Cumulative renal tubular damage associated with cisplatin nephrotoxicity

Goren, Marshall P.; Wright, Reba K.; Horowitz, Marc E.

doi:10.1007/bf00253068

Cited by 88 publications

(57 citation statements)

References 35 publications

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“…The results of this follow-up study confirm previous reports of the frequency, nature and severity of cisplatin-induced glomerular and proximal nephron nephrotoxicity in children, leading to clinically important reductions in GFR and serum magnesium concentration (Ettinger et al, 1981;Hayes et al, 1981;Womer et al, 1985;Goren et al, 1986;Sheldon et al, 1987;Bianchetti et al, 1990;Brock et al, 1991). These adverse effects occurred despite the use of hyperhydration protocols, which appear to reduce the frequency and severity of nephrotoxicity, rather than abolish it altogether (Daugaard and Abildgaard, 1989).…”

Section: Discussionsupporting

confidence: 86%

“…The results of this study suggest that cisplatin dose rates of 40 mg m-2 day-l should be used in preference to higher dose rates in children. The lack of a clear correlation between total cisplatin dose and the severity of nephrotoxicity is consistent with other detailed long-term follow-up studies in children (Womer et al, 1985;Sheldon et al, 1987;Brock et al, 1991), but contrasts with some earlier studies (Pratt et al, 1981;Sexauer et al, 1985;Goren et al, 1986). It is possible that children receiving higher total doses are at greater risk of significant toxicity, but that this effect is obscured by interindividual variability in susceptibility.…”

Section: Discussionsupporting

confidence: 84%

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Cisplatin dose rate as a risk factor for nephrotoxicity in children

Skinner

Pearson²,

English³

et al. 1998

Br J Cancer

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Summary The purpose of the study was to evaluate the incidence, risk factors and changes in severity with time of cisplatin nephrotoxicity in children. A total of 35 children underwent measurement of glomerular filtration rate (GFR) and tubular function after completion of cisplatin chemotherapy. No child received ifosfamide. A clinically relevant 'nephrotoxicity score' was derived from GFR and serum magnesium. Followup studies were performed in 16 children at 1 year and in 15 at 2 years after cisplatin. Considerable interpatient variability in nephrotoxicity was observed. Treatment was modified in three patients because of nephrotoxicity. GFR was low in 18 out of 31 patients. Proximal nephron toxicity caused hypomagnesaemia in ten patients and hypocalcaemia in five patients. Elevated urinary N-acetylglucosaminidase excretion was seen in 22 out of 30 children, indicating subclinical tubular toxicity. Nephrotoxicity was less severe in children who received cisplatin courses at a dose rate of 40 mg m-2 dar' than in those who received higher dose rates (P < 0.005), but there was no correlation with total dose received. Follow-up studies revealed partial recovery of GFR (P < 0.05). Glomerular and proximal nephron toxicity are common in children treated with cisplatin, and more severe at higher dose rates. Despite partial recovery of GFR, the long-term outcome of nephrotoxicity remains unknown and careful monitoring of chronic toxicity is necessary.Keywords: cisplatin; nephrotoxicity; children The use of combination chemotherapy has led to dramatic improvements in the survival rates from many childhood malignancies during the last three decades. However, cytotoxic drugs may also cause severe and chronic side-effects, leading to permanent ill-health, disability or even premature death (Morris Jones and Craft, 1990). The development of effective strategies to prevent these adverse events depends on careful evaluation of toxicity both during and after treatment.In view of its established efficacy, cisplatin has retained an important role in the treatment of several childhood solid tumours, including neuroblastoma, osteosarcoma, hepatic and brain tumours, despite the increasing use of its apparently less nephrotoxic analogue carboplatin. Indeed, recent evidence has suggested that cisplatin may be more active than carboplatin in some germ cell tumours in adolescents and adults (Bajorin et al, 1993). However, even with the use of hyperhydration and other protective measures, nephrotoxicity is still a common and potentially serious adverse effect of cisplatin in both adults (Madias and Harrington, 1978;Schilsky et al, 1982;Daugaard and Abildgaard, 1989) and children (Womer et al, 1985;Brock et al, 1991). Despite numerous publications concerning cisplatin nephrotoxicity in adults, there is less information and no clear consensus on the importance of patient-and treatment-related risk factors for the development of nephrotoxicity in children. Furthermore, as there are few data concerning the long-term outcome of cisplatin nep...

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 84%

Cisplatin dose rate as a risk factor for nephrotoxicity in children

Skinner

Pearson²,

English³

et al. 1998

Br J Cancer

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“…Given that cadmium is stored in the renal tubule, it is possible that the correlation of the metal and these biomarkers is the result of a common association with another factor (e.g., the natural turnover rate and exfoliation of tubular cells). However, in a study of cancer patients, urinary levels of NAG and AAP were associated with loss of renal tubular secretion function in response to the chemotherapeutic agent cisplatin (8,9). For low-level cadmium exposure, it is unclear whether the observed differences in the levels of these tubular enzymes indicates subclinical toxicity that may cause cumulative renal deficiencies.…”

Section: Discussionmentioning

confidence: 99%

“…Elevations in enzymes primarily of renal tubular origin, such as N-acetyl-β-Dglucosaminidase (NAG) and alanine aminopeptidase (AAP), have been observed at occupational cadmium exposures of 3.7-6.3 µg urinary cadmium/g creatinine (2,4,7). Increases in these enzymes have been associated with chemical-induced renal tubular damage (8,9) Most studies of cadmium-induced renal effects using these and other biomarkers have been conducted among individuals with occupational or high environmental exposures (4,7,(10)(11)(12)(13)(14)(15)(16). Results of a national health survey indicate that the geometric mean value (and 95th percentile) for urinary cadmium among the U.S. general population age 6 years or older is approximately 0.27 (1.48) µg/g creatinine (17), but little information is available on renal effects that may occur in people with urinary cadmium levels < 2 µg/g.…”

mentioning

confidence: 99%

Effects of exposure to low levels of environmental cadmium on renal biomarkers.

Noonan

Sarasua

Campagna

et al. 2002

Environ Health Perspect

149

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We conducted a study among residents of a small community contaminated with heavy metals from a defunct zinc smelter and residents from a comparison community to determine whether biologic measures of cadmium exposure were associated with biomarkers of early kidney damage. Creatinine-adjusted urinary cadmium levels did not differ between the smelter and comparison communities; thus we combined individuals from both communities (n = 361) for further analyses. The overall mean urinary cadmium level was low, 0.26 microg/g creatinine, similar to reference values observed in the U.S. general population. For children ages 6-17 years, urinary concentration of N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), and albumin were positively associated with urinary cadmium, but these associations did not remain statistically significant after adjusting for urinary creatinine and other potential confounders. For adults ages 18 or older, urinary concentration of NAG, AAP, and albumin were positively associated with urinary cadmium. The associations with NAG and AAP but not with albumin remained statistically significant after adjusting for creatinine and other potential confounders. We found a positive dose-effect relationship between levels of creatinine-adjusted urinary cadmium and NAG and AAP activity, and statistically significant differences in mean activity for these two enzymes between the highest (> or =1.0 microg cadmium/g creatinine) and the lowest (< or =0.25 microg cadmium/g creatinine) exposure groups. The findings of this study indicate that biologic measures of cadmium exposure at levels below 2.0 microg/g creatinine may produce measurable changes in kidney biomarkers.

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“…The question of cumulative toxicity is more controversial. Some have reported cumulative and unpredictable nephrotoxicity (Goren et al, 1986) while others have related cumulative toxicity to renal cortical platinum concentrations (Stewart et al, 1985). Others have denied any cumulative toxicity (Meijer et al, 1982;Chiuten et al, 1983) (Daugaard et al, 1988), in the stable pretreatment or long post-treatment situation an excellent correlation between serum creatinine and GFR is seen (Daugaard et al, 1988) and indeed some have suggested that serum creatinine is the preferred measure of GFR (Payne, 1986).…”

Section: Renal Functionmentioning

confidence: 99%

Long-term toxicity of chemotherapy for testicular cancer – the cost of cure

Stuart

Woodroffe²,

Grundy³

et al. 1990

Br J Cancer

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Summary Twenty-seven patients cured of advanced testicular cancer by cisplatin-based chemotherapy have been assessed, a median of 30 months after start of treatment, for the long-term effects of such treatment on renal, endocrine, audiometric, reproductive and respiratory function. To control for the effects of orchidectomy on endocrine function a similar group of 11 patients cured by orchidectomy alone was also assessed. The extents of impairment in hearing and renal function were related to the total dose of cisplatin received, while the majority of patients had respiratory impairment which was, in part, related to the total dose of bleomycin. TSH was significantly higher in the chemotherapy group although serum free thyroxine and free T3 were normal in all. FSH was raised in 67% of the chemotherapy group and in 45% of the orchidectomy group while LH was raised in 75% and 45% respectively. Serum testosterone was normal in all. MethodsClinical notes were reviewed to obtain details of investigations at presentation and of chemotherapy received. Hepatic and renal function, serum TSH, free thyroxine and free T3, serum FSH, LH and testosterone, tumour markers (afetoprotein and P-human chorionic gonadotrophin) and full blood count were measured. Standard laboratory normal ranges were used and serum hormones were measured by specific immunometric methods.Pulmonary function assessment comprised measurement of vital capacity (VC), forced residual capacity (FRC), residual volume (RV), total lung capacity (TLC), forced expiratory capacity in one second (FEV,), peak expiratory flow rate (PFR), transfer factor coefficient (KCO), total lung transfer factor (TLCO), total alveolar volume (TAV) and effective alveolar volume (EAV). TLCO was measured by single breath-hold method with correction for haemoglobin concentration, EAV by single breath helium dilution and lung volumes by steady state helium dilution. Values other than TAV and EAV were expressed as standardised residuals (Miller & Pincock, 1988) with expected values determined from height and age by published regression equations (European Coal and Steel Community Recommendations, 1983

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Cumulative renal tubular damage associated with cisplatin nephrotoxicity

Cited by 88 publications

References 35 publications

Cisplatin dose rate as a risk factor for nephrotoxicity in children

Cisplatin dose rate as a risk factor for nephrotoxicity in children

Effects of exposure to low levels of environmental cadmium on renal biomarkers.

Long-term toxicity of chemotherapy for testicular cancer – the cost of cure

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