Novel Assay Identifies Patients at High Risk for Kidney Injury

Pam Harrison

June 14, 2019

BUDAPEST, Hungary — A novel urinary biomarker is able to predict risk for acute kidney injury after cardiac surgery, and the subsequent decline in renal function, according to a new study.

"Dickkopf-3 [DKK3] is a specific modulator of a proinflammatory pathway that is used by tubular cells to communicate," said investigator Danilo Fliser, MD, from the Saarland University Medical Center in Homburg, Germany.

"If these cells have stress — any kind of stress — they produce DKK3, which you can measure in the urine," he told Medscape Medical News.

High preoperative levels of DKK3 in the urine were associated with a significant elevation in risk for acute kidney injury after surgery, he said.

And in the validation cohort of the study — which included participants who received remote ischemic preconditioning after the induction of anesthesia in the RenalRIP trial (JAMA. 2015;313:2133-2141) — there was no increase in the risk for acute kidney injury despite elevated preoperative levels of DDK3.

"So we showed that not only can you identify patients at high risk for acute kidney injury, but that if you do detect high levels of DKK3, you could do remote ischemic preconditioning and help prevent it," Fliser explained.

The study results, discussed during a news conference here at the European Renal Association–European Dialysis and Transplant Association 56th Congress and published online June 12 in the Lancet, will be presented during a session on how to prevent acute kidney injury.

In the derivation cohort of the study — consisting of 733 unselected patients scheduled for cardiac surgery — the risk for acute kidney injury was 65% higher in patients with presurgical urinary DKK3/creatinine concentrations above 471 pg/mg than in those with concentrations at or below that threshold (odds ratio [OR], 1.65: P = .015).

This association was independent of baseline estimated glomerular filtration rates (eGFR).

At a median follow-up of 820 days, eGFR was significantly lower in patients whose baseline urinary DKK3/creatinine concentrations were above the threshold than in those whose concentrations were at or below (63.1 vs 67.0 vs mL/min per 1.73 m²; P = .0060).

Similarly, patients with the high urinary DKK3/creatinine concentrations were twice as likely to have a persistently low eGFR — less than 60 mL/min per 1.73 m² — during follow-up as those with concentrations at or below the 471 pg/mg threshold (OR, 2.01; P = .0015).

Patients with elevated preoperative urinary DKK3/creatinine concentrations were also more likely to experience subsequent progression of chronic kidney disease.

Validation Cohort From the RenalRIP Trial

In the RenalRIP trial, participants had a presurgical Cleveland Clinical Foundation score of at least 6, indicating high risk for acute kidney injury, and were randomized to either remote ischemic preconditioning or a sham procedure.

In RenalRIP, "after multivariable adjustment, including kidney function at admission, urinary DKK3 higher than 471 pg/mg creatinine was associated with a significantly increased risk of AKI," Fliser and his colleagues write in their published results.

However, remote ischemic preconditioning in RenalRIP essentially halved the risk for acute kidney injury after cardiac surgery (OR, 0.53; P = .016). In that subgroup, there was no association between high DKK3/creatinine concentrations and risk for acute kidney injury (P = .31), even after adjustment for kidney function on admission, or risk for persistent renal dysfunction at 90 days.

Outcomes in RenalRIP Participants: Presurgical Urinary DKK3/Creatinine Concentrations Above 471 pg/mg vs Concentrations At or Below That Threshold
Outcome Odds Ratio P Value
Risk for acute kidney injury 1.94 .026
Risk for persistent renal dysfunction at 90 days 6.67 .0072
Risk for renal replacement therapy at 90 days 13.57 .020
Sham procedure subgroup    
Risk for acute kidney injury 2.79 .0022
Risk for persistent renal dysfunction at 90 days 3.82 .014

The remote ischemic preconditioning protocol evaluated in the RenalRIP trial involved a blood pressure cuff being placed on the patient's upper arm to increase systolic pressure by 15 mm Hg for 5 minutes, followed by 5 minutes of deflation. The protocol was repeated three times.

It is necessary to induce preconditioning after anesthesia is on board because the intervention is apparently quite painful, Fliser pointed out.

Why the protocol helps protect against kidney damage is not well understood, but Fliser speculated that it might be similar to the way a brief interlude of ischemia appears to protect the heart against further ischemia.

Until now, "we really had no decisive intervention to prevent AKI, but there are all kinds of drugs and interventions in development," said Fliser. The DKK3 assay "is a kind of precision-medicine step because if you go only for patients who are at high risk for AKI, you will see results."

Separate Processes

There are two separate processes leading to acute kidney injury — acute kidney impairment in function and acute kidney injury that is damaging the kidney — said Andreas Kribben, MD, from University Hospital in Essen, who is president of the Society of Nephrology in Germany.

"The problem with acute kidney injury is that it is now defined only by functional loss. This DKK3 is actually a marker for acute kidney damage, which we need," Kribben told Medscape Medical News.

This is particularly true because current clinical parameters are not predictive of acute kidney injury, especially in the setting of cardiac surgery, he explained. Identifying people at risk for kidney injury in this setting will allow providers to change their tactics, such as changing the surgery from an on-pump to an off-pump procedure to reduce risk.

"We have to be careful to limit these findings to patients who develop acute kidney injury in the setting of cardiac surgery, but in this setting, this tool works," Kribben emphasized.

"Acute kidney injury is associated with an elevated risk of mortality over the long-term," he noted, so "it's good to know what a patient's risk is for it."

Fliser is a cofounder of DiaRen, the company that is currently marketing a DKK3 ELISA assay. Kribben has served as an advisor to Ablynx and Alexion, and has received research grants from Alexion, Astellas, Chiesi, Novartis, Otsuka, and Shire.

European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) 56th Congress: Abstract SaO038. To be presented June 15, 2019.

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