Renal Dosing of Chemotherapeutic Agents
RENAL DOSING OF CHEMOTHERAPEUTIC AGENTS
This discussion focuses on the appropriate dosing of chemotherapeutic agents where renal compromise exists. It should be recalled that the following agents may precipitate acute renal failure, however not all of the agents that could provide an acute insult to the kidneys would have to be renally dosed. CHEMOTHERAPY DRUGS THAT CAN INDUCE RENAL DYSFUNCTION: In general, renal damage that might ocur secondary to chemotherapy is due to renal tubule damage. Certain parameters often correlate with state of hydration, drug dose, and conomittant administration of additional nephrotoxic agents (aminoglycosides, etc) In addition, where two drugs with known nephrotoxicity are used together, such as ifosfomide, MTX, or cisplatin, significant impact on renal function can be seen. 5-Azacytidine Acute tubular injury- both proximal and distal damage
  • Hypo-osmolar urine
  • Polyuria and rising creatinine 7-10 days post-dose
  • Treat with replacement of electrolytes, especially check for hypophosphatemia (signs are muscle pain and tenderness, difficulty breathing, etc)
Cisplatin Can cause acute necrosis of proximal convoluted tubules.
  • Improved use of hydration leads to decreased toxicity. Newer agents,such as carboplatin are considered less nephrotoxic, and used where possible.
  • Often nephrotoxicity not seen for as long as 7 days later
  • Also associated are modest proteinuria
  • Usually magnesium wasting strongly clinically associated with nephron damage
  • To treat, cessation of drug
  • Recovery is usually incomplete
Carboplatin Renal dysfunction less frequent than with cisplatin, rarely seen in those with pre-existing renal damage due to cisplatin Cyclophosphamide May cause acute tubular necrosis rarely, may produce ADH effects similar to SIADH, but cystitis and hematuria is seen more frequently
  • Hematuria can be seen in large doses or in prolonged infusions and is related to sterile hemorrhagic cystitis.
  • Adequate hydration decreases incidence of cystitis
  • Consider MESNA at doses greater than 1.5gm/m2
Gemcitabine
  • Appears to have nephrotoxic potential.
  • Proteinuria and hematuria described in up to 45% of patients
  • Very rare incidence of HUS syndrome ( 0.015-0.25%) but association with this drug uncertain at this time
  • Monitor BUN/SRCR
Interferon Rarely reported alone, may be interstitial nephritis type reaction
  • Proteinuria and possibly hypertension would suggest checking renal function, decreased GFR may be seen, however, BUN and SRCR may remain normal
Interleukin-2 Therapy associated with varying degrees of renal impairment.
  • Incidence and degree of abnormality correlates with dose and duration of aldesleukin
  • Azotemia, oliguria, edema probably point to pre-renal cause, not acute tubular necrosis
  • If renal dysfunction seen, usually within 1-2 days of therapy.
  • Usually reversible at 7 days post-dose
  • Where prophylatic NSAIDs are also used, renal prostaglandins production may decrease and add to or cause the renal impairment seen with aldesleukin
  • When renal damage seen, SRCR and BUN begin to rise several days after dose and hypotension and increasing interstitial edema is noted.
Isofosfamide May cause tubular damage leading to acute tubular necrosis and renal failure. Rare when given with MESNA.
  • Dose dependent, invariable when given in high doses
  • Can see uro-epithelial direct damage as with cyclophosphamide
Methotrexate
  • May cause acute tubular necrosis in the renal tubule and has been termed "crystalline hydronephrosis" as crystal deposits of MTX and its less soluble principle metabolite, 7 hydroxy-MTX in the renal tubules causes changes in GFR.
  • Avoid by assuring adequate hydration prior to drug, alkalinizing urine to pH of 7 or higher. Urine outflow should be 100ml/hr and hopefully more.
  • Weak organic acids like salicylates or sulfisoxizole increases MTX levesl by displacing drug on binding sites on plasma proteins.
  • Probenecid (may double serum MTX levels) and salicylates (especially in high-dose MTX infusions) diminish tubular transport and may lead to increased MTX levels and toxicity
  • Supportive dialysis; recovery is incomplete
Mithramycin
  • Sometimes used for blast crisis in CML, otherwise older product to reduce serum calcium concentration.
  • Rare acute tubular lesions
  • Abrupt renal failure presenting with mild proteinuria, rising creatinine and BUN
  • DC drug, may restart if renal function returns to normal, alternate day BUN/SRCR
Mitomycin C
  • A striking hemolytic-uremic syndrome (HUS) sometimes manifested by early elevation of serum creatinine or anemia with rise in serum lactic dehydrogenase (LDH) indicating hemolysis. Also focal glomerular necrosis can be seen.
  • HUS rarely seen with total accumulative doses of less than 30mg/m2 or 60mg. Microangiopathic (HCT less than 25%) in conjuction with thrombocytopenia and irreversible renal failure. Thombosis found in glomerular capillaries and arterioles.
  • Hypertension and anemia
  • Hematuria, proteinuria. See rising SRCR after 2 or more doses (12-40 weeks from start)
  • Treatment with plasmapheresis may be beneficial in HUS; using FFP ( 5 exchanges over 10 days; 1 plasma volume exchanged during each session) Permanent DC of drug.
  • Total dose seems to correlate with severity of lesions from glomerular, vascular, or tubular.
Nitrosoureas (CCNU, Methyl-CCNU, BCNU)
  • Renal damage due to interstitial nephritis, unclear mechanism, usually late complication
  • Limiting total dose is only mechanism for reducing incidence
  • Progressive and irreversible renal parenchymal damage noted without an acute phase of acute renal failure has been noted in substantial amount of patients receiving 6 courses at 8 week intervals for malignant brain tumors with carmustine CCNU.
  • Progressive azotemia, renal failure noted rarely with lomustine BCNU.
  • Hydration does not prevent renal damage
  • Monitor SRCR and urinanalysis
Streptozocin
  • Major dose-limiting adverse effect
  • Reported in 1/4 to 3/4 of patients
  • Tubular necrosis
  • Proteinuria, azotemia, anuria, hypophosphatemia, glycosuria, renal tubular acicosis
  • Rising creatinine during dosing
  • If drug DCd when symptoms are mild, usually damage is reversible
  • Hydration will not prevent injury
  • If drug continued in progressive renal compromize, irreversible damage may occur
  • ALSO, rare nephrogenic diabetes insipidus.
Topotecan
  • No major renal affects should be seen
  • Grade 1 or low grade microscopic hematuria seen in about 10% of patients
RENAL DOSING CHEMOTHERAPEUTIC DRUGS
Where a drug is cleared renally or doses are adjusted for renal disease it is important to dose the drug properly. Improper dosing can lead to unnecessary toxicities. Some of the more important and common toxicities related to over-dosing are given.
  1. Hematologic
  • Bone marrow depression may occur with chemotherapy. Normally stem cells differentiate into the myeloid or lymphoid line. Myeloid stems cells commit to
Erythrocyte, megakarocyte, granulocyte, or monocyte line.
  • RBCs survive 120 days in peripheral blood Anemia
  • Platelets survive about 10 days
Thrombocytopenia
  • Granulocytes survive about 6-8 hours
Infection Degree of suppression is dependent on:
  • Patient age (generally younger patients have a much more cellular marrow with a decreased percentage of fat, and therefore, are more tolerant of a given dose than an older patient
  • Degree of bone marrow reserve in relation to the amount of involvement by a particular neoplastic process (fibrosis and tumor cells including leukemic cells in the marrow)
  • The degree of compromise by previous chemotherapy, radiotherapy, or both
  • The nutritional status of the patient ( the greater the negative the nitrogen balance the less functional the marrow)
  • The ability of the kidney or liver to metabolize and excrete the drug
Gastrointestinal Toxicities Mucositis/stomatitis- chemo results in reduction of rate of renewal rate of basal epithelium, resulting in mucosal atrophy; mouth harbors extensive microbial flora and this is altered by chemotherapy. Nutritional status may be impaired if intolerant to orals. Oral antibacterial rinses. Dry mouth often in association with radiation to head and neck, may increase risk of mucositis. Maintain good hydration. Esophagitis: dysphagia. Avoid acidic or irritating foods or liquids. Nausea and vomiting: Some drugs cause increased n/v based on higher serum levels. Diarrhea and malabsorption: Some chemotherapy can cause intestinal changes (5FU. ARA-C) and can be life-threatening. High doses or improperly doses drugs can add to these side-effects. Usually constipation not noted (except with vinca alkaloids that can cause autonomic nerve dysfunction and possibly adynamic ileus) unless patient is on opoid or anticholinergic agent. Dermatologic Anti-neoplastic agents can reduce mitotic activity in the epridermis and nail beds. Cancer therapy also can cause a number of skin reactions with UV light. In order to minimize skin reactions, optimal dosing can help. Side effect Frequent Occasional Alopecia Cyclophosphamide Mechlorethamine Ifosfamide Thiotepa Fluorouracil Methotrexate Dactinomycin Vinblastine Daunorubicin Vincristine Bleomycin BCNU Vindesine Hydroxyurea Pigmentation Busulfan Cyclophosphamide Fluorouracil MTX Doxorubicin Dactinomycin Bleomycin Daunorubicin Hydroxyurea Nail Cyclophosphamide 5FU Daunorubicin Doxorubicin Bleomycin Hydroxyurea Neurotoxicities Cytarabine
  • dose and schedule related.
  • Cerebral dysfunction; gait, ataxia usually resolve after dc of drug
L-asparaginase-
  • encephalopathy presenting as lethargy and confusion.
Severe cerebral dysfunction is rare but manifested by coma, stupor, excessive somnolence, hallucination, severe depression. May occur early or late with resolution of early symptoms early. MTX
  • high dose may result in acute encephalopathy, transient and reversible usually.
Intrathecal has been associated with chemical meningitis and rarely paraplegia. 5FU
  • cerebellar dysfunction, gait, limb incoordination, nystagmus. Diffuse encephalopathy with headache, confusion, lethargy, seizures can rarely be seen.
Fludarabine-
  • severe when used in doses higher than 90mg/m2 for 5-7 days. Symptoms of photophobia, amaurosis, seizures, spastic or flaccid paralysis, coma. Dose related and with 25mg/m2 dose, rarely seen
Carmustine and other nitrosureas- have little CNS toxicity at usual doses. At high doses may produce encephalopathy with confusion and seizures. Alkylating agents: ifosfamide, procarbazine, cisplatin may produce CNS effects. Vinca alkaloids: cranial nerve toxicity, generally ptosis, usually due to damage of 3rd cranial nerve. Peripheral neuropathies. Autonomic neuropathies. Paclitaxel: peripheral neuropathies, generally stocking and hand distribution.
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