Brief Review Of Chemotherapeutic Agents And Renal Failure

Brief review of chemotherapeutic agents and renal failure

Grand rounds

2-2-2010

Lakshmi Turlapati

Introduction

Renal failure in a cancer patient can be multifactorial.

The various causes could range from pre-renal secondary to intravascular volume depletion to post renal from tumor obstruction or intrinsic renal disease from cancer itself or from Chemotherapeutic agents.

Introduction

Today we will briefly review the renal failure caused by chemotherapeutic agents.

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 appreciable renal toxicity only when used for a long time.

They can affect glomerulus, tubules, interstitium or renal microvasculature

Glomerulus VEGF inhibitors, Nitrosoureas,Interferons

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

Interstitium Cisplatin, Carboplatin

Renal microvasculature VEGF inhibitors, Mitomycin,Gemcitabine

Chemotherapeutic agents

Chemotherapy agents can also cause increased systemic toxicity due to delayed drug excretion especially in pts with CKD.

Also Concomitant use of non-chemotherapy nephrotoxic drugs like NSAIDs, amino glycosides might increase the toxicity.

So renal function should be carefully re-assessed frequently and dosing adjusted as needed

Chemotherapeutic Agents

Platinum compounds- Cisplatin, Carboplatin Alkylating Agents- Cyclophosphamide, Ifosfamide Nitrosoureas Antitumor antibiotics- Mitomycin C Antimetabolites- Methotrexate, Gemcitabine Anthracyclines- Daunorubicin, Doxorubicin VEGF pathway inhibitors EGFR Pathway inhibitors Interferons

Cisplatin

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

Pathophysiology and molecular mechanisms of cisplatin toxicity has been extensively studied.

Pathophysiology

Exposure of tubular cells to Cisplatin activates complex signaling pathways that lead to tubular injury and cell death.

This stimulates a inflammatory response and thus causing renal damage.

It is believed to primarily injure S3 segment of the proximal tubule.

Cisplatin also causes vasoconstriction in the renal vasculature thus reducing renal blood flow and causing ischemic injury causing further decrease in GFR.

All these events together culminate in loss of renal function.

References 3,4,5

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 , hypomagnesaemia and Fanconi like syndrome.

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 Amifostine: an organic thiophosphate may protect

against cisplatin-induced toxicity by donating a protective thiol group which is selective for normal but not malignant tissue. However, concerns still exist about possible interference with anti-tumor efficacy of cisplatin.

Other suggested agents which are believed to be chemo protective are Sodium thiosulphate, N- Acetyl cysteine, Theophylline, Glycine, Imatinib, Coreg.

References 9,10,11,12

Carboplatin

Carboplatin is 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

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

Hypomagnesaemia is a more common side effect.

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

warranted.

References 14,15,16

Cyclophosphamide

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.

Both are found to be equally affective.

J Clin Oncol 9:2016-2020.

Cyclophosphamide

Hyponatremia has also been reported with use likely due to increased ADH.

However, other possible mechanisms could be amplifications of the renal effects of ADH and 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.

Ifosfamide

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

Usually acute and reversible but chronic progressive toxicity has been reported and long term evaluation in children is needed.

Nephrogenic Diabetes insipidus can also occur.

Mesna can be given for prevention.

References 19,20

Nitrosoureas

Carmustine, Semustine, Lomustine and Streptozocin

They induce chronic interstitial nephritis which is slowly progressive and irreversible.

Streptozocin affects both glomeruli and tubules--glomerular cellular tufting, extensive tubular atrophy and interstitial inflammatory infiltrates may be seen.

Nitrosoureas

Semustine is most nephrotoxic causing progressive renal failure progressing to ESRD within 3-5 yrs.

Glomerular sclerosis and interstitial fibrosis has been seen.

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

Careful follow up is essential. No known therapy.

Mitomycin C

Most common form of nephrotoxicity is renal failure and microangiopathic hemolytic anemia.

Most likely occurs after 6 months of therapy. Overall incidence is related to cumulative

dose. 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

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 thus causes

tubular injury especially in pts who are dehydrated and excrete acidic urine.

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

Renal failure and microagiopathic hemolytic anemia-HUS/TTP 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.

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

plasmapheresis have been tried. Case fatality is high- 50-70%.

AJKD Volume 40, Issue 4 (October 2002)

Anthracyclines

Daunorubicin and Doxorubicin. They have been shown to cause

glomerulonephritis with nephritic syndrome in animals.

But nephrotoxicity in humans is very rare.

VEGF pathway inhibitors

Bevacizumab----monoclonal antibody that binds circulating VEGF and prevents activation of VEGF receptor.

Sunitinib, Sorefenib-----small molecule tyrosine kinase inhibitors that block the intracellular domain of the VEGF receptor.

VEGF pathway inhibitors

Proteinuria and hypertension are major side effects.

Incidence of mild and asymptomatic proteinuria may range from 21 to 63%

Heavy proteinuria leading to nephritic syndrome has been noted in 6.5% of renal cell carcinoma pts.

Proteinuria is also dose dependent.

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

VEGF pathway inhibitors

VEGF is expressed by podocytes and VEGF receptors are present on normal glomerular capillary endothelial cells.

Pharmacological inhibition of VEGF in Mice resulted in renal pathology manifested by loss of endothelial fenestrations in glomerular capillaries, proliferation of glomerular endothelial cells, loss of podocytes and proteinuria.

VEGF pathway inhibitors

Inhibition of VEGF signaling axis is believed to suppress nephrin, important protein in maintainence of glomerular slit membrane leading to proteinuria.

VEGF pathway inhibitors

In biopsy proven cases, sub acute glomerular thrombotic microangiopathy predominantly endotheliosis and membranoproliferative changes similar to preeclampsia/eclampsia have been seen.

One case report shows immunocomplex mediated focal proliferative glomerulonephritis.

References 26,27

VEGF pathway inhibitors

Management is conservative . ACE/ARBs are used but no evidence based

recommendations are available. One case report of pt developing TMA with

Sunitinib recovered with withdrawal of drug, antihypertensive treatment and administration of Fresh frozen plasma.

Ann Oncol 18: 1745-1747

VEGF pathway inhibitors

Periodic monitoring of proteinuria should be carried out in all anti-VEGF treated pts.

Anti-VEGF agents should be discontinued in pts with moderate persistent proteinuria.

In most of the cases, proteinuria improved after withdrawal of drug.

Occasionally, it may lead to progressive renal failure.

References 29,30

EGFR pathway inhibitors

Cetuximab, Panitumumab,Matuzumab Monoclonal antibodies targeting the

epidermal growth factor receptor Progressive development of

hypomagnesaemia 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

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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