Albuminuria, serum creatinine, and estimated glomerular filtration rate as predictors of cardio-renal outcomes in patients with type 2 diabetes mellitus and kidney disease: a systematic literature review

Abstract

Background: Albuminuria, elevated serum creatinine and low estimated glomerular filtration rate (eGFR) are pivotal indicators of kidney decline. Yet, it is uncertain if these and emerging biomarkers such as uric acid represent independent predictors of kidney disease progression or subsequent outcomes among individuals with type 2 diabetes mellitus (T2DM). This study systematically examined the available literature documenting the role of albuminuria, serum creatinine, eGFR, and uric acid in predicting kidney disease progression and cardio-renal outcomes in persons with T2DM.

Methods: Embase, MEDLINE, and Cochrane Central Trials Register and Database of Systematic Reviews were searched for relevant studies from January 2000 through May 2016. PubMed was searched from 2013 until May 2016 to retrieve studies not yet indexed in the other databases. Observational cohort or non-randomized longitudinal studies relevant to albuminuria, serum creatinine, eGFR, uric acid and their association with kidney disease progression, non-fatal cardiovascular events, and all-cause mortality as outcomes in persons with T2DM, were eligible for inclusion. Two reviewers screened citations to ensure studies met inclusion criteria.

Results: From 2249 citations screened, 81 studies were retained, of which 39 were omitted during the extraction phase (cross-sectional [n = 16]; no outcome/measure of interest [n = 13]; not T2DM specific [n = 7]; review article [n = 1]; editorial [n = 1]; not in English language [n = 1]). Of the remaining 42 longitudinal study publications, biomarker measurements were diverse, with seven different measures for eGFR and five different measures for albuminuria documented. Kidney disease progression differed substantially across 31 publications, with GFR loss (n = 9 [29.0%]) and doubling of serum creatinine (n = 5 [16.1%]) the most frequently reported outcome measures. Numerous publications presented risk estimates for albuminuria (n = 18), serum creatinine/eGFR (n = 13), or both combined (n = 6), with only one study reporting for uric acid. Most often, these biomarkers were associated with a greater risk of experiencing clinical outcomes.

Conclusions: Despite the utility of albuminuria, serum creatinine, and eGFR as predictors of kidney disease progression, further efforts to harmonize biomarker measurements are needed given the disparate methodologies observed in this review. Such efforts would help better establish the clinical significance of these and other biomarkers of renal function and cardio-renal outcomes in persons with T2DM.

Keywords: Albuminuria; Biomarker; Estimated glomerular filtration rate; Kidney disease progression; Serum creatinine; Type 2 diabetes mellitus.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart SLR systematic literature review, T2DM type 2 diabetes mellitus

Fig. 2

a Frequency of measures used to define kidney decline/chronic kidney disease progression in 31 longitudinal publications; (b) Frequency of measures used to define albuminuria/proteinuria in 33 longitudinal publications. *100% (3 out of 3) of 50% decline in eGFR, 60% (3 out of 5) of doubling of serum creatinine, and 33% (1 out of 3) of kidney disease progression measures included the composite end points of renal replacement therapy initiation, end-stage renal disease, or mortality. Nephropathy progression did not include composite end points, instead, three studies reported “nephropathy progression” and one reported “worsening of nephropathy stage”. CKD chronic kidney disease, Cr creatinine, eGFR estimated glomerular filtration rate, GFR glomerular filtration rate, s serum

Fig. 3

Number of publications reporting a significant (direct or inverse) or non-significant relationship for risk estimates with clinical outcomes according to the biomarkers albuminuria/proteinuria, serum creatinine/uric acid/eGFR, or both measured simultaneously, in patients with type 2 diabetes mellitus. eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, CV cardiovascular. Panel a. Hazard ratios for studies with albuminuria/proteinuria outcomes. Panel b. Hazard ratios for studies with serum creatinine/uric acid/eGFR outcomes. Panel c. Hazard ratios for studies with albuminuria/proteinuria and serum creatinine/uric acid/eGFR