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Higher levels of interleukin-6 (IL-6) are associated with faster progression of proteinuric diabetic kidney disease, new research shows. In addition, higher IL-6 levels are not affected by drugs that block the renin–angiotensin–aldosterone (RAAS) system, which are widely used to treat the disease.
“Diabetic kidney disease has classically been considered as a noninflammatory kidney disease and thought to be the consequence of an interaction between hemodynamic and metabolic factors,” Beatriz Sanchez Alamo, MD, Hospital Universitario Fundación Alcorcón, estradiol en mujeres fertiles Spain, told Medical Medical News in an email.
“However, there is increasing evidence supporting a role for inflammation in type 2 diabetes, [and] 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,” she added.
Alamo presented her findings during the 58th European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Virtual Congress in Berlin, Germany.
The study involved a total of 70 patients between age 35 and 75 years, all of whom had a clinical diagnosis of diabetic kidney disease.
“Most patients were men with a mean age of 69 years,” Alamo noted. Fifteen patients were randomly assigned to receive irbesartan (Avapro) alone at a maximal dose of 500 mg a day; 19 were assigned to receive lisinopril (Prinivil, Zestril) alone at a maximal dose of 40 mg a day; and 36 patients received dual RAAS blockade at a dose of 20 mg a day of lisinopril plus 300 mg a day of irbesartan.
At baseline, mean hemoglobin level was 13.3 g/dL and the mean A1c was 7.1%. Most patients had stage 3 chronic kidney disease (CKD) with a mean estimated glomerular filtration rate (eGFR) of 45.1 mL/min/1.73 m2 and a mean urinary protein/creatinine ratio (uPCR) of more than 300 mg/g. Baseline IL-6 values were recorded and patients were stratified into tertiles according to baseline IL-6 levels.
Patients in the lowest IL-6 tertile had an IL-6 value ranging from 0.65 to 2.65 pg/dL; those in tertile 2 had a baseline IL-6 value between 2.66 and 4.83 pg/mL, and those in the highest tertile had baseline IL-6 value of 4.84 to 13.3 pg/mL. Investigators also measured other inflammatory biomarkers, including C-reactive protein (CRP) and tumor necrosis factor (TNF)-α.
“The primary outcome was a composite of an increase of greater than 50% in serum creatinine, end-stage kidney disease (ESKD), or death,” Alamo said. The authors first noted that patients in the top third IL-6 tertile had significantly higher levels of CRP and TNF-α than patients in the lower two IL-6 tertiles.
“However, in univariate analysis, only IL-6 was significantly associated with the primary outcome — none of the other inflammatory biomarkers were associated with kidney disease progression,” Alamo reported. She also stressed that study participants overall had a poor prognosis, with almost 39% of the cohort reaching the primary endpoint at the end of the 48-month trial, including 5 patients who died.
The risk of reaching the primary endpoint was highest for 14 patients in the top IL-6 tertile compared with 8 patients in the second tertile and 5 patients in the lowest tertile.
“We found that those patients with IL-6 values higher than 4.68 pg/dL experienced a significantly faster progression toward the primary endpoint,” Alamo also reported. The researchers then confined their analysis to patients with stage 3 CKD and a uPCR above 1.5 g/g, again stratified according to their baseline IL-6 tertile.
“We again found that those patients with the highest IL-6 levels in the upper tertile had a faster and worse progression [of diabetic kidney disease],” she observed. Indeed, compared to patients in the lowest IL-6 baseline tertile, those in the highest IL-6 tertile had a more than 3.5-fold greater risk of progressing to the primary endpoint on multivariate analysis, she added.
RAAS Blockers Had No Effect
In contrast, neither monotherapy with RAAS blockade nor dual RAAS blockade had any effect on the IL-6 ratio 12 months after randomization. As Alamo explained, it has been hypothesized that RAAS blockade might have anti-inflammatory properties in addition to their well-known hemodynamic effects.
“RAAS blockers have proved to slow the rate of progression of diabetic kidney disease as well, but we wanted to know if they do so by inhibiting the production of proinflammatory cytokines,” Alamo explained.
However, as investigators observed, treatment with even maximal dual RAAS blockade did not influence IL-6 levels, indicating RAAS blockade does not modify the inflammatory mechanisms that drive the progression of diabetic kidney disease. “Serum IL-6 may be used as a noninvasive biomarker of progression to ESKD,” Alamo concluded.
“And anti-inflammatory drugs that modulate IL-6 could be promising therapeutic agents to improve outcomes in patients with proteinuric diabetic kidney disease,” she added.
For example, sodium-glucose cotransporter-2 (SGLT-2) inhibitors might be used to reduce inflammation as they have been shown to decrease urinary excretion of inflammatory markers such as IL-6.
As such, “we encourage the use of SGLT-2 inhibitors [in this patient population] as they appear to have a promising future in the treatment of diabetic kidney disease,” Alamo observed.
Precision Phenotyping
There is already widespread recognition that there is a major inflammatory component to diabetic kidney disease, commented Katherine Tuttle, MD, professor of medicine, University of Washington, and executive director for research, Providence Health Care, Seattle, Washington. “We’re not yet at a stage where we can do precision phenotyping because there are many different types and pathways of inflammation, so that is still a work in progress to understand what these mechanisms are and then which biomarkers are going to map to those kidney-specific mechanisms.” Tuttle was not involved in the study.
What Tuttle thinks is most relevant at the moment is therapeutic development — identifying patients with certain inflammatory phenotypes who might then respond to a specific anti-inflammatory agent. To this end, Tuttle and colleagues are currently involved in the ZEUS trial, in which the novel IL-6 ligand inhibitor ziltivekimab (Novo Nordisk) will be evaluated in patients with chronic kidney disease (CKD) to see whether treatment can reduce cardiovascular events.
However, major secondary outcomes of ZEUS are kidney disease outcomes. “So truthfully, this hypothesis is about to be directly tested and in the trial, we’ll be looking at IL-6 levels as well as other inflammatory mediators that are on the same pathway,” Tuttle said.
“So this trial is really innovative because it is focused on CKD patients with and without diabetes, but it really is looking at two risks that are driven by inflammation — namely the heart and the kidney — so the trial will have hard kidney outcomes, which is really taking it to the finish line,” she emphasized.
Alamo reports receiving a research grant from EUVAS, but it was not related to this research. Tuttle is on the steering committee of the ZEUS trial, which is being funded by Novo Nordisk.
European Renal Association–European Dialysis and Transplant Association Virtual Congress: Abstract SU 2130. Presented June 6, 2021.
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