An in-depth analysis shows a hidden atherogenic lipoprotein profile in non-diabetic chronic kidney disease patients

ABSTRACT

Background: Chronic kidney disease (CKD) is an independent risk factor for atherosclerotic disease. We hypothesized that CKD promotes a proatherogenic lipid profile modifying lipoprotein composition and particle number.

Methods: Cross-sectional study in 395 non-diabetic individuals (209 CKD patients and 186 controls) without statin therapy. Conventional lipid determinations were combined with advanced lipoprotein profiling by nuclear magnetic resonance, and their discrimination ability was assessed by machine learning.

Results: CKD patients showed an increase of very-low-density (VLDL) particles and a reduction of LDL particle size. Cholesterol and triglyceride content of VLDLs and intermediate-density (IDL) particles increased. However, low-density (LDL) and high-density (HDL) lipoproteins gained triglycerides and lost cholesterol. Total-Cholesterol, HDL-Cholesterol, LDL-Cholesterol, non-HDL-Cholesterol and Proprotein convertase subtilisin-kexin type (PCSK9) were negatively associated with CKD stages, whereas triglycerides, lipoprotein(a), remnant cholesterol, and the PCSK9/LDL-Cholesterol ratio were positively associated. PCSK9 was positively associated with total-Cholesterol, LDL-Cholesterol, LDL-triglycerides, LDL particle number, IDL-Cholesterol, and remnant cholesterol. Machine learning analysis by random forest revealed that new parameters have a higher discrimination ability to classify patients into the CKD group, compared to traditional parameters alone: area under the ROC curve (95% CI), .789 (.711, .853) vs .687 (.611, .755).

Conclusions: non-diabetic CKD patients have a hidden proatherogenic lipoprotein profile.

KEYWORDS:

• Atherosclerosis
• chronic kidney disease
• dyslipidemia
• lipoprotein subfractions
• Lp(a)
• PCSK9

Authors contributions

MBL, JMV: conception and design, analysis and interpretation of the data, drafting of the paper, revising it critically for intellectual content and final approval of the version to be published.

JLG, EF: Resources, methodology and supervision.

CF: Statistical analysis, original draft writing, editing and interpretation of the data.

NA: NMR analysis, drafting of the paper.

SC, MB, TB, MB: traditional lipid parameter and PCSK9 determinations, drafting of the paper

DA, NA, MDP, DM: draft writing and data analysis.

All authors agree to be accountable for all aspects of the work.

Acknowledgments

The authors would like to thank the NEFRONA team (Eva Castro, Virtudes María, Teresa Molí, Teresa Vidal, Meritxell Soria), the Biobank of RedInRen for their invaluable support and the NEFRONA study investigator group.

The NEFRONA study investigator group is composed by the following: Aladrén Regidor, Mª José. Hospital Comarcal Ernest Lluch (Calatayud); Almirall, Jaume; Ponz, Esther. Corporació Parc Taulí (Barcelona); Arteaga Coloma, Jesús. Hospital de Navarra (Pamplona); Bajo Rubio, Mª Auxiliadora; Díaz, Raquel Raquel Hospital La Paz (Madrid); Belart Rodríguez, Montserrat. Sistemes Renals (Lleida); Gascón, Antonio,  Hospital Obispo Polanco (Teruel); Bover Sanjuan, Jordi. Fundació Puigvert. IIB Sant Pau (Barcelona); Bronsoms Artero, Josep. Clínica Girona (Girona); Cabezuelo Romero, Juan B; Muray Cases, Salomé. Hospital Reina Sofía (Murcia); Calviño Varela, Jesús. Hospital Universitario Lugus Augusti (Lugo); Caro Acevedo, Pilar. Clínica Ruber (Madrid); Carreras Bassa, Jordi. Diaverum Baix Llobregat (Barcelona); Cases Amenós, Aleix; Massó Jiménez, Elisabet. Hospital Clínic (Barcelona); Moreno López, Rosario. Hospital de la Defensa (Zaragoza); Cigarrán Guldris, Secundino; López Prieto, Saray. Hospital Da Costa (Lugo); Comas Mongay, Lourdes. Hospital General de Vic (Barcelona); Comerma, Isabel. Hospital General de Manresa (Barcelona); Compte Jové, Mª Teresa, Hospital Santa Creu Jesús (Tarragona); Cuberes Izquierdo, Marta. Hospital Reina Sofía (Navarra); de Álvaro, Fernando; Hevia Ojanguren, Covadonga. Hospital Infanta Sofía (Madrid); de Arriba de la Fuente, Gabriel. Hospital Universitario Guadalajara (Guadalajara); del Pino y Pino, Mª Dolores. Complejo Hospitalario Universitario Torrecardenas (Almería); Diaz-Tejeiro Izquierdo, Rafael; Ahijado Hormigos, Francisco Hospital Virgen de la Salud (Toledo); Dotori, Marta. USP Marbella (Málaga); Duarte, Verónica. Hospital de Terrassa (Barcelona); Estupiñan Torres, Sara. Hospital Universitario Canarias (Santa Cruz de Tenerife); Fernández Reyes, Mª José. Hospital de Segovia (Segovia); Fernández Rodríguez, Mª Loreto. Hospital Príncipe de Asturias (Madrid); Fernández, Guillermina. Clínica Santa Isabel (Sevilla); Galán Serrano, Antonio. Hospital General Universitario de Valencia (Valencia); García Cantón, Cesar. Hospital Universitario Insular de Gran Canaria (Las Palmas); García Herrera, Antonio L. Hospital Universitario Puerto Real (Cádiz); García Mena, Mercedes. Hospital San Juan de Dios (Zaragoza); Gil Sacaluga, Luis; Aguilar, Maria. Hospital Virgen del Rocío (Sevilla); Górriz, José Luis. Hospital Universitario Doctor Peset (Valencia); Huarte Loza, Emma. Hospital San Pedro (Logroño); Lerma, José Luis. Hospital Universitario Salamanca (Salamanca); Liebana Cañada, Antonio. Hospital de Jaén (Jaén); Marín Álvarez, Jesús Pedro. Hospital San Pedro de Alcántara (Cáceres); Martín Alemany, Nàdia. Hospital Jose p Trueta (Girona); Martín García, Jesús. Hospital Nuestra Señora de Sonsoles (Ávila); Martínez Castelao, Alberto. Hospital Universitari de Bellvitge (Barcelona); Martínez Villaescusa, María. Complejo Hospitalario Universitario de Albacete (Albacete); Martínez, Isabel. Hospital Galdakao (Bilbao); Moina Eguren, Iñigo. Hospital Basurto (Bilbao); Moreno Los Huertos, Silvia. Hospital Santa Bárbara (Soria); Mouzo Mirco, Ricardo. Hospital El Bierzo, Ponferrada (León); Munar Vila, Antonia. Hospital Universitari Son Espases (Palma de Mallorca); Muñoz Díaz, Ana Beatriz. Hospital Virgen del Consuelo (Valencia); Navarro González, Juan F. Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife); Nieto, Javier; Carreño, Agustín. Hospital General Universitario de Ciudad Real (Ciudad Real); Novoa Fernández, Enrique. Complexo Hospitalario de Ourense (Ourense); Ortiz, Alberto; Fernandez, Beatriz. IIS-Fundación Jiménez Díaz (Madrid); Paraíso, Vicente. Hospital Universitario del Henares (Madrid); Pérez Fontán, Miguel. Complejo Hospitalario Universitario A Coruña (A Coruña); Peris Domingo, Ana. Hospital Francesc de Borja (Valencia); Piñera Haces, Celestino. Hospital Universitario Marqués de Valdecilla (Santander); Prados Garrido, Mª Dolores. Hospital Universitario San Cecilio (Granada); Prieto Velasco, Mario. Hospital de León (León); Puig Marí, Carmina. Hospital d'Igualada (Barcelona); Rivera Gorrín, Maite. Hospital Universitario Ramón y Cajal (Madrid); Rubio, Esther. Hospital Puerta del Hierro (Madrid); Ruiz, Pilar. Hospital Sant Joan Despí Moisès Broggi (Barcelona); Salgueira Lazo, Mercedes; Martínez Puerto, Ana Isabel. Hospital Virgen Macarena (Sevilla); Sánchez Tomero, José Antonio. Hospital Universitario de la Princesa (Madrid); Sánchez, José Emilio. Hospital Universitario Central de Asturias (Oviedo); Sans Lorman, Ramon. Hospital de Figueres (Girona); Saracho, Ramon. Hospital de Santiago (Vitoria); Sarrias, Maria; Serón, Daniel. Hospital Universitari Vall d’Hebron (Barcelona); Soler, María José; Barrios, Clara. Hospital del Mar (Barcelona); Sousa, Fernando. Hospital Rio Carrión (Palencia); Toran, Daniel. Hospital General de Jerez (Cadiz); Tornero Molina, Fernando. Hospital de Sureste (Arganda del Rey); Usón Carrasco, José Javier. Hospital Virgen de la Luz (Cuenca); Valera Cortes, Ildefonso. Hospital Virgen de la Victoria (Málaga); Vilaprinyo del Perugia, Mª Merce. Institut Catala d’Urologia i Nefrologia (Barcelona); Virto Ruiz, Rafael C. Hospital San Jorge (Huesca); Vicente Pallarés Carratalá  Clinica MEDEFIS (Vila-real. Castellón), Carlos Santos Altozano CS Azuqueca de Henares (Guadalajara); Miguel Artigao Ródenas CS Zona III (Albacete); Inés Gil Gil Área Básica Sanitaria de Arán. CAP Viella (Lleida); Francisco Adan Gil CS Alfaro (La Rioja); Emilio García Criado Centro de Salud del Carpio (Córdoba.); Rafael Durá Belinchón CS Godella (Valencia); Jose Mª Fernández Toro CS Zona Centro (Cáceres); Juan Antonio Divisón Garrote Centro de Salud de Casas Ibáñez. Consultorio de Fuentealbilla (Albacete).

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This study was funded by Amgen, the intramural program of the IRBLleida, the Instituto de Salud Carlos III (RETIC RD16/0009/0011, FIS PI16/01354) and FEDER funds.