Chemotherapy drugs can damage the kidneys through various mechanisms. Cisplatin is one of the most nephrotoxic drugs that directly injures the proximal tubules. Symptoms of kidney damage include decreased urine output and blood in the urine. Kidney function is assessed through blood tests of creatinine and BUN. Prevention strategies for cisplatin nephrotoxicity include IV fluids, sodium thiosulfate, and dose modifications based on glomerular filtration rate. Methotrexate requires monitoring and urine alkalinization due to precipitation in acidic urine causing tubular injury. Gemcitabine can cause thrombotic microangiopathy requiring dose reductions with glomerular filtration rate below 30 mL/

1. BY
RAMESH.KASARLA
PHARM D(PB) 5th YEAR
SVCP

2. WHAT IS CHEMOTHERAPY ..??
Chemotherapy: In the original sense, a chemical that binds
to and specifically kills microbes or tumor cells.
The term chemotherapy was coined in this regard
by Paul Ehrlich (1854-1915).
 In oncology, drug therapy for cancer. Also called "chemo" for
short.
 It may consist of single drugs or combinations of drugs.
 Chemotherapy is different from surgery or radiation
therapy in that the cancer-fighting drugs circulate in the
blood to parts of the body where the cancer may have spread
and can kill or eliminate cancers cells at sites great
distances from the original cancer. As a result,
chemotherapy is considered a systemic treatment.

3. Renal damage with chemotherapeutic drugs
 Some chemotherapy drugs can damage the kidneys
(nephrotoxicity).
 The kidneys break down and remove many chemotherapy
drugs from the body.
 When chemotherapy drugs break down, they make products
that can damage cells in the kidneys, ureters and bladder etc…
WHAT ARE THE SYMPTOMS OF KIDNEY DAMAGE..?
 Decrease in amount of urine or frequency
 Pain or urgency with urination
 Dark urine , Blood in urine ,Fatigue
 Muscle weakness , Swelling in feet or ankles
 Nausea or vomiting , Confusion, seizure

4. HOW IS KIDNEY DAMAGE DIAGNOSED ..?
 Blood urea nitrogen (BUN):
BUN levels range from 10-25 mg/dL (milligrams per deciliter) of blood.
 Creatinine:
creatinine levels range from 0.7-1.4 mg/dL(milligrams per deciliter) of
blood.
 GFR-glomerular filtration rate :- values are < 60 mL/min (they
state normal valuesas 90-120 mL/min)

5. Cytotoxic agents classification
Alkylating agents Anti- Metabolites
Cyclophosphamide** Methotrexate**
Ifosfamide** Gemcitabine**
Carmustine* Capecitabine
Streptozocin* Fludarabine
Melphalan Raltitrexed
Dacarbazine Asparaginas
Procarbazine Cytarabine
Bendamustine 5- Fluoro Uracil
Chlorambucil Pemetrexed
Temozolomide
Busulfan

6. Anti-Tumor Antibiotics Plant Alkaloids/
Microtubule Inhibitors
Mitomycin c ** Etoposide
Daunorubicin Topotecan
Bleomycin Docetaxel
Idarubicin Irinotecan
Actinomycin D / Dactinomycin Paclitaxel
Doxorubicin Vinblastine
Doxorubicin (pegylated liposomal) Vincristine
Epirubicin Vinorelbine
Mitoxantrone
DNA Linking Agents
Cisplatin**
Carboplatin*
Oxaliplatin
First FRCR Examination – Clinical Pharmacology moduleList of Anti-Cancer Drugs

7. DNA Linking Agents
Mechanism of Action
DNA Linking Agents 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
 One of the most widely used and most nephrotoxic chemotherapeutic
agents.
 Used for lymphoma, testicular carcinoma, bladder, gastric, head and
neck, non-small cell lung, ovarian, and small cell lung cancers.
Nephrotoxicity Profile:-
 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.
 It is usually dose dependent.

8. Pathophysiology

9.  Higher doses
 Previous cisplatin therapy
 Underlying kidney dysfunction
 Older age
 Female gender
 Smoking
 Hypoalbuminemia
Risk Factors
Clinical Features
• Clinically, Nephrotoxicity is seen usually within 10 days of Cisplatin
administration.
• It is manifested by acute renal failure, hypokalemia , hypomagnesemia
and Fanconi like syndrome.
• Hypomagnesemia may exacerbate Cisplatin toxicity.
• 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.

10. 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 etc.
Dose modification Dosage: 20-50 mg/m2
GFR (ml/min) Dose
>60 100%
45-59 75%
<45 consider carboplatin British Journal of Cancer (2003) 88, 1199 – 1206

11.  Used for lung, ovarian, head and neck cancer.
 Believed to be safer than cisplatin.
Nephrotoxicity Profile:-
 Acute renal failure has been reported with carboplatin.
 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.
Carboplatin

12.  Clinical Features
 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.
Prevention
Dosage adjustment by using Calvert formula:-
carboplatin dose(mg) = (GFR+25)*AUC AUC-area under curve
GFR- glomerular filtration rate
Am j kidney Dis . 2015;66(5):869-883
Low toxicity drugs
Drug Nephrotoxicity Profile prevention Recommendation
GFR (ml/min) - Dose
Oxaliplatin Renal impairment Dose modification <20m/min –dose reduce

13. Cyclophosphamide
 Nephrotoxicity Profile:-
 Major toxicity of cyclophosphamide is hemorrhagic cystitis.
 SIADH (syndrome of inappropriate antidiuretic hormone secretion)
 Nephrogenic diabetes insipidus
 One of the metabolites acrolein causes cystitis.
Clinical Features
 Hyponatremia has also been reported.
Mechanism could be increased 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.
Alkylating agents
Mechanism of Action
Metabolites interfere with malignant cell growth by cross-linking tumor
cell DNA. inhibits DNA synthesis and protein synthesis
J Clin Oncol 9:2016-2020.

14. Prevention
 Hypotonic solutions should be avoided while giving
cyclophosphamide to prevent severe hyponatremia.
 Mesna and IV hydration are mainly used for prevention.
 Mesna contains a sulfhydryl group that binds acrolein and detoxifies
it.
 IV hydration induces brisk diuresis and prevents accumulation of
acrolein in the urinary bladder and collecting system.
 Dose modification
GFR (ml/min) Dose
>20 100%
10-20 75%
<10 50%
Arch Intern Med 1985;145:548-549

15.  Nephrotoxicity Profile:-
 Nephrotoxicity is more prominent feature especially when given
along with other nephrotoxic agents like Cisplatin.
 Fanconi syndrome, CKD, SIADH,
 Nephrogenic diabetes insipidus; risk factors include cumulative
ifosfamide dose . 50 g/m2, preexisting GFR loss and/or
nephrectomy, age # 12 y
 Clinical Features
 Proximal tubular dysfunction is the most common presentation
which could lead to Fanconi’s syndrome, hypophosphatemic
rickets and proximal renal tubular acidosis.
 Chronic progressive toxicity has been reported and long term
evaluation in children is needed.
Ifosfamide

16. Prevention
 If possible, ifosfamide should be discontinued in
patients developing signs of moderate to severe AKI
during therapy.
 oral and/or IV fluid and electrolyte supportive therapy
should be provided
 Mesna can be given for prevention.
Dose modification
GFR (ml/min) Dose
>60 100%
40-59 70%
<40 Clinical decision

17. Carmustine, Semustine ,Lomustine and Streptozocin.
 Used for malignant brain tumors,melanomas.
 Of the four agents, Semustine and Streptozocin are more nephrotoxic.
Nephrotoxicity Profile:-
 Fanconi syndrome, CKD, glomerular toxicity, kidney failure
 They induce chronic interstitial nephritis which is slowly progressive and
irreversible.
 Glomerular sclerosis and interstitial fibrosis has been seen.
Clinical Features
 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.
Nitrosoureas

18. Prevention
 Administration of supplemental crystalloid fluid; reduction of the
carmustine infusion rate by 50%
 Discontinuation of the drug (continued treatment generally results in
irreversible injury)
 Dose modification
Carmustine Lomustine
GFR (ml/min) Dose CrCl (ml/min) Dose
60 80% >60 100%
45 75% 45-60 75%
<30 Clinical decision 30-45 50%
<30 not recommended

19. Low toxicity drugs
Drug Nephrotoxicity Profile prevention Recommendation
GFR (ml/min) - Dose
Dacarbazine Renal impairment Dose modification 45-60 80%
30-45 75%
<30 70%
Melphalan Renal impairment Dose modification >50 100%
10-50 75%
<10 50%
Procarbazine Renal impairment Dose modification serum creatinine
>177μmol/L, 50%
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)

20. Methotrexate
 Used for leukemias, head and neck cancer, lung cancer,
breast cancer, lymphoma.
 Nephrotoxicity Profile:-
 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.
Anti- Metabolites
Mechanism of Action:-
Inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid
synthesis, which in turn interferes with DNA synthesis, repair, and cellular
replication; cell cycle specific for S phase of cycle

21.  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.
Prevention:-
 Close Monitoring: Urine output, Fluid Balance (avoid negative balance) MTX
levels, Serum Cr.
 Hence IV hydration and urinary alkalinizations are mainstays in prevention.
 • Urine Alkalinization to keep urine pH 7 to 8.5 •
 Leucovorin •
 Dose modification
GFR (ml/min) Dose
>80 100%
60 65%
45 50%
<30 CI
Clinical Features
J Cancer Sci Ther ISSN:1948-5956 JCST, an open access journal

22.  Used for pancreatic tumors, metastatic breast cancer,
non-small cell lung cancer,ovarian cancer.
Nephrotoxicity Profile:-
 Thrombotic microangiopathy (TMA)
 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.
Gemcitabine
AJKD Volume 40, Issue 4 (October 2002)

23.  High index of suspicion is needed.
 Immunosuppressive therapies (azathioprine, corticosteroids
or vincristine), and antiplatelet/anticoagulant therapies
(heparin, prostacyclin or splenectomy)
 If the drug is still being given when gemcitabine-associated
TMA is identified, it must be discontinued
 Withdrawal of drug, steroids and plasmapheresis have been
tried with variable response.
 Dose modification
GFR >30ml/min – standard dosing
GFR <30ml/min – consider dose reduction – clinical decision.
Prevention:-
AJKD Volume 40, Issue 4 (October 2002)

24. Drug Nephrotoxicity Profile prevention Recommendation
GFR (ml/min) - Dose
Capecitabine Renal impairment Dose modification 51-80 100%
30-50 75%
<30 CI
Fludarabine Renal impairment Dose modification >70 100%
30-70 50%
<30 cl
Raltitrexed Renal impairment Dose modification >65 100%
55-65 75%
25-54 50%
<25 0%
Low toxicity drugs
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)

25. Mitomycin C
 Used for pancreatic and gastric cancers.
 Nephrotoxicity Profile:-
 Most common form of nephrotoxicity is renal failure and
microangiopathic hemolytic anemia.
 Most likely occurs after 6 months of therapy.
 Dose dependent.
 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.
Anti-Tumour Antibiotics
Mechanism of Action: -
Crosslinks DNA, preventing replication & transciption

26.  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.
Prevention:-
 Prompt diagnosis
 Early discontinuation of the drug,
 Supportive treatment may improve the outcome
 Dose modification
GFR (ml/min) Dose
>10 100%
<10 75%
Clinical Features
Journal of Clinical Oncology, Vol 7, 781-789 Nephron. 1989;51(3):409-12

27. Drug Nephrotoxicity Profile prevention Recommendation
Daunorubicin Renal impairment Dose modification Creatinine Dose
/μmol/L
<105 100%
105-265 75%
>265 50%
Bleomycin Renal impairment Dose modification GFR (ml/min) - Dose
>50 100%
10-50 75%
<10 50%
Idarubicin Renal impairment Dose modification <100 100%
100-175 50%
>175 Clinical decision
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Low toxicity drugs

28. Plant Alkaloids/ Microtubule Inhibitors
Drug Nephrotoxicity
Profile
prevention Recommendation
GFR (ml/min) - Dose
Etoposide Renal impairment Dose modification >50 100%
15-50 75%
<15 50%
Topotecan Renal impairment Dose modification >40 100%
20-39 50%
<20 cl

29.  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.
Summary

30. 1. Renal Failure Associated with Cancer and Its Treatment:An Update -56 J Am Soc Nephrol 16: 151–
161, 2005
2. Cisplatin nephrotoxicity: Mechanisms and Reno protective strategies. Kidney International (2008)
73, 994–1007
3. Mechanism of cisplatin nephrotoxicity. Fed Proc. 1983 Oct;42(13):2974-8
4. Cisplatin Decreases the Abundance of Aquaporin Water Channels in Rat Kidney. J Am Soc
Nephrol 12: 875–882, 2001
5. 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
6. Dose-related nephrotoxicity of carboplatin in children. British Journal of Cancer (1999) 81(2), 336–
341.
7. Nephrotoxicity of Nitroso ureas Cancer 48:1328-1334, 1981
8. Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior
leukencephalopathy syndrome E. Kapiteijn , A. Brand , J. Kroep , and H. Gelderblom
Ann Oncol 18: 1745-1747
9. Progressive bevacizumab-associated renal thrombotic Microangiopathy. NDT Plus (2009) 2: 36–
39
10. 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
11. Onco-Nephrology: Core Curriculum 2015 Eric P. Cohen, MD,1,* Jean-Marie Krzesinski
12. Am J Kidney Dis. 2015;66(5):869-883
13. UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated
January2009)
References