Of the many drugs reported to cause ATN, cisplatin is the most well-known and best-studied nephrotoxic chemotherapy agent. It has been one of the oldest and the most frequently used platinum-based compounds in the treatment of cancer [4], and its effect on the kidney is a prototype for chemotherapy-induced nephrotoxicity. Cisplatin is known to cause dose-dependent ATN in up to one third of the patients receiving therapy [4], and appears to exert its deleterious effect mainly on proximal tubular cells. The kidney serves as the principal pathway for cisplatin excretion from the body, and the drug tends to accumulate in the kidney more so than other organs. Cells of the proximal tubule uptake cisplatin via OCT-2 [5], which leads to drug accumulation within proximal renal tubular cells that is five times greater than serum concentration [6]. This accumulation of cisplatin and its metabolites explains the drug’s preference for toxicity and damage to proximal tubule cell [7]. Most commonly, this injury results in tubular necrosis with AKI but as discussed later, an isolated proximal cell tubulopathy with acidosis and electrolyte abnormalities can also develop .

Cisplatin-induced nephrotoxicity is mediated through several pathways, including oxidative stress injury, upregulation of inflammatory mediators, and triggering of cell apoptosis [8]. The primary step occurs when a chloride ion on the parent drug is hydrolyzed and releases free hydroxyl radicals [4]. Through this and various other pathways, the production of reactive oxygen species is upregulated in cisplatin-exposed tubular cells. The resulting free radicals are directly toxic to various cell structures and promote apoptosis [6]. Inflammatory changes that occur include enhanced renal expression of tumor necrosis factor-alpha (TNF-apha), a potent pro-inflammatory molecule. TNF-alpha, along with mitogen-activated protein kinase and p53, leads to kidney injury via apoptosis [4] , and further production of cytokines, chemokines, and reactive oxygen species [6] . Apoptosis also occurs through other mechanisms, including activation of initiator caspases through mitochondrial dysfunction and oxidative stress. A direct effect of cisplatin on caspase 1 which activates caspase 3, a final pathway in the apoptosis cascade, may also contribute [8]. Finally, cisplatin therapy may also decrease renal blood flow via damage to the renal vasculature, resulting in direct ischemic or hypoxic effects to the proximal tubule. Other platinum-based drugs appear to carry less of a risk for nephrotoxicity. In in vitro studies, carboplatin and oxaliplatin display no affinity for OCT-2, and both lack chloride ions on their stem [5, 9, 10]. However, in high cumulative doses and in patients with the appropriate risk factors, there is still an appreciable risk of ATN from these newer derivative platinum drugs [11T, 12].

The management of cisplatin-induced renal injury is centered on prevention. Volume repletion, usually with isotonic saline, is a standard treatment. Once ATN has occurred, avoiding further dosing of the drug is key, and the concomitant use of other potential nephrotoxins should be strictly avoided. Though diuretics have been used to increase urine flow as a prophylactic strategy, a randomized control trial by Santoso et al. comparing saline alone, furosemide with saline, and mannitol with saline, was closed early due to a trend toward increased AKI in the mannitol group [13]. There was no difference at the time between the subjects receiving furosemide compared to saline alone [13] . Other strategies to reduce AKI include the glutathione analog amifostine and sodium thiosulfate, which may protect against free radical injury [14]. However, use of these drugs is currently limited in clinical practice due to the lack of rigorous clinical data regarding their efficacy, significant side effects and cost of these drugs, and persistent concern that their use may hinder the antitumor effect of cisplatin. Several other agents studied in animals have not yet made it into clinical practice (nucleophilic sulfur thiols, neurotrophins, phosphonic acid, melanocortins, and free oxygen radical scavengers) [15]. Chemical substrates such as cimetidine compete with cisplatin for uptake via OCT-2, and have been suggested as therapeutic interventions to prevent intracellular concentration in the proximal tubule cells, but thus far there is a lack of clinical studies targeting this mechanism .

Similar to cisplatin, ifosfamide and its metabolites are known to be directly toxic to the cells of the proximal tubule. It is an alkylating agent commonly used for the treatment of several different solid organ tumors, as well as certain lymphomas and sarcomas. Renal toxicity occurs in up to 30 % of those on treatment [16], but unlike cisplatin, AKI is less frequent, and the more common manifestation is Fanconi syndrome (FS) or an isolated proximal renal tubular acidosis (Type 2 RTA) [17].

Unlike its parent drug, cyclophosphamide, ifosfamide (Fig. 4.2) produces the nephrotoxic metabolite chlorocetaldehyde. The kidney may be more susceptible to injury from ifosfamide and its metabolite because the cytochrome p450 enzymes that are responsible for the metabolism of ifosfamide are highly expressed in the kidney [18] . Furthermore, similar to cisplatin, ifosfamide is actively transported into the tubular cells via the basolateral transporter OCT-2, whereas cyclophosphamide is not, again suggesting a possible therapeutic target for renal injury prevention [19]. Despite this, the overall risk of AKI is less when compared to cisplatin. A cumulative lifetime dose of greater than 60–80 g/m² is associated with an increased risk for nephrotoxicity, but renal injury may happen at lower levels as well. Prior cisplatin use may also be an independent risk factor for injury [20]. Mesna, which is commonly used to prevent hemorrhagic cystitis, does not help to prevent AKI [16]. Not much is known about the mechanism of ifosfamide toxicity, but its effect on long-term renal function and the development of CKD will be discussed later.

An antifolate agent that is a structural analogue of MTX , pemetrexed acts to inhibit enzymes involved in purine and pyrimidine metabolism, thus interfering with the DNA and RNA synthesis which is necessary for cell replication of rapidly dividing tumor cells. It is used commonly for malignancies such as mesothelioma and non-small cell lung cancer among others. Uptake into proximal tubule cells occurs via both apical folate receptor-α transporters and basolateral-reduced folate carriers, and once in the cells, pemetrexed becomes trapped by polyglutamylation (Fig. 4.3) [15]. Increasing intracellular concentrations lead to further inhibition of folate metabolism, and likely contribute to renal tubular cell injury. Thus, both the toxicity and therapeutic effect of pemetrexed are tied to its antifolate action .

In addition to pemetrexed-induced AKI due to ATN [21], cases of nephrogenic diabetes insipidus (DI) and RTA have also been reported [22]. Patients who have received prior chemotherapy agents that are potential nephrotoxins, and those who have risk factors for CKD such as diabetes or HTN, have a higher risk of kidney injury. Biopsies of kidneys have shown loss of brush borders, tubular atrophy, with some interstitial inflammation [21].

As the armamentarium of chemotherapeutic agents expands, new drugs are now rapidly entering clinical use. Some of these newer drugs have been reported to cause AKI in a similar pattern to ATN, though their exact mechanisms of toxicity are not often well defined. Crizotinib, a tyrosine kinase inhibitor of multiple pathways including anaplastic lymphoma kinase (ALK), is in increasing use as a therapy for metastatic ALK-positive non-small cell lung cancer. Due to its expedited FDA approval, some of its side effects were not clearly known, and since its release in 2011, several reports of AKI and renal insufficiency have been reported [23–26]. A review of 38 patients who were given crizotinib for an average of 16 months reported a 23.9 % decline in estimated GFR during the initial 12 weeks of therapy. On withdrawal of the drug, the majority of patients recovered kidney function [25]. In one report of an episode of AKI associated with crizotinib, investigators were able to obtain a renal biopsy, which showed ATN as the primary lesion [24], though the mechanism of nephrotoxicity was not defined. In addition to ATN, non-nephrotic range and non-albuminuric proteinuria has also been reported [24] .

Another example of drug-induced injury is being reported in the treatment of multiple myeloma. Renal disease is not uncommon in multiple myeloma and therefore, a direct causal effect from a single drug is difficult to prove. Nonetheless, there are reports of AKI with carfilzomib, a next generation selective proteasome inhibitor approved for the treatment of relapsed and refractory multiple myeloma. Jhaveri and colleagues reported a case of a patient with IgG kappa multiple myeloma undergoing chemotherapy with carfilzomib and steroids who presented with fever and AKI 9 days after his last treatment, which resolved after conservative management, including drug discontinuation [27]. In a phase 2 trial of carfilzomib in the treatment of multiple myeloma, both acute and chronic renal failure were reported (5 and 3.8 %), and some of these subjects were managed with drug cessation, interruption, or dose reduction [28]. Though the mechanism of renal dysfunction is unknown, some have postulated that N-acetylcysteine may play a protective role in injury prevention, perhaps suggesting a partly prerenal or vasoconstrictive etiology to the AKI [29] .

Proteinuria is a well-known side effect of mammalian target of rapamycin (mTOR) inhibitors in some patients. However, a new association of mTOR inhibitors with ATN has recently surfaced. Four cases of biopsy-proven ATN occurred in patients undergoing therapy for lymphoma or metastatic malignancy [30]. Two of the cases rapidly recovered after drug discontinuation while the other two remained in renal failure, and one of the cases clearly showed signs of concomitant focal segmental glomerulosclerosis (FSGS). mTOR activity increases in the kidney after ischemic injury and may be involved in cell growth and repair; mTOR complex 1 (mTORC1), a protein complex formed in part by mTOR kinase, is specifically involved in the upstream inhibition of autophagy [30]. Therefore, induction of autophagy, particularly during times of renal tubular cell stress or injury, may be the mechanism by which these drugs cause renal damage [30]. MTOR inhibitors are used at much higher doses in cancer treatment compared to post-transplant immunosuppression, which may explain the lack of AKI associated with MTOR-inhibitor use in the solid organ transplant population [30] .

Clofarabine is a purine nucleoside analog that exerts its anti-neoplastic effect by inhibiting DNA synthesis and the enzyme ribonucleotide reductase (RNR). It is used routinely for the treatment of relapsed acute lymphoblastic leukemia in children, and it is increasingly also being used for relapsed or refractory acute myeloid leukemia in adults. Two case reports outline patients treated with clofarabine who developed severe renal injury shortly after drug administration; one of the patients was found to have 4 g of proteinuria, and the other was anuric and required dialysis [31, 32]. No biopsy data exist to help propose a mechanism of injury, but RNR inhibition may be contributing to podocyte injury [31] .

Recent epidemiological data has linked androgen deprivation therapy (ADT) to an increased risk of AKI in patients undergoing treatment for prostate cancer. In a group of over 10,000 patients with prostate cancer followed-up for 10 years and matched against selected controls, current ADT was associated with an adjusted odds ratio for hospitalization for AKI of 2.68; this was higher for those who received combined agent versus single agent regimens [33]. Given that ADT is still the mainstay of treatment for advanced prostate cancer, these results will require replication for clinical implications of these data to be confirmed. More population-wide epidemiological studies such as this one may alert us in the future to subtle associations of nephrotoxicity and commonly used chemotherapy agents .

Injury to the proximal tubule can impede reabsorption of several important electrolytes and compounds, including glucose, phosphate, bicarbonate, and amino acids. The clinical entity that ensues is named FS , and is thus characterized by glucosuria in the absence of hyperglycemia, phosphate wasting, and an RTA due to bicarbonate spilling. Incomplete or partial FS can present with some of these abnormalities but not all.

Ifosfamide is most commonly implicated in inducing FS, and though much of the literature is described in children, a few case reports in adults exist [34]. Even after cessation of therapy, tubular dysfunction from ifosfamide can persist for years, manifesting as partial FS with persistent phosphaturia, as described in childhood malignancy survivors [20]. In adults, this has been reported to lead to osteomalacia [35], and in children may possibly lead to issues with growth and bone development [20]. The doses of ifosfamide associated with FS are variable and not always at the levels associated with AKI or CKD, and the time to onset of symptoms can be immediate or delayed several months. Cisplatin, a proximal tubule cell toxin, is also associated with FS [36], though less commonly than its association with ATN. Imatinib use has also been reported to cause hypophosphatemia from hyperphosphaturia due to a partial proximal tubulopathy [37]. These defects can often go unrecognized and are important to monitor, if undergoing therapy with potential tubular toxins .

A principal site of sodium reabsorption, a defect in the loop of Henle can lead to salt wasting and volume depletion (Fig. 4.2, Table 4.1). Cisplatin, in addition to inducing ATN and FS, has been reported to induce a renal salt-wasting syndrome (RSWS) [38]. Affected patients can have profound volume depletion with orthostasis and polyuria, with laboratory tests indicating a hypoosmolar hyponatremia in the setting of a high rate of urinary sodium excretion. With these serum and urine indices, RSWS may be mistaken for syndrome of inappropriate antidiuretic hormone (SIADH) but the key difference between the two is that RSWS has a negative sodium balance despite hypovolemia. A single center report recorded an incidence of cisplatin-induced salt wasting as high as 10 % [39], though in another series a rate of < 1 % was noted [40]. Many of the patients in the former series had sodium wasting for months after discontinuation of cisplatin, and some cases were severe and irreversible [39]. As cases are uncommon, the mechanism is not well characterized at present. Proximal tubular damage likely leads to sodium delivery distally, but in other patients with FS the distal tubules assist in reabsorbing the increased sodium. Loop of Henle dysfunction is therefore postulated, as this is the site of sodium reabsorption that is critical to generating the medullary concentration gradient, which is noted to be impaired in cisplatin toxicity [38]. In support of the loop of Henle being a site of cisplatin injury, magnesium reabsorption occurs via paracellular pathways at the loop of Henle, and hypomagnesemia is reported with cisplatin use [41] (Fig. 4.2).

In addition to sodium, potassium, and water handling, the collecting duct is also responsible for magnesium homeostasis. Maintenance of magnesium stores occurs primarily via the epithelial channel transient receptor potential melastin subtype 6 (TRPM6) on the luminal surface of collecting duct cells. Magnesium reabsorption via TRPM6 has been found to be regulated by epidermal growth factor (EGF) receptor signaling. EGF binds to its receptor on the basolateral surface of the cell; this in turn sets off cellular signaling that facilitates insertion of TRPM6 channels into the apical membrane, thus allowing for magnesium reabsorption (Fig. 4.4) [42]. This interaction is directly antagonized in patients receiving anti-EGFR monoclonal antibodies such as cetuximab or panitumumab therapy, a novel class of chemotherapy agents increasingly associated with renal magnesium wasting.