Nuevos aspectos en el complejo inflamación-nutrición en el

paciente en diálisis

Juan Jesús Carrero Associate Professor, Div Renal Medicine, CLINTEC,

Karolinska Institutet , Stockholm, Sweden

Protein–energy wasting (PEW) Decreased body stores of protein and energy fuels (that is, body protein and fat masses)

Undernutrition Inadequate diet,

anorexia

Wasting/catabolism Inflammation:

cytokines and

adipokines

Metabolic acidosis,

reduced anabolic

drive, insulin

resistance, dialysis,

sedentary lifestyle

MIA syndrome, now known as...

PEW associates with Mortality

Albumin

NDT. 20, 1880–88 (2005). Prealbumin

AJCN 2008;88:1485-94

Protein intake

Muscle strength

Am J Clin Nutr 2009;89:787-793

SGA Vitamin D deficiency

AJCN. 2008 Jun;87(6):1631-8. AJCN. 2008 Jun;87(6):1860-6.

Amino acid deficiency

“A CONTINUOUS SUPPLY OF

NUTRIENTS IS NECESSARY FOR AN INDIVIDUAL TO LIVE”.

Do we prioritize nutritional management enough?

Am J Kidney Dis. 2012 Oct;60(4):591-600.

After propensity score matching, hypoalbuminemic patients receiving ONS had a

34% reduction in 1-year mortality risk than those who

did not receive the ONS

Clin J Am Soc Nephrol. 2013 Jan;8(1):100-7

470 HD patients with indication to ONS (2 consecutive monthly albumin values below 3.8

g/dl) but that were prescribed or not with the supplement

ONS

1. Amino acids are necessary for muscle synthesis 2. Glucose is needed for brain functioning 3. Vitamins and micronutrients are cofactors in all enzymatic

reactions, providing antioxidant and anti-inflammatory defenses

4. Fatty acids are the substrate for inflammatory mediators.

Not surprising that PEW leads to inflammation, oxidative stress, proteolysis, increased susceptibility to infections, poor wound healing....

We are what we eat. Nutrients are the substrates for energy, tissue synthesis and metabolism

In CKD we have insufficient intake, excess catabolism of inner reserves and losses into dialysate

1. We must ensure not only sufficient protein/calorie intake, but also good dietary quality

2. What BMI hides: understanding obesity and temporal trends

Presentation outline

Eating enough and eating well

Food is not only protein and calories

• Dietary fat (>30% of diet) • Essential amino acids • Vitamins A, C, D, E, K • Glucose • Iron • Selenium....

1

Cross-sectional study using the ‘‘Block Dialysis 1 Food Frequency Questionnaire’’ in 70 patients undergoing MHD in US

J Ren Nutr. 2011 Nov;21(6):438-47.

The majority of patients consumed too much fat in

their diets, particularly saturated fat.

Bossola et al. J Nephrol. 2012 Oct 8:0. [Epub ahead of print]

128 HD patients from Rome, 3-day dietary records

General considerations on dietary fat

Double bonds break the dimension and increase the

3D volume of the FA

Biological functions of FA

1. Source of energy: ATP synthesis

2. Structural component of membranes

3. Second messengers required for the translation of external cellular signals

4. Precursors of eicosanoids that initiate the inflammatory cascade

5. Several other unique biological roles as anti-oxidants, anti-inflammatory

agents, development of insulin sensitivity (diabetes), blood pressure,

endothelial function, coagulation, etc.

The Lipid Library. American Oil Chemists' Society. Retrieved 2012-04-15.

There are many good things we can expect from a healthy dietary fat intake

Dietary recalls: subjected to under/over reporting

Estimating dietary fat

FA biomarkers in plasma lipids or tissues. • An objective way to measure fat quality in epidemiological studies • Laborious and expensive for clinical use.

In plasma cholesterol esters

In adipose tissue

Adj for BMI, smoking, alcohol intake, physical activity, CVD, DM, hypertension, hyperlipidemia, GFR, UAe

In CKD patients, essential PUFAs in plasma and tissue validly reflect dietary intake as assessed by 7-day food records

Huang et al. Nephrol Dial Transplant. 2012 Dec 9. [Epub ahead of print]

Omega-3 fatty acids

Study Patients* Duration Intervention Outcome Diskin et al. [1990] n=3, HD 6 months Capsules, 3 g EPA/HD

session (3 times per week) No effect

Donnelly et al. [1992] n=18 (8 HD, 8 PD)

2x4 weeks (crossover)

Capsules, 3.6 g/d n-3 PUFA No effect

Ando et al. [1999] n=19 (11 HD, 8 PD)

3 months Capsules, 1.8 g/d EPA ↓ oxLDL

↓ cholesterol ↓ TG

Khajehdehi [2000] n=15, HD 2 months Capsules, 1.5 g/d n-3 PUFA ↑ HDL Schmitz et al. [2000] n=12, HD 12 months Capsules, 4 g/d n-3 PUFA ↓ TG Svensson et al. [2006] n=28, CKD with

creatinine 150 -400 µmol/L

8 weeks Capsules, 2.4 g/d n-3 PUFA ↓ TG ↑ HDL

Saifullah et al. [2007] n=9, HD 3 months Capsules, 1.3 g/d n-3 PUFA ↓ TG (P=0.08) Taziki et al. [2007] n=10, HD 12 weeks Capsules, 1.2 g/d n-3 PUFA ↓ TG

↑ HDL Svensson et al. [2008] n=103, HD 3 months Capsules, 1.7 g/d n-3 PUFA ↓ TG Bowden et al. [2009] n=18, HD 6 months Soft-gel pills, 0.96 g/d

EPA+0.6 g/d DHA No effects

Bowden et al. [2009] n=44, HD 6 months Capsules, 0.96 g/d EPA +0.6 g/d DHA

↑ HDL

↓ LDL particle nr

Beavers et al. [2009] n=18, HD 6 months Capsules, 0.96 g/d EPA +0.6 g/d DHA

No effect

Poulia et al. [2011] n=25, HD 2x4 weeks (crossover)

Capsules, 0.92 g/d EPA and 0.76 g/d DHA

No effects

Kooshki et al. [2011] n=17, HD 10 weeks Capsules, 2 g/d n-3 PUFA ↓ TG

RCTs using n-3 PUFA on lipids in CKD

Huang et al. J Nephrol (In Press, 2013)

Study Patients* Duration Intervention Outcome Peck et al. [1996] n=8, HD 8 weeks Capsules, 6 g/d fish oil ↑ PGE2 (0.10 > P >

0.05) Lossl et al. [1999] n=8, HD 12 weeks Capsules, 5.2 g/d n-3 PUFA ↓ LTB4

↑ LTB5 Begum et al. [2004] n=12, HD 16 weeks Capsules, 4.4 g/d n-3 PUFA ↓ LTB4 Saifullah et al. [2007] n=15, HD 3 months Capsules, 1.3 g/d n-3 PUFA ↓ CRP Madsen et al. [2007] n=22, CKD 3-4 8 weeks Capsules, 2.4 g/d n-3 PUFA ↓ CRP (P=0.06) Moreira et al. [2007] n=31, HD with

CRP < 50 mg/L 8 weeks A canned sardine

sandwich/HD session (3 times per week)

↓ CRP only in sensitivity analyses

Himmelfarb et al. [2007] n=31, HD 8 weeks Capsules, 0.8 g/d DHA ↓ IL-6, WBC,

neutrophil fraction of WBC

Ewers et al. [2009] n=40, HD 2x6 weeks (crossover)

Capsules, 3 g/d n-3 PUFA ↓ CRP

Bowden et al. [2009] n=18, HD 6 months Soft-gel pills, 0.96 g/d EPA and 0.6 g/d DHA

↓ CRP

Daud et al. [2006] n=32, HD with

albumin < 39 g/L 6 months Capsules, 1.8 g EPA and 0.6 g

DHA/HD session (3 times per week)

No effect on CRP

Huang et al. J Nephrol (In Press, 2013)

RCTs using n-3 PUFA on inflammation in CKD

Lock et al. JAMA. 2012 May 2;307(17):1809-16

Las protesis vasculares son una opcion importante en el acceso vascular del paciente en HD, pero pueden producir estenosis recurrente y trombosis. Un estudio piloto sugirio que la suplementacion con aceite de pescado previene estas complicaciones (JASN 2002).

201 CKD stage 5 patients randomly allocated to receive fish oil capsules (four 1-g capsules/d) or matching placebo (corn oil) on day 7 after graft creation. They were supplemented and followed for up to 12 months.

Primary outcome: the number of graft patency events after

12 months. Graft patency was defined as the graft having a primary event of thrombosis or requiring radiological or surgical intervention to maintain patency.

Reduccion de un 22% en el numero de complicaciones del acceso (p=0.06)

Lock et al. JAMA. 2012 May 2;307(17):1809-16

Secondary outcomes: the rate at which arteriovenous grafts

with loss of native patency occur (incidence rate per 1000 access dates).

Incidence rate 0.58 (0.44-0.75), P<0.001 (42% reduction)

Incidence rate 0.50 (0.35 to 0.72), P<0.001 (50% reduction)

Lock et al. JAMA. 2012 May 2;307(17):1809-16

El grupo con aceite de pescado tuvo una mayor supervivencia del acceso

(42%) y una reduccion significativa en la

incidencia de trombosis (50%)

RCT cross-over with 4g/day of fish oil in 30 new-onset diabetics with early proteinuria

Miller et al. Diabetes Care. 2013 Jan 24. [Epub ahead of print]

Implications for CKD

progression?

n-3 PUFAs in dialysis patients might have therapeutic potential in: • Reducing inflammation • Improving blood lipids • Improving graft patency Fish oil supplementation should also be advocated for cardioprotection (AHA recommendations).

Should we give n-3 PUFA to dialysis patients?

Dietary fish intake preferred over fish oil supplements: 1. AHA recommendations: Advice 2-3 fish servings per week of fatty fish. 2. But: Fish intake is in general low. Fatty fish is costly. Protein/phosphate ratio may not

be desirable in all species. 3. Farmed fish contains very low amounts of n-3 fatty acids (Clin Nutr 1993). 4. Because of all above, fish oil supplements may not be a bad idea.

What about other types of fat? Saturated fat

19,256 participants of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, an ongoing cohort study in US adults aged 45 y at time of enrollment. Dietary fat assessed by FFQ

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Q1 Q2 Q3 Q4 Q5

Energy-adjusted quintiles of SFA intake

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* * * * Individuals consuming higher amounts of saturated fat were 20-

30% more likely to have albuminuria or CKD

Am J Clin Nutr. 2010 Oct;92(4):897-904.

J Intern Med. 2012 Aug 17. [Epub ahead of print]

Serum SFA

Dietary SFA De novo SFA

Serum MUFA

SCD-1

SCD-1 preserves membrane fluidity by preventing excessive accumulation of SFA in plasma. The main driver of SCD-1 activity is excess dietary SFA Increase SCD-1 activity associates in humans with metabolic syndrome, IR, inflammation, oxidative stress, atherosclerosis, cardiovascular events... Curr Opin Clin Nutr Metab Care.

2010 Nov;13(6):703-8.

Inflammation (IL-6) and hypertriglyceridemia were the

main determinants of increased SCD-1 activity (excess dietary SFA)

J Intern Med. 2012 Aug 17. [Epub ahead of print]

222 dialysis patients with similar vintage; Median follow-up: 18.4 months [30% deaths and 50% kidney transplants]

N-6 PUFAs?

Nat Rev Nephrol. 2011 Feb;7(2):110-21.

Are we mixing pears with apples?

A high ratio n-6/n-3 has been hypothesized to be proinflammatory and thus detrimental

The n-6 family contains fatty acids with purported deleterious properties (AA) and FA with likely beneficial effects on the organism (LA). The omega-6/omega-3 ratio is not useful nor relevant in humans, and is not supported by randomized controlled trials (Griffin et al 2006, Giacco et al 2007)

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Below median proportion of LA

Above median proportion of LA

Warensjö et al. Am J Clin Nutr 2008.

n=2009 middle aged men

HR: 0.85 (0.78-0.94)

Linoleic acid is the main n-6 PUFA in the western diet, present in vegetable oils and margarines

Essential fatty acid

Adults at CVD risk should increase their ingestion of Linoleic Acid rich foods, in conjunction with increased n-3 PUFA intake, in order to achieve

optimal CVD outcomes.

Nephrol Dial Transplant. 2012 Sep;27(9):3615-20.

Prediction of Mortality Linoleic acid, per % increase in plasma: fully adj HR 0.89 (0.79-0.98)

67 abdominally obese subjects randomized to a 10-wk isocaloric diet high in vegetable n-6 PUFA (PUFA diet) or SFA mainly from butter (SFA diet), without altering the macronutrient intake.

Am J Clin Nutr. 2012 May;95(5):1003-12.

The n-6 PUFA diet increased total dietary fat, but with linoleic acid

The n-6 PUFA diet reduced liver fat content

The n-6 PUFA diet improved lipid profile.

The SFA diet raised insulin.

3 inflammatory markers (IL10, TNF and IL6) were also lower after the n-6 PUFA diet

Increased consumption of oily fish in the context of plant-based diets with low content of SFA is likely to benefit patients who have CKD, or are at risk of developing CKD. Such recommendations are in line with the “Mediterranean diet” concept and are in line with current dietary recommendations for CVD prevention.

ONGOING CONCLUSIONS

1. We must ensure not only sufficient calorie intake, but also good dietary quality

2. What BMI hides: understanding obesity and temporal trends

Presentation outline

2 Fine Tuned Weight Control in Health

WHAT IS OBESITY?

• A medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health and/or reduce life expectancy.

• WHO considers excess body fat as body fat per cent exceeding 25% in men and 35% in women.

• This generally translates in the general population as BMI>30 kg/m2.

Forecasted prevalence of total obesity and obesity stage ≥2 among incident dialysis patients by year of dialysis initiation.

Kramer H J et al. JASN 2006;17:1453-1459

Obesity is a US problem...

BMI is not a good marker of obesity in CKD due to: overhydration and the inability to separate muscle from fat mass

Ability of BMI to estimate obesity in CKD (comparison with gold standard air displacement plethysmography)

75%

BMI correctly classified adiposity in 75% of the cases. 25% were misclassified as non-obese

25%

Which patients are these?

Subclinical versus overt obesity; more than meets the eye

Gracia-Iguacel et al. Nephrol Dial Transplant, In Press 2013

56% 55%

9% 10 %

35% 35%

284 incident dialysis 209 prevalent hemodialysis

Overtly obese: BMI>30 and excess body fat (by skinfolds) Subclinically obese: Excess body fat but BMI<30 Non-obese

Subclinically

obese

Overtly obese

Malnutrition (SGA), n (%) 47 (30%) 4 (16%)

Handgrip strength, % 69±22 74±24*

Arm muscle area, cm2 29 (26-33) 33 (30-39)**

DEXA-lean body mass, kg 48.7±9.5 53.6±12.6 (P=0.06)

Subclinically

obese

Overtly obese

Malnutrition (SGA), n (%) 47 (41%) 8 (36%)

Handgrip strength, % 60±22 72±26*

Arm muscle area, cm2 24 (17-28) 28 (34-33) **

IGF-1, ng/mL 180±101 237±122*

284 incident dialysis

209 prevalent hemodialysis

Gracia-Iguacel et al. Nephrol Dial Transplant, In Press 2013

Subclinically obese patients tended to be more often malnourished and had both lower muscle mass and strength

In patients with mildly elevated BMI, complementary body composition techniques might be necessary to accurately diagnose obesity.

“Reverse Epidemiology” of obesity

Kalantar-Zadeh et al, Kidney International, 2003

BMI Associated Death Risk:

General Population versus Hemodialysis Patients

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General Population

Hemodialysis **

<20

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>30

23-25

Patients die of the short-term consequences of PEW and do not live long enough to die of obesity.

Changes in dry weight

6-months change in dry weight as a predictor of mortality in 57,247 patients receiving hemodialysis

Patients need to increase their body weight

Should we promote weight gain? Make the obese fatter? What about complications of obesity and access to Tx list?

The implications of weight gain or loss may be different for underweight than for obese individuals

One size fits all?

Malnutrition vs ageing...

Low muscle mass Low muscle strength ≠ Maybe difficult to target Amenable to training?

CONCLUSIONS

FIRST PART: WE ARE WHAT WE EAT

1. Individual nutrients and healthy dietary patterns can improve risk profile and patient outcomes.

2. Modifying dietary fat intake may improve patient risk profile: reduce saturated fat intake and increase both n-3 PUFA and n-6 PUFA of vegetable origin (linoleic acid).

SECOND PART: WHAT OBESITY HIDES

1. BMI is an imperfect metric of body fat. There is more fat (and less muscle) in dialysis patients than meets the eye.

2. Unintentional weight losses are a clear sign of health deterioration and a wake up call for nutritional management.

3. It is not muscle mass per se that is important but rather “functional” muscle mass.

Juan.jesus.carrero@ki.se