Defining the contribution of chronic kidney disease to all-cause mortality in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study

  • Giuseppe Penno
  • Anna Solini
  • Enzo Bonora
  • Emanuela Orsi
  • Cecilia Fondelli
  • Gianpaolo Zerbini
  • Roberto Trevisan
  • Monica Vedovato
  • Franco Cavalot
  • Luigi Laviola
  • Antonio Nicolucci
  • Giuseppe Pugliese
  • for the Renal Insufficiency and Cardiovascular Events (RIACE) Study Group
Original Article
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Abstract

Aims

To define the contribution of chronic kidney disease (CKD) to excess mortality in patients with type 2 diabetes and identify the baseline variables associated with all-cause death in those with and without CKD using the RECursive Partitioning and Amalgamation (RECPAM) method.

Methods

This observational, longitudinal, cohort study enrolled 15,773 consecutive non-dialytic patients with type 2 diabetes in 19 Diabetes Clinics throughout Italy in 2006–2008. Based on the presence of albuminuria ≥ 30 mg day−1 and/or estimated glomerular filtration rate (eGFR) < 60 mL min−1·1.73 m−2 at baseline, patients were classified as having or not CKD. Vital status was verified on October 31, 2015 for 99.26% of patients.

Results

Mortality increased with increasing albuminuria and eGFR category. Excess risk versus the general population was maximal in patients aged < 55 years in the worse albuminuria or eGFR category. Conversely, in subjects aged ≥ 75 years with albuminuria < 10 mg day−1 or eGFR ≥ 75 mL min−1·1.73 m−2, excess mortality was no longer detectable. At RECPAM analysis, the main correlates of death in the whole cohort were albuminuria > 44 mg day−1, prevalent CVD, and eGFR < ~ 75 mL min−1·1.73 m−2; gender, prevalent CVD, and higher albuminuria in the normoalbuminuric range, in patients without CKD; and CVD, eGFR ~ < 50 mL min−1·1.73 m−2, and albuminuria > 53 mg day−1, in those with CKD.

Conclusions

CKD is a major contributor to excess mortality in type 2 diabetes, conferring a very high risk in younger patients and fully accounting for excess risk in the older ones. Higher albuminuria and lower eGFR, even in the normal range, identify individuals with increased mortality risk.

Trial registration ClinicalTrials.gov (NCT00715481; https://clinicaltrials.gov/ct2/show/NCT00715481).

Keywords

Type 2 diabetes Chronic kidney disease Albuminuria Glomerular filtration rate All-cause mortality Cardiovascular risk factors 

Abbreviations

CVD

Cardiovascular disease

HR

Hazard ratio

CI

Confidence interval

CKD

Chronic kidney disease

eGFR

Estimated glomerular filtration rate

RECPAM

RECursive Partitioning and Amalgamation

RIACE

Renal Insufficiency and Cardiovascular Events

BP

Blood pressure

BMI

Body mass index

HbA1c

Hemoglobin A1c

AER

Albumin excretion rate

DR

Diabetic retinopathy

ISTAT

Italian National Institute of Statistics

Notes

Acknowledgements

This research was supported by the Research Foundation of the Italian Diabetes Society (Diabete Ricerca) and the Diabetes, Endocrinology and Metabolism (DEM) Foundation, and by unconditional grants from Eli Lilly, Sigma-Tau, Takeda, Chiesi Farmaceutici, and Boehringer Ingelheim.

Compliance with ethical standards

Conflict of interest

Dr. Penno reported receiving personal fees from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, and Merck Sharp & Dohme. Dr. Solini reported receiving grant from Astra-Zeneca and personal fees from Boehringer Ingelheim and Eli Lilly. Dr. Bonora reported receiving grants from Astra-Zeneca, Novo Nordisk, Roche, and Takeda and personal fees from Abbot, Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche, Sanofi-Aventis, and Takeda. Dr. Orsi reported personal fees from Abbot, Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Lifescan, Novo Nordisk, Sanofi-Aventis, and Takeda. Dr. Trevisan reported receiving personal fees from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Medtronic, Novartis, Novo Nordisk, and Sanofi-Aventis and grants from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. Dr. Cavalot reported receiving personal fees from Astra-Zeneca, Sanofi-Aventis, and Takeda. Dr. Nicolucci reported receiving grants from Artsana, Astra-Zeneca, Eli Lilly, Novo Nordisk, and Sanofi-Aventis and personal fees from Eli Lilly and Novo Nordisk. Dr. Pugliese reported receiving personal fees from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Mylan, Shire, Sigma-Tau, and Takeda. No other disclosures were reported.

Ethical standard

The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. The study protocol was approved by the locally appointed ethics committees.

Informed consent

Informed consent was obtained from all patients for being included in the study.

Supplementary material

592_2018_1133_MOESM1_ESM.doc (3.8 mb)
Supplementary material 1 (DOC 3853 kb)

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Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Giuseppe Penno
    • 1
  • Anna Solini
    • 2
  • Enzo Bonora
    • 3
  • Emanuela Orsi
    • 4
  • Cecilia Fondelli
    • 5
  • Gianpaolo Zerbini
    • 6
  • Roberto Trevisan
    • 7
  • Monica Vedovato
    • 8
  • Franco Cavalot
    • 9
  • Luigi Laviola
    • 10
  • Antonio Nicolucci
    • 11
  • Giuseppe Pugliese
    • 12
  • for the Renal Insufficiency and Cardiovascular Events (RIACE) Study Group
  1. 1.Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  2. 2.Department of Surgical, Medical, Molecular and Critical Area PathologyUniversity of PisaPisaItaly
  3. 3.Division of Endocrinology, Diabetes and MetabolismUniversity and Hospital Trust of VeronaVeronaItaly
  4. 4.Diabetes UnitIRCCS “Cà Granda - Ospedale Maggiore Policlinico” FoundationMilanItaly
  5. 5.Diabetes UnitUniversity of SienaSienaItaly
  6. 6.Complications of Diabetes Unit, Division of Metabolic and Cardiovascular SciencesSan Raffaele Scientific InstituteMilanItaly
  7. 7.Endocrinology and Diabetes UnitAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly
  8. 8.Department of Clinical and Experimental MedicineUniversity of PaduaPaduaItaly
  9. 9.Department of Clinical and Biological SciencesUniversity of TurinOrbassano, TurinItaly
  10. 10.Department of Emergency and Transplants - Section of Internal Medicine, Endocrinology, Andrology and Metabolic DiseasesUniversity of Bari Aldo MoroBariItaly
  11. 11.Center for Outcomes Research and Clinical Epidemiology (CORESEARCH)PescaraItaly
  12. 12.Department of Clinical and Molecular Medicine“La Sapienza” UniversityRomeItaly

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