Ketoacid Analogues Supplementation in CKD

Ketoacid Analogues Supplementation in CKD: Comparison

Please note this is a comparison between Version 1 by Laetitia KOPPE and Version 2 by Peter Tang.

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

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

^{][3][4][5][6]}[3,4,5,6,7] 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
	Study		Models			Diet Intervention			Design of Study		Follow-Up				Diet		Results (LPD vs. VLDP/LPD + KAs)
	Follow-Up			Results			Comments
	Wang et al., 2018 ^[7]	[8]
	Milovanova et al., 2018 ^[2]	[3]	5/6 nephrectomy rats			RCT		n = 42 in LPD + KA vs. LPD n = 37		Non-diabetic CKD 3B–4		NPD: 22% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA			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		24 weeks				14 months		↓ muscle atrophy		↑ activities of mitochondrial electron transport chain complexes and mitochondrial respiration,		↓ muscle oxidative damage			↑ eGFR (29.1 L/min/1.73 m ↑body weight		² 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
	Ca-Ketoeucine
	Similar protein intake in both group		Long follow up			Liu et al., 2018 ^[8]	[9]		101
	Di Iorio et al., 2018 ^[19]	[20]	KKAy mice, an early type 2 DN model			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		NPD: 22% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA			12 weeks			↓ proteinuria		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		↓ mesangial proliferation and oxidative stress		6 months		↑ serum albumin and body weight		No difference in creatinine and GFR			↓ 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		Ca-Ketophénylalanine	^9]	[10]
	Garneata et al., 2016 ^[20]		68
	[21]	3/4 nephrectomy rats			RCT		CKD stage 4–5,		proteinuria < 1 g/24 h		n = 207		NPD: 18% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA			12 weeks			LPD = 0.6 g protein/kg per day		vs.		VLPD + KA = vegetarian diet, 0.3 g protein/kg per day + KA			15 months		↓ proteinuria		↓ intrarenal RAS activation.		↓ transforming growth factor-β1 in the mesangial cells			↓ 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	Ca-Ketovaline		86
	Zhang et al., 2016 ^[
		Long follow up		Large effective		Only 14% of patients screened was included			Zhang et al., 2015 ^[10]	[11]
	Di Iorio et al., 2012 ^[21]	[22]	5/6 nephrectomy rats				RCT, crossover trial		eGFR < 55 and > 20 mL/min/1.73 m ²		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		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			LPD = 0.6 g protein/kg per day		24 weeks		vs. VLPD + KA = 0.3 g protein/kg per day + KA		↑ body weight, gastrocnemius muscle mass		↓ autophagy marker in muscle		No difference of inflammation markers			1 week			↓ phosphate (−12%), FGF23 (−33.5)		No change on calcium		a post hoc of this study, ↓ indoxyl sulfate ^[ ^22]	[ 23 ]	↑bicarbonates levels			Short exposition			Ca-Hydroxy-dl-methionine
	Wang et al., 2014 ^[11]	[12]
	Di Iorio et al., 2009 ^[23		59
^]	[24]	5/6 nephrectomy rats				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		NPD: 22% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA			LPD = 0.6 g protein/kg per day		vs.		VLPD + KA = 0.3 g protein/kg per day + KA		24 weeks			6 months		↑improved protein synthesis and increased related mediators such as phosphorylated Akt in the muscle		↓ protein degradation and proteasome activity in the muscle			↓proteinuria and AGE			Open label		Phosphor intake was different and lower in VLDP+ KA			l-Lysine monoacetate			105
	Gao et al., 2010 ^[12]	[13]
	Menon et al., 2009 ^[24]	[25]	5/6 Nephrectomy rats				Post hoc study of MDRD study B		NPD: 22% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA		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		24 weeks			10.2 years		↓ proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis		↑renal function		↑ body weight and albumin		↓ lipid and protein oxidative products				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			l-Threonine
	Gao et al., 2011 ^[13]	[14]		53
	5/6 Nephrectomy rats
	Teplan et al., 2008 ^[3]	[4]		RCT, double-blind placebo		CKD stage 4		n = 111		NPD: 22% protein		vs.		LPD: 6% protein		vs.		LPD + KAs: 5% protein plus 1% KA			LDP: 0.6 g protein/kg per day		vs.		LPD + KA: 0.6 g protein/kg per day + KA		6 months			36 months		↑ body weight and albumin			↓ADMA ↑ Kruppel-like factor-15, a transcription factor shown to reduce fibrosis			↓ BMI and visceral body fat in obese patients		↓proteinuria			l-Tryptophan
↓ glycated hemoglobin		↓LDL-cholesterol			Mean BMI was > 30 kg/m² at the inclusion		Long follow up		No difference of protein intake		Using a placebo			Maniar et al., 1992 ^[14]	[15]		23
	Mircescu et al., 2007 ^[25]	[26]	5/6 Nephrectomy rats			RCT		eGFR <30 mL/min/1.73 m ², nondiabetic		n = 53		NPD: 16% casein		vs.		LPD + EAA: 6% casein + EAA		vs.		LPD + KAs: 6% casein + KA			VLPD + KA =0.3 g/kg vegetable proteins + KA		3 months			vs.		LPD =0.6 g/kg/d)		No difference on body weight		No difference on proteinuria vs. LDP + EAA but reduction vs. NPD			48 weeks		↓ creatinemia, proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis vs. NPD but no difference vs. LPD + EAA		↑survival vs. NPD but no difference vs. LPD + EAA			↑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		l-Histidine			38
	No change in SBP			Open label			Laouari et al., 1991 ^[15]	[16]
	Gennari et al., 2006 ^[26]	[27]	5/6 Nephrectomy rats				Post hoc study of MDRD study		NPD: 12% casein		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

RCT

CKD stage 4–5

= 255

vs.

LPD + EAAs: 5% casein + EAA

vs.

LPD + KAs: 5% casein + KA

LPD = 0.6 g protein/kg per day

vs.

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

2,2 years

↓Appetite and growth

No increase in BCAAs

No significant effect of diet on serum total CO2 was seen

Benjelloun et al., 1993 ^[16]

[17]

Menon et al., 2005 ^[27]

[28]

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

Post oc study of MDRD study

RCT

NPD: 21% protein

vs.

LPD + KAs: 6% protein plus KA

15 days

↓ proteinuria

↓ glycosaminoglycan excretion and glomerular glycosaminoglycan contents

CKD stage 4–5

= 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

Barsotti et al; 1988 ^[17]

[18]

]

5/6 Nephrectomy rats

Feiten et al., 2005 ^[28]

RCT

= 24

eGFR <25 mL/min

NPD: 20.5% protein

vs.

LPD + KAs: 3.3% protein plus 7.5% KA

3 months

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

vs.

LPD = 0.6 g/kg/d

↑survival

4 months

↑ GFR

↓ proteinuria and histological damage of kidney

No difference in body weight and albuminuria

[29

↑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

Meisinger et al., 1987 ^[18]

[19]

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.

Short time of follow up

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

< 0.05)

Prakash et al., 2004

^29]

[30]

RCT, double-blind placebo

eGFR:28 mL/min/1.73 m

= 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]

[5]

RCT

eGFR: 22–36 mL/min/1.73 m

= 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]

[31]

RCT

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

= 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]

[6]

RCT

CKD stage 4–5

= 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]

[32]

RCT

eGFR<20 mL/min/1.73 m

= 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]

[33]

Post hoc study of MDRD study

RCT

CKD stage 4–5

= 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]

[34]

Post hoc study of MDRD study

RCT

CKD stage 4–5

= 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]

[35]

RCT

CKD stage 4–5

= 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]

[36]

Feasibility phase of the MDRD Study

eGFR: 8 to 56 mL/min/1.73 m

= 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]

[37]

RCT

eGFR<15 mL/min/1.73 m

= 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]

[38]

RCT

CKD stage 5

= 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]

[7]

RCT

Mean eGFR: 10.8 mL/min/1.73 m

= 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.