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Table of Contents

    Topic review

    Ketoacid Analogues Supplementation in CKD

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    Submitted by: Laetitia KOPPE

    Definition

    Diet is a key component of care during chronic kidney disease (CKD). In order to reduce the risk of nutritional disorders in very-low protein diets (VLDP), supplementation by nitrogen-free ketoacid analogues (KAs) have been proposed.

    1. Introduction

    End-stage kidney disease (ESKD) is a condition associated with a high mortality and poor quality of life combined with extremely high costs. Using interventions for delaying the need to start a kidney replacement treatment is, therefore, a major challenge. Experimentally, Brenner et al. [1] showed that high protein intake induced marked kidney hypertrophy, which is an increase in glomerular pressure and hyperfiltration that negatively impacts kidney function. Chronic kidney disease (CKD) is characterized by the accumulation of a number of organic solutes called uremic toxins. Many of these uremic toxins are produced by the degradation of dietary amino acids by intestinal microbiota and appears to accelerate CKD progression. Based on these observations, a reduction in protein intake can be expected to preserve renal function and reduce uremic toxicity. The main limitation of this diet is the risk of malnutrition and cachexia.
    Different dietary protein regimens have been tested: low–protein diets (LPD, 0.6 g protein/kg/day) or very low–protein diets (VLPD: 0.3–0.4 g protein/kg/day) supplemented with essential amino acids (EAAs) or nitrogen-free ketoacid analogues (KAs). KAs are precursors of corresponding amino acids since they can undergo a transamination, e.g., a chemical reaction that transfers an amino group to a ketoacid to form a new amino acid (Figure 1). This pathway is responsible for the deamination of most amino acids. Through this conversion, KAs can be utilized in place of their respective EAAs without providing nitrogen products while re-using available nitrogen already in excess during CKD. If a diet does not provide enough EAAs or calories, then the nitrogen balance can become negative and could partly induce cachexia. Therefore, administration of KAs has been proposed to improve protein status while limiting the nitrogen burden on the body. VLDP + KAs are likely also efficient because the calcium content of KA preparation could allow a better correction of mineral metabolism impairment. Different compositions of KAs and EAAs have been tested, with most of them containing four KAs (of the EAA isoleucine, leucine, phenylalanine, and valine), one hydroxyacid (of the EAA methionine), and four amino acids considered essential in CKD (tryptophan, threonine, histidine, and tyrosine) (Table 1).
    Figure 1. Amino-acid and transamination of ketoacid analogues of amino acids in order to synthesize protein.
    Table 1. Ketoacid analogues composition.

    Component Name

    mg/pill

    Ca-Keto-dl-isoleucine

    67

    Ca-Ketoeucine

    101

    Ca-Ketophénylalanine

    68

    Ca-Ketovaline

    86

    Ca-Hydroxy-dl-methionine

    59

    l-Lysine monoacetate

    105

    l-Threonine

    53

    l-Tryptophan

    23

    l-Histidine

    38

    l-Tyrosine

    30

    2. Potential Benefit of Ketoacid Analogues

    Do we have evidence in CKD of specific KAs actions on the reduction of kidney disease-associated comorbidity? New emerging studies suggest that restricted VLDP + KAs may improve renal function and nutritional status, while preventing hyperparathyroidism, insulin resistance, and accumulation of uremic retention solutes (URS), as summarized in Figure 2. The main concern about the interpretation of the literature is the fact that KAs are not given solely but in association with other EAAs and under LPD/VLPD condition. In particular, we do not know if a supplementation of KA alone without low protein diets has any benefit on metabolic disturbances related to CKD. Few studies [2][3][4][5][6] compared KAs supplementation with the same protein restriction and it is difficult to decipher if “KAs effects” are solely the consequence of a decrease of protein intake or if they act specifically. Another interrogation is the reproducibility of the diet composition in different groups. The composition of fibers, acid load, or sodium is difficult to assess and frequently not specified in dietary surveys, which can influence the results. In order to have a more detailed picture of the effects of KAs during CKD, the main experimental trials and RCTs have been summarized in Table 2 and Table 3.
    Figure 2. Proven and controversial mechanism of VLDP/LPD + KAs supplementation in CKD Abbreviations: URS: uremic retention solutes, EAAs: essential amino acids, BCAAs: branched-chain amino acids, LPD: low protein diet, VLDP: very low protein diet, GFR: glomerular filtration rate, and KAs: ketoacid analogues.
    Table 2. Animal studies that examined the effects of VLPD/LPD supplemented with ketoacid analogues on various endpoints.

    Study

    Models

    Diet Intervention

    Follow-Up

    Results (LPD vs. VLDP/LPD + KAs)

    Wang et al., 2018 [7]

    5/6 nephrectomy rats

    NPD: 22% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    24 weeks

    ↓ muscle atrophy

    ↑ activities of mitochondrial electron transport chain complexes and mitochondrial respiration,

    ↓ muscle oxidative damage

    ↑body weight

    Liu et al., 2018 [8]

    KKAy mice, an early type 2 DN model

    NPD: 22% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    12 weeks

    ↓ proteinuria

    ↓ mesangial proliferation and oxidative stress

    ↑ serum albumin and body weight

    No difference in creatinine and GFR

    Zhang et al., 2016 [9]

    3/4 nephrectomy rats

    NPD: 18% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    12 weeks

    ↓ proteinuria

    ↓ intrarenal RAS activation.

    ↓ transforming growth factor-β1 in the mesangial cells

    Zhang et al., 2015 [10]

    5/6 nephrectomy rats

    NPD: 11 g/kg/day protein

    vs.

    LPD: 3 g/kg/day protein

    vs.

    LPD + KAs: 3 g/kg/day protein which including 5% protein plus 1% KA

    24 weeks

    ↑ body weight, gastrocnemius muscle mass

    ↓ autophagy marker in muscle

    No difference of inflammation markers

    Wang et al., 2014 [11]

    5/6 nephrectomy rats

    NPD: 22% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    24 weeks

    ↑improved protein synthesis and increased related mediators such as phosphorylated Akt in the muscle

    ↓ protein degradation and proteasome activity in the muscle

    Gao et al., 2010 [12]

    5/6 Nephrectomy rats

    NPD: 22% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    24 weeks

    ↓ proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis

    ↑renal function

    ↑ body weight and albumin

    ↓ lipid and protein oxidative products

    Gao et al., 2011 [13]

    5/6 Nephrectomy rats

    NPD: 22% protein

    vs.

    LPD: 6% protein

    vs.

    LPD + KAs: 5% protein plus 1% KA

    6 months

    ↑ body weight and albumin

    ↑ Kruppel-like factor-15, a transcription factor shown to reduce fibrosis

    Maniar et al., 1992 [14]

    5/6 Nephrectomy rats

    NPD: 16% casein

    vs.

    LPD + EAA: 6% casein + EAA

    vs.

    LPD + KAs: 6% casein + KA

    3 months

    No difference on body weight

    No difference on proteinuria vs. LDP + EAA but reduction vs. NPD

    ↓ creatinemia, proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis vs. NPD but no difference vs. LPD + EAA

    ↑survival vs. NPD but no difference vs. LPD + EAA

    Laouari et al., 1991 [15]

    5/6 Nephrectomy rats

    NPD: 12% casein

    vs.

    LPD + EAAs: 5% casein + EAA

    vs.

    LPD + KAs: 5% casein + KA

     

    ↓Appetite and growth

    No increase in BCAAs

    Benjelloun et al., 1993 [16]

    Rats with after a single 5 mg/kg intravenous injection of Adriamycin: a model of induces glomerular damage in glomerulonephritis.

    NPD: 21% protein

    vs.

    LPD + KAs: 6% protein plus KA

    15 days

    ↓ proteinuria

    ↓ glycosaminoglycan excretion and glomerular glycosaminoglycan contents

    Barsotti et al; 1988 [17]

    5/6 Nephrectomy rats

    NPD: 20.5% protein

    vs.

    LPD + KAs: 3.3% protein plus 7.5% KA

    3 months

    ↑survival

    ↑ GFR

    ↓ proteinuria and histological damage of kidney

    No difference in body weight and albuminuria

    Meisinger et al., 1987 [18]

    5/6 Nephrectomy rats

    LPD: 8% protein

    vs.

    LPD + KAs: 8% protein plus KA

    3 months

    ↓ proteinuria

    NPD: normal protein diet. HPD: high protein diet. GFR: estimated Glomerular Filtration Rate. LPD: Low protein diet. KAs: ketoacid analogues. EAAs: essential amino acids. BCAAs: branched-chain amino acids; RAS: renin angiotensin system; NPD: normal protein diet.
    Table 3. Main RCTs that examined the effects of LPD or VLDP/LPD supplemented with ketoacid analogues on various endpoints in non-dialysis patients with eDFG under 60 mL/min/1.73 m2.

    Study

    Design of Study

    Diet

    Follow-Up

    Results

    Comments

    Milovanova et al., 2018 [2]

    RCT

    n = 42 in LPD + KA vs. LPD n = 37

    Non-diabetic CKD 3B–4

    LPD (0.6 g/kg of body weight/day, comprising 0.3 g of vegetable protein and 0.3 g of animal protein, phosphorus content ≤ 800 mg/day and calories: 34–35 kcal/kg/day) vs. LPD + KA: 0.6 g/kg of body weight/day

    14 months

    ↑ eGFR (29.1 L/min/1.73 m2 vs. 26.6)

    ↓SBP

    ↑BMI and muscle body mass

    NO change in albumin levels

    No change in lipids parameters

    ↓ phosphate, FGF23, and PTH levels ↑Klotho levels and phosphate binder uses

    ↑bicarbonates levels

    Similar protein intake in both group

    Long follow up

    Di Iorio et al., 2018 [19]

    RCT, crossover trial

    CKD stages 3B–4

    Group A1: 3 months of FD, 6 months of VLPD + KA, 3 months of FD and 6 months of MD

    Group B: 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD + KA.

    n = 30 in each group

    FD: proteins 1 g/kg body weight (bw)/day (animal proteins 50–70 g/day, vegetal proteins 15–20 g/day), energy 30–35 kcal/bw/day, calcium (Ca) 1.1–1.3 g/day, phosphorus (P) 1.2–1.5 g/day, sodium (Na) 6 g/day and potassium (K) 2–4 g/day.

    MD: proteins 0.7–0.8 g/kg bw/day (animal proteins 30–40 g/day, vegetal proteins 40–50 g/day), energy 30–35 kcal/bw/day, Ca 1.1–1.3 g/day, P 1.2–1.5 g/day, Na 2.5–3  g/day and K 2–4 g/day.

    VLPD + KA: proteins 0.3–0.5 g/kg bw/day (animal proteins 0 g/day, vegetal proteins 30–40 g/day), energy 30–35 kcal/bw/day, Ca 1.1–1.3 g/day, P 0.6–0.8 g/day, Na 6 g/day, K 2–4 g/day plus a mixture of KA

    6 months

    ↓ SBP

    No change in creatinuria

    ↓proteinuria

    ↓ phosphate, FGF23, and PTH levels

    ↑bicarbonates levels

    ↑Hg levels

    ↓protein carbamylation

    Sodium intake and phosphore intake was reduce in VLDP + KA group

    Garneata et al., 2016 [20]

    RCT

    CKD stage 4–5,

    proteinuria < 1 g/24 h

    n = 207

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = vegetarian diet, 0.3 g protein/kg per day + KA

    15 months

    ↓ RRT initiation or a >50% reduction in the initial GFR (13% in KA+LDP vs. 42% in LPD reached the primary composite efficacy point i.e., RRT initiation or a >50% reduction in the initial GFR)

    ↓CRP

    ↑bicarbonates levels

    ↓uric acid

    ↓ phosphate, FGF23 and PTH levels and phosphate binder uses

    No difference in proteinuria

    No difference of death and CV events

    No difference of albumin, BMI

    No change in lipids parameters

    Long follow up

    Large effective

    Only 14% of patients screened was included

    Di Iorio et al., 2012 [21]

    RCT, crossover trial

    eGFR < 55 and > 20 mL/min/1.73 m2

    Group A: VLDP + KA during the first week and LPD during the second week

    Group B: LPD during the first week and a VLPD + KA during the second week.

    n = 16 in each group

    LPD = 0.6 g protein/kg per day

    vs. VLPD + KA = 0.3 g protein/kg per day + KA

    1 week

    ↓ phosphate (−12%), FGF23 (−33.5)

    No change on calcium

    a post hoc of this study, ↓ indoxyl sulfate [22]

    ↑bicarbonates levels

    Short exposition

    Di Iorio et al., 2009 [23]

    RCT, crossover trial

    eGFR < 55 and > 20 mL/min

    Group A: VLDP + KA during 6 month and a LPD during 6 month

    Group B: LPD during 6 month and a VLDP + KA during 6 month.

    n = 16 in each group 32 patients

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    6 months

    ↓proteinuria and AGE

    Open label

    Phosphor intake was different and lower in VLDP+ KA

    Menon et al., 2009 [24]

    Post hoc study of MDRD study B

    CKD stage 4 nondiabetic

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    10.2 years

    No delay progression to kidney failure

    ↑the risk of death.

    Long follow up without intervention -Observance and protein intake was not monitored during the follow up

    Teplan et al., 2008 [3]

    RCT, double-blind placebo

    CKD stage 4

    n = 111

    LDP: 0.6 g protein/kg per day

    vs.

    LPD + KA: 0.6 g protein/kg per day + KA

    36 months

    ↓ADMA

    ↓ BMI and visceral body fat in obese patients

    ↓proteinuria

    ↓ glycated hemoglobin

    ↓LDL-cholesterol

    Mean BMI was > 30 kg/m2 at the inclusion

    Long follow up

    No difference of protein intake

    Using a placebo

    Mircescu et al., 2007 [25]

    RCT

    eGFR <30 mL/min/1.73 m2, nondiabetic

    n = 53

    VLPD + KA =0.3 g/kg vegetable proteins + KA

    vs.

    LPD =0.6 g/kg/d)

    48 weeks

    ↑bicarbonates levels

    ↑calcium levels and ↓ phosphate

    lower percentages of patients in group I required renal replacement therapy initiation (4% vs. 27%).

    No change of rate of eGFR and proteinuria

    No change in SBP

    Open label

    Gennari et al., 2006 [26]

    Post hoc study of MDRD study

    RCT

    CKD stage 4–5

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    2,2 years

    No significant effect of diet on serum total CO2 was seen

     

    Menon et al., 2005 [27]

    Post oc study of MDRD study

    RCT

    CKD stage 4–5

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    2.2 years

    ↓ homocysteinemia by 24% at 1 year

     

    Feiten et al., 2005 [28]

    RCT

    n = 24

    eGFR <25 mL/min

    VLPD + KA = 0.3 g/kg vegetable proteins + KA

    vs.

    LPD = 0.6 g/kg/d

    4 months

    ↑bicarbonates levels

    No change on calcium levels

    ↓ phosphate and PTH

    Decrease the progression of renal decline function of rate of eGFR

    No change in lipid parameters

    No change in nutritional status (BMI, albumin)

    Open label

    Short time of follow up

    Significant reduction in dietary phosphorus (529 ± 109 to 373 ± 125 mg/day, p < 0.05)

    Prakash et al., 2004 [29]

    RCT, double-blind placebo

    eGFR:28 mL/min/1.73 m2

    n = 34

    LPD = 0.6 g protein/kg per day + placebo

    vs.

    VLPD = 0.3 g protein/kg per day + KA

    9 months

    preserve mGFR (−2% in LDP + KA vs. −21% in LPD)

    No effect on proteinuria

    No effect of BMI and albumin

    Measure of GFR with 99mTc-DTPA

    The placebo is problematic because protein intake was different between both groups.

    Teplan et al., 2003 [4]

    RCT

    eGFR: 22–36 mL/min/1.73 m2

    n = 186

    LPD 0.6 g protein/kg per day + rhuEPO + KA

    vs. LPD: 0.6 g protein/kg per day + rhuEPO

    vs. LPD: 0.6 g protein/kg per day

    3 years

    Slower progression of CKD

    ↓proteinuria

    ↓LDL-cholesterol

    No change in SBP

    ↑albumin

    ↑ plasmatic leucine levels

    Role of rhuEPO unclear

    Insulin clearance

    Di Iorio et al., 2003 [30]

    RCT

    eGFR: < or =25 mL/min/1.73 m2

    n = 10 in each group

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD = 0.3 g protein/kg per day + KA

    2 years

    No difference on hemoglobin

    ↓ EPO dose

    ↓ phosphate and PTH

    No change in BMI and albumin

    No difference in the rate of RRT initiation (8 vs. 7)

    Slower rate of GFR decline (creatinine clearance)

    ↓SBP and 24 h NA excretion

    ↓LDL-cholesterol

    Very few populations

    Bernhard et al., 2001 [5]

    RCT

    CKD stage 4–5

    n = 6 in each group

    LPD = 0.6 g protein/kg per day

    vs.

    LPD + KA = 0.6 g protein/kg per day + KA

    3 months

    No difference could be attributed to the ketoanalogs total body flux and leucine oxidation

    No difference on phosphorus, calcium levels

    No difference on BMI and albumin

    No difference in renal function and proteinuria

    No difference on bicarbonatemia

    KA is metabolically safe

    Short follow-up

    Small effective

    Malvy et al., 1999 [31]

    RCT

    eGFR<20 mL/min/1.73 m2

    n = 50

    LPD:LPD = 0.65 g protein/kg per day + Ca+

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    3 months or time to eGFR < 5 mL/min/1.73 m2 or RRT

    No difference on GFR progression

    ↑calcium levels

    ↓ phosphate and PTH

    No difference on lipid parameters

     

    Kopple et al., 1997 [32]

    Post hoc study of MDRD study

    RCT

    CKD stage 4–5

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    2,2 years

    No difference of death and first hospitalization

    ↑ albumin

    ↓ transferrin, body wt, percent body fat, arm muscle area, and urine creatinine excretion

    No correlation between nutritional parameters and death or hospitalization

    ↓ energy intake

     

    Levey et al., 1996 [33]

    Post hoc study of MDRD study

    RCT

    CKD stage 4–5

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    2.2 years

    A 0.2 g/kg/d lower achieved total protein intake was associated with a 1.15 mL/min/yr slower mean decline in GFR (p = 0.011), which is equivalent to 29% of the mean GFR decline

    Reanalyze of MDRD study by using correlations of protein intake with a rate of decline in GFR and time to renal failure

    Klahr et al., 1994 Study 2 [34]

    RCT

    CKD stage 4–5

    n = 255

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    27 months

    Marginally slower eGFR decline (−19% in LPD vs. 12% in VLDP + KA, p 0.067)

    No significant interactions between blood-pressure interventions and the rate of decline in eGFR

    No difference on albumin

    No difference in proteinuria

    -Large RCT study

    -Good adherence of diet

    -Measured GFR with iothalamate

    Coggins et al. 1994 [35]

    Feasibility phase of the MDRD Study

    eGFR: 8 to 56 mL/min/1.73 m2

    n = 96

    25 participants were excluded

    LPD = 0.6 g protein/kg per day

    vs.

    VLPD + KA = 0.3 g protein/kg per day + KA

    6 months

    No difference on lipid parameters

    Pilot study

    Lindenau et al. 1990 [36]

    RCT

    eGFR<15 mL/min/1.73 m2

    n = 40

    LPD = 0.6 g protein/kg per day + Ca+ vs. VLPD + KA = 0.4 g protein/kg per day + KA

    12 months

    Improvement in osteo-fibrotic as well as in osteo-malacic changes

    A calcium supplementation was given in LPD diet as a control for KA

    Jungers et al. 1987 [37]

    RCT

    CKD stage 5

    n = 19

    LPD = 0.6 g protein/kg per day + Ca+ vs. VLPD + KA = 0.4 g protein/kg per day + KA

    12 months

    No difference on biochemical or morphometric sign of de-nutrition

    ↑mean renal survival duration until dialysis

    Small and effective

    Hecking et al., 1982 [6]

    RCT

    Mean eGFR: 10.8 mL/min/1.73 m2

    n = 15

    LPD = 0.6 g protein/kg per day + Ca+ vs. LPD + KA = 0.6 g protein/kg per day + KA or EAA or placebo

    3 weeks per periods

    ↓ phosphate

    No difference on GFR and proteinuria

    No difference on lipids parameters

    No difference on albumin

    Small and effective

    versus the placebo

    FD: Free diet. P: phosphorus. MDRD: Modification of Diet in the Renal Disease Study. eGFR: estimated Glomerular Filtration Rate. RRT: renal replacement therapy. FGF23: Fibroblast Growth Factor 23. LPD: Low protein diet. VLDP: Very low protein diet. KA: Keto-analogues. RCT: randomized controlled trial. EAA: essential amino acids; PTH: parathyroid hormone.

    The entry is from 10.3390/nu11092071

    References

    1. Brenner, B.M.; Meyer, T.W.; Hostetter, T.H. Dietary protein intake and the progressive nature of kidney disease: The role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N. Engl. J. Med. 1982, 307, 652–659.
    2. Milovanova, L.; Fomin, V.; Moiseev, S.; Taranova, M.; Milovanov, Y.; Lysenko Kozlovskaya, L.; Kozlov, V.; Kozevnikova, E.; Milovanova, S.; Lebedeva, M.; et al. Effect of essential amino acid кetoanalogues and protein restriction diet on morphogenetic proteins (FGF-23 and Klotho) in 3b-4 stages chronic кidney disease patients: A randomized pilot study. Clin. Exp. Nephrol. 2018, 22, 1351–1359.
    3. Teplan, V.; Schück, O.; Racek, J.; Mareckova, O.; Stollova, M.; Hanzal, V.; Malý, J. Reduction of plasma asymmetric dimethylarginine in obese patients with chronic kidney disease after three years of a low-protein diet supplemented with keto-amino acids: A randomized controlled trial. Wien. Klin. Wochenschr. 2008, 120, 478–485.
    4. Teplan, V.; Schück, O.; Knotek, A.; Hajný, J.; Horácková, M.; Kvapil, M. Czech multicenter study Enhanced metabolic effect of erythropoietin and keto acids in CRF patients on low-protein diet: Czech multicenter study. Am. J. Kidney Dis. 2003, 41, S26–S30.
    5. Bernhard, J.; Beaufrère, B.; Laville, M.; Fouque, D. Adaptive response to a low-protein diet in predialysis chronic renal failure patients. J. Am. Soc. Nephrol. 2001, 12, 1249–1254.
    6. Hecking, E.; Andrzejewski, L.; Prellwitz, W.; Opferkuch, W.; Müller, D.; Port, F.K. A controlled study of supplementation with essential amino acids and alpha-keto acids in the conservative management of patients with chronic renal failure. Z. Ernahrungswiss. 1982, 21, 299–311.
    7. Wang, D.; Wei, L.; Yang, Y.; Liu, H. Dietary supplementation with ketoacids protects against CKD-induced oxidative damage and mitochondrial dysfunction in skeletal muscle of 5/6 nephrectomised rats. Skelet Muscle 2018, 8, 18.
    8. Liu, D.; Wu, M.; Li, L.; Gao, X.; Yang, B.; Mei, S.; Fu, L.; Mei, C. Low-protein diet supplemented with ketoacids delays the progression of diabetic nephropathy by inhibiting oxidative stress in the KKAy mice model. Br. J. Nutr. 2018, 119, 22–29.
    9. Zhang, J.-Y.; Yin, Y.; Ni, L.; Long, Q.; You, L.; Zhang, Q.; Lin, S.-Y.; Chen, J. Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system. Br. J. Nutr. 2016, 116, 1491–1501.
    10. Zhang, Y.; Huang, J.; Yang, M.; Gu, L.; Ji, J.; Wang, L.; Yuan, W. Effect of a low-protein diet supplemented with keto-acids on autophagy and inflammation in 5/6 nephrectomized rats. Biosci. Rep. 2015, 35, e00263.
    11. Wang, D.-T.; Lu, L.; Shi, Y.; Geng, Z.-B.; Yin, Y.; Wang, M.; Wei, L.-B. Supplementation of ketoacids contributes to the up-regulation of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin-proteasome systems in the muscle of 5/6 nephrectomised rats. Br. J. Nutr. 2014, 111, 1536–1548.
    12. Gao, X.; Wu, J.; Dong, Z.; Hua, C.; Hu, H.; Mei, C. A low-protein diet supplemented with ketoacids plays a more protective role against oxidative stress of rat kidney tissue with 5/6 nephrectomy than a low-protein diet alone. Br. J. Nutr. 2010, 103, 608–616.
    13. Gao, X.; Huang, L.; Grosjean, F.; Esposito, V.; Wu, J.; Fu, L.; Hu, H.; Tan, J.; He, C.; Gray, S.; et al. Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: A role for KLF15. Kidney Int. 2011, 79, 987.
    14. Maniar, S.; Beaufils, H.; Laouari, D.; Forget, D.; Kleinknecht, C. Supplemented low-protein diets protect the rat kidney without causing undernutrition. J. Lab. Clin. Med. 1992, 120, 851–860.
    15. Laouari, D.; Jean, G.; Kleinknecht, C.; Broyer, M. Growth, free plasma and muscle amino-acids in uraemic rats fed various low-protein diets. Pediatr. Nephrol. 1991, 5, 318–322.
    16. Benjelloun, A.S.; Merville, P.; Cambar, J.; Aparicio, M. Effects of a low-protein diet on urinary glycosaminoglycan excretion in adriamycin-treated rats. Nephron 1993, 64, 242–248.
    17. Barsotti, G.; Moriconi, L.; Cupisti, A.; Dani, L.; Ciardella, F.; Lupetti, S.; Giovannetti, S. Protection of renal function and of nutritional status in uremic rats by means of a low-protein, low-phosphorus supplemented diet. Nephron 1988, 49, 197–202.
    18. Meisinger, E.; Gretz, N.; Strauch, M. Hyperfiltration due to amino and keto acid supplements of low-protein diets: Influence on proteinuria. Infus. Klin Ernahr 1987, 14 (Suppl. 5), 26–29.
    19. Di Iorio, B.R.; Marzocco, S.; Bellasi, A.; De Simone, E.; Dal Piaz, F.; Rocchetti, M.T.; Cosola, C.; Di Micco, L.; Gesualdo, L. Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease. Nephrol. Dial. Transplant. 2018, 33, 804–813.
    20. Garneata, L.; Stancu, A.; Dragomir, D.; Stefan, G.; Mircescu, G. Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression. J. Am. Soc. Nephrol. 2016, 27, 2164–2176.
    21. Di Iorio, B.; Di Micco, L.; Torraca, S.; Sirico, M.L.; Russo, L.; Pota, A.; Mirenghi, F.; Russo, D. Acute effects of very-low-protein diet on FGF23 levels: A randomized study. Clin. J. Am. Soc. Nephrol. 2012, 7, 581–587.
    22. Marzocco, S.; Dal Piaz, F.; Di Micco, L.; Torraca, S.; Sirico, M.L.; Tartaglia, D.; Autore, G.; Di Iorio, B. Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease. Blood Purif. 2013, 35, 196–201.
    23. Di Iorio, B.R.; Cucciniello, E.; Martino, R.; Frallicciardi, A.; Tortoriello, R.; Struzziero, G. Acute and persistent antiproteinuric effect of a low-protein diet in chronic kidney disease. G Ital. Nefrol 2009, 26, 608–615.
    24. Menon, V.; Kopple, J.D.; Wang, X.; Beck, G.J.; Collins, A.J.; Kusek, J.W.; Greene, T.; Levey, A.S.; Sarnak, M.J. Effect of a very low-protein diet on outcomes: Long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am. J. Kidney Dis. 2009, 53, 208–217.
    25. Mircescu, G.; Gârneaţă, L.; Stancu, S.H.; Căpuşă, C. Effects of a supplemented hypoproteic diet in chronic kidney disease. J. Ren. Nutr. 2007, 17, 179–188.
    26. Gennari, F.J.; Hood, V.L.; Greene, T.; Wang, X.; Levey, A.S. Effect of dietary protein intake on serum total CO2 concentration in chronic kidney disease: Modification of Diet in Renal Disease study findings. Clin. J. Am. Soc. Nephrol. 2006, 1, 52–57.
    27. Menon, V.; Wang, X.; Greene, T.; Beck, G.J.; Kusek, J.W.; Selhub, J.; Levey, A.S.; Sarnak, M.J. Homocysteine in chronic kidney disease: Effect of low protein diet and repletion with B vitamins. Kidney Int. 2005, 67, 1539–1546.
    28. Feiten, S.F.; Draibe, S.A.; Watanabe, R.; Duenhas, M.R.; Baxmann, A.C.; Nerbass, F.B.; Cuppari, L. Short-term effects of a very-low-protein diet supplemented with ketoacids in nondialyzed chronic kidney disease patients. Eur. J. Clin. Nutr. 2005, 59, 129–136.
    29. Prakash, S.; Pande, D.P.; Sharma, S.; Sharma, D.; Bal, C.S.; Kulkarni, H. Randomized, double-blind, placebo-controlled trial to evaluate efficacy of ketodiet in predialytic chronic renal failure. J. Ren. Nutr. 2004, 14, 89–96.
    30. Di Iorio, B.R.; Minutolo, R.; De Nicola, L.; Bellizzi, V.; Catapano, F.; Iodice, C.; Rubino, R.; Conte, G. Supplemented very low protein diet ameliorates responsiveness to erythropoietin in chronic renal failure. Kidney Int. 2003, 64, 1822–1828.
    31. Malvy, D.; Maingourd, C.; Pengloan, J.; Bagros, P.; Nivet, H. Effects of severe protein restriction with ketoanalogues in advanced renal failure. J. Am. Coll. Nutr. 1999, 18, 481–486.
    32. Kopple, J.D.; Levey, A.S.; Greene, T.; Chumlea, W.C.; Gassman, J.J.; Hollinger, D.L.; Maroni, B.J.; Merrill, D.; Scherch, L.K.; Schulman, G.; et al. Effect of dietary protein restriction on nutritional status in the Modification of Diet in Renal Disease Study. Kidney Int. 1997, 52, 778–791.
    33. Levey, A.S.; Adler, S.; Caggiula, A.W.; England, B.K.; Greene, T.; Hunsicker, L.G.; Kusek, J.W.; Rogers, N.L.; Teschan, P.E. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am. J. Kidney Dis. 1996, 27, 652–663.
    34. Klahr, S.; Levey, A.S.; Beck, G.J.; Caggiula, A.W.; Hunsicker, L.; Kusek, J.W.; Striker, G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N. Engl. J. Med. 1994, 330, 877–884.
    35. Coggins, C.H.; Dwyer, J.T.; Greene, T.; Petot, G.; Snetselaar, L.G.; Van Lente, F. Serum lipid changes associated with modified protein diets: Results from the feasibility phase of the Modification of Diet in Renal Disease Study. Am. J. Kidney Dis. 1994, 23, 514–523.
    36. Lindenau, K.; Abendroth, K.; Kokot, F.; Vetter, K.; Rehse, C.; Fröhling, P.T. Therapeutic effect of keto acids on renal osteodystrophy. A prospective controlled study. Nephron 1990, 55, 133–135.
    37. Jungers, P.; Chauveau, P.; Ployard, F.; Lebkiri, B.; Ciancioni, C.; Man, N.K. Comparison of ketoacids and low protein diet on advanced chronic renal failure progression. Kidney Int. Suppl. 1987, 22, S67–S71.
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