FC 085SERUM INTERLEUKIN-6 LEVELS PREDICT RENAL DISEASE PROGRESSION IN DIABETIC KIDNEY DISEASE
Authors: Sanchez Alamo Beatriz , Shabaka Amir , Cachofeiro Ramos María Victoria , Fernandez Juarez Gema Maria 
Published: May 2021

Abstract

Background and Aims
Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator and different studies have suggested its involvement in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes. We also tested whether the use of optimal doses of RAS blockade in monotherapy had an influence on the levels of IL-6 in comparison with dual blockade.

Method
IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in the PRONEDI trial (EUDRACT 2004-002470-31), a multicenter, randomized controlled clinical trial. The study included type 2 diabetes patients with a clinical diagnosis of DKD, stage 2 or 3 CKD, and a urinary protein/creatinine ratio (UPCR) &gt;300 mg/g (morning urine spot) on 2 separate opportunities. The primary composite endpoint was a &gt;50% increase in baseline serum creatinine, end stage kidney disease (ESKD) or death. Cox regression model was adjusted for potential confounders or modifiers including eGFR calculated using the CKD-EPI equation and UPCR. Mixed models were adjusted to study longitudinal data.

Results
The recruitment period was 18 months and the median follow-up was 36 (IQR: 20-48) months, after which 27 patients (38.6%) reached the primary endpoint. At baseline mean IL-6 levels in the whole cohort were 4.58 ± 2.90, at 4 months 4.61 ± 3.10 and at 12 months: 6.14 ± 4.97. Patients were further divided into three groups according to the tertiles of baseline IL-6 levels (tertile 1: 0.65–2.65 pg/mL; tertile 2: 2.66–4.83 pg/mL and tertile 3: 4.84–13.30 pg/mL). There were no differences among the groups in demographic characteristics, cardiovascular risk factors, serum creatinine or proteinuria among the groups.
Correlation analyses for IL6 and other inflammatory parameters were carried out for all subjects. The results showed that inflammatory parameters had a significant correlation between them. IL-6 levels correlated with TNFα (r: 0.29; 95% CI: 0.05 - 0.49 p= 0.02), C-reactive protein (r= 0.61; 95%CI: 0.44 - 0.74 p&lt;0.01), and PTH (r: 0.30, 95% CI: 0.03-0.54, p=0.03). However, in the univariate analysis only IL-6 tertiles were associated with the primary outcome (OR: 2.41; 95% CI 1.25-4.64, p=0.008).
Patients with the highest IL-6 levels (&gt;4.84 pg/ml) experienced a significantly faster evolution to endpoint (mean survival: 33.2 months, CI 95%: 25.2-41.3) than the other 2 groups.
In the multivariate Cox regression analysis, the highest levels of IL-6 (Tertile 3) were significantly associated with the primary outcome (HR:3.86; 95%CI: 1.08-13.86) after being adjusted for baseline serum creatinine and proteinuria.
The time-dependent area under the ROC curve at two years of follow-up was 0.88 (95% CI: 0.79 - 0.97). The best cut-off IL-6 level was found at 4.68 pg/ml (sensitivity: 100%, specificity: 78.7%)
Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade.

Conclusion
In conclusion, our results show that higher levels of IL-6 are independently associated with progression of DKD in patients with type 2 diabetes, and that treatment with RAS blockade does not influence these levels. Serum IL-6 may be used as a noninvasive biomarker of progression to ESKD. Since our results show that higher IL-6 levels are associated with a worse renal prognosis, anti- inflammatory drugs that modulate IL-6 could be promising therapeutic agents to improve outcomes. Further studies focusing on the potential applications of anti-IL6 treatment in DKD are warranted.