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Brief Review Of Chemotherapeutic Agents And Renal Failure

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  • Chemotherapy agents can also cause increased systemic toxicity due to delayed drug excretion especially in pts with CKD. Other nephrotoxic agents-NSAIDS, aminoglycosides. So renal function should be carefully re-assessed frequently and dosing adjusted as needed
  • Bifunctional??
  • Pt Cl Cl NH3 NH3
  • In 2002, Ishida et al showed that deletion of Ctrl, high affinity copper transporter results in reduced intracellular accumulation of cisplatin in yeast which is associated by increased resistance to cisplatin toxicity. It is interesting to note that CTrl is also highly expressed in proximal tubular cells.
  • Females may have increased toxicity due to lower unbound cisplatin clearance- found to 15% less in women according to a study.( OR 2.0) Smoking-speculative- may be due to increased oxidative stress( OR2.5) Hypoalbuminemia- increased plasma concentrations of unbound cisplatin( OR 3.4) Paclitaxel- unknown but OR(4.0)
  • A study “ Magnesium depletion enhances cisplatin-induced nephrotoxicity” in cancer chemotherapy and pharmacology, 2005 has shown. Conducted in rats. Mechanism unknown. Mg deprivation is believed to cause oxidative stress and cell death and cause pro-inflammatory stress response which could contribute.
  • In a study published in Annals of Internal medicine in 1982- “ Intraperitoneal cisplatin with systemic thiosuplhate protection” Seventeen patients with intraperitoneal tumors were treated by 4-hour intraperitoneal dialysis with cisplatin alone, or in combination with an intravenous neutralizing agent, sodium thiosulfate. Cisplatin alone, 90 mg/m2 body surface area intraperitoneally, produced nephrotoxicity. When intraperitoneal cisplatin therapy was combined with intravenous thiosulfate treatment, the dose of cisplatin could be escalated to 270 mg/m2 body surface area without causing an increase in serum creatinine levels or undue myelosuppression. NAC- again a thiol-believed to act on death receptor and mitochondrial apoptotic pathways.. One case report used it as salvage therapy with benefit. Theophylline-one small study Glycine-animal studies Coreg-rats studies-preventing mitochondrial dysfunction induced by cisplatin. Was shown earlier to be protective against doxorubicin cardiotoxicity-associated with free radical production. PPAR: mice.antiinflammatory
  • Both were ovarian carcinoma pts treated previously with cisplatin and received IP carboplatin, with normal baseline renal function. Creatinine increased upto 9.5 in both. One pt required HD briefly. Creatinine decreased to 4.6 and 2 respectively.
  • Renal salt wasting reported in a child treated with carboplatin and etoposide- resolved later- likely due to proximal tubular dysfunction.
  • Mesna vs hyperhydration for prevention of hemorrhagic cystitis in BMT- journal of oncology-1991.
  • Pathogenesis poorly understood. Fanconi’s syndrome---proximal tubular dysfunction leading to loss of bicarbonate, amino acids, glucose, potassium,phosphate,uric acid,magnesium,sodium in urine. Glomerular and distal tubular toxicity also may be seen.
  • Classified as an antibiotic. Causes crosslinking of DNA and inhibits DNA synthesis.
  • Relatively high incidence of proteniuria suggests possible ancillary role for adaptive hyperfiltration response to reduced nephron number either due to nephrectomy or replacement by tumor.

Transcript

  • 1. A Brief Review of Chemotherapeutic Agents and Renal Failure Nephrology Grand Rounds 2-2-2010 Dr. Lakshmi A Turlapati
  • 2. Introduction
    • Renal failure in a cancer patient can be multifactorial.
      • Prerenal
      • Intrinsic
      • Postrenal
  • 3.  
  • 4. Chemotherapeutic Agents
    • Cancer Chemotherapeutic agents can cause nephrotoxicity in various ways.
    • Some drugs are known to be more nephrotoxic than others.
    • Some cause immediate effects while some are known to cause appreciable renal toxicity only when used for a long time.
  • 5.  
  • 6. Chemotherapeutic Agents Glomerulus VEGF inhibitors, Nitrosoureas, Interferons Tubules Cisplatin, Carboplatin, Ifosfamide, Cyclophosphamide, Streptozocin, Nitrosoureas, Methotrexate Interstitium Cisplatin, Carboplatin Renal microvasculature VEGF inhibitors, Mitomycin, Gemcitabine
  • 7. Chemotherapeutic Agents
    • Risk Factors
      • Chronic kidney disease
      • Concomitant use of other nephrotoxic drugs.
      • Dehydration secondary to nausea/vomiting
      • Intrinsic kidney disease secondary to cancer.
  • 8. Chemotherapeutic Agents
    • Platinum compounds- Cisplatin, Carboplatin
    • Alkylating Agents- Cyclophosphamide, Ifosfamide
    • Nitrosoureas
    • Antitumor antibiotics- Mitomycin C
    • Antimetabolites- Methotrexate, Gemcitabine
    • VEGF pathway inhibitors
    • EGFR Pathway inhibitors
    • Interferons
  • 9. Cisplatin
    • One of the most widely used and most nephrotoxic chemotherapeutic agents.
    • Non-cell cycle specific, alkylating agent.
    • Used for lymphoma, testicular carcinoma, bladder, gastric, head and neck, non-small cell lung, ovarian, and small cell lung cancers.
  • 10. Cisplatin
    • In the blood, cisplatin is present in an inactive, uncharged state due to the high concentration of chloride ions.
    • Cisplatin enters cells by passive diffusion.
    • Intracellularly, cisplatin loses its two chloride groups and becomes a positively charged electrophilic compound.
    • Cisplatin then binds with DNA, RNA, or other macromolecules at two sites to form interstrand and intrastrand links that cause changes in the conformation of the DNA and affects DNA replication.
  • 11. Cisplatin
    • Cisplatin is renally excreted.
    • Concentration of platinum achieved in renal cortex is several folds greater than plasma and other organs.
    • Organic cationic transporters have been implicated in cisplatin uptake in renal tubular cells.
    • Primarily injures the S3 segment of the proximal tubule.
    • Tubular injury also stimulate inflammatory response causing further damage.
    • Also induces vasoconstriction in the renal vasculature thus reducing renal blood flow and causing ischemic injury.
  • 12.  
  • 13. Risk Factors
    • Higher doses
    • Previous cisplatin therapy
    • Underlying kidney dysfunction
    • Older age
    • Female gender
    • Smoking
    • Hypoalbuminemia
    • Paclitaxel co-administration
    British Journal of Cancer (2003) 88, 1199 – 1206
  • 14. Clinical Features
    • Clinically, Nephrotoxicity is seen usually within 10 days of Cisplatin administration.
    • It is usually dose dependent.
    • It is manifested by acute renal failure, hypokalemia , hypomagnesemia and Fanconi like syndrome.
    • Hypomagnesemia may exacerbate Cisplatin toxicity.
  • 15. Clinical Features
    • UOP typically remains above 1 liter/day (unless renal dysfunction is severe) due to induction of a concentrating defect, due to platinum induced damage to the loop of henle or decrease in aquaporin water channels in collecting tubules.
    • It is also believed that cisplatin treatment may lead to long term reduction in GFR as well.
  • 16. Strategies for prevention
    • Lower doses of cisplatin
    • Administration of intravenous saline.
    • Sodium thiosulphate- binds to cisplatin and render it non-toxic. Used in setting of IP cisplatin.
    • Amifostine: an organic thiophosphate, donates a thiol group selectively in normal tissues and not in malignant tissues, to bind to cisplatin. Major concerns are cost and possible interference with tumor efficacy.
    • Cimetidine-inhibitor of OCTs- could be used to decrease uptake.Imatinib, an anti-cancer agents also decreases uptake by affecting OCTs.
    • Antioxidants have been tried-unclear benefit.
    • Other agents that have been explored include N-acetylcysteine, theophylline,glycine,PPAR agonists,coreg etc.
  • 17. Carboplatin
    • Used for lung,ovarian,head and neck cancer.
    • Anti tumor activity is alkylation of DNA followed by killing of cancerous cells.
    • Believed to be safer than cisplatin.
    • This increase in safety is likely from enhanced stability of carboplatin which has carboxylate and cyclobutane moieties in the cis position, rather than choride.
    • However acute renal failure has been reported with carboplatin.
  • 18. Carboplatin
    • A case report describes 2 patients with carboplatin toxicity developing acute renal failure.
    • Biopsy specimens showed focal and moderate interstitial nephritis with periglomerular fibrosis in one specimen and edematous interstitium with diffuse mononuclear infiltrate and toxic changes in tubules in the other.
    • Renal function improved with prednisone treatment @1 mg/kg/day for 4 weeks.
    The American Journal of Medicine Volume 90, Issue 1 , January 1991, Pages 386-391
  • 19. Carboplatin
    • Decrease in GFR has been noted in children after treatment with carboplatin.
    • Direct tubular injury seems to be the mechanism and is dose dependent.
    • Hypomagnesemia is a more common side effect.
    • Renal salt wasting has also been reported.
    • Careful monitoring of renal function is warranted.
    References 14,15,16
  • 20. Cyclophosphamide
    • Cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as to inhibition of protein synthesis.
    • Used for hematologic malignancies.
    • Major toxicity of cyclophosphamide is hemorrhagic cystitis.
    • One of the metabolites acrolein causes cystitis.
    • Mesna and IV hydration are mainly used for prevention.
    • IV hydration induces brisk diuresis and prevents accumulation of acrolein in the urinary bladder and collecting system.
    • Mesna contains a sulfhydryl group that binds acrolein and detoxifies it.
    J Clin Oncol 9:2016-2020.
  • 21. Cyclophosphamide
    • Hyponatremia has also been reported.
    • Mechanism could be increased ADH or amplifications of the renal effects of ADH or a direct effect on the kidney resulting in enhanced permeability of distal tubules to water.
    • Water retention is usually acute and resolves within 24 hrs of withdrawal of drug.
    • Hypotonic solutions should be avoided while giving cyclophosphamide to prevent severe hyponatremia.
    Arch Intern Med 1985;145:548-549
  • 22. Cyclophosphamide
    • In experimental animals, cyclophosphamide can cause nephrotoxicity similar to acute tubular necrosis.
    • Rare in humans.
  • 23. Ifosfamide
    • Synthetic analog of cyclophosphamide.
    • Nephrotoxicity is more prominent feature especially when given along with other nephrotoxic agents like Cisplatin.
    • Usually used in children for Osteosarcoma, Ewing’s Sarcoma, Germ cell tumors, Lymphoma, Neuroblastoma etc.
  • 24. Ifosfamide
    • Proximal tubular dysfunction is the most common presentation which could lead to Fanconi’s syndrome, hypophosphatemic rickets and proximal renal tubular acidosis.
    • Usually acute and reversible.
    • Chronic progressive toxicity has been reported and long term evaluation in children is needed.
    • Mesna can be given for prevention.
    References 19,20
  • 25. Nitrosoureas
    • Carmustine, Semustine, Lomustine and Streptozocin.
    • Used for malignant brain tumors,melanomas.
    • They induce chronic interstitial nephritis which is slowly progressive and irreversible.
    • Glomerular sclerosis and interstitial fibrosis has been seen.
    • Exact mechanism is unknown but may be due to alkylation of tubular proteins.
  • 26. Nitrosoureas
    • Of the four agents, Semustine and Streptozocin are more nephrotoxic.
    • Mild proteinuria or an asymptomatic elevation of creatinine is usually the first sign of renal involvement.
    • Onset of clinical nephrotoxicity may be delayed up to months to years after last dose.
    • Careful follow up is essential.
    • No known therapy.
  • 27. Mitomycin C
    • Used for pancreatic and gastric cancers.
    • Most common form of nephrotoxicity is renal failure and microangiopathic hemolytic anemia.
    • Most likely occurs after 6 months of therapy.
    • Dose dependent.
    • Incidence ranges from less than 2 to 15%.
  • 28. Mitomycin C
    • It is believed that direct endothelial injury is the inciting event.
    • Few cases have shown glomerular nuclear degeneration, sclerosis and thickened basement membranes but most have fibrin deposition in the small renal arterioles.
    Cancer treatment Reviews(1982)9,37-56
  • 29. Mitomycin C
    • Clinical Features include slowly progressive renal failure and hypertension.
    • Patients may have bland urine sediment or may present with hematuria and proteinuria.
    • Non-cardiogenic pulmonary edema may be seen.
    • Renal failure may respond to plasmapheresis or immunoabsorption of serum on staphylococcal protein A column.
    Journal of Clinical Oncology, Vol 7, 781-789 Nephron. 1989;51(3):409-12
  • 30. Methotrexate
    • Used for leukemias, head and neck cancer, lung cancer, breast cancer, lymphoma.
    • At low doses it is not usually associated with renal toxicity but may be seen.
    • However with high doses, nephrotoxicity can occur significantly- 60% in one report.
  • 31. Methotrexate
    • Methotrexate is renally excreted.
    • At lower pH, it precipitates and causes tubular injury.
    • Pts who are dehydrated and excrete acidic urine are especially at risk.
    • Extensive necrosis of the epithelium of the convuluted tubules has been seen.
    • Hence IV hydration and urinary alkalinizations are mainstays in prevention.
    References 2,24
  • 32. Gemcitabine
    • Used for pancreatic tumors, metastatic breast cancer, non-small cell lung cancer,ovarian cancer.
    • Renal failure and microagiopathic hemolytic anemia has been associated.
    • Incidence lesser than mitomycin C. Approximately 0.008%-0.078% .
    • Interval from the last dose of gemcitabine to development of HUS ranged from 1 day to several months.
    AJKD Volume 40, Issue 4 (October 2002)
  • 33. Gemcitabine
    • Association with cumulative dose is less clear cut than Mitomycin C.
    • High index of suspicion is needed.
    • Withdrawal of drug, steroids and plasmapheresis have been tried with variable response.
    • Case fatality is high- 50-70%.
    AJKD Volume 40, Issue 4 (October 2002)
  • 34. VEGF Pathway Inhibitors
    • Bevacizumab
    • Monoclonal antibody that binds circulating VEGF and prevents activation of VEGF receptor.
    • Used for metastatic colorectal cancer, metastatic breast cancer, metastatic renal cell cancer, non-small cell lung cancer, glioblastoma
  • 35. VEGF Pathway Inhibitors
    • Sunitinib, Sorefenib
    • Small molecule tyrosine kinase inhibitors that block the intracellular domain of the VEGF receptor.
    • Used for advanced renal cell carcinoma and gastrointestinal stromal tumors.
  • 36. VEGF in Normal Kidney
    • VEGF is an endothelial-specific growth factor that promotes endothelial cell proliferation,differentiation and survival.
    • In the kidney, VEGF receptors are located on preglomerular,glomerular and peritubular endothelial cells.
    • VEGF is required for growth and proliferation of glomerular and peritubular endothelial cells.
  • 37. VEGF Pathway Inhibitors
    • VEGF may be an essential mediator of glomerular recovery in proliferative glomerulonephritis.
    • Loss of VEGF is associated with the development of glomerulosclerosis and tubulointerstitial fibrosis.
    • VEGF inhibition is believed to suppress nephrin affecting integrity of glomerular slit membrane causing proteinuria.
  • 38. VEGF Pathway Inhibitors
    • Proteinuria and hypertension are major side effects.
    • Incidence of Hypertension ranges from 2.7 to 35.9%.
    • Incidence of mild and asymptomatic proteinuria may range from 21% in colorectal cancer pts to 63% in renal cell cancer pts.
    • Heavy proteinuria up to >3.5 g/day is seen in 6.5% of renal cell carcinoma pts.
    EUROPEAN JOURNAL OF CANCER 4 6 ( 2 0 1 0 ) 4 3 9 –4 4 8
  • 39. VEGF Pathway Inhibitors
    • Renal pathological findings in cases of heavy proteinuria include 12 cases of thrombotic microangiopathy, 2 cases of collapsing glomerulopathy, one case of cryoglobulinemic glomerulonephritis, one case of immune complex associated focal proliferative glomerulonephritis and sorafenib-induced acute interstitial nephritis.
    References 26,27
  • 40. VEGF Pathway Inhibitors
    • Though Biopsies have shown TMA, clinical features may range from proteinuria, hematuria, renal insufficiency to microangiopathic hemolytic anemia.
    • However extrarenal manifestations of TMA are very rare.
  • 41. VEGF Pathway Inhibitors
    • Management is conservative .
    • Antihypertensive agents are used to control BP.
    • ACE/ARBs are used to minimize proteinuria but may not work.
    • Proteinuria usually responds to withdrawal of drug.
    • Occasionally it may lead to progressive renal failure.
    Ann Oncol 18: 1745-1747
  • 42. VEGF Pathway Inhibitors
    • Role of Plasma Exchange
      • One case of Bevacizumab associated TMA which resolved once with discontinuation of drug and subsequently had relapse when was treated again with sunitinib responded to discontinuation of treatment and plasma exchange.
      • Another case of TMA responded to drug withdrawal, anti Hypertensive agents, steriods and plasma exchange.
      • However, role of plasma exchange still needs to be evaluated.
  • 43.  
  • 44. EGFR pathway inhibitors
    • Cetuximab, Panitumumab,Matuzumab
    • Monoclonal antibodies targeting the epidermal growth factor receptor
    • Progressive development of hypomagnesemia due to magnesium wasting in the urine.
  • 45. Interferons
    • Interferon alpha can cause proteinuria, which can be nephrotic range- histology could be minimal change or FSGS.
    • Interferon gamma has been associated with Acute tubular necrosis.
    AJKD Vol 28, Issue 6 , December 1996, Pages 888-892
  • 46. Summary
    • Always look at the chemotherapy drugs which the patient has been on currently and in past when evaluating renal failure.
    • Some drugs can cause progressive renal failure/ HUS months after their last dose. ( like nitrosoureas, mitomycin, gemcitabine)
    • Some drugs though known to be safe may cause renal failure, like carboplatin. So have low threshold.
    • VEGF inhibitors may have TMA like pathology with minimal findings- only proteinuria without hemolytic anemia, low platelets, schistocytes etc. Consider biopsy.
  • 47. References
    • 1: Renal Failure Associated with Cancer and Its Treatment:An Update -56 J Am Soc Nephrol 16: 151–161, 2005
    • 2: The Renal toxicity of cancer chemotherapeutic agents. Cancer treatment reviews(1982)9,37-56
    • 3:Cisplatin nephrotoxicity: Mechanisms and Reno protective strategies. Kidney International (2008) 73, 994–1007
    • 4 Mechanism of cisplatin nephrotoxicity. Fed Proc. 1983 Oct;42(13):2974-8
    • 5: Reduced renal blood flow in early cisplatin-induced acute renal failure in the rat J. A. Winston and R. Safirstein Am J Physiol Renal Physiol 249: F490-F496, 1985
    • 6: Cisplatin Decreases the Abundance of Aquaporin Water Channels in Rat Kidney. J Am Soc Nephrol 12: 875–882, 2001
    • 7: Long-Term Renal Effect of Cisplatin in Man Am J Nephrol 1994;14:81-84
    • 8: Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. British Journal of Cancer (2003) 88, 1199 – 1206
    • 9:Amifostine reduces the incidence of cumulative nephrotoxicity from cisplatin: laboratory and clinical aspects. Semin Oncol. 1999 Apr;26(2 Suppl 7):72-81.
    • 10: Protective effect of concomitant administration of imatinib on cisplatin-inducednephrotoxicity focusing on renal organic cation transporter OCT2. Biochemical Pharmacology 78 (2009) 1263–1271
    • 11: Carvedilol protects against the renal mitochondrial toxicity induced by cisplatin in rats. Mitochondrion 10 (2010) 46–53
    • 12: Agents ameliorating or augmenting the nephrotoxicity of cisplatinand other platinum compounds: A review of some recent research. Food and Chemical Toxicology 44 (2006) 1173–1183
    • 13: Acute renal failure associated with the use of intraperitoneal carboplatin: A report of two cases and review of the literature. The American Journal of Medicine V olume 90, Issue 1 , January 1991, Pages 386-391
    • 14: Time response of carboplatin-induced nephrotoxicity in rats.Pharmacological Research 50 (2004) 291–300
    • 15: Dose-related nephrotoxicity of carboplatin in children. British Journal of Cancer (1999) 81(2), 336–341
  • 48. References
    • 16: Recurrent renal salt wasting in a child treated with carboplatin and etoposide. Volume 73 Issue 6 , Pages 1761 - 1763
    • 17: Water Intoxication Following Moderate-Dose Intravenous Cyclophosphamide.Robert B. Bressler, MD, David P. Huston, MD. Arch Intern Med 1985;145:548-549
    • 18: Mesna Versus Hyperhydration for the Prevention of Cyclophosphamide-Induced Hemorrhagic Cystitis in Bone Marrow Transplantation. J Clin Oncol 9:2016-2020. © 1991 by American Society of Clinical Oncology
    • 19 Chronic ifosfamide nephrotoxicity in children. Med Pediatr Oncol. 2003 Sep;41(3):190-7.
    • 20: Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J Clin Oncol. 2009 Nov 10;27(32):5350-5. Epub 2009 Oct 13.
    • 21: Nephrotoxicity of Nitroso ureas Cancer 48:1328-1334, 1981
    • 22: Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry. Journal of Clinical Oncology, Vol 7, 781-789.
    • 23: Successful treatment of mitomycin C-associated hemolytic uremic syndrome by plasmapheresis. Nephron. 1989;51(3):409-12
    • 24: Renal toxicity of methotrexate. PT Condit, RE Chanes - Cancer, 1969
    • 25: Gemcitabine-associated hemolytic-uremic syndrome. American Journal of Kidney Diseases - Volume 40, Issue 4 (October 2002
    • 26: VEGF signalling inhibition-induced proteinuria: Mechanisms,significance and management. EUROPEAN JOURNAL OF CANCER 4 6 ( 2 0 1 0 ) 4 3 9 –4 4 8
    • 27: Nephrotic Syndrome After Bevacizumab: Case Report and Literature Review American Journal of Kidney Diseases, Vol 49, No 2 (February), 2007: E23-E29
    • 28: Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome E. Kapiteijn , A. Brand , J. Kroep , and H. Gelderblom Ann Oncol 18: 1745-1747
    • 29: Guidelines for the management of side effects of bevacizumab in patients with colorectal cancer Cancer Therapy Vol 6, 327-340, 2008
    • 30: Progressive bevacizumab-associated renal thrombotic Microangiopathy. NDT Plus (2009) 2: 36–39
    • 31: Focal segmental glomerulosclerosis with acute renal failure associated with α-interferon therapy American Journal of Kidney Diseases Volume 28, Issue 6 , December 1996, Pages 888-892