Reba K. Wright

Cumulative renal tubular damage associated with cisplatin nephrotoxicity.

SummaryWe assessed the acute and chronic effect of multiple courses of cisplatin therapy on renal tubules by monitoring the urinary excretion of alanine aminopeptidase, N-acetyl-β-D-glucosaminidase, and total protein. Urine specimens were obtained before and after doses of cisplatin (90 mg/m2) given to 12 patients. Each dose of cisplatin induced transient increases in enzyme excretion, followed by proteinuria 3–5 days later. Transient enzymuria after the last cisplatin dose was significantly greater than that after the first dose. Moreover, persistent increases in urinary N-acetyl-β-D-glucosaminidase and serum creatinine concentrations over pretherapy levels indicated chronic renal tubular damage. Our findings disclosed striking differences between patients in susceptibility to progressive nephrotoxicity.

Enhancement of methotrexate nephrotoxicity after cisplatin therapy

We measured urinary levels of total protein, N‐acetyl‐β‐D‐glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase‐binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate‐induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate‐induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined‐drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.

Carboplatin (CBDCA), iproplatin (CHIP), and high dose cisplatin in hypertonic saline evaluated for tubular nephrotoxicity

SummaryWe compared the acute tubular nephrotoxicity of three platinum compounds in children and adults with solid tumors by monitoring the urinary excretion of alanine aminopeptidase, N-acetyl-β-D-glucosaminidase, and total protein. Cisplatin (100 mg/m2) was administered with mannitol, or at a twofold larger total dosage (50 mg/m2 per day for 4 days) in a 3% saline infusion. Carboplatin (300 mg/m2) was administered in combination with 5-fluorouracil, and iproplatin was administered in dosages ranging from 216 to 388 mg/m2. Enzymuria and proteinuria induced by cisplatin at a total dosage of 200 mg/m2 on a divided schedule did not significantly differ from that observed for the single 100 mg/m2 dose. Enzymuria and proteinuria induced by carboplatin and iproplatin were significantly less than that for cisplatin; however, one patient developed chronic tubular damage after three courses of carboplatin, and the acute tubular toxicity of iproplatin in one of 15 patients was exceptional. Our findings support the value of administering cisplatin in hypertonic saline on a divided schedule as a strategy to reduce acute tubular damage. Although carboplatin and iproplatin are less nephrotoxic than cisplatin, occasionally patients experience subclinical acute or chronic tubular damage that may lead to overt nephrotoxicity with continued therapy.

Increased levels of urinary adenosine deaminase binding protein in children treated with cisplatin or methotrexate

Levels of adenosine deaminase binding protein (ABP), a renal tubular cell antigen, were determined by enzyme immunoassay in urine specimens from seven children with solid tumors who were receiving the recognized nephrotoxins cisplatin or methotrexate. ABP excretion was uniformly increased within the first 3 days after administration of either drug. Elevated ABP levels were usually accompanied by increased excretion of the urinary enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase. In alkaline urine specimens associated with methotrexate therapy, ABP levels were increased whereas enzyme activities appeared to be unstable. Hence, immunochemical measurement of urinary ABP levels may be adjunctively useful for clinical studies of renal tubular damage.

Urinary N-acetyl-beta-D-glucosaminidase and serum creatinine concentrations predict impaired excretion of methotrexate

We determined the risk of impaired excretion of methotrexate (MTX) in children with osteosarcoma, who also were receiving cisplatin, by analyzing urinary markers of renal tubular damage, as well as serum creatinine measured before each dose of MTX. MTX clearance was impaired in seven of the ten patients studied after cisplatin therapy. Patients with a urinary N-acetyl-beta-D-glucosaminidase (NAG) concentration of greater than 1.5 U/mmol creatinine or a greater than 50% increase in serum creatinine relative to the pretherapy level were approximately 30 times more likely to have MTX half-lives greater than 3.5 hours than were patients with lower values for these markers; MTX clearance was always impaired if both markers were elevated. If neither urinary NAG nor serum creatinine concentrations increased, the risk of impaired MTX excretion was negligible. Our findings demonstrate that urinary NAG and serum creatinine levels, measured before MTX administration, can be used to identify patients who will have difficulty in clearing the drug.

Monitoring serum aminoglycoside concentrations in children with amphotericin B nephrotoxicity

We prospectively studied the effect of amphotericin B therapy on aminoglycoside clearance in 20 consecutive children during the remission-induction phase of chemotherapy for acute myelocytic leukemia. Increases (greater than 50%) in the half-life for aminoglycoside excretion were not associated with antileukemic or aminoglycoside therapy alone but occurred in 12 of 17 children when amphotericin B was added to the antimicrobial regimen. Seven children had impaired aminoglycoside clearance without increases (greater than 50%) in serum creatinine; hence the resulting adjustments in aminoglycoside dosage would not have been made had we relied solely on serial measurements of serum creatinine. Evidence for increased excretion of the renal enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase during amphotericin B therapy suggested that damage to proximal tubular cells may contribute to the renal impairment that has been associated with this drug. Our findings underscore the value of monitoring serum aminoglycoside concentrations in children being treated with amphotericin B.