Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC QsHDJPMKgpt99gwwdz8DLvq S0066-782X2025000800306 10.36660/abc.20240222 00306 Artigo Original Preditores Clínicos e Laboratoriais do Desenvolvimento de Valvopatias na Doença Renal Crônica: Uma Revisão Sistemática 0009-0003-0671-491X Conceição Hayala Machado Cavalcante Concepção e desenho da pesquisa e Obtenção de financiamento Obtenção de dados Análise e interpretação dos dados e Análise estatística Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Valois Ana Luísa Vaz Obtenção de dados Análise e interpretação dos dados e Análise estatística 1 Ramos Erick Magalhães Silva Análise e interpretação dos dados e Análise estatística Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 2 Ladeia Ana Marice Concepção e desenho da pesquisa e Obtenção de financiamento Obtenção de dados Análise e interpretação dos dados e Análise estatística Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo 1 Escola Bahiana de Medicina e Saúde Pública Salvador BA Brasil Escola Bahiana de Medicina e Saúde Pública, Salvador, BA – Brasil Universidade Salvador Salvador BA Brasil Universidade Salvador, Salvador, BA – Brasil Hayala Machado Cavalcante Conceição • Escola Bahiana de Medicina e Saúde Pública – Av. Dom João VI, 275. CEP 40290-000, Brotas, Salvador, BA – Brasil E-mail: hayalaconceicao19.1@bahiana.edu.br

Gláucia Maria Moraes de Oliveira

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 08 09 2025 2025 122 08 e20240222 09 12 2024 10 03 2025 16 04 2025 This is an open-access article distributed under the terms of the Creative Commons Attribution License Resumo Fundamento:

A doença renal crônica (DRC) está associada à maior prevalência de valvopatias e à maior mortalidade por causas cardiovasculares. Aspectos que exercem influência sobre a gênese da calcificação valvar cardíaca (CVC) nestes pacientes não estão bem definidos.

 Objetivo:

Determinar fatores de risco à calcificação valvar em pacientes com DRC.

 Métodos:

Revisão sistemática baseada no PRISMA, que incluiu estudos observacionais avaliando a associação entre aspectos clínicos e laboratoriais e CVC em pacientes com DRC, realizando ou não hemodiálise ou diálise peritoneal. Os artigos foram obtidos em bases de dados (MEDLINE; SCIELO; CENTRAL; EMBASE; LILACS/BVS) e selecionados por dois autores de forma cega; um terceiro atuou em discrepâncias. Coleta e síntese dos dados foi realizada pela autora principal. Avaliação da qualidade metodológica e risco de viés embasados no STROBE e Newcastle-Ottawa.

 Resultados:

Foram encontrados 783 estudos, dos quais 20 foram incluídos, englobando 13 314 pacientes em 10 países. Os aspectos mais fortemente associados à CVC foram idade > 55 anos, taxa de filtração glomerular < 53mL/min/1,73m2, terapia renal substitutiva (TRS) > 20 meses, hipoalbuminemia, proteína C reativa (PCR), níveis séricos de IL-6, TNF- α, paratormônio, hiperfosfatemia, hipercalcemia, produto Ca x P e FGF-23 decorrentes do hiperparatireoidismo secundário. Foram estudadas valvas mitral e aórtica. Não houve diferença entre hemodiálise versus diálise peritoneal.

 Conclusão:

Idade, TRS, inflamação crônica e hiperparatireoidismo favorecem a deposição de Ca e P nas válvulas, tornando os pacientes com DRC mais susceptíveis à CVC. O acompanhamento de tais parâmetros permite oportunidades de prevenção e tratamento.

 Palavras-chave: Doenças das Valvas Cardíacas Insuficiência Renal Crônica Fatores de risco Introdução

Causas cardiovasculares correspondem a mais de 50% dos óbitos em pacientes com doença renal crônica (DRC) em comparação à população geral,1 e a prevalência de valvopatias é significativamente maior neste grupo.2 Anormalidades valvulares, principalmente em válvulas aórtica e mitral, bem como necessidade de hemodiálise (HD) ou diálise peritoneal (DP) são marcadores de morbimortalidade. Entretanto, esse é um dos aspectos menos abordados no estudo da DRC, tendo sua relevância ignorada por muitos profissionais.

A patogênese das valvopatias envolve processos inflamatórios (sistêmicos e locais), ação modificada do hormônio paratireoidiano (PTH) no hipertireoidismo secundário,3–5 desordens no metabolismo cálcio-fósforo,5,6 tipo (HD ou DP), duração da diálise,3,7,8 níveis séricos de colesterol,3,9 albumina,3,9 além da volemia.9 Entretanto, os aspectos que de fato estão envolvidos na patogênese da calcificação valvar e valvopatias em pacientes com DRC, e que justifiquem a maior prevalência de tais condições neste grupo, não estão bem definidos.2

O objetivo desta revisão sistemática é identificar possíveis preditores clínicos e laboratoriais que constituam fatores de risco para a calcificação valvar em indivíduos com DRC que estejam ou não realizando HD ou DP.

 Métodos

A revisão sistemática foi conduzida de acordo com o Preferred Reporting Items for Systematic Reviews and Meta-Analysis para protocolos (PRISMA-P) e submetido ao registro no Prospective Register of Systematic Reviews (PROSPERO) (CRD42021291576).

Estratégia de busca

A estratégia de busca utilizou DeCS (Descritores em Ciências da Saúde) e MeSH Terms (Medical Subject Readings), nas plataformas MEDLINE (Medical Literature Analysis and Retrieval System), LILACS (Literatura LatinoAmericana e do Caribe em Ciências da Saúde), SCIELO (Scientific Electronic Library Online), Biblioteca Cochrane (CENTRAL) e EMBASE. A busca com MeSH Terms foi a seguinte: ((((((End-Stage Kidney Disease) OR (Chronic Kidney Failure) OR (End-Stage Renal Disease) OR (Chronic Renal Failure) OR (End-Stage Renal Failure)))))) OR (Dialysis) AND ((Risk Factor) OR (Risk Factors)) AND ((Heart Valve Disease) OR (Valvulopathy)) AND (Calcification). A busca com termos DeCS foi (Insuficiência Renal Crônica) OR (Doença Renal Crônica) AND (Valvulopatia) OR (Valvopatia).

 Critérios de elegibilidade

Estudos observacionais, em português, inglês e espanhol, que incluíssem pacientes com DRC (com ou sem diálise) e avaliassem a associação entre aspectos clínicos/laboratoriais e calcificação valvar foram considerados elegíveis. Estudos com dados incompletos ou que não atenderam a todos os critérios foram excluídos.

 Identificação e seleção de estudos

Dois autores realizaram a seleção de artigos no programa Rayyan QCRI, e um terceiro atuou nos casos de discordância. O Teste de Concordância Kappa (K) avaliou a concordância dos revisores. Referências de artigos relevantes foram verificadas e o fluxograma PRISMA resumiu as etapas de seleção.

 Extração e análise de dados

A coleta de dados foi realizada pela autora principal em formulário eletrônico baseado no Critical Appraisal and Data Extraction for Systematic Reviews of Prognostic Factor Studies (CHARMS-PF Checklist).

A qualidade metodológica e o risco de vieses foram avaliados pelo The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) e a escala Newcastle-Ottawa (NOS), respectivamente. Os estudos incluídos apresentaram desempenho moderado nas análises, conforme demonstrado nas tabelas a seguir.

 Resultados Seleção dos estudos

Foram identificados 790 artigos, sendo 783 por bancos de dados e sete por busca manual e listas de referências. Após remoção de duplicatas e aplicação dos critérios de elegibilidade, 20 artigos foram selecionados (Figura 1), sendo 13 de metodologia transversal, seis coortes e um caso-controle, englobando 13 314 pacientes em 10 países, com amostras variando de 30 a 3929 participantes. A concordância entre os examinadores, na seleção dos artigos, apresentou um valor de Kappa > 0,758 (boa concordância).

Fluxograma dos estudos avaliados nesta revisão.

Alguns estudos avaliaram pacientes com DRC sem categorização dos estágios da doença (que variam de 01 a 05 pela literatura),4 e outros estudos incluíram apenas pacientes em determinados estágios. Houve estudos que incluíram pacientes sob realização de terapia renal substitutiva (TRS) e outros que avaliaram especificamente HD ou DP. Os artigos incluídos empregaram análises multivariadas e adotaram metodologias distintas.

A Tabela 1 resume as principais características dos 20 estudos incluídos, com informações sobre amostras populacionais e pontuação obtida por cada um deles.

Características gerais dos estudos incluídos na revisão sistemática, amostras populacionais e pontuação na análise de qualidade
Autores, ano e país Desenho do estudo Descrição da amostra (n) Desfecho avaliado Sexo Masculino (%) Média de idade (anos) STROBE Newcastle-Ottawa
Alamir et al, 2015,EUA10 Transversal DRC leve a moderada (n=2070) CAM;TC não contrastada 53,7% 58 (21-74) 86,36% 4
Asselbergs et al, 2008, EUA20 Coorte retrospectiva DRC(n=3929) CAM, CAA e EVA; ECO-2D 60% 74 ± 5 90,9% 5
Avila-Díaz et al, 2013, México14 Coorte prospectiva DRC sob DP (CAPD ou DPA) (n=124) CVC geral; ECO-2D 68,5% 46 (30-54) 95,45% 7
Chen et al, 2021, China25 Caso-controle DRC estágios 2 a 5 (n=180) CVC geral; ECO-2D 63% 58 ± 14 86,36% 2
Di Lullo et al, 2015, Itália26 Transversal DRC estágios 3 e 4 (n=100) CVC geral; ECO-2D 60% 51 (46-56) 72,72% 4
Engole et al, 2020, República Democrática do Congo15 Transversal DRC sob HD (n=60) CVC geral; ECO-2D 71,6% 52,5 ± 15,9 72,72% 6
Fernández et al, 2021, Espanha11 Coorte prospectiva DRC estágios 2- 5, sob TRS ou não (n=397) CVC geral; ECO-2D 61% 59,1 ± 11,5 72,72% 5
Fox et al, 2006, EUA22 Transversal DRC(n=3047) CVC geral; ECO-2D 47,6% 59 ± 10 90,9% 5
Genctoy et al, 2015, Turquia38 Transversal DRC sob HD (n=76) CVC geral; ECO-2D 64,47% 60,5 ± 15,5 77,27% 6
Guerraty et al, 2015, EUA12 Transversal TFG 20-70 ml/min/1,73m2 e CVA (n=1923) CVA; TC não contrastada 53% 58,45 ± 11,45 90,9% 7
Guo et al, 2020, China16 Transversal DRC sob HD (n=145) CVC geral; ECO-2D com Doppler 54,5% 50 (23-74) 81,8 5
Hoshina et al, 2011, Japão27 Coorte retrospectiva DRC sob HD (n=30) Estenose aórtica; ECO-2D EAPR (n=30):40% EAPL (n=30): 53% EAPR:73,6 ± 6,1 EAPL:69,8 ± 7,5 81,81% 6
Ikee et al, 2010, Japão17 Transversal DRC sob HD (n=112) CVC geral; ECO-2D 68,7% 67 ± 10 86,36% 6
Plytzanopoulou et al, 2020, Grécia18 Transversal DRC sob HD(n=42) CVC geral; ECO-2D 69% 72,97 ± 11,6 95,45% 5
Rong et al, 2018, China13 Transversal DRC(n=288) CVC geral; ECO-2D 65,9% CVC: 70,42±11,83; Sem CVC:56,47±15,00 81,81% 3
Sayarlioglu et al, 2013, Turquia19 Transversal DRC sob HD (n-129) CVC geral; ECO-2D CVC: 52,3% Sem CVC: 46,5% CVC:48,2 ± 16,8 Sem CVC: 60,3 ± 13,5 77,27% 6
Silva et al, 2022, Portugal23 Transversal Diabéticos com DRC estágios 2- 4 (n=80) CVC geral; ECO-2D 71,3% 56 ± 8,1 81,81% 6
Tian et al, 2016, China3 Coorte prospectiva DRC sob DP(n=194) CVC geral; ECO-2D 54% 61,6 ± 12,5 90,9% 7
Usuku et al, 2019, Japão24 Coorte retrospectiva DRC sob HD (n=95) CAM; ECO-2D CAM (n=28): 54% Sem CAM (n=67): 54% CAM (n=28):65 ± 10,7 Sem CAM (n=67):62,6 ± 13,2 86,36% 7
Xiong et al, 2022,China21 Transversal DRC estágios terminais, sob HD(n=293) CVC geral; ECO-2D, TC e/ou AngioTC em alguns casos 54,6% 64 ± 7,0 77,27% 4

AngioTC: angiotomografia computadorizada; CAM: calcificação do anel mitral; CAA: calcificação do anel aórtico; CVC: calcificação de válvula cardíaca; capd: diálise peritoneal contínua ambulatorial; DPA: diálise peritoneal automática; DP: diálise peritoneal; DRC: doença renal crônica; EAPR: Estenose Aórtica de progressão rápida; EAPL: estenose aórtica de progressão lenta; EVA: esclerose do anel aórtico; ECO-2D: ecocardiograma bidimensional; HD: Hemodiálise; TC: tomografia computadorizada; TRS: terapia renal substitutiva; o nível de significância estatística foi p < 0,05, exceto para o estudo de Engole et al.,15 que não determinou o valor em seus métodos.

 Síntese dos resultados

Foram identificados 38 fatores de risco para calcificação valvar. A Tabela 2 resume os estudos que avaliaram fatores de risco em pacientes com DRC em geral. A Tabela 3 mostra os resultados dos estudos que incluíram apenas pacientes sob TRS, seja HD ou DP. Os resultados estão condensados na Figura Central.

Fatores de risco identificados em estudos que incluíram pacientes com doença renal crônica em geral
Autores, ano e país Desfecho avaliado e método de definição Fatores de risco identificados no estudo Calcificação valvar e/ou valvopatias encontradas
Alamir et al, 2015, EUA10 CAM em duas TCs pelo algoritmo de Agatston. CAM associada a TFG < 50ml/min/1,73m2(ORa = 2,30, IC95% 1,40-3,79),idade > 55 anos (OR = 4,01, IC95% 2,55-6,32),fosfato > 4,1 mg/dl (OR = 3,33, IC95% 1,37-8,09) Prevalência CVM: 331 (16%).
Asselbergs et al., 2008, EUA20 CAM e CAA; hiperecogenicidade em ECO-2D;espessamento da cúspide aórtica e velocidade de fluxo <2,0m/s. TFG <45 mL/min/1,73 m2 (OR =1,15, IC95% 1,03-1,12, p=0,015) e cistatina C (OR = 1,12; IC95% 1,03-1,23, p=0,013)associados a prevalência de CAM CAM leve: 1495, moderada: 133 grave: 12.CAA: leve: 1698, moderada: 49, grave: 1.Esclerose aórtica em 2114.
Chen et al., 2021, China25 CVC geral, massas hiperecogênicas de diâmetro ≥1 mm em ECO-2D Doppler. CVC associada creatinina sérica(DRC5, 845,09 ± 334,18 umol/L, p<0,05),FGF-23 (DRC5, 1039,43 ± 214,83 pg/ml, p<0,05) eproteína Klotho (DRC2-3, 159,05 ± 27,53 U/L, p<0,05)Pacientes em estágio 5 possuíram maiores níveis de Hb (90,52 ± 23,36 g/L, p<0,05), albumina (36,61 ± 4,37 g/L, p<0,05), osteocalcina (197,32 ± 78,88 ng/ml, p<0,05), PTH (392,40 ± 233,88 pg/ml, p=0,05) e FA ósseo-específica (86,36 ± 18,18 U/L, p=0,05) e menores níveis de cálcio sérico corrigido (2,06 ± 0,15 mmol/L, p<0,05). CVC total: 41 (22,7%);4 pacientes em DRC 2-3; 12 pacientes em DRC4, 25 pacientes em DRC5.
Di Lullo et al., 2015, Itália26 CVC geral por Escore de Wilkins em ECO-2D. CVA e PTH (r2 = 0,212 p=0,03) e FGF-23 (r2 = 0,272; p=0,01).Escore de CVM associado ao cálcio sérico (r2 = 0,565; p=0,01) CVC total: 100%. CVM: 96;61 em escore 1, 34 em escore 2, 1 em escore 3.CVA: 100 (100%).
Fernández et al., 2021, Espanha11 CVM massas > 5mm e CVA > 2mm, em ECO-2D. CVM associada a idade (OR = 1,05. IC95% 1,03-1,08), doença vascular periférica (OR = 4,22, IC95% 1,53-13,12) eproduto Ca x P (OR = 1,03, IC95% 1,01-1,05)CVA associada a idade (OR = 1,10, IC95%1,05-1,15),níveis de P (OR = 1,64, IC95% 1,16-2,42), aterosclerose e maior área total de placa carotídea (OR = 3,10, IC95% 1,18-8,80) CVM aumentou de 96 (24,2%) para 123 (31%).CVA Aumentou de 119 (30%) para 171 (43,1%).
Fox et al., 2006, EUA22 CVC geral; CVM se massas hiperecogênicas > 0,3cm no Modo M ou mais de 1/3 do anel na janela paraesternal.CVA se mais de ½ do anel hiperecogênico. CVC associada a HAS (67%, p<0,01),DM (21%, p<0,05), colesterol total/HDL (4,8 ± 1,8, p<0,01) eIMC (29,2 ± 5,2 kg/2, p<0,001);TFG significativamente menor nos pacientes com CVC(TFG = 78 ± 25ml/min/1,73m2, p<0,001) CVC total: 284 (9,3%).CVM: 130 (4,3%).CVA: 112 (3,7%). EVA: 188 (6,2%).
Guerraty et al, 2015, EUA12 CVA pela pontuação do algoritmo de Agatston, TC não contrastada. Associação independente entre CVA moderada/grave e idade (respectivamente, 62,26 ± 7,9 e 66,53 ± 7 p<0,001),IMC (31,73 e 31,72, p<0,0007),CA (105,01 ± 15,53 e 106,81 ± 14,31, p<0,001),PAS (127,75 ± 21,99 e 132,28±21,21, p <0,001),hipercolesterolemia (463/90% e 401 94%, p<0,001),HbA1c (6,73 ± 1,52% e 6,64 ± 1,36%, p<0,001), eMET reduzido (198,37 ± 25,59 e 178,24 ± 120,95, p<0,001) eDM (281/55% e 52/59%, p<0,001), HAS (478/93% e 409/96%), p<0,001 ou doença cardiovascular (149/29% e 176/41%, p<0,001); PCR (4,85 ± 7,29 e 5,48 ± 8,77, p=0,0100),homocisteína plasmática total (14,17 ± 4,86 e 16,55 ± 7,06, p<0,001) e ALP(a) (100,84 ± 34,99 e 99,7± 34,23), p=0,0041.TFG média foi de 44,6 ml/min/1,73 m2 e foi associada a CVA (p<0,0001). CVA leve a moderado: 515 (26,8%)CVA grave: 426 (22,1%).
Rong et al., 2018, China13 CVC total, massas hiperecogênicas > 1mm em ECO-2D com Doppler. CVC associada a idade(70,42 ± 11,83 anos, p<001; OR = 1,091, IC95% 1,048-1,136, p<0,05), níveis menores de pré-albumina (238,44 ± 91,48 g/L, p=0,05), colesterol (OR = 0,488, IC95% 0,306-0,780, p=0,03),TG (1,4 ± 0,65 mmol/L, p=0,37) eAPO-E (37,3, de 30,2-45,6 mg/L, p=0,09),LDL (OR = 163,028, IC95% 3.796-7002.467, p=0,08),PCR (5,5, de 0,5-16,35 mg/L, p=0,04) eIL-6 (18,76, de 5,95-46,9 pg/mL, p=0,05).Grupo com CVC em estágios mais avançados da DRC (em estágio 5 sob diálise, 30,3% com CVC vs. 18,9% sem CVC, p=0,048). CVC total: 66 (22,9%).CVM: 14(21,2% dos 66); CVA:100% dos 66).
Silva et al., 2022, Portugal23 CVC total; CVM pelo Escore de Wilkins e CVA com Escore proposto por Lullo et al, em ECO-2D. CVM e CVA possuíam menores TFGe (p< 0,0001), GRP (p< 0,0001), Mg (p= 0,029 para CVM e p= 0,001 para CVA) e α Klotho (p= 0,002), e níveis mais elevados de P (p= 0,001), PTH (p= 0,025 para CVM e p=0,030 para CVA), FGF-23 (p< 0,0001) e TNF-α (p=0,037). Houve correlação negativa entre GRP e CVM (r =-0,754, p< 0,0001) e níveis baixos são fatores de risco independente para CVM (ORa = 0,268, 95% IC 0,101-0,725, p= 0,005; aPR = 0,750; IC 95% 0,456–0,976;p= 0,024) e CVA (ORa = 0,202, IC95% 0,109-0,401, p= 0,022;aPR = 0,813; IC 95% 0,113–0,937; p< 0,0001).O mesmo para baixos níveis de Mg e CVM (ORa = 0,747, IC95% 0,263-0,921, p= 0,003; aPR = 0,762; IC95% 0,256–0,963; p = 0,02) e CVA (ORa = 0,580, IC95% 0,173-0,948, p= 0,008; aPR = 0,809; IC95% 0,391–0,974; p= 0,006).Também são fatores de risco altos níveis de P (para CVM,ORa = 1,078, IC95% 1,0-1,612, p= 0,001; para CVA, ORa = 1,497, IC95% 1,004-2,378, p= 0,002) e FGF-23 (para CVM, ORa = 1,209, IC95% 1,099-1,619, p= 0,035; para CVA, ORa = 1,126,IC95% 1,034-1,436, p= 0,011). CVM: 29 (36,2%);CVA: 29 (36,2%).

FA: fosfatase alcalina; APO-E: apolipoproteína E; aPR: adjusted prevalence ratio CAPD: diálise peritoneal ambulatorial contínua; CA: Circunferência abdominal; CAM: calcificação do anel mitral; CAA: calcificação do anel aórtico; CVC: calcificação da valva cardíaca; CVA: calcificação da valva aórtica; CVM: calcificação da valva mitral; DM: diabetes mellitus; DRC: doença renal crônica; DPA: diálise peritoneal automatizada; ECO-2D: ecocardiograma Bidimensional; EVA: esclerose do anel aórtico; FGF-23: fator de crescimento de fibroblastos 23; GRP: proteína Gla-Rich; HAS: hipertensão arterial sistêmica; Hb: hemoglobina; HbA1c : hemoglobina glicada; HDL: lipoproteína de alta densidade; IMC: índice de massa corporal; ITB: índice tornozelo-braquial; LDL: lipoproteína de baixa densidade; MET: "metabolic equivalent of task". Mg: magnésio; OR: odds ratio; ORa: odds ratio ajustado; P: fósforo; PAS: pressão arterial sistólica; PCR: proteína C Reativa; PTH: paratormônio; TC: tomografia computadorizada; TFG: taxa de filtração glomerular; TG: triglicerídeos; TNF-α: fator de necrose tumoral alfa; TRS: terapia renal substitutiva; o nível de significância estatística foi p < 0,05.

 Fatores de risco identificados em estudos que incluíram apenas pacientes com DRC sob terapia renal substitutiva
Autores,ano e país Desfecho avaliado e método de definição Fatores de risco identificados no estudo Calcificação valvar e/ou valvopatias encontradas
Avila-Díaz et al., 2013, México14 CVC geral, ecos brilhantes > 1 mm; ECO-2D. CVM associada a idade (RR=1,051, IC95% 1,06-1,09, p=0,02),DM (RR=0,287, IC95% 0,1-0,8, p=0,01),osteoprotegerina (RR=1,15, IC95% 1,03-1,21, p=0,008),PTH (RR=0,41, IC95% 1,08-50,5, p=0,04) ePCR (RR=1,09, IC95% 1,04-1,19, p=0,04).iPTH (RR = 2.002, IC95% 1,052–3,81, p<0,034) para CVA. CVC total: 57 (46%);CVM: 15 (26,3%); CVA: 33 (57,8%); calcificação em ambas as válvulas:9 (15,8%).
Engole et al., 2020, República Democrática do Congo15 CVC geral, ecos brilhantes > 1 mm;ECO-2D com Doppler. Idade > 60 anos (ORa = 4,48; IC95% 1,67-30,10, p=0,003), tabagismo (ORa=4,57; IC95% 1,15-13,36, p=0,016),níveis de P (ORa=2,17; IC95% 1,83-5,65, p=0,012) e hipertensão (ORa=3,963, 95% IC 1,24–15,7, p=0,014)foram independentemente associados a CVC. CVC total:23 (38%);desses,CVM: 23%;CVA: 64%.
Genctoy et al, 2015, Turquia38 CVC geral, ecos brilhantes > 1 mm; ECO-2D. CVC associada a T-PAFT(OR=1.006, não apresenta IC, p=0,04). CVC total:50 (65,8%);18 (23,7%) em uma cúspide e32 (42,1%)em duas.
Guo et al., 2020, China16 CVC geral com calcificação avaliado pelo GCCS; ECO-2D Doppler. Idade (r = 0,25; p=0,003), duração da hemodiálise (r = 0,27; p=0,001), e iPTH sérico (r = 0,18; p=0,03) e ALP sérica (r = 0,24; p=0,003; OR =3,87, IC95% 1,86–8,07, p<0,001; ORa = 3.92, IC95% 1,37–11,2, p=0,011; em análise por Splines Cúbicos, a probabilidade de GCCS = 1 aumentou significativamente quando FA ultrapassou o valor 232 U/L). Houve correlação negativa com albumina sérica (r = –0,22; p=0,008). FA>232 U/L e idade > 60 anos são determinantes para alto risco de CVC. CVC GCCS ≥ 1: 83.
Hoshina et al., 2011, Japão27 Estenose aórtica definida a partir da progressão do GPP entre dois ECO-2D com intervalo de3 meses. Pressão arterial sistólica(161 ± 21,5 mmHg, OR = 1,06, IC95% 1-1,11, p=0,04)e níveis séricos de cálcio(9,66 ± 1,05 mg/dl, OR = 6,08, IC95% 1,28-28,8, p=0,02). EAPR: 15;EAPL: 15.
Ikee et al, 2010, Japão17 CVC geral, ecos brilhantes > 1 mm; ECO-2D. Idade associada a CVC geral (para CVA, OR = 1,06, IC95% 1,01-1,11, p=0,01. Para CVM, OR = 1,04, IC95% 1,01-1,09, p=0,04).Cálcio associado à CVA (OR = 2,16, IC95% 1,05-4,44, p=0,03)B2-microglobulina sérica associada à CVM (OR = 1,10, IC95% 1,01-1,2, p=0,01) e correlacionou-se com a duração da HD(r = 0,273, p=0,004), albumina sérica (r = 0,209, p=0,02), colesterol total (r = 0,243, p=0,01), triglicerídeo (r = 0,189, p=0,04), HDL-C(r = 0,337, p=0,001), e PCR (r = 0,246, p=0,009). CVM: 58 (51,7%); CVA: 85 (75%); calcificação em ambas as válvulas:48 (42,8%).
Plytzanopoulou et al., 2020, Grécia18 CVC geral,ECO-2D. Idade (AUC 0,734, IC95% 0,58–0,89, p=0,011),PCR (AUC 0,692, IC95% 0,516–0,868, p =0,03) diminuição na albumina sérica (AUC 0,73, IC95% 0,57–0,89, p=0,012) são preditores positivos de CVC.Idade >76,5 anos (OR 9,56, IC95% 1,54–59,42, p= 0,015) e PCR>3,5 mg/dl (OR 9,26, IC95% 1,51–56,83), p=0,016)associados a CVC de alto grau. CVC ausente ou leve em24 (57,15%); CVC moderada ou grave em18 (42,85%).CVM: 21 (50%); CVA: 16 (38,10%).
Sayarlioglu et al, 2013, Turquia19 CVC geral,ECO-2D. Idade avançada (60,3 ± 13,5 anos, p<0,001) e baixa albumina sérica (3,7 ± 0,5 mg/dl, p=0,02) foram associadas a calcificação e ambas as válvulas. DM associada a CVM (16,3%, p=0,02).Duração da diálise dos pacientes com CVM e CVA foi significativamente maior do que a de outros grupos(19,6 ± 40,6 meses vs. 7,1 ± 5,8 meses, p=0,01). CVC total:43 (33,3%);CVM: 30 (23,3%); CVA: 28 (21,7%).
Tian et al, 2016, China3 CVC geral,se ecos brilhantes de > 1 mm;ECO-2D. CVC associada a DP crônica(OR=1.039, IC95% 1.004-1.075, p=0,03),níveis séricos de P (OR=2.569, IC95% 1.227-5.377, p=0,01),diminuição dos níveis séricos de albumina(OR albumina =0,935, IC95% 0,877-0,997, p=0,01). CVC total: 97 (32%).CVM: 7 novos casos;CVA: 30 novos casos;
Usuku et al, 2019, Japão24 CAM, definida como massa ecodensa ≥ 5mm na junção do sulco atrioventricular e folheto posterior da valva mitral; ECO-2D. A duração da terapia de hemodiálise foi significativamente maior em pacientes com CAM do que naqueles sem(13,4 ± 8,6 anos vs. 7,7 ± 8,4 anos; p<0,01) e houve associação entre duração da HD e CAM (OR-1,09, IC95% 1,02–1,16; p<0,01).O número de fatores de risco coronariano (HAS, dislipidemia, tabagismo e DM) foi significativamente maior no grupo progressão da CAM do que no grupo não progressão(1,91 ± 0,83 vs. 1,18 ± 0,99; p=0,03)e houve associação entre ambos(OR = 2,67; IC95% 1,24–5,76; p=0,01). CAM: 28 (29%), com diâmetro transverso do anel mitral = 12,4 ± 7,4 mm.
Xiong et al, 2022, China21 CVC geral, por ECO-2D;282 também realizaram TC. AngioTC se placa calcificada com mais de 130 na TC, HD há ≥ 36 meses (OR = 2,25; IC95% 1,26-4,02, p=0,006),DM (OR = 1,81, IC95% 1,04-4,12, p=0,037),níveis baixos de albumina sérica(considerando albumina ≥ 40 g/L vs. < 40 g/L comOR = 0,54, IC95% 0,29-0,99 p=0,047),cálcio sérico ≥ 2,11 mmol/L(OR = 2,04, IC95% 1,01-4,12, p = 0,046) epressão de pulso > 72 mmHg(OR = 3,22, IC95% 1,85-5,59, p<0,001)foram independentemente associados a CVC CVC total: 93; CVM: 37;CVA: 68; calcificação em ambas as válvulas: 12.

AngioTC: angiotomografia computadorizada; CAM: calcificação do anel mitral; CAPD: diálise peritoneal ambulatorial contínua; CVC: calcificação de válvula cardíaca; DM: diabetes mellitus; DPA: diálise peritoneal automatizada; EAPR: estenose aórtica de progressão rápida; EAPL: estenose aórtica de progressão lenta; FA: fosfatase alcalina; GCCS: sistema global de pontuação de cálcio cardíaco; GPP: gradiente de pico de pressão; HAS: hipertensão arterial sistêmica; HD: hemodiálise; PP: pressão de pulso; PCR: proteína C Reativa; T-PAFT: tecido adiposo periaórtico torácico; aOR: adjusted odd ratio; o nível de significância estatística foi p < 0,05, exceto para o estudo de Engole et al.,15 que não determina o valor em seus métodos.

O fator associado mais frequente foi idade avançada, presente em 10 publicações.10–19 Para Alamir et al.,10 houve associação positiva a partir dos 55 anos (OR = 4,01, IC95% 2,55-6,32). Observou-se associação acima de 60 anos nos estudos de Engole et al.15 (ORa = 4,48; IC95% 1,67-30,10; p=0,003) Guo et al.16 (r = 0,25; p=0,003), Guerraty et al.12 (CVA moderada/grave, respectivamente, 62,26 ± 7,9 e 66,53 ± 7 p<0,001), e Sayarlioglu et al.19 (60,3 ± 13,5 anos, p<0,001); e Rong et al.13 acima dos 70 anos (70,42 ± 11,83 anos, p<001; OR = 1,091, IC95% 1,048-1,136; p<0,05). Alguns estudos não estabeleceram um valor de referência.11,14,16–18

Baixa taxa de filtração glomerular (TFG) na ausência de TRS10,12,20–23 foi outro fator associado, sendo TFG < 50mL/min/1,73m2 no estudo de Alamir et al.10 (ORa = 2,30; IC95% 1,40-3,79), ou menor que 45mL/min/1,73m2 no estudo de Asselbergs et al.20 (OR =1,15; IC95% 1,03-1,12, p=0,015) e Guerraty et al.12 (p<0,0001). Fox et al.22 relataram associação com TFG = 78 ± 25mL/min/1,73m2 (p<0,001), nível considerado reduzido com base nos valores de TFG normais (90 mL/min/1,73 m2),4 mas acima do valor de corte determinante de DRC. A cistatina C obteve associação com Calcificação do Anel Mitral (CAM) no estudo de Asselbergs et al.20 (OR = 1.12; IC95% 1,03-1,23; p=0,013).

Em pacientes sob HD ou DP, a cronicidade desses procedimentos também foi associada à calcificação valvar cardíaca (CVC).3,16,19,21,24 Sayarlioglu et al.19 observaram que pacientes com CVC estavam realizando HD há mais tempo (19,6 ± 40,6 meses vs. 7,1 ± 5,8 meses em não TRS, p=0,01). Xiong et al.21 obtiveram associação significativa entre CVC e HD há mais de 36 meses (OR = 2,25; 95%IC 1.26-4.02, p=0,006,). Usuku et al.24 demonstraram resultado semelhante para calcificação da valva mitral (CVM), comparando grupos que iniciaram a TRS há mais tempo (13,4 ± 8,6 anos vs. 7,7 ± 8,4 anos; OR-1,09; IC95% 1,02–1,16; p<0,01). Tian et al.3 analisaram especificamente DP, obtendo associação positiva para duração superior a 20 meses (OR=1,039; IC95% 1,004-1,075, p=0,03).

Níveis reduzidos de albumina sérica foram associados a CVC em diversos estudos,3,13,16,18,19,21,25 com destaque para pacientes sob TRS. Rong et al.13 associaram a CVC a níveis de pré-albumina entre 238.44 ± 91.48 g/L, p=0,05. Para Plytzanopoulou et al.,18 essa diminuição é um preditor positivo de CVC, considerando a AUC 0,73, IC95% 0,57–0,89, p=0,012. Chen et al.25 identificaram maiores níveis de albumina sérica em pacientes com CVC em estágios mais avançados da DRC (36.61 ± 4.37 g/L, p<0.05).

O único marcador inflamatório associado à CVC foi a proteína C reativa (PCR).12–14,18 Guerraty et al.12 demonstraram correlação direta entre PCR e gravidade da Calcificação da Válvula Aórtica (CVA), considerando níveis 4.85 ± 7.29 mg/L para CVA moderada e 5.48 ± 8.77 mg/L para CVA grave, p=0,01. Rong et al.13 observaram que pacientes com qualquer CVC possuíam níveis superiores da PCR (valor médio de 5.5, de 0.5-16.35 mg/L, p=0,04.). Já dentre os estudos que abarcaram pacientes sob TRS, Avila-Díaz et al.14 obtiveram associação com RR=1.09, IC95% 1.04-1.19, p=0,04, enquanto Plytzanopoulou et al.18 relataram AUC = 0,692, IC95% 0,58–0,89, p=0,03.

As alterações em fatores minerais e hormonais apareceram com frequência nos estudos incluídos. Níveis séricos de fosfato,3,10,11,15,23 cálcio,17,21,25–27 produto CaxP,11,15 PTH,14,16,25,26 FGF-2323,25,26 e do cofator Klotho23,25 foram associados direta e positivamente a CVC.

 Discussão

Foram identificados diversos preditores de calcificação valvar e valvopatias em pacientes com DRC, sendo a idade avançada o mais citado, com valores de corte superiores a 55 anos. Os resultados foram similares em estudos que calcularam a chance de CVM e CVA separadamente, permitindo concluir que o envelhecimento afeta similarmente ambas as válvulas, corroborando com outros estudos.28,29 Mesmo em pacientes sem DRC, a idade é relevante para o desenvolvimento de calcificação valvar de etiologia degenerativa, com prevalência em 10% da população idosa,30 além de ser um fator de risco tradicional para outras condições cardiovasculares.9

A redução progressiva e irreversível da TFG, persistente por ao menos três meses, e em níveis inferiores a 60 mL/min/1,73m2,2 constituiu um dos critérios para o diagnóstico de DRC.4 Nesta revisão sistemática, os estudos mostraram associação entre TFG e CVC a partir de 45-50ml/min/1,73m2.10,12,20 A duração da TRS e hipoalbuminemia também foram identificados como fatores de risco. A maioria dos estudos investigou a possibilidade de associação da cronicidade da HD com CVC, 16,19,21,24 e a duração variou entre 19,6 meses e 13,4 anos. London et al.31 afirmaram que os mecanismos de diálise promovem um ciclo repetitivo de estresse valvar devido à velocidade do fluxo sanguíneo e o grau de turbulência. Em relação à comparação entre HD e, Wang et al.29 afirmaram que condições cardiovasculares são similares entre os pacientes de ambas as modalidades. Em contrapartida, Mary Laxton,32 em artigo de revisão, apontou que a DP pode lentificar o processo de calcificação por preservar certa função renal residual, superando a HD. Não é possível afirmar que a maior frequência de achados em relação à HD, nesta presente revisão sistemática, deva-se a um maior risco de tal modalidade, uma vez que aproximadamente 90% da população sob alguma TRS a realiza.33

Esta revisão sistemática observou associação entre baixos níveis séricos de albumina (< 3,5 g/d) e CVC em pacientes sob TRS. Santos et al.34 concluíram que, além da desnutrição, fatores como redução na taxa de síntese devido a acidose metabólica, inflamação e insuficiência na ingestão proteica, a hemodiluição e a membrana utilizada na TRS (principalmente quando esterilizadas com hipoclorito de sódio) favorecem essa redução de albumina sérica em pacientes sob HD.34 Disfunção endotelial e aterosclerose secundárias à ação das proteínas de fase aguda e de citocinas inflamatórias também poderiam explicar a CVC.9 Vale ressaltar que Wang et al.35 observaram que pacientes com CVC sob DP eram significantemente mais desnutridos e tinham menores níveis de albumina sérica do que aqueles sem CVC, e a prevalência de CVC era maior quanto menor fossem tais níveis. Extrapolando a CVC, hipoalbuminemia é um conhecido preditor independente de eventos cardiovasculares de forma geral e de mortalidade e inflamação sistêmica crônica na DRC.9

A evidência científica atual aponta para uma relação positiva entre a elevação de marcadores inflamatórios e DRC, como observado por Shankar et al.36 que avaliou os fatores IL-6, TNF- α, PCR e contagem das células brancas, com maior associação para o TNF- α. Nesta revisão sistemática, três marcadores foram associados à CVC: a PCR, IL-6 e TNF- α, sendo apenas a primeira citada também em pacientes sob TRS. É sabido que a inflamação é comum nos estágios mais terminais da DRC e que o processo de calcificação tem origem principalmente em áreas sob inflamação crônica, como observado na gênese de placas ateroscleróticas.

O hiperparatireoidismo secundário à DRC parece estar relacionado ao desenvolvimento de CVC. A hiperfosfatemia decorrente da incapacidade de excreção está associada à calcificação de ambas as válvulas mitral e aórtica.37 Hipercalcemia e níveis elevados de FGF-23 também já foram estudados em pacientes com DRC. Nesta revisão sistemática, esses indicadores se associaram a CVC. Na DRC, a perda de néfrons prejudica a capacidade de o rim excretar fosfatos, levando à formação aumentada de complexos de cálcio-fósforo. A redução resultante dos níveis de cálcio ionizado estimula os receptores sensíveis ao cálcio existentes nas glândulas paratireoides a secretarem PTH a fim de aumentar a excreção renal destes componentes. Entretanto, o PTH aumenta o cálcio sérico ao estimular a reabsorção a partir dos ossos e dos rins. Concomitantemente, a conversão da vitamina D ao calcitriol ainda aumenta a reabsorção intestinal de ambos os íons. Tais desordens culminam no depósito extracelular de cálcio.

Esta revisão sistemática possui algumas limitações: alguns dos estudos incluídos possuíam pequenas amostras e curto tempo de seguimento. Apenas estudos de metodologia observacional foram englobados, sendo a maioria deles de corte transversal, que limita as inferências de causalidade. Os estudos também apresentaram variações em populações analisadas, grupos de comparação, critérios de inclusão e exclusão, bem como nas formas de mensuração dos resultados, escores e técnicas estatísticas divergentes entre si, o que dificulta uma adequada comparação dos resultados.

Esta heterogeneidade constitui uma limitação, visto que compromete a comparabilidade e validade externa dos achados. Entretanto tal fator não invalida os achados da revisão sistemática. A heterogeneidade dos achados obtidos pode ser explorada por meio de análises estatísticas apropriadas, como modelos de efeitos aleatórios em meta-análises, observando-se uma oportunidade para novas investigações e fornecendo direções para futuras pesquisas. Diferentes metodologias oferecem perspectivas complementares, enriquecendo a compreensão do tema, de forma que dezenas de fatores de risco foram apontados pelos estudos incluídos. O acompanhamento regular e a vigilância desses parâmetros na prática clínica podem propiciar a identificação precoce dos pacientes com DRC sob risco de calcificação valvar e valvopatias, possibilitando melhores oportunidades de prevenção e tratamento, com consequente aumento de sobrevida e qualidade de vida.

 Conclusão

Neste estudo, foram identificados diversos fatores de risco para o desenvolvimento de calcificação valvar em pacientes com DRC, sendo os principais a idade, estágios avançados da doença, duração da TRS, hipoalbuminemia, citocinas e outros agentes inflamatórios, além de produtos envolvidos no metabolismo do hiperparatireoidismo secundário.

O presente estudo foi parcialmente financiado pela Escola Bahiana de Medicina e Saúde Pública (EBMSP) (Bolsa de Iniciação Científica).

Não há vinculação deste estudo a programas de pós-graduação.

Este artigo não contém estudos com humanos ou animais realizados por nenhum dos autores.

Os autores não utilizaram ferramentas de inteligência artificial no desenvolvimento deste trabalho.

Os conteúdos subjacentes ao texto da pesquisa estão contidos no manuscrito.

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Differences in Associated Factors Between Aortic and Mitral Valve Calcification in Hemodialysis. Hypertens Res. 2010;33(6):622-6. doi: 10.1038/hr.2010.44. Plytzanopoulou P Papasotiriou M Politis P Mavrikakis M Karagiannis G Tzavella E Malnutrition as a Risk Factor for Cardiac Valve Calcification in Patients Under Maintenance Dialysis: A Cross-Sectional Study Int Urol Nephrol 2020 52 2205 2212 10.1007/s11255-020-02590-z 18 Plytzanopoulou P, Papasotiriou M, Politis P, Mavrikakis M, Karagiannis G, Tzavella E, et al. Malnutrition as a Risk Factor for Cardiac Valve Calcification in Patients Under Maintenance Dialysis: A Cross-Sectional Study. Int Urol Nephrol. 2020;52:2205–12. doi: 10.1007/s11255-020-02590-z. Sayarlioglu H Acar G Sahin M Altunoren O Yavuz YC Nacar AB Prevalence and Risk Factors of Valvular Calcification in Hemodialysis Patients Iran J Kidney Dis 2013 7 2 129 134 19 Sayarlioglu H, Acar G, Sahin M, Altunoren O, Yavuz YC, Nacar AB, et al. Prevalence and Risk Factors of Valvular Calcification in Hemodialysis Patients. Iran J Kidney Dis. 2013;7(2):129-34. Asselbergs FW Mozaffarian D Katz R Kestenbaum B Fried LF Gottdiener JS Association of Renal Function with Cardiac Calcifications in Older Adults: The Cardiovascular Health Study Nephrol Dial Transplant 2009 24 3 834 840 10.1093/ndt/gfn544 20 Asselbergs FW, Mozaffarian D, Katz R, Kestenbaum B, Fried LF, Gottdiener JS, et al. Association of Renal Function with Cardiac Calcifications in Older Adults: The Cardiovascular Health Study. Nephrol Dial Transplant. 2009;24(3):834-40. doi: 10.1093/ndt/gfn544. Xiong JQ Chen XM Liang CT Guo W Wu BL Du XG Prognosis and Risk Factors for Cardiac Valve Calcification in Chinese End-Stage Kidney Disease Patients on Combination Therapy with Hemodialysis and Hemodiafiltration Ren Fail 2022 44 1 224 232 10.1080/0886022X.2022.2032742 21 Xiong JQ, Chen XM, Liang CT, Guo W, Wu BL, Du XG, et al. Prognosis and Risk Factors for Cardiac Valve Calcification in Chinese End-Stage Kidney Disease Patients on Combination Therapy with Hemodialysis and Hemodiafiltration. Ren Fail. 2022;44(1):224-32. doi: 10.1080/0886022X.2022.2032742. Fox CS Larson MG Vasan RS Guo CY Parise H Levy D Cross-Sectional Association of Kidney Function with Valvular and Annular Calcification: The Framingham Heart Study J Am Soc Nephrol 2006 17 2 521 527 10.1681/ASN.2005060627 22 Fox CS, Larson MG, Vasan RS, Guo CY, Parise H, Levy D, et al. Cross-Sectional Association of Kidney Function with Valvular and Annular Calcification: The Framingham Heart Study. J Am Soc Nephrol. 2006;17(2):521-7. doi: 10.1681/ASN.2005060627. Silva AP Viegas CSB Guilherme P Tavares N Dias C Rato F Gla-Rich Protein, Magnesium and Phosphate Associate with Mitral and Aortic Valves Calcification in Diabetic Patients with Moderate CKD Diagnostics 2022 12 2 496 496 10.3390/diagnostics12020496 23 Silva AP, Viegas CSB, Guilherme P, Tavares N, Dias C, Rato F, et al. Gla-Rich Protein, Magnesium and Phosphate Associate with Mitral and Aortic Valves Calcification in Diabetic Patients with Moderate CKD. Diagnostics. 2022;12(2):496. doi: 10.3390/diagnostics12020496. Usuku H Yamamoto E Arima Y Kaikita K Matsui H Tsujita K Accumulation of Coronary Risk Factors is Associated with Progression of Mitral Annular Calcification in Patients Undergoing Dialysis Therapy: A Long-Term Follow-Up Study Int J Cardiol 2019 293 248 253 10.1016/j.ijcard.2019.05.001 24 Usuku H, Yamamoto E, Arima Y, Kaikita K, Matsui H, Tsujita K, et al. Accumulation of Coronary Risk Factors is Associated with Progression of Mitral Annular Calcification in Patients Undergoing Dialysis Therapy: A Long-Term Follow-Up Study. Int J Cardiol. 2019;293:248-53. doi: 10.1016/j.ijcard.2019.05.001. Chen Y Chen YX Huang C Duan ZB Xu CY The Clinical Value of Klotho and FGF23 in Cardiac Valve Calcification among Patients with Chronic Kidney Disease Int J Gen Med 2021 14 857 866 10.2147/IJGM.S299197 25 Chen Y, Chen YX, Huang C, Duan ZB, Xu CY. The Clinical Value of Klotho and FGF23 in Cardiac Valve Calcification among Patients with Chronic Kidney Disease. Int J Gen Med. 2021;14:857-66. doi: 10.2147/IJGM.S299197. Di Lullo L Gorini A Bellasi A Morrone LF Rivera R Russo L Fibroblast Growth Factor 23 and Parathyroid Hormone Predict Extent of Aortic Valve Calcifications in Patients with Mild to Moderate Chronic Kidney Disease Clin Kidney J 2015 8 6 732 736 10.1093/ckj/sfv073 26 Di Lullo L, Gorini A, Bellasi A, Morrone LF, Rivera R, Russo L, et al. Fibroblast Growth Factor 23 and Parathyroid Hormone Predict Extent of Aortic Valve Calcifications in Patients with Mild to Moderate Chronic Kidney Disease. Clin Kidney J. 2015;8(6):732-6. doi: 10.1093/ckj/sfv073. Hoshina M Wada H Sakakura K Kubo N Ikeda N Sugawara Y Determinants of Progression of Aortic Valve Stenosis and Outcome of Adverse Events in Hemodialysis Patients J Cardiol 2012 59 1 78 83 10.1016/j.jjcc.2011.10.003 27 Hoshina M, Wada H, Sakakura K, Kubo N, Ikeda N, Sugawara Y, et al. Determinants of Progression of Aortic Valve Stenosis and Outcome of Adverse Events in Hemodialysis Patients. J Cardiol. 2012;59(1):78-83. doi: 10.1016/j.jjcc.2011.10.003. Strózecki P Odrowaz-Sypniewska G Manitius J Cardiac Valve Calcifications and Left Ventricular Hypertrophy in Hemodialysis Patients Ren Fail 2005 27 6 733 738 10.1080/08860220500243296 28 Strózecki P, Odrowaz-Sypniewska G, Manitius J. Cardiac Valve Calcifications and Left Ventricular Hypertrophy in Hemodialysis Patients. Ren Fail. 2005;27(6):733-8. doi: 10.1080/08860220500243296. Wang AY Wang M Woo J Lam CW Li PK Lui SF Cardiac Valve Calcification as an Important Predictor for All-Cause Mortality and Cardiovascular Mortality in Long-Term Peritoneal Dialysis Patients: A Prospective Study J Am Soc Nephrol 2003 14 1 159 168 10.1097/01.asn.0000038685.95946.83 29 Wang AY, Wang M, Woo J, Lam CW, Li PK, Lui SF, et al. Cardiac Valve Calcification as an Important Predictor for All-Cause Mortality and Cardiovascular Mortality in Long-Term Peritoneal Dialysis Patients: A Prospective Study. J Am Soc Nephrol. 2003;14(1):159-68. doi: 10.1097/01.asn.0000038685.95946.83. Tarasoutchi F Montera MW Ramos AIO Sampaio RO Rosa VEE Accorsi TAD Update of the Brazilian Guidelines for Valvular Heart Disease - 2020 Arq Bras Cardiol 2020 115 4 720 775 10.36660/abc.20201047 30 Tarasoutchi F, Montera MW, Ramos AIO, Sampaio RO, Rosa VEE, Accorsi TAD, et al. Update of the Brazilian Guidelines for Valvular Heart Disease - 2020. Arq Bras Cardiol. 2020;115(4):720-75. doi: 10.36660/abc.20201047. London GM Pannier B Marchais SJ Guerin AP Calcification of the Aortic Valve in the Dialyzed Patient J Am Soc Nephrol 2000 11 4 778 783 10.1681/ASN.V114778 31 London GM, Pannier B, Marchais SJ, Guerin AP. Calcification of the Aortic Valve in the Dialyzed Patient. J Am Soc Nephrol. 2000;11(4):778-83. doi: 10.1681/ASN.V114778. Laxton MK Peritoneal Dialysis: An Effective Yet Underused Renal Replacement Therapy JAAPA 2016 29 5 40 46 10.1097/01.JAA.0000482300.94949.e4 32 Laxton MK. Peritoneal Dialysis: An Effective Yet Underused Renal Replacement Therapy. JAAPA. 2016;29(5):40-6. doi: 10.1097/01.JAA.0000482300.94949.e4. Marinho AWGB Penha AP Silva MT Galvão TF Prevalência de Doença Renal Crônica em Adultos no Brasil: Revisão Sistemática da Literatura Cad Saúde Coletiva 2017 25 3 379 388 10.1590/1414-462X201700030134 33 Marinho AWGB, Penha AP, Silva MT, Galvão TF, et al. Prevalência de Doença Renal Crônica em Adultos no Brasil: Revisão Sistemática da Literatura. Cad Saúde Coletiva. 2017;25(3):379-88. doi: 10.1590/1414-462X201700030134. Santos NSJ Draibe SA Kamimura MA Cuppari L Albumina Sérica como Marcador Nutricional de Pacientes em Hemodiálise Rev Nutr 2004 17 3 339 349 10.1590/S1415-52732004000300007 34 Santos NSJ, Draibe SA, Kamimura MA, Cuppari L. Albumina Sérica como Marcador Nutricional de Pacientes em Hemodiálise. Rev Nutr. 2004;17(3):339-49. doi: 10.1590/S1415-52732004000300007. Wang AYM Woo J Wang M Sea MMM Ip R Li PKT Association of Inflammation and Malnutrition with Cardiac Valve Calcification in Continuous Ambulatory Peritoneal Dialysis Patients J Am Soc Nephrol 2001 12 9 1927 1936 10.1681/ASN.V1291927 35 Wang AYM, Woo J, Wang M, Sea MMM, Ip R, Li PKT, et al. Association of Inflammation and Malnutrition with Cardiac Valve Calcification in Continuous Ambulatory Peritoneal Dialysis Patients. J Am Soc Nephrol. 2001;12(9):1927-36. doi: 10.1681/ASN.V1291927. Shankar A Sun L Klein BE Lee KE Muntner P Nieto FJ Markers of Inflammation Predict The Long-Term Risk of Developing Chronic Kidney Disease: A Population-Based Cohort Study Kidney Int 2011 80 11 1231 1238 10.1038/ki.2011.283 36 Shankar A, Sun L, Klein BE, Lee KE, Muntner P, Nieto FJ, et al. Markers of Inflammation Predict The Long-Term Risk of Developing Chronic Kidney Disease: A Population-Based Cohort Study. Kidney Int. 2011;80(11):1231-8. doi: 10.1038/ki.2011.283. Ureña-Torres P D’Marco L Raggi P García-Moll X Brandenburg V Mazzaferro S Valvular Heart Disease and Calcification in CKD: More Common than Appreciated Nephrol Dial Transplant 2020 35 12 2046 2053 10.1093/ndt/gfz133 37 Ureña-Torres P, D’Marco L, Raggi P, García-Moll X, Brandenburg V, Mazzaferro S, et al. Valvular Heart Disease and Calcification in CKD: More Common than Appreciated. Nephrol Dial Transplant. 2020;35(12):2046-53. doi: 10.1093/ndt/gfz133. Genctoy G Eldem O Ergun T Arikan S Periaortic Fat Tissue: A Predictor of Cardiac Valvular Calcification, Malnutrition, Inflammation, and Atherosclerosis Components in Hemodialysis Patients International Center for Artificial Organs and Transplantation and Wiley Periodicals 2015 39 9 748 755 38 Genctoy G, Eldem O, Ergun T, Arikan S. Periaortic Fat Tissue : A Predictor of Cardiac Valvular Calcification, Malnutrition, Inflammation, and Atherosclerosis Components in Hemodialysis Patients, International Center for Artificial Organs and Transplantation and Wiley Periodicals, 2015, 39(9):748–755. 10.36660/abc.20240222i Original Article Clinical and Laboratory Predictors for the Development of Heart Valve Diseases in Chronic Kidney Disease: A Systematic Review 0009-0003-0671-491X Conceição Hayala Machado Cavalcante Conception and design of the research and Obtaining financing Acquisition of data Analysis and interpretation of the data and Statistical analysis Writing of the manuscript and Critical revision of the manuscript for content 1 Valois Ana Luísa Vaz Acquisition of data Analysis and interpretation of the data and Statistical analysis 1 Ramos Erick Magalhães Silva Analysis and interpretation of the data and Statistical analysis Writing of the manuscript and Critical revision of the manuscript for content 2 Ladeia Ana Marice Conception and design of the research and Obtaining financing Acquisition of data Analysis and interpretation of the data and Statistical analysis Writing of the manuscript and Critical revision of the manuscript for content 1 Salvador BA Brazil Escola Bahiana de Medicina e Saúde Pública, Salvador, BA – Brazil Salvador BA Brazil Universidade Salvador, Salvador, BA – Brazil Hayala Machado Cavalcante Conceição • Escola Bahiana de Medicina e Saúde Pública – Av. Dom João VI, 275. Postal Code 40290-000, Brotas, Salvador, BA – Brazil E-mail: hayalaconceicao19.1@bahiana.edu.br

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

Gláucia Maria Moraes de Oliveira

 Abstract Background:

Chronic kidney disease (CKD) is associated with a higher prevalence of valvular diseases and increased mortality from cardiovascular causes. Factors that influence the genesis of cardiac valve calcification (CVC) in these patients are not well-defined.

 Objective:

To determine the risk factors for valvular calcification in patients with CKD.

 Methods:

Systematic review based on PRISMA, which included observational studies evaluating the association of clinical and laboratory data with CVC in patients with CKD, undergoing or not hemodialysis or peritoneal dialysis. Articles were retrieved from databases (MEDLINE; SCIELO; CENTRAL; EMBASE; LILACS/BVS) and selected blindly by two authors; discrepancies were resolved by a third author. Data collection and synthesis were carried out by the main author. The assessment of methodological quality and risk of bias was based on STROBE and Newcastle-Ottawa guidelines.

 Results:

A total of 783 studies were identified, of which 20 were included, encompassing 13,314 patients from 10 countries. The factors most strongly associated with CVC were age >55 years, glomerular filtration rate <53 mL/min/1.73m2, renal replacement therapy (RRT) >20 months, hypoalbuminemia, C-reactive protein (CRP), serum levels of IL-6, TNF-α, parathyroid hormone, hyperphosphatemia, hypercalcemia, Ca × P product, and FGF-23 resulting from secondary hyperparathyroidism. Both mitral and aortic valves were studied, and no differences were observed between hemodialysis and peritoneal dialysis.

 Conclusion:

Age, RRT, chronic inflammation, and secondary hyperparathyroidism promote calcium and phosphate deposition in the valves, making CKD patients more susceptible to CVC) Monitoring these parameters provides opportunities for prevention and treatment.

 Keywords: Heart Valve Diseases Chronic Renal Insufficiency Risk Factors Introduction

Cardiovascular causes account for more than 50% of deaths in patients with chronic kidney disease (CKD) compared to the general population,1 and the prevalence of valvular heart diseases is significantly higher in this group.2 Valvular abnormalities, mainly in the aortic and mitral valves, as well as the need for hemodialysis (HD) or peritoneal dialysis (PD), are markers of morbidity and mortality. However, this is one of the least addressed aspects in the study of CKD, with its relevance often overlooked by many professionals.

The pathogenesis of valvular heart diseases involves inflammatory processes (both systemic and local), modified action of parathyroid hormone (PTH) in secondary hyperparathyroidism,3–5 disorders in calcium-phosphorus metabolism,5,6 the type of dialysis (HD or PD), duration of dialysis,3,7,8 serum cholesterol levels,3,9 albumin levels,3,9 and blood volume.9 However, the aspects truly involved in the pathogenesis of valvular calcification and valvular diseases in patients with CKD, which justify the higher prevalence of such conditions in this group, are not well defined.2

The objective of this systematic review is to identify possible clinical and laboratory predictors that constitute risk factors for valvular calcification in individuals with CKD, undergoing or not HD or PD.

 Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols (PRISMA-P) and submitted for registration in the Prospective Register of Systematic Reviews (PROSPERO) (CRD42021291576).

Search strategy

The search strategy used DeCS (Health Sciences Descriptors) and MeSH Terms (Medical Subject Headings) on MEDLINE (Medical Literature Analysis and Retrieval System), LILACS (Latin American and Caribbean Health Sciences Literature), SCIELO (Scientific Electronic Library Online), Cochrane Library (CENTRAL), and EMBASE platforms. The MeSH Terms search was as follows: ((((((End-Stage Kidney Disease) OR (Chronic Kidney Failure) OR (End-Stage Renal Disease) OR (Chronic Renal Failure) OR (End-Stage Renal Failure)))))) OR (Dialysis) AND ((Risk Factor) OR (Risk Factors)) AND ((Heart Valve Disease) OR (Valvulopathy)) AND (Calcification). The search of DeCS terms was as follows: (Insuficiência Renal Crônica) OR (Doença Renal Crônica) AND (Valvulopatia) OR (Valvopatia).

 Eligibility criteria

Observational studies in Portuguese, English, and Spanish that included patients with CKD (with or without dialysis) and assessed the association between clinical/laboratory parameters and valvular calcification were considered eligible. Studies with incomplete data or those that did not meet all the criteria were excluded.

 Identification and selection of studies

Two authors selected the articles using the Rayyan QCRI software, and disagreements were resolved by a third author. The Kappa Concordance Test (K) assessed agreement between reviewers. References from relevant articles were checked, and the selection steps were summarized in PRISMA flowchart.

 Data extraction and analysis

Data collection was performed by the main author using an electronic form based on the Critical Appraisal and Data Extraction for Systematic Reviews of Prognostic Factor Studies (CHARMS-PF Checklist).

The methodological quality and risk of bias were assessed using The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and the Newcastle-Ottawa Scale (NOS), respectively. The studies included showed moderate performance in the analyses, as shown in the tables below.

 Results Study selection

A total of 790 articles were retrieved; 783 from databases and seven through manual search and reference lists. After removing duplicates and applying eligibility criteria, 20 articles were selected (Figure 1), including 13 cross-sectional studies, six cohort studies, and one case-control study, encompassing 13,314 patients from 10 countries, with sample sizes ranging from 30 to 3,929 participants. The agreement between examiners in the article selection process showed a Kappa value > 0.758 (good agreement).

Flowchart of the studies evaluated in this review.

Some studies evaluated patients with CKD without categorizing the stages of the disease (which range from 1 to 5 according to the literature),4 while others included only patients in specific stages. There were studies that included patients undergoing renal replacement therapy (RRT) and others that specifically evaluated HD or PD. The included articles employed multivariate analyses and adopted distinct methodologies.

Table 1 summarizes the main characteristics of the 20 included studies, with information on population samples and scores obtained by each of them.

General characteristics of the studies included in the systematic review, population samples, and scoring in quality analysis
Authors,year, country Study design Sample description (n) Endpoint Male sex(%) Mean age(years) STROBE Newcastle-Ottawa
Alamir et al., 2015, USA10 Cross-sectional Mild/moderate CKD (n=2070) MAC;noncontrast CT 53.7% 58 (21-74) 86.36% 4
Asselbergs et al., 2008, USA20 Retrospective cohort DRC(n=3929) MAC, AAC, AAS; 2D-ECHO 60% 74 ± 5 90.9% 5
Àvila-Díaz et al., 2013, Mexico14 Prospective cohort CKD under PD (CAPD ou DPA) (n=124) CVC; 2D-ECHO 68.5% 46 (30-54) 95.45% 7
Chen et al., 2021, China25 Case-control CKD stages 2 - 5 (n=180) CVC; 2D-ECHO 63% 58 ± 14 86.36% 2
Di Lullo et al., 2015, Italy26 Cross-sectional CKD stages 3 - 4 (n=100) CVC; 2D-ECHO 60% 51 (46-56) 72.72% 4
Engole et al., 2020, Democratic Republic of the Congo15 Cross-sectional CKD under HD (n=60) CVC; 2D-ECHO 71.6% 52.5 ± 15.9 72.72% 6
Fernandez et al., 2021, Spain11 Prospective cohort CKD stages 2- 5, under RRT or not (n=397) CVC; 2D-ECHO 61% 59.1 ± 11.5 72.72% 5
Fox et al., 2006, USA22 Cross-sectional DRC(n=3047) CVC; 2D-ECHO 47.6% 59 ± 10 90.9% 5
Genctoy et al., 2015, Turkey38 Cross-sectional CKD under HD (n=76) CVC; 2D-ECHO 64.47% 60.5 ± 15.5 77.27% 6
Guerraty et al., 2015, USA12 Cross-sectional TFG 20-70 ml/min/1,73m2 e CVA (n=1923) CVA; noncontrast CT 53% 58.45 ± 11.45 90.9% 7
Guo et al., 2020, China16 Cross-sectional CKD under HD (n=145) CVC; 2D-ECHO with Doppler 54.5% 50 (23-74) 81.8 5
Hoshina et al., 2011, Japan27 Retrospective cohort CKD under HD (n=30) AS; 2D-ECHO Rapid progression of AS (n=30):40% Slow progression of AS (n=30): 53% Rapid progression of AS:73.6 ± 6.1 Slow progression of AS:69.8 ± 7.5 81.81% 6
Ikee et al., 2010, Japan17 Cross-sectional CKD under HD (n=112) CVC; 2D-ECHO 68.7% 67 ± 10 86.36% 6
Plytzanopoulou et al., 2020, Grécia18 Cross-sectional CKD under HD (n=42) CVC; 2D-ECHO 69% 72.97 ± 11.6 95.45% 5
Rong et al., 2018, China13 Cross-sectional DRC(n=288) CVC; 2D-ECHO 65.9% CVC: 70.42±11.83; Without CVC:56.47±15.00 81.81% 3
Sayarlioglu et al., 2013, Turkey19 Cross-sectional CKD under HD (n-129) CVC; 2D-ECHO CVC: 52.3% Sem CVC: 46.5% CVC:48. 2 ± 16.8 Without CVC: 60.3 ± 13.5 77.27% 6
Silva et al., 2022, Portugal23 Cross-sectional Diabetic patients with CKD stages 2- 4 (n=80) CVC; 2D-ECHO 71.3% 56 ± 8.1 81.81% 6
Tian et al., 2016, China3 Prospective cohort DRC sob DP(n=194) CVC; 2D-ECHO 54% 61.6 ± 12.5 90.9% 7
Usuku et al., 2019, Japan24 Retrospective cohort CKD under PD (n=95) MAC; 2D-ECHO CAM (n=28): 54% Without CAM (n=67): 54% CAM (n=28):65 ± 10.7 Without CAM (n=67):62.6 ± 13.2 86.36% 7
Xiong et al., 2022, China21 Cross-sectional End-stage CKD,under HD(n=293) CVC; 2D-ECHO,CT and/or CTA in some cases 54.6% 64 ± 7.0 77.27% 4

CTA: computed tomography angiography; MAC: mitral annulus calcification; AAC: aortic annulus calcification; CVC: cardiac valve calcification; PD: peritoneal dialysis; CKD: chronic kidney disease; AS: aortic stenosis; SLAS: slow progression aortic stenosis; AAS: aortic annulus sclerosis; 2D-ECHO: two-dimensional echocardiography; HD: hemodialysis; CT: computed tomography; RRT: renal replacement therapy; the statistical significance level was p < 0.05, except for the study by Engole et al.,15 which did not specify the p-value.

 Summary of results

A total of 38 risk factors for valvular calcification were identified. Table 2 summarizes studies that evaluated risk factors in patients with CKD in general. Table 3 describes the results of studies that included only patients undergoing RRT, whether HD or PD. The findings are compiled in the Central Figure.

Risk factors identified in studies that included patients with chronic kidney disease
Authors, year, country Endpoints and methods of definition Risk factors identified in the study Valve calcification and/or heart valve diseases identified
Alamir et al, 2015, USA10 MAC in two CTs by the Agatston algorithm MAC associated with GFR < 50mL/min/1.73m2(ORa = 2.30, 95%CI 1.40-3.79), age > 55 years(OR = 4.01, 95%CI 2.55-6.32),phosphate > 4.1 mg/dL (OR = 3.33, 95%CI 1.37-8.09) Previous MVC: 331 (16%).
Asselbergs et al, 2008, USA20 MAC and AAC; hyperechogenicity in 2D-ECHO AAS; aortic cuspid thickening and flpw velocity <2.0m/s TFG <45 mL/min/1,73 m2 (OR =1.15, 95%IC 1.03-1.12, p=0,015) and cystatin C (OR = 1.12; 95%CI 1.03-1.23, p=0,013) associated with previous CAM Mild ACM: 1495, moderate MAC: 133, severe MAC: 12. AAC: mild: 1698, moderate: 49, severe: 1. Aortic sclerosis in 2114.
Chen et al., 2021, China25 CVC hyperechogenic masses with a diameter ≥1 mm in 2D-ECHO Doppler CVC was associated with serum creatinine(CKD stage 5, 845.09 ± 334.18 μmol/L, p<0.05),FGF-23 (CKD stage 5, 1039.43 ± 214.83 pg/ml, p<0.05), andKlotho protein (CKD stages 2-3, 159.05 ± 27.53 U/L, p<0.05).Patients in stage 5 had higher levels of Hb (90.52 ± 23.36 g/L, p<0.05), albumin (36.61 ± 4.37 g/L, p<0.05),osteocalcin (197.32 ± 78.88 ng/ml, p<0.05), PTH (392.40 ± 233.88 pg/ml, p=0.05), and bone-specific ALP (86.36 ± 18.18 U/L, p=0.05), along with lower corrected serum calcium levels (2.06 ± 0.15 mmol/L, p<0.05) Total CVCl:41 (22,7%);4 patients with CKD 2-3;12 patients with CKD 4,25 patients with CKD 5
Di Lullo et al., 2015, Italy26 CVC by Wilkins score in 2D-ECHO AVC and PTH (r2 = 0,212 p=0,03) and FGF-23 (r2 = 0,272; p=0.01)MVC score associated with serum calcium (r2 = 0,565; p=0.01) CVC total: 100%. MVC: 96;61 had score 1; 34 had score 2,1 had score 3 AVC: 100 (100%)
Fernandez et al., 2021, Spain11 MVC masses> 5mm andAVC > 2mm,in 2D-ECHO MVC associated with age (OR = 1.05. 95%CI 1.03-1.08),peripheral vascular disease (OR = 4.22, 95%CI 1.53-13.12) andCa x P product (OR = 1.03, 95%CI 1.01-1.05).AVC associated with age (OR = 1.10, 95%CI1.05-1.15),P levels (OR = 1.64, 95%CI 1.16-2.42), atherosclerosis and greater carotid plaque area (OR = 3.10, 95%IC 1.18-8.80). MVC increased from 96 (24.2%) to 123 (31%).AVC increased from 119 (30%) to 171 (43.1%).
Fox et al., 2006, USA22 CVC; MVC hyperechogenic masses > 0.3cmin M-modeor > 1/3 of annulus in the parasternal window AVC if > ½ of hyperechogenic annulus CVC associated with SAH (67%, p<0,01),DM (21%, p<0,05), total cholesterol/HDL (4.8 ± 1.8; p<0.01) andBMI (29.2 ± 5.2 Kg/2; p<0.001);GFR significantly lower in patients with CVC(GFR = 78 ± 25mL/min/1.73m2, p<0.001) CVC total:284 (9,3%).MVC: 130 (4,3%). AVC: 112 (3,7%). AAS: 188 (6,2%).
Guerraty et al., 2015, USA12 AVC byAgatston score,noncontrast CT Independent association with moderate/severe AVC and age(62.26 ± 7.9 and 66.53 ± 7; p<0.001, respectively);BMI: 31.73 and 31.72 (p<0.0007);AC (105.01 ± 15.53 and 106.81 ± 14.31; p<0.001);SBP (127.75 ± 21.99 and 132.28 ± 21.21; p<0.001); hypercholesterolemia (463/90% and 401/94%; p<0.001);HbA1c (6.73 ± 1.52% and 6.64 ± 1.36%; p<0.001);reduced MET (198.37 ± 25.59 and 178.24 ± 120.95; p<0.001;DM (281/55% and 52/59%; p<0.001); SAH (478/93% and 409/96%; p<0.001; cardiovascular disease (149/29% and 176/41%; p<0.001); CRP (4.85 ± 7.29 and 5.48 ± 8.77; p=0.0100);total plasma homocysteine (14.17 ± 4.86 and 16.55 ± 7.06; p<0.0001); ALP (100.84 ± 34.99 and 99.7 ± 34.23; p=0.0041). Mean GFR was 44.6 mL/min/1.73m2 and was associated with AVC (p<0.0001). mild/moderate AVC: 515 (26.8%) Severe AVC:426 (22.1%).
Rong et al, 2018, China13 CVC total, hyperechogenic masses > 1mm in 2D-ECHO with Doppler CVC was associated with age(70.42 ± 11.83 years, p<0.001; OR = 1.091, 95% CI 1.048–1.136, p<0.05), lower levels of pre-albumin (238.44 ± 91.48 g/L, p=0.05), cholesterol (OR = 0.488, 95% CI 0.306–0.780, p=0.03), triglycerides (1.4 ± 0.65 mmol/L, p=0.37), andAPO-E (37.3, ranging from 30.2–45.6 mg/L, p=0.09),LDL (OR = 163.028, 95% CI 3.796–7002.467, p=0.08),CRP (5.5, ranging from 0.5–16.35 mg/L, p=0.04), andIL-6 (18.76, ranging from 5.95–46.9 pg/mL, p=0.05). The group with CVC at more advanced stages of CKD (stage 5 under dialysis) showed a prevalence of 30.3% with CVC compared to 18.9% without CVC, p=0.048. CVC total:66 (22,9%).MVC: 14(21.2% of 66); AVC: 100% of 66)
Silva et al,, 2022, Portugal23 CVC total;MVC by Wilkins score andAVC according to the score proposed by Lullo et al, in 2D-ECHO MVC e AVC were associated with lower eGFR (p< 0.0001),GRP (p< 0.0001), Mg (p= 0.029 for MVC and p= 0.001 for AVC), and α-Klotho (p= 0.002), as well as higher levels of P (p= 0.001), PTH (p= 0.025 for MVC and p=0.030 for AVC), FGF-23 (p< 0.0001), and TNF-α (p=0.037). There was a negative correlation between GRP and MVC (r = −0.754, p< 0.0001), and low levels of GRP were identified as an independent risk factor for MVC (ORa = 0.268, 95% CI 0.101–0.725, p= 0.005; aPR = 0.750; 95% CI 0.456–0.976; p= 0.024) and AVC (ORa = 0.202, 95% CI 0.109–0.401, p= 0.022; aPR = 0.813;95% CI 0.113–0.937; p< 0.0001). Similarly, low levels of Mg were risk factors for MVC (ORa = 0.747, 95% CI 0.263–0.921, p= 0.003; aPR = 0.762; 95% CI 0.256–0.963; p= 0.02) and AVC (ORa = 0.580, 95% CI 0.173–0.948, p= 0.008; aPR = 0.809; 95% CI 0.391 0.974;p= 0.006). High levels of P were also identified as risk factors(for MVC, ORa = 1.078, 95% CI 1.0–1.612, p= 0.001;for AVC, ORa = 1.497, 95% CI 1.004–2.378, p= 0.002) andFGF-23 (for MVC, ORa = 1.209, 95% CI 1.099–1.619, p= 0.035; for AVC, ORa = 1.126, 95% CI 1.034–1.436, p= 0.011). CVM: 29 (36.2%);AVC: 29 (36.2%).

AAC: aortic annulus calcification; ALP: alkaline phosphatase; APO-E: apolipoprotein E; aPR: adjusted prevalence ratios; BMI: body mass index; CAPD: continuous ambulatory peritoneal dialysis; CA: abdominal circumference; MAC: mitral annulus calcification; CVC: cardiac valve calcification; AVC: aortic valve calcification; MVC: mitral valve calcification; DM: diabetes mellitus; CKD: chronic kidney disease; APD: automated peritoneal dialysis; 2D-ECHO: two-dimensional echocardiography; AAS: aortic annulus sclerosis; FGF-23: fibroblast growth factor 23; GRP: Gla-rich protein; SAH:: systemic arterial hypertension; Hb: hemoglobin; HbA1c: glycated hemoglobin; HDL: high density lipoprotein; ABI: ankle-brachial index; LDL: low density lipoprotein; MET: metabolic equivalent of task; Mg: magnesium; OR: odds ratio; ORa: adjusted odds ratio; P: phosphorus; SBP: systolic blood pressure; CRP: C-reactive protein; PTH: parathyroid hormone; CT: computed tomography; GFR: glomerular filtration rate; TG: triglycerides; TNF-α: tumor necrosis factor-alpha; RRT: renal replacement therapy; the level of significance was set at p<0.05.

 Risk factors identified in studies that included only chronic kidney disease patients under renal replacement therapy
Authors, year, country Endpoints and methods of definition Risk factors identified in the study Valve calcification and/or heart valve diseases identified
Àvila-Díaz et al, 2013, Mexico14 CVC in general, luminousecho > 1 mm; 2D-ECHO MVC associated with age (RR=1.051, 95%CI 1.06-1.09, p=0,02), DM (RR=0.287, 95%CI 0.1-0.8, p=0,01),osteoprotegerin (RR=1.15, 95%CI 1.03-1.21, p=0,008),PTH (RR=0.41, 95%CI 1.08-50.5, p=0,04) andPCR (RR=1.09, 95%CI 1.04-1.19, p=0,04).iPTH (RR = 2.002, 95%CI 1.052–3.81, p<0,034) for AVC CVC total:57 (46%);MVC: 15 (26.3%); AVC: 33 (57.8%);calcification in both valves:9 (15.8%)
Engole et al., 2020, Democratic Republic of the Congo15 CVC in general, luminousecho > 1 mm; 2D-ECHO com Doppler. Age > 60 years (aOR = 4.48; 95%CI 1.67-30.10, p=0.003),smoking (aOR=4.57; 95%CI 1.15-13.36, p=0.016),P levels (aOR=2.17; 95%CI 1.83-5.65, p=0.012) andhypertension (aOR=3.963, 95%CI 1.24–15.7, p=0.014) were independently associated with CVC CVC total:23 (38%);MVC: 23%;AVC: 64%
Genctoy et al., 2015, Turkey38 CVC in general, luminousecho > 1 mm; 2D-ECHO. CVC associated with T-PAFT(OR=1.006, CI not presented; p=0,04) CVC total:50 (65,8%);18 (23,7%) inone cuspid and 32 (42,1%)in two
Guo et al,, 2020, China16 CVC in general; calcification was assessed by GCCS; 2D-ECHO Doppler. Age (r = 0.25; p=0.003), duration of hemodialysis(r = 0.27; p=0.001), serum iPTH (r = 0.18; p=0.03), and serum PA (r = 0.24; p=0.003; OR = 3.87, 95%CI 1.86–8.07, p<0.001;aOR = 3.92, 95% CI 1.37–11.2, p=0.011). In an analysis usingcubic splines, the probability of GCCS = 1 significantly increased when PA exceeded 232 U/L.There was a negative correlation with serum albumin(r = −0.22; p=0.008). PA > 232 U/L and age > 60 years are determinants for high risk of CVC. CVC GCCS ≥ 1: 83
Hoshina et al., 2011, Japan27 Aortic stenosis defined based on PPG progression between two 2D-ECHO within3 months Systolic blood pressure(161 ± 21.5 mmHg, OR = 1.06, 95%CI 1-1.11, p=0,04) andcalcium serum levels(9.66 ± 1.05 md/dL, OR = 6.08, 95%CI 1.28-28.8, p=0,02). Fast progression of AS: 15;rapid progression of AS: 15
Ikee et al., 2010, Japan17 CVC in general, luminousecho > 1 mm; 2D-ECHO Age associated with CVC(for AVC, OR = 1.06, 95%CI 1.01-1.11, p=0,01).For MVC, OR = 1.04, 95%CI 1.01-1.09, p=0.04).Calcium associated with AVC (OR = 2.16, 95%CI 1.05-4.44, p=0.03)Serum B2-microglobulin was associated withMVC (OR = 1.10, 95%CI 1.01-1.2, p=0,01) and correlated with HD duration (r = 0.273; p=0.004), serum albumin (r = 0.209; p=0.02), total cholesterol (r = 0,243, p=0.01), triglycerides (r = 0.189, p=0.04), HDL-C (r = 0.337, p=0.001), and CRP (r = 0.246, p=0.009). CVM: 58 (51,7%); AVC: 85 (75%); calcification in both valves:48 (42,8%)
Plytzanopoulou et al., 2020, Greece18 CVC in general, 2D-ECHO. Age (AUC 0.734, 95% CI 0.58–0.89, p=0.011),CRP (AUC 0.692, 95% CI 0.516–0.868, p=0.03), anddecreased serum albumin (AUC 0.73, 95% CI 0.57–0.89, p=0.012) are positive predictors of CVC.Age >76.5 years (OR 9.56, 95% CI 1.54–59.42, p=0.015) andCRP >3.5 mg/dL (OR 9.26, 95% CI 1.51–56.83, p=0.016) are associated with severe CVC Absent or mild CVC in 24 (57,15%); moderate or severe CVC in18 (42,85%). MVC: 21 (50%); AVC: 16 (38,10%).
Sayarlioglu et al, 2013, Turkey19 CVC in general, 2D-ECHO. Advanced age (60.3 ± 13.5 years, p<0.001) andlow serum albumin (3.7 ± 0.5 mg/dL, p=0.02) were linked to calcification in both valves.DM was associated with MVC (16.3%, p=0.02).The duration of dialysis in patients with MVC and AVC was significantly longer compared to other groups(19.6 ± 40.6 months vs. 7.1 ± 5.8 months, p=0.01) CVC total:43 (33,3%);CVM: 30 (23,3%); CVA: 28 (21,7%).
Tian et al, 2016, China3 CVC in general,if luminousecho > 1 mm; 2D-ECHO CVC associated with chronic PD(OR=1.039, 95%CI 1.004-1.075, p=0,03),serum P (OR=2.569, 95%CI 1.227-5.377, p=0,01),decreased serum albumin(OR albumin =0.935, 95%CI 0.877-0.997, p=0.01) CVC: 97 (32%). MVC:7 new cases;AVC: 30 new cases;
Usuku et al, 2019, Japan24 MAC defined by echo-dense mass ≥ 5mm in the atrioventricular junction and inthe posteriormitral leaflet, 2D-ECHO The duration of hemodialysis therapy was significantly longer in patients with MAC compared to those without MAC(13.4 ± 8.6 years vs. 7.7 ± 8.4 years; p<0.01), andan association was observed between the duration of HD andMAC (OR = 1.09, 95% CI 1.02–1.16; p<0.01)The number of coronary risk factors(SAH, dyslipidemia, smoking, and DM) was significantly higher in the MAC progression group compared to the non-progression group (1.91 ± 0.83 vs. 1.18 ± 0.99; p=0.03), and an association was noted between them (OR = 2.67, 95% CI 1.24–5.76; p=0.01) MAC: 28 (29%), with transverse diameter ofmitral annuls = 12.4 ± 7.4 mm
Xiong et al, 2022, China21 CVC by 2D-ECHO; 282 also underwent computed tomography. Calcified plaque if CT value greater than 130 HD duration ≥ 36 months(OR = 2.25; 95% CI 1.26–4.02, p=0.006),DM (OR = 1.81; 95% CI 1.04–4.12, p=0.037),low serum albumin levels (considering albumin ≥ 40 g/L vs < 40 g/L, OR = 0.54; 95% CI 0.29–0.99, p=0.047),serum calcium ≥ 2.11 mmol/L(OR = 2.04; 95% CI 1.01–4.12, p=0.046) andpulse pressure > 72 mmHg (OR = 3,22, 95%CI 1.85-5.59, p<0.001) were independently associated with CVC CVC: 93;MVC: 37;AVC: 68; calcification of both valves: 12

AS: aortic stenosis; CTA: computed tomography angiography; MAC: mitral annulus calcification; CAPD: continuous ambulatory peritoneal dialysis; CT: computed tomography; CVC: cardiac valve calcification; DM: diabetes mellitus; APD: automated peritoneal dialysis; AP: alkaline phosphatase; GCCS: Global Cardiac Calcium Score; PPG: peak pressure gradient; SAH: systemic arterial hypertension; HD: hemodialysis; PP: pulse pressure; CRP: C reactive protein; T-PAFT: thoracic periaortic fat; the level of significance was set at p < 0.05, except for the study by Engole et al.,15 which did not specify the p-value; aOR: adjusted odd ratio.

The most common associated factor was advanced age, found in 10 publications.10–19 According to Alamir et al.,10 there was a positive association starting at 55 years old (OR = 4.01, 95% CI 2.55-6.32). An association above 60 years was observed in the studies by Engole et al.15 (ORa = 4.48; 95% CI 1.67-30.10, p=0.003), Guo et al.16 (r = 0.25; p=0.003), Guerraty et al.12 (moderate/severe VCA, respectively, 62.26 ± 7.9 and 66.53 ± 7, p<0.001), and Sayarlioglu et al.19 (60.3 ± 13.5 years, p<0.001); as well as Rong et al.13 above 70 years (70.42 ± 11.83 years, p<0.001; OR = 1.091, 95% CI 1.048-1.136, p<0.05). Some studies did not establish a reference value.11,14,16–18

Low glomerular filtration rate (GFR), in the absence of RRT,10,12,20–23 was another associated factor, as was a GFR < 50mL/min/1.73m2 in the in the study by Alamir et al.,10 (ORa = 2.30; 95% CI 1.40-3.79), or a GFR less than 45mL/min/1.73m2 in the study by Asselbergs et al.20 (OR = 1.15; 95% CI 1.03-1.12, p=0.015) and Guerraty et al.12 (p<0.0001). Fox et al.22 reported an association with a GFR = 78 ± 25mL/min/1.73m2 (p<0.001), a level considered reduced based on normal GFR values (90mL/min/1.73m2),4 but above the cutoff value for determining CKD. Cystatin C was associated with mitral annulus calcification (MAC) in the study by Asselbergs et al.20 (OR = 1.12; 95% CI 1.03-1.23; p=0.013).

In patients undergoing HD or PD, the chronicity of these procedures was also associated with Cardiac Valve Calcification (CVC).3,16,19,21,24 Sayarlioglu et al.19 observed that patients with CVC had undergone HD for a longer time (19.6 ± 40.6 months vs. 7.1 ± 5.8 months in non-RRT patients, p=0.01). Xiong et al.21 found a significant association between CVC and HD lasting more than 36 months (OR = 2.25; 95% CI 1.26-4.02, p=0.006). Usuku et al.24 demonstrated a similar result for Mitral Valve Calcification (MVC), comparing groups that started RRT earlier (13.4 ± 8.6 years vs. 7.7 ± 8.4 years, OR = 1.09; 95% CI 1.02–1.16; p<0.01). Tian et al.3 specifically analyzed PD, finding a positive association for durations exceeding 20 months (OR = 1.039; 95% CI 1.004-1.075; p=0.03).

Reduced serum albumin levels were associated with CVC in several studies,3,13,16,18,19,21,25 particularly among patients undergoing RRT. Rong et al.13 linked CVC to pre-albumin levels of 238.44 ± 91.48 g/L, p=0.05. According to Plytzanopoulou et al.,18 this decrease is a positive predictor of CVC, with an AUC of 0.73, 95% CI 0.57–0.89, p=0.012. Chen et al.25 identified higher serum albumin levels in patients with CVC at more advanced stages of CKD (36.61 ± 4.37 g/L, p<0.05).

The only inflammatory marker associated with CVC was C-reactive protein (CRP).12–14,18 Guerraty et al.12 demonstrated a direct correlation between CRP levels and the severity of aortic valve calcification (AVC), with levels of 4.85 ± 7.29 mg/L for moderate AVC and 5.48 ± 8.77 mg/L for severe AVC, p=0.01. Rong et al.13 observed that patients with any CVC had higher CRP levels (mean value of 5.5, ranging from 0.5–16.35 mg/L, p=0.04). Among studies involving patients on RRT, Ávila-Díaz et al.14 found an association with RR = 1.09, 95% CI 1.04–1.19, p=0.04, while Plytzanopoulou et al.18 reported an AUC = 0.692, 95% CI 0.58–0.89, p=0.03.

Alterations in mineral and hormonal factors appeared frequently in the studies. Serum levels of phosphate,3,10,11,15,23 calcium,17,21,25–27 CaxP product,11,15 PTH,14,16,25,26 FGF-2323,25,26 and the Klotho cofactor23,25 were directly and positively associated with CVC.

 Discussion

Several predictors of valvular calcification and valvular diseases were identified in patients with CKD. Advanced age was the most cited, with cutoff values above 55 years. The results were similar in studies that separately calculated the likelihood of MVC and AVC, allowing the conclusion that aging similarly affects both valves, consistent with other studies.28,29 Even in patients without CKD, age is relevant to the development of valvular calcification of degenerative etiology, with a prevalence of 10% in the elderly population,30 and is also a traditional risk factor for other cardiovascular conditions.9

The progressive and irreversible reduction of GFR, persisting for at least three months and at levels below 60 mL/min/1.73m2,2 was one of the criteria for diagnosing CKD.4 In this systematic review, studies showed an association between GFR and CVC starting at 45-50 mL/min/1.73m2.10,12,20 The duration of RRT and hypoalbuminemia were also identified as risk factors. Most studies investigated the possibility of an association between the chronicity of HD and CVC,16,19,21,24 with the duration ranging between 19.6 months and 13.4 years. London et al.31 stated that dialysis mechanisms promote a repetitive cycle of valvular stress due to blood flow speed and the degree of turbulence. Regarding the comparison between HD and PD, Wang et al.29 stated that cardiovascular conditions are similar between patients in both modalities. Conversely, Mary Laxton,32 in a review article, pointed out that PD might slow the calcification process by preserving some residual kidney function, outperforming HD. It cannot be confirmed that the higher frequency of findings related to HD in this systematic review reflects a greater risk of this modality, as approximately 90% of the population under any RRT undergoes it.33

This systematic review observed an association between low serum albumin levels (<3.5 g/dL) and CVC in patients undergoing RRT. Santos et al.34 concluded that, beyond malnutrition, factors such as reduced synthesis rate due to metabolic acidosis, inflammation, insufficient protein intake, hemodilution, and the type of membrane used in RRT (especially when sterilized with sodium hypochlorite) contribute to the reduction of serum albumin in patients on HD.34 Endothelial dysfunction and atherosclerosis secondary to the action of acute-phase proteins and inflammatory cytokines could also explain CVC.9 It is worth noting that Wang et al.35 observed that patients with CVC undergoing PD were significantly more malnourished and had lower serum albumin levels compared to those without CVC, and the prevalence of CVC was higher as albumin levels decreased. Extrapolating beyond CVC, hypoalbuminemia is a well-known independent predictor of cardiovascular events in general, as well as mortality and chronic systemic inflammation in CKD.9

Current scientific evidence points to a positive relationship between elevated inflammatory markers and CKD, as observed by Shankar et al.,36 who evaluated IL-6, TNF-α, CRP, and white blood cell count, with the strongest association for TNF-α. In this systematic review, three markers were associated with CVC – CRP, IL-6, and TNF-α, with only the first also reported in patients undergoing RRT. It is well known that inflammation is common in the later stages of CKD and that the calcification process originates mainly in areas under chronic inflammation, as observed in the genesis of atherosclerotic plaques.

Secondary hyperparathyroidism due to CKD appears to be related to the development of CVC. Hyperphosphatemia, resulting from the inability to excrete phosphate, is associated with calcification of both the mitral and aortic valves.37 Hypercalcemia and elevated levels of FGF-23 have also been studied in CKD patients. In this systematic review, these indicators were associated with CVC. In CKD, the loss of nephrons impairs the kidney's ability to excrete phosphates, leading to increased formation of calcium-phosphate complexes. The resulting reduction in ionized calcium levels stimulates calcium-sensitive receptors in the parathyroid glands to secrete PTH to increase renal excretion of these components. However, PTH raises serum calcium by stimulating reabsorption from bones and kidneys. Concurrently, the conversion of vitamin D to calcitriol further increases intestinal absorption of both ions. These disorders ultimately result in extracellular calcium deposition.

This systematic review has some limitations: some of the included studies had small sample sizes and short follow-up periods. Only studies with observational methodologies were included, most of which were cross-sectional, limiting causal inferences. The studies also presented variations in analyzed populations, comparison groups, inclusion and exclusion criteria, as well as in the methods for measuring outcomes, scoring systems, and statistical techniques, which made adequate comparison of results challenging.

This heterogeneity constitutes a limitation as it compromises the comparability and external validity of the findings. However, this does not invalidate the findings of the systematic review. The heterogeneity of the results obtained can be explored through appropriate statistical analyses, such as random-effects models in meta-analyses, presenting an opportunity for new investigations and providing directions for future research. Different methodologies offer complementary perspectives, enriching the understanding of the topic, with dozens of risk factors identified by the included studies. Regular monitoring and vigilance of these parameters in clinical practice can enable the early identification of CKD patients at risk of valvular calcification and valvular diseases, allowing better opportunities for prevention and treatment, ultimately leading to increased survival and improved quality of life.

 Conclusion

This study identified several risk factors for the development of valvular calcification in patients with CKD. The main ones were age, advanced stages of the disease, duration of RRT, hypoalbuminemia, cytokines and other inflammatory agents, as well as products involved in the metabolism of secondary hyperparathyroidism.

This study was partially funded by Escola Bahiana de Medicina e Saúde Pública (EBMSP) (Scientific Initiation Grant).

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

This article does not contain any studies with human participants or animals performed by any of the authors.

The authors did not use any artificial intelligence tools in the development of this work.

The underlying content of the research text is contained within the manuscript.