New test identifies patients at high risk of kidney disease

BUDAPEST, Hungary – New urinary biomarker predicts risk of acute kidney injury after cardiac surgery and resulting deterioration of kidney function, according to a new study.

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

"If these cells have stress – no matter what kind of stress – they produce DKK3, which you can measure in the urine," he said. Medscape Medical News.

High levels of preoperative DKK3 in the urine have been badociated with a significant increase in the risk of acute kidney injury after surgery, he said.

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

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

The results of the study, discussed at a press conference at the 56th Congress of the European Renal Association and the European Dialysis and Transplant Association, and published online June 12 in the Lancet, will be presented at a session on the prevention of acute kidney injury.

In the cohort of study derivatives – comprising 733 unselected patients undergoing cardiac surgery – the risk of acute renal injury was 65% higher in patients with urinary DKK3 / creatinine concentrations greater than 471 pg / mg compared to those with concentrations equal to or lower than this threshold (odds ratio) [OR]1.65: P = 0.015).

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

After a median follow-up of 820 days, eGFR was significantly lower in patients with baseline concentrations of DKK3 / creatinine in the urine than in those whose concentrations were equal to or less than (63.1 vs 67, 0 vs mL / min per 1.73 m²; P = .0060).

Similarly, patients with elevated urine levels of DKK3 / creatinine were twice as likely to have consistently low GFRF – less than 60 mL / min per 1.73 m² – at follow-up compared with those with equal concentrations. or below the threshold of 471 μg / mg (OR, 2.01; P = 0.0015).

Patients with high concentrations of DKK3 / creatinine in preoperative urine were also more likely to experience further progression of chronic renal failure.

RenalRIP validation test cohort

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

In RenalRIP, "after multivariable adjustment, including renal function at admission, a urine DKK3 greater than 471 pg / mg creatinine was badociated with a significantly increased risk of AKI," explain Fliser and his colleagues. colleagues in their published results.

However, remote ischemic preconditioning in RenalRIP essentially reduced by half the risk of acute kidney injury after cardiac surgery (OR, 0.53; P = 0.016). In this subgroup, there was no badociation between high concentrations of DKK3 / creatinine and the risk of acute renal injury (P = 0.31), even after adjustment of renal function at admission, or risk of renal dysfunction persisting at 90 days.

Results in RenalRIP participants: DKK3 / preoperative urinary creatinine concentrations greater than 471 pg / mg compared to concentrations at or below this threshold
Result	Odds ratio	P Value
Risk of acute kidney injury	1.94	.026
Risk of persistent renal dysfunction at 90 days	6.67	.0072
Risk of 90-day renal replacement therapy	13.57	.020
Sub-group of sham procedure
Risk of acute kidney injury	2.79	.0022
Risk of persistent renal dysfunction at 90 days	3.82	.014

The remote ischemic preconditioning protocol evaluated in the RenalRIP trial involved placing a blood pressure cuff on the patient's upper arm to increase the 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 once the anesthesia aboard, since the intervention is apparently quite painful, Fliser pointed out.

The reasons the protocol helps to protect against kidney damage are not well understood, but Fliser has hypothesized that this might sound like the way a brief interlude of ischemia appears to protect the heart against subsequent ischemia.

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

Separate processes

According to Andreas Kribben, MD, of the Essen University Hospital, president of the Society of Nephrology in Germany, two distinct lesions cause acute kidney injury: functional renal failure and acute kidney damage. damage the kidney.

"The problem with acute kidney injury is that it is more defined than functional loss, and this DKK3 is actually a marker of acute kidney damage, which we need," Kribben said. Medscape Medical News.

This is all the more true as current clinical parameters do not predict acute kidney injury, especially during cardiac surgery, he explained. Identifying people at risk of kidney damage in this context will allow providers to change tactics, such as moving from surgery to out-of-pump intervention to reduce risk.

"We have to be careful to limit these results to patients who develop acute kidney injury in cardiac surgery, but in this context, this tool works," said Kribben.

"Acute kidney damage is badociated with a high risk of long-term mortality," he said. "It is therefore good to know what is the risk of a patient for this disease".

Fliser is a co-founder of DiaRen, the company currently marketing a DKK3 ELISA. Kribben served as adviser to Ablynx and Alexion, and received research grants from Alexion, Astellas, Chiesi, Novartis, Otsuka and Shire.

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

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