1. The document discusses various chemotherapy agents that can cause kidney toxicity, including cisplatin, methotrexate, gemcitabine, calcineurin inhibitors, and tyrosine kinase inhibitors. 2. It presents five case studies of patients who developed acute kidney injury following treatment with specific chemotherapy agents: ifosfamide, clofarabine, carfilzomib, temsirolimus, and anthracyclines. 3. For each case, it analyzes the likely offending agent and possible mechanisms of nephrotoxicity based on previous literature and known renal side effect profiles of the drugs.

1. Kenar D. Jhaveri, MD
Associate Prof of Medicine

2. Potential compartments of drug
induced injury

3. Why is the Kidney Vulnerable to
Chemotherapy?
• Patient Specific Factors
• Kidney Specific Factors
• Drug Specific Factors

4. Kidney Pathology 101
Glomeruli
Tubules
Interstitium
Vasculature

6. Outline
Older agents known to be
nephrotoxic
Cisplatinum
Methotrexate
Gemcitabine
Calcineurin Inhibitors
Bisphosphanates
Tyrosine Kinase Inhibitors
Anti VEGF agents

7. CASE 1
• Mr. Fos is a 68 Y old male with un-resectable retroperitoneal
seminoma pre-treated with cisplatin 6 months ago with
baseline SCr. of 1.3mg/dL and bland urine now presents with
AKI after Drug X one dose of daily 2000mg/m2
x3d and 2 doses
330mg/m2
x2. Pt also received two concomitant doses of
carboplatin (AUC of 7 daily for 3days). Post-treatment pt
developed rising SCr; glucosuria, proteinuria, hypokalemia,
metabolic acidosis and hypophosphatemia. Despite d/c of
Drug X pt’s renal insufficiency progressed and he required
dialysis 10 months after last dose of Drug X but remains NED
from seminoma
• WHAT IS “DRUG X”?

8. H
L 0.0
2.5
5.0
7.5
10 .0
12 .5
J a n 2 009 A pr J ul O c t
C rea tin in e
mg/dl
FE R A TO V IC , S A B A N
C reatinine (m g/dl)

9. IFOSFAMIDE NEPHROTOXICITY
 Alkylating agent
 Proximal dysfunction-Fanconi Syndrome
 Most Data in children
– Tubulopathy-30%
– Clinically significant Fanconi syndrome-5%
• Glucosuria with normal blood glucose levels
• Hypophosphatemia, hypokalemia, metabolic acidosis,
hypouricemia, aminoaciduria
 AKI-usually resolves prior to next course
 Chronic renal disease
– Up to 50% suffer some degree of impairment
– Average decline in GFR 35ml/min/1.73m2
(51
Cr-EDTA)
– Progressive even after IFOS stopped
Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645Skinner R., et al. British Journal of Cancer (2000) 82(10): 1635-1645

10. IFOSFAMIDE NEPHROTOXICITY:
RISK FACTORS
 Cumulative dose >60-100gm/2
(*)
 Age at treatment 3-5yrs (?)
 Prior or concurrent treatment with cisplatin/carboplatin
 H/o nephrectomy
 Renal irradiation
 Hydronephrosis
Jones D., et al. Pediatr Blood Cancer (2008); 51(6):724-731

11. LONG-TERM IFOSFAMIDE TOXICITY IN ADULTS
 Retrospective review
 259 patient
▫Pts who received cisplatin were excluded
Decline in GFR correlated with
▫ Age (p<0.001)
▫ Carboplatin exposure (p<0.001)
No Correlation with
▫ Ifosfamide dose-(?low overall dose)
▫Aminoglycoside exposure
▫Auto BMT
Mean GFR decline vs. ifosfamide dose
quartiles
Latcha S., Flombaum CD. Personal communication, MSKCCLatcha S., Flombaum CD. Personal communication, MSKCC

12. Case 2
Mr. Kohl Farabean is a 48 year old with AML who presented to the
hospital with fever and headaches for one week. His neutropenic fever
was treated with intravenous vancomycin, cefepime and voriconazole and
oral acyclovir.
There was no prior kidney disease and on admission the serum creatinine
was 1.15 mg/dL with good urine output. On hospital day 9 re-induction
therapy with “Drug Z” 30 mg/m2
intravenous(IV) daily days 1 to 5 (his first
exposure to this drug) and “Drug Y “(he had previously been treated with
this agent) 2 g/m2
IV daily days 1 to 5 two hours after “Drug Z” was
initiated.
On hospital day 11, AKI was detected with rise in serum creatinine from
0.97 mg/dL prior to initiation of chemotherapy on day 9 to 2.14 mg/dL on
day 11. Urine output decreased and he became anuric on day 11. There
was no laboratory evidence of tumor lysis syndrome. Later on hospital day
11 the serum creatinine increased to 3.56 mg/dL. Hemodialysis was
started on hospital day 12 due to worsening azotemia and anuria.

13. Clofarabine induced renal
disease
• Drug Z = clofarabine
• Drug Y = cytarabine
Jhaveri KD, Chidella S, Allen S, Fishbane S. Clofarabine induced kidney disease. J Onco Pharm Pract 2013 in press

14. Literature review
Type study % patients with renal
insult
Renal injury grade Other
Case report – 1 patient 1 Proteinuria, Aki No biopsy ( reversible)
Phase trials( AML)-112
adults patients
36% rise in creatinine Grade 3( 6%) No biopsy
Phase trials(AML)- 106
adults patients
14-16% Grade 4 No biopsy
FAERS database ( our
review)
29 patients reported No grade reported No biopsy
Kintzel PE, Visser JA, Campbell AD. Clofarabine-associated acute kidney injury and proteinuria. Pharmacotherapy. 2011
Sep;31(9):923.
Kantarjian H et al;. J Clin Oncol. 2010 Feb 1;28(4):549-55
Burnett AK et al. J Clin Oncol, 2010 May 10;28(14):2389-95
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm
accessed January 23, 2013

15. Mechanism?
• No biopsies till date
• Tubular vs. glomerular vs. endothelial damage
• Clofarabine inhibits DNA synthesis and is also a ribonucleotide reductase (RNR) inhibitor
• RNR is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides
which in turn facilitates DNA synthesis.
• Depleting RNR could result in kidney injury??
• Powell et al studied a knockout model of mice with no functional RNR. The animals died early
at 6 weeks of age. Interestingly, there was progressive podocyte damage and significant foot
process effacement. In the few mice that survived beyond 9 weeks, collapsing
glomerulopathy with widespread avascular glomeruli was noted
Powell DR et a;l. Rapid development of glomerular injury and renal failure in mice lacking p53R2. Pediatr Nephrol. 2005
Mar;20(3):432-40.

16. Case 3
Mr. Kia Prol is a 68-year-old man with IgG κ-type refractory multiple myeloma
presented to the hospital with fever and acute-on-chronic kidney disease
(creatinine 3.65 mg/dL, baseline 1.6 mg/dL). He had been switched to carfilzomib
and steroids 1 month prior to presentation because his disease had failed to
respond to bortezomib and thalidomide, and had received 1 cycle of carfilzomib
and dexamethasone 9 days prior to presentation. During the hospital course, his
creatinine peaked at 4.59 mg/dL
Prior to administration of carfilzomib, his free κ:λ ratio was 78. His renal function
worsened as the κ:λ ratio decreased to 16.8. His serum calcium was in the range
of 8.5 to 9.0 mg/dL. His uric acid was normal. Urinalysis revealed a urine pH of 6,
specific gravity of 1.009, mild glucosuria, small amount of blood, 75 mg/dL of
protein, 2 to 5 white blood cells per high power field, and 0 to 2 red blood cells per
by high power field. No granular, red blood cell, or white blood cell casts were
noted. His proteinuria was unchanged, at 1.6 g per 24 hours.

17. Initial phase 2 trials: Increased serum creatinine was the most
frequently reported renal adverse event , affecting 25% of the 266
patients in this study.
Acute kidney injury was reported in 13 patients (5%), 9 of whom
experienced serious grade 3 acute renal failure. Chronic renal failure was
reported in 10 patients (3.8%), with 3 of these events considered severe
and 2 resulting in discontinuation of carfilzomib.
Siegel DS et al, Blood 2012

18. But does it really exist?-counter
evidence
• Badros et al- the pharmacokinetics and safety of carfilzomib among MM patients
in predefined cohorts identified by various degrees of renal function . The
researchers studied 50 patients who had disease progression after 2 or more prior
lines of therapy, and observed no differences between patients with and without
normal renal function in carfilzomib clearance and exposure.
•
Harvey et al - analysis of renal dysfunction in 526 patients treated with single-
agent carfilzomib in 4 phase 2 trials. The analysis showed that overall, 87% of
patients did not have worsening renal function during treatment. Of the patients
who experienced worsening of renal function, 46% experienced transient
worsening of a median duration of 1.4 weeks, and 54% experienced non transient
worsening. A total of 8 of the 37 patients with non transient worsening
discontinued carfilzomib treatment owing to an adverse event related to renal
dysfunction
Badros AZ et al. Leukemia 2013
Harvey D et al. Haematologica 2012

19. Pre renal insult?
Personal communication, Dr R. Niesvizky and Dr.R Wanchoo

20. Case 4
Mr. Rapa Moin is a 76 year old was admitted for acute renal failure. He had a
history of hypertensive chronic kidney disease (basal serum creatinine level 2.27
mg/dl). A mantle cell lymphoma diagnosed on February 2009 was treated by
chemotherapy (rituximab , adriamycin, bortezomib, and dexamethazone, six
cycles) replaced by rituximab, dexamethasone, oxaliplatin, and citarabin in
August 2010.
Temsirolimus as maintenance therapy was introduced in January 2011. The
serum creatinine level was 2.78 mg/dl) and rises to 4.61 mg/dl 1 month later.
On admission, after 5 weeks of temsirolimus, his blood pressure was 180/90
mmHg. Laboratory studies revealed a serum creatinine level of 5.5 mg/dl, blood
urea of 34 mmol/l, a hemoglobin of 8.6 g/dl and platelets count of 27.000/mm3.
Urinalysis revealed a daily protein excretion of 3 g and red 20 red cell per high-
power field. Haptoglobin was low. Renal sonography finding was normal.
Immunological tests were negative. The patient required iterative hemodialysis.
• Kidney biopsy showed?

21. Huh?

22. mTOR inhibitors and renal
toxicities
• Proteinuria and TMA( you know this) from Renal transplantation literature
• Sirolimus and everolimus have been reported to cause FSGS, collapsing FSGS and
TMA and other proteinuric diseases.
• New reports of these agents causing ATN
• mTOR activity is low or absent in the normal kidney, but increased markedly after
ischemic injury. Additionally, inhibition of mTOR delays renal recovery and repair.
This begs the question of whether mTOR inhibition is the true cause of the renal
dysfunction or this is an indirect effect, in not allowing renal tissue repair in
response to nephrotoxic stress.
Izzadine H et al. Acute tubular necrosis associated with mTOR inhibitor therapy:
a real entity biopsy-proven. Ann Oncol 2013

23. Case 5
• Mr. Don Rubinson is a 44-year-old white male diagnosed in September
2010 with peripheral T-cell lymphoma, His renal function was normal.
He received two cycles of standard
cyclophosphamide/daunomycin/vincristine/prednisone (standard CHOP
chemotherapy).
• Approximately 11 weeks after starting therapy, Creatinine was 3.6 mg/dL
(319 µmol/L Antinuclear (ANA), hepatitis C and human immunodeficiency
virus (HIV) antibodies, and hepatitis B surface antigen (HbsAgHBsAg)
were negative. 24-hour hr urine collection contained 10g of protein with
1+ blood. A renal biopsy was performed.

24. Anthracyclines and kidney diseases
Mohammed N et al. Am J Kidney Dis 2013

25. Glomerular lesions caused by chemotherapy
Jhaveri KD , Shah HH et al. Glomerular Diseases seen with cancer
and chemotherapy, Kidney Int 2013.

26. Watch out kidney, chemo is
here!