1. Cancer & the Kidney Theory to Practice
Brussels, Belgium
April 2015
Plenary Session 1
Cancer & the Kidney
Theory to Practice

2. How to evaluate the renal function in cancer patients
Dr. Vincent LAUNAY-VACHER, PharmD
Service ICAR
Pitié-Salpêtrière University Hospital
Paris, France

3. Disclosure Past 3 years
Pharmaceutical industry: Amgen, Bayer-Schering, Boehringer-Ingelheim, Daiichi-Sankyo, Gilead, Helsinn, Hospira, Ipsen, Leo Pharma, Roche, TEVA, Vifor Pharma (direct and/or indirect)
French Health Authorities: Haute Autorité de Santé (HAS), Institut National du Cancer (INCa) (direct)
Principles and definitions1:
Links of interest can generate conflicts of interest
Every link of interest does not necessarily result in a conflict of interest
1Haute Autorité de Santé. Guide des déclarations d’intérêts et de gestion des conflits d’intérêts. Juillet 2013

4. Short introduction Clinical Pharmacologist
Nephro-Pharmacology
Onco-Pharmacology
Founded Service ICAR in 1999
With Pr. Gilbert Deray, Head of Nephrology Department
ICAR = Information and Counselling on drug Adjustments in Renal disease
Director of SiteGPR®
online Guidelines on how to Prescribe in Renal disease
President of C-KIN
Cancer & the Kidney International Network

5. How to evaluate renal function
Measuring the Glomerular Filtration Rate (GFR)
IV administration of a marker of GFR
Inulin, 51Cr-EDTA, 99mTC-DTPA, …
Urine and blood samples
Calculation of the renal clearance of the marker => GFR
Limits:
Time-consuming
Requires expert and trained staff
Costs
Constraining for the patient

6. How to evaluate renal function
Measuring the Glomerular Filtration Rate (GFR)
Not for routine clinical practice
Creatinine clearance (CrCl)
Endogenous
Only excreted unchanged in the urine (not metabolized)
Renal clearance of creatinine = Renal function (GFR)
Advantage: does not require the administration of a radioisotope
Limits:
Require a 24-hour urine collection
Constraining and often incomplete
CrCl is not linearily linked to GFR

7. How to evaluate renal function
Measuring the Glomerular Filtration Rate (GFR)
Not for routine clinical practice
Creatinine clearance (CrCl)
Serum creatinine (SCr)
Creatinine plasma concentration is stable
Thus: If SCr ⬈ => Renal function ⬊

8. SCr and renal function Serum creatinine Creatinine production Muscle
SCr production must be evaluated with:
Weight
Gender
Age
Creatinine production
Muscle
catabolism =
Serum creatinine
Creatinine elimination
Glomerular
filtration =

9. SCr and renal function SCr 75 µmol/L Renal function ~ 100 mL/mn
Age: 37
Weight: 58 kg
Age: 72
Weight: 53 kg
SCr
75 µmol/L
Renal function
~ 100 mL/mn
Renal function
~ 50 mL/min

10. Important decrease in GFR
SCr and renal function
SCr
Small increase
in SCR
GFR
Important decrease in GFR

11. Formulae to estimate renal function
Measuring the Glomerular Filtration Rate (GFR)
Not for routine clinical practice
Creatinine clearance (CrCl)
Serum creatinine (SCr)
Should not be used at all anymore as an index of normal/abnormal renal function
Estimates of GFR with formulae

12. Formulae to estimate renal function
Units
Year
Jeliffe1
CrCl
ml/min
1973
Cockcroft-Gault2
1976
MDRD3
GFR
ml/min/1.73m2
2000
Wright4
2001
CKD-EPI5
2009
Which formula to use in cancer patients ?
1Jelliffe RW. Ann Intern Med. 1973; 2Cockcroft DW, Gault MH. Nephron 1976; 3Levey AS et al. Ann Intern Med J Am Soc Nephrol 2000 (poster); 4Wright JG, et al. Br J Cancer 2001; 5Levey AS, et al. Ann Intern Med 2009

13. Formulae to estimate renal function
In non-cancer patients: aMDRD equation is recommended.
In cancer patients: confounding evidence
Example from the most recent literature:
Authors’ conclusion: aMDRD understimates GFR in cancer patients…
What should we do in clinical practice ?

14. Formulae to estimate renal function
Always look at the Methods:
Ainsworth’s study1: “*the raw results of aMDRD calculation in mL/min/1.73m2 were compared to measures of the actual GFR in mL/min and other formulae estimates in mL/min.”
50% of the patients had a BSA > 1.88 m2
1Ainsworth NL et al. Ann Oncol 2012; *Not mentionned in the article. Personal communication from Nicola Ainsworth.

15. Formulae to estimate renal function
Comparisons with appropriate units: aMDRD is more precise
Faluyi’s study: authors converted aMDRD raw result into mL/min using the actual BSA of the patients and then compared to CG and isotopic GFR. “the MDRD equation was observed to provide more accurate GFR estimates than the C&G equation”
1Faluyi OO et al. Med Oncol 2011

16. Formulae to estimate renal function
Performance of formulae in special populations
Adults
Age < 65
Normal BMI
Elderly
(Age ≥ 65)
High BMI
(≥ 30)
Low BMI
(< 18.5)
Cockcroft-Gault
Correct
False
Not recommended
MDRD
More precise
Accurate
CKD-EPI
≈ MDRD
Froissart et al. J Am Soc Nephrol 2005; Holweger K et al. Ann Pharmacother 2008; Barraclough LH et al. Clin Oncol 2008; Kleber M et al. Ann Oncol 2007; Launay-Vacher V et al. Ann Oncol 2007; Flamant M, et al. Am J Kidney Dis 2012; Michels WM, et al. Clin J Am Soc Nephrol 2010

17. Formulae to estimate renal function
When BMI is lower than 18.5
No formula is precise enough
Renal function cannot be estimated => Measured CrCl
Cockcroft-Fault formula should be abandoned
Modern formulae are as precise in young adults with normal BMI
Modern formulae can be used when BMI > 30 (CG is false)
Modern formulae ca be used when Age is ≥ 65 (CG false)
Either MDRD or CKD-EPI can be used

18. Formulae to estimate renal function
Comparing MDRD and CKD-EPI in the general population
116’321 subjects included in KEEP (Kidney Early Evaluation Program)
Similar prevalence of eGFR < 60 mL/min/1.73m2 with MDRD or CKD-EPI
Respectively 16.8% vs. 14.3%
Stevens LA et al. Am J Kidney Dis 2011

19. Formulae to estimate renal function
When BMI is lower than 18.5 => Measured CrCl
No formula is precise enough
Cockcroft-Fault formula should be abandoned
Modern formulae are as precise in young adults with normal BMI
Modern formulae can be used when BMI > 30 (CG is false)
Modern formulae ca be used when Age is ≥ 65 (CG false)
MDRD or CKD-EPI must be used

20. International definition and stratification of chronic kidney disease
Stage
Description
eGFR
(mL/min/1.73m²) At
Increased
Risk
Risk factors for kidney disease
(e.g., diabetes, high blood pressure, family history, older age, ethnic group)
≥ 90 1
Kidney damage (protein in the urine)
and Normal GFR 2
Kidney damage and Mild decrease in GFR
60 to 89 3
Moderate decrease in GFR
30 to 59 4
Severe decrease in GFR
15 to 29 5
Kidney failure
(dialysis or kidney transplant needed)
Less than 15
K/DOQI : National Kidney Foundation. Am J Kidney Dis 2002.; KDIGO : Levey AS, et al. Kidney Int 2005.

21. Why evaluate the renal function ?
CKD is highly frequent in cancer : 12 to 25%
CKD is associated with reduced survival and increased cancer-related mortality
Why and how CKD may impair survival ?

22. CKD impacts survival in other conditions
CKD is a risk factor for mortality in a number of chronic diseases or acute conditions:
Type 1 diabetes1
HIV infection2
Patients hospitalized for upper GI bleeding3
Atrial fibrillation4
Non-cardiac surgery5
Coronary heart disease and mortality6
Type 2 diabetes mellitus, especially in the elderly7
…/…
1Groop PH et al. Diabetes 2009; 2Ibrahim F et al. Am J Kidney Dis. 2012; 3Sood P et al. Am J Nephrol. 2012; 4Nakagawa K et al. Am J Cardiol 2011; 5Mathew A et al. Kidney Int 2008; 6Astor BC et al. Am Heart J. 2006; 7 Drion I et al. Age Ageing. 2012

23. How CKD may impact survival in cancer
CKD patients are at risk for cardiovascular mortality
Deaths
CV events
Hospit.
HR : 1, ,2 1,8 3,2 5,9
HR : 1,0 1, ,0 2,8 3,4
HR : 1,0 1, ,5 2, ,1
1’120’295 subjects included…
Go AS et al. N Engl J Med 2004

24. How CKD may impact survival in cancer
CKD patients are at risk for cardiovascular mortality
RR for venous thromboembolism increases as eGFR decreases
RR becomes significant when eGFR is below 88 mL/min/1.73m2
Especially when eGFR < 60 mL/min/1.73m2
A: Mahmoodi BK. Circulation 2012

25. How CKD may impact survival in cancer
CKD patients are at risk for cardiovascular mortality B
Reduced survival in CKD patients experiencing venous thromboembolism / pulmonary embolism
B: Parikh AM. Am J Kidney Dis 2011

26. How CKD may impact survival in cancer
CKD patients are at risk for cardiovascular mortality
Cancer patients with CKD may present with higher CV mortality
=> Reduced overall survival
CKD patients are at risk for non-optimal drug management

27. How CKD may impact survival in cancer
CKD patients are at risk for non-optimal drug management
If Kidney Disease has not been identified OR
If Kidney Disease has been diagnosed,
but no dosage adjustment performed
If Kidney Disease has been
diagnosed but dose
too much reduced
UNDER-DOSE
Lack of efficacy
OVER-DOSE
Toxicity
delayed courses,
treatment modification
palliative care, …

28. How CKD may impact survival in cancer
CKD patients are at risk for cardiovascular mortality
Cancer patients with CKD may present with higher CV mortality
=> Reduced overall survival
CKD patients are at risk for non-optimal drug management
Overdosage => Toxicity => Reduced survival
Under-dosage => Lack of efficacy => Reduced survival

29. CONCLUSIONS
In cancer patients, renal function must be evaluated with MDRD or CKD-EPI formulae
Except in patient with BMI < 18.5 => Measured CrCl
CKD cancer patients:
Are probably at risk for CV increased morbi-mortality
Require dosage adjustments
For curative treatments
For supportive care treatments
For any other associated treatments

30. GFR estimate with MDRD or CKD-EPI formula
at cancer diagnosis
before each treatment course
eGFR < 90 ? NO
Normal renal function
Usual care
eGFR < 60
eGFR ≥ 60
YES
Determine the appropriate dose:
SmPC
Evidence-based tools
Dosage adjustment may be required
Increased risk for
renal toxicity
Prevention measures
Monitor GFR and SCr
EXCEPTION: Carboplatin
Dose is adjusted to the GFR in the Calvert formula, whatever the GFR
No dosage adjustment required

31. Thank you for your attention!
Vincent Launay-Vacher
Service ICAR
Pitié-Salpêtrière University Hospital