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Ketoacid Analogues Supplementation in CKD
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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.

  • chronic kidney disease
  • low protein diet
  • ketoacid analogues
  • intestinal microbiota
  • dialysis
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Update Time: 06 Sep 2021

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.

References

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    Koppe, L. Ketoacid Analogues Supplementation in CKD. Encyclopedia. Available online: https://encyclopedia.pub/entry/13875 (accessed on 02 July 2022).
    Koppe L. Ketoacid Analogues Supplementation in CKD. Encyclopedia. Available at: https://encyclopedia.pub/entry/13875. Accessed July 02, 2022.
    Koppe, Laetitia. "Ketoacid Analogues Supplementation in CKD," Encyclopedia, https://encyclopedia.pub/entry/13875 (accessed July 02, 2022).
    Koppe, L. (2021, September 03). Ketoacid Analogues Supplementation in CKD. In Encyclopedia. https://encyclopedia.pub/entry/13875
    Koppe, Laetitia. ''Ketoacid Analogues Supplementation in CKD.'' Encyclopedia. Web. 03 September, 2021.
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