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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 5

Drug-induced acute kidney injury: Epidemiology, mechanisms, risk factors, and prevention via traditional chinese medicine

Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Date of Submission05-Feb-2022
Date of Decision12-Apr-2022
Date of Acceptance18-Apr-2022
Date of Web Publication31-May-2022

Correspondence Address:
Prof. Xuezhong Gong
Department of Nephrology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Road, Shanghai 200071
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-0387.345767

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Drug-induced nephrotoxicity is a common cause of acute kidney injury (AKI), and drug-induced AKI (DI-AKI) is becoming a serious public health concern. DI-AKI can be triggered by multiple drugs, alone or in combination. The incidence, pathological mechanisms, and risk factors of DI-AKI are largely unknown. Thus, there is a need for greater monitoring of DI-AKI to reduce the risks of serious complications and other hazards related to DI-AKI. This review summarizes the epidemiology of DI-AKI, along with its potential pathogenesis, associated drugs, independent risk factors, and possible early biomarkers. Additionally, because certain traditional Chinese medicine (TCM) prescriptions and their components have been reported to prevent and treat some types of DI-AKI (e.g., contrast-induced AKI), this review summarizes TCM methods for the prevention and treatment of DI-AKI.

Keywords: Drug-induced acute kidney injury, epidemiology, pathogenesis, risk factors, traditional Chinese medicine

How to cite this article:
Chen L, Gong X. Drug-induced acute kidney injury: Epidemiology, mechanisms, risk factors, and prevention via traditional chinese medicine. Integr Med Nephrol Androl 2022;9:5

How to cite this URL:
Chen L, Gong X. Drug-induced acute kidney injury: Epidemiology, mechanisms, risk factors, and prevention via traditional chinese medicine. Integr Med Nephrol Androl [serial online] 2022 [cited 2023 Mar 26];9:5. Available from: https://journal-imna.com//text.asp?2022/9/1/5/345767

  Introduction Top

Acute kidney injury (AKI) is characterized by a rapid decrease in glomerular filtration rate; it is one of the most serious complications in hospitalized patients, and it is linked to increases in mortality and medical costs.[1] Kidney injury caused by the use of one or more drugs or their metabolites at seven-day intervals is known as drug-induced acute kidney injury (DI-AKI).[2],[3] DI-AKI is increasingly recognized as a common adverse drug reaction during the treatment process.[3] Drug-induced injury is included among the five most common causes of AKI in hospitalized patients.[4],[5] Various drugs cause AKI in 18% to 27% of in-hospital patients with AKI in the United States.[6] In the past few years, the proportion of DI- AKI among patients with AKI in China has increased from 26.5% to 42.9%.[7],[8] A national multi-center survey showed that 71.6% of patients with hospital-acquired AKI in China are exposed to potentially nephrotoxic drugs either before or during the onset of kidney injury.[9]

Although many cases of DI-AKI have been reported, the drug categories and risk factors associated with AKI have not been thoroughly explored. Because DI-AKI is a severe disease that can be elicited by various drugs, there is a critical need to fully identify the causative drugs and other possible risk factors. It is difficult to predict the onset of DI-AKI and ensure prompt treatment; early biomarkers for DI-AKI will help to address this problem.

Traditional Chinese medicine (TCM) is effective for clinical treatment. Herbal medicine and compounds have recently been shown to prevent DI-AKI and alleviate kidney injury.[10],[11],[12] TCM is reportedly able to reduce the clinical manifestations of DI-AKI (e.g., proteinuria, hematuria, and edema).[10] Therefore, the identification of potential nephrotoxicity associated with the intake of herbal medicine and compounds promptly is critical for preventing and treating DI-AKI. This review summarizes the epidemiology of DI-AKI, along with its potential pathogenesis, associated drugs, independent risk factors, and possible early biomarkers. Additionally, this review summarizes TCM methods for the prevention and treatment of DI-AKI, based on recent evidence that certain TCM prescriptions and their components can prevent and treat some types of DI-AKI (e.g., contrast-induced AKI [CI-AKI]).

  Epidemiological Data of DI-AKI Top

DI-AKI can be caused by various drugs, each with its own set of clinical characteristics and involving diverse clinical disciplines. To our knowledge, no nationwide data have been published regarding the exact incidence of DI-AKI in China. Additionally, the drug categories that cause AKI differ among regions of China; this hinders the development of DI-AKI prevention strategies on a national scale.

Among adults with AKI, 14% to 26% have DI-AKI; moreover, DI-AKI is present in approximately 16% of children with AKI.[13],[14] In a study of 1,960 patients with hospital-acquired AKI, Liu et al.[15] found that 37.5% had DI-AKI. Furthermore, 13.88% of in-hospital patients died during hospitalization; 54.34% of the surviving patients did not fully recover their kidney function. Another study[6] found that professional medical staff informed all analyzed DI-AKI participants, 55% of whom were women with a mean age of 68.7 ± 15 years. The morbidity rate among enrolled participants was 4.6%; 80.7% of participants demonstrated complete or near-complete recovery, while the outcome was unknown for 14.7% of participants.[6] Globally, drugs are a major cause of AKI. Drugs that cause DI-AKI differ among countries; additionally, the characteristics of DI-AKI differ among regions (e.g., between developing and developed countries). Studies from South Africa and Japan[16],[17] have suggested that DI-AKI is present in 21.0% to 37.4% of all patients with AKI in developing countries (e.g., South Africa), while it is present in 14.4% to 25.7% of such patients in developed countries (e.g., Japan). The incidence of DI-AKI in China is significantly higher in economically underdeveloped regions (40.81%) than in more developed areas (31.76%).[15] Overall, DI-AKI is a critical problem worldwide, particularly in economically underdeveloped areas.

  Potential Pathogenesis of DI- AKI Top

The most common cause of nephrotoxicity is drug use related to tubule interstitial injury, which manifests as acute tubular injury or interstitial nephritis.[6] Several evidence-based studies have also highlighted the risk of drug-induced glomerulus diseases (e.g., diseases that involve direct cellular injury and immune-mediated injury). There is a need to identify drug- induced nephropathy and promptly discontinue drug use; these actions will help to prevent kidney injury.

Drugs can cause kidney injury through various mechanisms,[18] including direct nephrotoxicity, immune-mediated injury, renal ischemia, and renal tubular obstruction. Additionally, the long-term risk of kidney injury is increased by drug accumulation in tubule cells and accumulation in other cells that lack appropriate metabolic enzymes, as well as the interaction between innate direct cytotoxicity and tubule cell type. Depending on the injured area and the underlying pathophysiological mechanism, DI-AKI can manifest through one of three mechanisms.[19],[20] The first is a dose-dependent mechanism that causes proximal tubular injury and acute tubular necrosis. The primary mechanism comprises direct contact between renal tubules and drugs or their metabolites; such contact includes apical contact, transportation through the apical surface, and transportation from the basolateral surface into the tubular lumen. The second is a dose-dependent mechanism that involves tubular obstruction by crystals or casts containing drugs or their metabolites. The third is a dose- independent mechanism that involves interstitial nephritis, which is caused by drugs or their metabolites.

Direct DI-AKI can be caused by drug-induced ischemia and toxicity in renal tissues. Drug crystal deposits can also form in the urinary tubule when drug concentrations in the tubule exceed a particular drug’s solubility because of active transporter secretion or altered pH along the nephron;[21] these deposits cause obstructive renal injury. Damage to glomerular cells (podocytes or capillary endothelium) can impair the barrier function and filtration efficiency of the glomerulus, while damage to renal tubules can impair the reabsorption and active secretion of solutes. Certain drugs are transported by kidney-specific uptake transporters or other uptake mechanisms (e.g., megalin-mediated uptake); this transport can lead to increased renal toxicity. Various uptake and efflux transporters have been discovered in the kidney.[22] Uptake transporters (e.g., organic anion transporters 1, 2, and 3; organic cation transporter 1; copper transporter 1; and plasma membrane monoamine transporter) contribute to increased intracellular drug concentrations, causing kidney- specific cellular injury.[23] For example, gentamicin is absorbed into proximal tubule cells by megalin-mediated[24] and organic cation transporter 2-mediated[25] uptake. Gentamicin is entrapped in lysosomes because of its basic nature, resulting in extremely high intracellular concentrations and toxicity.[24]

  DI-AKI: Associated Drugs and Independent Risk Factors Top

DI-AKI is a serious condition that can be caused by numerous drugs and manifest in a various ways. Notably, a cross- sectional survey[15] found that 1,642 drugs were linked to AKI. The three drugs most frequently linked to DI-AKI were anti-infectives (34.35%), diuretics (21.80%), and proton pump inhibitors (10.48%); these contributed to the onset of DI-AKI in 66.63% of all cases. Another study found that 46 drugs had been administered to 115 patients with DI-AKI; the five drugs most frequently associated with morbidity were teicoplanin (5.30%), meropenem (1.60%), vancomycin (0.93%), cefoperazone sodium and sulbactam sodium (0.84%), and cefmetazole sodium (0.74%).[8] Nearly 66% of patients with DI-AKI had been administered more than one drug associated with morbidity.[6]

In China, there remains minimal comprehensive, evidence-based data regarding DI-AKI.[26] Certain herbal medicines, which contain multiple natural compounds with various active ingredients, can cause nephrotoxicity; this causative effect is often overlooked by clinicians. There is some evidence[27] that aristolochic acids and plant alkaloids can cause kidney injury; such injury has also been linked to anthraquinones, flavonoids, and glycosides extracted from herbs. In TCM, nephrotoxicity can be caused by various factors, including intrinsic toxicity, improper processing method or dosage, and interactions among herbal medicines. Clinicians should carefully monitor the use of herbal medicine in patients with unexplained AKI or progressive chronic kidney disease.[28]

DI-AKI is a common complication among hospitalized patients, particularly patients in critical condition.[29] Prescriptions, over-the-counter drugs, and herbal medicines are all readily available.[30],[31] However, DI-AKI does not consistently occur in all patients who are exposed to nephrotoxic.[32],[33] The disease onset is dependent on a combination of risk factors, such as drug nephrotoxicity, potential AKI-inducing characteristics, renal metabolism, and excretion of pathogenic substances.[34] In addition to age (>60 years), possible risk factors for in- hospital DI-AKI-related mortality include AKI stage, severe concomitant symptoms, plasma substitute administration, and diuretic therapy. The early identification of risk factors for DI-AKI during hospitalization can promote the efficient use of healthcare resources and the development of prevention strategies.

  Possible Early Biomarkers of DI-AKI Top

Although an increase in serum creatinine is the most widely known indicator of AKI, it is ineffective and inaccurate for several reasons.[35] AKI biomarkers such as cystatin C and neutrophil gelatinase-associated lipocalin may improve prediction accuracy,[36],[37] but their clinical applications remain limited because of the high laboratory costs involved.

After rats had been treated with cisplatin, a proximal tubule-specific renal toxicant, the secretion of the miRNA miR-192-5p in their urine is increased by 68- fold.[38] In preclinical studies, tubule cell mRNA and miRNA contents have been quantified using real-time reverse transcription-polymerase chain reaction assays. Interleukin-18, neutrophil-gelatinase-associated lipocalin, netrin-1, tissue inhibitor of metalloproteinases-2, and insulin-like growth factor-binding protein 7 are other potential biomarkers for DI-AKI that have shown promise in preclinical studies of animals and humans.[39] miR-221- 3p and miR-222-3p are reportedly specific for proprietary compound-induced injury to the thick ascending limb of the Henle’s loop, while miR-210-3p is reportedly specific for N-phenylanthranilic acid- and proprietary compound- related injury to the collecting duct.[38]

DI-AKI is one of the most common causes of drug development failure. The early detection of potentially nephrotoxic drugs is crucial for drug development programs. Several novel biomarkers are under investigation for the detection of early renal injury, both in vitro and in vivo. The challenges involved in renal injury detection are exacerbated by the dynamic nature of renal excretion and detoxification, as well as the functions of drug uptake proteins.[40]

  Prevention of DI-AKI via Traditional Chinese Medicine Top

TCM, which originated in China, is used in many countries worldwide to prevent kidney disease.[41] In recent years, herbal prescriptions and compounds extracted from Chinese herbs have been used in the prevention and treatment of several types of DI-AKI.[10]

Arsenic nephrotoxicity is influenced by reactive oxygen species that are produced during metabolic activation and oxidative stress processes.[12],[42] We previously showed that Chuanhuang Formulation has an antioxidant effect and may reduce CI- AKI.[11] Gong et al. reported that sodium arsenite can cause apoptosis and autophagy in human renal tubular epithelial cells.[43] In addition to oxidative stress and mitochondrial damage, inflammatory signals have important roles in this process. Tetramethylpyrazine (TMP), an active ingredient in the herbal medicine Ligusticum wallichii (Chuan Xiong), is one of the main ingredients in Chuanhuang Formulation. Our findings suggested that TMP can prevent AKI by reducing oxidative stress injury, inhibiting inflammation, preventing apoptosis in intrinsic renal cells, and regulating autophagy.[44],[45],[46] These findings indicated that Chuanhuang Formulation and TMP are effective for CI-AKI; moreover, they suggest that TCM is beneficial for DI-AKI [Figure 1].
Figure 1: Chuanhuang Formulation has an antioxidant effect and may reduce CI-AKI. Sodium arsenite can cause apoptosis and autophagy in human renal tubular epithelial cells. Oxidative stress, mitochondrial damage, and inflammatory signals have important roles in this process. TMP may prevent AKI by reducing oxidative stress injury, inhibiting inflammation, preventing intrinsic renal cell apoptosis, and regulating autophagy. TMP, tetramethylpyrazine; RTE cell, renal tubular epithelial cell; ROS, reactive oxygen species; CI-AKI, contrast-induced acute kidney injury

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Shenfushu granules have been demonstrated to relieve cisplatin-induced nephrotoxicity by significantly lowering serum creatinine and urea nitrogen levels. Upregulation of the nuclear factor erythroid 2-related factor2 (Nrf2) pathway, along with enhanced protein expression of multidrug resistance protein2 and multidrug and toxic compound extrusion protein1, are involved in the underlying mechanism in rat kidney tissues.[47]

In a rat model of aristolochic acid nephropathy, cordyceps sinensis intervention reduced serum creatinine, blood urea nitrogen, and renal collagen area, thus inhibiting the progression of renal fibrosis.[48] Furthermore, the expression levels of type III collagen, α-smooth muscle actin, and transforming growth factor-β 1 decrease, while the expression level of keratin increases, suggesting that cordyceps sinensis could delay the progression of renal tubule-interstitial injury by preventing the trans-differentiation of renal tubular epithelial cells.[48],[49] In another study, berberine was found to reduce methotrexate-induced nephrotoxicity by modulating the Kelch-like ECH-associated protein1/Nrf2, nuclear factor kappa-light chain-enhancer of activated B cells/p38 mitogen- activated protein kinase, and Bax/Bcl-2/Caspase-3 signaling pathways. Thus, berberine may enhance the cytotoxic activity of methotrexate in Caco-2, HepG2, and MCF-7 human cancer cells.[50] According to Han Hedan et al., Rhodiola rosea extract can reduce intracellular levels of malondialdehyde and glutathione, as well as superoxide dismutase activity. The extract may improve the viability of HEK293 cells, reduce cisplatin-induced cell oxidative stress, and protect against renal cytotoxicity[51] [Table 1].
Table 1: Traditional Chinese medicine formulations for DI-AKI prevention

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In this review, we have summarized TCM methods for the prevention and treatment of DI-AKI, based on reports that certain TCM prescriptions and their components can prevent and treat some types of DI-AKI. Thus, there is a need to identify potential herbal medicines or components that are both easy to carry and effective in the alleviation or prevention of DI-AKI.

  Discussion Top

The kidneys are complex organs with functions that include the removal of toxins from the bloodstream, maintenance of internal fluid-electrolyte balance, and maintenance of metabolic homeostasis.[52],[53] The kidneys are particularly vulnerable to toxins in the blood because they receive one- fourth of the cardiac output; they are vulnerable to DI-AKI because of their central role in drug excretion.[54] The clinical applications of various drugs worldwide have led to the emergence of DI-AKI as a significant medical and economic burden. Nephrotoxic drugs should be properly managed to reduce the risk of renal injury and prevent DI-AKI— prevention is the most important tool for reducing the burden of AKI. Early detection of DI-AKI will promote more effective management of this intractable disease, in combination with robust DI-AKI prevention strategies and treatment protocols. The diagnosis, prevention, and treatment of DI-AKI in China are challenging because of the large number of affected patients, the diverse clinical manifestations of DI-AKI, and the wide range of drugs that can cause localized renal injury. Nephrologists and experts from related disciplines should collaborate to develop effective prevention and control strategies. Large amounts of various drugs are currently used in clinical practice worldwide; although some of these drugs are necessary, many are overused. These overused drugs can cause AKI, and there is substantial evidence that they can promote the onset of chronic kidney disease. Thus, there is a need to understand the mechanisms of kidney injury, types of drugs that cause kidney injury, risk factors for kidney injury, and methods for the prevention and treatment of kidney injury.

TCM prescriptions and their components have had important roles in disease treatment and human health; such applications are expected to continue.[28] TCM institutions have now been established in more than 120 countries and regions; nearly one-third of the world’s population uses TCM.[55] Thus far, the incidence of nephrotoxic herbal medicine-related DI-AKI is unknown. Herbal medicines should always be considered when investigating unexplained DI-AKI. As mentioned above, herbal medicine nephrotoxicity is commonly encountered in clinical practice worldwide. Nephrologists and experts from other related disciplines should collaborate in the management of DI-AKI to determine an affected patient’s full drug history, which should include both prescribed medications and unimpressive supplements (e.g., TCM).

Increased global awareness of DI-AKI, as well as recognition and management of this complex disease, will aid the collection of sufficient evidence to develop effective prevention strategies and therapies. As noted above, certain TCM prescriptions and their components may prevent and treat some types of DI- AKI; therefore, additional TCM methods for the prevention and treatment of DI-AKI should be explored.

Conflicts of interest

Xuezhong Gong is an Editorial Board Member of the journal. The article was subject to the journal’s standard procedures, with peer review handled independently of this member and his research group.

Authors Contribution

Gong X contributed valuable ideas to this manuscript and guided the writing process. Chen L collected papers, drafted the manuscript, and assisted other aspects of manuscript preparation. All authors contributed to, critically reviewed, and approved the final version of the manuscript.

Financial support and sponsorship

This work was supported by grants from National Natural Science Foundation of China (No. 82074387 and No. 81873280) and Traditional Chinese Medicine Guidance Project of Shanghai Science and Technology Commission (No. 20Y21902200). The funders had no role in data collection and analysis, decision to publish, or preparation of the manuscript.

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