Mechanism of action

The mechanism of cytotoxicity of carboplatin is similar to that of cisplatin (discussed in detail in the cisplatin section), because it also interferes with deoxyribonucleic acid (DNA) duplication.

Pharmacokinetics

Carboplatin or cis-diammine (1,1-cyclobutane dicarboxylate) platinum(II) is administered intravenously. In general, the dosage of carboplatin is four times the dosage of cisplatin. More than 50% of the administered dosage is excreted unchanged in the urine within 24 hours. The importance of renal clearance to the metabolism and excretion of carboplatin is highlighted by its usual dosing schema, which is based upon an eGFR, along with the desired level of drug exposure, according to the area under the concentration-time curve (AUC, mg/mL × min), rather than the more common dosing calculation based upon the BSA (mg/m ² ). Using the desired target AUC (which typically varies between 5 and 7 mg/mL/min) and the eGFR, the dose of carboplatin is then calculated using the Calvert formula: dose (mg) = AUC (mg/mL × min) × [GFR (mL/min) + 25 (mL/min)]. This dose calculation using the Calvert formula has to be repeated before each course of carboplatin to take into account possible changes in weight or renal function. A possible issue related to the use of this formula is the appropriate weight to use when calculating the eGFR. The original CG formula to estimate GFR used actual body weight, but none of the patients considered were obese. Most clinicians use actual body weight in the CG formula for nonobese patients. However, the use of actual body weight in the CG calculation can overestimate the GFR resulting in higher carboplatin dose in obese individuals. The Gynecological Oncology Group (GOG) recommends that actual weight be used to determine eGFR when using the CG equation as long as patients have a body mass index (BMI) of less than 25. For other patients, the use of an adjusted weight is suggested (adjusted weight [kg] = [{actual weight – ideal weight} × 0.40] + ideal weight). Another issue is that the Calvert formula was developed measuring GFR using Cr-EDTA, whereas in clinical practice CrCl or eGFR (using the MDRD or CKD-EPI formula) are used. It is not clear at this point how accurate it is to calculate the carboplatin dosage using these estimates. Carboplatin should not be administered to patients with CrCl lower than 20 mL/min and a maximum carboplatin dose of 250 mg/m ² has been suggested in patients with CrCl=20 to 39 mL/min.

As far as carboplatin administration in patients undergoing dialysis concerns, polychemotherapy regimens incorporating carboplatin have been successfully used in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD) without evidence of increased toxicity or reduced efficacy. Few cases of HD patients treated with carboplatin, either alone or in combination, are reported in the literature. The Calvert formula has been initially used in HD patients by assuming that GFR is zero. This is applicable to patients who receive HD within 12 to 18 hours after carboplatin infusion. After the first 24 hours, the majority of carboplatin, which is bound to serum proteins, is not easily dialyzable and remains in the blood stream despite repeated sessions of HD. Guddati et al. have proposed a correction factor to calculate the resultant AUC in HD patients; the AUC can increase by eightfold in patients who received the adjusted dose, but whose HD was delayed beyond 24 hours after infusion. The correction factor proposed can also be used to calculate the dose adjustment required, a priori, in patients who may receive delayed HD. The same authors have also developed a formula to adjust carboplatin dosage in PD patients; this formula takes into account the frequency of dialysis sessions and the time delay between carboplatin infusion and the initiation of dialysis, and predicts an approximately similar dosage of carboplatin as that of the Calvert formula in patients undergoing PD 4 times per day, if dialysis is initiated 12 hours after infusion. In another patient, HD was performed for 3.5 hours starting 90 minutes after completion of carboplatin, and pharmacokinetic assessments were performed at 1, 2, 4, and 12 hours after its infusion. Total carboplatin concentrations in plasma and platinum ultrafiltrate were measured. The plasma concentration of free platinum at the end of the infusion was 31,000 ng/mL and the AUC was 2.9 minutes times mg/mL. No significant carboplatin-related toxicities were reported. This case report clearly indicates that carboplatin can be safely administered in HD patients.

Toxicity

In general, platinum-based chemotherapeutics are associated with numerous and potentially severe side effects. Most common side effects include nausea, bone marrow suppression, and electrolyte disturbances.

Kidney toxicity

Although carboplatin is a nephrotoxic drug, its nephrotoxicity is much lower compared with cisplatin. Carboplatin is significantly less nephrotoxic than carboplatin because of its enhanced stability; this is mainly related to the fact that carboplatin has carboxylate and cyclobutane moieties in the cis position, rather than chloride. In a study involving patients treated with carboplatin in combination with vincristine, a 19% decrease in CrCl was observed as early as from the second course. In contrast, in another study comparing patients treated with carboplatin alone or in combination with etoposide and bleomycin, no significant change in kidney function before and after (1 month, < 3 months, and > 3 months) treatment with carboplatin was noted. AKI has been anecdotally reported in patients who have been treated with intraperitoneal carboplatin, in association with high dose carboplatin (1500–2000 mg/m ² ) ^, or in combination with ifosfamide and etoposide. In this setting, AKI occurs within days after carboplatin administration and is often only partially reversible.

In a single center study including 50 children with Wilms tumors, treated between 2002 and 2012 and followed for 2 years, it was reported that patients treated with cyclophosphamide and carboplatin were at higher risk of kidney function deterioration. Skinner et al. evaluated the long-term nephrotoxicity of platinum-based chemotherapy in 63 childhood cancer survivors (27 cisplatin, 24 carboplatin, and 12 both cisplatin and carboplatin). There was no significant overall change in kidney function over time in any treatment group except for a slight reduced median GFR (84 mL/min/1.73 m ² ) and serum magnesium level (0.68 mmol/L) in the cisplatin-treated group. At 10 years, reduced GFR (< 60 mL/min/1.73 m ² ) and need for magnesium supplements were present in 11% and 7% of cisplatin-treated patients, respectively. In the patients treated with carboplatin, older age was associated with lower GFR during follow-up, higher cumulative carboplatin dose associated with lower serum magnesium levels at 1 year, and increased nephrotoxicity at 1 and 10 years. Hypomagnesemia is a frequent complication in childhood cancer survivors (7%–29%). Both cisplatin and carboplatin are associated with the development of Fanconi syndrome. The occurrence of hypomagnesemia after carboplatin administration has been widely reported. In one study, 6 months following carboplatin therapy, hypomagnesemia was observed in 15.6% of the children treated for solid tumors. In combination with the antiepidermal growth factor receptor monoclonal antibody, cetuximab (which also causes hypomagnesemia ), grade 3 to 4 hypomagnesemia occurred in 3% to 7.5% in lung cancer patients. ^, Also in combination with proton pump inhibitors, carboplatin is associated with the development of severe hypomagnesemia. Hypokalemia and hyponatremia may also rarely occur after carboplatin administration. ^{, ,} Carboplatin has only rarely been associated with the development of TMA and most often in combination with other chemotherapeutics (gemcitabine, cyclophosphamide and thiotepa, docotaxel and trastumab). Finally, there are case reports concerning obstructive AKI caused by bladder obstruction by blood clots in two patients with ovarian cancer treated with carboplatin, in combination with paclitaxel. ^,

Prevention of nephrotoxicity of platinum-based chemotherapeutics through sufficient hydration is essential. In patients with preexisting kidney impairment secondary to cisplatin, the effectiveness of hydration was shown in patients treated with carboplatin (800 mg/m ² ) with or without hydration (250 mL/h of isotonic saline 3 hours before and after carboplatin infusion). Without hydration, a decrease in CrCl of 36% to 61% was noted versus no reduction in patients receiving hydration.

Pharmacokinetics

Cisplatin is nonenzymatically transformed into multiple metabolites after its administration. Cisplatin and its metabolites are removed from the body through the kidney (20%–80% within 24 hours) and the dose has to be reduced in patients with a decreased CrCl. In clinical trials, it is commonly required that patients receiving cisplatin have a serum creatinine of less than 2.0 mg/dL or a CrCl of 60 mL/min or higher. We suggest a 25% dose reduction for CrCl 46 to 60 mL/min and a 50% dose reduction for CrCl 30 to 45 mL/min. Cisplatin has been administered to patients undergoing HD ^{, ,} and 50% to 75% and 50% dose reductions are suggested for patients undergoing HD and PD, respectively. ^{, ,} HD should be performed within 3 hours after administration of cisplatin. Furthermore, it has been suggested to consider carboplatin instead of cisplatin in patients with CrCl less than 45 mL/min.

Mechanism of action

The main mechanism of action of cisplatin is the binding of DNA and inhibition of DNA replication ( Fig. 16.1 ). Inhibition of DNA replication mainly affects rapidly proliferating cells. After administration, cisplatin undergoes aquation intracellularly, in which one of the two chloride ligands is replaced by H ₂ O. This aqua ligand is thereafter displaced by a DNA base, preferentially guanine. Cross-linking of DNA interferes with mitosis and results in apoptosis.

Cisplatin nephrotoxicity. Cisplatin enters the proximal tubular cells through organic cation transporter-2 (OCT2) and accumulates in the cell cytoplasm. Cisplatin-mediated cellular injury involves several mechanisms. Cisplatin induces endoplasmic reticular stress (ER stress) and production of reactive-oxygen species (ROS), resulting in apoptosis. Moreover, cisplatin induces mitochondrial dysfunction, which is also associated with caspase-independent and caspase-dependent apoptosis. Moreover, cisplatin induces deoxyribonucleic acid (DNA) damage with phosphorylation and activation of p53. p53 subsequently induces transcription of apoptic genes such as PUMA- α and PIDD . PIDD forms the PIDDosome and activation of caspase 2 and caspase-independent apoptosis. PUMA-α neutralizes Bcl-XL, resulting in mitochondrial dysfunction and caspase-dependent apoptosis. Finally, cisplatin activates the death receptor pathway apoptosis pathway. Cisplatin also induces inflammation through the production of tumor necrosis factor (TNF)α and other chemokines. MRP , Multidrug-resistant protein; OAT , organic anion transporter; OCT , organic cation transporter; Pgp, P glycoprotein.

Toxicity

The most commonly reported side effects associated with cisplatin include nephrotoxicity, nausea/vomiting, bone marrow suppression and hemolytic anemia, ototoxicity, and neurotoxicity.

Kidney toxicity

As far as the clinical manifestations of cisplatin kidney injury, AKI has been reportedly observed in approximately 20% to 30% of patients, but the more common one is hypomagnesemia, observed between 40% and 100% of the cases. Other rarer, but not less challenging, manifestations include Fanconi-like syndrome, distal renal tubular acidosis (RTA), renal concentrating defect, and TMA. Cisplatin-induced nephrotoxicity mostly affects the corticomedullary S3 segment of the proximal tubule and to a lesser degree the loop of Henle and distal tubular segments. In proximal tubular cells in the S3 segment, cisplatin accumulates to a great degree, resulting in a cisplatin concentration 5 times higher than the serum concentration. After cisplatin enters the tubular cell, it appears to undergo a complex series of reactions that results in the formation of more potent (toxic) metabolites. However, it is unclear if all cisplatin-induced cytotoxic effects are mediated via its activated metabolites. Once within the tubular cell, cisplatin exerts many different biological effects, which culminate in cell apoptosis/necrosis (see Fig. 16.1 ). Although cisplatin targets nuclear DNA, it has been reported that only 1% of the cytosolic cisplatin is present within the nucleus. Multiple cellular targets have been identified for cisplatin toxicity, including: (1) DNA damage; (2) cytoplasmic organelle dysfunction, with endoplasmic reticulum stress and mitochondrial dysfunction; (3) apoptotic pathways both caspase-dependent and death receptor-mediated; (4) oxidative stress with formation of reactive oxygen species; and (5) inflammation mediated via tumor necrosis factor and other chemokines. In addition, there also appears to be an immune component to cisplatin-induced nephrotoxicity. ^, Several nonmodifiable factors have been identified to increase the risk for cisplatin-induced nephrotoxicity, such as genetic factors, race, gender, age, cardiac disease, malnutrition, dehydration, comorbidities such as diabetes or cirrhosis (hypoalbuminemia is associated with a higher unbound fraction of cisplatin, resulting in greater peak plasma concentrations), concomitant use of other nephrotoxic agents, or preexisting kidney diseases.

It is well known that cisplatin-induced kidney injury is dose-, duration-, and frequency-dependent. ^, Higher peak plasma concentrations result in greater injury. Furthermore, a higher cumulative dose has also been shown to increase the risk for future kidney injury. Early trials with cisplatin reported that greater than 70% of patients developed dose-related AKI. In more recent trials, at high cisplatin doses, 42% of treated patients had nephrotoxic injury. A recent study reported cisplatin-induced nephrotoxicity to occur in more than one-third of patients after the fourth cycle of chemotherapy and preventive strategies were ineffective. In a meta-analysis of randomized phase 2 and 3 clinical trials comparing first-line platinum-based chemotherapy with the same regimen without platinum, platinum was associated with a significant increase in nephrotoxicity (18 trials; 4384 patients; odds ratio, 3.09; 95% confidence interval, 1.88–5.06; p < .0001). With improved survival in cancer patients, it has become evident that cytotoxic chemotherapeutics can also result in CKD. In childhood cancer, loss of GFR occurs, especially in older children treated with ifosfamide and higher doses of cisplatin. ^, The long-term effect of cisplatin on kidney function in 859 adult patients treated with cisplatin who had survived 5 years or more after initial dose showed most patients experienced small but permanent declines in eGFR, although none progressed to ESRD requiring HD.

Cisplatin is associated with the development of TMA either as monotherapy ^, or in combination with other chemotherapeutics (with bleomycin and vincristine/vinblastine, ^, with bleomycin and epirubicin, ^, with bleomycin and methotrexate, with gemcitabine, with 5-fluorouracil [5-FU], with cyclophosphamide and adriamycin ). TMA can develop up to 4 months after the last administration of cisplatin. There is no established treatment for cisplatin-induced TMA as variable efficacies have been described for plasma exchange and infusion of fresh frozen plasma, aspirin, and dipyridamole.

Clinical practice guidelines have been published on the prevention of cisplatin-induced kidney injury. ^{, ,} Different preventive strategies have been tested to reduce cisplatin-induced nephrotoxicity. A recent systematic review concluded that: (1) hydration is essential for all patients; (2) short-duration, low-volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate- to high-dose cisplatin; (3) magnesium supplementation (8–16 mEq) may limit cisplatin-induced nephrotoxicity; and (4) mannitol might be considered for high-dose cisplatin regimens and/or for patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin-induced nephrotoxicity. In animal models, amifostine (a free radical scavenger) ameliorates cisplatin-mediated nephrotoxicity. However, cisplatin-induced nephrotoxicity cannot be completely prevented with current available measures and several aspects regarding optimal management are still controversial, such as duration of hydration, use of magnesium, and use of diuretics. ^, Diuretics should probably be avoided in patients receiving platinum-based chemotherapy, because they are potentially harmful. Cisplatin is transported into the tubular cell by the basolateral organic cation transporter 2 (OCT2) channel; therefore blockers of the OCT2 channel have potential to prevent/reduce nephrotoxicity. A recent trial demonstrated that proton pump inhibitors (which are known blockers of the OCT2 channel) are associated with reduced cisplatin-mediated nephrotoxicity.

Mechanism of action

As other platinum-based chemotherapeutics, its action is through the blockade of DNA production. Oxaliplatin forms both inter- and intrastrand cross-links in DNA, causing cell death. However, recently it was reported that oxaliplatin does not only kill cells through DNA damage response, but also by inducing ribosome biogenesis stress. This might explain the distinct clinical implementation of oxaliplatin compared with other platinum-based chemotherapeutics.

Pharmacokinetics

Oxaliplatin undergoes extensive nonenzymatic biotransformation and platinum is mainly excreted by the kidneys. Approximately half of the total dose is recovered in the urine by day 5. Dose reduction is recommended in patients with a CrCl less than 20 mL/min. Doses up to 130 mg/m ² every 3 weeks proved to be well tolerated in patients with CrCl greater than 20 mL/min and do not require dose reduction. Some experts recommend oxaliplatin dose reduction in patients with ESRD undergoing HD. Although others suggest this is not necessary if HD is performed shortly after drug administration, and the dosing interval is extended to 3 weeks.

Toxicity

Common side effects include neurotoxicity (peripheral neuropathy), fatigue, nausea and vomiting, neutropenia, nephrotoxicity, and ototoxicity (less than cisplatin and carboplatin). Other serious side effects include allergic reactions and rhabdomyolysis.

Kidney toxicity

Oxaliplatin is less nephrotoxic than cisplatin and carboplatin, but all platinum-based chemotherapeutics cause proximal tubular cell damage. There are few cases of AKI associated with oxaliplatin-induced immune-mediated intravascular hemolysis and the occurrence of acute tubular necrosis (ATN). ^, In these reported cases, the evolution was favorable with recovery of kidney function. Another well-known side effect of oxaliplatin is the development of hypokalemia during treatment. ^, In a prospective study of 772 patients treated with oxaliplatin, seven patients developed hypokalemia rapidly after oxaliplatin administration. It is suggested that oxaliplatin shifts potassium into cells. Oxaliplatin has also been associated with the development of TMA. Data from the Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) registry and BloodCenter of Wisconsin concluded that there was a definite association between oxaliplatin and the occurrence of TMA. It has been suggested that TMA associated with oxaliplatin is immune mediated. Prevention of platinum-based chemotherapeutic-related nephrotoxicity is based on intravenous (IV) administration of isotonic saline fluids and treatment of nausea and vomiting.

Mechanism of action

Busulfan is an alkylating chemotherapeutic.

Pharmacokinetics

Busulfan is extensively metabolized in the liver and these metabolites are predominantly excreted as inactive metabolites by renal excretion. No dose reductions are recommended in patients with renal dysfunction.

Toxicity

Busulfan-associated side effects include interstitial pulmonary fibrosis, seizures, hepatic veno-occlusive disease, and wasting syndrome.

Kidney toxicity

The nephrotoxicity of busulfan seems to be limited. In a phase I study, only one of 15 refractory acute leukemia patients received busulfan and clofarabine, as preparation for allogeneic hematopoietic stem cell transplantation, developed AKI (attributed to clofarabine).

Mechanism of action

Cyclophosphamide is an alkylating agent and a member of the nitrogen mustard family. It acts through interfering with DNA replication and ribonucleic acid (RNA) production. The active metabolite of cyclophosphamide is phosphoramide mustard. This metabolite is only formed in cells that have low levels of aldehyde dehydrogenase activity. Phosphoramide mustard forms DNA inter- and intrastrand cross-links, which leads to cell apoptosis.

Pharmacokinetics

When administered orally, cyclophosphamide is rapidly absorbed and converted to its active metabolites in the liver. Several metabolites are produced: 4-hydroxycyclophosphamide, aldophosphamide, carboxycyclophosphamide ( Fig. 16.2 ). A fraction of aldophosphamide diffuses into cells and is there metabolized into phosphoramide mustard (the active metabolite of cyclophosphamide) and acrolein. Aldophosphamide is oxidized to carboxycyclophosphamide by the enzyme aldehyde dehydrogenase, and the formation of phosphoramide mustard only occurs in cells with low aldehyde dehydrogenase activity. Similarly, it has been demonstrated that high aldehyde dehydrogenase activity results in cyclophosphamide resistance in certain leukemia cell lines. Conversion of aldophosphamide to carboxycyclophosphamide by aldehyde dehydrogenase prevents toxicity as carboxycyclophosphamide does not result in nitrogen mustard formation and alkylation.

Ifosfamide nephrotoxicity. Ifosfamide is transported in the proximal tubular cells through organic cation transporter-2 (OCT2). Ifosfamide undergoes substantial metabolization with the production of acrolein (responsible for bladder irritation and hemorrhagic cystitis) and chloroacetaldehyde (responsible for development of proximal tubulopathy). In this figure, the metabolism of ifosfamide is represented in the renal tubular cells, while this happens mainly in liver cells. FR-α , folate receptor-alpha; RFC, reduced folate carrier.

Some 30% of the cyclophosphamide dose is excreted in unchanged form in the urine, whereas highly protein-bound metabolites are primarily excreted through the kidney. Cyclophosphamide pharmacokinetics are clearly altered in patients with renal insufficiency. However, there is no consensus whether cyclophosphamide dose adjustments are needed in patients with reduced kidney function, because studies are unable to demonstrate an association between kidney function and cyclophosphamide clearance or hematologic toxicity. ^, We recommend no dose reduction, a 25% dose reduction, and a 50% dose reduction in patients with a CrCl greater than 20 mL/min, 10 to 20 mL/min, and less than 10 mL/min, respectively. Cyclophosphamide is moderately hemodialyzable and should always be administered after HD and HD held until 12 hours later. ^, In PD patients, a 25% dose reduction has been suggested. ^,

Toxicity

Common adverse effects include low white blood cell counts, nausea/vomiting, hair loss, and hemorrhagic cystitis. Other severe adverse effects include increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis. Cardiotoxicity occurs mainly with high cumulative doses of cyclophosphamide. Infertility has been reported in both females and males, and the risk for infertility increases with both cumulative dose of cyclophosphamide and patient age.

Kidney toxicity

Cyclophosphamide nephrotoxicity includes syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia, and hemorrhagic cystitis. Cyclophosphamide might either directly induce SIADH or stimulate ADH through cyclophosphamide-induced nausea. ^, Hyponatremia typically occurs with high dose IV cyclophosphamide but has also been reported after oral cyclophosphamide or low-dose IV cyclophosphamide. Hyponatremia often resolves after drug discontinuation, but high-dose IV cyclophosphamide and concomitant IV fluids to prevent hemorrhagic cystitis, the combination of SIADH, and enhanced water administration can lead to severe, occasionally fatal hyponatremia. Therefore it is recommended to administer isotonic saline rather than hypotonic solutions.

The cyclophosphamide metabolite acrolein is highly toxic to the bladder epithelium and may cause hemorrhagic cystitis. The risk of hemorrhagic cystitis can be minimized by administration of fluids and sodium 2-mercaptoethane sulfonate (mesna), which binds and inactivates acrolein. ^,

Mechanism of action

Diaziquone is an aziridinylbenzoquinone, which rapidly penetrates the central nervous system. The most probable mechanism of action is that of bioreductive alkylation.

Pharmacokinetics

After administration, diaziquone is rapidly absorbed and it has a volume of distribution exceeding that of total body water. Diaziquone is rapidly metabolized by the liver.

Toxicity

The main toxicity associated with diaziquone is bone marrow suppression resulting in leukopenia, granulocytopenia, and thrombocytopenia.

Kidney toxicity

Data regarding diaziquone-related nephrotoxicity are very limited, although acute renal failure has been reported subsequent to treatment with diaziquone.

Mechanism of action

Ifosfamide is an alkylating agent and a member of the nitrogen mustard family. It is believed to act through interfering with DNA replication and RNA production.

Pharmacokinetics

Ifosfamide is primarily excreted in the urine (80% to the total dose as unchanged ifosfamide). Guidelines vary substantially in regard to dosing in patients with kidney failure. We recommend a 25% dose reduction in patients with a CrCL 40 to 60 mL/min, a 50% dose reduction for patients with a CrCl 10 to 40 mL/min, and drug discontinuation in patients with CrCl lower than 10 mL/min. Ifosfamide is dialyzable, and it should be administered after HD with a dose reduction of 50%. The same dose reduction is recommended for PD patients. No dialysis should be performed for 12 hours after ifosfamide administration.

Toxicity

Common side effects include hair loss, vomiting, nephrotoxicity, neurotoxicity (encephalopathy and peripheral neuropathy), and bone marrow suppression.

Kidney toxicity

Ifosfamide is associated with numerous possible adverse kidney manifestations; AKI caused by ATN, Fanconi syndrome, ^, interstitial nephritis, glomerular disease, and hemorrhagic cystitis. Ifosfamide-induced tubular toxicity can be associated with metabolic acidosis with a normal anion gap (hyperchloremic acidosis) because of type 1 (distal) or type 2 (proximal) RTA; hypophosphatemia induced by decreased proximal phosphate reabsorption; renal glucosuria, aminoaciduria, and a marked increase in β ₂ -microglobulin excretion, all from generalized proximal dysfunction; polyuria caused by nephrogenic diabetes insipidus; and hypokalemia, resulting from increased urinary potassium losses. Ifosfamide is more nephrotoxic than cyclophosphamide and this is caused by selective uptake of ifosfamide in proximal tubular cells through the OCT2 (see Fig. 16.2 ). Several risk factors for ifosfamide-induced nephrotoxicity have been identified including preexisting kidney disease, combination with platinum-based chemotherapy and/or other nephrotoxins, cumulative dose of ifosfamide (> 119 g/m ² ), and renal irradiation. Although there are few data on long-term kidney function in ifosfamide-treated adults, a progressive decline in GFR has been described after as little as one course of ifosfamide in adults. This reduction in kidney function occurs in a minority of patients, is permanent and progressive, and can also occur long after exposure to ifosfamide. In a Dutch study, it was demonstrated that patients who received ifosfamide in childhood had a lower GFR than patients with the same pathologies who did not receive this treatment. The main risk factors for nephrotoxicity in children are a cumulative dose greater than 45 mg/m ² , young age (< 3 years), previous or concurrent cisplatin treatment, Wilms tumor, and unilateral nephrectomy. Hemorrhagic cystitis can occur even when mesna is used.

Tubular involvement is generally very prolonged, potentially progressive and may lead to advanced CKD. ^, Ifosfamide-induced proximal tubular toxicity is characterized by aminoaciduria (28%), glucosuria (90%), low molecular weight proteinuria, Fanconi syndrome (1%–7%), hypophosphatemia, proximal RTA, hypokalemia, phosphaturia, and more rarely, calciuria, magnesiuria, and natriuria. Distal tubular toxicity has also been reported with type 1 RTA, a defect in urine concentration, and nephrogenic diabetes insipidus. Ifosfamide can induce SIADH characterized by hyponatremia, plasma hypoosmolality, and inadequate urinary osmolality. ^,

Mesna and hydration are the main measures to minimize the urogenital and nephrologic involvement of ifosfamide, but N-acetylcysteine is recommended by some. ^, Patients who received ifosfamide should be followed long-term to detect CKD early.

Mechanism of action

Melphalan is a member of the nitrogen mustard alkylating agent family. Melphalan alkylates guanine, which results in inter- and intrastrand links of DNA. This results in the inhibition of DNA and RNA synthesis and cytotoxicity.

Pharmacokinetics

Melphalan is metabolized primarily in the liver, and 10% to 30% is eliminated by the kidneys. Melphalan is both secreted and reabsorbed in the renal tubules. In patients with decreased kidney function, elimination of melphalan is reduced and systemic exposure is increased, which may result in bone marrow suppression. Recommendations regarding dose reduction for decreased kidney function differ substantially. We recommend a 25% dose reduction in patients with CrCl between 10 and 50 mL/min and a 50% dose reduction with CrCl less than 10 mL/min. Melphalan is removed during dialysis and should be administered at 50% of the dose after HD.

Toxicity

The most common side effects are nausea, vomiting, and bone marrow suppression.

Kidney toxicity

Nearly 19% of 80 consecutive patients with AL amyloidosis treated with high-dose melphalan followed by peripheral blood stem cell transplantation developed AKI. Patients who developed AKI had a worse 1-year survival ( p =.03). A few case reports note nephrotic syndrome after melphalan administration. ^, During 1-year follow-up, kidney function improved with disappearance of the nephrotic syndrome. Finally, melphalan has been associated with the development of SIADH. ^,

Mechanism of action

Procarbazine is an alkylating agent. Its mechanism of action is incompletely understood but involves inducing breaks in DNA strands.

Pharmacokinetics

Oral procarbazine is rapidly metabolized in the liver. After 24 hours, up to 70% of the dose is recovered in the urine. The use of procarbazine is not recommended in patients with severe kidney impairment, and a 50% dose reduction is recommended with a serum creatinine greater than 2.0 mg/dL.

Toxicity

Common side effects include: bone marrow suppression, nausea, vomiting, peripheral neuropathy, and fatigue. In combination with ethanol, procarbazine may cause a disulfiram-like reaction.

Kidney toxicity

Procarbazine monotherapy is not nephrotoxic. However, renal insufficiency after administration of procarbazine and high doses of methotrexate has been reported. The authors suggested procarbazine augmented the nephrotoxicity of methotrexate.

Mechanism of action

Temozolomide is an alkylating agent that alkylates/methylates guanine residues, resulting in DNA damage and cell death.

Pharmacokinetics

Temozolomide is administered orally and the kidney is the major route of elimination (5%–10% as unchanged temozolomide and 90–95% as metabolites). However, studies in patients with mild to moderate kidney dysfunction showed unaltered pharmacokinetics, suggesting no dose adjustment is required. Experience with temozolomide in HD patients is very limited.

Toxicity

The main toxicity associated with the use of temozolomide is bone marrow suppression.

Kidney toxicity

Temozolomide nephrotoxicity appears to be very limited. Few AKI cases were described with temozolomide treatment. Only one of 42 patients treated with temozolomide and irinotecan died after developing AKI.

Mechanism of action

Trabectedin is an alkylating agent that binds DNA at the N2 position of guanine promoting degradation of RNA polymerase and generating DNA double-strand breaks. Furthermore, trabectedin blocks DNA binding of the transcription factor FUS-CHOP and reverses the oncogenic phenotype of liposarcoma cells.

Pharmacokinetics

Dose adjustments are not recommended in patients with CrCl greater than 30 mL/min and no data are available in patients with more severe kidney disease. Therefore the drug, which is not dialyzable, should not be used in patients with CrCl lower than 30 mL/min. ^,

Toxicity

Adverse effects associated with trabectedin include bone marrow suppression, hepatotoxicity, nausea, vomiting, and fatigue.

Kidney toxicity

Cases of AKI (occasionally fatal) have been reported, some of which are attributable to rhabdomyolysis. Furthermore, elevations in serum creatinine grade 3 or 4 were observed in 4.2% of patients treated with trabectedin for liposarcoma or leiomyosarcoma. Nephrotoxicity complicated by hepatic failure and death was reported in a 79-year-old patient with sarcoma after a second course of trabectedin.

Mechanism of action

Azacitidine is a chemical analog of cytidine and is incorporated in DNA and RNA, resulting in cytotoxic effects on hematopoietic cells in the bone marrow at high doses. Azacitidine is incorporated in RNA more than in DNA, and incorporation of azacitidine into RNA results in disaggregation of polyribosomes, accumulation of 80S ribosomes, decreased transfer RNA acceptor activity, and inhibition of protein synthesis. At low doses, azacitidine inhibits DNA methyltransferase by formation of covalent bonds between DNA-cytosine methyltransferase and DNA containing 5-azacytosine, resulting in DNA hypomethylation. Decitabine is a deoxyribonucleoside that can only be incorporated in DNA.

Pharmacokinetics

Azacitidine and its metabolites are primarily excreted by the kidneys, thereby requiring close monitoring in patients with kidney disease. Although the initial dose does not require adjustment, a 50% reduction is recommended when an unexplained elevation in serum creatinine occurs. The next azacitidine cycle should be postponed until kidney function normalizes.

Toxicity

The most common toxicity associated with azacitidine is hematologic toxicity: anemia, neutropenia, and thrombocytopenia. Hepatotoxicity has also been reported, especially in patients with underlying liver abnormalities. Therefore azacitidine is contraindicated in patients with advanced hepatic tumors. Other reported toxicities include gastrointestinal adverse effects (nausea, diarrhea, constipation, anorexia, vomiting), fever, arthralgia, headache, and dizziness.

Kidney toxicity

Adverse kidney effects are variable and range from increased serum creatinine levels to AKI. Risk of AKI is increased in patients receiving IV azacitidine in combination with other chemotherapeutics, and possibly in patients with preexisting kidney disease. Fanconi syndrome has been reported with azacitidine use in combination with etoposide for the treatment of chronic myelogenous leukemia. RTA, polyuria, aminoaciduria, phosphaturia, and glucosuria have also been observed. Two patients with very severe hypophosphatemia and associated muscle cramps have been reported (serum phosphate levels 0.6–1 mg/dL). Nine of 22 patients with acute leukemia treated with azacitidine at a dose of 200 mg/m ² /day developed glucosuria, whereas seven had polyuria. In addition, nephrogenic diabetes insipidus has been reported with azacitidine. Treatment of azacitidine-associated nephrotoxicity is drug discontinuation.

Mechanism of action

Capecitabine is an oral fluoropyrimidine (besides 5-FU and tegafur) with approximately 100% bioavailability and is converted to 5-FU by thymidylate phosphorylase. 5-FU inhibits thymidylate synthase, resulting in the inhibition of thymidine monophosphate production necessary for de novo DNA synthesis. High levels of thymidylate phosphorylase are found in several tumor cells and hepatocytes, rendering these cells more susceptible to toxicity.

Pharmacokinetics

Capecitabine is primarily removed from the body by the kidneys (up to 96% of the dose is recovered in the urine) and therefore dose reduction is required for kidney dysfunction. A 25% dose reduction in patients with CrCl between 30 to 50 mL/min and no administration of capecitabine with CrCl less than 30 mL/min are recommended. Some experts have suggested that capecitabine can be administered to patients with CrCl less than 30mL/min with close monitoring and dose adjustments. To this point, 12 patients with a CrCl less than 30 mL/min (including HD patients) were treated with capecitabine in reduced dose (up to 50%) and the drug was well tolerated. It is recommended that capecitabine is administered after HD.

Toxicity

The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Other adverse effects include abdominal pain, vomiting, weakness, fatigue, and myelosuppression. Bolus capecitabine is associated with more frequent hand-foot syndrome but less stomatitis, alopecia, neutropenia, diarrhea, and nausea.

Kidney toxicity

Because capecitabine is usually given in combination with other cytotoxics and/or targeted agents, it is difficult to appreciate the relative role of each agent within a given combination causing nephrotoxicity. Kidney function, along with BSA and age, are factors associated with risk of early-onset nephrotoxicity with capecitabine-based anticancer regimens. However, exclusion of capecitabine-based treatments in patients with kidney disease, but otherwise good performance status, may not be justified with appropriate dosing modifications. In fact, good renal tolerance of capecitabine was reported with no delayed toxicity greater than grade 2. Also, in the elderly, capecitabine is not associated with deterioration of kidney function. An incidence of hypokalemia of 20%, which was reversible in 91% of cases, occurred with capecitabine but did not require treatment discontinuation.

Mechanism of action

Cladribine is a prodrug, which undergoes intracellular phosphorylation only in lymphocytes. Phosphorylated cladribine is a purine analog and is similar to adenosine. It inhibits the enzyme adenosine deaminase, which results in inhibition of DNA production.

Pharmacokinetics

Approximately 20% of the administered dose is recovered in the urine. There are insufficient data available to make recommendations regarding dose reduction in patients with kidney disease.

Toxicity

The most important adverse effect of cladribine is bone marrow suppression and increased susceptibility for infections.

Kidney toxicity

Nephrotoxicity of cladribine is limited and there is only one case available in the literature reporting AKI after high doses of cladribine, in combination with other chemotherapeutics and irradiation. In animal studies, renal proximal tubule injury was reported with cladribine.

Mechanism of action

Clofarabine is a purine analog and inhibits DNA synthesis and the enzyme ribonucleotide reductase.

Pharmacokinetics

As clofarabine is partially removed from the body through renal excretion (60% of the dose is excreted unchanged in the urine after 24 hours), underlying kidney disease increases drug exposure, which might worsen treatment-related toxicity. ^, Therefore 50% dose reduction is advised with a CrCl between 30 and 60 mL/min. No recommendation can be made for patients with CrCl lower than 30 mL/min: we consider this a contraindication for clofarabine administration. It has been suggested that clofarabine is not dialyzable. When kidney function deterioration develops during clofarabine treatment, the drug should be discontinued and restarted at 75% of the original dose after kidney function recovery.

Toxicity

Clofarabine-associated adverse effects include bone marrow suppression, hepatotoxicity, gastrointestinal complaints, and fatigue.

Kidney toxicity

Two case reports have been reported on nephrotoxicity after clofarabine administration. ^, AKI and need for renal replacement therapy were described in a 48-year-old man with refractory acute myeloid leukemia treated with clofarabine. The second case demonstrated AKI and proteinuria in a 65-year-old man treated with clofarabine for relapsed acute myeloid leukemia. Twenty-nine cases of adverse kidney events were described in the Food and Drug Administration Adverse Event Reporting System. Collapsing glomerulopathy, severe tubular injury, or a combination of both may be the mechanism of clofarabine-induced AKI. Unfortunately, biopsy data are lacking. In clinical trials involving clofarabine in adults with acute myeloid leukemia, nephrotoxicity was reported in 10% to 42% of patients, and severe kidney injury in 6% to 19% of treated patients. In patients undergoing hematopoietic stem cell transplantation, the incidence of AKI was 55% and age and clofarabine AUC were notable risk factors.

Mechanism of action

Cytarabine is an antimetabolic agent and blocks the function of DNA polymerase. After cellular uptake, cytarabine is converted to cytarabine-5´-triphosphate, which is the active metabolite incorporated into DNA during DNA synthesis. This results in a cell cycle arrest in the S phase. In cohorts of both pediatric and adult patients with acute myeloid leukemia, the response to cytosine arabinoside-containing therapy was inversely correlated with sterile α motif and HD domain-containing protein 1 or SAMHD1 (this protein has deoxynucleoside triphosphate triphosphohydrolase activity) expression levels. ^,

Pharmacokinetics

Cytarabine is concentrated in the liver, where a major portion is inactivated by the enzyme cytidine deaminase. After 24 hours, 80% of the drug is eliminated either unchanged or as inactive metabolite in the urine. There are no data available on the use of cytarabine in HD patients. Dose reductions are recommended for high-dose cytarabine (1–3 g/m ² ): a 40% dose reduction and a 50% dose reduction in patients with a CrCl of 46 to 60 mL/min and 31 to 45 mL/min, respectively. High-dose cytarabine should not be administered in patients with a CrCl less than 30 mL/min.

Toxicity

The side effects of cytarabine include bone marrow suppression (leukopenia, thrombocytopenia, anemia), stomatitis, conjunctivitis, pneumonitis, and dermatologic side effects.

Kidney toxicity

Cytarabine may be potentially nephrotoxic, although there are very few data available in the literature reporting its nephrotoxicity. AKI is probably the most common renal side effect. In a study by Slavin et al., 85% of patients experienced a doubling of serum creatinine or a decrease in CrCl greater than 50%. Histologic examination showed interstitial edema and dilation of tubules with flattening, focal atypia, and occasional mitotic figures in tubular epithelium. Besides AKI, hypokalemia and hypocalcemia have been reported in patients treated with cytarabine, especially in patients experiencing diarrhea. TMA has also been described although all patients were also receiving other agents associated with the development of TMA.

Mechanism of action

Deoxycofomycin is a purine analog and antimetabolite, which inhibits adenosine deaminase and DNA replication.

Pharmacokinetics

Deoxycofomycin is administered intravenously and is primarily excreted unchanged in the urine (30%–90%) within 24 hours. To prevent deoxycofomycin-induced nephrotoxicity, 250 to 600 mL/m ² of 5% dextrose solution or 0.45% sodium chloride should be administered before each injection of pentostatin and 300 mL/m ² after each administration. Dose reduction is required in patients with decreased CrCl: 25% and 50% dose reduction are recommended in patients with a CrCl of 40 to 59 mL/min and 35 to 39 mL/min, respectively. Deoxycofomycin should not be administered with CrCl less than 35 mL/min.

Toxicity

Deoxycofomycin is a well-tolerated chemotherapeutic, whose main toxicities are nausea/vomiting, neurologic toxicity, opportunistic infections, and nephrologic toxicity. The toxicity seen with pentostatin is dose-dependent and therefore the dose of deoxycofomycin should never exceed 4 mg/m ² .

Kidney toxicity

Deoxycofomycin possesses dose-dependent nephrotoxicity. The risk for AKI is increased with doses of deoxycofomycin greater than 4 g/m ² /week. In addition, hematuria and dysuria develop with deoxycofomycin use, whereas TMA has also been associated with deoxycofomycin. ^, Data from the Oklahoma TTP-HUS registry and BloodCenter of Wisconsin concluded that there was a definite association between deoxycofomycin and the occurrence of TMA.

Mechanism of action

Fludarabine is a purine analog and inhibits DNA duplication.

Pharmacokinetics

Approximately 50% to 60% of the fludarabine dose is excreted by the kidneys within 24 hours, making dose adjustments necessary in patients with kidney disease. A 20% to 50% dose reduction is advised for patients with a CrCl of 30 to 70 mL/min and fludarabine should not be given to patients with CrCl less than 30 mL/min. In HD patients, no recommendations can be made. A 50% dose reduction has been suggested for PD patients.

Toxicity

The most common adverse effects are nausea, diarrhea, fever, rash, and dyspnea. Cardiac and hematologic toxicity also occur with fludarabine. ^,

Kidney toxicity

Fludarabine is not considered to be significantly nephrotoxic. ^, However, in a retrospective study of 241 patients receiving allogeneic bone marrow transplantation, fludarabine and older age were risk factors for the development of posttransplant AKI.

Mechanism of action

5-FU is a pyrimidine analog and an inhibitor of thymidylate synthase, which blocks production of DNA. Thymidylate synthase converts deoxyuridine monophosphate to thymidine monophosphate. 5-FU administration reduces deoxythymidine monophosphate, blocks DNA synthesis, and causes cell death. Calcium folinate stabilizes the complex between 5-FU and thymidylate synthase and thus augments 5-FU cytotoxicity.

Pharmacokinetics

5-FU is a prodrug that requires intracellular activation to exert its effects: more than 80% of the administered 5-FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase, which is highest in the liver. The metabolism of 5-FU is significantly reduced by older age, high serum alkaline phosphatase, length of drug infusion, and low peripheral blood mononuclear cell dihydropyrimidine dehydrogenase activity. Dose reduction of 5-FU should only be considered in patients with severe kidney failure.

Toxicity

Common adverse effects include stomatitis, bone marrow suppression, hair loss, and nausea.

Kidney toxicity

5-FU alone is not nephrotoxic. However, in combination with folinic acid in high doses, mitomycin, and cisplatin, 5-FU may be nephrotoxic. Folinic acid augments 5-FU cytotoxicity, and treatment with this drug combination decreased CrCl by 50% in three patients with normal baseline kidney function. Tubular damage was observed in all patients. Also in combination with cisplatin, 5-FU may be associated with hyponatremia. Hyponatremia occurred in all patients with gastric cancer; 20% of patients had a serum sodium less than 125 mmol/L. In patients with cervical cancer, severe hyponatremia (grade 3–4) was found in 11.1% of patients treated with cisplatin and 5-FU. The combination of cisplatin and 5-FU may also cause hypokalemia. Finally, 5-FU may be associated with TMA. ^,

Mechanism of action

Gemcitabine is a cell cycle-specific pyrimidine antagonist and blocks the production of DNA resulting in cell death.

Pharmacokinetics

Gemcitabine is rapidly metabolized by cytidine deaminase. Active metabolites have not been detected in plasma or urine. However, greater than expected toxicity (mainly hematologic toxicity) has been reported in patients with reduced kidney function, requiring dose reduction in patients with CrCl less than 30 mL/min. HD patients have been treated with gemcitabine, with retrospective reports suggesting that gemcitabine treatment in ESRD with intermittent standard HD treatment is safe and well tolerated. Pharmacokinetic data suggest that dose adjustment of gemcitabine should be avoided to ensure its full cytotoxic activity, and that HD treatment should be initiated 6 to 12 hours after its administration to minimize the potential side effects of its noncytotoxic metabolite 2’,2’-difluorodeoxyuridine. There are no data available regarding gemcitabine administration in PD patients.

Toxicity

Common adverse effects include bone marrow suppression, hepatic toxicity, vomiting and nausea, fever, rash, dyspnea, and hair loss. Rare but potentially severe toxic effects include reversible posterior encephalopathy syndrome, capillary leak syndrome, and adult respiratory stress syndrome.

Kidney toxicity

A meta-analysis of 979 patients treated with gemcitabine noted that AKI occurred in 0.7% of patients. However, proteinuria and hematuria developed in 36% and 31% of patients, respectively. The most severe adverse kidney effect associated with gemcitabine is TMA. ^, The incidence of gemcitabine-induced TMA is estimated to range from 0.015% to 2.7%, and it usually develops within 1 to 2 months following gemcitabine therapy. ^{, ,} Data from the Oklahoma TTP-HUS registry and BloodCenter of Wisconsin concluded that there was a definite association between gemcitabine and the occurrence of TMA. Prior treatment with mitomycin C or cisplatin, prolonged treatment with gemcitabine (> 18 courses), and a cumulative dose of gemcitabine (> 20 g/m ² ) are risk factors for the development of gemcitabine-induced TMA. ^{, ,} The clinical picture consists of arterial hypertension, decreased renal function, nonnephrotic range proteinuria, and microscopic hemolytic anemia and thrombocytopenia.

Besides cessation of gemcitabine, different treatment modalities have been used to treat gemcitabine-induced TMA, but the best prevention and/or treatment strategy has not been established. Plasma exchange, infusion of fresh frozen plasma, HD, immunoadsorption, plasmapheresis, azathioprine, corticosteroids, vincristine, antiplatelet/anticoagulant therapies, and splenectomy have all been used. The role of plasma exchange in the management of gemcitabine-induced TMA is unclear. Although an improvement in hematologic parameters is often observed during plasma exchange, the beneficial effect on kidney function is less obvious. In addition, doxycycline may be useful in the treatment of gemcitabine-induced TMA. ^, The C5 inhibitor eculizumab has been increasingly used for the treatment of gemcitabine-induced TMA. Early diagnosis improves chances of renal function recovery, whereas delayed diagnosis is associated with development of CKD, progression to ESRD, and death. The overall outcome of gemcitabine-induced TMA is poor, with a reported mortality ranging from 40% to 90%.

Mechanism of action

Mercaptopurine is an antimetabolite and member of the thiopurine family, which includes azathioprine, 6-mercaptopurine, and 6-thioguanine. As inactive prodrugs, the thiopurines require intracellular activation—catalyzed by multiple enzymes—to exert cytotoxicity. The cytotoxic effects of thiopurine drugs are achieved through different mechanisms: inhibition of de novo purine synthesis by methylmercaptopurine nucleotides, inhibition of Rac1 inducing apoptosis, incorporation of thio-deoxyguanosine triphosphate, and thioguanine triphosphate into DNA and RNA, respectively.

Pharmacokinetics

The clearance of mercaptopurine is mainly hepatic, and renal clearance is only important when high doses of mercaptopurine are administered. The dose interval should be increased in patients with decreased kidney function to 24 to 36 hours and to 48 hours in patients with a CrCl of 50 to 80 mL/min and 10 to 50 mL/min, respectively.

Toxicity

Common adverse effects include rash, flu-like symptoms, bone marrow suppression, hepatotoxicity, pancreatitis, nausea and vomiting, and bone marrow suppression. The toxicity of mercaptopurine can be linked to genetic polymorphisms in thiopurine S -methyltransferase, nudix hydrolase 15, and inosine triphosphate pyrophosphatase.

Kidney toxicity

Mercaptopurine has only been associated with AKI when tumor lysis syndrome follows tumor therapy. Fanconi syndrome has also been associated with mercaptopurine.

Mechanism of action

Methotrexate can be given orally or by injection. Methotrexate is an antimetabolite and is a competitive inhibitor of dihydrofolate reductase, an enzyme involved in tetrahydrofolate synthesis. Tetrahydrofolate is needed for de novo synthesis of the nucleoside thymidine. Methotrexate inhibits the production of DNA, RNA and proteins.

Pharmacokinetics

Methotrexate is predominantly (60%–90%) excreted by glomerular filtration and tubular secretion. Methotrexate is excreted by the kidneys both in the intact form and as its insoluble metabolite 7-hydroxymethotrexate. In acid urine (pH < 5.5) both compounds precipitate, whereas solubility is 10-fold greater at neutral pH. AKI is associated with higher incidence of bone marrow suppression and gastrointestinal toxicity. Guidelines regarding dose recommendations of methotrexate in patients with kidney disease vary. We advise that high-dose methotrexate should be administered only when CrCl is greater than 60 mL/min before the start of treatment. A 50% dose reduction is advised in patients with CrCl between 10 to 50 mL/min and the drug should be avoided with CrCl lower than 10 mL/min. Methotrexate is protein-bound and only partially removed by HD, ^, although HD using high-flux HD membranes can remove more methotrexate. For HD patients treated with low-dose oral methotrexate, a 50% to 75% dose reduction and administration after dialysis is advised (no dialysis for 12 hours after administration) Methotrexate is contraindicated in PD patients. High-dose methotrexate should be avoided in ESRD patients.

Toxicity

The most common adverse effects include hepatotoxicity, stomatitis, bone marrow suppression, nausea, fatigue, pneumonitis, rarely pulmonary fibrosis, and neurotoxicity (including amnesia).

Kidney toxicity

Doses of methotrexate lower than 0.5 to 1.0 g/m ² are usually not associated with nephrotoxicity, unless underlying kidney disease is present. Methotrexate-induced crystalline nephropathy is caused by the precipitation of the drug and/or its metabolite in the renal tubule, causing tubular obstruction (promoted by urinary pH < 7) and ATN. Direct tubular injury mediated by methotrexate has also been reported. The incidence of AKI associated with methotrexate varies widely, with reports from the 1970s and 1980s noting AKI in 30% to 50% of patients after high-dose methotrexate therapy with leucovorin rescue. In contrast, only 1.8% of patients with osteosarcoma who were treated with high-dose methotrexate developed significant nephrotoxicity. The variable incidence of high-dose methotrexate-induced AKI may be genetically determined. Anionic drugs such as methotrexate can be eliminated by multidrug resistance protein 2 (MRP2) transporter (encoded by the gene ABCC2 ), which is expressed at the luminal side of renal proximal tubular cells. A heterozygous mutation of MRP2 is associated with reduced methotrexate excretion and increased nephrotoxicity. In addition, organic anion transporters also appear to play a role in crystalluria and tubular dysfunction. ^, Nephrotoxicity mainly occurs in patients who are volume-depleted and are treated with high doses of methotrexate. In children, it was shown that nephrotoxicity is determined by the dose administered and not the cumulative dose. Because of low solubility of methotrexate at low urinary pH, metabolic changes resulting in tubular acidification are an additional risk factor for AKI. Methotrexate administration is also associated with short-term transient decrease in GFR, with complete recovery within 8 hours of discontinuing the drug as a consequence of afferent arteriolar constriction or mesangial cell constriction. In most cases, methotrexate-induced AKI is reversible and kidney function will usually recover in 1 to 3 weeks. However, even at low doses, methotrexate administration can be associated with a significant decrease in CrCl and progressive kidney dysfunction. One of 19 psoriatic patients with normal kidney function receiving methotrexate for prolonged period of time experienced AKI, which showed interstitial fibrosis and focal calcifications of renal tubular cells. Methotrexate has also been associated with the development of the SIADH and polyuria.

Prevention of methotrexate nephrotoxicity includes adjusting the methotrexate dose for kidney function, assuring euvolemia of the patients along with intense hydration, urinary alkalization to obtain a urine pH greater than 7.5, coadministration of high-dose leucovorin, thymidine, and discontinuation of other potentially nephrotoxic drugs. Several drugs have been associated with increased nephrotoxicity when coadministered with methotrexate because they compete with the renal tubular secretion of methotrexate, for example, probenecid, salicylates, sulfisoxazole, penicillins, and nonsteroidal antiinflammatory drugs (NSAIDs), and these drugs should be avoided. Glucarpidase (carboxypeptidase-G ₂ ), in combination with leucovorin, may be considered in cases of nephrotoxicity attributed to high-dose methotrexate administration or methotrexate intoxication. Administration of glucarpidase, which cleaves methotrexate to inactive metabolites, is associated with a rapid and near total reduction in methotrexate levels (plasma methotrexate concentrations decreased by 98.7% within 15 minutes after glucarpidase administration). HD and continuous veno-venous hemodiafiltration can also decrease methotrexate serum levels. ^,

Mechanism of action

Pemetrexed is a novel multitargeted antifolate that inhibits three or more enzymes involved in folate metabolism and purine and pyrimidine synthesis ( Fig. 16.3 ). These enzymes include thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Tetrahydrofolate is needed for de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Similar to methotrexate, pemetrexed inhibits the production of DNA, RNA, and proteins.

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