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Chemotherapy-induced Nephrotoxicity Scottish Paediatric Renal & Urology Network 10 th May 2011 Jennifer Smith & Sepi Taheri.

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Presentation on theme: "Chemotherapy-induced Nephrotoxicity Scottish Paediatric Renal & Urology Network 10 th May 2011 Jennifer Smith & Sepi Taheri."— Presentation transcript:

1 Chemotherapy-induced Nephrotoxicity Scottish Paediatric Renal & Urology Network 10 th May 2011 Jennifer Smith & Sepi Taheri

2 Content Case presentation, RA Discussion regarding renal pathology in oncology patients Review of current literature

3 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

4 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

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6 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.

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8 Intervention Balloon dilatation right PUJ Oct 2008 Stent removed November 2008 USS post stent removal: “ pelvis diameter 23mm, previously 44mm ”

9 Progress DMSA April 2009: ” 70% function left, 30% right ” MAG-3 May 2009: ” sluggish uptake and gradual excretion on right, normal excretion left ”

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11 New problems…. August 2009: right lower eyelid swelling 8/52 history, gradual worsening Clinically represented rhabdomyosarcoma USS confirmed likely diagnosis Biopsy 3/8/09

12 Baseline bloods Urea 3.6 Creatinine 45 Na 141 K 3.9 Ca/Mg/PO4 normal GFR: 113ml/min/1.73m 2

13 Treatment options Embryonal rhabdomyosarcoma No metastases European Soft Tissue Sarcoma Protocol 2005 (standard risk subgroup C) Ifosfamide 6g/m 2, vincristine, actinomycin Initially 3 cycles Radiotherapy only if residual disease

14 Chemotherapy Chemotherapy commenced 11/8/09 Completed end Sept 2009 MRI: 50% reduction; still residual disease Plan for radiotherapy to orbit 4 th cycle IVA chemotherapy 14/10/09

15 PUJ USS: right renal pelvis 15mm, reduced from 23mm Plan for repeat USS and MAG-3 in three months

16 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

17 Progress 5 th cycle vincristine + actinomycin only 6 th cycle IVA Nov 2009 Subsequent three cycles in Florida all included ifosfamide Extra because of delays starting radiotherapy TOTAL = 36g/m 2 ifosfamide

18 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%

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20 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

21 GFR trend DateGFR ( ml/min/1.73m 2) 11/08/ /03/ /02/1179

22 Other parameters DateCreatinine (15-42umol/L) Phosphate ( mmol/L) Urine phosphate 11/3/ /1/ /2/ /2/ /2/ /3/

23 Renal Clinic BP 95/52 Height and weight 90 th centiles Urine ++ protein, + glucose Started phosphate supps Protein:creatinine ratio 218mg/mmol

24 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

25 Nephrotoxicity Pre-renal Intrinsic/Renal Post-renal

26 Nelsons Textbook of Paediatrics © 2005 Elsevier Glomerulus Site of ultrafiltration Fluid and solutes pass though endothelium, basement membrane and podocytes into the proximal tubule

27 Downloaded from: Nelson Textbook of Pediatrics (on 17 May :29 PM) © 2005 Elsevier Nephron Proximal tubule: 2/3 H 2 O + sodium, phosphate, glucose, amino acids, urea, potassium Distal tubule: Bicarbonate, potassium, sodium, calcium

28 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

29 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

30 Disease-related renal dysfunction Renal tumours Pelvic tumours Tumour infiltration Hypercalcaemia Hyperviscosity Tumour-lysis syndrome Younger children < 5y, worse off Sepsis-related hypotension

31 Renal tubulointerstitial toxicity Clinical signs: Electrolyte wasting Renal tubular acidosis Loss of urine concentrating ability GFR Glycosuria Aminoaciduria (Fanconi syndrome)

32 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

33 Glomerular injury Proteinuria: Albumin and Ig ’ s GFR Pl Creat +Urea ps: PC won ’ t rise until 30% reduction in GFR

34 Assessment of renal function GFR EDTA GFR 24-hour Urinary creatinine clearance Proximal tubules Wasting of Ca, PO 4, Mg, glucose, LMW proteins Distal tubules Urine osmo and pH Urinalysis, +/- microscopy for casts

35 Serum creatinine Not always accurate in cancer patients Secondary loss of muscle mass Cachexia physical activity Corticosteroid-induced myopathy Limited protein intake

36 Anticancer drugs with inherent nephrotoxicity Alkylating and platinating agents Chloroethylnitrosoureas carmustine semustine streptozocin Cisplatin Carboplatin Ifosfamide Antimetabolites Azacitidine Gemcitabine Methotrexate Pentostatin Miscellaneous Diaziquone Interferon α Mitomycin

37 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

38 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

39 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 % Most common sequelae is hypo-PO 4

40 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

41 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

42 Skinner et al Dose = 6-9g/m 2 Continuous 72 hours or bursts for 3 days Median total dose = 62g/m 2 over eight cycles at three weekly intervals All received high dose IV fluids All received continuous infusion Mesna

43 Skinner et al 121 of 148 patients also had other nephrotoxic agents: Cisplatin Aminoglycoside antibiotics Vancomycin Aciclovir Amphotericin

44 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)

45 Skinner et al GFR < 90ml/min/1.73m 2 in 50% GFR < 60ml/min/1.73m 2 in 9% Statistical reduction in GFR from diagnosis to end of Rx in 67 patients Serum creatinine elevated in 43%

46 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%.

47 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

48 Nephrotoxicity Nephrotoxicity score: 76 patients Severity nephrotoxicityPercentage None22% Mild50% Moderate20% Severe8%

49 Risk factors Only factor to have significant effect after multiple regression analysis is TOTAL DOSE No safe dose discernible Dose >80g/m 2 = greater proximal tubular damage Dose >50g/m 2 = increased risk of moderate-severe rather than mild

50 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

51 Long term prognosis Skinner et al, 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/1.73m 2 in 13%

52 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

53 Other drugs Cisplatin / carboplatin Bonding with DNA, RNA Dose-related nephrotoxicity Cisplatin:at standard doses Carbaplatin: high doses Aminoglycosides potentiate effect

54 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

55 Prevention of nephrotoxicity Avoid combination of nephrotoxic medication Vigorous saline-based hyperhydration – 3 l/m²/24h Amifostine for Cisplatin Urinary alkalinisation with Methotrexate

56 Management of Nephrotoxicity Meticulous fluid balance:daily weight Replace losses: PO 4, Mg, Ca Optimise nutrition

57 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

58 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): 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); 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


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