brief review of chemotherapeutic agents and renal failure

A Brief Review of Chemotherapeutic Agents and Renal Failure

Nephrology Grand Rounds

2-2-2010

Dr. Lakshmi A Turlapati

Introduction

Renal failure in a cancer patient can be multifactorial. Prerenal Intrinsic Postrenal

Chemotherapeutic Agents

Cancer Chemotherapeutic agents can cause nephrotoxicity in various ways.

Some drugs are known to be more nephrotoxic than others.

Some cause immediate effects while some are known to cause appreciable renal toxicity only when used for a long time.


Glomerulus VEGF inhibitors, Nitrosoureas, Interferons

Tubules Cisplatin, Carboplatin, Ifosfamide, Cyclophosphamide, Streptozocin, Nitrosoureas, Methotrexate

Interstitium Cisplatin, Carboplatin

Renal microvasculature VEGF inhibitors, Mitomycin, Gemcitabine


Risk Factors Chronic kidney disease Concomitant use of other nephrotoxic drugs. Dehydration secondary to nausea/vomiting Intrinsic kidney disease secondary to cancer.


Platinum compounds- Cisplatin, Carboplatin Alkylating Agents- Cyclophosphamide,

Ifosfamide Nitrosoureas Antitumor antibiotics- Mitomycin C Antimetabolites- Methotrexate, Gemcitabine VEGF pathway inhibitors EGFR Pathway inhibitors Interferons

Cisplatin

One of the most widely used and most nephrotoxic chemotherapeutic agents.

Non-cell cycle specific, alkylating agent. Used for lymphoma, testicular carcinoma,

bladder, gastric, head and neck, non-small cell lung, ovarian, and small cell lung cancers.

Cisplatin

In the blood, cisplatin is present in an inactive, uncharged state due to the high concentration of chloride ions.

Cisplatin enters cells by passive diffusion. Intracellularly, cisplatin loses its two chloride groups

and becomes a positively charged electrophilic compound.

Cisplatin then binds with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links that cause changes in the conformation of the DNA and affects DNA replication.

Cisplatin

Cisplatin is renally excreted. Concentration of platinum achieved in renal cortex is

several folds greater than plasma and other organs. Organic cationic transporters have been implicated in

cisplatin uptake in renal tubular cells. Primarily injures the S3 segment of the proximal

tubule. Tubular injury also stimulate inflammatory response

causing further damage. Also induces vasoconstriction in the renal vasculature

thus reducing renal blood flow and causing ischemic injury.

Risk Factors

Higher doses Previous cisplatin therapy Underlying kidney dysfunction Older age Female gender Smoking Hypoalbuminemia Paclitaxel co-administration

British Journal of Cancer (2003) 88, 1199 – 1206

Clinical Features

Clinically, Nephrotoxicity is seen usually within 10 days of Cisplatin administration.

It is usually dose dependent. It is manifested by acute renal failure,

hypokalemia , hypomagnesemia and Fanconi like syndrome.

Hypomagnesemia may exacerbate Cisplatin toxicity.

Clinical Features

UOP typically remains above 1 liter/day (unless renal dysfunction is severe) due to induction of a concentrating defect, due to platinum induced damage to the loop of henle or decrease in aquaporin water channels in collecting tubules.

It is also believed that cisplatin treatment may lead to long term reduction in GFR as well.

Strategies for prevention

Lower doses of cisplatin Administration of intravenous saline. Sodium thiosulphate- binds to cisplatin and render it non-toxic.

Used in setting of IP cisplatin. Amifostine: an organic thiophosphate, donates a thiol group

selectively in normal tissues and not in malignant tissues, to bind to cisplatin. Major concerns are cost and possible interference with tumor efficacy.

Cimetidine-inhibitor of OCTs- could be used to decrease uptake.Imatinib, an anti-cancer agents also decreases uptake by affecting OCTs.

Antioxidants have been tried-unclear benefit. Other agents that have been explored include N-acetylcysteine,

theophylline,glycine,PPAR agonists,coreg etc.

Carboplatin

Used for lung,ovarian,head and neck cancer. Anti tumor activity is alkylation of DNA

followed by killing of cancerous cells. Believed to be safer than cisplatin. This increase in safety is likely from

enhanced stability of carboplatin which has carboxylate and cyclobutane moieties in the cis position, rather than choride.

However acute renal failure has been reported with carboplatin.

Carboplatin

A case report describes 2 patients with carboplatin toxicity developing acute renal failure.

Biopsy specimens showed focal and moderate interstitial nephritis with periglomerular fibrosis in one specimen and edematous interstitium with diffuse mononuclear infiltrate and toxic changes in tubules in the other.

Renal function improved with prednisone treatment @1 mg/kg/day for 4 weeks.

The American Journal of MedicineVolume 90, Issue 1, January 1991, Pages 386-391

Carboplatin

Decrease in GFR has been noted in children after treatment with carboplatin.

Direct tubular injury seems to be the mechanism and is dose dependent.

Hypomagnesemia is a more common side effect.

Renal salt wasting has also been reported. Careful monitoring of renal function is

warranted.

References 14,15,16

Cyclophosphamide

Cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as to inhibition of protein synthesis.

Used for hematologic malignancies. Major toxicity of cyclophosphamide is hemorrhagic cystitis. One of the metabolites acrolein causes cystitis. Mesna and IV hydration are mainly used for prevention. IV hydration induces brisk diuresis and prevents accumulation

of acrolein in the urinary bladder and collecting system. Mesna contains a sulfhydryl group that binds acrolein and

detoxifies it.

J Clin Oncol 9:2016-2020.

Cyclophosphamide

Hyponatremia has also been reported. Mechanism could be increased ADH or amplifications

of the renal effects of ADH or a direct effect on the kidney resulting in enhanced permeability of distal tubules to water.

Water retention is usually acute and resolves within 24 hrs of withdrawal of drug.

Hypotonic solutions should be avoided while giving cyclophosphamide to prevent severe hyponatremia.

Arch Intern Med 1985;145:548-549

Cyclophosphamide

In experimental animals, cyclophosphamide can cause nephrotoxicity similar to acute tubular necrosis.

Rare in humans.

Ifosfamide

Synthetic analog of cyclophosphamide. Nephrotoxicity is more prominent feature

especially when given along with other nephrotoxic agents like Cisplatin.

Usually used in children for Osteosarcoma, Ewing’s Sarcoma, Germ cell tumors, Lymphoma, Neuroblastoma etc.

Ifosfamide

Proximal tubular dysfunction is the most common presentation which could lead to Fanconi’s syndrome, hypophosphatemic rickets and proximal renal tubular acidosis.

Usually acute and reversible. Chronic progressive toxicity has been

reported and long term evaluation in children is needed.

Mesna can be given for prevention.

References 19,20

Nitrosoureas

Carmustine, Semustine, Lomustine and Streptozocin.

Used for malignant brain tumors,melanomas. They induce chronic interstitial nephritis

which is slowly progressive and irreversible. Glomerular sclerosis and interstitial fibrosis

has been seen. Exact mechanism is unknown but may be due

to alkylation of tubular proteins.

Nitrosoureas

Of the four agents, Semustine and Streptozocin are more nephrotoxic.

Mild proteinuria or an asymptomatic elevation of creatinine is usually the first sign of renal involvement.

Onset of clinical nephrotoxicity may be delayed up to months to years after last dose.

Careful follow up is essential. No known therapy.

Mitomycin C

Used for pancreatic and gastric cancers. Most common form of nephrotoxicity is renal

failure and microangiopathic hemolytic anemia.

Most likely occurs after 6 months of therapy. Dose dependent. Incidence ranges from less than 2 to 15%.

Mitomycin C

It is believed that direct endothelial injury is the inciting event.

Few cases have shown glomerular nuclear degeneration, sclerosis and thickened basement membranes but most have fibrin deposition in the small renal arterioles.

Cancer treatment Reviews(1982)9,37-56

Mitomycin C

Clinical Features include slowly progressive renal failure and hypertension.

Patients may have bland urine sediment or may present with hematuria and proteinuria.

Non-cardiogenic pulmonary edema may be seen.

Renal failure may respond to plasmapheresis or immunoabsorption of serum on staphylococcal protein A column.

Journal of Clinical Oncology, Vol 7, 781-789 Nephron. 1989;51(3):409-12

Methotrexate

Used for leukemias, head and neck cancer, lung cancer, breast cancer, lymphoma.

At low doses it is not usually associated with renal toxicity but may be seen.

However with high doses, nephrotoxicity can occur significantly- 60% in one report.

Methotrexate

Methotrexate is renally excreted. At lower pH, it precipitates and causes

tubular injury. Pts who are dehydrated and excrete acidic

urine are especially at risk. Extensive necrosis of the epithelium of the

convuluted tubules has been seen. Hence IV hydration and urinary alkalinizations

are mainstays in prevention.

References 2,24

Gemcitabine

Used for pancreatic tumors, metastatic breast cancer, non-small cell lung cancer,ovarian cancer.

Renal failure and microagiopathic hemolytic anemia has been associated.

Incidence lesser than mitomycin C. Approximately 0.008%-0.078% .

Interval from the last dose of gemcitabine to development of HUS ranged from 1 day to several months.

AJKD Volume 40, Issue 4 (October 2002)

Gemcitabine

Association with cumulative dose is less clear cut than Mitomycin C.

High index of suspicion is needed. Withdrawal of drug, steroids and

plasmapheresis have been tried with variable response.

Case fatality is high- 50-70%.

AJKD Volume 40, Issue 4 (October 2002)

VEGF Pathway Inhibitors

Bevacizumab Monoclonal antibody that binds circulating

VEGF and prevents activation of VEGF receptor.

Used for metastatic colorectal cancer, metastatic breast cancer, metastatic renal cell cancer, non-small cell lung cancer, glioblastoma


Sunitinib, Sorefenib Small molecule tyrosine kinase inhibitors that

block the intracellular domain of the VEGF receptor.

Used for advanced renal cell carcinoma and gastrointestinal stromal tumors.

VEGF in Normal Kidney

VEGF is an endothelial-specific growth factor that promotes endothelial cell proliferation,differentiation and survival.

In the kidney, VEGF receptors are located on preglomerular,glomerular and peritubular endothelial cells.

VEGF is required for growth and proliferation of glomerular and peritubular endothelial cells.


VEGF may be an essential mediator of glomerular recovery in proliferative glomerulonephritis.

Loss of VEGF is associated with the development of glomerulosclerosis and tubulointerstitial fibrosis.

VEGF inhibition is believed to suppress nephrin affecting integrity of glomerular slit membrane causing proteinuria.


Proteinuria and hypertension are major side effects.

Incidence of Hypertension ranges from 2.7 to 35.9%.

Incidence of mild and asymptomatic proteinuria may range from 21% in colorectal cancer pts to 63% in renal cell cancer pts.

Heavy proteinuria up to >3.5 g/day is seen in 6.5% of renal cell carcinoma pts.

EUROPEAN JOURNAL OF CANCER 4 6 ( 2 0 1 0 ) 4 3 9 –4 4 8


Renal pathological findings in cases of heavy proteinuria include 12 cases of thrombotic microangiopathy, 2 cases of collapsing glomerulopathy, one case of cryoglobulinemic glomerulonephritis, one case of immune complex associated focal proliferative glomerulonephritis and sorafenib-induced acute interstitial nephritis.

References 26,27


Though Biopsies have shown TMA, clinical features may range from proteinuria, hematuria, renal insufficiency to microangiopathic hemolytic anemia.

However extrarenal manifestations of TMA are very rare.


Management is conservative . Antihypertensive agents are used to control

BP. ACE/ARBs are used to minimize proteinuria

but may not work. Proteinuria usually responds to withdrawal of

drug. Occasionally it may lead to progressive renal

failure.

Ann Oncol 18: 1745-1747


Role of Plasma Exchange One case of Bevacizumab associated TMA which

resolved once with discontinuation of drug and subsequently had relapse when was treated again with sunitinib responded to discontinuation of treatment and plasma exchange.

Another case of TMA responded to drug withdrawal, anti Hypertensive agents, steriods and plasma exchange.

However, role of plasma exchange still needs to be evaluated.

EGFR pathway inhibitors

Cetuximab, Panitumumab,Matuzumab Monoclonal antibodies targeting the

epidermal growth factor receptor Progressive development of

hypomagnesemia due to magnesium wasting in the urine.

Interferons

Interferon alpha can cause proteinuria, which can be nephrotic range- histology could be minimal change or FSGS.

Interferon gamma has been associated with Acute tubular necrosis.

AJKD Vol 28, Issue 6, December 1996, Pages 888-892

Summary

Always look at the chemotherapy drugs which the patient has been on currently and in past when evaluating renal failure.

Some drugs can cause progressive renal failure/ HUS months after their last dose. ( like nitrosoureas, mitomycin, gemcitabine)

Some drugs though known to be safe may cause renal failure, like carboplatin. So have low threshold.

VEGF inhibitors may have TMA like pathology with minimal findings- only proteinuria without hemolytic anemia, low platelets, schistocytes etc. Consider biopsy.

References 1: Renal Failure Associated with Cancer and Its Treatment:An Update -56 J Am Soc Nephrol 16: 151–161, 2005 2: The Renal toxicity of cancer chemotherapeutic agents. Cancer treatment reviews(1982)9,37-56 3:Cisplatin nephrotoxicity: Mechanisms and Reno protective strategies. Kidney International (2008) 73, 994–1007 4 Mechanism of cisplatin nephrotoxicity. Fed Proc. 1983 Oct;42(13):2974-8 5: Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat J. A. Winston and R. Safirstein Am J Physiol

Renal Physiol 249: F490-F496, 1985 6: Cisplatin Decreases the Abundance of Aquaporin Water Channels in Rat Kidney. J Am Soc Nephrol 12: 875–882, 2001 7: Long-Term Renal Effect of Cisplatin in Man Am J Nephrol 1994;14:81-84 8: Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. British

Journal of Cancer (2003) 88, 1199 – 1206 9:Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol. 1999

Apr;26(2 Suppl 7):72-81. 10: Protective effect of concomitant administration of imatinib on cisplatin-inducednephrotoxicity focusing on renal organic cation

transporter OCT2. Biochemical Pharmacology 78 (2009) 1263–1271 11: Carvedilol protects against the renal mitochondrial toxicity induced by cisplatin in rats. Mitochondrion 10 (2010) 46–53

12: Agents ameliorating or augmenting the nephrotoxicity of cisplatinand other platinum compounds: A review of some recent research. Food and Chemical Toxicology 44 (2006) 1173–1183

13: Acute renal failure associated with the use of intraperitoneal carboplatin: A report of two cases and review of the literature. The American Journal of MedicineVolume 90, Issue 1, January 1991, Pages 386-391

14: Time response of carboplatin-induced nephrotoxicity in rats.Pharmacological Research 50 (2004) 291–300 15: Dose-related nephrotoxicity of carboplatin in children. British Journal of Cancer (1999) 81(2), 336–341

References 16: Recurrent renal salt wasting in a child treated with carboplatin and etoposide. Volume 73 Issue 6, Pages 1761 - 1763 17: Water Intoxication Following Moderate-Dose Intravenous Cyclophosphamide.Robert B. Bressler, MD, David P. Huston, MD.

Arch Intern Med 1985;145:548-549 18: Mesna Versus Hyperhydration for the Prevention of Cyclophosphamide-Induced Hemorrhagic Cystitis in Bone Marrow

Transplantation. J Clin Oncol 9:2016-2020. © 1991 by American Society of Clinical Oncology 19 Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol. 2003 Sep;41(3):190-7. 20: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol. 2009 Nov 10;27(32):5350-5. Epub 2009

Oct 13. 21: Nephrotoxicity of Nitroso ureas Cancer 48:1328-1334, 1981 22: Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry. Journal of Clinical Oncology,

Vol 7, 781-789. 23: Successful treatment of mitomycin C-associated hemolytic uremic syndrome by plasmapheresis. Nephron. 1989;51(3):409-12 24: Renal toxicity of methotrexate. PT Condit, RE Chanes - Cancer, 1969 25: Gemcitabine-associated hemolytic-uremic syndrome. American Journal of Kidney Diseases - Volume 40, Issue 4 (October

2002 26: VEGF signalling inhibition-induced proteinuria: Mechanisms,significance and management. EUROPEAN JOURNAL OF

CANCER 4 6 ( 2 0 1 0 ) 4 3 9 –4 4 8 27: Nephrotic Syndrome After Bevacizumab: Case Report and Literature Review American Journal of Kidney Diseases, Vol 49,

No 2 (February), 2007: E23-E29 28: Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome E.

Kapiteijn , A. Brand , J. Kroep , and H. GelderblomAnn Oncol 18: 1745-1747

29: Guidelines for the management of side effects of bevacizumab in patients with colorectal cancer Cancer Therapy Vol 6, 327-340, 2008

30: Progressive bevacizumab-associated renal thrombotic Microangiopathy. NDT Plus (2009) 2: 36–39 31: Focal segmental glomerulosclerosis with acute renal failure associated with α-interferon therapy American Journal of Kidney

Diseases Volume 28, Issue 6, December 1996, Pages 888-892

brief review of chemotherapeutic agents and renal failure

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