Urinary Platinum Research Articles

Association of Urine Platinum With Acute Kidney Injury in Children Treated With Cisplatin for Cancer.

Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24 hours after cisplatin infusion is associated with AKI, and to evaluate the association between urine platinum and tubular damage biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Children treated with cisplatin in 12 Canadian centers (April 2013 to December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for urine platinum, NGAL, and KIM-1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of urine platinum with AKI, NGAL, and KIM-1 were assessed. A total of 115 participants (54% boys, median age, 8.5 years; interquartile range, 4.0-13.4) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher urine platinum was associated with higher cisplatin dose (Spearman rho, 0.21) and with younger age (Spearman rho, -0.33). Urine platinum was not associated with postinfusion AKIor KIM-1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r, 0.22). Urine platinum may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI.

Effectiveness of Personal Protective Equipment in Reducing Skin Exposure to Soluble Platinum

Various forms of personal protective equipment (PPE), including disposable coveralls and gloves, are used to help reduce skin exposure to soluble platinum in precious metals refineries. We aimed to investigate the effectiveness of PPE in reducing workers' skin exposure to soluble platinum. Thirty precious metals refinery workers were divided into two groups according to their use of PPE and related procedures. Group A (n = 13) used disposable coveralls worn over standard overalls along with long-sleeved rubber gloves, while Group B (n = 17) used standard overalls only and surgical nitrile gloves. The skin (palm, wrist, neck, and forehead) and respiratory exposure of these groups to soluble platinum were concurrently measured (using Ghostwipes™ and MDHS 46/2, respectively) along with their urinary platinum excretion. Both groups of workers experienced comparable geometric mean (GM) respiratory exposure to soluble platinum (Group A = 0.744 µg m-3 versus Group B = 0.711 µg m-3) (P = 0.789), but significantly lower skin exposure (average of all measured anatomical areas) was found for Group A (Group A = 0.005 µg cm-2 versus Group B = 0.033 µg cm-2) (P = 0.018). Significantly lower skin exposure was measured on the palm (P = 0.017), wrist (P = 0.017), forehead (P = 0.027) of Group A workers compared with Group B. No significant difference was found for the urinary platinum excretion of the two groups (Group A GM = 0.208 µg g-1 creatinine versus Group B GM = 0.361 µg g-1 creatinine) (P = 0.273). The use of disposable coveralls and long-sleeved rubber gloves, along with strict usage procedures, proved effective in reducing precious metals refinery workers' skin exposure to soluble platinum.

Analysis of Renal Platinum Content as a Novel Approach to Protect against Cisplatin Nephrotoxicity: A Review

Cisplatin (cis-diamine-dichloroplatinum (II), CDDP) is a prominent member of the effective broad-spectrum antitumor drugs. However, its clinical usage is restricted due to serious side effects particularly nephrotoxicity. The vulnerability of the kidney to CDDP is almost certainly related to its primary role in the excretion of the drug as intact CDDP and its platinum containing products are excreted mainly in the urine. There is a correlation between the level of platinum in urine and nephrotoxicity because of renal uptake of the drug. Some analytical methods were applied for the determination of platinum content in biological fluids such as plasma, urine, serum, and peritoneal fluid. Studies have not documented a strong correlation between the renoprotective mechanism and the diminution of renal platinum content.

Pharmacokinetic determinants of cisplatin-induced subclinical kidney injury in oncology patients.

The ability to predict and detect clinical and subclinical nephrotoxicity early in the course of therapy has the potential to improve long-term outcomes in cancer patients receiving cisplatin chemotherapy. Pharmacokinetic parameters could serve as predictors of cisplatin-induced nephrotoxicity. Participants [n = 13] were treated with a 1-h cisplatin infusion [30-75mg/m2]. Blood was collected pre-dose and up to 6h post-dose. Urinary biomarkers [KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, MCP-1, cystatin C, and TFF3] were measured at baseline, days 3 and 10. Total and unbound platinum concentrations were measured using ICP/MS. Noncompartmental analysis was performed, and correlation and regression analyses evaluated the relationships between platinum pharmacokinetics and nephrotoxicity. Peak platinum urinary concentrations correlated with urinary levels of KIM-1, calbindin, clusterin, GST-pi, β2M, albumin, NGAL, osteopontin, clusterin, cystatin C, and TFF3 at day 10. Unbound platinum plasma concentrations at 2h also correlated with urinary clusterin, β2M, cystatin C, NGAL, osteopontin, and TFF3 at day 3. Regression analyses suggested 2-h total plasma platinum concentrations greater than 2000ng/ml, and peak urinary platinum concentrations above 24,000ng/ml may serve as potential approximations for elevated risk of nephrotoxicity. Platinum area under the plasma concentration time curve was associated with serum creatinine and estimated glomerular filtration rate. Peak plasma and urinary platinum concentrations and pharmacokinetic parameters were associated with risk of subclinical cisplatin-induced kidney injury as assessed using novel urinary biomarkers. Future studies will examine these relationships in larger clinical populations of cisplatin-induced acute kidney injury.

Occupational exposure to platinum drugs during intraperitoneal chemotherapy. Biomonitoring and surface contamination

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) has been introduced over the last decade for the treatment of peritoneal carcinomatosis. In this procedure, heated cytotoxic drugs are administered directly into the abdominal cavity, ensuring cancer cells to be exposed while reducing systemic toxicity. More recently, pressurized intraperitoneal aerosol chemotherapy (PIPAC), where the chemotherapeutic drug is injected into the peritoneal cavity as an aerosol under pressure, has been proposed to patients in palliative situation, as a new approach. The amount of drug used is up to 10 fold lower than in HIPEC. The use of cytotoxic drugs poses an occupational risk for the operating room personnel. This study investigated the potential exposure of the medical staff by biomonitoring and surface contamination measurements, during a HIPEC procedure and a PIPAC procedure. MethodWipe samples were collected from various locations in operating rooms including gloves, hands, devices and floor. Urines samples were collected from 10 volunteers of the medical staff and from a control group. The platinum analysis was performed by inductively coupled plasma mass spectrometry. ResultsSignificant contaminations were observed on the floor, gloves, shoes and devices. However, urinary platinum was below the limit of quantification (<10 ng/L) for more than 50% of samples from the healthcare workers performing HIPEC and PIPAC. Concentrations did not differ significantly from those reported for the control group. ConclusionThere appears to be little risk of exposure to platinum drugs during HIPEC and PIPAC providing the adequate safety measures are implemented.

Environmental and biological monitoring on an oncology ward during a complete working week

Workplace exposure to antineoplastic drugs (AD) is still of evident concern to all occupationally exposed persons in the healthcare sector as residues in relevant concentrations continue to be present. With respect to the carcinogenic and mutagenic potential of ADs and their toxicity on reproduction, occupational exposure should be kept as low as reasonably achievable (ALARA). In the oncology patient care, the medical staff is involved both in chemotherapy administration and handling of AD-contaminated body fluids of the patients. For this purpose, in this study, surface monitoring on an oncology ward and concurrent urine monitoring of the complete healthcare staff was performed during five consecutive days for 5-fluorouracil (5-FU), cyclophosphamide (CP) and platinum (Pt). Contamination was detected on all surfaces in various ranges (5-FU 0.7–12,600 pg/cm2, Pt 0.2–181,800 pg/cm2, CP (<LOD – 221 pg/cm2). However, regarding 5-FU and CP, all urine samples (n = 98) were below the detection limits and urinary platinum was below the German reference value (10 ng/l) in 98% of the samples, when gloves were regularly worn. This indicates that gloves may be an important protection measure against dermal AD uptake.

Modelling and sensitivity analysis of urinary platinum excretion in anticancer chemotherapy for the recovery of platinum

Platinum (Pt) based antineoplastics are important in cancer therapy. To date the Pt which is urinary excreted by the patients ends up in wastewater. This is disadvantageous from both an economic as from an ecological point of view because Pt is a valuable material and the excretion products are toxic for aquatic organisms. Therefore, efforts should be made to recover the Pt. The urinary excretion of Pt from two antineoplastics are taken under consideration, i.e. cisplatin and carboplatin. Using these reference compounds, a scenario analysis based on administration statistics from Ghent University Hospital in combination with compartmental models for urinary Pt excretion was performed to simulate the average Pt excretion profile during common treatment schemes. These average profiles can be used to assess the technical, social and economic feasibility of Pt-recovery from urine or wastewater. A one-compartment model is used for cisplatin, which is calibrated using the experimental data of six patients. In contrast, a two-compartment model with parameters from literature is used for carboplatin. A Global Sensitivity Analysis revealed kel, the rate constant of elimination, is the most sensitive parameter in the one-compartment model whereas Qu, the urine production rate, was the most sensitive in the two-compartment model for the Pt concentration Cu in urine and the excreted mass of Pt via urine. A GLUE uncertainty analysis showed that all experimental data are within the 95% uncertainty boundaries.

A simple, sensitive analytical method for platinum trace determination in human urine

Quantification of platinum in human urine is a valuable technique for assessing occupational and environmental exposure to platinum. We hereby present a simple and sensitive method to monitor urinary platinum in hospital workers exposed to platinum-based anticancer agents. This method consists in: i) the sample digestion with an ultrapure HNO3/HCl (5:1) mixture in a sonicator for 2h, and ii) the Inductively Coupled Plasma Mass Spectrometry (ICP–MS) platinum determination on the 1:10 diluted solutions. Sample pre-treatment is simpler and faster when compared to other published procedures, which are typically multistep and time-consuming and often require expensive equipments. The ICP–MS analysis of all pre-treated samples shows good selectivity, sensitivity, repeatability and recoveries. It is noteworthy that in the present case both standard addition mode and the direct platinum determination with reference to an external calibration curve give satisfactory results for urinary platinum, while the standard addition mode is typically required in the literature methods.

Silicone implants – a possible confounder for urinary platinum background concentrations?

IntroductionUrinary platinum excretion from occupationally unexposed population is very low. Up to now, in Germany, dental noble metal alloys and a platinum based chemotherapy have been identified as reason for elevated urine concentrations. As fabrication of silicone involves platinum as catalyst, this study examines the potential release of platinum from silicone breast implants by quantifying urinary platinum concentration. Methods and resultsPlatinum release from three different types of silicone implants into saline solution was measured in a laboratory experiment. It showed a strong increase of platinum concentration during the first 30min and high platinum concentrations even after 60h. In the following field study urinary platinum concentrations were determined from 30 women with dental gold alloy restorations and 28 women without such dental inlays. Median platinum concentrations were 5.2ng/l urine (21.2ng/g creatinine) for the women with dental gold inlays and 6.0ng/l urine (5.4ng/g creatinine) for those without. Compared with the urinary platinum concentrations provided by the German Environmental Survey (GerES) for the general female population the urinary platinum levels of women with silicone implants of the presented study were significantly higher, both for the study groups with and without dental gold alloy inlays. ConclusionsSilicone breast implants must be considered as a new confounder and as a further contributor to elevated urinary platinum concentrations in human platinum background reference values of women.

Environmental and Biological Monitoring of Platinum-Containing Drugs in Two Hospital Pharmacies Using Positive Air Pressure Isolators

Environmental and biological monitoring of platinum containing drugs was implemented in two French hospital pharmacies using positive air pressure isolators and having similar working procedures when preparing antineoplastic drugs. Wipe sampling of surfaces, gloves, and vials was performed in the preparation room and in storage areas. All employees involved in the preparation of antineoplastic drugs were tested for urinary platinum on Monday before work and Friday after shift. Only traces of platinum were detected on surfaces in the preparation room outside the isolators (less than 1.61 pg cm(-2)). However, in one center, significant contamination was found in the storage area of the drug vials, which can most likely be linked to the rupture of a platinum vial and due to inefficient cleaning procedures. Surfaces inside the isolators were found to be contaminated (maximum: 198.4 pg cm(-2)). A higher level of contamination was detected in one pharmacy and could be explained by the lack of overgloving with regular changes during the preparation process. Nitrile gloves used during drug handling outside the isolator showed the highest platinum concentration (maximum: 5.86 ng per pair). With regards to platinum urine concentration, no significant difference was found between exposed and unexposed pharmacy personnel. Isolator technology combined with individual protective measures seems to be efficient to protect workers from occupational exposure to antineoplastic drugs, whereas specific individual protective procedures implemented were focussing on the risk of handling vials outside the isolator (e.g. high frequency of glove changing). Moreover, overgloving inside the isolator would contribute to substantially decrease inner surface contamination and should be recommended in order to limit the transfer of chemical contamination to the end products.

Development of highly effective three-component cytoprotective adjuncts for cisplatin cancer treatment: synthesis and in vivo evaluation in S180-bearing mice

A series of chelants (3a-s) composed of a glucosyl tail, an amino acid side chain and a dithiocarbamate group were designed, synthesized, and evaluated. By co-administering with cisplatin, 3a-s were able to decrease the accumulation of platinum in the organs, maintain the accumulation of platinum in the tumor tissues, and increase the urinary and fecal platinum, as well as increasing the voided volume of the treated S180-bearing mice. Compared to S180-bearing mice treated with cisplatin alone, the co-administered mice lost no spleen, kidney, liver, brain and heart weights, lost less body weight, and showed no increase in tumor weight.

Time course of the change and amelioration of nedaplatin‐induced nephrotoxicity in rats

Nedaplatin (NDP) is a second-generation antineoplastic platinum complex, with reduced nephrotoxicity. Two experiments were conducted to characterize the time course of changes of its nephrotoxicity and to further evaluate whether hydration is useful for amelioration of nephrotoxicity. In the first experiment, 8-week-old male rats treated with 6 or 9 mg kg(-1) NDP at a single intravenous dose were killed 2, 4, 7 and 14 days after dosing. In the second experiment, nonhydrated (Nhyd) or hydrated (Hyd) rats, treated with a single intravenous dose of 20 mg kg(-1) NDP, were killed 7 days after dosing. Besides renal function and histopathological examinations, the urinary excretion of platinum was measured. Histopathologically, NDP-induced nephrotoxicity was initially characterized by single cell and/or focal necrosis in the epithelium of distal tubules and collecting ducts as well as proximal tubules. In the later stage, subsequent cystic dilatation and regeneration occurred in these affected tubules, but incomplete tissue repair was still observed in the kidney 14 days after dosing. However, NDP-induced nephrotoxicity was dramatically reduced by hydration, while it had no clear effects on myelotoxicity. Measurement of urinary platinum excretion revealed that the total amount of platinum excretion was significantly higher in Hyd-NDP rats than that in Nhyd-NDP rats. In terms of urinary concentration, Hyd-NDP rats showed a lower concentration compared with that in Nhyd-NDP rats. The current results suggest that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre- and post-hydration at dosing can ameliorate this nephrotoxicity.

Comments on Total Platinum Concentration and Platinum Oxidation States in Body Fluids, Tissue, and Explants from Women Exposed to Silicone and Saline Breast Implants by IC−ICPMS

The paper by Lykissa and Maharaj (Lykissa, E. D.; Maharaj, S. V. M Anal. Chem. 2006, 78, 2925-2933) purports to provide evidence that the urine of women with silicone breast implants contain 60 to over 1700 times more platinum in their urine that the urine of people with no known exposure to platinum. Further, they purport to show evidence that the platinum used in the manufacture of breast implants (Pt0) is converted by a unknown process to yield highly oxidized platinum species, stable in biological matrixes, up to and including Pt6+. This correspondence poses three questions associated with the work and directs the reader's attention to the data, which clearly show that the blood and urine platinum levels in implanted women and their healthy control group were not significantly different from one another.

Comparison of inductively coupled plasma mass spectrometry techniques in the determination of platinum in urine: quadrupole vs. sector field

In recent years the increasing use of platinum (Pt) both in medical and in industrial applications has caused its growing anthropogenic emission and spread in the environment. Pt is released into the atmosphere by exhaust catalytic converters, and Pt compounds are often used in antitumour therapies. As a consequence, significant amounts of Pt can be detected in hospital wastewaters. This can lead to an increase in the exposure levels to Pt, especially in urban areas. It is therefore necessary to determine Pt reference values in the general population, by using suitable procedures able to achieve adequate analytical performances. Several measurements of Pt in biological fluids have been reported, but the analytical methods used for the determination of Pt often lack information about the uncertainty of the results, especially for low concentrations of urinary Pt in non-occupationally exposed subjects. The present paper considers the measurement of urinary Pt levels in a general population group from central Italy, by both quadrupole (Q) and sector field (SF) inductively coupled plasma mass spectrometry (ICP-MS). The two procedures were validated and their expanded uncertainties were evaluated. The limits of detection (LODs), calculated taking into account dilution factors, were 0.18 and 0.05 ng L(-1) of Pt for the Q and SF procedures, respectively. The median value observed was 4.13 ng L(-1) of Pt in urine, while the relative combined uncertainty at 5 ng L(-1) was below 20% with both ICP-MS techniques. These data are in good agreement with those reported in the literature for similar studies.

Biomonitoring of traffic police officers exposed to airborne platinum

Background: Over the past two decades there has been a substantial increase in environmental levels of palladium, platinum, and rhodium, the platinum group elements (PGEs), due to the widespread use...

Determination of platinum in urine and airborne particulate matter from Budapest and Vienna

Urine samples taken from 100 adults living in the city centres of the two capitals were analysed by the same inductively coupled plasma quadrupole mass spectrometer following their 10-fold dilution with bidistilled water. The mean concentration values of platinum related to creatinine were about three times higher in the Hungarian samples than in the Austrian ones. Six particulate matter samples were collected by a Gent-type two-stage sampler in the districts of the two capitals, which have high traffic density. The polycarbonate filters containing the fine (d<2 μm) and the coarse (d=2–10 μm) fractions were digested in a microwave assisted digestion system and analysed by the same high-resolution inductively coupled plasma mass spectrometer. The respirable, fine fractions of aerosols collected in Budapest contained approximately twice as much platinum than the aerosols from Vienna. However, the coarse fraction showed a contrary picture, with five times higher Pt concentration in the samples collected in Vienna.

Determination of platinum in urine and airborne particulate matter from Budapest and Vienna

Urine samples taken from 100 adults living in the city centres of the two capitals were analysed by the same inductively coupled plasma quadrupole mass spectrometer following their 10-fold dilution with bidistilled water. The mean concentration values of platinum related to creatinine were about three times higher in the Hungarian samples than in the Austrian ones. Six particulate matter samples were collected by a Gent-type two-stage sampler in the districts of the two capitals, which have high traffic density. The polycarbonate filters containing the fine ( d<2 μm) and the coarse ( d=2–10 μm) fractions were digested in a microwave assisted digestion system and analysed by the same high-resolution inductively coupled plasma mass spectrometer. The respirable, fine fractions of aerosols collected in Budapest contained approximately twice as much platinum than the aerosols from Vienna. However, the coarse fraction showed a contrary picture, with five times higher Pt concentration in the samples collected in Vienna.

Revised and new reference values for some trace elements in blood and urine for human biomonitoring in environmental medicine

Reference values for environmental pollutants related to the German population are established continuously by the Human Biomonitoring Commission of the German Federal Environmental Agency. The reference values for arsenic, cadmium, lead, mercury and platinum in blood or urine were derived from the German Environmental Survey 1998 (adults aged 18 – 69 years). The reference value for lead in blood was lowered for females from 90 to 70 μg/l and for males from 120 to 90 μg/l, while the values for cadmium of 1.0 and for mercury of 2.0 μg/l in blood remained unchanged. For cadmium in urine the reference value was lowered from 1.5 to 0.8 μg/l and for mercury in urine from 1.4 to 1.0 μg/l. New reference values were derived for arsenic (15 μg/l) and platinum in urine (0.01 μg/l). Additionally, for nickel in urine a new reference value of 3.0 μg/l based on data from the literature was established. Reference values for estimation of the selenium status were summarized from the literature. For aluminium in blood or urine no reference values were derived and the use of human biomonitoring to estimate aluminium exposure in environmental medicine is not recommended.

Influences on human internal exposure to environmental platinum.

Different influences on internal exposure to platinum are investigated and for the first time weighted in environmentally exposed subjects as far as individual internal platinum concentrations are concerned. Detailed medical and environmental histories as well as oral cavity status were assessed in 84 dermatological patients, and internal platinum exposure was determined by analyzing platinum in urine using adsorptive voltammetry (AV). Platinum concentrations ranged from <0.9 (detection limit) to 65.5 ng Pt/l urine. Influence of different types and age of alloy restorations and therefore relevance of the exposure pathway due to solubilization of platinum in saliva could be demonstrated. No platinum-related health effects (contact stomatitis, asthma or kidney conditions) were observed. Analysis of covariance showed the number of noble dental alloy restorations (P<0.0001) and to a lesser extent age (P=0.0017) to independently influence internal platinum exposure. Even though spread of environmental platinum has increased, internal platinum exposure is low in subjects without assessable medical or dental devices (usually <4.5 ng/l urine) and not related to adverse health effects. For the first time, detailed individual information on possible exposure pathways to platinum were considered in an analysis of relevant influential factors: Car traffic exposure and dermatological condition showed no association with internal platinum exposure. Uptake from platinum containing noble metal dental alloy restorations (NMDAR) is of greatest relevance, surmounting the influence of each year of lifetime on platinum body load by more than 10-fold.

Population pharmacokinetics of oxaliplatin.

The objective of this study was to explore correlations between a variety of covariates and oxaliplatin ultrafilterable and blood pharmacokinetic parameters. Data from 40 patients receiving oxaliplatin combined with 5-fluorouracil and levofolinic acid as standard treatment for advanced colorectal cancer were analysed. Plasma ultrafilterable, blood, and urine platinum concentrations were determined by flameless atomic absorption spectrophotometry. Data were analysed according to a population pharmacokinetic method using the NONMEM program. The best fit for oxaliplatin plasma ultrafilterable clearance (CL) was given by the following equation, which considers four covariates: body surface area (BSA, in metres squared), age (in years), sex (0 if male, 1 if female), and serum creatinine (Scr, in micromoles per liter): CL (l/h)=5.49xBSA+4.55xBSAx(140-AGE)x(1-0.15xSEX)/Scr. By taking into account these covariates, the interindividual variability in CL decreased from 43% to 33%. Renal clearance represented 34% of the overall elimination. This value was obtained by recovering urine over only 5 h from the beginning of the infusion and modelling the data using NONMEM. We would recommend the use of this methodology for pharmacokinetic studies in oncology in which renal clearances of the drug are presently rarely explored. The oxaliplatin blood concentrations versus time observed during the three-cycle period were well-described by a three-compartment model with first-order elimination from the central compartment. No significant intrapatient pharmacokinetic variability was observed between cycles. The relationship we obtained using the population approach between oxaliplatin CL and covariates may allow rational reduction of oxaliplatin dose in cases of elevated serum creatinine levels.