4% worldwide inflammation, OxS, and activation of the renin-angiotensin-
(CKD stages 1–5) [1], close to 850 million people worldwide aldosterone system (RAAS).
[2], although in many cases it is underdiagnosed, and the In order to fill this gap this consensus statement from
disease is identified only in its late stages [1]. CKD is also a the Italian Society of Endocrinology (SIE), working group
crucial health concern since it is historically recognised as of the Club Nutrition–Hormones and Metabolism; the
a cause of associated comorbidities, mainly cardiovascular Italian Society of Nutraceuticals (SINut), Club Ketodiets
diseases (CVD), as well as decreased quality of life, and and Nutraceuticals “KetoNut-SINut”; and the Italian
mortality [3–6]. Society of Nephrology (SIN) is intended to be a guide for
Overweight and obesity represent two main contributors Endocrinologist, Nutritionists and Nephrologist who deal
playing a major role in the development of CKD [7], acting with the management of patients with obesity with non-
through direct and indirect mechanisms [8]. In general, dialysis CKD providing a practical guidance on assessing
at renal level, obesity leads to a physiological adaptation nutritional status and prescribing the optimal diet in order
that results in morpho-functional alterations [9, 10], finally to best manage obesity to prevent CKD and its progression
culminating in the development of CKD and faster decline to dialysis.
of kidney function [11, 12]. This harmful association
needs a “call for action” given that obesity is today a major
feature of approximately 50% patients with CKD, with The chronic kidney disease: clinical aspects
increasing prevalence in the last two decades [13]; even and treatment
in Italy, the country where Mediterranean Diet (MD) was
born, the prevalence of obesity in CKD patients was 39%, CKD is defined as abnormalities of kidney structure or
approximately 15% higher than in adult population without function, present for at least 3 months, and it is classified
CKD, at the last national survey on CKD [14]. based on its etiology, eGFR category, and albuminuria
In this scenario, a multidisciplinary management of category [29]. Five categories of eGFR (Table 1) and three
CKD, in cooperation with Endocrinologists, Nutritionists, of Albumin Excretion Rate (AER) or urinary Albumin-to-
and Nephrologists, is important. In particular, a basal Creatinine Ratio (UACR) (Table 2) are recognized, with
in-depth assessment of the nutritional status is needed to their combination used for stratification of adverse outcomes
evaluate the body weight (BW) and the body composition risk in clinical practice where higher albuminuria heralds
(BC) before prescribing the optimal dietary intervention, higher cardiorenal risk even if isolated [29–31].
according to the reference guidelines [15]. Various dietary A precise assessment of GFR is critical in patients with
strategies have been studied for the management of CKD obesity, since they represent a risk group. Measured GFR
patients, including the low-protein diet and MD [16, 17], using urinary or plasma clearance of exogenous filtration
this latter, however, properly adapted to this class of patients markers is the gold standard for the evaluation of kidney
[18]. Interestingly, low-carbohydrate/ketogenic diets (LCD/ function; however due to the invasive nature and complexity
KDs) have been proposed as potential therapeutic alternative of these techniques, endogenous creatinine clearance and
eGFR equations are commonly used. Unfortunately there is type 2 diabetes mellitus (T2DM), and obesity [38, 39], this
no consensus on the best equation (creatinine-based and/or latter extensively discussed in the next section, as focus of
Cystatin C-based) to estimate GFR in the setting of obesity the present document. This results in development of dis-
or longitudinally in the setting of weight change [32], given eases comorbidities, such as diabetic nephropathy and hyper-
that renal function prediction can be significantly biased in tensive nephropathy, as a severe complication of T2DM and
this patient category. A retrospective cohort study in 2011 hypertension, respectively [40, 41], causing end-stage renal
revealed that the Cockcroft-Gault formula provided the best disease [40]. Other causes of CKD include glomerulone-
estimate of kidney function [33]. A later study conducted in phritis, autoimmunity, malignancy, infectious disease (i.e.,
CKD patients with obesity concluded that the performance pyelonephritis), renal atherosclerosis, gout, nephrolithiasis
of eGFR CKD-EPI (Epidemiology Collaboration) was and obstructive uropathies, polycystic kidney disease, and
valid up to a body mass index (BMI) range of 40 kg/m2 for other congenital anomalies of the kidney and urinary tract
GFR ≤ 60 ml/min per 1.73 m 2 [34]. In summary, most but [42–46]. Interestingly, there is emerging evidence on the
not all studies have found that the Cockcroft-Gault equation relationship between altered gut microbiota and CKD [47].
(using actual BW) tends to overestimate GFR in individuals More specifically, local inflammation at gut level, as well as
with obesity, whereas the CKD-EPI and Modification of impaired permeability of the intestinal barrier promote the
Diet in Renal Disease (MDRD) study equations tend to gut-to-blood translocation of uremic toxins (i.e., p-Cresyl
slightly underestimate GFR [35]. Other studies suggest sulphate, TMAO, indoxyl sulphate), that cause inflammation
that serum Cystatin C may be less influenced by BC and is and OxS, damaging organs and systems, including kidneys
more strongly associated with measured GFR than serum [48].
creatinine [36]. In a more recent study, Rothberg et al. Clinically, patients with advanced stages of CKD present
showed that in subjects with severe obesity undergoing extracellular volume expansion (salt-sensitive hypertension),
medical weight loss, estimating equations using Cystatin altered acid–base balance (metabolic acidosis), electrolyte
C and indexed to actual body surface area, may provide a imbalance (muscle cramps, cardiac arrythmias), and hyper-
more accurate assessment of renal function [37]. Therefore, uraemia [49]. General and nonspecific symptoms are
current limitations of renal function prediction should be appetite loss, fatigue and weakness, dyspnoea, decreased
carefully considered in patients with obesity. mental acuity, sleep disturbances, vomiting and nausea
Among the main risk factors for CKD development and [50, 51]. Abnormalities in laboratory parameters highlight
progression are listed non-modifiable factors (ie., genetic, various complications related to a decline of kidney function,
race, age, and sex), nephrotoxic agent exposure [38, 39], as including anaemia, impaired bone metabolism (i.e., altered
well as modifiable factors including CVDs, hypertension, levels of calcium, phosphate, parathyroid hormone and
vitamin D deficiency) [31, 50], and inflammation (increased
Table 1 GFR categories levels of c-reactive protein (CRP), interleukin 6 (IL-6),
tumour necrosis factor-α) [21].
GFR categories GFR (ml/min/1.73m2) Renal function The pharmacological treatment is based on the first-line
G1 ≥ 90 Normal use of renin-angiotensin-aldosterone pathway modulators
G2 89 – 60 Mildly decreased and SGLT-2 inhibitors that reduce the intraglomerular pres-
G 3a 59 – 45 Mildly to moderately sure, the first acting on the efferent arteriole and the second
decreased on the afferent one, thus helping to preserve kidney function
G 3b 44 – 30 Moderately to severely by counteracting single nephron hypertension-hyperfiltration
decreased [52]. Novel agents used for their anti-inflammatory and anti-
G4 29 – 15 Severely decreased fibrotic effects are the non-steroidal mineralocorticoid recep-
G5 < 15 Kidney Failure tor antagonists. Other drugs commonly used in the treat-
GFR glomerular filtration rate ment of CKD are loop diuretics, statin or statin/ezetimibe,
erythropoietin, calcium, and vitamin D supplements.
Table 2 Albuminuria categories Albuminuria AER (mg/24 h) ACR Description and range
categories (approximate equivalent)
A1 < 30 < 3 mg/mmol or < 30 mg/g Normal to mildly increased

A2 30–300 3–30 mg/mmol or 30–300 mg/g Moderately increased
A3 > 300 > 30 mg/mmol or > 300 mg/g Severely increased
AER albumin excretion rate, ACRalbumin-to-creatinine ratio

When the patient with end-stage kidney disease (ESKD, In addition to the well-known cardiometabolic effects, the
eGFR < 15 mL/min/1.73m2) shows complications no longer adipose tissue distribution plays a role also in renal injury
responsive to medical (conservative) treatment, dialysis [61, 62]. More specifically, central obesity is associated with
or kidney transplant remain the only possible therapeutic several signs of kidney impairment, including albuminuria,
options [30, 31, 50, 53]. increased filtration fraction, reduced renal plasma and blood
flow [63]. Interestingly, such negative renal effects seem to
be due to a central pattern of fat distribution itself, indepen-
Principal mechanisms involved dently of the BMI [24]. In this sense, a remarkable study on
in obesity‑related kidney disease a large number of middle-aged subjects (n.1261) reported
that metabolic syndrome (MetS) is an independent risk fac-
Obesity is an independent risk factor for CKD onset [12], tor for accelerated GFR (measured not estimated) decline,
and the prevalence of these two diseases increases in parallel unlike BMI, waist circumference (WC), or waist-hip ratio.
[54]. BMI, indeed, is associated with increasing albuminuria According to the authors, this MetS-measured GFR decline
[55], and decreasing eGFR; on the other hand, these two association was mainly governed by triglyceride levels (as
outcomes improve with weight loss [56]. a criterion for defining the MetS) which, when elevated, are
Mechanistically, obesity affects renal function via differ- associated with an increased risk of developing CKD caus-
ent mechanisms (summarised in Fig. 1), among which one of ing renal dysfunction via their atherogenic and proinflamma-
the main is related to a physiological kidney adaptation [9]. tory effects, as well as acting as a marker of IR [64].
In obesity states, indeed, kidneys increase renal blood flow, Central obesity is characterised by an enlargement of the
eGFR, and sodium (Na+) reabsorption, resulting in glomeru- visceral adipose tissue (VAT) that is associated with various
lar hypertension and hyperfiltration [9]. Such alterations of metabolic aberrations implicated in CKD development
the renal hemodynamic are principally due to afferent arte- and progression, including MetS, IR, and T2DM [65].
riole vasodilation and increased expression of N a+ channels Overall, this is mainly mediated and promoted by its pro-
+
in proximal tubular cells causing water and N a reabsorption inflammatory effect; in subjects with obesity, indeed, VAT
[9]. This phenomenon leads to renal hypertrophy and hyper- presents an altered balance between pro-inflammatory
filtration culminating in glomerulosclerosis, thus resulting in immune cells and anti-inflammatory regulatory cells, with a
impaired renal function [8]. In this scenario, a central role prevalence of the first ones [66]. This results in the increased
in modulation of vasocontraction is played by the RAAS, production and release of cytokines and adipokines [67],
which is more active in obesity. RAAS activation, contrib- suggesting its role in triggering and exacerbating the
uting to hypertension, glomerulosclerosis, and endothelial chronic low-grade inflammation [25] that, in turn, lead to
dysfunction, exerts detrimental effects on CKD progression CKD development [68]. In obesity, indeed, hypertrophic
[9]. More specifically, along with the effects of (i) angioten- and dysfunctional adipocytes, as well as VAT, due to their
sin II in inducing proteinuria, increasing intra-glomerular endocrine function, promote the expansion of adipose
pressure, and inflammation, and (ii) aldosterone in inducing tissue through the release of adipokines (i.e., angiopoietin,
insulin and leptin resistance and regulating blood pressure, vascular endothelial growth factor, and cathepsin) that, in
salt homeostasis, and plasma volume, RAAS activation also turn, stimulate rearrangements of stroma, neoangiogenesis,
promotes the differentiation of adipocytes and the produc- and adipogenesis. Angiogenesis and adipogenesis are, thus,
tion of adipokines [57], suggesting the existence of an obe- closely linked, and circulating adipokines reach the kidney,
sity-RAAS activation-CKD vicious cycle. where they act locally on tubular, mesangial, and Bowman’s
From a metabolic point of view, obesity is commonly capsule cells promoting altered and non-physiological
associated with insulin resistance (IR), a further causative responses to cope with glomerular hyperfiltration, resulting
factor of kidney dysfunction [58, 59]. IR, indeed, impairing in albuminuria, focal and segmental glomerulosclerosis
glomerular hemodynamic and inducing the expression (FSGS), and interstitial fibrosis [69]. Leptin and adiponectin
of pro-fibrotic and pro-inflammatory genes, contributes exert pro-inflammatory and anti-inflammatory effects,
to promote onset and progression of CKD [58, 59]. An respectively [9]. Both adipokines are involved in kidney
additional metabolic feature of obesity is represented by the function. In particular, overexpression of leptin stimu-
ectopic lipid accumulation [60] that, at renal level, causes lates hypertrophy of glomerular mesangial cells via PI3K
glomerular and tubulointerstitial damages and promotes the and ERK1/2 activation, resulting in increased protein and
local inflammation and OxS [9]. Also, lipid accumulation albumin filtration and activating inflammatory pathways.
exerts lipotoxicity [60] which, in the kidney, is responsible Also, leptin promotes the secretion of transforming growth
for morpho-functional changes in podocytes, tubular, and factor-β1, which causes basement membrane thickening,
mesangial cells [9]. leading to glomerulosclerosis [70]. On the other hand, lower
levels of adiponectin have been associated with impaired
Endothelial
dysfunction
Adipocyte growth
Adipokine production RAAS
RAAS
Kidney hypertrophy
Glomerulosclerosis
Hypertension
Impaired glomerular Hyperfiltration
hemodynamic and IR
IR Kidney
gene expression
adaptation
Renall blood
Ren
Renal blood
bl d flow,
flo
flow, GFR,
GFR, N
Na+
a+
+ rea
reab
reabsorption
bsorption
bsor
bso
Ectop
Ect
Ectopic
opiic lip
op lipi
lipid
id
accumu
accumullati
accumulationtion
tion
Organ damage,
inflammation, oxidative
stress and lipotoxicity
Renal
dysfunction
Fig. 1 Main mechanisms involved in obesity-related kidney disease. production and release of adipokines that, in general, provoke albu-
A kidney adaptation to obesity causes increase in renal blood flow, minuria, FSGS, and interstitial fibrosis. More specifically, increased
GFR, and Na+ reabsorption, resulting in hypertension and hyperfil- levels of leptin cause mesangial cell hypertrophy (with consequent
tration that culminates in kidney hypertrophy and glomerulosclero- increased inflammation and albumin and protein filtration) and thick-
sis. Moreover, obesity is responsible for an overactivation of RAAS ening of basement membranes (resulting in glomerulosclerosis). On
that primarily causes hypertension, glomerulosclerosis, and endothe- the contrary, reduced levels of adiponectin induce albuminuria (via
lial dysfunction; also, RAAS induces adipocyte growth and adipokine podocyte fusion) and tubular inflammation (via reduced AMPK acti-
production. The main metabolic effects of obesity affecting renal vation). Finally, increased levels of restin and visfatin also increase
function refer to insulin resistance (IR) (impairing glomerular hemo- the inflammatory status. Overall, such mechanisms are responsible
dynamic and expression of pro-fibrotic and pro-inflammatory genes), for the development of ORG. AMPK 5’ adenosine monophosphate-
and to ectopic lipid accumulation (causing glomerular and tubuloint- activated protein kinase, OxS oxidative stress, IR insulin resistance,
erstitial damages, inflammation, OxS, and lipotoxicity). Central obe- FSGS focal segmental glomerulosclerosis, GFR glomerular filtration
sity is directly involved in renal dysfunction, as it causes albuminu- rate, RAAS renin-angiotensin-aldosterone system
ria, increased filtration fraction and reduced renal plasma and blood
flow. In addition, this type of obesity is responsible for the increased
kidney function and CKD, since they cause podocyte fusion, played by inflammation [69]. In patients with ORG, indeed,
resulting in albuminuria. Also, by decreasing AMPK acti- an increased expression of inflammatory cytokines, includ-
vation, hypoadiponectinemia is responsible for increasing ing TNF-α (associated with glomerulonephritis and tubu-
tubular inflammation [70]. Other adipokines, such as resistin lointerstitial damage) and IL-6 (mediating IR, activation of
and visfatin, whose levels are increased in obesity, have been RAAS, and regulation of the transforming growth factor-β1
demonstrated to play a role in renal dysfunction [9, 70], via pathway) has been observed [9, 73].
increased inflammation [70].
Due to these mechanisms, obesity is directly involved in Obesity related clinical feature in CKD
the development of obesity-related glomerulopathy (ORG)
[8, 11], a glomerular disease characterized by glomerulo- Investigations in humans highlighted the association
megaly with or without FSGS [69] that presents clinically between obesity and CKD [24], including the Coronary
with albuminuria and kidney dysfunction [71]. Hemody- Artery Risk Development in Young Adults (CARDIA)
namic changes, overactivation of RAAS, and ectopic lipid study involving 2354 subjects with normal kidney function
accumulation are the main determinant in ORG pathogen- and reporting a significant association between obesity and
esis [69, 72]. Also, a central role in development of ORG is microalbuminuria during a 15 year follow-up [74]. Another
large study carried out on 2585 subjects without renal failure A complete assessment of the nutritional status in CKD
reported that BMI increased the odds of CKD development patients should comprise both monitoring of laboratory
by 23% per standard deviation unit [75]. Similarly, in the parameters and the evaluation of the BC. As suggested by
Physicians’ Health Study, involving 11,104 healthy men, the KDOQI guidelines [15], monitoring creatinine kinetics
the CKD risk increased for each 1-unit increase in BMI, is necessary to estimate muscle mass, in particular in stage 5
and for subjects with BMI > 26.6 kg/m2 the OR was 1.45 patients. However, cautions should be used in its evaluation,
(95% CI 1.19–1.76; p < 0.001) [76]. The role of obesity in including a proper sampling procedure (collecting urine for
the increased risk of kidney disease was also reported by a 24 h), as well as considering the eventual consumption of
prospective cohort study (2676 subjects) demonstrating that meat or creatine supplement intake, that may increase the
the odds of stage 3 CKD development increased by 68% in creatine excretion. Other suggested laboratory parameters
subjects with obesity during 18.5 year follow-up [77], as include serum albumin and pre-albumin, and normalised
well as by a retrospective cohort study (320,252 subjects) protein catabolic rate (nPCR) [15]. Albumin is the main
reporting that end-stage renal disease risk increased in circulating protein, and its low levels predict protein mal-
tandem with BMI [78]. Cumulative evidence on this nutrition and mortality, and may indicate pathological con-
association is provided by a recent meta-analysis reporting ditions, including inflammation, renal and liver diseases,
that, compared to normal weight, subjects with overweight oedema, and infections. The albumin half-life, however, is
or obesity have a higher risk of CKD (RR: 1.15, 95% CI long (about 20 days), making this parameter not sensitive to
1.08, 1.22 and RR: 1.21, 95% CI 1.10, 1.33, respectively a short-term monitoring of the nutritional status. In contrast,
[79]. the half-life of prealbumin is shorter (about 2–3 days), thus,
it is more reliable to monitor rapid changes [83]. However,
albuminemia is a good predictor of illness or mortality, thus,
Assessment of nutritional status in patients its use in nutritional status assessment has been re-evaluated
with chronic kidney disease [15]. In non-dialysed CKD patients, nPCR is calculated from
urinary urea (after 24 h urine collection) plus non-urinary
CKD is one of the primary causes of disease-related urea daily excretion. This marker is easily quantifiable and
malnutrition and protein-energy wasting (PEW), especially used to estimate the intake of protein. It should be taken
in older subjects, in whom aging, as well as comorbidities, into account, however, that these markers are influenced by
act synergistically in exacerbating such conditions [80]. several conditions, including inflammation, protein loss, ill-
Importantly, both disease-related malnutrition and PEW are ness, body fluids. They, thus, should be integrated and not
independent prognostic factors of several clinical outcomes, evaluated singularly to obtain a more comprehensive evalu-
including mortality. This suggests the remarkable role ation [15].
played by a proper and global nutritional status assessment KDOQI guidelines suggest also monitoring BW, BMI,
that, combined with monitoring the inflammatory status, and BC. The use of specific techniques is related to the
represents a reliable prognostic marker of CKD progression, stage of renal failure, as reported in Table 3. In particu-
morbidity, and mortality [80, 81]. This scenario, thus, lar, BW should be monitored periodically, since substantial
implies the integration of nutritional and inflammatory changes may suggest clinical concerns. As well as BW, BMI
biomarkers in prognostic score, rather than their individual should be calculated periodically, using the WHO catego-
use [81]. Nonetheless, the nutritional assessment is poorly ries [15] (underweight, BMI < 18.5 kg/m2; normal weight,
applied in the renal clinical practice [82]. BMI = 18.5–24.9 kg/m2; overweight, BMI = 25.0–29.9 kg/
A proper assessment of the nutritional status should be m2, and obesity, BMI > 30.0 kg/m2) [84]. The principal limi-
performed by qualified nutritionists (or international equiv- tation of BMI is that it does not provide information on BC,
alent) or physician and should follow the medical evaluation since it does not give any precise discrimination between
of both general health status and stage of renal failure. This fat mass (FM) and fat-free mass (FFM). In this sense, the
is necessary to cover the single competencies of the health- routinely measurement of other reliable anthropometric
care personnel who take care of the patient, but also because parameters is suggested, including WC, an indicator of cen-
a clinical evaluation is fundamental to establish the appro- tral adiposity, and arm skinfold and circumference to assess
priate method and parameter for the nutritional assessment, muscle mass [81]. Among the various techniques licensed
as well as the dietary intervention. This concept should be for the BC estimation, skinfold thickness, dual-energy x-ray
applied both at the first visit and during the follow-up, due absorptiometry (DXA), and bioelectrical impedance analysis
to the need to carefully monitor the diseases progression, (BIA) are suggested for CKD patients [15]. In general, skin-
with a network between the healthcare personnel including fold thickness measurement can be used in all CKD patients,
endocrinologist, nutritionists, and nephrologists. including transplanted ones, with periodic evaluations in
order to assess accurately eventual changes in body FM.
Table 3 Main parameters to be monitored and techniques to be used for the assessment of nutritional status in CKD, according to KDOQI
Guidelines [15]
Method/parameter CKD stage Special recommendation
Laboratory parameters for nutritional assessment

Creatinine kinetics S5 Suggested to estimate muscle mass
Serum albumin, serum prealbumin, nPCR S1-5 To be used as complementary tools for the nutritional status
assessment; such measurements, however, should not be used
singularly, but interpreted in combination
Serum albumin S5 To be used a hospitalization and mortality predictor
Parameters for evaluation of BC
BW/BMI S1-5 To be assessed at the first visit and monitored periodically
BW/BMI/BC S1-5 To be monitored at least:
• Monthly: MHD and PD
• Every three months: S4-5 or post-transplantation
• Every six months: S1-3
WC S5 Suggested to assess abdominal changes, but changes need to be
interpreted with caution
Skinfold thickness S1-5 To be used, in absence of oedema, to assess BF
Technical devices for evaluation of BC
BIA S1-5 No sufficient evidence suggesting its use to assess BC
S5 Use of MF-BIA suggested to assess BC, preferably performed at
least 30 min or more after the haemodialysis session
DXA S1-5 To be used when feasible to assess BC
HGS S1-5 Suggested as an indicator of protein-energy status, but during
the follow-up data should be compared with baseline
Techniques for estimation of the energy requirements
Indirect calorimetry S1-5 Suggested to measure REE, when feasible and indicated
REE equations S5 metabolically stable Suggested in absence of indirect calorimetry
BC body composition, BIA bioelectrical impedance analysis, BMI body mass index, BW body weight, DXA dual-energy x-ray absorptiometry,
HGS handgrip strength, MF-BIA multifrequency bioelectrical impedance analysis, MHD maintenance haemodialysis, nPCR normalised protein
catabolic rate, PD peritoneal dialysis, REE resting energy expenditure, S stage, WC waist circumference
However, in subjects with obesity, this technique may be while in case of retention of fluids, the alteration of cell
not accurate, since the high subcutaneous adiposity makes membranes reflects in decreased Xc values [88]. It has
difficult the measurement with the callipers. DXA is the been reported, indeed, that CKD patients exhibit low R and
reference method of BC assessment [85], able to discrimi- Xc, suggesting the presence of hyperhydration or, at least,
nate bone mineral content, lipids, and lipid-free soft tissues, altered hydration status since the early stages [87, 88]. On
these latter two referring to FM and FFM, respectively [86]. the other hand, BC estimation is based on the use of pre-
Although its limitations (i.e., technical expertise, high costs, dictive equations that, however, are not validated in CKD;
contraindications) [85], DXA is suggested as a valid method although that, the BIA-obtained BC estimation revealed
for BC measurement in CKD and transplanted patients, pay- lower body mass cell and FM in mild to moderate CKD
ing the attention to the radiation exposure, thus considering compared to controls [87]. Also it suffers the influence of
the risk-benefit ratio of such technique [81]. hydration status, suggesting the importance to interpret
Currently, BIA is recognized as a reliable method for carefully the results, as well as to use BIA row parameters,
BC estimation. Advantages are the low-cost, the non- in particular in subjects presenting hydration abnormali-
invasiveness and low-time consuming. BIA estimates the ties [89]. BIA row parameters are R, Xc and their derived
hydration status, discerning from total, extracellular and phase angle (PhA (°) = arc tangent (Xc/R) x (180/π)) [90].
intracellular water (TBW, ECW, and ICW, respectively), PhA is the most important BIA-derived parameter, provid-
through the measurement of body tissue electrical prop- ing information about the intra- and extracellular water
erties, namely resistance (R) and reactance (Xc) [85], distribution, and reflecting the cell membrane integrity,
that, briefly, are related to TBW and to the cell membrane with a linear relationship (low PhA values = reduced cell
capacitance, respectively [85, 87, 88]. More specifically, integrity or cell death) [90]. Interestingly, information on
low R values are detected in case of elevated TBW [87], the inflammatory status can be obtained from PhA values
[90]. More specifically, PhA values are inversely cor- an independent predictor of mortality in CKD patients
related to the levels of inflammatory markers, including [109–111]. Mechanistically, there is an inverse association
CRP [91–93]. This correlation is explained considering between muscle mass and IR [112], which contributes to
that chronic and unregulated inflammation, such as the kidney dysfunction [113]. In addition, it is well-known that
obesity-related chronic low-grade inflammation [94, 95], muscle exerts antioxidant and anti-inflammatory effects
causes tissue damages [94, 96] that are evidenced by lower [114, 115] contributing to maintain the kidney health.
PhA values in terms of decreased cell integrity. This sug- Overall, such biological functions explain the associations
gests, thus, the importance to observe PhA values during between HGS and clinical outcomes in CKD [103] and
the nutritional follow-up also in CKD patients to moni- suggest the importance to use the method during the
tor eventual variations in inflammatory status. Previous nutritional screening and follow-up in this class of patients.
studies, indeed, reported lower PhA values in patients Specific precautions in the use of HSG, however, should be
with intermediate [88] and mild to severe renal failure taken for T2DM (considering that a reduction in strength
(− 22% compared to controls) [87], which are associated should be due to the peripheral neuropathy) [15, 116].
with mortality in non-dialysed CKD patients [97]. Also, Once assessed the BC, a proper estimation of the resting
in such patients, PhA has been found to be an independ- energy expenditure (REE) is suggested to calculate the
ent factor associated with malnutrition; in particular, PhA nutritional requirements and, thus, elaborate the optimal
values < 4.46° predict a higher risk of PEW (ROC analy- dietary prescription. In this sense, the guidelines suggest
sis: (AUC = 0.749, sensitivity + specificity = 120.8%) [98]. the use of indirect calorimetry, when available and feasible,
Since, as aforementioned, CKD patients present as the best method to estimate accurately the REE; however,
alterations in the hydration status, in addition to the in other cases (i.e., absence of indirect calorimetry or
conventional BIA, bioelectrical impedance vector analysis contraindications), predictive equations can be used [15].
(BIVA) is suggested as a valid method to avoid bias in
BC and hydration estimation [88]. In BIVA, the single
components R and Xc are normalised to height and then Medical dietary therapy in patients
plotted in the R-Xc graph [85, 99, 100]. In the R-Xc graph, with chronic kidney disease
the vector distribution pattern provides direct information
on the hydration status, defining decreases in body In CKD patients, besides the pharmacological treatment,
hydration (when the vector moves up along the major axis dietary interventions are necessary to ensure adequate
of the ellipse) or fluid retention (when the vector moves care for kidney preservation and to improve life quality
in the opposite direction along the same axis) [85]. The and reduce mortality. Moreover, as the main causes and
distribution patterns are defined as vector length [88]. In several risk factors of CKD are strongly influenced by
these terms, shorten vector lengths indicate overhydration dietary habits, it is essential for these patients to improve
and have been reported to be associated with heart failure in their eating behaviours, following health-promoting dietary
non-dialysed CKD patients [97]. It appears clear, thus, the patterns [15, 29–31, 50, 117]. In particular, for management
usefulness of BIVA for a more comprehensive assessment of obesity, the first-line intervention is advised to be based
in this class of patients [101]. on lifestyle modifications, including physical activity and
KDOQI guidelines also suggest handgrip strength (HGS) nutritional recommendations [26], suggesting the important
as simple and valid method to evaluate the muscle function and primary role played by a proper medical dietary therapy
and as a nutritional status indirect measure in CKD patients, during, and ideally before, the pharmacological treatment.
both receiving and not receiving dialysis [15]. It has been
reported that such patients have a higher odd ratio to the General dietary requirements in CKD
low HGS prevalence, compared to controls (OR 1.896,
95% CI 1.467–2.450 and OR 1.684, 95% CI 1.294–2.191, According to KDOQI Clinical Practice Guideline for
for men and women, respectively) [102]. Similarly, HGS Nutrition in CKD, it is recommended an energy intake of
is directly correlated with eGFR ( R2 = 0.069, F = 633.5, 25–35 kcal/kg BW/day to maintain an adequate nutritional
p < 0.001 and R2 = 0.045, F = 483.1, p < 0.001, for men and status [15]. This recommendation should be adapted
women, respectively) [102] and inversely associated with considering age, gender, physical activity level, BC, target
the risk of incident CKD (HR (95% CI) 0.84, 0.76, and 0.72 weight, CKD stage, and presence of concurrent disease or
in quartiles 2, 3, and 4, respectively, compared to quartile 1) inflammation [15, 18]. However, taking into account the
[103]. Such results are explained by the progressive muscle negative nitrogen balance ensured, the total calorie intake
wasting, a pathological condition commonly observed in (TCI) should be increased by 30–35 kcal/kg/day in order
CKD [104, 105]. More specifically, HGS is included within to avoid the risk of malnutrition in this class of patients. To
the screening tests for diagnosis of sarcopenia [106–108], note, in patients with obesity, the daily calorie intake should
be calculated according to adjusted weight or normal weight patient with obesity, both in terms of weight reduction and
BMI (23.0 kg/m2) [18]. the management of associated comorbidities [122–124].
With regard to macronutrient intake, there is no In addition to the existence of an inverse relationship
recommendations about carbohydrates. Lipids should range between adherence to MD and BMI and weight gain [125,
from 30–35 to 50–60% of TCI in all CKD stages and in 126], in fact, there is evidence that this dietary pattern is
transplanted patients. However, there is no recommendation associated with a twofold greater likelihood of maintaining
about polyunsaturated fatty acids (PUFA), one of the weight loss [127]. In fact, it has been reported that, compared
main elements of MD. As expected, instead, specific to other control diets, MD is associated with greater weight
recommendations are provided for protein intake according loss [128] and that this result in subjects with overweight/
to the different CKD stages. In particular, the optimal obesity is greater than that obtained with low-fat diets, but
daily needs for protein intake is 0.8 g/kg/day in stages similar to that obtained with LCD [129].
1–2, 0.55–0.6 g/kg/day in stages 3–5 (without dialysis). MD, with some modifications, is often recommended for
Regarding the micronutrient intake, in absence of altered individuals with CKD. As suggested, indeed, the adherence
blood biochemistry, there are no specific restrictions. In to such a healthy dietary pattern can lead to a lower risk of
general, potassium (K) and phosphorus (P) intakes should CKD, delayed progression of CKD, and a reduced risk of
be individualised, but they should be adapted if their blood kidney disease-related complications [18]. This is thought to
values are elevated (K: 1500–2000 mg/day for stages 3–5 be due to the anti-inflammatory and antioxidant properties
and dialysed patients; P: 600–1000 mg/day for stages 3–5 of this dietary pattern, as well as its beneficial effects on
and peritoneal dialysed patients, and 800–1000 mg/day for blood pressure and blood lipid levels, glucose control,
haemodialyzed ones). Recommendations for NaCl intake is hyperinsulinemia, IR, and satiety [18, 130].
about 5 g/day for all stages [18]. In general, the beneficial effects of MD on CKD
Although the general dietary requirements for CKD prevention can be attributed to the main features
patients refer to single nutrients, it should be noted that characterising this dietary pattern. For example, the protein
they are not consumed alone, but as part of a whole dietary intake in MD is very similar to that recommended for CKD
pattern. Single nutrient-based recommendations, thus, patients [17, 131]. Also, protein intake in MD mainly refers
may be difficult to follow for many patients, due to the to a low red meat consumption, resulting in a lower Na,
multiple and simultaneous restrictions, as well as to the P and K intake [17, 131]. Notably, there is a difference in
non-personalised approach used that focuses on indicating the absorption rate of P from animal and plant sources;
foods to be avoided, rather than those that can be consumed. in particular, about 40–60% of animal P is absorbed,
In particular, it seems that such strategies have neither while that of plant origin is less absorbed by the human
conclusive effects nor are able to substantially modify the gastrointestinal tract [132, 133]. Also, the use of K binders
renal failure degree [23]. Moreover, available evidence might counterbalance a possible increase in serum K due to
on dietary intervention in CKD is of low quality and not higher dietary K intake; however, treatment with the old K
sufficient to guide the clinical practice [118]. Of interest, binders Na+ polystyrene sulfonate or calcium polystyrene
recommendations based on consideration of the global sulfonate, causes severe gastrointestinal side effects and,
dietary pattern are, in general, associated with improvements to date, evidence on their clinical use is scarce [134]. The
in renal outcomes, but also protective against chronic novel K binders, patiromer and Na zirconium cyclosilicate,
metabolic diseases, such as T2DM and obesity [23]. indicated for treatment of CKD patients have no side effects
and may favour a more healthy diet with adequate intake of
fruits, vegetables, nuts and olive oil that are associated with
Medical dietary therapy a reduction in inflammation and OxS [131, 135].
Mediterranean diet MD adaptation at different CKD stages
MD is a dietary pattern inspired by the traditional eat- Due to its inherent characteristics, MD is classified as
ing habits of countries bordering the Mediterranean Sea, a plant-based diet (PBD), as it contemplates the regular
mainly characterized by a an abundance of plant-based foods consumption of plant foods, with low to moderate
(such as fruits, vegetables, legumes) and non-saturated fats consumption of animal foods. This characteristic supports
(derived from olive oil, nuts, seeds and fish), and limited the rationale behind the use of MD in CKD [136]. PBDs,
consumption of red meat and processed foods [119–121]. in fact, are suggested as valid and safe dietary approaches
Among the well-known beneficial effects of MD, which for both primary prevention of CKD and delaying disease
have earned it the appellation of health-promoting diet, of progression [136], as reported in previous large studies [137,
no little interest is its role in the nutritional treatment of the 138]. This appears to be due to several mechanisms. Among
the main ones are (i) the production by the gut microbiota monitored, considering the role played by this macronutrient
of anti-inflammatory compounds promoted by fibres, with in controlling metabolic parameters and renal function,
a reduction in the production of uremic toxins promoted as profoundly described in the following paragraphs. In
by animal food components, (ii) the anti-inflammatory this sense, the negative impact of added sugars on renal
and anti-atherogenic effects exerted by vegetable fats, in function is well established [139], leading to the suggestion
particular olive oil, (iii) the reduction of metabolic acidosis of carbohydrate-reduced diets for their beneficial effects
due to the low net load of endogenous acids, (iv) the lower [16]. However, although to the best of our knowledge there
bioavailability of vegetable P compared to animal P [136]. are no studies that have directly investigated the effect of
Beside a mere qualitative aspect, quantitatively the MD carbohydrate-reduced diets (not KD) in patients with obesity
composition should be adapted in function of the stage of and CKD, nor specific indications to this effect from current
CKD [18], as represented in Fig. 2. The recommended daily guidelines, it should be noted that, as previously reviewed,
consumption of cereals and derived foods, and fruit and veg- MD is characterised by a low glycaemic index, mainly due
etable is similar to that for the general population (5–6 times to regular consumption of high quality carbohydrate sources
daily and 2 times daily, respectively) [18]. The daily con- (i.e. whole grains, fruits, vegetables, nuts, not refined sugars)
sumption of dairy products is considerably reduced in CKD resulting in an optimal daily intake of fibre. This attenuates
patients compared to that for the general population (1.5 the postprandial glycaemic and insulinemic response,
serving daily for all stages). The use of extra virgin olive oil improving IR and serum lipid profile, ultimately reducing
is strongly recommended in CKD patients, with a consump- the risk of developing T2DM, with consequent beneficial
tion frequency corresponding to the maximum range limit effects on renal function [17, 130]. In this scenario, however,
for the general population (6 servings daily) [18]. Recom- it must be considered that, in addition to the actual role of
mendations for the consumption of nuts or seeds (without macronutrients in the progression of CKD, the general
added salt, sugar, or fat) are available only for stages 1–2 (1 health-promoting effects of MD are due to the overall dietary
serving daily), while for the other classes of CKD patients pattern and not to its individual components [17], so the
their consumption should be individualised [18]. qualitative aspect of the diet should be emphasised or, at
The consumption frequency of protein sources (both least, considered on a par with the quantitative one.
animal and vegetal sources) is established weekly and Among the historically known beneficial and health-
reduced compared to that for the general population. promoting effects of MD, those on blood pressure,
Minimum 4 serving of legumes weekly are recommended inflammation, lipid profile, and endothelial function may be
for stages 1–5. Fish rich in omega-3 is recommended, paying related to a better-preserved renal function [140]. A meta-
attention to the P/protein ratio; its consumption frequency is analysis of study carried out on the general population,
minimum 3 servings/week for all CKD patients, except for indeed, concluded that MD adherence is associated with
stages 3–5 patients, for whom it is reduced by one serving a lower risk to develop CKD (10% lower odds for every
(minimum 2/week). Similarly, P/protein ratio needs to be 1-point greater adherence to MD) [131].
considered for meat consumption, preferring lean meat In patients with manifest CKD, MD has been reported
such as poultry products; its frequency recommendation is to exert beneficial effects [130, 141], including (i) preven-
maximum 3 servings weekly for all CKD patients, except tion or reduction of disease progression [130, 131, 142],
for stages 3–5 patients (maximum 2 servings/week). Finally, (ii) reduced risk of CVDs [143, 144], in particular lowering
the recommended weekly consumption of eggs corresponds blood pressure and, thus, reducing the strain on kidney [143,
to the minimum range limit for the general population 145], and (iii) reduced mortality rates [16].
(maximum 4 servings weekly) for all CKD patients, except These protective effects on renal function seem to be
for stages 3–5 [18]. Such proposal of adapted MD in CKD is due to the unique features of MD, as suggested by the
in line with the evidence that within the variants of PBD, the CORDIOPREV study reporting that CHD patients following
healthy one is significantly associated with lower incidence a MD had a 1.58 mL/min/1.72m2 lower eGFR decline rate
and slower progression rate of CKD [137, 138]. compared to those following a low-fat diet, after 5 years of
In developing an MD for patients with CKD, however, dietary intervention [146]. In this sense, anti-inflammatory
the above recommendations regarding food consumption and antioxidant properties of MD are undoubtedly the most
frequencies should inevitably be merged with the general relevant for prevention and management of CKD. Chronic
dietary requirements in this clinical setting, paying low-grade inflammation, indeed, has been established as a
attention to both the energy intake and the distribution major underlying cause for CKD, and it is observed that
of macronutrients, as recommended by the guidelines. some components of MD, including olive oil, omega-3
Indeed, in addition to the obvious calculation of protein fish, fruits or vegetables can decrease the levels of classic
intake according to the stage of CKD, the qualitative- inflammatory biomarkers, such as CRP and IL-6, improving
quantitative intake of carbohydrates should also be renal function [142].
Fig. 2 Recommendations for

consumption frequency of Med-
iterranean diet foods for general
population and CDK patients.
This graphical representation
shows the recommendations for
consumption frequencies of typ-
ical Mediterranean Diet foods,
highlighting the differences
between the general population
and non-dialysis CKD patients
and providing a useful scheme
for adapting the dietary pattern
to this clinical setting. S stages,
CKD Chronic kidney disease
Ketogenic Diet from adipocytes that are then converted into ketone body
(KB) at liver level. In such biochemical scenario, the body
As previously reported in both animal and human studies, uses FA-deriving KB as main fuel for brain and other tissues
KD represents a valid strategy to achieve a weight loss [9, 26, 27]. This mechanism is, thus, operated as a strategy
[9], as well as to contrast inflammation and OxS [25] and to induce weight loss in management of obesity, since it
to improve metabolic parameters [26, 27], resulting in a promotes selectively the loss of FM, preserving lean mass
promising dietary approach for management of subjects with and allowing a better control of the glucose homeostasis, in
obesity and MetS [147]. addition to a KB-deriving increased satiety contributing to
Actually, the term “ketogenic diet” is generically used to enhance the compliance [9].
identify various nutritional schemes that share, as main fea- The proposed use of LCD/KD in CKD is mainly based
ture, a minimal carbohydrate intake (no more than 30–50 g on the beneficial metabolic effects of this dietary pattern in
daily), and thus they belong to the LCD category [9]. Apart terms of weight loss, glycaemic control, and normalisation
from the daily carbohydrate intake, however, LCD/KD may of insulin levels, three outcomes closely linked to
be formulated with different total calories, mainly based improvements in kidney damages [9]. In short term, indeed,
on the lipid content rather than protein (though the pro- LCDs exert a blood glucose and insulin lowering effect
tein intake may be still higher than recommended for the [20], resulting in increased diuresis and natriuresis, with
level of kidney function impairment), since an increased consequent blood pressure reduction [20, 150, 151]. Notably,
protein intake stimulates gluconeogenesis, thus inhibiting LCDs do not exert negative effects on kidney function, as
endogenous ketosis. This results in three main kinds of KD, reported in a meta-analysis of studies on diabetics following
namely isocaloric KD (ICKD), low-calorie KD (LCKD), and this diet [152]; similarly, another meta-analysis reported a
very-low-calorie KD (VLCKD) [9, 25–27, 148]. Of interest, greater eGFR-increasing effect of LCD compared to control
very recently, we proposed a change in the nomenclature diet in subjects with overweight/obesity without CKD [153].
and acronym of VLCKD [149]. Therefore, we now prefer It has been observed, indeed, that reducing the percentage
to use the term Very Low-Energy Ketogenic Therapy with of carbohydrate intake results in increase eGFR by 3 ml/
the acronym VLEKT, which is more appropriate and avoids min/1.73m2 [154].
confusion in the definition of the very low carbohydrate diets Apart from the relative higher protein intake, a general
[149]. concern with KDs that may limit their use in CKD is the
In KD, the drastic reduction in carbohydrate intake is possible blood acidification due to the excessive KB
used to stimulate a physiological ketogenesis, starting from production. It should be note, however, that ketosis induced
a glucose level reduction, with consequent decreases in liver by KDs is physiological and different from the pathological
glycogen, and promotion of gluconeogenesis and fatty acid diabetic ketoacidosis, since excessive circulating KBs
(FA) oxidation. In particular, it occurs a lipogenesis-to-lipol- stimulate the secretion of insulin, resulting in reduced FA
ysis metabolic shift, resulting in mobilization of triglycerides release from adipocytes [25, 155].
Main putative mechanisms of KDs in improving renal pathway, resulting in down-regulation of pro-inflammatory
function cytokines [21].
As described in previous sections, certain types of KDs
Over the years, an extensive literature profoundly described (LCKD and VLEKT) provide a caloric restriction that
and discussed that KDs exert marked metabolic (i.e., itself exerts anti-inflammatory effects via modulating the
weight loss, glucose/insulin/lipid control) [26] and extra- expression of several inflammation-related genes (i.e.,
metabolic effects (i.e., anti-inflammatory and antioxidant TIMP-3, NFKBIA, PPARs) and reducing the levels of pro-
properties) [25]. Such effects of KDs support their use inflammatory factors (i.e., TNFα, IL-6, ICAM-1, VCAM-
also in CKD, where this diet should be considered as 1, COX-2, iNOS) [25]. Again, regarding the main features
a nutritional strategy to manage collateral conditions of this dietary pattern, KDs are characterised by increased
that can worsen the progression of renal failure. In this lipid intake. This results in elevated circulating levels of
context, the main actor are the KBs, which production is FAs (including long-chain PUFAs) that bind and activate
endogenously stimulated by KDs [24]. KBs, indeed, have PPAR-γ, exerting anti-inflammatory effects [25].
been suggested as a therapy for kidney disease [24, 156], Another interesting mechanism by which KDs reduce
due to their multiple effects, such as acting as signalling inflammation is a gut microbiota modulation, in particular,
molecules [157], protecting of kidneys against stress, aging increasing Bacteroidetes and reducing Firmicutes and
and diseases, and contrasting inflammation, OxS, apoptosis, Bifidobacteria, in this last case with consequent reduction of
and fibrosis [25, 156, 157]. In general, ketosis seems to Th-17 cells, involved in inflammatory response. In addition,
increase the circulating levels of fibroblast growth factor-21, such KD-induced shift of gut microbiota come forth from
a hepatokine exerting anti-inflammatory effects [25]. More a decrease in Ruminoccocus, Eubacterium, Clostridium,
specifically, β-hydroxybutyrate (β-HB), the principal and Bifidobacterium and an increase in Eggerthella,
KD-produced KB, directly inhibits both assemblage and Streptococcus, and Lactococcus. This two last strain produce
activation of NLRP3 inflammasome (involved in regulation folate, thus their increase is associated with increased levels
of innate immune system linked to inflammation related to of such vitamin, resulting in improved lipid metabolism, as
obesity), and decreases interferon-γ and TNFα in human well as reduced OxS and inflammation [25].
PBMCs [25]. In addition, β-HB is an endogenous agonist Of no less importance, KDs exert a plethora of metabolic
of the hydroxycarboxylic acid receptor 2 (GRP190A), effects that could also contribute to manage CKD as well
which exerts, among other, anti-inflammatory effects. as slow disease progression. First among all is their effect
Similarly, via increasing adenosine levels, β-HB attenuates in reducing rapidly the BW and selectively FM [26], which
the inflammation induced by HIF-1α, that mediates the role in renal function has been extensively discussed in pre-
cellular response to hypoxia [25]. Notably, KBs have been vious sections. The weight loss obtained following KDs (in
demonstrated to act as epigenetic factors able to increase particular VLEKT) seems to be marked and constant during
the histone acetylation via inhibiting the class I histone the intervention (− 7.48 kg at 1 month follow-up, − 15.04 kg
deacetylases, with consequent regulation of both chromatin at 2 month follow-up; − 16.76 kg at 4–6 month follow-up;
architecture and gene transcription, and mainly resulting − 21.48 kg at 12 month follow-up) [26]. The mechanisms
in up-regulation of genes encoding for OxS resistance behind the KD-induced weight loss are multifactorial and
factors [25]. Moreover, KBs regulate the gene expression, mainly include the general calorie restriction as well as the
including down-regulation of mTOR, PKA, insulin, and reduction of FM due to the ketosis-induced FA mobilization.
IGF-1 (involved in anabolic pathways), and up-regulation These effects are easily maintained in long-term by a KB-
of AMPK (involved in catabolic/autophagy mechanisms); induced appetite suppression that, in turn, ensures a greater
also, KBs contribute to reduce inflammation and OxS via dietary compliance. This aspect is of relevant importance
activation of antioxidant and anti-inflammatory pathways considering that, in general, subjects with obesity are prone
[9]. to dropout classical calorie restriction diets due to constant
Beyond the effects of KBs, KDs have been reported to sense of hunger [25].
decrease OxS and prevent OxS-mediated mitochondrial The weight loss achieved with this type of diet reflects a
dysfunction via up-regulation of Nrf2 transcription [25], favourable BC, in terms of FM reduction (− 11.12 kg from
resulting in stimulation of antioxidant defences (i.e., SOD1/2 baseline) and minimal loss of fat-free mass (− 2.96 kg from
and NQO1) [158], with consequent regulation of the reactive baseline) that, however, is not statistically significant from
oxygen species concentrations [21]. Being OxS closely that obtained with other weight loss-dietary intervention.
related to flogosis, the anti-inflammatory potential of KDs Interestingly, it can be speculated that VLEKT mainly acts
is easily understood. However, KDs exert a direct effect on on central obesity, thus decreasing abdominal FM, as sug-
inflammation, mainly via various mechanisms [25], among gested by the marked reduction in WC (− 16.53 cm from
which the main is undoubtedly the suppression of the NF-κB baseline [26].
The metabolic benefits of KDs (in particular VLEKT) across diets, suggesting that LCDs, beyond weight loss
have been extensively described by a meta-analysis included do not impact negatively on renal function [161]. Similar
into the European Guidelines for the use of VLEKT in results were obtained in a study on patients with T2DM
subjects with obesity, suggesting significant reductions and mild-to-moderate kidney disease showing that LCD, in
in fasting glycaemia (− 8.85 mg/dl), HbA1c (− 0.43%), addition to significant reduction of weight, WC, IL-6 and
HOMA-IR index (− 2.30), total cholesterol (− 7.12 mg/ total daily insulin dose, did not worsen serum creatinine,
dl), LDL-cholesterol (− 9.04 mg/dl), and triglycerides despite a minimal decrease in eGFR, compared to a standard
(− 49.68 mg/dl), while no changes are observed for HDL- low-protein diet. Also, both diets resulted in significant
cholesterol [26]. reductions in fasting glucose and HbA1c, and no adverse
The effects of KDs on both BC and circulating lipids are events were reported [19].
closely linked by the low carbohydrate intake that induces The absence of apparent organ damages, but potential
reductions in hepatic glycogen stores and FA de novo benefits at renal level following LCD/KDs was confirmed
synthesis in adipocytes, resulting in stimulation of body fat by a large retrospective study involving 2000 CKD
catabolism, that culminates in reduced blood and liver lipids patients (stages 1–3). LCD/KD promoted weight loss and
[148]. amelioration of eGFR in stages 2–3; however, in stage 1
Another important metabolic effect of KDs that could an eGFR worsening was observed, suggesting that in
contribute to preserve and/or manage the renal function CKD intermediate stages the benefits related to rapid and
is reduction of insulin levels [25]. Such insulin-reducing significant weight loss outweigh the risk of early renal
effect is exerted by various mechanisms, including reduction function decline, probably through improvements in blood
of visceral adipose tissue depots and improvement in pressure and glucose homeostasis [20].
mitochondrial capacity and efficiency of skeletal muscle Although no long-term studies are available to evaluate a
[148], acting with an “exercise-type” mechanism [159]. risk/benefit ratio of LCD in CKD [9], a consensus suggests
At liver level, KDs reduce rapidly and markedly the fat that in such patients with early CKD, in particular T2DM
content, improving the IR and reducing the excessive ones, an elevated carbohydrate intake is associated with a
gluconeogenesis and compensatory hyperinsulinemia. 15% increased odd of incident or progression of CKD, while
This KD-induced reduction in hepatic fat seems to the same probability associated with the relative increased
improve insulin sensitivity also via amelioration of the protein intake provided by LCD is less than 14% [162]. In
mitochondrial efficiency, as well as reduction in both local this sense, in subjects with eGFR > 80 ml/min/1.73m2 a high
OxS and inflammation [148]. In addition to these molecular intake of protein is not associated with eGFR decline [162].
mechanisms, the intrinsic features of KDs contribute to Among the LCD/KDs, VLEKT is suggested as an
reduce insulinemia. The reduced intake of carbohydrates, attractive and valid nutritional strategy for management
indeed, reduces postprandial glycaemia, with consequent of obesity, in particular to achieve weight loss in subjects
decrease in insulin requirements [148]. who failed previous dietary and/or pharmacological inter-
ventions. Although this is a very restrictive diet (in terms
Studies of TCI and distribution of macronutrients), VLEKT have
been demonstrated to be effective and safe. As reported
The main concern that LCDs, due to the relative higher in a recent study conducted on 106 non-CKD subjects
protein intake, could impair kidney function was investigated with obesity underwent VLEKT, indeed, no serious
in a study on subjects with abdominal obesity without pre- side effects were recorded during the entire duration of
existing renal failure randomised into two intervention the protocol. Also, no signs of kidney dysfunction were
groups, LCD and high-carbohydrate diet. Authors observed recorded, as suggested by no significant changes in eGFR
that, in addition to weight loss, there were no significant (94.13 ± 19.00 vs 89.00 ± 20.83 ml/min/1.73m2, baseline
changes in serum creatinine, eGFR, and urinary albumin vs end of VLEKT; p = 0.123) [163]. A safety study was
excretion. The same results were observed in subjects also carried out to evaluate the feasibility of VLEKT in
following an high-carbohydrate diet, suggesting that LCDs patients with T2DM. In addition to greater weight loss,
does not exert adverse effect at renal level [160]. Similarly, WC reduction, and HbA1c decline in VLEKT group com-
in 2013, Tirosh and colleagues compared the effects of MD, pared to standard low-calorie diet one; no significant dif-
LCD, and low-fat diet on renal function in subjects with ferences were recorded in safety parameters between the
overweight/obesity with or without T2DM, and pre-existing groups; as well, no serious side effects were reported. With
mild to moderate kidney dysfunction. Authors observed regard to the kidney function, authors did not observe sig-
that all the three dietary strategies improved eGFR and nificant changes in UCRA, BUN, creatinine, and eGFR,
urinary albumin-creatinine ratio with similar magnitude
suggesting that VLEKT does not impair renal function in approaches (i.e. the classical MD), in LCD/KDs the per-
this class of patients [164]. centage of protein (on the total calories) is higher than that
Remarkable insights on the use of KDs in CKD are of carbohydrates, but this does not imply an effective high
provided by a study investigating the effects of VLEKT amount of protein consumed daily. In the context of LCD/
in this class of patients [22]. In particular, a replacement KDs, indeed, the protein intake generally ranged between
meal-based VLEKT was prescribed to 38 mild chronic 0.8 and 1.2 g of high-biological-value protein per kg of
kidney disease (MCKD, eGFR: 60–89 ml/min/1.73m 2) ideal BW [26, 27, 148], resulting in a normoprotein (and
patients and 54 subjects with normal kidney function not hyperprotein) diet. It is plausible to speculate, thus,
(NKF) (eGFR: ≥ 90 ml/min/1.73m2). The VLEKT protocol the use of properly adapted LCD/KDs for CKD patients,
consisted of five steps. In the first two steps (ketosis except for stages 3—5 ones, for whom a protein restriction
steps), the diet provided daily 450–800 kcal, 20–50 g of (0.55–0.6 g/kg without T2DM, 0.6–0.8 g/kg with T2DM) is
carbohydrates, 1–1.4 g/kg of ideal BW of proteins, and recommended to retard the progression of renal failure [15]
15–30 g of lipids. In the following steps (3–5, carbohydrate (Fig. 3). Such adaptations refer to (i) the TCI, established
reintroduction steps), a gradual increase in total energy on the basis of the nutritional outcome to achieve (weight
and carbohydrate intakes was carried out [22]. Overall, the maintenance = ICKD, weight loss = LCKD or VLEKT), (ii)
entire duration of the protocol was about 14 weeks (about the protein intake, established on the basis of the CKD stage,
7 weeks covered by steps 1–2, and the same duration for and (iii) the overall diet quality, in terms of choice of food,
steps 3–5). In both NKF and MCKD, it was observed a and in particular the source of dietary fats and protein. In
significant weight loss, mainly represent by FM reduction this sense, beneficial metabolic effects would be obtained
(assessed by BIA). In addition, reductions in TBW, ECW, replacing animal-based food with unprocessed plant food
ICW, and blood pressure (both systolic and diastolic) by reducing saturated fatty acid and trans fats and increasing
were observed, mainly due to the diuretic effect of KD. mono-unsaturated fatty acids and PUFA content. A higher
Similarly, all study participants experienced improvements consumption of red meat seems to be deleterious for kidney
in fasting glycaemia, HbA1c, cholesterol, and triglyceride function, while other animal-based protein sources (i.e., fish,
levels. No significant changes were observed for liver and eggs, poultry, and dairies) do not show the same negative
kidney function markers; only an increase in blood urea effects [165]. Differently, although no general consensus are
nitrogen was found, that, according to the authors, might available to establish the effective benefits of a PBD in CKD
be due to the significant dehydration [22]. Finally, P only [16], evidence suggests a possible nephroprotective role of
increased significantly in NKF, remaining unchanged plant proteins [136–138, 166, 167]. In this context, non-meal
in MCKD, while no changes were observed in both replacement LCD/KDs for CKD patients should be properly
groups for N a + and K + levels. Noteworthy, in MCKD formulated proving a balanced distribution between animal
creatinine and uric acid significantly reduced (from and plant protein sources. On the other hand, VLEKT is
0.93 ± 0.16 to 0.88 ± 0.17 mg/dl, p = 0.002 and from generally based on meal replacements formulated with both
5.49 ± 1.10 to 4.96 ± 0.94 mg/dl, p = 0.008, respectively), plant (i.e., soy and peas) and/or animal (i.e., whey, eggs) pro-
eGFR significantly increased (from 76.32 ± 10.44 to teins, thus resulting in a suitable approach for CKD patients
82.21 ± 15.14 ml/min/1.73m 2 , p = 0.002), while total in terms of protein source choice [22, 26, 163]. Moreover,
protein, albumin and urinary protein levels remained further cautions have been suggested to be adopted: (i) pre-
unchanged. Among these, however, the most remarkable scribing no more than 1.4 g protein per kg of ideal BW
result was a full recovery of kidney function at the end of during all the VLEKT phases, preferring as much as pos-
the VLEKT protocol observed in a significant number of sible plant-based proteins (> 50%) and choosing as much as
MCKD patients (27.7%) that reported an eGFR ≥ 90 ml/ possible low Phosphate/Protein food, (ii) monitoring care-
min/1.73m2. Overall, thus, this study suggests that VLEKT fully the protein intake during the carbohydrate reintroduc-
is an effective and safe tool to achieve weight loss in tion phases, (iii) avoiding red meat consumption during the
patients with MCKD and obesity, but also this dietary reintroduction phases, (iv) recommending optimal water
strategy is able to ameliorate renal function [22]. Table 4 intake (at least 2 l daily), and (v) recommending supple-
summarises the main studies investigating the effects of mentation with minerals and vitamins during the protocol
LCD/KDs on kidney function. to avoid micronutrient deficiencies [22], according to the
current guidelines [26, 155]. Of note, plant-derived proteins
Adaptation of LCD/KDs in CKD differently from animal proteins, are well known to be not
associated with the detrimental effects of hyperfiltration on
In previous section, we referred to the increased protein kidney function [168].
intake provided by LCD/KDs defining it as “relative”. This
is due by the fact that, actually, compared to other dietary
Table 4 Effects of LCD/KDs on kidney function

LCD/KDs Population Main results Reference
LCD Subjects with obesity without pre-existing renal • Weight loss [160]
dysfunction • Unchanged creatinine and eGFR
LCD Subjects with overweight/obesity and with or without type • Improved eGFR [161]
2 diabetes, and pre-existing mild to moderate kidney • Improved UACR
dysfunction
LCD Subjects with overweight/obesity with normal or high (E1), • Weight loss [20]
mildly reduced (E2) or moderately to severely reduced • Unchanged or improved eGFR in E2 and E3 patients
(E3) kidney function • Decreased eGFR in E1 patient
LCD Subjects with type 2 diabetes with mild to moderate kidney • Weight loss and reduced WC [19]
diseases • No changes in creatinine levels
• Reduced eGFR
• Decreased HbA1c, fasting glycaemia, and IL-6 levels
VLEKT Subjects with obesity and type 2 diabetes • Weight loss and reduced WC [164]
• Reduced HbA1c and glycaemia
• No significant changes in UACR, BUN, creatinine, and
eGFR
VLEKT Subjects with obesity, NKF and MCKD • Weight loss [22]
• Reduced FM
• Reduced TBW, ECW, and ICW
• Reduced systolic and diastolic BP
• Improved fasting glucose, HbA1c, cholesterol, and TG
• Increased BUN
• Increased P in NKF
• Unchanged Na and K
• Reduced creatinine and uric acid in MCKD
• Increased eGFR in MCKD
• Unchanged T-Pr, albumin, and U-Pr
VLEKT Subjects with obesity without renal failure • Weight loss and reduction in WC [163]
• Unchanged eGFR
• Minimal increase in creatinine, azotemia, uricemia, Ca,
and Na
• Unchanged K
BP blood pressure, BUN blood urea nitrogen, Ca calcium, ECW extracellular water, FM fat mass, ICW intracellular water, IL-6 Interleukin-6, K
potassium, LCD/KD low-carb diet/ketogenic diet, MCKD mild chronic kidney disease, Na sodium, NKF normal kidney function, P phosphorus,
PTH parathyroid hormone, TBW total body water, TG triglyceride, T-Pr total protein, UACR urinary albumin-creatinine ratio, U-Pr urinary
protein, VLEKT very-low energy ketogenic therapy, WC waist circumference
General indication and contraindication of KD detailed in a consensus statement from the working group of
the Club of SIE [147].
Although it is a dietary intervention, it should be emphasised
that KD represents a medicalised therapeutic approach, also
referred to as ketogenic nutritional therapy (KeNuT) [147]. Conclusion
Therefore, it is crucial to consider the main indications for
which this therapy may be prescribed, among which over- This is a consensus statement from the Italian Society of
weight, obesity and related comorbidities stand out in the Endocrinology (SIE), the Italian Society of Nutraceuticals
first place. Similarly, however, in the context of a medical (SINut), and the Italian Society of Nephrology (SIN).
nutritional therapy appropriately tailored to the patient’s Due to its specific features (decline in kidney function),
characteristics, KeNuT also has the following contraindi- as well as the associated pathological conditions (such as
cations: pregnancy, lactation, childhood, type 1 diabetes, inflammation, OxS, fibrosis, and autophagy), CKD requires
T2DM with beta-cellular insufficiency or being treated profound lifestyle modifications, including a proper dietary
with glyphozines, rare metabolic disorders, organ failure, program [21]. This becomes even more important when
heart attack and stroke, severe psychiatric disorders, eat- considering that obesity and T2DM (two diseases strongly
ing disorders, alcohol and substance abuse. The indications linked to diet) contribute to the development of renal fail-
and contraindications of KeNuT, and supporting studies, are ure and adversely affect the progression of kidney disease
[9, 20]. Treatment and management of these two conditions
Weight loss
Reducing fat mass
Glucose control
OUTCOMES
Insulin control
Lipid control
Phosphate control
Acidosis control
Reducing inflammation
Reducing oxidative stress
LCD/KD
NUTRITIONAL STRATEGY
ICKD LCKD VLEKT
• E = TEE • E = 700-800 kcal/d • E <700-800 kcal/d

• CHO <30-50 g/d • CHO <30-50 g/d • CHO <30-50 g/d
• Lip >70-80% • Lip >30-40 g/d • Lip >30-40 g/d
• Pro = 0.8-1.2 g/kg/d • Pro = 0.8-1.2 g/kg/d • Pro = 0.8-1.2 g/kg/d
NORMAL WEIGHT OVERWEIGHT/OBESITY
• S1-2 Pro=0.8 g/kg/d

ADAPTATIONS FOR CKD
• Replace or, at least,

• PD Pro=1-1.2 g/kg/d reduce animal-based
food consumption
• Prefer MUFA- and
• HD Pro=1-1.2 g/kg/d
PUFA (in particular
omega-3)-rich foods
• T Pro=1 g/kg/d and dietary fats
• S3-5 Pro=0.55-0.6 g/kg/d
Fig. 3 Prescription of LCD/KDs in CKD and relative adaptations for of KD prescribed (ICKD, LCKD or VLEKT), the nutritional inter-
the various stages according to KDOQI guidelines [15], EASO guide- vention must always be adapted by establishing the optimal protein
lines [26], Barrea et al.,2022 [25], and Paoli et al.2023 [148]. Obesity intake according to the degree of CKD. Green checkmark and red-
with the presence of related metabolic complications is an indica- cross indicate whether KDs can be prescribed or not, respectively.
tion for the prescription of KD, which, in particular, should include LCD/KD low-carb/ketogenic diet, ICKD isocaloric ketogenic diet,
a hypocaloric approach (LCKD, VLEKT). However, it should be LCKD low-calorie ketogenic diet, VLEKT very low-energy ketogenic
emphasised that, with the appropriate adjustments in terms of energy therapy, E energy, CHO carbohydrates, Lip lipid, Pro proteins, g
intake and macronutrient distribution (ICKD), it is also possible to grams, kg kilograms, d day, S stages, PD peritoneal dialysis, HD hae-
develop this type of diet in subjects in whom it is not necessary to modialysis, T transplant, TEE total energy expenditure, MUFA mono-
achieve weight loss, but still utilise the benefits of ketosis for thera- unsaturated fatty acids, PUFA polyunsaturated fatty acids
peutic purposes. However, in both cases, and irrespective of the type
Assessment of • Creatin kinetic

• Serum albumin
nutritional status and prealbumin,
nPCR
• BW
• BMI
• WC
• Skinfold
thickness
• BIA (or DXA)
• HGS
• REE
• Follow-up
• Counselling and
re-counselling
Clinical Diet
evaluation prescription
Properly adapted MD
or LCD/KD
Fig. 4 The complete evaluation of the CKD patients. After the clini- the risk/benefit ratio, the proper diet is prescribed. nPCR normalised
cal evaluation (performed by Endocrinologist and Nephrologist), protein catabolic rate, BW body weight, BMI body mass index, WC
qualified Nutritionists (or international equivalent) or physicians per- waist circumference, BIA bioelectrical impedance analysis, DXA dual-
form a deep assessment of the nutritional status comprising labora- energy X-ray absorptiometry, HGS handgrip strength, REE resting
tory parameters, measurements, and use of technical devices. Such energy expenditure, MD mediterranean diet, LCD/KD low-carbohy-
assessment is, then, followed by the estimation of the required energy drate/ketogenic diet
that is necessary for the dietary intervention. Finally, after evaluating
with dietary interventions aimed at weight loss, thus, is nec- to determine when to start a dietary intervention, which, in
essary in CKD [20]. In general, the initiation of a dietary any case, should be undertaken as soon as possible to slow
intervention in a critical clinical setting (as in the case of down the progression of the disease.
CKD) can sometimes be challenging, especially due to psy- Besides the mere caloric aspect, different dietary pat-
chological/motivational concerns that sometimes complicate terns have been suggested to be suitable and effective in
the pre-existing clinical condition. In this sense, therefore, management of obesity, also in patients with CKD. Among
it is important that all nutritional interventions, in general, these, MD/PBD and LCD/KDs emerge as the main stud-
and those for CKD, in particular, are finely tuned to the ied and investigated. Although presenting intrinsic and
patient’s needs, condition and, above all, approval. If the marked differences, these two dietary patterns exert ben-
patient does not approve of a particular dietary interven- eficial effects in reducing BW, inflammation and OxS, and
tion, physicians and nutritionists must work to find other improving metabolic parameters and insulin sensitivity [16],
possible and more compliant strategies to achieve the same with understandable differences in terms of the extent of
clinical results. However, although the patient’s wishes must improvement and the timing to achieve the results. Properly
always be taken into account in a patient-centred disease adapted (Figs. 2 and 3), thus, MD and LCD/KDs can be
management perspective, the decision on the optimal strat- prescribed to CKD patients. For the MD, such adaptations
egy to be adopted always remains at the physician’s discre- mainly refer to the amount and consumption frequencies of
tion after careful clinical evaluation. In this context, KD will Mediterranean foods [18]. For LCD/KDs, instead, the pro-
certainly be suggested in cases of obesity with coexisting tein intake needs to be adapted according to the guideline
metabolic complications, in the absence of which MD may recommendations for the single CKD stages [16], while car-
be opted for. Likewise, it will be at the physician’s discretion bohydrate intake remains below the 50 g threshold to allow
the ketosis, and fats are included compensatively to reach the Research involving human participants and/or animals Not applicable.
total daily calorie intake, resulting in ICKD (energy = total
Informed consent Not applicable.
energy expenditure), LCKD (energy = 700–800 kcal/day),
or VLEKT (energy < 700–800 kcal/day) [25, 26, 148]. This
allows obtaining a dietary pattern that effectively and con-
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Authors and Affiliations
G. Annunziata1,2 · M. Caprio3,4 · L. Verde5 · A. M. Carella1,6 · E. Camajani4 · A. Benvenuto6 · B. Paolini7 ·

L. De Nicola8 · F. Aucella9 · V. Bellizzi10 · S. Barberi11 · D. Grassi12 · F. Fogacci13,14 · A. Colao15,16,17 ·
A. F. G. Cicero13,14 · F. Prodam18,19 · G. Aimaretti18 · G. Muscogiuri15,16,17 · L. Barrea16,20
* G. Muscogiuri M. Caprio
[email protected] [email protected]
G. Annunziata L. Verde
[email protected] [email protected]
6
A. M. Carella Internal Medicine Department, “T. Masselli-Mascia”
[email protected] Hospital—San Severo (Foggia), Foggia, Italy
7
E. Camajani Department of Innovation, experimentation and clinical
[email protected] research, Unit of dietetics and clinical nutrition, S. Maria
Alle Scotte Hospital, University of Siena, Siena, SI, Italy
A. Benvenuto
8
[email protected] Nephrology and Dialysis Unit, University of Campania
“Luigi Vanvitelli”, Naples, Italy
B. Paolini
9
[email protected] Nephrology and Dialysis Unit, “Casa Sollievo Della
Sofferenza” Foundation, Scientific Institut for Reserch
L. De Nicola
and Health Care, San Giovanni Rotondo, FG, Italy
[email protected]
10
Nephrology and Dialysis Division, AORN “Sant’Anna E San
F. Aucella
Sebastiano” Hospital, Caserta, Italy
[email protected]
11
Department of Clinical and Molecular Medicine, Renal Unit,
V. Bellizzi
Sant’Andrea University Hospital, “Sapienza” University
[email protected]
of Rome, Rome, Italy
S. Barberi 12
Internal Medicine Unit—Val Vibrata Hospital—Sant’Omero
[email protected]
(TE)—Department of Life, Health and Environmental
D. Grassi Sciences, University of L’Aquila, L’Aquila, Italy
[email protected] 13
Hypertension and Cardiovascular Risk Factors Research
F. Fogacci Centre, Medical and Surgical Sciences Department, Alma
[email protected] Mater Studiorum University of Bologna, 40100 Bologna,
Italy
A. Colao
14
[email protected] Cardiovascular Medicine Unit, IRCCS Azienda
Ospedaliero-Universitaria Di Bologna, 40138 Bologna, Italy
A. F. G. Cicero
15
[email protected] Unità di Endocrinologia, Diabetologia e Andrologia,
Dipartimento di Medicina Clinica e Chirurgia, Università
F. Prodam
degli Studi di Napoli Federico II, Via Sergio Pansini 5,
[email protected]
80131 Naples, Italy
G. Aimaretti 16
Centro Italiano per la Cura e il Benessere del Paziente con
[email protected]
Obesità (C.I.B.O), Unità di Endocrinologia, Diabetologia e
L. Barrea Andrologia, Dipartimento di Medicina Clinica e Chirurgia,
[email protected]; [email protected] Università Degli Studi di Napoli Federico II, Via Sergio
Pansini 5, 80131 Naples, Italy
1
Facoltà di Scienze Umane, della Formazione e dello 17
Cattedra Unesco “Educazione Alla Salute e Allo Sviluppo
Sport, Università Telematica Pegaso, Via Porzio, Centro
Sostenibile”, University Federico II, 80131 Naples, Italy
Direzionale, Isola F2, 80143 Naples, Italy
18
2 Department of Translational Medicine, Università del
Department of Experimental Medicine, University
Piemonte Orientale, Novara, Italy
of Campania “Luigi Vanvitelli”, Naples, Italy
19
3 Department of Health Sciences, University of Piemonte
Laboratory of Cardiovascular Endocrinology, IRCCS San
Orientale, Novara, Italy
Raffaele, Rome, Italy
20
4 Dipartimento di Benessere, Nutrizione e Sport, Università
Department for the Promotion of Human Sciences
Telematica Pegaso, Centro Direzionale, Via Porzio, Isola F2,
and Quality of Life, San Raffaele Roma Open University, Via
80143 Naples, Italy
di Val Cannuta 247, 00166 Rome, Italy
5
Department of Public Health, University of Naples Federico
II, Via Sergio Pansini 5, 80131 Naples, Italy

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Journal of Endocrinological Investigation

Nutritional assessment and medical dietary therapy for management

Received: 8 February 2024 / Accepted: 19 August 2024

Giuseppe Annunziata, Massimiliano Caprio and Ludovica Verde

Giovanna Muscogiuri and Luigi Barrea equally contributed to this

Extended author information available on the last page of the article

Abbreviations IR Insulin resistance

A1 < 30 < 3 mg/mmol or < 30 mg/g Normal to mildly increased

AER albumin excretion rate, ACR​albumin-to-creatinine ratio

Laboratory parameters for nutritional assessment

Mediterranean diet MD adaptation at different CKD stages

Fig. 2 Recommendations for

Table 4 Effects of LCD/KDs on kidney function

ICKD LCKD VLEKT

• E = TEE • E = 700-800 kcal/d • E <700-800 kcal/d

NORMAL WEIGHT OVERWEIGHT/OBESITY

• S1-2 Pro=0.8 g/kg/d

• Replace or, at least,

• S3-5 Pro=0.55-0.6 g/kg/d

Assessment of • Creatin kinetic

Authors and Affiliations

G. Annunziata1,2 · M. Caprio3,4 · L. Verde5 · A. M. Carella1,6 · E. Camajani4 · A. Benvenuto6 · B. Paolini7 ·

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Abbreviations IR Insulin resistance

AER albumin excretion rate, ACRalbumin-to-creatinine ratio