21/02/2012 The Protein-Phosphorus issue in CKD Current & future - - PDF document

21/02/2012 1 CKD & Nutrition: Role of protein intake & phosphate levels

Denis Fouque University of Lyon France

Current & future management of chronic kidney disease

The Protein-Phosphorus issue in CKD

1 g protein = 13 mg Phosphorus

Nutritional Intake

Healthy adults in Western countries:

• 1.3 – 1.4 g protein/kg/day
• 35 - 40 kcal/kg/day
• 9 -12 g NaCl per day
• 1200 - 1800 mg phosphate
• 1000 mg calcium

Nutritional profile during CKD Nutritional profile during CKD

Pre Pre-ESRD ESRD

LPD LPD 0.7 0.7-

• 0.8

0.8 30 30-

• 40

40 800 mg/day 800 mg/day + ++ ++

Transplant* Transplant*

HPD HPD 1.4 1.4 30 30-

• 40

40 ++ ++ + +

Dialysis Dialysis

SPD SPD 1.2 1.2-

• 1.4

1.4 30 30-

• 40

40 ++ ++ + +

* first 3 months * first 3 months

Transplant Transplant

LPD LPD 0.8 0.8 30 30-

• 40

40 +/ +/-

• ++

++ Diet Diet Prot Prot (g/kg/d) (g/kg/d) Energy Energy (kcal/kg/d (kcal/kg/d) ) Phosphorus Phosphorus

• 1. Malnourished
• 1. Malnourished
• 2. Obese
• 2. Obese

Cochrane systematic review

Fouque et al, Cochrane Database Syst Rev Apr 2009 2000 pts, p= 0.0002

1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Fouque, Aparicio, Nature Nephrology 2007;3:383-392

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Nephroprotection

Fundamental experimental work of Brenner, Hostetter and colleagues More difficult to be confirmed in humans:

Men are not rats Multifactorial disease Less protein gradient Clinical trials caveats (eg, duration, speed of progression, various renal disease, interference with outcome measures, compliance)

Surrogate: proteinuria ++

Reducing Protein intake

Aparicio et al, Nephron 1988 Serum albumin Proteinuria 0.3 g prot/kg + ceto-analogs

Proportionate reduction in protein intake and proteinuria

Gansevoort et al, NDT 1992 Baseline protein intake ≥ 1 g/kg/day

VLPD reduces Proteinuria better than LPD

Bellizzi et al, Kidney Int 2007

• VLPD + KA (0.3 g/kg/d) / LPD (0.6 g/kg/d) / Free Diet
• Parallel reduction in Protein intake and Sodium intake

Proteinuria (g/d)

Protein intake induces renal inflammation

Tovar-Palacio et al, Am J Physiol 2011 300:F263

Oxidant stress Mesangial cell proliferation Urine H2O2

Rats fed 2 different sources and 3 different levels of protein for 2 months

Protein intake induces renal pathology

casein 45% 30% 20% Proteinuria (mg/day) 186 ±23 248 ±32 141 ±42 * S insulin 14.6 ±1.9 12.0 ±1.4 11.7 ±1.9 * casein 45% 30% 20% SREBP1 2.2 ±0.2 2.2 ±0.2 1.0 ±0.2 * TNF-alpha 3.5 ±0.6 2.7 ±0.4 1.1 ±0.3 * IL-6 2.1 ±0.3 2.0 ±0.2 1.0 ±0.1 * IV collagen 1.65 ±0.2 2.0 ±0.3 1.0 ±0.2 * TGF-beta 1.9 ±0.2 1.4 ±0.2 1.0 ±0.1 *

Renal expression Lipids inflam mation Matrix expansion fibrosis

Tovar-Palacio et al, Am J Physiol 2011 300:F263

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LPD reduces renal inflammation

Gao X et al, Kidney Int 2011 79:987

5/6 Nx rats followed for 8 months Protein intake: 22% - 6% - 5% +1%KA Kruppel-like factor 15 (KLF15): antifibrotic transcription factor

Ketoacids reduces renal fibrosis

Gao X et al, Kidney Int 2011 79:987

Fibronectin staining LPD – KA reduce renal matrix accumualation

Gao X et al, Kidney Int 2011 79:987

Renal TGF beta and collagen expression

Overexpression of KLF15 and renal inflammation

Gao X et al, Kidney Int 2011 79:987

Transfected mesangial cells

LPD restores renal KLF15 expression

Gao X et al, Kidney Int 2011 79:987

The role of Klotho on vascular calcifications

Ohkido et al. ASN 2011

WT Kl-/- + sevel Kl-/- +LPD Kl-/-

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1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Reduction in serum urea nitrogen

After 3 months at 0.3 g/kg/d + ketoanalogues

Rigalleau et al. Am J Clin Nutr 1997

1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status and safety 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Optimal Protein Intake

Minimal intake 0.46 g/kg/d (FAO/WHO, RDA) +30% for mixed protein = 0.60 +30% for safety (at population level ) = 0.80

in CKD patients:

• Nitrogen balances (Kopple)
• Leucine fluxes (Maroni, Fouque)
• Metabolic analyses (Aparicio)

(bone, CV risk, acidosis, proteinuria, insulinoresistance…)

0.6-0.7 g/kg/d 0.6-0.7 g/kg/d

Aminoacid oxidation after reducing protein intake

Bernhard et al, J Am Soc Nephrol 2001

From 1.1 to 0.7 g/kg/day during three months

21/02/2012 5

Urinary urea excretion (mmol/d)

Fouque et al. J Am Soc Nephrol 1995

from 1.1 to 0.7 g prot/kg/d

Serum albumin in the MDRD study

Kopple et al, Kidney Int 1997

MDRD study A Mild CKD MDRD study B Severe CKD

Nutritional status after the start of dialysis

Vendrely et al. Kidney Int 2003

FM LBM

DEXA No difference whatever the predialysis diet

Vendrely et al. Kidney Int 2003

Nutritional intake after the start of Dialysis

Protein intake Energy intake No difference whatever the predialysis diet

1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Low protein diet and inflammation

Kozlowska et al, Nephrology 2004

• 17 males, non diabetic, mild proteinuria and CKD

st III (39 ml/min)

• 4 month at 0.68 g prot/kg/day (free protein intake

before)

• 3 day diet records - same dietician

No weight change - no change in BMI or body fat S urea to drop from 14.5 to 10.6 mmol/l (- 27 %, <0.001)

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Low protein diet and inflammation

Kozlowska et al, Nephrology 2004

Leptin TNF alpha

From 1.05 to 0.68 g protein /kg/d 1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Improvement in serum glucose and insulinemia (after OGT)

Gin et al. Metabolism 1987 Serum glucose insulinemia

Protein intake decreased from 1 g/kg/d to 0.3 g + ketoacids during 4 months Adipocyte ? OGT

Improvement in insulin resistance

Rigalleau et al. Am J Clin Nutr 1997

After 3 months at 0.3 g/kg/d + ketoanalogues

Insulin clamp 1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

Phosphate and bone

• Hyperphosphatemia is independently

associated with mortality even before dialysis

• Hyperparathyroidism starts around 60 ml/min
• Phosphate is strongly bound to protein:

100 g protein = 1300 mg phosphate

• FGF 23 is « the new player »

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Reduction in oral phosphate load

Rigalleau et al. Am J Clin Nutr 1997

From 15 to 8 mg/kg/d (a regular intake is 1500 mg/d)

Fibroblast Growth Factor 23

Hormone synthezised by the bone (osteocyte) Strong modulator of renal phosphate excretion Strongly reduces 1-25 Vit D Increases with CKD worsening (x10 to 1000) Associated with increased mortality in dialysis

FGF 23 and renal function

Isakova et al. Kidney Int 2011;79:1370

FGF 23, mortality and renal death

Kendrick et al. JASN, on line Sept 2011

HOST study 1099 stage IV CKD Mean Fup 3 yr mortality renal death

FGF 23: modulated by phosphate/protein intake

Ferrari et al. J Clin Endocrinol Metab 2005 29 healthy volunteers 3 different phosphate intakes:

• Normal
• Oral binder
• Supplement of 1500 mg/d

FGF 23: modulated by nutrients

Phosphate intake, 800 mg/d, either from meat or vegetarian (randomized cross over)

Moe et al. C JASN 2011;6:257

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Modulating phosphate/FGF23 by binders

Am J Kidney Dis 2012;59:177

8-wk RCT in 100 CKD patients Ca acetate vs sevelamer

Artery stifness / FGF23 / binders

J Renal Nutr 2011:21:285-294

Warning: Risk of low energy intake Warning: Risk of low energy intake

kcal/kg/d kcal/kg/d

1988 1988 1993 1993 1996 1996 Results from large CKD trials

MDRD start MDRD end HEMO start

1.Progression of chronic renal disease 2.Urea production and excretion 3.Nutritional status 4.Inflammation 5.Dyslipidemia 6.Insulin resistance 7.Mineral and bone disease 8.Acidosis, anemia and blood pressure 9.Compliance 10.Evidence 11.Implementation 12.Future directions

Agenda

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Caveats to low protein diets

Reduction in energy intake: possible Impairment in body composition: no Bone disease: improvement Unconvinced patients ? Unconvinced nephrologists…and authors !

NephSAP September 2011

Livre Blanc de la Néphrologie, 1996, 400 nephrologists «Would you recommend a protein intake of 0.7-0.8 g/kg/day?» Yes: 15 % early + diet + urin Urea/24 h 15 % early (no diet, no Fup) 37 % above Screat of 250 µmol/l (GFR of 20 ml/min) w/o Fup No: 7 %

• nly in pre-ESRD (st V)

23 % I do not want to bother the patient

From Research to Patient...

67% did not comply with evidence 67% did not comply with evidence The Urgent Need for Renal Dietitians

UK National Workforce Planning 2002 1 full time dietician for 180 stage IV - V ND patients for France

38 000 ESRD 100 000 st IV-V patients We need at least 600 renal dieticians and we have

• nly … 50

Summary

Everything is here !

Bellizzi et al, Kidney Int 2007

Conclusion

• Strong Evidence of Effectiveness in reducing « Renal Death »
• Still uncertainty in effect on protection of renal function

(although many experimental data in favor)

• On patient’s view what is important is NOT starting dialysis
• On health care costs ALSO
• Additive to well accepted renal preservation strategies
• Adaptive response (at least as good if not better) after starting

EER

• Inclusion of nutritional care in a more general CKD patient

follow-up

21/02/2012 10 Backlog

Facteurs de variabilité de la phosphorémie

Block et al. J Am Soc Nephrol 2004

Serum phosphate and albumin

Observatoire 2008

WCN, Milan, 2009

Serum phosphate, albumin and survival

Serum phosphate control over time

• !"# $"

%& !"# $" ' !"# $"

A success story !

Pelletier et al, Nephrol Dial Transplant 2011