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An introduction to chemotherapy-associated nephrotoxicity.

With advances in therapy, patients with cancer are surviving longer. This aging population includes patients who have or are at risk of developing chronic kidney disease (CKD), either due to their cancer or treatments that have kidney-related complications. Unsurprisingly, there is a growing interest in understanding the relationship between oncology and nephrology, and a new field of onco-nephrology has emerged (Berns & Rosner, 2012; Kintzel, 2001). Thus, there is growing importance to understand how antineoplastic agents can affect the kidneys, and when and how antineoplastic drug doses may need to be reduced or discontinued.

Risk factors that can potentiate or contribute to antineoplastic-related renal dysfunction are related to both drug- and patient-specific factors (Merchan, Drews, & Savarese, 2015; Shirali & Perazella, 2014). Examples of drug-specific factors include their cytotoxic effect on cells, mechanisms of clearance, and concomitant use with other non-chemotherapeutic nephrotoxic agents. Examples of patient-specific factors may include intravascular volume depletion, comorbid conditions (e.g., congestive heart failure), and urinary tract obstruction due to an underlying tumour.

Many antineoplastic drugs used to treat malignant diseases can cause renal disease, which can range from a subtle injury (e.g., electrolyte imbalance) to acute renal failure requiring dialysis. The inherent nephrotoxicity of certain antineoplastic drugs is problematic since renal dysfunction can hinder continued anti-cancer treatment and impede use of supportive medications and measures (Kintzel, 2001). In addition, the kidneys are a major elimination pathway for many antineoplastic agents, and renal dysfunction can delay excretion resulting in increased systemic toxicity. Therefore, it is important to recognize when dose adjustments are required for antineoplastic medications in order to limit exacerbating renal dysfunction and adverse effects from drug accumulation (Kintzel, 2001).

This article will review our understanding of common nephrotoxic chemotherapeutic agents, and highlight therapies with potential renal implications for a variety of targeted pathways. Table 1 lists the Health Canada approved indications for these agents, whereas Table 2 summarizes their associated nephrotoxicity, the dose adjustments required, and monitoring parameters.

STANDARD CHEMOTHERAPY

Many standard chemotherapy agents inherently cause nephrotoxicity (Table 3). Commonly used standard chemotherapies such as Cisplatin and Methotrexate have been well studied, and will be discussed in detail.

Cisplatin

Cisplatin is a platinum compound that inhibits DNA synthesis through formation of DNA cross-links. It is used to treat a broad spectrum of malignancies (Table 1).

Dose-related nephrotoxicity is one of its major adverse effects, occurring in about one-third of patients (Pabla & Dong, 2008). Onset of renal toxicity usually occurs three to 10 days after administration (Lameire, Kruse, & Rottey, 2011; Safirstein, 2007). Cisplatin has several mechanisms of nephrotoxicity such as vascular injury and an inflammatory response. However, the most common mechanism is injury and death of renal tubular cells exposed to the drug (Pabla & Dong, 2008). Uptake of Cisplatin in renal tubular cells is via the basolateral organic cation transporters (OCT) (Pabla & Dong, 2008), more specifically OCT2 (Ciarimboli et al., 2005). Once inside, Cisplatin can cause intracellular injury through a number of pathways, which can ultimately cause an increase in serum creatinine and lead to acute kidney injury (AKI) (Perazella, 2012). Saline hydration is usually given to prevent nephrotoxicity; however, the mechanism of protection is not known (Safirstein, 2007). Cisplatin can also cause a number of electrolyte disorders including hypomagnesemia, which has been reported to affect as many as 90% of patients (Lajer & Daugaard, 1999). Hypomagnesemia can also increase in severity with subsequent treatment courses (Cancer Care Ontario, 2015). Intravenous magnesium can be co-administered to prevent complications of hypomagnesemia. Patients receiving Cisplatin should have their serum creatinine and magnesium monitored.

Methotrexate

Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, ultimately inhibiting DNA synthesis, repair, and cellular replication. Although infrequent and often reversible, Methotrexate-induced nephrotoxicity can occur with high-dose Methotrexate therapy (1 to 15 g/[m.sup.2]) (Merchan et al., 2015; Schmiegelow, 2009; Widemann & Adamson, 2006). Nephrotoxicity is usually due to a phenomenon called crystal nephropathy, which occurs when Methotrexate precipitates in the renal tubules (Bleyer, 1978; Schmiegelow, 2009) causing tubular obstruction (Lameire et al., 2011). Precipitation occurs when urine pH is acidic. An increase of urine pH from 6 to 7 results in a 5-8 fold increase in Methotrexate solubility (Widemann & Adamson, 2006).

Risk factors for nephrotoxicity include intravascular volume depletion, acid urine pH, and underlying kidney disease (Perazella, 2012). Thus, prevention is geared towards maintaining adequate urinary output and urinary alkalinisation (pH greater than 7.1) (Perazella, 2012) in order to reduce the risk of Methotrexate precipitation. This can often be achieved by giving intravenous (IV) hydration along with sodium bicarbonate before Methotrexate (Lameire et al., 2011; Widemann & Adamson, 2006). As well, Leucovorin (a Methotrexate rescue agent) is routinely given with high dose Methotrexate to replenish folic acid and reduce Methotrexate-associated toxicities, including nephrotoxicity. Monitoring of patients receiving high dose Methotrexate should include serum creatinine and Methotrexate levels.

TARGETED CHEMOTHERAPY

The next evolution of antineoplastic agents has been targeted therapies, which exert their anticancer effect by interfering with molecules involved in tumour growth and progression. It is important that clinicians understand the potential nephrotoxicity of these newer agents, and recognize that our knowledge of these agents is continually evolving.

Bevacizumab

Tumour growth is highly dependent on angiogenesis, which is the process of creating new vasculature. Vascular endothelial growth factors (VEGF) are a key regulator of this pathway, and many agents target VEGF, as their anti-tumour mechanism of action. In the kidney, VEGF is produced by glomerular podocytes and tubular epithelial cells, and bind to VEGF receptors found on mesangium, glomerular, and peritubular capillaries (Gurevich & Perazella, 2009). Bevacizumab is a humanized monoclonal antibody that prevents VEGF from binding to its receptor. Unsurprisingly, it has kidney-related adverse effects (Eremina et al., 2008). The most common renal effects are proteinuria and hypertension, at 38% and 35%, respectively (Cancer Care Ontario, 2014a).

Eremina and colleagues (2008) reported six cases where patients on Bevacizumab developed proteinuria and thrombotic microangiopathy localized in the kidney. In their study, the authors postulated that the loss of VEGF inside the glomerulus leads to a loss of healthy fenestrated phenotypes and promotes the development of microvascular injury and thrombotic microangiopathy. This conclusion was supported by their animal experiments, where they removed the VEGF-producing podocytes in adult mice, which resulted in profound thrombotic glomerular injury. In most of the patient cases, renal function either stabilized or returned to normal, and proteinuria resolved after discontinuation of the agent (Gurevich & Perazella, 2009).

No guidelines currently are available on the treatment of proteinuria secondary to toxic effects from targeted therapies. The product monograph recommends holding Bevacizumab if proteinuria is equal to or greater than two grams in 24 hours, and to stop if nephrotic syndrome develops or the proteinuria of equal to or greater than two grams in 24 hours does not completely resolve (Cancer Care Ontario, 2014a). Antihypertensives should be used to control any pre-existing hypertension before therapy is initiated (Porta, Cosmai, Gallieni, Pedrazzoli, & Malberti, 2015), and Bevacizumab should be held if uncontrolled hypertension develops (Cancer Care Ontario, 2014a).

Cetuximab and Panitumumab

Cetuximab and Panitumumab are both monoclonal antibodies that are used in the treatment of colorectal cancer and competitively inhibit epidermal growth factor receptor (EGFR). Hypomagnesemia is a relatively common side effect for both Cetuximab and Panitumumab (Saif, 2008); their product monographs cite incidences of 43% and 39%, respectively (Cancer Care Ontario, 2014b, 2014c). It is thought that reabsorption of magnesium in the distal convoluted tube is, in part, dependent on EGFR activation, and that blocking EGFR likely impairs the active transport of magnesium from the urinary space back into the cells (Perazella, 2012; Saif, 2008). Magnesium should always be monitored, and management of hypomagnesemia depends on the severity but usually involves IV replacement (Perazella, 2012; Saif, 2008).

Crizotinib

Crizotinib is an oral small molecule inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. ALK gene rearrangements are found in non-small cell lung cancers (NSCLC). No renal side effects were reported in the initial phase one clinical trial, although adverse events in at least 10% of the safety population were reported (Camidge et al., 2012). Among the two largest clinical trials, 2% of patients had treatment-related renal cysts (Schnell et al., 2015). The mechanism of cyst development is unknown. Some cases have shown cysts regressing after the discontinuation of Crizotinib (Lin et al., 2014). In another case, a patient who was asymptomatic to the cysts eventually spontaneously regressed with no Crizotinib cessation required (Klempner & Aubin, 2014).

A number of case reports have emerged regarding Crizotinib and increased serum creatinine (Gastaud et al., 2013; Martorell, Alvaro, Salguero, & Molla, 2014). In both cases, serum creatinine improved with Crizotinib cessation, though not always returning to baseline. Brosnan and colleagues (2014) retrospectively assessed a cohort of patients and calculated their estimated glomerular filtration rate (eGFR) for the first 12 weeks of Crizotinib therapy and after Crizotinib but before the introduction of any further systemic therapy (Brosnan et al., 2014). Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, they found an average decrease of 23.9% in eGFR during the first 12 weeks of treatment (N=38), and where data were available (N=16), a recovery by all participants to at least 84% of the baseline eGFR after Crizotinib cessation.

Vemurafenib

Vemurafenib is an oral small molecule inhibitor of the BRAF kinase, and is used to treat cancers such as melanoma caused by the BRAF (V600E) mutation. Launay-Vacher et al. (2014) reported a case series of eight patients who experienced severe renal impairment with Vemurafenib treatment. All patients experienced some degree of decreased eGFR, with five of eight improving or recovering with Vemurafenib discontinuation. In one patient, acute tubular necrosis was seen on renal biopsy.

There is one published case report of a patient undergoing dialysis who initially developed a prolonged QTc, which persisted despite a subsequent dose reduction (Iddawela et al., 2013).

As QTc prolongation is a common side effect of Vemurafenib, this case report shows one instance of safe use of Vemurafenib in chronic renal failure, but demonstrates the importance of careful ECG monitoring required in this patient population.

CONCLUSIONS

Chemotherapy has improved survival for patients with cancer, and the field of oncology is continuing to advance with newer agents and treatment pathways. Most kidney effects are recognized after these agents are introduced into clinical practice and are described in case reports and series, therefore, all health care providers should have increased awareness and vigilance on how these agents can impact the kidneys (Perazella & Izzedine, 2015).

As well, clinicians should be able to provide preventative measures, when possible, and know how to monitor for signs and symptoms of nephrotoxicity. As the field of onco-nephrology continues to grow, patient care providers must work together to ensure proper management of patients with cancer and kidney concerns.

CONTINUING EDUCATION STUDY QUESTIONS

1. Which of the following drug-specific factors can contribute to renal dysfunction?

a) cytotoxic effect on cells

b) mechanisms of clearance

c) concomitant use with other nephrotoxic drugs

d) all of the above

2. Which of the following is a reason why kidney dysfunction during anticancer treatment is problematic?

a) hinders giving treatment

b) impedes giving supportive medications

c) delays excretion of treatment resulting in potentially increased toxicity

d) all of the above

3. What is the incidence of Cisplatin dose-related nephrotoxicity?

a) 20%

b) 30%

c) 40%

d) 50%

4. What is Cisplatin's main mechanism of nephrotoxicity?

a) crystal nephropathy

b) injury and death of renal tubular cells

c) renal vascular damage

d) inflammation

5. Which of the following is not part of reducing the risk of Methotrexate-induced nephrotoxicity?

a) IV hydration

b) sodium bicarbonate

c) ensuring urine pH > 7

d) magnesium replacement

6. High dose Methotrexate is often given with what agent to reduce Methotrexate-associated toxicities?

a) Lansoprazole

b) Leucovorin

c) Levemir

d) Levothyroxine

7. Which of the following are the two most common renal effects of Bevacizumab?

a) proteinuria and hypertension

b) UTI and hypertension

c) proteinuria and hyperkalemia

d) hyperkalemia and UTI

8. What is the main monitoring parameter for Cetuximab and Panitumumab?

a) hypermagnesia

b) hypomagnesia

c) hyperkalemia

d) dypokalemia

9. Which of the following targeted therapies does not have a Health Canada approved indication for treatment of colorectal cancer?

a) Bevacizumab

b) Cetuximab

c) Crizotinib

d) Panitumumab

10. Which of the following chemotherapy agents does not have a known nephrotoxicity risk?

a) Cyclophosphamide

b) Pemetrexed

c) Streptozocin

d) Temozolomide

[ILLUSTRATION OMITTED]

REFERENCES

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Camidge, D.R., Bang, Y.J., Kwak, E.L., Iafrate, A.J., Varella-Garcia, M., Fox, S.B., ... Shaw, A.T. (2012). Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. The Lancet Oncology, 13(10), 1011-1019. doi.org/10.1016/ S1470-2045(12)70344-3

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Iddawela, M., Crook, S., George, L., Lakkaraju, A., Nanayakkara, N., Hunt, R., & Adam, W.R. (2013). Safety and efficacy of vemurafenib in end stage renal failure. BMC Cancer, 13, 581. doi.org/10.1186/1471-2407-13-581

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Merchan, J.R., Drews, R.E., & Savarese, D.M. (2015). Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency. Retrieved from http://www.uptodate.com/ contents/chemotherapy-related-nephrotoxicity-and-dose-modification-in-patients-with-renal-insufficiency

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ABOUT THE AUTHORS

Ian Pang, BMSc, MSc, BScPhm, ACPR candidate, Leslie Dan Faculty of Pharmacy, University of Toronto, University Health Network, Toronto, ON

Karen Cameron, BScPhm, ACPR, CGP, Adjunct Lecturer, Leslie Dan Faculty of Pharmacy, University of Toronto, Education Coordinator, Department of Pharmacy, University Health Network, Toronto, ON

Marisa Battistella, BScPhm, PharmD, ACPR, Pharmacy Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Clinical PharmacistNephrology, University Health Network, Toronto, ON
Table 1: Health Canada-approved Oncological Indications

Drug                    Health Canada Approved
                        Cancer Indications
Standard Chemotherapy

Cisplatin               Bladder, ovarian, testicular
Methotrexate            Acute lymphocytic leukemia,
                        breast, bladder,
                        choriocarcinoma, gastric, head
                        and neck, non-Hodgkin's
                        lymphoma, metastasis of
                        unknown primary, osteogenic
                        sarcoma, leptomeningeal spread
                        of malignancies

Targeted Therapy

Bevacizumab             Colorectal, lung (NSCLC), brain
Cetuximab               Colorectal
Crizotinib              Lung (NSCLC)
Panitumumab             Colorectal
Vemurafenib             Melanoma

Note: Many of the agents above have numerous uses in
non-approved indications. This list is not meant to be
exhaustive. (Source: Cancer Care Ontario)

Table 2: Chemotherapeutic Agents Associated with Nephrotoxicity
and Management Indications

                                                     Dose Adjustment
                                                        in Renal
                                                       Impairment

               Potential                                 Mild to
               Renal                    Renal         Moderate CKD
Drug           Toxicity                 Excretion    (30/90 ml/min)

Standard Chemotherapy

Cisplatin      Tubular necrosis,        >90%        Yes
               tubular abnormalities,               46-60 ml/min--75%
               hypomagnesemia                       30-45 ml/min--50%

Methotrexate   Acute kidney injury,     80-90%      Yes
               crystal nephropathy                  (give high
                                                    dose only
                                                    if > 60
                                                    ml/min)
Targeted Therapy

Bevacizumab    Proteinuria,             No          No
               Hypertension,
               Thrombotic
               microangiopathy

Cetuximab      Hypomagnesemia           No          No

Crizotinib     Decreased eGFR,          22%         No
               renal cysts                          (when 30-60
                                                    ml/min use
                                                    with caution)

Panitumumab    Hypomagnesemia,          No          No
               other electrolyte
               disorders

Vemurafenib    AKI                      <1%         No data

                    Dose Adjustment in
                     Renal Impairment

               Severe CKD
Drug           (<30 ml/min)    Dialysis      Monitoring

Standard Chemotherapy

Cisplatin      Discontinue    Yes           Creatinine,
                                            magnesium

Methotrexate   Discontinue    Yes           Creatinine,
                                            Methotrexate

                                            level

Targeted Therapy

Bevacizumab    No data        No            Creatinine

Cetuximab      No data        No            Magnesium

Crizotinib     50% dose       No data       Creatinine

Panitumumab    No data        No data       Magnesium

Vemurafenib    No data        Possible      Creatinine
                              (?risk of
                              arrhythmia)

* Details regarding 'what to do' in the event of
chemotherapy-associated nephrotoxicity are purposefully not
included, as the clinicians must weigh the nephrotoxicity
against the patient's goal of therapy (e.g., if the
chemotherapy treatment is curative in intent).

Table 3: Standard Chemotherapies with Known Nephrotoxicity Risk

Carboplatin
Cisplatin
Cyclophosphamide
Gemcitabine
Methotrexate
Mitomycin
Nitrosureas
Pemetrexed
Streptozocin
Vinca alkaloids
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Title Annotation:CONTINUING EDUCATION SERIES
Author:Pang, Ian; Cameron, Karen; Battistella, Marisa
Publication:CANNT Journal
Article Type:Report
Geographic Code:1CONT
Date:Oct 1, 2015
Words:3313
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