Parallel assessment of albuminuria and plasma sTNFR1 in people with type 2 diabetes and advanced chronic kidney disease provides accurate prognostication of the risks of renal decline and death

Abstract

Identification of people with diabetes and chronic kidney disease at high-risk of early mortality is a priority to guide intensification of therapy. We aimed to investigate the complementary prognostic value of baseline urine albumin-to-creatinine ratio (uACR) and plasma soluble tumour necrosis factor receptor-1 (sTNFR1) with respect to early mortality and renal functional decline in a population with type 2 diabetes and advanced chronic kidney disease. We measured plasma sTNFR1 in people with type 2 diabetes (HbA1c ≥ 48 mmol/mol) at 2 hospital sites in Dublin between October 15th, 2014 and July 17th, 2015. In a subgroup of patients with advanced chronic kidney disease at baseline (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/BSA) (n = 118), we collected clinical and longitudinal laboratory data to investigate relationships between sTNFR1 and renal and mortality endpoints by multivariable linear mixed-effects models and Cox proportional hazards regression models. The cohort was 64% male and 97% Caucasian. Mean age was 74 years, with a median type 2 diabetes duration of 16 years. Mean CKD-EPI eGFR was 42 mL/min/BSA and median [IQR] uACR was 3 [11] mg/mmol. Twenty-three (39%) people in quartiles 3 and 4 for plasma sTNFR1 died over 4-year follow-up. After adjustment for clinical variables, annual CKD-EPI eGFR decreased by − 0.56 mL/min/BSA/year for each logarithm unit increase in baseline uACR, corresponding to an annual loss of renal function of 3% per year. Furthermore, elevated uACR, but not sTNFR1, increased the risk of ≥ 40% decline in CKD-EPI eGFR (HR 1.5, p = 0.001) and doubling of serum creatinine (HR 2.0, p < 0.001). Plasma sTNFR1 did not predict a more negative trajectory in eGFR slope. However, for those people in quartiles 3 and 4 for plasma sTNFR1, an increased risk of incident mortality was detected (HR 4.9, p = 0.02). No such association was detected for uACR. In this elderly cohort of patients with type 2 diabetes and chronic kidney disease, sTNFR1 predicted short-to-medium term mortality risk but not risk of progressive renal functional decline. In contrast, parallel assessment of uACR predicted renal functional decline but not mortality, highlighting the complementary prognostic information provided by both parameters.

Multiplex Serum Biomarker Assays Improve Prediction of Renal and Mortality Outcomes in Chronic Kidney Disease

“…Predictive performance of the biomarkers was further enhanced when incorporated alongside clinical variables. sTNFR1 and NGAL were the two most important biomarkers to classification by random forests, reaffirming their predictive value, which has been demonstrated across multiple cohorts (23 –25,27,38 –40). C-reactive protein ranked as the fifth most important variable to random forest classification of the composite renal and mortality end point, both in models trained on serum biomarkers alone and in models trained on both clinical variables and biomarkers, which further endorses its role in prognosticating the risk of renal functional decline in CKD (41,42).…”

“…However, the latter cohort of patients exclusively had type 2 diabetes for a median duration of 10 years and were enrolled up to a decade before patients in this study (10). The eGFR slope trajectory of this cohort was more similar to, albeit still lower than, a group of patients with type 2 diabetes and CKD (mean eGFR of 42 ml/min per BSA) enrolled in Dublin, Ireland during 2014-2015, in whom annual change in eGFR was 22 ml/ min per BSA per year (27). Thus, improvements in CKD management and a lower prevalence of diabetes (25%) in this study cohort may explain the modest rates of renal functional decline observed.…”

“…Compared with individuals who did not develop the composite renal and mortality end point, those who did were older (67615 versus 60617 years, P50.01), more likely to be male (71% versus 46%, P50.005), had a higher prevalence of diabetes mellitus (43% versus 13%, P,0.001), lower eGFR (26 [IQR,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) versus 43 ml/min per BSA, P,0.001), higher uACR (283 [IQR, 83-993] versus 104 mg/g, P,0.001), and higher 5-year KFRE scores (22.5% [IQR, 6.1%-55.1%] versus 2.1% [0.3%-9.0%], P,0.001). Concentrations of several serum biomarkers were higher in those who developed the composite renal and mortality end point, including sTNFR1, sTNFR2, NGAL, cystatin C, and-to a lesser extent-C-reactive protein, FABP1, and MIP-1-a.…”

Diabetes, Albuminuria and the Kidney—Brain Axis

“…Albuminuria represents a marker of microvascular disease preceding the loss of kidney function, accumulation of cSVD lesions and stroke [ 36 , 63 , 64 , 65 ]. After BBB breakdown occurs, several mechanisms may explain the connection between UACR and cognitive impairment, including an exacerbated inflammatory response.…”

Soluble tumor necrosis factor receptor type 1 predicts cardiorenal outcomes and better associated with distinct cardiovascular or renal outcomes than precedential renal or cardiovascular events in type 2 diabetes mellitus

“…The previous reports showed inconsistent conclusions about the predictability of sTNFR1 levels for cardiovascular and renal outcomes in subjects with stable coronary artery disease or advanced CKD versus subjects without apparent signs of cardiovascular or renal complications. 14 , 25 – 28 The discrepancies might be originating from the differences of characteristics of participants or definitions of outcomes. Our cohort enrolled the subjects with and without cardiovascular or renal complications at baseline.…”