Moving toward a contemporary classification of drug-induced kidney disease

Abstract

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including "dysfunction without damage," "damage without dysfunction," "both dysfunction and damage," and "neither dysfunction nor damage" using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient's kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers.

Keywords: Acute kidney injury; Adverse drug event; Critical care; Critically ill; Drug-related side effects and adverse reactions; Intensive care units.

Fig. 1

Classification system of drug-induced kidney injury based on functional and damage biomarkers suggested by Ostermann et al. [10]. Since most experts prefer the term “damage” to “injury” for describing the pathology and pathophysiology of AKI induced by different etiologies such as medications, we have replaced “injury” with “damage” in the title of each DIKD category introduced primarily by the ADQI expert group [10]. Drug or drug class examples for each category have been provided just to clarify more this classification system of DIKD. Listed medications are only examples of each category, and they should not be considered all-inclusive. In the presence of susceptibility factors, medications belonging to “neither dysfunction nor damage group” can move to other categories. This is also true for the “dysfunction without damage” and “damage without dysfunction” categories. Arrows depict the possible movements between categories. The movement of a given patient at a specific time course from the “damage without dysfunction” category to the “dysfunction without damage” category or vice versa makes no sense from pharmacological and clinical perspectives. The bidirectional arrows mean that both the progression and recovery of DIKD are possible in certain categories

Fig. 2

Some novel functional and damage biomarkers of the kidney can help to classify drug-induced kidney disease based on the suggested framework by Ostermann et al. [10]. Damage biomarkers are related to different sites of the kidney and are mostly site-specific. KIM-1 is a cell membrane glycoprotein upregulated in the presence of nephrotoxic/ischemic damage to proximal tubule epithelial cells. NGAL is a glycoprotein expressed in various tissues, including the kidney. Its expression is markedly upregulated after kidney ischemia. IL-18 is a pro-inflammatory cytokine expressed during proximal tubular injury. L-FABP is expressed in the proximal tubule, and its expression is augmented by hypoxic stress. β2M is a low molecular weight polypeptide that presents on the cell surface of all nucleated cells. In the case of tubular dysfunction, its level in urine will increase. TIMP-2 and IGFBP7 are preferentially expressed and secreted from distal and proximal tubules, respectively, in response to stress and damage. All these damage biomarkers have preliminary clinical evidence that is promising. Urinary KIM-1 and NGAL have the most clinical evidence in the setting of drug-induced kidney disease  [42]. Besides these two biomarkers, urinary IL-18, L-FABP, and TIMP-2·IGFBP7 can also help diagnose ATI early and differentiate injury from dysfunction. Urinary TIMP-2·IGFBP7 appears to be an appropriate candidate damage biomarker of DIKD, particularly in preoperative and critically ill settings, because of its features discussed elsewhere [43, 44]. Three novel functional biomarkers in serum have been introduced and studied in clinical settings. CysC is a low molecular weight protein produced by all nucleated cells and cleared only by glomerular filtration [41]. PENK is the precursor polypeptide hormone of the enkephalin family freely filtered in the glomerulus [40]. BTP is a small protein primarily produced in the cerebral fluid and eliminated by glomerular filtration [41]. Except for plasma CysC, there are currently no clinical data on other novel functional biomarkers of the kidney associated with medications. Despite promising findings with novel functional and damage biomarkers, they should be interpreted cautiously because AKI, the primary endpoint in these studies, is mostly diagnosed by changes in serum creatinine concentration rather than specific biomarkers. CysC, Cystatin C; PENK, Proenkephalin A; BTP, β-trace protein; KIM-1, Kidney injury molecule-1; NGAL, Neutrophil gelatinase-associated lipocalin; IL-18, Interleukin-18; L-FABP, Liver-type fattyacid-binding protein; β2M, Beta-2 microglobulin; IGFBP7, Insulin-like growth factor binding protein 7; TIMP-2, Tissue inhibitor of metalloproteinases-2