chemotherapy-induced nephrotoxicity scottish paediatric renal & urology network 10 th may 2011...
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Chemotherapy-induced Nephrotoxicity
Scottish Paediatric Renal & Urology Network
10th May 2011Jennifer Smith & Sepi Taheri
Content
Case presentation, RA
Discussion regarding renal pathology in oncology patients
Review of current literature
ZZ 3 year old male
38/40, LUSCS for failure to progress
28/40 scan: normal left renal pelvis right APD 22mm
Prophylactic trimethoprim at birth
Progress Renal USS Day 13 of life:
“gross dilatation of right renal pelvis of 44mm with no ureters visualised.”
Left kidney normal Referred urgently to Paediatric Urology
Progress Repeat USS aged 4 weeks: APD
19mm Pelvic wall thickened at 3mm Right kidney 5.6cm, left kidney 6cm MCUG: normal bladder, no VUR DMSA: 35% function right, 65% left MAG-3: prolonged uptake on right;
dilatation and poor drainage.
Intervention
Balloon dilatation right PUJ Oct 2008
Stent removed November 2008
USS post stent removal: “pelvis diameter 23mm, previously 44mm”
Progress
DMSA April 2009: ”70% function left, 30% right”
MAG-3 May 2009: ”sluggish uptake and gradual
excretion on right, normal excretion left”
New problems….
August 2009: right lower eyelid swelling
8/52 history, gradual worsening Clinically represented
rhabdomyosarcoma USS confirmed likely diagnosis Biopsy 3/8/09
Baseline bloods Urea 3.6 Creatinine 45 Na 141 K 3.9 Ca/Mg/PO4 normal GFR: 113ml/min/1.73m2
Treatment options Embryonal rhabdomyosarcoma No metastases European Soft Tissue Sarcoma Protocol
2005 (standard risk subgroup C) Ifosfamide 6g/m2, vincristine,
actinomycin Initially 3 cycles Radiotherapy only if residual disease
Chemotherapy Chemotherapy commenced 11/8/09 Completed end Sept 2009 MRI: 50% reduction; still residual
disease Plan for radiotherapy to orbit 4th cycle IVA chemotherapy 14/10/09
PUJ
USS: right renal pelvis 15mm, reduced
from 23mm
Plan for repeat USS and MAG-3 in three months
Progress Parents appeal for proton beam
therapy Lesser effects than radiotherapy Only available in USA Funded by NHS Lothian No long term data Delay in therapy because of
discussions
Progress 5th cycle vincristine + actinomycin
only 6th cycle IVA Nov 2009 Subsequent three cycles in Florida all
included ifosfamide Extra because of delays starting
radiotherapy
TOTAL = 36g/m2 ifosfamide
Progress Completed 9 cycles chemo Feb 2010 MRI March 2010: no residual disease Clinically and radiological remission USS: no increased dilatation (3mm) MAG-3: right drainage “sluggish” DMSA: left 81%, right 19%
Progress
Nov 2010: USS - stable appearance of right kidney
Jan 2011: routine bloods and CXR Creatinine 44umol/l Phosphate 0.7mmol/l Referred to Renal Clinic
GFR trend
Date GFR(ml/min/1.73m2)
11/08/09 113
11/03/10 109
01/02/11 79
Other parameters
Date Creatinine(15-42umol/L)
Phosphate(1 - 2.1 mmol/L)
Urine phosphate
11/3/10 33 1.27
17/1/11 44 0.7
01/2/11 67 0.97 9.08
15/2/11 63 0.86
28/2/11 50 2.14
14/3/11 86 1.18
Renal Clinic
BP 95/52 Height and weight 90th centiles Urine ++ protein, + glucose Started phosphate supps
Protein:creatinine ratio 218mg/mmol
Renal Further Ix: C3/C4, autoimmune profile ANCA Urine amino acid profile: 3-6x raised PTH and HCO3 normal Likely result of ifosfamide ? Any effect from previous PUJ
pathology Regular review planned
Nephrotoxicity
Pre-renal
Intrinsic/Renal
Post-renal
Nelsons Textbook of Paediatrics © 2005 Elsevier
Glomerulus
Site of ultrafiltration
Fluid and solutes pass though endothelium, basement membrane and podocytes into the proximal tubule
Downloaded from: Nelson Textbook of Pediatrics (on 17 May 2006 01:29 PM)
© 2005 Elsevier
NephronProximal tubule:
2/3 H2O + sodium, phosphate, glucose, amino acids, urea, potassium Distal tubule:
Bicarbonate, potassium, sodium, calcium
Pre-renal uraemia Renal hypoperfusion/ischaemia
Hypovolaemia Low cardiac output Renal vasoconstriction Impaired autoregulation of renal
blood flow Hyperviscosity syndrome
Plasma Creat, Urea, urinary Na
Intrinsic/Renal impairment Nephrotoxic xenobiotics Endogenous nephrotoxins Precipitation of xenobiotics or
endogenous toxins within renal tubules Renovascular obstruction Glomerular disease Renal microvascular damage or
disease Tubulointerstitial damage or disease Insiduous or fulminant
Disease-related renal dysfunction Renal tumours Pelvic tumours Tumour infiltration Hypercalcaemia Hyperviscosity Tumour-lysis syndrome Younger children < 5y, worse off Sepsis-related hypotension
Renal tubulointerstitial toxicity Clinical signs:
Electrolyte wasting Renal tubular acidosis Loss of urine concentrating ability GFR Glycosuria Aminoaciduria (Fanconi syndrome)
Fanconi syndrome Proximal tubular dysfunction Inherited, drugs, heavy metals Loss of glucose, amino acids, uric
acid, phosphate and bicarbonate
Long term sequelae: poor growth, rickets, hypo-K+, hypo-PO4-, glycosuria, proteinuria
Glomerular injury Proteinuria: Albumin and Ig’s GFR Pl Creat +Urea
ps: PC won’t rise until 30% reduction in GFR
Assessment of renal function GFR
EDTA GFR 24-hour Urinary creatinine clearance
Proximal tubules Wasting of Ca, PO4, Mg, glucose, LMW
proteins Distal tubules
Urine osmo and pH Urinalysis, +/- microscopy for casts
Serum creatinine Not always accurate in cancer
patients Secondary loss of muscle mass
Cachexia physical activity Corticosteroid-induced myopathy
Limited protein intake
Anticancer drugs with inherent nephrotoxicity
Alkylating and platinating agents
Chloroethylnitrosoureas
carmustine
semustine
streptozocin
Cisplatin
Carboplatin
Ifosfamide
AntimetabolitesAzacitidineGemcitabineMethotrexatePentostatin
MiscellaneousDiaziquoneInterferon αMitomycin
Ifosfamide Alkylating oxazaphosphorine Advantages over cyclophosphamide
esp in Ewing’s and rhabdomyosarcoma
May cause nephrotoxicity in up to 30% of children
May limit further chemotherapy use if occurs early in treatment
Ifosfamide Tubular damage
Electrolyte wasting Glucose Fanconi syndrome
Haemorrhagic cystitis Glomerular dysfunction Dose and age-related:
Cumulative dose >45.5 g/m² Age <5 y
May persist long term
Ifosfamide Case reports document toxicity in
children < 5 years or those receiving higher cumulative doses
Increased risk if nephrectomy May cause acute renal failure or
present many months later Reported incidence 1.4 - 30% Most common sequelae is hypo-PO4
Evidence Skinner et al British Journal of Cancer 2000 Risk factors for nephrotoxicity after
ifosfamide in children: Late Effects Group study
UK Children’s Cancer Study Group
Skinner et al 148 patients with ifosfamide-
containing schedules studied 147 received ifosfamide as primary
Rx Rhabdo, Ewing’s, sarcoma, PNET,
osteosarcoma 147/148 normal renal function at
beginning
Skinner et al Dose = 6-9g/m2
Continuous 72 hours or bursts for 3 days
Median total dose = 62g/m2 over eight cycles at three weekly intervals
All received high dose IV fluids All received continuous infusion Mesna
Skinner et al 121 of 148 patients also had other
nephrotoxic agents:
Cisplatin Aminoglycoside antibiotics Vancomycin Aciclovir Amphotericin
Skinner et al Nephrotoxicity graded on basis of
GFR Serum HCO3 Urine pH and osmolality Electrolytes, creatinine, calcium,
magnesium, phosphate, glucose Tubular phosphate absorption
None, mild, moderate, severe (0-4)
Skinner et al GFR < 90ml/min/1.73m2 in 50%
GFR < 60ml/min/1.73m2 in 9%
Statistical reduction in GFR from diagnosis to end of Rx in 67 patients
Serum creatinine elevated in 43%
Tubular function Hypo-PO4 occurred in 21%
Phosphaturia was present in 44%
Acidosis occurred in 23% Hypo-K+ occurred in 15% Hypo-Mg2+ occurred in 4% Hypo-Ca2+ occurred in 5%.
Other markers of function 67 had protein:creatinine ratios
performed Only 4% were elevated However 40% had elevated
albumin:creatinine ratio Most with glomerular toxicity had
tubular impairment and vice versa
Nephrotoxicity Nephrotoxicity score: 76 patients
Severity nephrotoxicity Percentage
None 22%
Mild 50%
Moderate 20%
Severe 8%
Risk factors Only factor to have significant
effect after multiple regression analysis is TOTAL DOSE
No safe dose discernible Dose >80g/m2 = greater proximal
tubular damage Dose >50g/m2 = increased risk of
moderate-severe rather than mild
Reversibility? Rare in severe cases Glomerular and tubular toxicity may progress
over months or years Partial improvement may be expected Risk factors
Young age Higher total dose Previous or concurrent Rx with cisplatin Nephrectomy Pre-existing renal impairment
Long term prognosis Skinner et al, 2010 25 patients GFR, PO4, HCO3, tubular threshold for
phosphate and nephrotoxictry score 1 year and 10 years post treatment By 10 years tubular toxicity resolved GFR <60ml/min/1.73m2 in 13%
Protection? MESNA is used therapeutically to
reduce haemorrhagic cystitis and haematuria
Antioxidant properties Detoxifies urotoxic metabolites by
reaction of its sulphydryl group with vinyl in metabolites.
Also increases urinary excretion of cysteine
Other drugs Cisplatin / carboplatin Bonding with DNA, RNA Dose-related nephrotoxicity Cisplatin:at standard doses Carbaplatin: high doses Aminoglycosides potentiate effect
Antimetabolites Azacitidine Gemcitabine Methotrexate: Dihydrofolate reductase
inhibitor ATN 2° to crystallisation of parent drug and
metabolite: 7-hydroxymethotrexate in renal tubules
U&Creat, haematuria, ARF Prevention:urinary alkalinisation
and hydration
Prevention of nephrotoxicity Avoid combination of nephrotoxic
medication Vigorous saline-based
hyperhydration – 3 l/m²/24h Amifostine for Cisplatin Urinary alkalinisation with
Methotrexate
Management of Nephrotoxicity
Meticulous fluid balance:daily weight
Replace losses: PO4, Mg, Ca
Optimise nutrition
Conclusions Chemotherapy induced toxicity may
occur some months-years after treatment even when cumulative doses are not particularly high
There are no effective treatments to reverse the process
It is important to monitor renal function on a regular basis, especially in patients who are young at the time of treatment
Questions? References Skinner R et al. Risk factors for nephrotoxicity after ifosfamide treatment in children: a
UKCCSG Late Effects Group Study. Br Journal of Cancer 2000;82(10):1636-45 Ashraf MS et al. Ifosfamide toxicity in paediatric cancer patients. Eur Journ Paediatr
1994;153:90-94 Skinner R et al. Glomerular toxocity persists 10 years after ifosfamide treatment in children
and is not predictable by age or dose. Pediatr Blood & Cancer 2010;54(7):983-8 Skinner R et al. Glomerular toxicity perssts ten years after ifosfamide treatment in childhood
and is not predictable by age or dose. Paediatric Blood & Cancer 2010;57(4):983-9 Stohr W et al. Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the
Late Effects Surveillance System. Paediatric Blood & Cancer 2007;48(4);447-52 Skinner R. Chronic ifosfamide nephrotoxicity in children 2003;41(3):190-7 Oberlin O et al. Long-term evaluation of ifosfamide-related nephrotoxicity in children. Journal
of clinical oncology 2009;27(32):5350-5