The European Federation of Pharmaceutical Industries and Associations (EFPIA) explain how SAFE-T DIKI is advancing research into drug-induced kidney injury

Drug-induced kidney injury (DIKI) is not an uncommon adverse event in drug development. Kidney injury leads to a permanent impairment of the kidney function (chronic kidney disease) as the kidney is an organ with low regeneration capability. In clinical practice, acute kidney injury is defined using the Kidney Disease Improving Global Outcomes (KDIGO) criteria, which are based on serum creatinine and urine output changes.

One of the greatest problems is the late identification of acute kidney injury due to the current standards – i.e. serum creatinine (sCr) and blood urea nitrogen (BUN). Both of these are in fact delayed indicators of injury and may not be changed significantly until two-thirds of kidney function has already been lost.

Species differences in drug toxicity in preclinical safety tests, the lack of sensitive translational biomarkers and non-representative patient populations in clinical trials are among the probable reasons for the failures in predicting human drug toxicity. However, changes in drug discovery practices and the implementation of specific and sensitive safety biomarkers are expected to decrease these drug development failures.


This is where the Safer and Faster Evidence-based Translation (SAFE-T) Consortium comes in. SAFE-T is a non-profit, public-private partnership set up within the framework of the Innovative Medicines Initiative-Joint Undertaking (IMI-JU) – the world’s largest public/private partnership in the life sciences sector. The objective of the IMI-JU is to support projects for the development of tools and methodologies to address key “bottlenecks” in the pharmaceutical research and development process. Within this framework, the overall objective of the IMI SAFE-T consortium is the regulatory qualification of clinical safety biomarkers of drug-induced injury to 3 organs, including the kidney.

The objectives of the SAFE-T DIKI work package are to address the current gaps in sensitive and specific clinical tests to diagnose, predict and monitor drug-induced injury to the kidney. After an initial assessment of glomerular damage biomarkers, the work package focused on clinical biomarkers of drug-induced renal tubular injury.

The primary objective has been to identify biomarkers with improved sensitivity and specificity relative to conventional measures. A secondary aim was to determine which biomarkers allow an earlier detection of a renal tubular injury event. Other objectives include identifying prognostic markers and markers of repair, but these require large scale studies and may be addressed in future consortia.

Within the framework of the SAFE-T DIKI work package, the following 3 studies were conducted: a study in cancer patients receiving cisplatin chemotherapy, a study to collect samples in healthy volunteers, and a study in patients being administered contrast medium for a radiological procedure.

The Cisplatin study enrolled cancer patients with normal renal function who were scheduled to receive a 1st cycle of high dose (>65mg/m2/cycle) cisplatin chemotherapy. A total of 114 patients had blood and urine samples collected at the following time-points: pre-dose (baseline) and within 12 hours and 1, 2, 4, 7, 14 and 21 days after cisplatin administration. A control group of 21 patients with similar cancers receiving non-nephrotoxic treatment for the malignancy were also enrolled. The control patients had blood and urine samples collected at 2 separate visits.

Healthy subjects were recruited in 2 different studies. In one study, healthy male and female subjects attended for 3 separate visits 1 week apart to have blood and urine samples collected (N=25 subjects). In a second sample collection study, healthy male and female subjects had samples collected during 3 study visits (N=39 subjects) over a 2-4 week period.

The data for the study in patients receiving contrast media were not included in the main analysis because patients with impaired baseline renal function were enrolled and therefore this study does not represent the intended use of the novel biomarkers in subjects with normal baseline renal function.

The performance of novel urinary biomarkers was compared to that of standard measures such as serum creatinine, serum cystatin C and BUN. The novel biomarkers under review were: Urinary Alpha-Glutathione S-Transferase (α-GST), Clusterin (CLU), Cystatin-C (CysC), Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase- Associated Lipocalin (NGAL), Osteopontin (OPN), Urinary Total Protein.

Based on maximum percent change from baseline, serum creatinine showed relatively good performance. In this same analysis, serum cystatin C and BUN also showed good performance. Nevertheless, urinary osteopontin, albumin, KIM-1 and total protein all outperformed serum creatinine. Moreover, while urinary alpha-GST was comparable to serum creatinine, urinary cystatin C, clusterin and NGAL showed relatively poor performance.

Considering these results, the conclusion was that urinary osteopontin, albumin, KIM-1, total protein and possibly alpha-GST might all be used as individual markers in monitoring for acute nephrotoxicity.


European Federation of Pharmaceutical Industries and Associations (EFPIA)



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