Chemotherapy and Renal Toxicity

1. Chemotherapy andRenal Toxicity Christine Lau, M.D. UCLA Nephrology February 24, 2010

2. Outline • Platinum-based therapies • Antimetabolites • Antitumor antibiotic • Alkylating agents • VEGF pathway inhibitor • Tumor lysis syndrome • Hematopoietic cell transplantation

3. Risk factors • Intravascular volume depletion • Other nephrotoxic medications: NSAIDs, antibiotics, concurrent chemotherapy • IV contrast • Urinary tract obstruction by tumor • Intrinsic renal disease

4. Platinum-based therapies:Cisplatin • Antitumor effects: binds to DNA creating inter- and intrastrand cross-links  defective DNA templates  arrest of DNA synthesis and replication • Dose-related renal toxicity occurs in 1/3 of patients • Can lead to progressive chronic kidney disease • >50% excreted in urine in first 24 hours • Concentrated in renal cortex leading to injury of proximal tubule

5. Cisplatin Cisplatin uptake by renal tubular cells Vascular injury ROS P53 MAPK TNF-α p21 Ischemia Renal tubular cell death Inflammation Renal tissue damage Decrease in GFR Acute kidney injury Platinum-based therapies:Cisplatin Pabla N. Cisplatin nephrotoxicity. Kidney Int. 2008.

6. Platinum-based therapies:Cisplatin • Clinical manifestations • Acute kidney injury • Hypomagnesemia from urinary magnesium wasting • Fanconi-like syndrome • Salt wasting • Prevention of nephrotoxicity • Lower doses, IVF hydration, amifostine, use of other platinum-based therapies • Renoprotection • Sodium thiosulfate, N-acetylcysteine, theophylline, glycine

7. Platinum-based therapies:Carboplatin • Less renal toxicity than cisplatin unless used at high doses in hematopoietic cell transplantation • Similar clinical manifestations as cisplatin • Higher risk when used with other chemotherapeutic agents

8. Antimetabolites:Methotrexate • Antitumor effects: blocks nucleotide synthesis by inhibiting dihydrofolate reductase • Renal toxicity occurs when serum levels are elevated as 90% cleared by kidneys • Poorly soluble at acidic pH • Precipitation of MTX and metabolites in renal tubules • Worsening renal function  decreased clearance of drug

9. Antimetabolites:Methotrexate • Renal protection • IVF hydration • Urinary alkalinization to keep urine pH>7 • Leucovorin rescue • Carboxypeptidase-G2 • Role of dialysis for clearance

10. Antimetabolites:Methotrexate Widemann BC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006.

11. Antimetabolites:Gemcitabine • Antitumor effects: pyrimidine analogue that inhibits DNA synthesis • Associated with TMA with incidence 0.015% per manufacturer’s estimate • TMA: renal failure, thrombocytopenia, MAHA • Case series from MGH showed new or exacerbated HTN in 7 of 9 patients

12. Antimetabolites:Gemcitabine Humphreys BD. Gemcitabine-associated thrombotic microangiopathy. Cancer. 2004. Thickening of glomerular capillary walls, widespread basement membrane reduplication in chainlike pattern Subendothelial basement membrane reduplication, widespread foot process effacement

13. Antitumor antibiotic:Mitomycin • Antitumor effects: activated to super-oxide radicals  inhibition of DNA synthesis and function • Associated with TTP/HUS with incidence ~10% • May be dose-related: higher risk when cumulative dose >40-50 mg/m2

14. Antitumor antibiotic:Mitomycin • Pathogenesis • Damaged endothelial cells form unusually large vWF multimers  intravascular platelet clumping and microangiopathy • Idiopathic TTP now shown to be caused by ultralarge vWF multimers

15. Alkylating agents:Cyclophosphamide • Antitumor effects: crosslinks DNA  impairs DNA replication and transcription • Hyponatremia: inability to dilute urine • SIADH vs. enhanced permeability of distal tubule to water • Worsened by nausea/vomiting and hypotonic fluid hydration • Usually seen in high dose (50 mg/kg) but case reports in low-moderate dose

16. Alkylating agents:Cyclophosphamide • Hemorrhagic cystitis • Metabolite acrolein causes denudation of bladder epithelium • Association with BK virus in late onset HC • Renoprotection: mesna, IVF hydration, limit duration of use, avoidance of nighttime dosing, pulsed dosing instead of daily

17. Alkylating agents:Ifosfamide • Hemorrhagic cystitis • Proximal tubular damage • Electrolyte wasting • Fanconi-like syndrome • Can progress to ESRD • Risk increased with previous use of cisplatin

18. VEGF pathway inhibitor:Bevacizumab • Antitumor effects: inhibits vascular endothelial growth factor  decreased angiogenesis • Proteinuria • Incidence ranges from 23 to 65% depending on malignancy • Can present with HTN also • Pathogenesis: inhibition of VEGF causes loss of endothelial fenestrations in glomerular capillaries, loss of podocytes • Subacute TMA: similar to pathology of preeclampsia/ eclampsia

19. VEGF pathway inhibitor:Bevacizumab • Management • Hold treatment for nephrotic range proteinuria • ACE inh or ARBs for BPs>130/80 • Renal biopsy: metastatic disease with proteinuria, progressive kidney disease, unexplained AKI, nephritic syndrome, persistent proteinuria despite discontinuation of drug

20. VEGF pathway inhibitor:Bevacizumab Izzedine H. VEGF signalling inhibition-induced proteinuria. Eur J Cancer. 2009.

21. Tumor lysis syndrome • Massive tumor cell lysis with release of K, phos, and nucleic acids into systemic circulation • Diagnosis: two or more lab abnormalities 3 days before or 7 days after starting chemotherapy • Uric acid  8 mg/dL or 25% increase above baseline • K  6 mmol/L or 25% increase above baseline • Phos  4.5 mg/dL or 25% increase above baseline • Ca  7 mg/dL or 25% decrease below baseline • Uric acid • Allopurinol: can cause xanthinuria • Rasburicase: use as prophylaxis in high risk patients

22. Tumor lysis syndrome • Prevention • IVF hydration to maintain UOP ~100 cc/hr • Allopurinol/rasburicase • Urinary alkalinization not recommended unless there is metabolic acidosis • Dialysis • 5% will require HD • Prognosis is excellent if initiated early

23. Hematopoietic cell transplantation • IVIG • Hepatic veno-occlusive disease • Graft versus host disease • Hemolysis in ABO incompatible transplant • Calcineurin inhibitor toxicity • Sepsis

24. Hematopoietic cell transplantation:IVIG • Osmotic nephrosis 2/2 sucrose stabilizers • “Pinocytosis theory”: sucrose enters tubular cells by pinocytosis  vacuoles fuse with each other and lysosomes  form vacuoles that contain agent and hydrolytic enzymes • Risk factors: pre-existing renal dysfunction, kidney transplant • Usually reversible AKI with discontinuation of drug • Hyponatremia: pseudo vs. true

25. Hematopoietic cell transplantation:Hepatic veno-occlusive disease • Pathogenesis • Injury to hepatic venous endothelium  deposition of fibrinogen and factor VIII in walls and sinusoids  occlusion of terminal hepatic venules and sinusoids  centrilobular hemorrhagic necrosis • Clinical manifestations • Hepatomegaly, RUQ pain, jaundice, ascites; occurs in up to 50% of allogeneic HCT • AKI in 80% of patients • Hepatorenal-like syndrome (FeNa <1%, portal HTN) • Often triggered by superimposed event • Initiation of HD portends poor prognosis

26. Hematopoietic cell transplantation:Graft versus host disease • GVHD of kidney • Case reports of nephrotic syndrome after cessation of immunosuppression and GVHD of other organs • Membranous GN and minimal change disease usually seen on biopsy • GVHD of liver • Severe GVHD can cause cirrhosis and associated hepatorenal syndrome

27. Hematopoietic cell transplantation:Hemolysis in ABO incompatible transplant • AKI secondary to ATN: • Obstruction with intratubular heme pigment casts • Proximal tubular cell injury from free chelatable iron • Concurrent volume depletion and renal ischemia • Diagnosis • Hemoglobinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, high LDH, low haptoglobin

28. Hematopoietic cell transplantation:Calcineurin inhibitor toxicity • Acute • Vasoconstriction of glomerular arterioles • Oliguric ATN with elevated doses • Chronic • Arteriolar hyalinosis • Glomerulosclerosis • Tubular atrophy and interstitial fibrosis • TMA • Prothrombotic effects of cyclosporine

29. Hematopoietic cell transplantation:Sepsis • ATN from decreased renal perfusion • Incidence reported ranges from 13% to 60% • Increased risk of mortality • Supportive care

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