The clinical research of 5 steps sequential method for whole treatment of hemorrhagic radiation cystitis in china.

Background: Curing hemorrhagic cystitis remains a challenge. We explore a continuous and effective treatment for hemorrhagic radiation cystitis. Methods: The data of patients in 6 provincial cancer hospital urology departments between April 2015 and December 2019 was reviewed retrospectively. Patients were classified as moderate and severe groups. The 5-steps sequential method was adopted. Two groups were initiated with step 1 and step 3 respectively. Step 1 was symptomatic treatment. Thrombin solution or sodium hyaluronate was administrated for bladder irrigation in step 2. Step 3 was transurethral electrocoagulation. Step 4 was interventional embolization. Step 5 was HBO therapy. OABSS was used to assess the improvement of patients' symptoms. The outcome was evaluated after at least 6 months of follow-up. Results: A total of 650 patients (56 men and 594 women), mean age 71.2 years, were enrolled in the 5 steps sequential method. 582 patients were classified as moderate and 68 severe group. In moderate group, the cure rate of step 1 was 61.2% (356/582), 80.4% (468/582) after step 2, 93.1% (542/582) after step 3, 96.2% (560/582) after step 4, and 99.8% (581/582) after step 5. In severe group, the cure rate was 54.4% (37/68) after step 3, 76.5% (52/68) after step 4, and 94.1% (64/68) after the step 5 respectively. The mean OABSS scores of both groups significantly decreased after 5 steps sequential method treatment (P<0.01). Conclusions: Our results show hemorrhagic radiation cystitis can be cured in 5 steps, and the 5 steps sequential method is welcomed and effective. Therapy efficacy depends on the number of steps adopted and the severity of hematuria.

Dose Assessment Following a 238Pu-contaminated Wound Case with Chelation and Excision.

The urinary excretion and wound retention data collected after a Pu-contaminated wound were analyzed using Markov Chain Monte Carlo (MCMC) to obtain the posterior distribution of the intakes and doses. An empirical approach was used to model the effects of medical treatments (chelation and excision) on the reduction of doses. It was calculated that DTPA enhanced the urinary excretion, on average, by a factor of 17. The empirical analysis also allowed calculation of the efficacies of the medical treatments-excision and chelation averted approximately 76% and 5.5%, respectively, of the doses that would have been if there were no medical treatment. All bioassay data are provided in the appendix for independent analysis and to facilitate the compartmental modeling approaches being developed by the health physics community.

Response to a Skin Puncture Contaminated with 238Pu at Los Alamos National Laboratory.

The three principal pathways for intakes of plutonium are ingestion, inhalation, and contaminated wounds. In August 2018, a glovebox worker at Los Alamos National Laboratory (LANL) sustained a puncture from a thread of a braided steel cable contaminated with Pu. The puncture produced no pain, no blood, and little or no visible mark. As a result, the potential for a contaminated wound was not immediately recognized, and a wound count was not conducted until elevated urine bioassay results were received 12 d after the incident. This paper discusses the circumstances of the incident, along with the medical response and dose assessment, and a discussion of the risks and benefits of the medical interventions.

Development of a New Chelation Model: Bioassay Data Interpretation and Dose Assessment after Plutonium Intake via Wound and Treatment with DTPA.

The administration of chelation therapy to treat significant intakes of actinides, such as plutonium, affects the actinide's normal biokinetics. In particular, it enhances the actinide's rate of excretion, such that the standard biokinetic models cannot be applied directly to the chelation-affected bioassay data in order to estimate the intake and assess the radiation dose. The present study proposes a new chelation model that can be applied to the chelation-affected bioassay data after plutonium intake via wound and treatment with DTPA. In the proposed model, chelation is assumed to occur in the blood, liver, and parts of the skeleton. Ten datasets, consisting of measurements of C-DTPA, Pu, and Pu involving humans given radiolabeled DTPA and humans occupationally exposed to plutonium via wound and treated with chelation therapy, were used for model development. The combined dataset consisted of daily and cumulative excretion (urine and feces), wound counts, measurements of excised tissue, blood, and post-mortem tissue analyses of liver and skeleton. The combined data were simultaneously fit using the chelation model linked with a plutonium systemic model, which was linked to an ad hoc wound model. The proposed chelation model was used for dose assessment of the wound cases used in this study.

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine.

Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch's t-test. In prostate cancer survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments.

Label-free SERS diagnostics of radiation-induced injury via detecting the biomarker Raman signal in the serum and urine bio-samples based on Au-NPs array substrates.

A sensitive approach based on surface enhanced Raman spectroscopy (SERS) has been developed to evaluate the radiation caused biological injury. To achieve the effective SERS substrate, canonical anodic aluminum oxide (AAO) templates with regular array of nanotips were fabricated, and by plasma sputtering the gold nanoparticles (Au-NPs) were distributed on the nanotips to form the Au-NPs array with plenty of hotspots. The SERS substrates were utilized to examine the serum samples taken from the mice with the treatment of total body irradiation (TBI) of X-ray. The impact of TBI on the mice was analyzed and it was found that the SERS peak intensity at 532 cm-1 increased as a function of duration or dose of TBI. We confirmed that this Raman signature belongs to the myoglobin as a biomarker for the muscle damage due to the radiation caused injury. Furthermore, we also tested several blood and urine specimen of cancer patients who received radiotherapy. The results showed that our approach to some extent could distinguish the bio-samples from normal, X-ray treated and untreated individuals. Therefore, the proposed methodology may have the potential for prompt prognosis of radiation injury at early stage.

Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model.

After a radiological incident, there is an urgent need for fast and reliable bioassays to identify radiation-exposed individuals within the first week post exposure. This study aimed to identify candidate radiation-responsive protein biomarkers in human lymphocytes in vivo using humanized NOD scid gamma (Hu-NSG) mouse model. Three days after X-irradiation (0-2 Gy, 88 cGy/min), human CD45+ lymphocytes were collected from the Hu-NSG mouse spleen and quantitative changes in the proteome of the human lymphocytes were analysed by mass spectrometry. Forty-six proteins were differentially expressed in response to radiation exposure. FDXR, BAX, DDB2 and ACTN1 proteins were shown to have dose-dependent response with a fold change greater than 2. When these proteins were used to estimate radiation dose by linear regression, the combination of FDXR, ACTN1 and DDB2 showed the lowest mean absolute errors (≤0.13 Gy) and highest coefficients of determination (R2 = 0.96). Biomarker validation studies were performed in human lymphocytes 3 days after irradiation in vivo and in vitro. In conclusion, this is the first study to identify radiation-induced human protein signatures in vivo using the humanized mouse model and develop a protein panel which could be used for the rapid assessment of absorbed dose 3 days after radiation exposure.

Rapid Response, Dose Assessment, and Clinical Management of a Plutonium-contaminated Puncture Wound.

Internalization of radionuclides occurs not only by inhalation, ingestion, parenteral injection (i.e., administration of radioactive material for a medical purpose), and direct transdermal absorption, but also by contaminated wounds. In June 2010, a glove-box operator at the U.S. Department of Energy's Savannah River Site sustained a puncture wound while venting canisters containing legacy materials contaminated with Pu. To indicate the canisters had been vented, a flag was inserted into the vent hole. The shaft of the flag penetrated the protective gloves worn by the operator. Initial monitoring performed with a zinc-sulfide alpha detector indicated 300 dpm at the wound site. After being cleared by radiological controls personnel, the patient was taken to the site medical facility where decontamination was attempted and diethylenetriaminepentaacetic acid (DTPA) was administered intravenously within 1.5 h of the incident. The patient was then taken to the Savannah River Site In Vivo Counting Facility where the wound was counted with a Canberra GL 2820 high-purity germanium detector, capable of quantifying contamination by detecting low-energy x rays and gamma rays. In addition to the classic 13, 17, and 20 keV photons associated with Pu, the low-yield (0.04%) 43.5 keV peak was also detected. This indicated a level of wound contamination orders of magnitude above the initial estimate of 300 dpm detected with handheld instrumentation. Trace quantities of Am were also identified via the 59.5 keV peak. A 24 h urine sample collection was begun on day 1 and continued at varying intervals for over a year. The patient underwent a punch biopsy at 3 h postincident (14,000 dpm removed) and excisional biopsies on days 1 and 9 (removal of an additional 3,200 dpm and 3,800 dpm, respectively). The initial post-DTPA urine sample analysis report indicated excretion in excess of 24,000 dpm Pu. Wound mapping was performed in an effort to determine migration from the wound site and indicated minimum local migration. In vivo counts were performed on the liver, axillary lymph nodes, supratrochlear lymph nodes, and skeleton to assess uptake and did not indicate measurable activity. Seventy-one total doses of DTPA were administered at varying frequencies for 317 d post intake. After allowing 100 d for removal of DTPA from the body, five 24 h urine samples were collected and analyzed for dose assessment by using the wound model described in National Council on Radiation Protection and Measurements Report No. 156. The total effective dose averted via physical removal of the contaminant and DTPA administration exceeded 1 Sv, demonstrating that rapid recognition of incident magnitude and prompt medical intervention are critical for dose aversion.

Elevated Urine Levels of Macrophage Migration Inhibitory Factor in Inflammatory Bladder Conditions: A Potential Biomarker for a Subgroup of Interstitial Cystitis/Bladder Pain Syndrome Patients.

OBJECTIVE: To investigate whether urinary levels of macrophage migration inhibitory factor (MIF) are elevated in interstitial cystitis/bladder pain syndrome (IC/BPS) patients with Hunner lesions and also whether urine MIF is elevated in other forms of inflammatory cystitis. METHODS: Urine samples were assayed for MIF by enzyme-linked immunosorbent assay. Urine samples from 3 female groups were examined: IC/BPS patients without (N = 55) and with Hunner lesions (N = 43), and non-IC/BPS patients (N = 100; control group; no history of IC/BPS; cancer or recent bacterial cystitis). Urine samples from 3 male groups were examined: patients with bacterial cystitis (N = 50), radiation cystitis (N = 18) and noncystitis patients (N = 119; control group; negative for bacterial cystitis). RESULTS: Urine MIF (mean MIF pg/mL ± standard error of the mean) was increased in female IC/BPS patients with Hunner lesions (2159 ± 435.3) compared with IC/BPS patients without Hunner lesions (460 ± 114.5) or non-IC/BPS patients (414 ± 47.6). Receiver operating curve analyses showed that urine MIF levels discriminated between the 2 IC groups (area under the curve = 72%; confidence interval 61%-82%). Male patients with bacterial and radiation cystitis had elevated urine MIF levels (2839 ± 757.1 and 4404 ± 1548.1, respectively) compared with noncystitis patients (681 ± 75.2). CONCLUSION: Urine MIF is elevated in IC/BPS patients with Hunner lesions and also in patients with other bladder inflammatory and painful conditions. MIF may also serve as a noninvasive biomarker to select IC/BPS patients more accurately for endoscopic evaluation and possible anti-inflammatory treatment.

ANALYSIS OF URINARY EXCRETION DATA FROM THREE PLUTONIUM-CONTAMINATED WOUNDS AT LOS ALAMOS NATIONAL LABORATORY.

The National Council on Radiation Protection (NCRP)-156 Report proposes seven different biokinetic models for wound cases depending on the physicochemistry of the contaminant. Because the models were heavily based on experimental animal data, the authors of the report encouraged application and validation of the models using bioassay data from actual human exposures. Each of the wound models was applied to three plutonium-contaminated wounds, and the models resulted in a good agreement to only one of the cases. We then applied a simpler biokinetic model structure to the bioassay data and showed that fitting the transfer rates from this model structure yielded better agreement with the data than does the best-fitting NCRP-156 model. Because the biokinetics of radioactive material in each wound is different, it is impractical to propose a discrete set of model parameters to describe the biokinetics of radionuclides in all wounds, and thus each wound should be treated empirically.

Urinary miRNAs as Biomarkers for Noninvasive Evaluation of Radiation-Induced Renal Tubular Injury.

Radiation nephropathy is one of the common late effects in cancer survivors who received radiotherapy as well as in victims of radiation accidents. The clinical manifestations of radiation nephropathy occur months after exposure. To date, there are no known early biomarkers to predict the future development of radiation nephropathy. This study focuses on the development of urinary biomarkers providing readout of acute responses in renal tubular epithelial cells. An amplification-free hybridization-based nCounter assay was used to detect changes in mouse urinary miRNAs after irradiation. After a single LD50 of total-body irradiation (TBI) or clinically relevant fractionated doses (2 Gy twice daily for 3 days), changes in urinary levels of microRNAs followed either an early pattern, peaking at 6-8 h postirradiation and gradually declining, or later pattern, peaking from 24 h to 7 days. Of 600 miRNAs compared, 12 urinary miRNAs showed the acute response and seven showed the late response, common to both irradiation protocols. miR-1224 and miR-21 were of particular interest, since they were the most robust acute and late responders, respectively. The early responding miR-1224 also exhibited good dose response after 2, 4, 6 and 8 Gy TBI, indicating its potential use as a biomarker for radiation exposure. In situ hybridization of irradiated mouse kidney sections and cultured mouse primary renal tubular cells confirmed the tubular origin of miR-1224. A significant upregulation in hsa-miR-1224-3p expression was also observed in human proximal renal tubular cells after irradiation. Consistent with mouse urine data, a similar expression pattern of hsa-miR-1224-3p and hsa-miR-21 were observed in urine samples collected from human leukemia patients preconditioned with TBI. This proof-of-concept study shows the potential translational utility of urinary miRNA biomarkers for radiation damage in renal tubules with possible prediction of late effects.

Interpretation of Urinary Excretion Data From Plutonium Wound Cases Treated With DTPA: Application of Different Models and Approaches.

After a chelation treatment, assessment of intake and doses is the primary concern of an internal dosimetrist. Using the urinary excretion data from two actual wound cases encountered at Los Alamos National Laboratory (LANL), this paper discusses several methods that can be used to interpret intakes from the urinary data collected after one or multiple chelation treatments. One of the methods uses only the data assumed to be unaffected by chelation (data collected beyond 100 d after the last treatment). This method, used by many facilities for official dose records, was implemented by employing maximum likelihood analysis and Bayesian analysis methods. The impacts of an improper assumption about the physicochemical behavior of a radioactive material and the importance of the use of a facility-specific biokinetic model when available have also been demonstrated. Another method analyzed both the affected and unaffected urinary data using an empirical urinary excretion model. This method, although case-specific, was useful in determining the actual intakes and the doses averted or the reduction in body burdens due to chelation treatments. This approach was important in determining the enhancement factors, the behavior of the chelate, and other observations that may be pertinent to several DTPA compartmental modeling approaches being conducted by the health physics community.

Urinary metabolic signatures and early triage of acute radiation exposure in rat model.

After a large-scale radiological accident, early-response biomarkers to assess radiation exposure over a broad dose range are not only the basis of rapid radiation triage, but are also the key to the rational use of limited medical resources and to the improvement of treatment efficiency. Because of its high throughput, rapid assays and minimally invasive sample collection, metabolomics has been applied to research into radiation exposure biomarkers in recent years. Due to the complexity of radiobiological effects, most of the potential biomarkers are both dose-dependent and time-dependent. In reality, it is very difficult to find a single biomarker that is both sensitive and specific in a given radiation exposure scenario. Therefore, a multi-parameters approach for radiation exposure assessment is more realistic in real nuclear accidents. In this study, untargeted metabolomic profiling based on gas chromatography-mass spectrometry (GC-MS) and targeted amino acid profiling based on LC-MS/MS were combined to investigate early urinary metabolite responses within 48 h post-exposure in a rat model. A few of the key early-response metabolites for radiation exposure were identified, which revealed the most relevant metabolic pathways. Furthermore, a panel of potential urinary biomarkers was selected through a multi-criteria approach and applied to early triage following irradiation. Our study suggests that it is feasible to use a multi-parameters approach to triage radiation damage, and the urinary excretion levels of the relevant metabolites provide insights into radiation damage and repair.

Urinary 8-Hydroxy-2'-Deoxyguanosine: A Biomarker for Radiation-Induced Oxidative DNA Damage in Pediatric Cardiac Catheterization.

OBJECTIVE: To determine the utility of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a sensitive biomarker for radiation-induced cellular DNA damage in children undergoing cardiac catheterization. STUDY DESIGN: We enrolled pediatric patients with congenital heart diseases requiring cardiac catheterization in conjunction with healthy children and children under sedation as control. Demographic, clinical, laboratory and invasive hemodynamic data, urinary 8-OHdG levels, and radiation exposure measurements were collected prospectively. RESULTS: Nineteen patients, 10 healthy children and 9 children under sedation, were studied. In 19 patients who underwent cardiac catheterization, the median level of 8-OHdG in urine obtained at 24-48 hours after the procedure was significantly higher than at baseline (44.0 vs 17.3 ng/mg creatinine, P = .0001). Furthermore, the urinary 8-OHdG level after the procedure increased in 18 of the 19 study subjects. In contrast, there was no significant difference in 8-OHdG levels between the 2 spot urine samples obtained at arbitrary intervals of 24-48 hours in 10 healthy children (P = .7213), and at baseline and 24-48 hours following echocardiography in 9 children under sedation (P = .1097). Stepwise multiple regression analysis revealed that the cumulative air kerma during the cardiac catheterization was the variable which was strongly and significantly associated with the ratio of post- to precardiac catheterization urinary 8-OHdG levels among the evaluated variables (R(2) = 0.7179, F = 11.0256, P = .0007). CONCLUSIONS: Urinary 8-OHdG could be a useful biomarker for radiation-induced cellular DNA damage in children undergoing diagnostic cardiac catheterization.

Assessing patient characteristics and radiation-induced non-targeted effects in vivo for high dose-rate (HDR) brachytherapy.

PURPOSE: To test whether blood, urine, and tissue based colony-forming assays are a useful clinical detection tool for assessing fractionated treatment responses and non-targeted radiation effects in bystander cells. MATERIALS AND METHODS: To assess patients' responses to radiation treatments, blood serum, urine, and an esophagus explant-based in vivo colony-forming assay were used from oesophageal carcinoma patients. These patients underwent three fractions of high dose rate (HDR) intraluminal brachytherapy (ILBT). RESULTS: Human keratinocyte reporters exposed to blood sera taken after the third fraction of brachytherapy had a significant increase in cloning efficiency compared to baseline samples (p < 0.001). Such results may suggest an induced radioresistance response in bystander cells. The data also revealed a clear inverse dose-rate effect during late treatment fractions for the blood sera data only. Patient characteristics such as gender had no statistically significant effect (p > 0.05). Large variability was observed among the patients' tissue samples, these colony-forming assays showed no significant changes throughout fractionated brachytherapy (p > 0.05). CONCLUSION: Large inter-patient variability was found in the urine and tissue based assays, so these techniques were discontinued. However, the simple blood-based assay had much less variability. This technique may have future applications as a biological dosimeter to predict treatment outcome and assess non-targeted radiation effects.

Assessment of early triage for acute radiation injury in rat model based on urinary amino acid target analysis.

Rapid radiation injury early triage after a radiological or nuclear exposure is vital for treatment of a large number of wounded people. Owing to the high-throughput analysis and minimally invasive nature of sample collection, radiation metabolomics has been recently applied to radiation damage research. In the present study, exploring the feasibility of estimating the acute radiation injury for early triage by means of urinary amino acid target analysis was attempted using a high performance liquid chromatography electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) technique combined with multivariate statistical analysis. The non-linear kernel partial least squares (KPLS) model was used to separate the control and different radiation dose groups. The classification of different groups was performed after feature selection instead of before feature selection, because of its better separation. The classification accuracy at various radiation injury levels at different time points (5, 24, 48 and 72 h) post-irradiation exposure was investigated. For most of the radiation damage levels, the classification accuracy at 72 h after exposure was superior to that at earlier time points. Additionally, the potential radiation injury biomarkers selected suggested that the urea cycle, glycine, serine and threonine metabolism, alanine, aspartate and glutamine metabolism and related metabolic pathways were involved. The findings suggest that non-invasive urinary biomarkers have great potential for serving as an effective tool for rapid triage of mass casualties in nuclear accidents and understanding the pathogenesis of radiation injury.

Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy), and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

The urine proteome as a radiation biodosimeter.

The global rise in terrorism has increased the risk of radiological events aimed at creating chaos and destabilization, although they may cause relatively limited number of immediate casualties. We have proposed that a self-administered test would be valuable for initial triage following terrorist use of nuclear/radiological devices. The urine proteome may be a useful source of the biomarkers required for developing such a test. We have developed and extensively used a rat model to study the acute and late effect of total body (TBI) and partial body irradiation on critical organ systems. This model has proven valuable for correlating the structural and functional effects of radiation with molecular changes. Results show that nephron segments differ with regard to their sensitivity and response to ionizing radiation. The urine proteome was analyzed using LC-MS/MS at 24 h after TBI or local kidney irradiation using a 10 Gy single dose of X rays. LC-MS/MS data were analyzed and grouped under Gene Ontology categories Cellular Localization, Molecular Function and Biological Process. We observed a decrease in urine protein/creatinine ratio that corroborated with decreased spectral counts for urinary albumin and other major serum proteins. Interestingly, TBI caused greater decline in urinary albumin than local kidney irradiation. Analysis of acute-phase response proteins and markers of acute kidney injury showed increased urinary levels of cystatin superfamily proteins and alpha-1-acid glycoprotein. Among proteases and protease inhibitors, levels of Kallikrein 1-related peptidase b24, precursor and products of chymotrypsin-like activity, were noticeably increased. Among the amino acids that are susceptible to oxidation by free radicals, oxidized histidine levels were increased following irradiation. Our results suggest that proteomic analysis of early changes in urinary proteins will identify biomarkers for developing a self-administered test for radiation biodosimetry.

Long-term nephrotoxicity in adult survivors of childhood cancer.

BACKGROUND AND OBJECTIVES: Because little is known about long-term treatment-related nephrotoxicity, the aim was to determine risk factors for renal impairment long after childhood cancer treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 763 adult childhood cancer survivors (414 men) were obtained during regular visits at the late-effects clinic between 2003 and 2009. Median follow-up time was 18.3 years (range=5.0-58.2). Glomerular function was assessed by estimated GFR (using the Modification of Diet in Renal Disease formula), urinary albumin creatinine ratio, and tubular function by urinary ß2-microglobulin creatinine ratio. The association with treatment factors was analyzed with covariance analysis for estimated GFR and logistic regression for urinary albumin and urinary ß2-microglobulin creatinine ratios. RESULTS: Survivors treated with nephrectomy and abdominal irradiation had significantly lower estimated GFR than survivors not treated with nephrectomy/abdominal irradiation (estimated mean=90 ml/min per 1.73 m(2) versus 106, P<0.001). Estimated GFR was significantly lower in survivors after treatment with high-dose ifosfamide (88 versus 98, P=0.02) and high-dose cisplatin (83 versus 101, P=0.004) compared with survivors not treated with these regimen. Nephrectomy combined with abdominal radiotherapy (odds ratio=3.14, 95% confidence interval=1.02; 9.69) and high-dose cisplatin (odds ratio=5.19, 95% confidence interval=1.21; 22.21) was associated with albuminuria. High-dose ifosfamide (odds ratio=6.19, 95% confidence interval=2.45; 15.67) was associated with increased urinary ß2-microglobulin creatinine ratio. Hypertension was present in 23.4% of survivors and 31.4% of renal tumor survivors. CONCLUSIONS: Treatment with unilateral nephrectomy, abdominal radiotherapy, cisplatin, and ifosfamide was associated with lower estimated GFR. Persisting tubular damage was related to ifosfamide treatment.