Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 1678-4170 0066-782X Sociedade Brasileira de Cardiologia - SBC 3q4qtbpSPXX3tbDtW4fvgLr S0066-782X2022005001207 S0066-782X2022000400703 abc.20201144 10.36660/abc.20201144 Artigo Original Microalbuminúria e seu Significado Prognóstico em Pacientes com Insuficiência Cardíaca Aguda com Fração de Ejeção Preservada, Intermediária e Reduzida 0000-0003-1574-3846 Alataş Ömer Doğan 1 Biteker Murat 2 Demir Ahmet 1 Yıldırım Birdal 1 Acar Ethem 1 Gökçek Kemal 1 Gökçek Aysel 2 Muğla Sıtkı Koçman University Training and Research Hospital Department of Emergency Medicine Mugla Turquia Muğla Sıtkı Koçman University, Training and Research Hospital, Department of Emergency Medicine, Mugla – Turquia Muğla Sıtkı Koçman University Faculty of Medicine Department of Cardiology Mugla Turquia Muğla Sıtkı Koçman University, Faculty of Medicine, Department of Cardiology, Mugla – Turquia Correspondência: Ömer Doğan Alataş • Muğla Sıtkı Koçman Üniversitesi Tıp Fakültesi - Orhaniye Mah. Haluk Özsoy Cad. 48000/MUĞLA E-mail: omerdoganalatas@gmail.com

Contribuição dos autores

Concepção e desenho da pesquisa: Alataş OD; Obtenção de dados: Alataş OD, Demir A, Yıldırım B, Acar E, Gökçek K, Gökçek A; Análise e interpretação dos dados: Alataş OD, Gökçek K; Análise estatística: Biteker M, Acar E; Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Alataş OD, Biteker M.

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 07 02 2022 04 2022 118 4 703 709 24 10 2020 02 05 2021 12 05 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Resumo Fundamento

A prevalência e o significado da microalbuminúria não foram bem estudados em pacientes com diferentes subtipos de insuficiência cardíaca.

 Objetivo

A prevalência e o significado da microalbuminúria não foram bem estudados em pacientes com diferentes subtipos de insuficiência cardíaca. Portanto, nosso objetivo foi investigar a frequência e o valor prognóstico da microalbuminúria em pacientes hospitalizados por insuficiência cardíaca aguda (ICA) com fração de ejeção preservada (ICFEp), fração de ejeção de faixa média (ICFEfm) e fração de ejeção reduzida (ICFEr).

 Métodos

Todos os pacientes adultos consecutivos encaminhados ao hospital devido a ICA entre junho de 2016 e junho de 2019 foram inscritos. A microalbuminúria é definida como o nível de albumina urinária para relação de creatinina (AURC) na faixa de 30–300 mg/g. A mortalidade hospitalar foi o critério de valoração deste estudo.

 Resultados

Dos 426 pacientes com ICA (idade média de 70,64 ± 10,03 anos, 53,3% do sexo feminino), 50% tinham ICFEr, 38,3% tinham ICFEp e 11,7% tinham ICFEfm na apresentação. A prevalência de microalbuminúria foi de 35,2%, 28,8% e 28,0% em ICFEr, ICFEp e ICFEfm, respectivamente. Um total de 19 (4,5%) pacientes morreram durante o curso intra-hospitalar, e a mortalidade intra-hospitalar foi maior em pacientes com ICFEr (6,6%) em comparação com pacientes com ICFEr (2,5%) e ICFEfm (2,0%). A análise multivariada mostrou que a presença de microalbuminúria previu mortalidade intra-hospitalar em pacientes com ICFEr e ICFEfm, mas não em ICFEp.

 Conclusão

Embora a microalbuminúria fosse comum em todos os subgrupos de pacientes com ICA, descobriu-se que ela prediz o prognóstico apenas em pacientes com ICFEr e ICFEfm.

 Albuminúria/fisiopatologia Prognóstico Insuficiência Cardíaca Volume Sistólico Hospitalização Adultos Mortalidade Introdução

A insuficiência cardíaca (IC) foi classificada em três grupos com base na fração de ejeção do ventrículo esquerdo (FEVE) nas diretrizes atuais; IC com FE reduzida (ICFEr), IC com FE de faixa média (ICFEfm) e IC com FE preservada (ICFEp). 1 A insuficiência cardíaca aguda (ICA), que pode ser desenvolvida em todos os tipos de IC, é uma causa significativa de mortalidade e custos de saúde em países industrializados e em desenvolvimento. 2, 3 Apesar dos avanços no manejo da ICA nas últimas décadas, 4% a 7% dos pacientes morrem durante a internação, e metade deles morre em cinco anos. 4, 5 Portanto, a predição precoce da mortalidade é essencial para o manejo de pacientes com ICA, e existem muitas variáveis clínicas e laboratoriais que predizem a mortalidade na ICA. 6 - 8

Embora a disfunção renal também tenha sido associada ao aumento do risco de mortalidade na ICFEp, 9 estudos anteriores apresentaram achados conflitantes sobre a importância da doença renal crônica na ICFEp em comparação com a ICFEr; 10 e a importância das funções renais na ICFEfm não é clara. O aumento da excreção urinária de albumina, que pode ser um marcador de inflamação, disfunção endotelial e ativação do sistema renina-angiotensina, é um preditor de mortalidade e eventos adversos na população em geral, 12 em pacientes com diabetes 13 e hipertensão. 14 A relação albumina/creatinina urinária (AURC) em uma amostra de urina aleatória é aceita como um método mais útil para avaliar as funções renais e evita limitações de outros testes, como a taxa de filtração glomerular. 15 Na insuficiência cardíaca crônica, mesmo a disfunção renal leve, determinada pela presença de microalbuminúria (definida como níveis de albumina urinária maiores ou iguais a 30-300 mg na coleta de urina de 24 h ou AURC de> 30-300 mg/g em amostra aleatória de urina), está associada a resultados adversos. 16 Existem, no entanto, poucos relatórios que examinaram o efeito prognóstico do AURC em pacientes com ICA. Além disso, a prevalência e a significância da microalbuminúria não foram comparadas em ICFEr, ICFEfm e ICFEp. Portanto, nosso objetivo foi examinar a prevalência e a importância da microalbuminúria em pacientes com ICA secundária a ICFEr, ICFEfm e ICFEp.

 Métodos

Os dados de pacientes consecutivos hospitalizados por ED devido a ICA entre junho de 2016 e junho de 2019 foram registrados retrospectivamente. Este estudo foi conduzido no Hospital Universitário Muğla Sıtkı Koçman e aprovado pelo conselho de revisão institucional local.

Critério de inclusão

Todos os pacientes adultos (≥ 18 anos) admitidos em nosso pronto-socorro com sinais e/ou sintomas de ICA e com níveis aumentados de peptídeo natriurético tipo B-N-Terminal (NT-proBNP) foram incluídos.

 Critério de exclusão

Pacientes que não tiveram avaliação de AURC, LVEF ou NT-proBNP na admissão, pacientes com idade <18 anos, pacientes em diálise e pacientes com alta o domicílio foram excluídos.

 Coleta de dados e definições

Os pacientes foram divididos em três grupos de acordo com a FEVE; pacientes com FEVE <50% foram definidos como ICFEr, pacientes com FEVE de 40-49% foram descritos como ICFEfm e pacientes com FEVE <40% foram definidos como ICFE. Além disso, os critérios ecocardiográficos de disfunção diastólica ou doença cardíaca estrutural também foram necessários para determinar a ICFEP.

As características demográficas e as comorbidades dos pacientes foram coletadas e anotadas no banco de dados do hospital. As definições das variáveis demográficas são fornecidas na Tabela 1 . Além disso, amostras de sangue e urina foram obtidas na admissão, incluindo NT-proBNP e níveis estimados da taxa de filtração glomerular (eTFG). 17

– Dados demográficos e características dos pacientes
ICFEr (n = 213) ICFEfm (n = 50) ICFEp (n = 163) valor p
Sexo feminino 110 (51,6) 22 (44,0) 95 (58,3) <0,001
Idade 68,09 ± 9,58 70,85 ± 10,15 72,83 ± 10,70 0,015
Fumar 40 (18,8) 10 (20,0) 30 (18,4) 0,344
Uso de álcool 10 (4,7) 3 (6,0) 8 (4,9) 0,632
Índice de massa corporal, kg/m 2 27,56 ± 5,66 28,98 ± 5,92 29,43 ± 6,24 0,004
Comorbidades
Fibrilação atrial 65 (30,5) 15 (30,0) 50 (30,7) 0,845
Hipertensão 160 (75,2) 38 (76,0) 121 (74,2) 0,921
Diabetes mellitus 63 (29,6) 14 (28,0) 45 (27,6) 0,814
Doença renal crônica 25 (11,7) 5 (10,0) 16 (9,8) 0,623
Doença arterial coronária 95 (44,6) 26 (52,0) 66 (40,5) 0,014
Doença cerebrovascular 10 (4,7) 3 (6,0) 12 (7,4) 0,131
DPOC 21 (9,9) 5 (10,0) 15 (9,2) 0,755
Sinais e sintomas
Dispneia, classe NYHA III/IV 171 (80,3) 42 (84,0) 134 (82,2) 0,510
Palpitação 130 (61,1) 30 (60,0) 105 (64,4) 0,212
Inchaço do tornozelo 70 (32,9) 15 (30,0) 51 (31,3) 0,815
Dor no peito 60 (28,2) 20 (40,0) 43 (26,4) 0,004
Exame físico
Pressão arterial sistólica, mmHg 122,5 ± 15,41 131,22 ± 20,66 132,30 ± 20,11 0,001
Pressão arterial diastólica, mmHg 79,12 ± 11,96 80,10 ± 12,07 80,65 ± 11,86 0,109
Frequência cardíaca, bpm 88,75 ± 18,23 82,36 ± 18,05 82,55 ± 17,98 <0,001
Crepitações pulmonares 160 (75,2) 37 (74,0) 119 (73,0) 0,081
Laboratório
NT-ProBNP, pg/ml 5859 (1896 - 11857) 3421 (1104-8455) 2544 (986 - 5487) <0,001
Glicose, mg/dl 118 (94 - 158) 120 (96 - 161) 119 (95 - 159) 0,742
BUN, mg/dl 22 (18 - 37) 23 (17 - 35) 22 (16 - 36) 0,291
Creatinina sérica, mg/dl 1,2 (0,8 - 1,7) 1,2 (0,8 - 1,8) 1,1 (0,7 - 1,7) 0,366
Hemoglobina, g/dl 12,5 (10,1 - 14,5) 12,6 (10,5 - 13,5) 12,4 (10,8 - 14,2) 0,113
AURC 12,5 (5,9 - 1357,7) 10,3 (2,9 - 725,7) 10,1 (4,5 - 878,7) 0,001
eTFG (mL/min/1,73 m 2 ) 68,7 ± 21,6 70,9 ± 21,3 70,7 ± 22,5 0,032
Internação Hospitalar, mediana, dias 8 7 7 0,106
Mortalidade hospitalar 14 (6,6) 1 (2,0) 4 (2,5) 0,003

Os dados são apresentados como média ± desvio padrão, número (%) ou mediana e intervalo interquartil. ICFEr: insuficiência cardíaca com fração de ejeção reduzida; ICFEfm: insuficiência cardíaca com fração de ejeção de faixa média; ICFEp: insuficiência cardíaca com fração de ejeção preservada; NYHA: New York Heart Association; DPOC: doença pulmonar obstrutiva crônica; NT-proBNP: peptídeo natriurético do tipo pro B do terminal N; BUN: nitrogênio da ureia no sangue; AURC: relação albumina/creatinina urinária; eTFG: taxa de filtração glomerular estimada.

A albuminúria foi definida de acordo com a relação albumina/creatinina na urina: normoalbuminúria: <30 mg/g, microalbuminúria: 30 -299 mg/ge macroalbuminúria:> 300 mg/g). O desfecho primário foi a mortalidade hospitalar.

 Análise estatística

Os dados foram analisados usando SPSS para Windows (versão 24; SPSS Inc, Chicago, IL). Um valor de P ≤0,05 foi considerado significativo. As análises de regressão univariada e multivariada foram realizadas para estudar o efeito de vários fatores de risco, incluindo microalbuminúria e macroalbuminúria, no desfecho primário.

 Resultados

Um total de 586 pacientes adultos com ICA foram admitidos em nosso Pronto Socorro durante o período do estudo. No entanto, 24 pacientes sem dados de FEVE, 56 pacientes sem dados do NT-proBNP ou AURC, 64 pacientes que receberam alta para casa e 16 pacientes com doença renal em estágio terminal foram excluídos do estudo ( Figura 1 ). A população final do estudo incluiu 426 pacientes (idade média de 70,64 ± 10,03 anos, 53,3% do sexo feminino).

– Fluxograma do participante. NT-proBNP: peptídeo natriurético tipo B-N-Terminal; FEVE: fração de ejeção do ventrículo esquerdo; AURC: albumina urinária para relação de creatinina; ICFEr: insuficiência cardíaca com fração de ejeção reduzida; ICFEfm: insuficiência cardíaca com fração de ejeção de faixa média;ICFEp: insuficiência cardíaca com fração de ejeção preservada.

Comparação das características basais em subgrupos de insuficiência cardíaca

Entre a população do estudo, 50% tinham ICFEr, 38,3% tinham ICFEp e 11,7% tinham ICFEfm.

As características basais dos pacientes são apresentadas na Table 1 . Os pacientes com ICFEP eram mais velhos, tinham um índice de massa corporal mais alto e eram mais propensos a serem mulheres. Os pacientes com ICFEr eram mais jovens, tinham níveis de NT-pro-BNP e AURC na admissão significativamente mais altos, tinham pressão arterial sistólica mais baixa, mas frequência cardíaca mais alta na apresentação. Pacientes com ICFEfm tinham um perfil de biomarcador intermediário e fenótipo intermediário para comorbidades. Pacientes com ICFEfm diferiam de ICFEp e ICFEr, pois eram mais frequentemente do sexo masculino e tinham maior probabilidade de ter história de doença arterial coronariana.

Dos 426 pacientes, 185 (43,4%) tinham AURC aumentado na admissão; 136 pacientes tinham (31,9%) microalbuminúria, 49 pacientes tinham macroalbuminúria (11,5%) e 241 (56,6%) pacientes tinham normoalbuminúria. Não houve diferenças significativas na prevalência de normo-, micro- e macroalbuminúria em pacientes com ICFEp e ICFEr. No entanto, em comparação com ICFEp e ICFEfm, os pacientes com ICFEr eram mais propensos a ter micro e macroalbuminúria e eram menos propensos a normoalbuminúria ( Figura 2 ). A prevalência de microalbuminúria foi de 35,2%, 28,8% e 28,0% em ICFEr, ICFEp e ICFEfm, respectivamente. A prevalência de microalbuminúria foi de 13,1%, 9,8% e 10% em ICFEr, ICFEp e ICFEfm, respectivamente.

– Comparação da prevalência de normo-, micro- e macroalbuminúria em relação aos subtipos de insuficiência cardíaca. ICFEr: insuficiência cardíaca com fração de ejeção reduzida; ICFEfm: insuficiência cardíaca com fração de ejeção de faixa média;ICFEp: insuficiência cardíaca com fração de ejeção preservada.

Comparação de resultados

Não houve diferença no tempo de internação hospitalar entre os pacientes com ICFEp, ICFEfm ou ICFEr. Um total de 19 (4,5%) pacientes morreram durante o curso intra-hospitalar, e a mortalidade intra-hospitalar foi maior em pacientes com ICFEr (6,6%) em comparação para pacientes com ICFEp (2,5%) e ICFEfm (2,0%) (p = 0,004).

 Preditores de mortalidade hospitalar

A análise multivariada mostrou que o NT-pro-BNP e a macroalbuminúria foram associados à mortalidade hospitalar em todos os grupos com FEVE ( Table 2 ). Doença arterial coronariana, sexo masculino e diabetes mellitus predisseram mortalidade intra-hospitalar apenas em pacientes com ICFEfm, enquanto a fibrilação atrial previu mortalidade intra-hospitalar apenas em pacientes com ICFEr. A idade avançada foi um preditor independente de mortalidade hospitalar em pacientes com ICFEr e ICFEp.

– Preditores de mortalidade hospitalar em subtipos de IC
ICFEr ICFEfm ICFEp
OR (IC 95%) Valor p OR (IC 95%) Valor p OR (IC 95%) Valor p
Doença arterial coronária 2,10 (1,55-3,04) 0,065 3,45 (1,23-5,67) 0,043 1,49 (1,14-5,34) 0,089
NT-ProBNP 2,68 (1,23-7,75) <0,001 2,12 (1,34-3,45) 0,011 2,01 (0,09-3,23) 0,022
Idade (por 10 anos) 1,75 (1,13-3,45) 0,016 1,13 (0,80-1,51) 0,076 3,12 (1,38-4,81) 0,019
Diabetes mellitus 1,21 (0,81-1,43) 0,121 2,34 (1,03-4,16) 0,043 1,20 (0,89-2,55) 0,291
Microalbuminúria 1,94 (0,91-4,21) <0,001 1,56 (1,19-3,45) 0,001 1,25 (1,12-1,68) 0,124
Macroalbuminúria 2,45 (1,34-5,65) <0,001 1,92 (1,23-2,98) 0,024 1,66 (1,34-3,84) 0,032
Doença renal crônica 1,15 (1,01-1,33) 0,293 1,32 (1,11-2,77) 0,101 1,23 (0,82-1,56) 0,451
Fibrilação atrial 1,07 (0,83-1,42) 0,013 1,23 (0,89-1,55) 0,234 1,33 (1,18-2,01) 0,098
Sexo masculino 1,22 (0,83-1,88) 0,462 3,31 (1,13-4,23) 0,001 0,89 (0,66-1,39) 0,453

ICFEr: insuficiência cardíaca com fração de ejeção reduzida; ICFEfm: insuficiência cardíaca com fração de ejeção de faixa média; ICFEp: insuficiência cardíaca com fração de ejeção preservada; NT-proBNP: peptídeo natriurético do tipo pro B do terminal N.

Microalbuminúria e prognóstico

A presença de microalbuminúria na admissão foi associada à mortalidade intra-hospitalar em pacientes com ICFEr e ICFEfm, mas não em pacientes com ICFEp. Pacientes com microalbuminúria e macroalbuminúria tiveram risco 1,94 e 2,45 vezes maior, respectivamente, de mortalidade hospitalar em comparação com pacientes com normoalbuminúria na ICFEr. Em comparação com pacientes com normoalbuminúria, pacientes com microalbuminúria e macroalbuminúria tiveram 1,56 e 1,92 vezes maior risco de mortalidade hospitalar em ICFEfm, respectivamente.

 Discussão

Nosso estudo tem várias importantes implicações clínicas: (i) Dos pacientes hospitalizados com ICA, 50% tinham ICFEr, 11,7% tinham ICFEfm e 38,3% tinham ICFEp. (ii) 43,4% dos pacientes apresentavam AURC anormal na admissão ao PS. (iii) Os valores de NT-proBNP e AURC e as taxas de mortalidade hospitalar foram os mais elevados em pacientes com ICFEr. (iv) A prevalência de micro e macroalbuminúria em ICFEp foi semelhante a ICFEfm e menor do que ICFEr. (v) A prevalência de microalbuminúria foi de 35,2%, 28,8% e 28,0% em ICFEr, ICFEp e ICFEfm, respectivamente. (vi) A microalbuminúria previu mortalidade intra-hospitalar em ICFEfm e ICFEr, mas não em ICFEp.

As doenças cardiovasculares e renais compartilham comorbidades e fatores de risco semelhantes. Estudos de coorte extensos mostraram que o aumento do AURC está associado ao desenvolvimento de IC na população em geral. 18 - 20 No entanto, a maioria dos estudos descreveu a importância do AURC em ICFEr, e os estudos que examinam os subtipos de HF separadamente apresentam achados divergentes. 21, 22 Em um estudo comunitário, Nayor et al., 21 descobriram que a microalbuminúria foi associada a um risco aumentado de ICFEr incidente, mas não ICFEp. 21 Em contraste, o estudo de coorte PREVEND mostrou que AURC mais alta estava mais fortemente associada a ICFEp incidente do que ICFEr. 22 Em uma pesquisa recente com 24433 pacientes, a associação entre AURC e ICFEp foi maior do que ICFEr após 9,3 anos de acompanhamento. 23

Os testes de função renal também estão associados a resultados adversos, independentemente da gravidade da doença em pacientes com IC estabelecida. No entanto, estudos que investigam o impacto da disfunção renal no prognóstico nos diferentes grupos de FEVE também apresentam resultados conflitantes. 24, 25 Em uma metanálise, Damman et al., 24 mostraram que a disfunção renal crônica foi um preditor mais forte de mortalidade na ICFEp do que na ICFEr. 24 Em contraste, em uma metanálise de vinte e cinco estudos prospectivos, a disfunção renal foi um preditor mais forte de mortalidade em pacientes com ICFEr do que em ICFEp. 25 Ambas as metanálises definiram a doença renal crônica como um eTFG inferior a 60 ml/min /1,73m 2, e os estudos que examinam o valor prognóstico da microalbuminúria ou AURC em pacientes com IC crônica com diferentes grupos de FEVE são muito mais limitados. 26 - 30 Em um estudo transversal, 72 pacientes com IC crônica foram inscritos, e a microalbuminúria foi observada em 40% dos pacientes com ICFEp e em 24% dos pacientes com ICFEr (p = 0,04). 26 No entanto, o impacto prognóstico da microalbuminúria não foi avaliado neste estudo. No estudo CHARM, que incluiu pacientes com IC crônica, a prevalência de micro e macroalbuminúria foi de 30% e 11%, respectivamente. 27 Ao estratificar em diferentes grupos de FEVE, 31% dos pacientes com FEVE ≤40% tinham microalbuminúria, e 10% tinham macroalbuminúria. Dos pacientes com FEVE> 40%, 29% tinham microalbuminúria e 12% macroalbuminúria. Os resultados do estudo CHARM também revelaram que a albuminúria foi um preditor de mortalidade. O risco associado ao AURC foi semelhante em pacientes com FEVE baixa e preservada. 27 No estudo GISSI-HF, micro e macroalbuminúria foram observados em 19,9% e 5,4% dos pacientes, respectivamente. O AURC previu mortalidade independentemente em pacientes com IC crônica. 28 No entanto, como 90,8% dos pacientes com GISSI-HF tinham FEVE ≤ 40%, uma análise separada para diferentes grupos de FEVE não foi realizada. No estudo CHART-2, 2.039 pacientes com IC crônica foram inscritos. 29 Os autores mostraram que não apenas a microalbuminúria, mas também a microalbuminúria subclínica, que foi definida como AURC 10,2–27,3 mg/g, estava significativamente associada a eventos cardiovasculares adversos em comparação com a normoalbuminúria, particularmente em pacientes com eTFG preservada ou levemente reduzido. 28 O estudo TOPCAT incluiu apenas pacientes com ICFEp para investigar o benefício da terapia com espironolactona. 30 Em uma análise de subgrupo do estudo TOPCAT, micro e macroalbuminúria conferiram um risco aumentado de 1,47 e 1,67 vezes para desfechos primários em ICFEp. 30

Embora se espere que a prevalência de disfunção renal seja maior em pacientes com ICA do que em pacientes com IC crônica, poucos estudos avaliaram a albuminúria no contexto de ICA. Em um estudo prospectivo de 115 pacientes com ICA, Koyama et al., 31 mostraram que 69% dos pacientes tinham AURC anormal na admissão (27% tinham macroalbuminúria, 42% tinham microalbuminúria). 31 No entanto, no dia 7, 10% dos pacientes tinham macroalbuminúria e 30% tinham microalbuminúria. A resolução do AURC foi associada a diminuições nos níveis de NT-proBNP. 31 A frequência de AURC anormal na admissão foi de 43,4% em nosso estudo, menor do que o estudo de Koyama e colegas. Essa diferença pode ser devido à idade mais jovem e menor carga de comorbidades em nosso estudo.

Nosso estudo demonstrou que a microalbuminúria na admissão no Pronto Socorro é um preditor independente de mortalidade intra-hospitalar em ICFEfm e ICFEr, mas não em ICFEp. Em ICFEp, o prognóstico pode estar mais relacionado a comorbidades do que em ICFEfm e ICFEr, onde com subsequente disfunção renal pode ser mais pronunciada. A relação entre IC e albuminúria é complexa. É de natureza bidirecional, e os mecanismos responsáveis pela relação da microalbuminúria e o prognóstico na ICFEr e ICFEfm merecem investigações adicionais.

Limitações do estudo

Nosso estudo é limitado por seu desenho retrospectivo e por ter sido realizado em um único centro. Como as mudanças diárias no AURC não foram registradas, não pudemos examinar a relação entre as alterações no AURC e o prognóstico. Uma amostra única de urina foi usada para determinar o AURC, que pode flutuar.

 Conclusões

Em pacientes com ICA, a microalbuminúria na admissão está associada ao aumento da mortalidade intra-hospitalar em ICFEfm e ICFEr. Mais estudos prospectivos são necessários para explorar o papel do AURC como um marcador prognóstico na ICA.

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Sasaki N, Kunisawa S, Ikai H, Imanaka Y, Differences between determinants of in-hospital mortality and hospitalisation costs for patients with acute heart failure: a nationwide observational study from Japan. BMJ Open. 2017;7(3):e013753. Sasaki N Kunisawa S Ikai H Imanaka Y Differences between determinants of in-hospital mortality and hospitalisation costs for patients with acute heart failure: a nationwide observational study from Japan BMJ Open 2017 7 3 e013753 3. Salam A, Sulaiman K, Alsheikh A, Singh R, AlHabib KF, Al-zakwani KF, et al. Precipitating Factors for Hospitalization with Heart Failure: Prevalence and Clinical Impact Observations from the Gulf CARE (Gulf aCute heArt failuRe rEgistry).Med Princ Pract. 2019;2020;29(3):270-8. doi: 10.1159/000503334. Salam A Sulaiman K Alsheikh A Singh R AlHabib KF Al-zakwani KF et al Precipitating Factors for Hospitalization with Heart Failure: Prevalence and Clinical Impact Observations from the Gulf CARE (Gulf aCute heArt failuRe rEgistry) Med Princ Pract 2019 2020 29 3 270 278 10.1159/000503334 4. Adams Jr KF, Fonarow GC, Emerman CL, Lejemtel TH, Costanzo MR, Abraham WT, et al. ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J.2005;149(2):209–16. Adams KF Jr Fonarow GC Emerman CL Lejemtel TH Costanzo MR Abraham WT et al ADHERE Scientific Advisory Committee and Investigators Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE) Am Heart J 2005 149 2 209 216 5. Fonarow GC, Abraham WT, Albert N, Gattis W, Gheorghiade M, Greenberg B, et al. Impact of evidence-based heart failure therapy use at hospital discharge on treatment rates during follow-up: a report from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure(OPTIMIZE-HF). J Am Coll Cardiol. 2005;45:345A. 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Int J Cardiol. 2013;168(1):185-9. Parissis JT Mantziari L Kaldoglou N Ikonomidis I Nikolaou M Mebazaa N et al Gender-related differences in patients with acute heart failure: management and predictors of in-hospital mortality Int J Cardiol 2013 168 1 185 189 8. Castello LM, Molinari L, Renghi A, Peruzzi E, Capponi A, Avanzi GC, et al.Acute decompensated heart failure in the emergency department: Identification of early predictors of outcome. Medicine (Baltimore). 2017;96(27):e7401. Castello LM Molinari L Renghi A Peruzzi E Capponi A Avanzi GC et al Acute decompensated heart failure in the emergency department: Identification of early predictors of outcome Medicine (Baltimore) 2017 96 27 e7401 9. Givertz MM, Postmus D, Hillege HL, Mansoor GA, Massie BM, Davison BA, et al. Renal function trajectories and clinical outcomes in acute heart failure.Circ Heart Fail. 2014;7(5):59-67. Givertz MM Postmus D Hillege HL Mansoor GA Massie BM Davison BA et al Renal function trajectories and clinical outcomes in acute heart failure Circ Heart Fail 2014 7 5 59 67 10. Casado J, Sánchez M, Garcés V, Manzano L, Cerqueiro JM, Epelde F, et al; RICA Investigators Group. Influence of renal dysfunction phenotype on mortality in decompensated heart failure with preserved and mid-range ejection fraction. Int J Cardiol. 2017;243:332-9. Casado J Sánchez M Garcés V Manzano L Cerqueiro JM Epelde F et al RICA Investigators Group Influence of renal dysfunction phenotype on mortality in decompensated heart failure with preserved and mid-range ejection fraction Int J Cardiol 2017 243 332 339 11. Park CS, Park JJ, Oh IY, Yoon CH, Choi DJ, Park HA, et al.; KorHF Investigators.Relation of Renal Function with Left Ventricular Systolic Function and NT-proBNP Level and Its Prognostic Implication in Heart Failure with Preserved versus Reduced Ejection Fraction: an analysis from the Korean Heart Failure (KorHF) Registry. Korean Circ J. 2017;47(5):727-41. Park CS Park JJ Oh IY Yoon CH Choi DJ Park HA et al KorHF Investigators Relation of Renal Function with Left Ventricular Systolic Function and NT-proBNP Level and Its Prognostic Implication in Heart Failure with Preserved versus Reduced Ejection Fraction: an analysis from the Korean Heart Failure (KorHF) Registry Korean Circ J 2017 47 5 727 741 12. Chong J, Fotheringham J, Tomson C, Ellam T. Renal albumin excretion in healthy young adults and its association with mortality risk in the US population. Nephrol Dial Transplant. 2020;35(3):458-64. doi: 10.1093/ndt/gfy242. Chong J Fotheringham J Tomson C Ellam T Renal albumin excretion in healthy young adults and its association with mortality risk in the US population Nephrol Dial Transplant 2020 35 3 458 464 10.1093/ndt/gfy242 13. Lunetta M, Infantone L, Calogero AE, Infantone E. Increased urinary albumin excretion is a marker of risk for retinopathy and coronary heart disease in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 1998;40(1):45-51. Lunetta M Infantone L Calogero AE Infantone E Increased urinary albumin excretion is a marker of risk for retinopathy and coronary heart disease in patients with type 2 diabetes mellitus Diabetes Res Clin Pract 1998 40 1 45 51 14 Wachtell K, Ibsen H, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. Ann Intern Med.2003;139(92): 901–6. Wachtell K Ibsen H Olsen MH Borch-Johnsen K Lindholm LH Mogensen CE et al Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study Ann Intern Med 2003 139 92 901 906 15. Takahashi S, Tanaka F, Yonekura Y, Tanno K, Ohsawa M, Sakata K, et al. The urine albumin-creatinine ratio is a predictor for incident long-term care in a general population. PLoS One. 2018;13(3):e0195013. Takahashi S Tanaka F Yonekura Y Tanno K Ohsawa M Sakata K et al The urine albumin-creatinine ratio is a predictor for incident long-term care in a general population PLoS One 2018 13 3 e0195013 16. Villacorta H, Ferradaes P de V, Mesquita ET, Nobrega AC. Microalbuminuria is an independent prognostic marker in patients with chronic heart failure. Arq Bras Cardiol. 2012;98(1):62-9. doi:10.1590/s0066-782x2011005000120. Villacorta H Ferradaes P de V Mesquita ET Nobrega AC Microalbuminuria is an independent prognostic marker in patients with chronic heart failure Arq Bras Cardiol 2012 98 1 62 69 doi:10.1590/s0066-782x2011005000120 17. Levey AS, Coresh J, Greene T, Marsh J, Stevens LA, Kusek JW, et al. Chronic Kidney Disease Epidemiology Collaboration. Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values. Clin Chem. 2007;53(4):766–72. Levey AS Coresh J Greene T Marsh J Stevens LA Kusek JW et al Chronic Kidney Disease Epidemiology Collaboration Expressing the Modification of Diet in Renal Disease Study equation for estimating glomerular filtration rate with standardized serum creatinine values Clin Chem 2007 53 4 766 772 18. Arnlov J, Evans JC, Meigs JB, Wang T, Fox C, Levy D, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation. 2005; 112(7):969–75. Arnlov J Evans JC Meigs JB Wang T Fox C Levy D et al Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study Circulation 2005 112 7 969 975 19. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293(13):1609–16. Kistorp C Raymond I Pedersen F Gustafsson F Faber J Hildebrandt P N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults JAMA 2005 293 13 1609 1616 20. Ingelsson E, Sundstrom J, Lind L, Riserus U, Larsson A, Basu S, et al. Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men. Eur Heart J. 2007; 28(14):1739–45. Ingelsson E Sundstrom J Lind L Riserus U Larsson A Basu S et al Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men Eur Heart J 2007 28 14 1739 1745 21. Nayor M, Larson MG, Wang N, Santhanakrishnan R, Lee DS, Tsao CW, et al.The association of chronic kidney disease and microalbuminuria with heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail. 2017;19(5):615-23. Nayor M Larson MG Wang N Santhanakrishnan R Lee DS Tsao CW et al The association of chronic kidney disease and microalbuminuria with heart failure with preserved vs. reduced ejection fraction Eur J Heart Fail 2017 19 5 615 623 22. Brouwers FP, de Boer RA, van der Harst P, Voors A, Gansevoort RT, Bakker SJ, et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34(19):424-31. Brouwers FP de Boer RA van der Harst P Voors A Gansevoort RT Bakker SJ et al Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND Eur Heart J 2013 34 19 424 431 23. Bailey LN, Levitan EB, Judd SE, Sterling MR, Goyal P, Cushman M, et al. Association of Urine Albumin Excretion With Incident Heart Failure Hospitalization in Community-Dwelling Adults. JACC Heart Fail. 2019;7(5):394-401. Bailey LN Levitan EB Judd SE Sterling MR Goyal P Cushman M et al Association of Urine Albumin Excretion With Incident Heart Failure Hospitalization in Community-Dwelling Adults JACC Heart Fail 2019 7 5 394 401 24. Damman K, Valente MA, Voors AA, O’Connoor CM, van Veldhuisen DJ, Hillege HL. 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Orea-Tejeda A, Colín-Ramírez E, Hernández-Gilsoul T, Castillo-Martinez L, Abasta-Jimemnez M, Asensio Lafuente E, et al. Microalbuminuria in systolic and diastolic chronic heart failure patients.Cardiol J. 2008;15(2):143-9. Orea-Tejeda A Colín-Ramírez E Hernández-Gilsoul T Castillo-Martinez L Abasta-Jimemnez M Asensio Lafuente E et al Microalbuminuria in systolic and diastolic chronic heart failure patients Cardiol J 2008 15 2 143 149 27. Jackson CE, Solomon SD, Gerstein HC, Zetterstrand S, Olofsson B, Michelson EL, et al. Albuminuria in chronic heart failure: prevalence and prognostic importance.Lancet. 2009;374(9689):543-50. Jackson CE Solomon SD Gerstein HC Zetterstrand S Olofsson B Michelson EL et al Albuminuria in chronic heart failure: prevalence and prognostic importance Lancet 2009 374 9689 543 550 28. Masson S, Latini R, Milani V, Moretti L, Rossi MG, Carbonieri E, et al. GISSI-HF Investigators. Prevalence and prognostic value of elevated urinary albumin excretion in patients with chronic heart failure: data from the GISSI-Heart Failure trial. Circ Heart Fail. 2010;3(1):65-72. Masson S Latini R Milani V Moretti L Rossi MG Carbonieri E et al GISSI-HF Investigators Prevalence and prognostic value of elevated urinary albumin excretion in patients with chronic heart failure: data from the GISSI-Heart Failure trial Circ Heart Fail 2010 3 1 65 72 29. Miura M, Sakata Y, Miyata S, Nochioka K, Takada T, Tadaki S, et al. CHART-2 Investigators. Prognostic impact of subclinical microalbuminuria in patients with chronic heart failure.Circ J.2014;78(9):2890-8. Miura M Sakata Y Miyata S Nochioka K Takada T Tadaki S et al CHART-2 Investigators Prognostic impact of subclinical microalbuminuria in patients with chronic heart failure Circ J 2014 78 9 2890 2898 30. Selvaraj S, Claggett B, Shah SJ, E,Anand I, Rouleau JL, O’Meara E, et al.Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2018;11(11):e00528. Selvaraj S Claggett B Shah SJ, E Anand I Rouleau JL O’Meara E et al Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction Circ Heart Fail 2018 11 11 e00528 31. Koyama S, Sato Y, Tanada Y, Fujiwara H, Takatsu Y.Early evolution and correlates of urine albumin excretion in patients presenting with acutely decompensated heart failure. Circ Heart Fail. 2013;6(2):227-32. Koyama S Sato Y Tanada Y Fujiwara H Takatsu Y Early evolution and correlates of urine albumin excretion in patients presenting with acutely decompensated heart failure Circ Heart Fail 2013 6 2 227 232

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 Original Article Microalbuminuria and its Prognostic Significance in Patients with Acute Heart Failure with Preserved, Mid-Range, and Reduced Ejection Fraction 0000-0003-1574-3846 Alataş Ömer Doğan 1 Biteker Murat 2 Demir Ahmet 1 Yıldırım Birdal 1 Acar Ethem 1 Gökçek Kemal 1 Gökçek Aysel 2 Turkey Muğla Sıtkı Koçman University, Training and Research Hospital, Department of Emergency Medicine, Mugla – Turkey Turkey Muğla Sıtkı Koçman University, Faculty of Medicine, Department of Cardiology, Mugla – Turkey Mailing Address: Ömer Doğan Alataş • Muğla Sıtkı Koçman Üniversitesi Tıp Fakültesi - Orhaniye Mah. Haluk Özsoy Cad. 48000/MUĞLA E-mail: omerdoganalatas@gmail.com

Author Contributions

Conception and design of the research: Alataş OD; Acquisition of data: Alataş OD, Demir A, Yıldırım B, Acar E, Gökçek K, Gökçek A; Analysis and interpretation of the data: Alataş OD, Gökçek K; Statistical analysis: Biteker M, Acar E; Writing of the manuscript and Critical revision of the manuscript for intellectual content: Alataş OD, Biteker M.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Abstract Background

The prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes.

 Objective

The prevalence and significance of microalbuminuria have not been well studied in patients with different heart failure subtypes. Therefore, we aimed to investigate the frequency and prognostic value of microalbuminuria in patients hospitalized for acute heart failure (AHF) with preserved ejection fraction (HFpEF), mid-range ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF).

 Methods

All consecutive adult patients referred to the hospital due to AHF between June 2016 and June 2019 were enrolled. Microalbuminuria is defined as urinary albumin to creatinine ratio (UACR) level in the range of 30–300 mg/g. Hospital mortality was the endpoint of this study

 Results

Of the 426 AHF patients (mean age 70.64 ± 10.03 years, 53.3 % female), 50% had HFrEF, 38.3% had HFpEF, and 11.7% had HFmrEF at presentation.The prevalence of microalbuminuria was 35.2%, 28.8%, and 28.0% in HFrEF, HFpEF, and HFmrEF, respectively. A total of 19 (4.5%) patients died during the in-hospital course, and in-hospital mortality was higher in HFrEF patients (6.6%) compared to patients with HFpEF (2.5%) and HFmrEF (2.0%). Multivariate analysis showed that the presence of microalbuminuria predicted in-hospital mortality in patients with HFrEF and HFmrEF but not in HFpEF.

 Conclusion

Although microalbuminuria was common in all subgroups of AHF patients, it has been found to predict prognosis only in patients with HFrEF and HFmrEF.

 Albuminuria/physiopathology Prognosis Heart Failure Stroke Volume Hospitalization Adults Mortality Introductıon

Heart failure (HF) has been classified into three groups based on left ventricular ejection fraction (LVEF) in current guidelines; HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF), and HFwith preserved EF (HFpEF).1Acute heart failure (AHF), which can be developed in all types of HF, is a significant cause of mortality and healthcare costs in industrialized and developing countries.2, 3Despite the advances in the management of AHF in the last decades, 4% to 7% of the patients die during hospitalization, and half of them die within five years.4, 5Therefore, early prediction of mortality is essential for the management of patients with AHF, and there are many clinical and laboratory variables that predict mortality in AHF.6 - 8

Although kidney dysfunction has also been associated with increased mortality risk in AHF,9previous studies had conflicting findings regarding the importance of chronic renal disease in HFpEF compared to HfrEF,10, 11and the significance of renal functions in HFmrEF is unclear. Increased urinary albumin excretion, which might be a marker of inflammation, endothelial dysfunction, and activated the renin-angiotensin system, is a predictor of mortality and adverse events in the general population,12in patients with diabetes,13and hypertension.14The urinary albumin/creatinine ratio (UACR) in a random urine specimen is accepted as a more helpful method for evaluating renal functions. It avoids limitations of other tests such as glomerular filtration rate.15In chronic heart failure, even mild renal dysfunction, determined by the presence of microalbuminuria (defined as urinary albumin levels of more than or equal to 30-300 mg in 24 h urine collection or UACR of >30-300 mg/g in random spot urine sample), is an associated with adverse outcomes.16There are, however, few reports that examined the prognostic effect of UACRin patients with AHF. Furthermore, the prevalence and significance of microalbuminuria have not been compared in HFrEF, HFmrEF, and HFpEF. Therefore, we aimed to examine the prevalence and importance of microalbuminuria in patients with AHF secondary to HFrEF, HFmrEF, and HFpEF.

 Methods

Data of consecutive patients hospitalized through EDdue to AHF between June 2016 and June 2019 were retrospectively recorded. This study was conducted in Muğla Sıtkı Koçman University Hospital, and approved by the local institutional review board.

Inclusion Criteria

All adult patients (≥ 18 years)admitted to our ED with signs and/or symptoms of AHF and with increased N-Terminal pro-B-Type Natriuretic Peptide (NT-proBNP) levels were included.

 Exclusion Criteria

Patients who did not have UACR, LVEF, or NT-proBNP evaluation at admission, patients aged <18 years, dialysis patients, and patients discharged to home were excluded.

 Data Collection and Definitions

Patients were divided into three groups according to LVEF; patients with an LVEF <50% were defined as HFrEF, patients with an LVEF 40-49% were described as HFmrEF and patients with an LVEF < 40% were defined as HFpEF. In addition, echocardiographic criteria of diastolic dysfunction or structural heart disease were also required to determine HFpEF.

Patients’demographic characteristics and comorbidities were collected and noted from the hospital database. Definitions of demographic variables are given in the Table 1 . In addition, blood and urine samples were obtained at admission, including NT-proBNP and estimated glomerular filtration rate (eGFR) levels.17

– Patient demographics and characteristics
HFrEF (n=213) HFmrEF (n=50) HFpEF (n=163) p value
Female sex 110 (51.6) 22 (44.0) 95 (58.3) <0.001
Age, years 68.09 ± 9.58 70.85 ± 10.15 72.83 ± 10.70 0.015
Smoking 40 (18.8) 10 (20.0) 30 (18.4) 0.344
Alcohol use 10 (4.7) 3 (6.0) 8 (4.9) 0.632
Body mass index, kg/m2 27.56 ± 5.66 28.98 ± 5.92 29.43 ± 6.24 0.004
Comorbidities
Atrial fibrillation 65 (30.5) 15 (30.0) 50 (30.7) 0.845
Hypertension 160 (75.2) 38 (76.0) 121 (74.2) 0.921
Diabetes mellitus 63 (29.6) 14 (28.0) 45 (27.6) 0.814
Chronic renal disease 25 (11.7) 5 (10.0) 16 (9.8) 0.623
Coronary artery disease 95 (44.6) 26 (52.0) 66 (40.5) 0.014
Cerebrovascular disease 10 (4.7) 3 (6.0) 12 (7.4) 0.131
COPD 21 (9.9) 5 (10.0) 15 (9.2) 0.755
Signs and Symptoms
Dyspnea, NYHA class III/IV 171 (80.3) 42 (84.0) 134 (82.2) 0.510
Palpitation 130 (61.1) 30 (60.0) 105 (64.4) 0.212
Ankle swelling 70 (32.9) 15 (30.0) 51 (31.3) 0.815
Chest pain 60 (28.2) 20 (40.0) 43 (26.4) 0.004
Physical Exam
Systolic blood pressure, mmHg 122.5 ± 15.41 131.22 ± 20.66 132.30 ± 20.11 0.001
Diastolic blood pressure, mmHg 79.12 ± 11.96 80.10 ± 12.07 80.65 ± 11.86 0.109
Heart rate, bpm 88.75 ± 18.23 82.36 ± 18.05 82.55± 17.98 <0.001
Pulmonary crepitations 160 (75.2) 37 (74.0) 119 (73.0) 0.081
Laboratory
NT-proBNP, pg/ml 5859 (1896 - 11857) 3421 (1104 - 8455) 2544 (986 - 5487) <0.001
Glucose, mg/dl 118 (94 - 158) 120 (96 - 161) 119 (95 - 159) 0.742
BUN, mg/dl 22 (18 - 37) 23 (17 - 35) 22 (16 - 36) 0.291
Serum creatinine, mg/dl 1.2 (0.8 - 1.7) 1.2 (0.8 - 1.8) 1.1 (0.7 - 1.7) 0.366
Hemoglobin, g/dl 12.5 (10.1 - 14.5) 12.6 (10.5 - 13.5) 12.4 (10.8 - 14.2) 0.113
UACR 12.5 (5.9 - 1357.7) 10.3 (2.9 - 725.7) 10.1 (4.5 - 878.7) 0.001
eGFR (mL/min/1.73 m2) 68.7 ± 21.6 70.9 ± 21.3 70.7 ± 22.5 0.032
Hospitalstay,median,days 8 7 7 0.106
In-hospital mortality 14 (6.6) 1 (2.0) 4 (2.5) 0.003

Data are presented as mean ± standard deviation, number (%), or median and interquartile range. HfrEF: heart failure with reduced ejection fraction; HfmrEF: heart failure with mid-range ejection fraction; HfpEF: heart failure with preserved ejection fraction; NYHA: New York Heart Association; COPD: chronic obstructive pulmonary disease; NT-proBNP: N-terminal pro B-type natriuretic peptide; BUN: blood urea nitrogen; UACR: urinary albumin/creatinine ratio; eGFR: estimated glomerular filtration rate.

The albuminuria was defined according to the urine albumin to creatinine ratio: normoalbuminuria: <30 mg/g, microalbuminuria: 30 -299 mg/g, and macroalbuminuria: > 300 mg/g).The primary end point was in-hospital mortality.

 Statistical analysis

Data were analyzed using SPSS for Windows (version 24; SPSS Inc, Chicago, IL). A p-value of ≤0.05 was considered significant. The univariate and multivariate regression analyses were performed to study the effect of various risk factors, including microalbuminuria and macroalbuminuria, on the primary outcome.

 Results

A total of 586 adult AHF patients were admitted to our ED during the study period. However, 24 patients without LVEF data, 56 patients without NT-proBNPor UACR data, 64 patients who were discharged to home, and 16 patients with end-stage renal disease were excluded from the study ( Figure 1 ). The final study population included 426 patients (mean age 70.64 ± 10.03 years, 53.3 % female).

– Participant flow chart. NT-proBNP: N-Terminal proB-Type Natriuretic Peptide; UACR: urinary albumin/creatinine ratio; LVEF: left ventricular ejection fraction; HfrEF: heart failure with reduced ejection fraction; HfmrEF: heart failure with mid-range ejection fraction; HfpEF: heart failure with preserved ejection fraction

Comparison of baseline characteristics in heart failure subgroups

Among the study population, 50% had HFrEF, 38.3% had HFpEF, and 11.7% had HFmrEF.

The baseline characteristics of the patients are shown in Table 1 . Patients with HFpEF were older, had a higher body mass index, and were more likely to be female. Patients with HFrEF were younger, had significantly higher admission NT-pro-BNP and UACR levels, had lower systolic blood pressures but higher heart rates at presentation. Patients with HFmrEF had an intermediate biomarker profile and intermediate phenotype for comorbid diseases. Patients with HFmrEF differed from HFpEF and HFrEF, as they were more often male and more likely to have a history of coronary artery disease.

Of the 426 patients, 185 (43.4%) had increased UACR at admission; 136 patients had (31.9%) microalbuminuria, 49 patients had macroalbuminuria (11.5%), and 241 (56.6%) patients had normoalbuminuria. There were no significant differences in the prevalence of normo-, micro- and macroalbuminuria in patients with HFpEF and HFrEF. However, compared with HFpEF and HFmrEF, HFrEF patients were more likely to have micro- and macroalbuminuria and were less likely to normoalbuminuria ( Figure 2 ). The prevalence of microalbuminuria was 35.2%, 28.8%, and 28.0% in HFrEF, HFpEF, and HFmrEF, respectively. The prevalence of microalbuminuria was 13.1%, 9.8%, and 10% in HFrEF, HFpEF, and HFmrEF, respectively.

– Comparison of the prevalence of normo-, micro- and macroalbuminuria in relation to heart failure subtypes. HfrEF: heart failure with reduced ejection fraction; HfmrEF: heart failure with mid-range ejection fraction; HfpEF: heart failure with preserved ejection fraction

Comparison of Outcomes

There was no difference in length of hospital stay between patients with HFpEF, HFmrEF or HFrEF.A total of 19 (4.5%) patients died during the in-hospital course, and in-hospital mortality was higher in HFrEF patients (6.6%) compared to patients with HFpEF (2.5%), and HFmrEF (2.0%) (p = 0.004).

 Predictors of In-hospital Mortality

Multivariate analysis showed that NT-pro-BNP and macroalbuminuria had been associated with in-hospital mortality in all LVEF groups ( Table 2 ). Coronary artery disease, male gender, and diabetes mellitus predicted in-hospital mortality only in patients with HFmrEF, whereas atrial fibrillation predicted in-hospital mortality only in patients with HFrEF. Older age was an independent predictor of in-hospital mortality in patients with HFrEF and HFpEF.

– Predictors of in-hospital mortality in HF subtypes
HFrEF HFmrEF HFpEF
OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value
Coronary artery disease 2.10 (1.55-3.04) 0.065 3.45 (1.23-5.67) 0.043 1.49 (1.14-5.34) 0.089
NT-proBNP 2.68 (1.23-7.75) <0.001 2.12 (1.34-3.45) 0.011 2.01 (0.09-3.23) 0.022
Age (per 10 years) 1.75 (1.13-3.45) 0.016 1.13 (0.80-1.51) 0.076 3.12 (1.38-4.81) 0.019
Diabetes mellitus 1.21 (0.81-1.43) 0.121 2.34 (1.03-4.16) 0.043 1.20 (0.89-2.55) 0.291
Microalbuminuria 1.94 (0.91-4.21) <0.001 1.56 (1.19-3.45) 0.001 1.25 (1.12-1.68) 0.124
Macroalbuminuria 2.45 (1.34-5.65) <0.001 1.92 (1.23-2.98) 0.024 1.66 (1.34-3.84) 0.032
Chronic renal disease 1.15 (1.01-1.33) 0.293 1.32 (1.11-2.77) 0.101 1.23 (0.82-1.56) 0.451
Atrial fibrillation 1.07 (0.83-1.42) 0.013 1.23 (0.89-1.55) 0.234 1.33 (1.18-2.01) 0.098
Male gender 1.22 (0.83-1.88) 0.462 3.31 (1.13-4.23) 0.001 0.89 (0.66-1.39) 0.453

HFrEF: heart failure with reduced ejection fraction; HFmrEF: heart failure with mid-range ejection fraction; HFpEF: heart failure with preserved ejection fraction; NT-proBNP: N-terminal pro B-type natriuretic peptide.

Microalbuminuria and Prognosis

The presence of microalbuminuria on admission has been associated with in-hospital mortality in HFrEF and HFmrEF, but not in HFpEF patients. Patients with microalbuminuria and macroalbuminuria had 1.94-, and 2.45-fold higher risk, respectively, for in-hospital mortality compared to patients with normoalbuminuria in HFrEF.Compared to patients with normoalbuminuria, patients with microalbuminuria and macroalbuminuria had 1.56-, and 1.92-fold higher risk for in-hospital mortality in HFrmEF, respectively.

 Discussion

Our study has several important clinical implications: (i) Of the hospitalized AHF patients, 50% had HFrEF, 11.7% hadHFmrEF, and 38.3% had HFpEF. (ii) 43.4 % of the patients had abnormal UACR at admission to the ED. (iii) The NT-proBNP and UACRvalues and in-hospital mortality rates were the highest in HFrEF patients. (iv) The prevalence of micro- and macroalbuminuria in HFpEF was similar to HFmrEF’s and lower than HFrEF’s. (v) The prevalence of microalbuminuria was 35.2%, 28.8%, and 28.0% in HFrEF, HFpEF, and HFmrEF, respectively. (vi) The microalbuminuria predicted in-hospital mortality in HFmREF and HFrEF, but not in HFpEF.

Cardiovascular and renal diseases share similar comorbidities and risk factors. Extensive cohort studies have shown that increased UACR is associated with the development of HF in the general population.18 - 20 However, most studies have described the significance of UACR in HFrEF, and studies examining the HF subtypes separately have divergent findings.21, 22In a community-based study, Nayor et al.21found that microalbuminuria was associated with an increased risk of incident HFrEF but not HFpEF.21In contrast, the PREVEND cohort study showed that higher UACR was more strongly associated with incident HFpEF than HFrEF.22In a recent survey of 24433 patients, the association between UACR and HFpEF was greater than HFrEF after 9.3 years of follow-up.23

Renal function tests are also associated with adverse outcomes regardless of the severity of the disease in patients with established HF. However, studies investigating the impact of renal dysfunction on prognosis in the different LVEF groups also have conflicting results.24, 25In a meta-analysis, Damman et al.24showed that chronic renal dysfunction was a stronger predictor of mortality in HFpEF than in HfrEF.24In contrast, in a meta-analysis of twenty-five prospective studies, renal dysfunction was a stronger predictor of mortality in patients with HFrEF than in HFpEF.25Both meta-analyses defined chronic renal disease as an eGFR of less than 60 ml/min/1.73m2, and studies examining the prognostic value of microalbuminuria or UACR in chronic HF patients with different LVEF groups are much more limited.26 - 30 In a cross-sectional study, 72 chronic HF were enrolled, and microalbuminuria was observed in 40% of HFpEF and 24% of HFrEF patients (p = 0.04).26However, the prognostic impact of microalbuminuria was not evaluated in this study. In the CHARM study, which included chronic HF patients, the prevalence of micro- and macroalbuminuria was 30% and 11%, respectively.27When stratifying into different LVEF groups, 31% of the patients with an LVEF ≤40% had microalbuminuria, and 10% had macroalbuminuria. Of the patients with an LVEF >40%, 29% had microalbuminuria, and 12% had macroalbuminuria. The findings of the CHARM study also revealed that albuminuria was a predictor of mortality. The risk associated with UACR was similar in patients with low and preserved LVEF.27In the GISSI-HF trial, micro- and macroalbuminuria were observed in 19.9% and 5.4% of the patients, respectively. UACR independently predicted mortality in patients with chronic HF.28Nevertheless, as 90.8% of the GISSI-HF patients had an LVEF≤ 40%, a separate analysis for different LVEF groups was not performed. In the CHART-2 study, 2039 chronic HF patients were enrolled.29The authors showed that not only microalbuminuria but also subclinical microalbuminuria, which was defined as UACR 10.2–27.3 mg/g, was significantly associated with adverse cardiovascular events as compared with normoalbuminuria, particularly in patients with preserved or mildly reduced eGFR.28TOPCAT study included only HFpEF patients to investigate the benefit of spironolactone therapy.30In a subgroup analysis of the TOPCAT study, micro- and macroalbuminuria conferred a 1.47- and 1.67-fold increased risk for primary outcomes in HFpEF.30

Although the prevalence of renal dysfunction is expected to be higher in AHF patients than patients with chronic HF, few studies assessed albuminuria in the AHF setting. In a prospective study of 115 AHF patients, Koyama et al.31showed that 69% of the patients had abnormal UACR at admission (27% had macroalbuminuria, 42% had microalbuminuria).31However, on day 7, 10% of the patients had macroalbuminuria, and 30% had microalbuminuria. The resolution of UACR was associated with decreases in NT-pro BNP levels.31The frequency of abnormal UACR at admission was 43.4% in our study, lower than the Koyama and colleagues’ study. This difference may be due to younger age and lower comorbidity burden in our study.

Our study demonstrated that the microalbuminuria at admission to ED is an independent predictor of in-hospital mortality in HFmREF and HFrEF, but not in HFpEF.In HFpEF, the prognosis may be more related to comorbidities than in HFmrEF, and HFrEF, where progressive HF with subsequent renal dysfunction may be more pronounced. The relationship between HF and albuminuria is complex. It has a bidirectional nature, and the mechanisms responsible for the relation of microalbuminuria and prognosis in HFrEF and HFmrEF warrant further investigation.

Study Limitations

Our study is limited by its retrospective design and by having been conducted at a single center. Because daily changes in UACR were not recorded, we could not examine the relationship between alterations in UACR and prognosis. A single spot urine sample was used to determine UACR, which may fluctuate.

 Conclusions

In patients with AHF, microalbuminuria on admission is associated with increased in-hospital mortality in HFmrEF and HFrEF. Further prospective studies are required to explore the role of UACR as a prognostic marker in AHF.

Study Association

This study is not associated with any thesis or dissertation work.

Sources of Funding: There were no external funding sources for this study.