Cisplatin nephrotoxicity

INTRODUCTION — Cisplatin is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Renal tubular dysfunction and a cumulative impairment in kidney function, as manifested by a decline in the glomerular filtration rate (GFR), can be dose limiting. The laboratory observation that forced hydration and diuresis may prevent nephrotoxicity facilitated the subsequent clinical development of cisplatin [1-3].

Cisplatin-induced kidney toxicity is reviewed here. The use of cisplatin in patients with preexisting kidney dysfunction and the kidney effects of the platinum analogs, carboplatin and oxaliplatin, are discussed elsewhere. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)

PATHOGENESIS — Multiple mechanisms contribute to kidney dysfunction following cisplatin administration. Exposure of tubular cells to cisplatin activates complex signaling pathways that result in tubular cell injury and cell death. A robust inflammatory response, as well as injury to the renal vasculature, results in vasoconstriction, reduced blood flow, and ischemic injury. Collectively, these changes lead to acute kidney injury (AKI) [4]. It is important to note that for many malignancies, cisplatin is used in combination with other drugs that may also be nephrotoxic.

●Cellular toxicity – Cisplatin (cis-diamminedichloroplatinum II [CDDP]), a platinum compound that is predominantly eliminated through renal clearance. Inside cells, the low chloride concentration facilitates CDDP hydrolysis with generation of charged species. This hydrolysis product is believed to be the active species, reacting with glutathione in the cytoplasm and DNA in the nucleus [5]. In tumors and other dividing cells, cisplatin-DNA intrastrand crosslinks result in cytotoxicity [6]. These molecular events are thought to be responsible for arresting cancer cell proliferation. More than 50 percent of the drug is excreted in the urine in the first 24 hours following cisplatin administration, and the concentration of platinum achieved in the kidney cortex is several fold greater than that in plasma and other organs [7,8]. Cisplatin primarily injures the S3 segment of the proximal tubule, causing a decrease in the glomerular filtration rate (GFR) [9].

Experimental studies suggest that basolateral drug transporters play a role in cisplatin uptake [10]. Changes in expression of proximal tubule organic cation transporter 2 (OCT2) have been shown to mediate the accumulation of cisplatin in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of cisplatin-mediated nephrotoxicity [11-13]. The organic anion transporters OAT1 and OAT3 may also play a role via a mechanism that is independent of OCT2 [14]. In addition, cisplatin uptake may be mediated through the copper transporter protein 1 (Ctr1), which is expressed in basolateral membranes of both proximal and distal tubular cells [15,16].

●Vasoconstriction – Vasoconstriction in the kidney microvasculature appears to contribute to decreased renal blood flow soon after cisplatin injection, which may lead to ischemic renal tubular injury [17,18].

●Proinflammatory effects – Cisplatin increases the expression of proinflammatory cytokines, such as tumor necrosis factor (TNA)-alpha, interleukin (IL) 6, interferon (IFN)-gamma, and caspases, which promote the differentiation, maturation, and activation of neutrophils, T cells, and other components of the cellular inflammatory response [19,20]. Experimental models of cisplatin-induced AKI demonstrate increased expression of endothelial cell adhesion molecules and subsequent infiltration of leukocytes and T cells in kidney tissue [21-23]. The potential importance of these mediators was illustrated by the lesser severity of AKI following exposure to cisplatin in mice with defects in these inflammatory pathways [19,20,24-26].

●Effects on the proximal tubule – The proximal tubule cells are selectively injured by cisplatin, as manifested by both necrosis and apoptosis, even though nonproliferating cells are generally less sensitive to the toxicity of agents that damage DNA [27].

Possible reasons for the observed nephrotoxicity of cisplatin include its enhanced kidney uptake by organic transporters [10], followed by cisplatin-mediated reduced expression and function of sodium-dependent glucose and amino acid transporters [28], reduced expression and function of magnesium and water transporters [7,8], metabolism of cisplatin to glutathione and cysteinyl-glycine conjugates [29], and the generation of reactive oxygen species [30-36].

Other cellular effects that have been proposed as the cause of cisplatin-induced nephrotoxicity include the following:

•Inhibition of mitochondrial F1F0-ATPase and reduction of mitochondrial oxidative phosphorylation precede apoptotic cell death [37,38].

•Induction of hyperlipidemia and the accumulation of triglyceride and nonesterified fatty acids (NEFAs) in kidney tissue, perhaps due to inhibition of fatty acid oxidation in the proximal tubule [38,39].

•Significant reduction in messenger RNA (mRNA) levels and enzyme activity of mitochondrial medium chain acyl-CoA dehydrogenase (MCAD).

•Possible direct inhibition of peroxisome proliferator-activated receptor (PPAR)-alpha activity in renal epithelial cells [40,41]. This may decrease the expression of PPAR-regulated genes, including those encoding potentially protective fatty acid-binding proteins [42].

RISK FACTORS FOR ACUTE KIDNEY INJURY — An increasing risk of acute kidney injury (AKI) is associated with higher doses of cisplatin that result in high peak plasma free platinum concentrations, previous exposure to cisplatin, preexisting kidney damage, and the concomitant use of other nephrotoxic agents:

●High peak plasma free platinum concentrations – High peak plasma free platinum concentrations are associated with an increased risk of AKI, which suggests that the cumulative dose of platinum may play a role in the development of nephrotoxicity. As an example, in a study of 22 patients receiving their first course of cisplatin (50 to 140 mg/m²), a peak plasma ultrafiltrable platinum level (free platinum level) in excess of 400 ng/mL was associated with >30 percent decline in creatinine clearance by the fourth course of therapy [43].

Additional evidence supporting the importance of high peak plasma platinum concentrations comes from the observation that glomerular filtration rate (GFR) and serum magnesium levels were significantly decreased following cisplatin administration at doses ≥50 mg/m² [44]. By comparison, the GFR was maintained in patients receiving cisplatin at a lower daily dose of 20 mg/m² over five consecutive days [44].

●Previous cisplatin chemotherapy – Patients who have previously been treated with cisplatin and receive additional cisplatin therapy are at increased risk for developing kidney injury. An increased risk of nephrotoxicity may also be observed when carboplatin, a less nephrotoxic platinum analog, is used instead of cisplatin in a subsequent-line regimen [45].

●Preexisting kidney damage – There is an increased risk of AKI with cisplatin among patients with underlying kidney dysfunction, primarily due to the decreased renal clearance of cisplatin. Cisplatin-based chemotherapy should be used cautiously or avoided in patients with elevated serum creatinine levels. Many of the ongoing national clinical trials exclude patients with creatinine levels >1.5 mg/dL (133 micromol/L) from receiving cisplatin [46]. (See 'Use of cisplatin in patients with kidney impairment' below and "Nephrotoxicity of chemotherapy and other cytotoxic agents", section on 'Cisplatin'.)

●Concomitant use of other nephrotoxic agents – The risk of AKI with cisplatin is increased in patients who are concomitantly receiving potentially nephrotoxic agents, such as aminoglycosides, amphotericin B, and nonsteroidal antiinflammatory drugs.

Other factors that are potentially associated with an increased risk of kidney toxicity include older age, female sex, smoking, cisplatin dose >100 mg, hypoalbuminemia, history of hypertension, and paclitaxel coadministration [47-49]. The risk related to sex may be due in part to lower unbound cisplatin clearance in females.

In adult survivors of childhood cancer, high-dose cisplatin therapy (cumulative dose >450 mg) has been associated with long-term nephrotoxicity, including lower estimated GFR (eGFR) and albuminuria [50].

CLINICAL PRESENTATIONS — The most important clinical manifestation of cisplatin nephrotoxicity is kidney injury, which may be acute or chronic. Other kidney manifestations have been described, including electrolyte disturbances, thrombotic microangiopathy, and anemia (due to decreased erythropoietin production).

Acute kidney injury — Acute kidney injury (AKI) from cisplatin exposure typically manifests with a slow rise in serum creatinine after five to seven days of therapy. The timing of AKI may be earlier (within three to five days of therapy) in patients with comorbid risk factors, such as preexisting chronic kidney disease (CKD), older age, hypoalbuminemia, or concomitant nephrotoxic drugs. (See 'Risk factors for acute kidney injury' above.)

Most patients will experience a mild to moderate increase in serum creatinine (ie, 1.5 to 2.9 times baseline), while some may progress to more severe AKI (serum creatinine >3.0 times baseline) or require kidney replacement therapy. Severe AKI is uncommon in the absence of preexisting CKD and/or other comorbid risk factors as mentioned above.

Unless the kidney injury is severe, the urine output in patients with cisplatin nephrotoxicity typically remains above 1000 mL per day due to the induction of a concentrating defect. This defect may reflect platinum-induced damage to the loop of Henle, where the countercurrent gradient required for urinary concentration is established, or to the collecting tubules, the site of action of antidiuretic hormone [51].

Urinalysis usually shows no or low-grade proteinuria and may have trace amounts of leukocyte esterase; microscopic hematuria is usually absent. The urine sediment may reveal white blood cells, renal tubular epithelial cells, renal tubular epithelial cell casts, and/or granular casts. AKI may be accompanied by tubulopathies, such as a Fanconi-like syndrome, distal renal tubular acidosis, and magnesium and salt wasting, as described below. (See 'Electrolyte disturbances' below.)

Although AKI with cisplatin can recover within a few weeks after the initial insult, progressive CKD from chronic tubulointerstitial fibrosis and irreversible chronic tubulopathies may develop [52].

The incidence of AKI after cisplatin administration varies depending upon the dose and frequency of drug administration and the criteria used to define nephrotoxicity. Nephrotoxicity was observed in the initial phase I and phase II studies with cisplatin and was seen in more than 50 percent of cases in some of the early trials prior to the use of intensive hydration regimens [1,53]. More contemporary human studies have reported AKI in approximately 30 percent of adult patients receiving a single dose of cisplatin >50 mg/m² [54]. A prospective study of children (age <18 years) treated with cisplatin found a similar frequency of AKI among those receiving early (first or second cycle) cisplatin infusions and a lower frequency of AKI (16 percent) among those receiving late (last or second to last cycle) infusions [55].

The incidence and severity of AKI increase with subsequent courses, and kidney damage can eventually become irreversible. As a result, discontinuing therapy with cisplatin is generally indicated in those who develop evidence of progressive kidney impairment. (See 'Patients with acute kidney injury' below.)

Electrolyte disturbances

Hypomagnesemia — Hypomagnesemia due to urinary magnesium wasting occurs in over one-half of cases of cisplatin-induced nephrotoxicity and can be severe [56-58]. It is dose related and can occur without the presence of concomitant AKI. In patients who receive cisplatin for several months, urinary magnesium wasting may persist even after discontinuation of cisplatin therapy. In addition to its direct clinical manifestations, hypomagnesemia may exacerbate cisplatin toxicity [59].

The healthy kidney is able to make the urine virtually magnesium free once the plasma magnesium concentration falls below 1.2 mEq/L (1.5 mg/dL or 0.6 mmol/L) [57]. Thus, a fractional excretion of magnesium (FEMg) above 2.5 percent in the presence of hypomagnesemia is indicative of some component of magnesium wasting. A review of magnesium handling and of the different units used to measure the plasma magnesium concentration is available in a separate topic review. (See "Regulation of magnesium balance".)

Fanconi-like syndrome — Cisplatin-mediated nephrotoxicity is accompanied by the development of a Fanconi-like syndrome, with increased urinary excretion of glucose and amino acids (such as alanine, valine, leucine, methionine) and the presence of tricarboxylic acid (TCA) cycle metabolites (lactate and pyruvate) in the urine. In addition to being a marker of tubular damage, glucosuria may also occur due to cisplatin-induced glucose intolerance and hyperglycemia due to abnormal insulin and glucagon responses to a glucose stimulus [38,60-62]. Classic Fanconi syndrome has not been reported, although mild tubular dysfunction may persist [63]. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance", section on 'Proximal (type 2) RTA'.)

Distal renal tubular acidosis — A distal renal tubular acidosis has been described among patients receiving cisplatin therapy. In one case series, 4 out of 12 patients who received several courses of cisplatin developed acidifying or concentrating defects despite having normal kidney function [64].

Salt wasting — Clinically apparent renal salt wasting is a rare manifestation of cisplatin nephrotoxicity that has been described in case reports and small series [65-67]. Patients typically present with polyuria, hypovolemia, and hyponatremia and, because of similarities in clinical presentation and laboratory findings, may be misdiagnosed with syndrome of inappropriate antidiuretic hormone. Renal salt wasting after cisplatin exposure is usually dose related, although it may occur after even a few doses. Salt wasting usually persists with continued cisplatin exposure and may be permanent despite discontinuation of cisplatin.

Thrombotic microangiopathy — There are rare case reports of thrombotic microangiopathy in patients treated with cisplatin, either alone [68] or in combination with other anticancer agents such as bleomycin [69,70] and gemcitabine [71]. This disorder presumably reflects direct vascular injury with secondary platelet activation.

The onset of kidney injury may be abrupt or insidious; in the latter setting, it can develop months after treatment has been discontinued. The diagnosis of this form of nephrotoxicity is suggested by the concurrent presence of microangiopathic hemolytic anemia and thrombocytopenia. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

Anemia — Cisplatin is frequently associated with anemia that is out of proportion to its myelosuppressive effect on the other blood cell lines. Animal and human studies suggest that the renal tubular injury induced by cisplatin results in a deficiency of erythropoietin, which contributes to the anemia [72].

Treatment with erythropoiesis-stimulating agents may be useful in this situation. (See "Role of ESAs in adults with non-hematologic cancers".)

USE OF CISPLATIN IN PATIENTS WITH KIDNEY IMPAIRMENT — Cisplatin should be used cautiously in patients with preexisting kidney impairment. There are no definitive studies to help guide the threshold level of kidney function at which cisplatin should not be administered. In our centers, we make every effort to avoid using cisplatin among patients with a serum creatinine concentration >1.5 mg/dL (133 micromol/L) or an estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73 m². Possible exceptions are situations in which cisplatin has a proven curative role, such as patients with testicular cancer. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

In addition, cisplatin should be used cautiously in patients with older age (age >60 years), volume depletion, hypoalbuminemia, or poor functional status, and those receiving concomitant nephrotoxic agents [49,54,73]. In such cases, carboplatin may be a viable alternative, though this will be a matter of judgment that depends, in part, on the extent of data with carboplatin substitution for that particular cancer setting. (See 'Risk factors for acute kidney injury' above and 'Use of cisplatin analogs' below.)

PREVENTION OF NEPHROTOXICITY — The standard approach to prevent cisplatin-induced nephrotoxicity is the administration of intravenous (IV) isotonic saline, avoidance of potential nephrotoxins, and, when appropriate, use of lower doses of cisplatin. Although a number of pharmacologic agents have been evaluated to decrease nephrotoxicity, none has an established role.

General measures

Intravenous saline — The administration of IV saline to induce a diuresis remains the primary approach for preventing cisplatin-induced nephrotoxicity and must be used in all patients treated with cisplatin. The optimal hydration solution and regimen to prevent nephrotoxicity associated with cisplatin administration is unclear. We suggest a solution consisting of isotonic saline supplemented with potassium chloride and magnesium sulfate rather than isotonic saline alone or isotonic saline with only potassium chloride. The addition of furosemide is generally not required, unless there is evidence of fluid overload.

We prepare a solution consisting of 1000 mL of isotonic saline plus 20 mEq of potassium chloride and 2 grams of magnesium sulfate. We administer intravenously a minimum of 1000 mL of this solution over two to three hours prior to, and a minimum of 500 mL over the two hours following, the cisplatin administration. This fluid administration should be adequate to establish a urine flow of at least 100 mL/hour for two hours prior to, and two hours after, chemotherapy administration. The rationale for adding potassium and magnesium to the solution is to avoid the development of hypokalemia and hypomagnesemia that may occur with forced diuresis; in addition, magnesium supplementation may help to limit cisplatin nephrotoxicity [74,75]. Among patients in whom this regimen is contraindicated, alternate chemotherapeutic regimens that do not include cisplatin should be considered.

It is difficult to accurately characterize the effectiveness of IV saline in preventing cisplatin nephrotoxicity. This is because, among the trials that have evaluated cisplatin, there were varying definitions of nephrotoxicity, variable cisplatin doses, and patient populations that differed by comorbidity and underlying malignancy. In general, the administration of IV saline with the resultant diuresis significantly lowers the risk of nephrotoxicity. In the initial phase I and II studies, nephrotoxicity was observed in more than 50 percent of cases administered cisplatin [1,53]. It was subsequently observed that the induction of a diuresis using the administration of IV saline dramatically lowered the incidence of nephrotoxicity to very low levels (0 percent in some small, uncontrolled series) [76]. This allowed the development of cisplatin for clinical use [3].

There are few randomized trials that have compared different regimens and/or types of IV fluids. In one small pilot trial, 30 adults with head and neck cancer who received low-dose weekly cisplatin for seven to eight weeks were randomly assigned to prehydration with isotonic saline plus potassium chloride and magnesium sulfate or isotonic saline plus only potassium chloride [75]. Although the incidence of cisplatin-associated acute kidney injury (defined as an increase in serum creatinine ≥0.3 mg/dL within seven days) was similar between the groups (1.3 versus 4.6 percent), the incidence of cisplatin-associated acute kidney disease (defined as increase in serum creatinine ≥0.3 mg/dL between the last creatinine measurement and baseline precisplatin creatinine) was lower in the group that received magnesium (7 versus 47 percent, respectively) [75]. A systematic review of 24 studies that examined hydration strategies found that short-duration (over two to six hours), lower-volume (2 to 4 L) hydration with magnesium supplementation in the outpatient setting was effective and safe in preventing cisplatin-induced nephrotoxicity, even in those receiving intermediate- to high-dose cisplatin [74]. However, given the differences in cancer types, cisplatin doses, study types, hydration regimens, and definitions of nephrotoxicity across studies, no definitive conclusions could be made regarding optimal hydration regimens.

Avoidance of potential nephrotoxins — In patients receiving cisplatin, we discontinue medications that may increase the risk for cisplatin nephrotoxicity, including nonsteroidal antiinflammatory drugs, aminoglycosides, and amphotericin B. However, there may be clinical situations in which such medications cannot be discontinued (eg, those that are being used to treat life-threatening conditions). In addition, we try to limit exposure to intravascular iodinated contrast unless it is required for an emergency or life-saving procedure.

Lower doses of cisplatin — Lower doses of cisplatin may help to prevent cisplatin nephrotoxicity, particularly in patients with preexisting kidney impairment or other risk factors for kidney toxicity with cisplatin (see 'Risk factors for acute kidney injury' above). Consideration of dose reduction should be discussed with the patient's oncologist to determine if this approach may be appropriate without lowering the therapeutic efficacy of cisplatin. Doses of cisplatin are generally not lowered in settings in which cure is the goal of therapy (eg, small cell lung and testicular germ cell tumors).

Use of cisplatin analogs — The less nephrotoxic analog carboplatin has been substituted for cisplatin in many chemotherapy regimens (eg, ovarian cancer, non-small cell lung cancer). The relative activity of cisplatin and carboplatin in different diseases needs to be considered in determining whether this is a feasible approach. (See "First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tube, and peritoneal cancer" and "Subsequent line therapy in non-small cell lung cancer lacking a driver mutation".)

Unclear role for mannitol — Mannitol has been used to induce diuresis in patients treated with cisplatin. However, we do not routinely use mannitol to prevent nephrotoxicity in patients receiving cisplatin, given the lack of clear evidence of benefit. It may be appropriate in select patients, such as those treated with high-dose cisplatin (≥100 mg/m²) and/or those with preexisting hypertension [74].

Data evaluating the benefits of mannitol are conflicting. As examples:

●In a phase II trial that randomly assigned 48 patients with various solid cancers receiving cisplatin (plus two liters of prehydration) to mannitol (20 g) or placebo, there was no significant difference between the groups in the rates of acute kidney injury (AKI; defined using Acute Kidney Injury Network [AKIN] criteria) at 48 hours (30 versus 40 percent, respectively) or seven days (75 versus 80 percent, respectively) after cisplatin [77]. However, compared with patients in the placebo group, fewer patients in the mannitol group had a 24-hour urine creatinine clearance <60 mL/min/1.73 m² at day 7 (5 versus 36 percent). Univariate analysis suggested that patients receiving >80 mg/m² of cisplatin gained the greatest benefit from mannitol.

●In a retrospective analysis of 1821 patients with various cancers who received cisplatin plus prehydration with or without mannitol (12.5 or 25 g), use of mannitol was associated with a lower risk of all-grade AKI (driven primarily by a reduction in grade 1 AKI) in patients with gynecologic, upper gastrointestinal, or urinary tract cancers or lymphoma but not in those with head and neck, lung, germ cell, or other cancers [78].

●In an observational study that evaluated the addition of mannitol (20 g) to standard saline hydration (1 to 2 liters) in 110 patients with cancer receiving cisplatin, 14 of the 63 patients (23 percent) who received mannitol plus saline hydration developed AKI (defined by an increase in serum creatinine >0.3 mg/dL) compared with 5 of 47 patients (10 percent) receiving saline hydration only [79]. An increase in serum creatinine >1.5 mg/dL was also more frequent in mannitol treated patients (10 versus 4 percent).

Approaches we do not use

●Amifostine – Amifostine, an organic thiophosphate, may protect against cisplatin-induced toxicity by donating a protective thiol group, an effect that is highly selective for normal, but not malignant, tissue [80].

We do not use amifostine to prevent cisplatin-induced nephrotoxicity. The principal reasons include the availability of newer regimens that use lower doses of cisplatin or substitute carboplatin for cisplatin and the significant toxicity (nausea, vomiting, hypotension) and costs associated with the administration of amifostine. Furthermore, concerns persist about possible interference with the antitumor efficacy of cisplatin. Amifostine should not be used in settings in which chemotherapy can produce a significant survival advantage or chance of cure.

Treatment with amifostine prior to cisplatin administration decreased nephrotoxicity in animal models and preliminary clinical studies [81]. A phase III trial in women with ovarian cancer found that amifostine reduced the incidence of nephrotoxicity (≥40 percent reduction in creatinine clearance) from 33 to 10 percent with six cycles of a chemotherapy regimen that included cisplatin (100 mg/m²) [46].

On the basis of these results, the 2002 guidelines from the American Society of Clinical Oncology stated that amifostine could be considered in patients receiving repeated administrations of cisplatin for ovarian or non-small cell lung cancer [82], a position that was reiterated in the updated 2008 guidelines, with no new data on which to base a change in the recommendation [83]. However, these studies used higher doses of cisplatin than are typical of contemporary regimens (which almost all use either a single bolus dose of 75 to 80 mg/m² or, in the setting of a germ cell tumor, a split dose of 20 mg/m² daily for five days), and there are no data supporting the use of amifostine in other settings. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors" and "Extensive-stage small cell lung cancer: Initial management".)

●Other chemoprotective agents – Several other approaches have been evaluated to prevent cisplatin-induced nephrotoxicity, including sodium thiosulfate [84,85], N-acetylcysteine [86], theophylline [87,88], glycine [89], peroxisome proliferator-activated receptor (PPAR)-alpha ligand [38], polymeric cisplatin nanoparticles [90], cell cycle inhibitors [91], and lithium [92]. However, none of these agents have an established role in patients being treated with cisplatin.

MONITORING FOR NEPHROTOXICITY — All patients who receive cisplatin therapy should be monitored for the development of nephrotoxicity. In general, patients should have monitoring of serum creatinine and electrolyte levels (including sodium, potassium, magnesium, and phosphorus) following treatment. A urinalysis should also be obtained periodically, especially if there is an increase in serum creatinine concentration. The frequency of monitoring may vary depending upon the clinical scenario and institutional practice. In patients with risk factors for cisplatin nephrotoxicity (see 'Risk factors for acute kidney injury' above), more frequent monitoring (ie, daily for the first few days after cisplatin administration) may be advisable.

MANAGEMENT OF NEPHROTOXICITY

Patients with acute kidney injury — The general approach to the management of acute kidney injury (AKI) after cisplatin administration is the same as that for other causes of AKI. These issues are discussed separately. (See "Overview of the management of acute kidney injury (AKI) in adults".)

Cisplatin discontinuation is appropriate in patients who develop AKI, particularly those with moderate to severe AKI (increase in serum creatinine to >2.0 times baseline). If the inclusion of cisplatin in the treatment regimen is considered to be life-saving or life-extending, retreatment with cisplatin may be considered after recovery from AKI.

Patients with electrolyte disturbances — In general, patients with electrolyte disturbances after cisplatin administration are treated with appropriate supplementation. Discontinuation of cisplatin is not required in this setting, especially if the patient's cancer is being effectively treated with cisplatin or treatment with cisplatin is potentially life-saving or life-extending. However, discontinuation of cisplatin may be necessary if the patient has concurrent AKI or if the electrolyte disturbances are difficult to manage even with aggressive supplementation:

●Hypomagnesemia – Treatment of hypomagnesemia generally consists of magnesium supplementation. High doses may be required since raising the plasma magnesium concentration will increase the degree of urinary magnesium wasting. In patients with refractory hypomagnesemia, the addition of a potassium-sparing diuretic such as amiloride may be of benefit, although there are no data to support its use in patients with cisplatin-mediated hypomagnesemia. The treatment of hypomagnesemia is discussed elsewhere [93]. (See "Hypomagnesemia: Evaluation and treatment".)

●Fanconi-like syndrome – Patients who develop proximal tubular dysfunction (Fanconi-like syndrome) after cisplatin administration should be managed with oral or intravenous (IV) supplementation depending upon the severity of the deficiency. Patients with evidence of a renal tubular acidosis should receive alkali therapy (eg, sodium bicarbonate, sodium citrate, potassium citrate) to correct their metabolic acidosis.

•(See "Hypophosphatemia: Evaluation and treatment".)

•(See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)

•(See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) renal tubular acidosis'.)

●Salt wasting – Patients with renal salt wasting following cisplatin should be acutely treated with IV saline to correct volume depletion and hyponatremia if present. Salt tablets can be administered once the patient is volume repleted and should be dose titrated to symptoms and blood pressure to avoid symptomatic hypotension and hypovolemic hyponatremia.

Patients with thrombotic microangiopathy — The specific treatment of thrombotic microangiopathy resulting from cisplatin and other chemotherapeutic agents is discussed separately. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Management'.)

PROGNOSIS — Long-term follow-up of patients exposed to cisplatin indicates that kidney function either remains stable or improves over time in patients with a glomerular filtration rate (GFR) >60 mL/min/1.73 m² at the end of therapy [94,95]. Whether such improvement reflects an increase in the number of functioning nephrons or hypertrophy of nephrons that remained relatively intact is unclear [96,97].

The largest study to evaluate long-term kidney outcomes included 821 adults who received cisplatin for treatment (cumulative dose range ≤100 to >701 mg/m²) across multiple tumor types and survived for at least five years after the initial dose [54]. At baseline, 32 percent of patients had stage 1 chronic kidney disease (CKD), 58 percent had stage 2 CKD, 11 percent had stage 3 CKD, and none had an estimated GFR (eGFR) <29 mL/min/1.73 m². Over a median of six years, acute kidney injury (AKI; defined as an increase in serum creatinine of ≥25 percent from baseline) occurred in 31 percent of patients. The following observations were noted:

●At the completion of cisplatin therapy, 17 percent had stage 1 CKD, 52 percent had stage 2 CKD, 29 percent had stage 3 CKD, and 2 percent had an eGFR <29 mL/min/1.73 m². Progression to a higher stage of CKD occurred in 64 percent of patients with stage 1 CKD, 33 percent of those with stage 2 CKD, and 6 percent of those with stage 3 CKD at baseline.

●At year 5 after the first cycle of cisplatin therapy, 11 percent had stage 1 CKD, 57 percent had stage 2 CKD, 30 percent had stage 3 CKD, and 3 percent had an eGFR <29 mL/min/1.73 m². Between years 1 and 5, progression to a higher stage of CKD occurred in 74 percent of patients with stage 1 CKD, 22 percent of those with stage 2 CKD, and 6 percent of those with stage 3 CKD.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY AND RECOMMENDATIONS

●General principles – Cisplatin is a potent anticancer agent usually administered in combination with other chemotherapy agents to treat a broad spectrum of malignancies. Cisplatin-induced nephrotoxicity is a dose-limiting side effect, which most commonly is manifested by acute and chronic impairment of kidney function. (See 'Introduction' above.)

●Pathogenesis – Multiple mechanisms contribute to kidney dysfunction following cisplatin administration. Exposure of tubular cells to cisplatin activates complex signaling pathways that result in tubular cell injury and cell death. A robust inflammatory response, as well as injury to the renal vasculature, results in vasoconstriction, reduced blood flow, and ischemic injury. Collectively, these changes lead to acute kidney injury (AKI). (See 'Pathogenesis' above.)

●Clinical presentations – The most important clinical manifestation of cisplatin nephrotoxicity is kidney injury, which may be acute or chronic. Other kidney manifestations have been described, including electrolyte disturbances, thrombotic microangiopathy, and anemia. (See 'Clinical presentations' above.)

●Prevention of nephrotoxicity – A number of measures are potentially useful to prevent acute cisplatin nephrotoxicity and chronic kidney disease (CKD):

•Intravenous saline – Intravenous (IV) isotonic saline is generally administered to all patients before and after cisplatin therapy to induce a diuresis. The optimal IV solution and regimen is unclear. We suggest a solution consisting of isotonic saline plus potassium chloride and magnesium sulfate rather than isotonic saline alone or isotonic saline with only potassium chloride (Grade 2C). (See 'Intravenous saline' above.)

•Avoiding nephrotoxins – In patients receiving cisplatin, we discontinue medications that may increase the risk for cisplatin nephrotoxicity, including nonsteroidal antiinflammatory drugs, aminoglycosides, and amphotericin B. We also try to limit exposure to intravascular iodinated contrast unless it is required for an emergency or life-saving procedure. (See 'Avoidance of potential nephrotoxins' above.)

•Lower doses of cisplatin – Lower doses of cisplatin may help to prevent cisplatin nephrotoxicity, particularly in patients with preexisting kidney impairment or other risk factors for kidney toxicity with cisplatin. Consideration of dose reduction should be discussed with the patient's oncologist to determine if this approach may be appropriate without lowering the therapeutic efficacy of cisplatin. (See 'Lower doses of cisplatin' above and 'Use of cisplatin analogs' above.)

●Monitoring for nephrotoxicity – All patients who receive cisplatin therapy should be monitored for the development of nephrotoxicity. In general, patients should have monitoring of serum creatinine and electrolyte levels (including sodium, potassium, magnesium, and phosphorus) following treatment. A urinalysis should also be obtained periodically, especially if there is an increase in serum creatinine concentration. The frequency of monitoring may vary depending upon the clinical scenario and institutional practice. (See 'Monitoring for nephrotoxicity' above.)

●Management of nephrotoxicity – Discontinuation of cisplatin is appropriate in patients who develop AKI, particularly those with moderate to severe AKI. In general, patients with electrolyte disturbances after cisplatin administration are treated with appropriate supplementation. Discontinuation of cisplatin is not required in this setting, especially if the patient's cancer is being effectively treated with cisplatin or treatment with cisplatin is potentially life-saving or life-extending. However, discontinuation of cisplatin may be necessary if the patient has concurrent AKI or if the electrolyte disturbances are difficult to manage even with aggressive supplementation. (See 'Management of nephrotoxicity' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Richard T Penson, MD, MRCP, and Melissa L Shannon, MD, who contributed to an earlier version of this topic review.