Historical Perspective of Nephrotoxicity

The kidney is a critical organ for maintaining electrolyte, water, and acid-base balance in the body and excreting a wide variety of endogenous and exogenous compounds. Unfortunately, the kidney is also the target for many drugs and non-therapeutic chemicals, which can induce toxicity in 1 or more segments of the nephron, the functional unit of the kidney. The term “nephrotoxin” first appears in the scientific literature around 1900, with many of the early studies examining the renal effects of nephrotoxic serum (Pearce, 1903). Searching PubMed using “nephrotoxicity” as the search term results in 16,008 related papers, with the earliest paper cited describing the nephrotoxicity induced by cystine (Bell, 1933). Reports of nephrotoxicity research continue to increase each decade with only 80 articles before 1970 to over 5300 papers between 2010 and 2018 (Figure 1).

Figure 1.

Timeline of publications cited in PubMed using the search word “nephrotoxicity.”

Many early papers documented the nephrotoxic effects of antibiotics. Some examples include bacitracin and polymixin A nephrotoxicity in animals and man (Brownlee et al., 1949; Michie et al., 1949), aminoglycoside-induced nephrotoxicity (Berman and Katz, 1958; Niebel and Rosenberg, 1956), and cephalosporin (eg cephaloridine) nephrotoxicity noted in many animal models and humans during the 1960s and 1970s. Subsequently, a number of these drugs had their use limited to topical application or were removed from the market. Others remain important clinically used drugs, such as the antifungal drug amphotericin B (Takacs et al., 1963), in spite of the risk of drug-induced nephrotoxicity.

Members of other classes of drugs have been studied in detail because of their potential to harm the human kidney. The non-opioid analgesics, phenacetin (synthesized in 1878 by Bayer) and its metabolite acetaminophen (discovered in 1877), can cause nephrotoxicity when taken in excess, and almost 2000 papers have been published related to the renal effects induced by these analgesics. Phenacetin was removed from the United States market by the FDA in 1983 because of its potential to cause nephrotoxicity and renal cancer, while acetaminophen remains a popular analgesic. The anticancer drug cisplatin is a staple for treating solid tumors. Yet, over 2800 papers have been published describing the nephrotoxicity induced by cisplatin or ways to prevent the renal injury. Similarly, the immunosuppressive drug cyclosporine, is a key drug for preventing organ rejection, including kidney, following transplantation. However, nephrotoxicity is an important side effect of cyclosporine use, and presents challenges for the physician to determine rejection of the transplanted kidney versus drug-induced nephrotoxicity. Based on these and many other examples of nephrotoxic drugs, pharmaceutical company screening of drug candidates for nephrotoxic potential is now, more than ever, a key component of drug development. As a result, fewer drugs reach the market that have the potential to induce nephrotoxicity.

While the nephrotoxic properties of drugs have been examined for decades, so have the renal effects of pesticides, environmental pollutants and industrial chemicals. Many heavy metals, including mercury, cadmium, and lead, induce nephrotoxicity, primarily in the proximal tubule, in humans and animal models. The renal effects, mechanisms of uptake, intracellular targets and potential antidotes for metals have been explored in detail for well over a century (Pavy, 1860). Yet questions remain about the nephrotoxic mechanisms and ways to attenuate nephrotoxicity for many metals.

In most cases, glutathione protects cells from toxicants by reacting with electrophiles or free radicals to neutralize them. However, evidence appeared in the 1980s that glutathione conjugation of halogenated alkanes, alkenes, and quinones can lead to nephrotoxic metabolites (Dekant, 2005). There are several mechanisms by which glutathione and/or cysteine S-conjugates can lead to nephrotoxicity (eg formation of episulfonium ions, enhanced proximal tubular uptake of redox cycling quinones), but perhaps the best studied mechanism is activation of cysteine S-conjugates by cysteine conjugate β-lyase to produce reactive acyl halides or thioketenes. These studies served to explain the mechanisms by which halogenated compounds, such as trichloroethylene, could induce nephrotoxicity and renal cancer. Ultimately, the use of many of these halogenated compounds was reduced and/or they were replaced by safer alternatives.

Although nephrotoxicity may occur in animal models, the risk to humans may depend on the mechanism by which the injury results. Early work with pentachlorobenzene (Linder et al., 1980) and 2,2,4-trimethylpentane (Stonard et al., 1986) documented nephrotoxicity in male, but not female, rats characterized by hyaline droplet formation in proximal tubules. The mechanism of the nephrotoxicity involved chemical-induced excessive accumulation of α2u-globulin in S2 segment lysosomes only in male rats, although homologous proteins exist in female rats and humans (Lash et al., 2000). As a result, nephrotoxicity induced by this mechanism is not considered to be relevant to humans.

Research areas in the realm of nephrotoxicity continue to develop. One recent area of focus relates to finding highly sensitive biomarkers to detect early signs of nephrotoxicity, with over 500 papers published on this topic in the last 5 years. Another recent research area has been the investigation of the role of microRNAs in chemical-induced nephrotoxicity. The increasing number of publications related to nephrotoxicity cited in PubMed each year (Figure 1) indicates that interest in the nephrotoxic effects of drugs and non-therapeutic chemicals remains high and many new discoveries should be on the horizon.