Nephrotoxicity of chemotherapy and other cytotoxic agents

INTRODUCTION — A variety of kidney diseases and electrolyte disorders can result from the drugs that are used to treat cancer, including chemotherapy, molecularly targeted agents, and immunotherapeutic agents. These drugs can affect the glomerulus, tubules, interstitium, or kidney microvasculature via different mechanisms, with clinical manifestations ranging from an asymptomatic elevation of serum creatinine and electrolyte disorders to acute kidney injury (AKI) requiring dialysis. One study estimated that potentially nephrotoxic drugs were used in 80 percent of chemotherapy sessions [1].

The nephrotoxicity of select conventional cytotoxic chemotherapy agents will be reviewed here. Kidney toxicities seen with molecularly targeted and biologic agents, drugs that target the vascular endothelial growth factor pathway, and immune checkpoint inhibitors are discussed separately.

●(See "Nephrotoxicity of molecularly targeted agents and immunotherapy".)

●(See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Kidney toxicity'.)

●(See "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney'.)

RISK FACTORS FOR NEPHROTOXICITY — Several factors can potentiate kidney function impairment and contribute to the nephrotoxic potential of antineoplastic drugs. These include:

●Intravascular volume depletion, either due to external losses or fluid sequestration (as in ascites or edema). This is one of the most common factors contributing to the nephrotoxic potential of antineoplastic drugs.

●The concomitant use of nonchemotherapeutic nephrotoxic drugs (eg, certain antibiotics [including aminoglycoside antibiotics], nonsteroidal antiinflammatory agents, and proton pump inhibitors) or radiographic ionic contrast media in patients with or without preexisting kidney function impairment. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".)

●Urinary tract obstruction secondary to the underlying tumor.

●Intrinsic or acquired kidney disease that is idiopathic, related to other comorbidities, age-related, or related to the cancer itself. (See "The aging kidney" and "Overview of kidney disease in patients with cancer".)

DOSING CONSIDERATIONS FOR NEPHROTOXICITY — Some chemotherapy agents may require close monitoring and dose adjustments in patients with baseline kidney disease and those who develop kidney toxicity while on cancer treatment. When known, individual drug dosing guidelines and adjustments for kidney toxicity are available through the drug monographs included within UpToDate.

PLATINUM AGENTS

Cisplatin — Cisplatin is one of the most commonly used antineoplastic drugs and one of the most nephrotoxic. Cisplatin is associated with acute kidney injury (AKI), thrombotic microangiopathy (TMA), hypomagnesemia, proximal tubular dysfunction (ie, Fanconi-like syndrome), and anemia that is out of proportion to the drug's myelosuppressive effects. Hydration is essential for all patients to prevent cisplatin-induced nephrotoxicity [2].

Monitoring and management of cisplatin-induced kidney insufficiency is discussed in detail separately. (See "Cisplatin nephrotoxicity".)

Carboplatin — In both experimental and clinical studies, carboplatin is significantly less nephrotoxic than cisplatin [3,4]. This increase in safety may reflect the enhanced stability of carboplatin, which has carboxylate and cyclobutane moieties in the cis position rather than chloride [4]. Hypomagnesemia appears to be the most common manifestation of nephrotoxicity, although it occurs less often than with cisplatin [5,6]. (See "Cisplatin nephrotoxicity".)

AKI has been reported, particularly in patients previously treated with several courses of cisplatin [4]. Direct tubular injury leading to acute tubular necrosis is the primary mechanism. A less common kidney side effect is renal magnesium wasting [7,8].

Oxaliplatin — In contrast with cisplatin and carboplatin, clinically significant kidney toxicity (such as acute tubular necrosis) occurs rarely with the third-generation platinum compound oxaliplatin, sometimes in the setting of immune-mediated intravascular hemolysis [9-12]. Limited data with oxaliplatin suggest no exacerbation of pre-existing mild kidney impairment during treatment [13]. Oxaliplatin has been associated with TMA in rare single case reports. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Oxaliplatin'.)

ALKYLATING AGENTS

Ifosfamide — Similar to cyclophosphamide, the predominant toxicity of ifosfamide on the urinary tract is hemorrhagic cystitis. Ifosfamide can also cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

However, nephrotoxicity is more likely with ifosfamide than with cyclophosphamide. Ifosfamide nephrotoxicity affects the proximal tubule and is characterized by one or more of the following signs of acute tubular dysfunction:

●Metabolic acidosis with a normal anion gap (hyperchloremic acidosis) due to type 1 (distal) or type 2 (proximal) renal tubular acidosis

●Hypophosphatemia induced by decreased proximal phosphate reabsorption, which can lead to rickets in children

●Renal glucosuria, aminoaciduria, and a marked increase in beta-2-microglobulin excretion, all from generalized proximal dysfunction

●Polyuria due to arginine vasopressin resistance (AVP-R, previously known as nephrogenic diabetes insipidus)

●Hypokalemia, which may be severe, resulting from increased urinary potassium losses

These data on tubular dysfunction come predominantly from pediatric patients treated with ifosfamide. There are few data on long-term kidney function in adults who have received ifosfamide. However, a persistent decline in glomerular filtration rate (GFR) over time has been described after as little as one course of ifosfamide in adults [14]. Prevention and management of nephrotoxicity due to ifosfamide is discussed in detail separately. (See "Ifosfamide nephrotoxicity".)

Cyclophosphamide — The main urologic toxicity of cyclophosphamide is hemorrhagic cystitis. This is discussed in more detail separately. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

The primary kidney effect of cyclophosphamide is hyponatremia, which is due to an increased effect of antidiuretic hormone (SIADH) impairing the kidney's ability to excrete water [15-17]. Chemotherapy-induced nausea may also play a contributory role since nausea is a potent stimulus to antidiuretic hormone release. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients" and "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Hyponatremia is usually seen in patients receiving high doses of intravenous (IV) cyclophosphamide (eg, 30 to 50 mg/kg or 6 g/m² in the setting of hematopoietic stem cell transplantation). Although less common, hyponatremia can also occur with oral therapy or with lower IV doses (eg, 10 to 15 mg/kg) given as pulse therapy in autoimmune diseases such as lupus nephritis. (See "Kidney disease following hematopoietic cell transplantation".)

Hyponatremia typically occurs acutely and resolves within approximately 24 hours after discontinuation of the drug. Hyponatremia poses a particular problem for patients undergoing high-dose IV cyclophosphamide, who are often fluid loaded to prevent hemorrhagic cystitis [17]. The combination of increased antidiuretic hormone effect and enhanced water intake can lead to severe, occasionally fatal hyponatremia within 24 hours. This complication can be minimized by using isotonic saline rather than hypotonic solutions to maintain a high urine output. However, hyponatremia can worsen even with isotonic saline administration. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Therapies to raise the serum sodium'.)

Melphalan — Melphalan is an alkylating agent that is used mainly for the treatment of multiple myeloma, either as a conditioning regimen prior to hematopoietic cell transplantation or in the palliative setting. Melphalan has been associated with the development of SIADH [18,19]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Nitrosoureas — A slowly progressive, chronic interstitial nephritis that is generally irreversible can be induced by prolonged therapy with the nitrosoureas carmustine (BiCNU), lomustine (CCNU), and streptozocin [20,21]. Although the exact mechanism of nephrotoxicity is not completely elucidated, these agents may produce nephrotoxicity through alkylation of tubular cell proteins. Their metabolites, which are thought to be responsible for nephrotoxicity, persist in the urine for up to 72 hours following administration [22].

●Carmustine – Although the primary dose-limiting toxicity of carmustine is pulmonary injury, it has been associated with kidney function impairment in several reports [23]. Histologic changes include mild interstitial infiltrates and tubular changes. (See "Nitrosourea-induced pulmonary injury".)

●Streptozocin – Streptozocin, a non-myelosuppressive nitrosourea, has been associated with nephrotoxicity in up to 75 percent of patients treated for prolonged periods of time. Although nephrotoxicity is not necessarily dose related, it is rare in patients treated with <1 to 1.5 g/m² per week [24]. Streptozocin damages the kidney tubules, causing atrophy and tubulointerstitial nephritis [25]; other case reports describe uric acid nephrolithiasis and acute kidney injury (AKI) [26], and AVP-R (arginine vasopressin resistance, previously known as diabetes insipidus [27]) following streptozocin.

Mild proteinuria or an asymptomatic elevation in the plasma creatinine concentration is usually the first sign of kidney involvement, followed by signs of proximal tubular damage (eg, phosphaturia, glycosuria, aminoaciduria, uricosuria, and bicarbonaturia). In one study of 52 patients treated for advanced islet cell carcinoma, the most common sign of nephrotoxicity was proteinuria (51 percent), followed by renal tubular acidosis (17 percent), Fanconi syndrome (13 percent), and azotemia (26 percent) [28]. Nephrotoxicity contributed to death in 11 percent of treated patients.

The onset of clinical nephrotoxicity may be delayed from several months to as long as several years after nitrosoureas have been discontinued. As a result, careful long-term follow-up is essential. If it develops, nephrotoxicity typically persists for approximately two to three weeks after the drug is stopped. There is no known therapy for this disorder once it has begun. It has been suggested, however, that the nephrotoxicity can be diminished by the use of forced diuresis (2 liters of isotonic saline per hour for two hours) when the drug is being given [29].

Trabectedin — Trabectedin is a marine-derived alkylating agent that is approved for treatment of advanced soft tissue sarcoma. Cases of kidney failure (occasionally fatal) have been reported, some of which are attributable to rhabdomyolysis [30-34].

ANTIMETABOLITES

Methotrexate — Methotrexate at doses less than 0.5 to 1 g/m² is usually not associated with kidney toxicity unless underlying kidney function impairment is present. By contrast, high-dose intravenous (IV) methotrexate (1 to 15 g/m²) can precipitate in the tubules and induce tubular injury; at particular risk are patients who are volume depleted and those who excrete acidic urine. Maintenance of adequate urinary output and alkalinization will lessen the probability of methotrexate precipitation. The management of methotrexate kidney toxicity is discussed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Renal toxicity' and "Crystal-induced acute kidney injury", section on 'Methotrexate'.)

Methotrexate can also produce a transient decrease in glomerular filtration rate (GFR), with complete recovery within six to eight hours of discontinuing the drug. The mechanism responsible for this functional kidney impairment involves afferent arteriolar constriction or mesangial cell constriction that produces reduced glomerular capillary surface area and diminished glomerular capillary perfusion and pressure [35]. Methotrexate has also been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Pemetrexed — Pemetrexed is a derivative of methotrexate that is approved for treatment of advanced non-small cell lung cancer and pleural mesothelioma. (See "Systemic treatment for unresectable malignant pleural mesothelioma" and "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation", section on 'Pemetrexed or docetaxel (with or without ramucirumab)'.)

Pemetrexed has been associated with kidney damage (including acute tubular necrosis, interstitial edema, renal tubular acidosis, and arginine vasopressin resistance [AVP-R, previously known as diabetes insipidus]) [36-38]. The risk of acute kidney injury (AKI) is thought to be low (1 to 5 percent), but higher risks have been reported by others (21 to 54 percent), mainly in patients with non-small cell lung cancer treated with combination chemotherapy that includes pemetrexed [38,39]. The mechanisms of pemetrexed-mediated kidney injury are not completely understood, but several reports suggest tubular injury due to pemetrexed polyglutamation, retention of intracellular polyglutamates, and impairment of nucleic acid synthesis [40]. Baseline kidney function impairment appears to be a risk factor for AKI [38,39]. Some cases may not be reversible [38,39,41]. (See "Overview of the management of acute kidney injury (AKI) in adults".)

Gemcitabine — Gemcitabine is a cell cycle-specific pyrimidine antagonist; the most common form of kidney toxicity is AKI with microangiopathic hemolytic anemia (thrombotic microangiopathy [TMA], previously referred to as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome [TTP-HUS]) [42-44]. The incidence ranges from 0.015 to 1.4 percent, and in some reports (but not others [45]), risk is highest in those who have received cumulative gemcitabine doses over 20,000 mg/m² [44] Prior therapy with mitomycin C may be a risk factor for the development of TMA [43]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

The diagnosis of TMA should be considered in a patient who develops Coombs-negative hemolytic anemia, thrombocytopenia, AKI, and/or neurologic findings while receiving gemcitabine. Proteinuria is common but may not occur in all patients with TMA [46]. Management of TMA includes drug discontinuation and supportive care. Further details on the treatment of drug-induced TMA, including anticomplement therapy, is discussed separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)

Clofarabine — Clofarabine is a purine nucleoside analog that exerts its antineoplastic effect by inhibiting DNA synthesis and the enzyme ribonucleotide reductase. It is approved for acute lymphoblastic leukemia in children, and it is also being used for relapsed or refractory acute myeloid leukemia and acute lymphoblastic leukemia in adults. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Clofarabine' and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction'.)

Two case reports describe severe kidney injury shortly after drug administration; one patient was found to have 4 g of proteinuria, and the other developed anuria and required dialysis [47,48]. No biopsy data exist to help propose a mechanism of injury in these patients, but ribonucleoside reductase may be contributing to podocyte injury and the development of proteinuria [47].

The magnitude of nephrotoxicity risk is unclear. In one study, the risk of AKI was as high as 55 percent following use of clofarabine in patients undergoing hematopoietic cell transplantation [49]. Age was the strongest predictor of AKI. The area under the curve of concentration X time (AUC, mg/mL x min) was higher in patients who developed AKI; those with the highest dose-normalized AUCs experienced the most severe grades of AKI. One of those patients had a kidney biopsy that showed acute toxic tubular necrosis as the likely mechanism of injury. (See "Overview of the management of acute kidney injury (AKI) in adults".)

ANTIMICROTUBULE AGENTS

Taxanes — The taxanes paclitaxel and docetaxel have not been associated with nephrotoxicity.

Cabazitaxel is a semisynthetic taxane. Cases of kidney failure were reported in a randomized trial conducted in men with metastatic prostate cancer, including four with a fatal outcome. Most occurred in association with sepsis, dehydration, or obstructive uropathy. Hemorrhagic cystitis has also been reported. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Males who have received prior docetaxel' and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Chemotherapy'.)

Vinca alkaloids — Vincristine, vinblastine, and vinorelbine have all been associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in a small number of treated patients [50,51]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

ANTITUMOR ANTIBIOTICS

Anthracyclines and related agents — Anthracyclines such as daunorubicin and doxorubicin have been known to cause nephrotic syndrome with kidney lesions consistent with minimal change disease, focal segmental glomerular sclerosis not otherwise specified (NOS), or collapsing glomerulopathy [52]. In addition, pegylated liposomal doxorubicin has been associated with renal thrombotic microangiopathy (TMA), nephrotic syndrome, and acute kidney injury (AKI) [53-55]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

Mitomycin — There is a possible association of mitomycin with drug-induced TMA that has not been definitively established. This subject is discussed in detail separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

IMMUNOMODULATORY DRUGS — Immunomodulatory imide drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, are used for the treatment of relapsed or recurrent multiple myeloma, a disease that frequently is associated with kidney impairment. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs' and "Multiple myeloma: Treatment of first relapse", section on 'Lenalidomide sensitive'.)

Thalidomide — Thalidomide, a first-generation IMiD, is metabolized via nonenzymatic hydrolysis, and <1 percent of the unchanged drug is excreted in the urine [56]. In the initial report showing thalidomide activity against multiple myeloma, 8 out of 84 patients had a >50 percent increase in serum creatinine; however, the kidney injury was attributed to underlying disease progression and not drug-related toxicity [57]. In clinical practice, the use of thalidomide has not been associated with clinically significant acute kidney injury (AKI). However, there are reports of otherwise unexplained hyperkalemia in patients with myeloma treated with thalidomide [58,59].

Lenalidomide — Lenalidomide is an analog of thalidomide that, in contrast with thalidomide, is predominantly excreted in the urine as unchanged drug.

Cases of lenalidomide-induced AKI have been reported, including a case of biopsy-proven acute interstitial nephritis [60,61]. In a series of 41 patients with immunoglobulin light chain amyloidosis who were treated with lenalidomide, 27 (66 percent) developed kidney function impairment (defined as a ≥50 percent increase in serum creatinine) during treatment, including four of the eight patients without underlying renal amyloidosis [62]. Severe kidney function impairment occurred in 13 patients (32 percent), four of whom required dialysis. The median time to kidney function impairment after starting lenalidomide was 44 days (interquartile range 15 to 108 days).

Other types of kidney injury have been reported but seem to be rare overall:

●At least one patient has developed Fanconi syndrome (generalized proximal tubular dysfunction characterized by phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis) while receiving lenalidomide [63].

●One patient has been described with acute interstitial nephritis and a drug reaction with eosinophilia, rash, and systemic symptoms (DRESS syndrome) [64]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●A case of minimal change disease was reported in a patient with Waldenström macroglobulinemia being treated with lenalidomide [65].

●Lenalidomide has multiple immunomodulatory effects, and activation of the immune system may result in immune-mediated complications. As examples, there have been several case reports of acute allograft rejection after treatment with this drug [66-68]. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Treatment and prognosis".)

Pomalidomide — Pomalidomide is a second-generation IMiD that is used for treatment of multiple myeloma and Kaposi sarcoma. (See "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Pomalidomide' and "Multiple myeloma: Treatment of first relapse", section on 'Bortezomib, pomalidomide, dexamethasone (VPd)'.)

Pomalidomide is predominantly metabolized by the liver. In one of the three trials that evaluated its efficacy in multiple myeloma, the incidence of grade 3 to 4 kidney toxicity (table 1) was 5.9 percent [69]. In addition, a single case of AKI with crystal nephropathy was attributed to pomalidomide; however, the confounding factors included concurrent use of levofloxacin, which may have contributed to both the AKI and the crystal formation [70].

PROTEASOME INHIBITORS — Proteasome inhibitors block the action of proteasomes, which are enzyme complexes responsible for the degradation of intracellular proteins. These agents have been approved for use in the treatment of multiple myeloma. (See "Multiple myeloma: Initial treatment" and "Treatment protocols for multiple myeloma" and "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)

Carfilzomib — There have been reports of creatinine elevations in up to 25 percent of patients treated with carfilzomib:

●In a phase II study of 266 patients with relapsed and refractory myeloma treated with single-agent carfilzomib, acute kidney injury (AKI) was reported in 25 percent [71]. Although the majority of kidney adverse effects were mild, progressive kidney disease occurred in 3.8 percent of patients, leading to discontinuation of the drug in two patients.

●In another phase III trial of patients with relapsed or refractory multiple myeloma who received carfilzomib or a control regimen of low-dose glucocorticoids with optional cyclophosphamide, the incidence of grade 3 AKI (table 1) was higher in the carfilzomib arm (8 versus 3 percent) [72]. Kidney adverse events of any type also occurred more frequently in the carfilzomib group (24 versus 9 percent); in both groups, these events were more likely to occur among patients with lower creatinine clearance (CrCl; <30 mL/min) and in those with evidence of a urine monoclonal protein.

Potential mechanisms for AKI in patients treated with carfilzomib include prerenal causes (eg, hypovolemia), tumor lysis-like syndrome, or acute tubular necrosis [73-78]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies' and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation", section on 'Less common causes of albuminuria'.)

Thrombotic microangiopathy (TMA) has also been described in patients treated with carfilzomib. In one case series, the median time between drug initiation and diagnosis was 21 days (range 5 days to 17 months), and the majority had complete resolution of TMA after discontinuation of the proteasome inhibitor [79-81]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

Bortezomib — In general, nephrotoxicity is uncommon with bortezomib, although several cases of TMA have been reported. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

In addition, a case of biopsy-proven acute interstitial nephritis with granuloma formation has been described [82].

Ixazomib — Ixazomib is an orally active proteasome inhibitor; as with other proteasome inhibitors, TMA has been reported rarely [83]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

SUMMARY AND RECOMMENDATIONS

●Risk factors – Several factors can potentiate kidney function impairment and contribute to the nephrotoxic potential of antineoplastic drugs. These include intravascular volume depletion, concomitant use of nonchemotherapeutic nephrotoxic drugs or radiographic ionic contrast media, urinary tract obstruction secondary to the underlying tumor, and intrinsic or acquired kidney disease. (See 'Risk factors for nephrotoxicity' above.)

●Dosing considerations – Some chemotherapy agents may require close monitoring and dose adjustments in patients with baseline kidney disease and those who develop kidney toxicity while on cancer treatment. When known, individual drug dosing guidelines and adjustments for kidney toxicity are available through the drug monographs included within UpToDate. (See 'Dosing considerations for nephrotoxicity' above.)

●Nephrotoxicity of conventional cytotoxic agents – The kidney toxicities of different classes of conventional cytotoxic agents are described in detail above. Selected agents are highlighted below:

•Platinum agents

-Cisplatin – Cisplatin, one of the most commonly used antineoplastic drugs, is associated with acute kidney injury (AKI), thrombotic microangiopathy (TMA), hypomagnesemia, proximal tubular dysfunction (ie, Fanconi-like syndrome), and anemia that is out of proportion to the drug's myelosuppressive effects. (See 'Cisplatin' above.)

-Carboplatin – Carboplatin is less nephrotoxic than cisplatin, but hypomagnesemia and AKI can occur. (See 'Carboplatin' above.)

-Oxaliplatin – Clinically significant kidney toxicity is rare with oxaliplatin. (See 'Oxaliplatin' above.)

•Ifosfamide – Ifosfamide nephrotoxicity is manifested by signs of proximal tubular dysfunction including glucosuria, aminoaciduria, tubular proteinuria (ie, increased urine excretion of low-molecular-weight proteins such as beta-2-microglobulin, but not of albumin), and, rarely, polyuria due to arginine vasopressin resistance (AVP-R, previously known as diabetes insipidus). Ifosfamide can also cause hemorrhagic cystitis. (See 'Ifosfamide' above.)

•Methotrexate – High-dose intravenous (IV) methotrexate (1 to 15 g/m²) can precipitate in the tubules and induce tubular injury, particularly in patients who are volume depleted and those who excrete acidic urine. Methotrexate at doses less than 0.5 to 1 g/m² is usually not associated with kidney toxicity unless underlying kidney function impairment is present. (See 'Methotrexate' above.)

•Pemetrexed – Pemetrexed has been associated with kidney damage including acute tubular necrosis, interstitial edema, renal tubular acidosis, and AVP-R. (See 'Pemetrexed' above.)

•Gemcitabine – The most common form of kidney toxicity with gemcitabine is AKI with microangiopathic hemolytic anemia (TMA). The risk is highest in those who have received cumulative gemcitabine doses over 20,000 mg/m². (See 'Gemcitabine' above.)

•Proteosome inhibitors – Proteosome inhibitors, including carfilzomib, bortezomib, and ixazomib, have been associated with the development of TMA. (See 'Proteasome inhibitors' above.)