ASPECTOS NUTRICIONAIS NO

TRATAMENTO CONSERVADOR E NA
DIÁLISE

Prof. Dra Cristiane Moraes

Cristiane Moraes, Nutricionista

 Pós Doutorado em Ciências Cardiovasculares com Ênfase em
Nefrologia-UFF
 Doutorado em Ciências Cardiovasculares com Ênfase em
Nefrologia-UFF
 Mestrado em Saúde Coletiva-UFF
 Pós Graduada em Nutrição Esportiva- UNIRP/SP
 Pós Graduada em Fisiologia do Exercício - UGF
 Clinical Economics – Universität Ulm– Alemanha
 Coordenadora do Comitê de Nutrição da Sociedade Brasileira de
Nefrologia (SBN) Gestão 2021-2022
 Voluntária Fundação Abrinq
 Consultora da Operadora de Saúde Careplus- a part of Bupa

Em 2017, a prevalência global de DRC foi de 9,1% (697,5

milhões casos).

Em 2017, DRC resultou em 1,2 milhões de mortes e foi o

12ª maior causa de morte em todo o mundo.

Além disso, 7,6% de todas as mortes por DCV (1,4

milhões) podem ser atribuídas à função renal
prejudicada. Juntas, as mortes devido a DRC ou a DCV
atribuível a DRC foram responsáveis por 4,6% da
mortalidade por todas as causas.

A mortalidade global por DRC aumentou em 41,5% entre

1990 e 2017.
Carney, E.F. Nat Rev Nephrol 16, 251 (2020).

1
 Doenças
Principal causa
Pacientes DRC de morte
complicações

Inflamação, estresse oxidativo e disbiose intestinal

DCV

Di Angelantonio et al. Medicine, 2007 ; Perkovic et al. PLoS Medicine, 2008

Kidney International (2008) 73, 391–398.

LOW GRADE INFLAMMATION

Acúmulo de Disbiose e
citocinas alterações da
inflamatórias; barreira Intestinal.

Obesidade
(paradox da Estresse oxidativo;
obesidade?);

Infecções
Inflamação
sistêmicas
periodontal;
recorrentes;

Akchurin & Kaskel, Blood Purif. 2015.

2
 INFLAMAÇÃO

Active Inactive

Nrf2 Keap1 Nrf2

Keap1

Cheung et al., Pediatr Nephrol 2010; Mak et al., J Cachexia Sarcopenia Muscle 2011.
Pedruzzi et al. J Nephrol. 2015.

VIA NRF2- KEAP1

NO
ē

EROs
LDLo
x -glutamylcysteine synthetase

Nucleous quinone oxidoreductase 1

Keap1 (NQO1)
Cul3
Nrf2 Heme oxygenase-1
(HO-1)
Mafs
ERA Glutationa peroxidase
Cytoplasm 

EROs 
NFB

Pedruzzi et al. Biochemie. 2012.

NFkB P65

NRF2

3
UMA GRANDE
BATALHA CONTRA A
INFLAMAÇÃO

ATUALIZAÇÃO DAS DIRETRIZES NUTRICIONAS

Já se passaram 20 anos desde que a National Kidney

Foundation (NKF) publicou a primeira diretriz nutricional
da Kidney Disease Outcomes Quality Initiative (KDOQI)
para pacientes com doença renal em estágio terminal.

O tratamento de doença renal crônica (DRC) mudou

dramaticamente desde a publicação da diretriz
nutricional original. Esta atualização das diretrizes reflete
as muitas mudanças tanto no desenvolvimento das
diretrizes quanto no manejo dos aspectos nutricionais da
DRC durante esse período.

4
 AS DIRETRIZES ATUALIZADAS SE CONCENTRAM EM

Avaliação nutricional

Terapia nutricional

Ingestão proteica / energética

Suplementação

Micronutrientes e Eletrólitos

O ênfase principal na diretriz atualizada é fornecer informações

sobre gestão dietética, em vez de cobrir todas as estratégias
de intervenção nutricional possíveis.

Avaliação nutricional

• Triagem nutricional: pelo menos semestralmente com o intuito de identificar

aqueles em risco de perda de energia proteica;

• Não se sugere o uso de uma ferramenta em detrimento de outras para

identificar aqueles em risco de wasting (PEW);

• O nutricionista deve conduzir avaliação nutricional abrangente (incluindo, mas

não se limitando ao apetite, história de ingestão alimentar, peso corporal e
índice de massa corporal, dados bioquímicos, medidas antropométricas e com
foco na nutrição achados físicos) ;

• Em diálise: pelo menos nos primeiros 90 dias após o início da diálise,

anualmente, ou quando indicado por triagem nutricional ou referência do
provedor.

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

Avaliação nutricional

COMO AVALIAR A EVOLUÇÃO DO PACIENTE?

• BIA (HD);
• Dobras Cutâneas;
• IMC : cautela;
• Creatinina urinária;
• Peso corporal (histórico, evolução);
• Albumina, pre-albumina, nPCR (PNA);
• Handgrip;
• ASG -7 pontos;
• MIS score (HD);
• MST (HD);

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

5
 Avaliação nutricional

Ferramentas e medidas antropométricas

para avaliar a composição corporal
Bioimpedancia elétrica

• Estágio 5D – HD: uso de bioimpedância e de preferência a multifrequencial

(MF-BIA) para avaliar a composição corporal, quando disponível (no mínimo
30 minutos ou mais após o final da sessão de hemodiálise);

• Adultos com DRC 1-5 ou 5D- DP: sem evidências suficientes para sugerir o uso
de impedância bioelétrica para avaliar composição corporal; DEXA, quando
possível: padrão ouro;

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

EWGSOP2, 2019

Massa muscular e qualidade muscular: ultrassom

 uso recente , mas promissor;

 quadríceps: avaliar espessura muscular ao longo das avaliações;

6
 MIOESTEATOSE

Quadriceps Direito Mulher 37 anos ativa Quadriceps Direito Mulher 36 anos sedentária

Avaliação nutricional

Ferramentas e medidas antropométricas

para avaliar a composição corporal

• IMC e PEW (DRC 1-5D) : IMC x PEW (diagnóstico de PEW IMC<18 kg/m2)
• Dobras Cutâneas: na ausência de edema
• Handgrip (DRC 1-5D) : indicador de PEW

• Marcadores bioquímicos de estado nutricional: albumina, pré albumina, taxa

catabólica de proteína (nPCR). Albumina como marcador de hospitalização e
mortalidade em HD.

• Para Avaliar Estado nutricional HD: MIS (malnutrition Inflammation Score)

• Para avaliar Estado Nutricional em DRC 5D: SGA (Avaliação Subjetiva Global)

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

7
 8
Kalantar-Zadeh K, et al. Am J Kidney Dis. 2001. Steiber AL, et al. J Ren Nutr. 2004.

Ikizler et al., Kidney Int 2013.

Avaliação nutricional
 Avaliação nutricional

SARCOPENIA COEXISTE COM O TECIDO ADIPOSO

Nutr Metab Cardiovasc Dis 18, 388–395

Avaliação nutricional

Fatores que levam a inatividade

física na DRC

Exercício
Físico Anormalidades
Inflamação, Inapetência,
funcionais e
x estruturais do estresse Anemia anorexia,
Estilo de oxidativo; PEW.
músculo;
Vida Ativo

Avaliação nutricional

RENAL SARCOPENIA

Front Physiol. 2018 Nov 26;9:1648.

9
 Avaliação nutricional

Ferramentas de ingestão alimentar

• DRC 3-5D : avaliar fatores além da ingestão alimentar (por exemplo,

medicações, conhecimento da dieta, crenças, atitudes, comportamento,
acesso a alimentos, depressão, função cognitiva);

• DRC 3-5D: uso de registro alimentar de 3 dias. Em HD/DP  realizado

durante a diálise e não diálise como um método preferido para avaliar a
ingestão alimentar (2C);

• DRC 3-5 (OPINIÃO) ou DRC 5D (2D), recordatório de 24 horas, questionários

de frequência alimentar e nPCR podem ser considerados como métodos
alternativos de avaliação da ingestão de energia e proteína na dieta (2D).

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

TERAPIA NUTRICIONAL

Ingestão de Proteína

Conservador
1) Metabolicamente estáveis: 0,55-0,6g/kg/dia OU 0,28-0,43g/kg/dia com análogos
de cetoácido/aminoácido adicionais para atender necessidades de proteína
(0,55-0,6g/kg/dia)

1) Diabeticos: 0,6-0,8g/kg/dia;

Hemodiálise e Diálise Peritoneal

1) Metabolicamente estáveis: 1 – 1,2g/kg/dia

2) Pacientes DM, em risco nutricional: considerar incremento

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

TERAPIA NUTRICIONAL

ESTÁGIO RECOMENDAÇÃO

Estágio 3-5 0,55 – 0,6g/kg/dia

Estágio 3-5 DM 0,6 – 0,8 g/kg/dia

INGESTÃO Estágio 3-5 (VLP) 0,28 – 0,43g/kg/dia +

PROTEICA E cetoanálagos

CALÓRICA HD ou PD 1,0 – 1,2g /kg/dia

HD ou PD *risco Ajustar
hiperglicêmico

Kcal 25-35kcal/kg/dia

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

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TERAPIA NUTRICIONAL

TERAPIA NUTRICIONAL

Anjos et al, JREN, 2018.

TERAPIA NUTRICIONAL

Nrf2/NF-kB ratio

Black et al, JREN, 2018; Anjos et al, JREN, 2020.

11
 TERAPIA NUTRICIONAL

Muscle protein turnover and low-protein diets in patients with

chronic kidney disease
ADAPTAÇÃO!!!
Nephrol Dial Transplant (2020) 35: 741–751.

TERAPIA NUTRICIONAL

Muscle protein turnover and low-protein diets in patients with

chronic kidney disease

 POR QUE ESSA DEGRADAÇÃO PROTEICA SE ADAPTA? Estudos em

animais: aumento da sensibilidade à insulina com aumento do
receptor de insulina e fosforilação da Akt;
 Catabolismo: acidose metabólica e inflamação são grandes
problemas;
 Pacientes Idosos (0,8kg?): depende do condição clínica do paciente.

Nephrol Dial Transplant (2020) 35: 741–751.

TERAPIA NUTRICIONAL

CATABOLISMO RELACIONADO A HEMODIÁLISE COMO

SOLUCIONAR?

J Ren Nutr. 2020;30(1):61-68.

12
 TERAPIA NUTRICIONAL

 alto teor de P em proteínas de origem

animal  alto teor de fósforo anula qualquer
efeito protetor da proteína e resulta em
O PARADOXO: aumento do risco de mortalidade

PROTEÍNA X
PEW X  controle da proteína para reduzir o fósforo
FÓSFORO sérico  resultados que mostram que a
hipoalbuminemia anula os benefícios do
controle do fósforo sérico.

Kidney Int Suppl (2011). 2013 Dec;3(5):462–8/ Am J Clin . Nutr. 2008 Dec;88(6):1511–8. Lancet. 2013 Oct;382(9900):1268–77.

TERAPIA NUTRICIONAL

Ingestão de Proteína
Tipo de proteína: DRC 1-5D (1B) : não há evidências suficientes para
recomendar um determinado tipo de proteína (planta vs animal) em termos de
efeitos no estado nutricional, níveis de cálcio ou fósforo ou no sangue perfil
lipídico.

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

J Ren Nutr. 2015 Nov;25(6):459-65

13
 TERAPIA NUTRICIONAL

Nutrients. 2020 Jun 29;12(7):1931.

Nutrients. 2020 Apr 6;12(4):1007.

Kidney Med. 2020 Jun 15;2(4):476-487.

TERAPIA NUTRICIONAL

PLANT-DOMINANT LOW-PROTEIN DIET FOR CONSERVATIVE

MANAGEMENT OF CHRONIC KIDNEY DISEASE

Nutrients. 2020 Jun 29;12(7):1931.

TERAPIA NUTRICIONAL

PLANT-DOMINANT LOW-PROTEIN DIET FOR CONSERVATIVE

MANAGEMENT OF CHRONIC KIDNEY DISEASE

Nutrients. 2020 Jun 29;12(7):1931.

14
 TERAPIA NUTRICIONAL

Comparison of a vegetable-based (soya) and an animal-based low-

protein diet in predialysis chronic renal failure patients

Nephron. 1998;79(2):173-180.

TERAPIA NUTRICIONAL

Atenção na prescrição de um modelo PLADO

ADEQUAR CONFORME RISCO DE PEW, POTÁSSIO

EVLUIR CONFORME ESTADO NUTRICIONAL E ADESÃO DO PACIENTE

MONITORAMENTO , ACONSELHAMENTO

URINA DE 24H: INGESTÃO DE PROTEÍNA, SÓDIO E POTÁSSIO

INGESTÃO CALÓRICA E SUPLEMENTAÇÃO

GORDURAS: W3, W9

FONTES E QUALIDADE DOS CARBOIDRATOS

ESTRUTURAR CONFORME PRESCRIÇÃO DE EXERCÍCIOS

Nutrients. 2020 Jun 29;12(7):1931.

TERAPIA NUTRICIONAL

 COMO FICA A ANEMIA?

 INFLAMAÇÃO x HEPCIDINA NA DRC

15
 Exp Gerontol. 2020 Oct 1;139:111017.
INFLAMATÓRIO: Il-6 e TNF-a

√
ANTIINFLAMATÓRIA, IL-10

FERRO x HEPCIDINA

TERAPIA NUTRICIONAL

Ingestão Energética
 DRC 1-5D metabolicamente estáveis: 25-35 kcal / kg de peso corporal por dia com
base na idade, sexo, nível de atividade física, composição corporal, metas de
status de peso, estágio de DRC e doença concomitante ou presença de
inflamação para manter o estado nutricional normal.

 Pacientes desnutridos/ em reabilitação: rever ingestão energética/ densidade

calórica das refeições/alimentos

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

TERAPIA NUTRICIONAL

Padrões de dieta

 Dieta mediterrânea para pacientes em

conservador;

 Frutas, verduras e legumes para estágios

1-4 para melhora da acidose metabólica.

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

16
  reduction in creatinine (−5.3%; P < .001)
 urea nitrogen levels (-9%; P = .001),
 blood urea nitrogen (BUN) (-8.7%; P = .001)
 BUN/creatinine ratio (-5.8%; P < .001)
 increase eGFR (+3.5%; P = .001)

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

TERAPIA NUTRICIONAL

Suplementação
 Suplementação Oral: quando não atingir necessidades , em risco de desnutrição ou
desnutridos (3 meses- acompanhamento rigoroso);

 Suplementação enteral: quando VO não atinge recomendações/ alto risco

 Suplementação de ômega 3

• Mortalidade e doença cardiovascular (HD-PD): não recomendado

• Melhora do Perfil Lipídico
HD-PD: 1,3-4g/dia
DRC 3-5: 2g/dia

Vitamina A e E: toxicidade (se necessário: monitoramento e cautela)

Vitamina K x pacientes em uso de anticoagulantes

TERAPIA NUTRICIONAL

Suplementação
Suplementação Ácido fólico

• DRC 3-5D: hiperhomocisteinemia associada a DRC, contraindicada

• DRC 3-5D: deficiência de ácido fólico, indicada

Vitamina C

• DRC 1-5D: em risco de deficiência, considerar suplementação para atingir

90mg/d (homens) 75mg/dia (mulheres)

Vitamina D
• DRC 1-5D: prescrever na forma de colecalciferol OU erfocalciferol para
corrigir deficiência
• DRC 1-5 com proteinúria :considerar a suplementação de colecalciferol,
ergocalciferol, ou outros precursores de 25 (OH) D seguros e eficazes

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

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 KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020
TERAPIA NUTRICIONAL

ELETRÓLITOS

1) Carga ácida: Aumento de frutas , verduras e legumes

2) Bicarbonato, DRC 3-5D: prescrição de bicarbonato para manter níveis de

24-26mmol/L

3) Calcio:
DRC 3-4 : 800-1000mg/dia;
DRC 5D: ajustar ingestão de cálcio (monitorar hipercalcemia)

Figure 1

Kidney International 2012 81, 7-9DOI: (10.1038/ki.2011.331)

KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020

TERAPIA NUTRICIONAL

ELETRÓLITOS

Fósforo

• DRC 3-5D: quantidade da ingestão controlada com

exames bioquímicos
• DRC 1-5D: importante controlar as fontes (animal x
vegetal e, ultraprocessados!!!!!)

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 KDOQI. AJKD Vol 76 | Iss 3 | Suppl 1 | September 2020
TERAPIA NUTRICIONAL

ELETRÓLITOS

Potássio – INDIVIDUALIZAR!

DRC 3-5D: sempre considerar exames bioquímicos ,

individualizar

Sódio (pressão arterial, proteinuria)

DRC 3-5: < 2,3g/dia
DRC 3-5D: controle + estilo de vida

TERAPIA NUTRICIONAL

HIGHLIGHTS SUPLEMENTOS

 Suplemento oral para pacientes em risco de PEW (3

meses);
 Vitamina C para pacientes em risco (idosos, ie.);
 Ácido Fólico: depende (Hiperhomocisteinemia OU
deficiência de ácido fólico);
 Vitamina D deficiente ou insuficiente: colecalciferol ou
ergocalciferol;
 Proteinuria : suplementação de Vitamina D;
 Vitamina A e E: toxicidade (conservador);
 Vitamina K: anticoagulantes (varfarina, ie.);

Am J Kidney Dis. 2020;76(3S1):S1-S107.

Am J Kidney Dis. 2020;76(3S1):S1-S107.

TERAPIA NUTRICIONAL

Não Esquecer...
 Manejo da carga ácida estágio 1-4 (NEAP): legumes e frutas;
 Manejo de Bicarbonato estágio 3-5D: suplementação com
bicarbonato;
 Fósforo: considerar a fonte de fósforo;
 Potássio: individualizar!;
 MEV!

19
 Table 1. Summary of studies related to zinc status in CKD patients

References Sample/study Results

Damianaki et al. [9]
Pan et al. [10]
Lin et al. [11]
Tonelli et al. [12]
Sada et al. [13]
Aziz et al. [14]
108 non-dialysis CKD patients
42 healthy individuals
39 patients with arterial hypertension
2853 NHANESparticipants
204 non-dialysis CKD patients
148 CKD diabetic patients
198 HD patients
18 HD patients
49 non-dialysis CKD patients
# Zinc plasma levels in CKD (60.66 10.6 l g/dL versus 66.66 10.1 l g/dL)
" Urinary zinc excretion according to CKD stage
# Zinc plasma in CKD (76.866 1.29 l g/dL versus 82.786 0.67 l g/dL)
# Zinc plasma levels upon CKD progression
No evidence of zinc deficiency
# Zinc plasma levels [52 (34–68)] l g/dL
No difference between groups (836 10 l g/dL in CKD and 1126 19 l g/dL in healthy

Downloaded from https://academic.oup.com/ndt/advance-article-abstract/doi/10.1093/ndt/gfaa045/5838318 by guest on 26 May 2020

Panorchan and
Davenport [15]
Hasanato [16]
Lobo et al. [17]
Yang et al. [18]
Shih et al. [19]
Ari et al. [20]
Guo et al. [21]
Dashti-Khavidaki
et al. [22]
Kiziltaset al. [23]
Batista et al. [7]
Mafra et al. [8]
PD, peritoneal dialysis.
42 healthy individuals
152 PD patients
42 HD patients
18 healthy individuals
45 HD patients
20 healthy individuals
111 HD patients
145 non-dialysis CKD patients
50 HD patients
48 healthy individuals
20 HD patients
20 patients
20 healthy individuals
94 HD patients
47 healthy individuals
30 HD patients
30 healthy individuals
63 HD patients
20 healthy individuals
29 non-dialysis CKD patients
19 healthy individuals
individuals)
11.016 2.83 l mol/L (normal range 11–24 l mol/L) with 57.2%of patients presenting
with zinc deficiency
# Zinc plasma levels (9.50 nmol/L versus 13.20 nmol/L)
# Zinc plasma levels (54.96 16.1l g/dL versus 78.86 9.4l g/dL) in 83.3%patients
79.266 33.16mg/dL (normal values: 61 and 130 mg/dL)
# Zinc plasma levels according to stages (Stage 1: 886 13; Stage 2: 836 17; Stage 3:
766 16; Stage 4: 696 13l g/dL)
# Zinc plasma levels (0.536 0.30l g/dL versus 1.476 0.32l g/dL)
PD: 0.686 0.03l g/dL
HD: 0.366 0.04l g/dL
Healthy individuals: 0.766 0.08l g/dL
# Zinc serum levels (69.166 17.29l g/dL versus 82.936 14.75l g/dL)
# Zinc serum levels (15.156 1.83l mol/L versus 23.306 1.89l mol/L)
# Zinc plasma and " zinc erythrocyte levels in CKD compared with control group
# Zinc plasma levels (746 17.7l g/dL versus 82.16 15.5l g/dL) and " zinc in eryth-
rocytes (50.06 7.2l g/gHb versus 39.96 7.26l g/gHb)

Como esperado, os níveis plasmáticos de zinco foram

mais baixos nos pacientes com DRC. A percepção do
paladar amargo foi menor no grupo com DRC.

A sensibilidade ao gosto azedo, salgado e amargo foi

Fi gur e 1: Causes and consequences of zinc deficiency in CKD patients.
significativamente menor nos participantes com níveis
plasmáticos mais baixos de zinco.
Cardozo et al, NDT, 2020.
Tavares et al, JREN, 2020.
2 L.F.M.F. Cardozo and D. Mafra

REVIEWS

Senotherapeutics
Agents that target senescent
cells, such as geroprotectors
(which prevent or reverse the
senescent state), senescence-
associated secretory
phenotype inhibitors,
senolytics (which induce the
death of senescent cells),
senomorphics (which suppress
senescent phenotypes without
killing cells) and gene therapy
strategies (which increase
resistance to ageing).
At acellular level, senescenceischaracterized by afinite
replicativecapacity in primary cells144 with consequential
growth arrest and a characteristic senescence-associated
secretory phenotype (SASP)139. The SASP engenders
a toxic pro-inflammatory environment, mediates the
generation of secondary senescence in adjacent cells145
and/or promotesnon-autonomouscellular senescencein
distal tissues146. A component of the SASP, interferon-γ
(IFNγ), hasbeen identified asamarker of impaired phys-
iological function in the kidney41,142. IFNγ regulates an
expression network of genes that are involved in cellular
stress responses, including immune stress responses in
the kidney41,142.
CKD147, T2DM148 and uraemic vascular calcification149
are characterized by increased cellular senescence, pro-
viding opportunitiesfor novel treatment strategiesusing
senotherapeutics including senolytic drugs (i.e. therapeu-
tic agents that induce apoptosis of senescent cells), such
asdasatinab150. Senolytic efficacy often requiressynergis-
tic use of another agent, such asquercetin, that mitigates
collateral damage to non-senescent cells and enhances
the senescent cell specificity of the apoptotic effect141.
Quercetin and other natural senolytic compounds, such
as resveratrol, fisetin, piperlongumine, tocopherol, cur-
cumin, berberine, rutin, catechin, proanthocyanidin
and ginkgo biloba extract, can be acquired nutritionally,
emphasizing the potential of the FAM approach151,152.
Many of these compounds are alkyl catechols that are
derived from microbial processing of phenolic acidsthat
are present in fruits, vegetables, wine, tea and chocolate.
Alkyl catechols arenatural agonists of NRF2 (REF.4). They
are often missing in the Western diet, which has been
associated with poor healthspan153.
The health benefits of nutritionally derived polyphe-
nols are manifold. Resveratrol, for example, is thought to
mediate geroprotective (i.e. anti-ageing) effects through
agonism of NAD-dependent deacetylasesirtuin 1 (SIRT1),
which enhances chromatin stability and modulates cel-
lular metabolism in response to stress, thereby reducing
theoxidativeand inflammatory burden154. SIRT1 agonism
also promotesdownregulation of senescence-related pro-
teins and pro-inflammatory cytokines155. As SIRT1 has
a vital role in regulating endothelial function, arterial
remodelling and vascular ageing156, a strong rationale
exists for interventional strategies using SIRT1 agonists.
A range of studies have indicated that diets lack-
ing sufficient polyphenol intake accelerate ageing and
age-related diseases and promote inflammation157,158.
In the context of CKD, foods that are rich in polyphe-
nolsthat exert antioxidant and anti-inflammatory effects
have the potential to be used as senotherapeutics in a
nutraceutical approach to healthier ageing. Although the
use of senotherapeutic agents could potentially mitigate
someof theeffectsof CKD, evidencefrom clinical studies REV I EW S
is limited. Flavonoids seem to be important polyphenols
in thecontext of senotherapy. For example, fisetin, which
CKD

Nucleus
Inflamatorycytok
ines
andchemok ines Inflamation NF-kB
ROS Senescent cells
Cytokines
NF-kB •DNA da mage IFN
NRF2 •Telomereshortening TGF 1
•p1 6accumulation PAI1
Gut microbiota imbalance •Mitochondrialdysfunction
Antioxidant Gut microbiota balance MCP1
Uraemictoxins
m
enzymes WNT16B
•Apoptosis SA- ga l
NLRP3m resistance
•SASP Premature
Oxidative ageing
TLR4 phenotype
stress
LPS
Phenolic metabolites Non-senescent cells mTORpa thw a
y
OAT ROS
NF- B
Uraemic toxins Uraemic toxins SA- ga l
Cytokines
NRF2
Mitochondrial SCFAs HO1
H2S dysfunction SASP
FFAR Calorie intake
SIRT1
•Nutraceutical senolytics,
e such as
SCFAs quercetin, fistina
nd c urcumin

Fig. 3 | Mechanisms by which food might modulate premature ageing in CKD. Chronic kidney disease (CKD) is
Fig. 2 | The effect of food intake on the gut microbiota in CKD. A decline through an organic anion transporter (OAT) and also activate inflammatory associated with increased production of reactive oxygen species (ROS) and other factors that lead to apoptosis resistance
in kidney function can lead to gut dysbiosis with changes in gut microbial signalling. A leaky gut and uraemic toxinsalso contribute to NACHT, LRRand and the accumulation of senescent cells with a characteristic senescence-associated secretory phenotype (SASP). The
composition that in turn lead to increased microbial production of uraemic PYD domains-containing protein 3 (NLRP3) inflammasome activation. H2S SASPleads to activation of nuclear factor-κB (NF-κB) and other inflammatory mediators such as transforming growth
toxinsand reduced production of short-chain fatty acids(SCFAs). Food isthe can cause mitochondrial dysfunction and oxidative stress. On the other factor-β (TGFβ), plasminogen activator inhibitor 1 (PAI1), monocyte chemoattractant protein 1 (MCP1) and WNT16B.
Consumption of red meat, particularly when processed, is associated with increased generation of uraemic toxins and may
master modulator of gut microbial populationsand can therefore influence hand, foods that are rich in prebiotic fibres (i.e. fruits and vegetables)
contribute to senescence and premature ageing. By contrast, dietary modifications, such as reduced calorie intake and
the production and release of bacterial components and metabolites. and polyphenols (i.e. grapes, red wine, pomegranates, garlic, coffee, green the consumption of foods that contain senolytics might delay premature ageing in CKD by inhibiting the mTORpathway,
High-protein diets, especially those that are rich in processed meat, can tea, chocolate, turmeric, blueberries and cranberries) can favour generation and/or release of ROS, NF-κB, senescence-associated β-galactosidase (SA-βgal) and inflammatory cytokines
favour proteolytic bacteria and increase the generation of toxic products, SCFA-producing bacteria and beneficially modulate gut microbial and by activating nuclear factor erythroid 2-related factor 2 (NRF2), haem oxygenase 1 (HO1) and sirtuin 1 (SIRT1).
such asuraemic toxins and hydrogen sulfide (H2S). High-fat diets, saturated composition and function. Fish oil, which is a source of omega-3, and olive
fatty acids and trans fatty acids can increase intestinal permeability and oil, which providesmonounsaturated fatty acidsand polyphenols, also have is found in large amounts in strawberries (160 µg/g) and and senescence requires further study. However, the
contribute to an increase in gut-bacteria-derived lipopolysaccharide (LPS). beneficial effects on the gut microbiota and intestinal barrier. SCFAs apples (27µg/g), hasbeen identified as a potent senolytic available data suggest that adoption of a diet that is rich
In addition, a high intake of sugar, salt and artificial sweeteners can exert attenuate inflammation in a free fatty acid receptor (FFAR)-dependent agent in mice and human tissue159,160. Moreover, fisetin in potentially senolytic compounds could be a prom-
negative effects on gut microbiota profile and function, inducing dysbiosis manner, whereas low-molecular-weight phenolic metabolites can has been demonstrated to attenuate metabolic dysfunc- ising strategy for reducing premature ageing and the
and gut barrier disruption. LPS binds to Toll-like receptor 4 (TLR4) and upregulate nuclear factor erythroid 2-related factor 2 (NRF2) and attenuate tion after a high-fructose diet in mice161. Apples are also complications of senescence in CKD151 (FIG. 3).
Mafra et al, Nature Reviews Nephrology, 2020
initiates an inflammatory response, whereas uraemic toxins enter the cell oxidative stress. CKD, chronic kidney disease; NF-κB, nuclear factor-κB. rich in quercetin, which has anti-inflammatory and anti-
oxidant capacity. The clinical observation that increased Targeting mitochondrial dysfunction
intakeof apples protects against abdominal aortic calcifi- Mitochondria have many important functions includ-
cation in older women162 is consistent with experimental ing production of ATP via oxidative phosphorylation
NATURE REVIEWS | NEPHROLOGY
REV I EW S
data. Apple polyphenols are the major antioxidants in and regulation of the cellular redox state171,172. Owing
apples and have been shown to possess wide-ranging to their key role in cellular biochemistry, mitochondria
biological functions that could benefit patients with have been implicated in the pathogenesis of the chronic
CKD163. In dipterans, acutetreatment with quercetin was burden of non-communicable diseases172,173. The main
geroprotective164, and in a rat model of CKD quercetin regulator of energy metabolism and mitochondrial bio-
protected kidney function165. Curcumin, a lipophilic genesis, peroxisome proliferator-activated receptor-γ
skeletal muscle expression of mitochondrial-derived New insights intopolyphenol
the role of mitochondrial
derived from turmeric, acts asdysfunction
a NRF2 co-activator 1α (PGC1α), interacts with nuclear res-
agonist 4,166 and has been reported to reduce oxidative piratory transcription factor 1 (NRF1), NRF2 and mito-
peptides and decreased NRF2 expression in patients with in CKD suggest that mitochondria could be a therapeutic
stress via activation of haem oxygenase 1 (HO1) and to chondrial transcription factor A (TFAM), which has a
CKD suggest a link between mitochondrial dysfunction target for treatment
reducewith food
the number compounds,
of senescent such asrole
cells and inflammation fattyin mitochondrial DNA (mtDNA) replication and
in a murine model of vascular ageing167. transcription171,174,175. CKD is characterized by mitochon-
and systemic inflammation177. acids, amino acids, dietary fibre, selenium, resveratrol,
Micronutrient supplementation is another poten- drial dysfunction166,176 with downregulation of PGC1α
A bidirectional relationship exists between the gut curcumin, allicin,
tialvitamin C and
senolytic strategy. Vitaminpropolis (FIG. 4)
E supplementation . and dysregulation of mitochondrial biogenesis171.
has
been reported to reduce the numbers of senescent cells Mitochondria are extremely susceptible to oxidative
microbiota and mitochondria178,179. The gut microbiota Animal studies have demonstrated that increased
in vitro168. Zinc may also be involved in senescence as stress and mitochondrial dysfunction leads to a vicious
influences mitochondrial function through bacterial fatty acid supplyhighsaturates mitochondrial
and low zinc levels in endothelial cells haveoxidative
been cycle of overproduction of reactive oxygen species
associated with apoptosis169. As the senolytic effects of (ROS)171 and activation of theinflammasomeand nuclear
metabolites, such as H 2S, secondary bile acids, uraemic capacity, resulting in the generation of lipid peroxides
zinc seem to be cell-type dependent169, the link between factor-κB (NF-κB), which triggers further mitochon-
toxins, LPS and SCFAs, whereas mitochondria dys- that contribute micronutrient
to lipotoxic damage
bioavailability170
to mtDNA
, the uraemic and
phenotype drial dysfunction and inflammation175. Indeed, reduced
function could contribute to perturbation of the gut mitochondrial dysfunction180. Palmitic acid, the most
microbiota through impairment of redox balance178,179. common long-chain saturated fatty acid in the Western www.nature.com/ nrneph

Together, gut dysbiosis and mitochondrial dysfunction diet, has been reported to increase mitochondrial ROS
promote oxidative stress and inflammation in CKD179. production and decrease protein levels of PGC1α and
TFAM in rat skeletal muscle181. By contrast, omega-3
fatty acids upregulate PGC1α and NRF1 (REF.182) and
therefore induce or increase the mitochondrial activ-
Outer membrane ity of carnitine palmitoyl transferase 1 and fatty acid
Electron transport chain β-oxidation183. These effects contribute to decreased
mitochondrial lipid accumulation, whereas long-chain
Complex Complex Complex Complex Complex saturated fatty acids promote lipotoxicity173.
I II III IV V Dairy products may influence energy metabolism, in
PTP
Curcumin part owing to their high leucine content184. This amino
Inner membrane acid stimulates the expression of SIRT1, PGC1α and
Matrix NRF1, as well as oxygen consumption in myocytes
O2– O2– and adipocytes185. Another amino acid, l -carnitine,
has been suggested as a therapeutic agent to improve
-oxidation mitochondrial energy metabolism in CVD186. Carnitine
Omega-3
inhibits FFA induced mitochondrial membrane damage
Vitamin C and subsequent downstream effects186,187. Approximately
75% of the total body pool of carnitine originates from
food sources (red meat, fish, egg and dairy products) or
via nutritionally derived lysine and methionine, which
Propolis Allicin Selenium
ROS are used for endogenous biosynthesis of carnitine186,187.
A meta-analysis of randomized controlled trials
mtDNA reported no evidence that l -carnitine supplementa-
Lipotoxic tion could improve uraemic dyslipidaemia in patients
damage Mitochondrial on haemodialysis188. As oral carnitine supplementation
biogenesis
can contribute to TMAO production by gut micro-
biota fermentation, the overall effect on mitochondrial
biogenesis is uncertain and may be context sensitive189,190.
NRF1 Elevated TMAO level is an independent predictor
Saturated fatty acids of poor outcome in CKD 50,191,192. A randomized trial
in healthy volunteers who consumed red meat, white
PGC1 SIRT1
meat or non-meat protein showed that chronic intake
of dietary red meat increases systemic TMAO levels
via enhanced levels of dietary precursors, increased
microbial trimethylamine and TM AO production
Fibre (SCFA) Dairy products Omega-3 Resveratrol from carnitine and reduced renal TMAO excretion193.
(leucine) Among 29,682 US adults, a higher intake of processed
Fig. 4 | Mechanisms by which food and nutrients might affect mitochondrial and unprocessed red meat, but not fish or poultry, was
function. Saturated fatty acids can saturate the oxidative capacity of the mitochondria, reported to correlate with increased mortality, suggest-
Mafra et al,toNature
contributing Reviews
mitochondrial Nephrology,
DNA damage 2020 reactive
and increased mitochondrial ing that the source of meat is an important determinant
oxygen species (ROS) production. By contrast, omega-3 fatty acids upregulate of health194. Replacement of red meat with white meat
peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α) and nuclear (chicken) in the diet reduced microalbuminuria in a
respiratory transcription factor 1 (NRF1) leading to mitochondrial biogenesis. Dairy randomized crossover-controlled trial in patients with
products contain high levels of leucine, which also stimulates the expression of T2DM 195. Thus, a diet with chicken as the only source of
mitochondrial biogenesis genes and so may influence energy metabolism. Short-chain
meat is an attractive strategy for treatment of T2DM and
fatty acids (SCFAs) produced by gut microbial fermentation of dietary fibre can also
increase mitochondrial biogenesis by increasing the expression of PGC1α. Resveratrol microalbuminuria195.
can activate sirtuin 1 (SIRT1) and reduce mitochondrial ROS production, whereas Tryptophan and tyrosine are also fermented by gut
curcumin and vitamin C decrease oxidative stress, inhibit mitochondrial permeability microbiota, leading to the formation of uraemic toxins,
transition pore (PTP) opening and enhance oxidative phosphorylation capacity. Allicin such as indoxyl sulfate and p-cresyl sulfate. Indoxyl
and propolis reduce mitochondrial ROS production. mtDNA, mitochondrial DNA. sulfate downregulates the expression of NRF2 (REF.196)

NATURE REVIEWS | NEPHROLOGY

20
Mafra et al, Nature Reviews Nephrology, 2020

Concentration of GPX, cytokines and oxidative stress markers levels

PARAMETERS BEFORE AFTER P-VALUE

8-isoprostane (pg/mL) 12.2 ± 4.6 6.6 ± 4.1 <0.0001
8-hydroxy-2-deoxy-guanosine (pg/mL) 53.4 (31.4–66.1) 11.3 (7.8–14.4) <0.0001
GPx (nmol/mL/min) 33.6 ± 5.1 40.0 ± 8.5 <0.0001
IL-6 (pg/mL) 64.8 ± 10.6 14.0 ± 1.6 <0.0001
TNF-α (pg/mL) 21.0 ± 0.3 14.3 ± 8.8 <0.0001

21
 2.0
NFkB mRNA expression

Control Group
Treatment group
1.5

1.0

0.5

0.0
Pre Post Pre Post
up

up
ro
ro

tg
G
ol

en
tr

tm
on

ea
C

Tr

Alvarenga et al, J Functional Foods, 40:715-721, 2018.

EFEITOS DA SUPLEMENTAÇÃO DE CÚRCUMA SOBRE

MARCADORES DE RISCO CARDIOVASCULAR, DE INFLAMAÇÃO,
ESTRESSE OXIDATIVO E MICROBIOTA INTESTINAL EM PACIENTES
EM HEMODIÁLISE

O grupo cúrcuma recebeu 100 ml de suco de laranja, 12 g de

cenoura e 2,5g de cúrcuma diluída e grupo placebo, recebeu suco
na mesma quantidade de ingredientes, porém sem adição de
cúrcuma. A suplementação durou 3 meses.

22
Alvarenga et al, Clinical Nutrition, 2020.

P-cresil sulfato
Int Urol Nephrol. 2021

MICROBIOTA INTESTINAL NA DRC

Ramezani et al. Am J Kidney Dis. 2016.

23
Vaziri et al. Kidney Int. 2013.

IS plasma levels were increased after 3 months with probiotic

supplementation in HD patients

Borges et al. JREN, 2017.

24
Mafra et al. Nutrients, 2019.

NRF2

TOXINAS UREMICAS. AIA

Esgalhado et al, Food & Function, 2018;; Esgalhado et al, Food & Function, 2020.

25
 To bee or not to bee? The bee extract propolis as a bioactive compound in the burden of lifestyle
disease.
Livia Alvarenga¹; Ludmila FMF Cardozo2, Natália A. Borges2,3,4; Tuany R. Chermut3, Marcia Ribeiro³; Maurilo Leite Jr5; Paul
G. Shiels6, Peter Stenvinkel7, Denise Mafra1,2,3

PROPOLIS
Galangin
Pinoresinol POLYPHENOLS
Flavonoids, phenylpropanoids, terpenenes,
s3lbenes, lignans, coumarins Artepillin C
Chrysin

Querce: n Linalool
Naringenin kaempferol
Caffeic acid Luteolin
/

Gut microbiota
balance
Low absorption CKD ↓Gut barrier
permeability
Gut microbial
enzyma3c ac3vi3es ↓Oxidative stress

↓Inflammation

Alvarenga et al, Nutrition, 2020

Myrosinase

Gut Microbiota

Glucoraphanin Sulforaphane

1 Cruciferous vegetables: Rationale for exploring potential salutary effects of

2 sulforaphane-rich foods in patients with chronic kidney disease

3
4 Ludmila FMF Cardozo1, Livia A Alvarenga2, Marcia Ribeiro3, Lu Dai4, Paul G Shiels5,
5 Peter Stenvinkel4, Bengt Lindholm4, Denise Mafra1,2,3
6
1
7 Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói, RJ,
8 Brazil
2
9 Graduate Program in Medical Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
3
10 Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói, RJ, Brazil
4
11 Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Technology and
12 Intervention, Karolinska Institutet, Stockholm, Sweden.
5
13 Wolfson Wohl Translational Research Centre, Institute of Cancer Sciences, University of Glasgow
14
15 -Article type: Lead Article
16
17 - Financial support: Conselho Nacional de Pesquisa (CNPq), Coordenação de
18 Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à
19 Pesquisa do Estado do Rio de Janeiro (FAPERJ) support Denise Mafra research.
20
21 - There are no conflicts of interest to declare.
22 - Running title: Sulforaphane and CKD
23
24
25
Cardozo et al, Nutrition Reviews, 2020
26 Corresponding author:
27 Professor Denise Mafra
28 Unidade de Pesquisa Clínica-UPC. Rua Marquês de Paraná, 303/4 andar
29 Niterói-RJ, Brazil, Zip Code 24033-900
30 Federal Fluminense University Niterói-Rio de Janeiro (RJ), Brazil
31 Phone: +55 21 985683003
32 E-mail: dmafra30@gmail.com

33 Abbreviations: Chronic Kidney Disease, CKD; DNA methyltransferases, DNMTs;

34 Glucosinolates, GLS; Heme oxygenase 1, HO-1; Histone deacetylase, HDAC; Indole-3 acetic
35 acid, IAA; Indoxyl sulfate, IS; Lipopolysaccharide, LPS; Kelch-like ECH-associated protein
36 1, Keap1; Mitochondrial transcription factor-A, TFAM; NAD (P) H quinone oxidoreductase
37 1, NQO1; Nuclear factor-erythroid 2-related factor 2, Nrf2; Nuclear factor-κB, NF-κB;
38 Nuclear respiration factors, Nrfs; Peroxisome proliferator-activated receptor-γ co-
39 activator 1-α, PGC-1α; p-cresyl sulfate, pCS; Sulforaphane, SFN.
40

1
Bioactive food and exercise in chronic kidney disease: Targeting the
mitochondria

Eur J Clin Invest. 2018 Aug 25:e13020.

26
Mafra et al, JREN, 2020.

MENSAGEM FINAL

Nephrol Dial Transplant 2019 Jul 13;gfz120.

27
Obrigada!

28