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Diabetologia

, Volume 61, Issue 11, pp 2277–2289 | Cite as

Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study

  • Giuseppe Penno
  • Anna Solini
  • Emanuela Orsi
  • Enzo Bonora
  • Cecilia Fondelli
  • Roberto Trevisan
  • Monica Vedovato
  • Franco Cavalot
  • Olga Lamacchia
  • Marco Scardapane
  • Antonio Nicolucci
  • Giuseppe Pugliese
  • for the Renal Insufficiency And Cardiovascular Events (RIACE) Study Group
Article

Abstract

Aims/hypothesis

Non-albuminuric renal impairment has become the prevailing diabetic kidney disease (DKD) phenotype in individuals with type 2 diabetes and an estimated GFR (eGFR) <60 ml min−1 1.73 m−2. In the present study, we compared the rate and determinants of all-cause death in individuals with this phenotype with those in individuals with albuminuric phenotypes.

Methods

This observational prospective cohort study enrolled 15,773 individuals with type 2 diabetes in 2006–2008. Based on baseline albuminuria and eGFR, individuals were classified as having: no DKD (Alb/eGFR), albuminuria alone (Alb+/eGFR), reduced eGFR alone (Alb/eGFR+), or both albuminuria and reduced eGFR (Alb+/eGFR+). Vital status on 31 October 2015 was retrieved for 15,656 individuals (99.26%).

Results

Mortality risk adjusted for confounders was lowest for Alb/eGFR (reference category) and highest for Alb+/eGFR+ (HR 2.08 [95% CI 1.88, 2.30]), with similar values for Alb+/eGFR (1.45 [1.33, 1.58]) and Alb/eGFR+ (1.58 [1.43, 1.75]). Similar results were obtained when individuals were stratified by sex, age (except in the lowest age category) and prior cardiovascular disease. In normoalbuminuric individuals with eGFR <45 ml min−1 1.73 m−2, especially with low albuminuria (10–29 mg/day), risk was higher than in microalbuminuric and similar to macroalbuminuric individuals with preserved eGFR. Using recursive partitioning and amalgamation analysis, prevalent cardiovascular disease and lower HDL-cholesterol were the most relevant correlates of mortality in all phenotypes. Higher albuminuria within the normoalbuminuric range was associated with death in non-albuminuric DKD, whereas the classic ‘microvascular signatures’, such as glycaemic exposure and retinopathy, were correlates of mortality only in individuals with albuminuric phenotypes.

Conclusions/interpretation

Non-albuminuric renal impairment is a strong predictor of mortality, thus supporting a major prognostic impact of renal dysfunction irrespective of albuminuria. Correlates of death partly differ from the albuminuric forms, indicating that non-albuminuric DKD is a distinct phenotype.

Trial registration:

ClinicalTrials.gov NCT00715481

Keywords

Albuminuria All-cause mortality Diabetic kidney disease Glomerular filtration rate Type 2 diabetes 

Abbreviations

ACR

Albumin-to-creatinine ratio

CKD

Chronic kidney disease

CVD

Cardiovascular disease

DKD

Diabetic kidney disease

eAER

Estimated AER

eGFR

Estimated GFR

eWC

Estimated waist circumference

KDIGO

Kidney Disease: Improving Global Outcomes

mAER

Measured AER

NHANES III

Third National Health and Nutrition Examination Survey

RAS

Renin–angiotensin system

RECPAM

recursive partitioning and amalgamation

RIACE

Renal Insufficiency And Cardiovascular Events

Notes

Acknowledgements

The authors thank the participants and the RIACE Investigators (see ESM for a complete list) for participating in this study.

Some of the data have been presented as an abstract at the EASD meeting in 2017.

Contribution statement

GPe, AS, AN and GPu conceived and designed the study. All authors contributed to data acquisition or analysis, and interpretation. GPu drafted the manuscript. GPe, AS, EO, EB, CF, RT, MV, FC, OL, MS and AN revised the manuscript critically for important intellectual content. All authors approved the final version. GPu is responsible for the integrity of the work as a whole.

Funding

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. The funders had no role in the study’s design, conduct or reporting.

Duality of interest

GPe has received: consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly; and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and MSD. AS has received: consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly; lecture fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly; and grant support from AstraZeneca. EO has received consulting fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Sanofi Aventis; and lecture fees from Abbot, AstraZeneca, Eli Lilly, Lifescan, Sanofi Aventis and Takeda. EB has received: consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly; lecture fees from Bristol-Myers Squibb, Eli Lilly, Janssen, MSD, Novo Nordisk, Roche, Sanofi Aventis and Takeda; and grant support from AstraZeneca, Novo Nordisk, Roche and Takeda. RT has received: consulting fees from Boehringer Ingelheim and Sanofi Aventis; lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Medtronic, Novartis, Novo Nordisk and Sanofi Aventis; and grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Sanofi Aventis. FC has received lecture fees from AstraZeneca, Sanofi Aventis and Takeda. OL has received: consulting fees from AstraZeneca and Boehringer Ingelheim; lecture fees from AstraZeneca, Eli Lilly, MSD, Sigma-Tau, Sanofi Aventis and Takeda; and grant support from AstraZeneca. AN has received consulting fees from Eli Lilly and Novo Nordisk; lecture fees from Eli Lilly and Novo Nordisk; and grant support from Artsana, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi Aventis. GPu has received: consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Shire; and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Mylan, Sigma-Tau and Takeda. All other authors declare that there is no duality of interest associated with their contribution to this manuscript.

Supplementary material

125_2018_4691_MOESM1_ESM.pdf (834 kb)
ESM (PDF 833 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Giuseppe Penno
    • 1
  • Anna Solini
    • 2
  • Emanuela Orsi
    • 3
  • Enzo Bonora
    • 4
  • Cecilia Fondelli
    • 5
  • Roberto Trevisan
    • 6
  • Monica Vedovato
    • 7
  • Franco Cavalot
    • 8
  • Olga Lamacchia
    • 9
  • Marco Scardapane
    • 10
  • Antonio Nicolucci
    • 10
  • Giuseppe Pugliese
    • 11
  • 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.Diabetes UnitIRCCS ‘Cà Granda - Ospedale Maggiore Policlinico’ FoundationMilanItaly
  4. 4.Division of Endocrinology, Diabetes and MetabolismUniversity and Hospital Trust of VeronaVeronaItaly
  5. 5.Diabetes UnitUniversity of SienaSienaItaly
  6. 6.Endocrinology and Diabetes UnitAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly
  7. 7.Department of Clinical and Experimental MedicineUniversity of PaduaPaduaItaly
  8. 8.Department of Clinical and Biological SciencesUniversity of TurinOrbassanoItaly
  9. 9.Department of Medical SciencesUniversity of FoggiaFoggiaItaly
  10. 10.Centre for Outcomes Research and Clinical Epidemiology (CORESEARCH)PescaraItaly
  11. 11.Department of Clinical and Molecular Medicine‘La Sapienza’ UniversityRomeItaly

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