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