Alzheimer Disease Cerebrospinal Fluid Biomarkers in a Tertiary Neurology Practice.

OBJECTIVE: To evaluate the performance of Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers in a tertiary neurology clinic setting with high frequency of non-AD cases, including normal pressure hydrocephalus (NPH). METHODS: There were 534 patients who underwent AD CSF biomarkers (Roche Elecsys Aß42, p-Tau181, total-Tau) from April 1, 2020, through April 23, 2021. A behavioral neurologist blinded to CSF results assigned a clinical diagnosis retrospectively on the basis of consensus criteria, and a neuroradiologist blinded to the diagnosis and CSF studies graded brain magnetic resonance images for indicators of CSF dynamics disorders. Associations between biomarkers, diagnoses, and imaging were assessed by χ2, analysis of covariance, and linear regression methods. RESULTS: Median age at time of testing was 67 years (range, 19 to 96 years), median symptom duration was 2 years (range, 0.4 to 28 years), and median Short Test of Mental Status score was 30 (range, 0 to 38). Clinical diagnoses significantly correlated with different CSF biomarker values (χ2=208.3; P=10e-4). p-Tau181/Aß42 ratios above 0.023 positively correlated with Alzheimer dementia (more than individual measures). This ratio also had the best performance for differentiating Alzheimer dementia from NPH (area under the curve, 0.869). Imaging markers supportive of CSF dynamics disorders correlated with low Aß42, p-Tau181, and total-Tau. CONCLUSION: In a heterogeneous clinical population, abnormal p-Tau181/Aß42 ratios (>0.023) have the strongest association with Alzheimer dementia and probably represent a comorbid AD pathologic component in persons clearly matching non-AD neurodegenerative syndromes. Altered CSF dynamics were associated with lower concentrations of AD CSF biomarkers regardless of clinical diagnosis, but the ratio compensates for these changes. In the appropriate clinical setting, an isolated abnormal Aß42 should prompt consideration of NPH.

Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays.

BACKGROUND: Neurofilament Light Chain (NfL) is an emerging blood biomarker of neuro-axonal injury and neurodegeneration with the potential to be used in the clinical management of various neurological conditions. Various NfL immunoassays are in development on high-throughput automated systems, but little information is available related to the comparability between assays. In this study, we performed a head-to-head comparison of four NfL immunoassays using plasma samples from individuals with various neurological conditions. METHODS: EDTA plasma samples in which NfL was ordered clinically were stratified according to diagnosis. NfL concentrations (pg/mL) in plasma were obtained using the Quanterix Simoa®, the Roche Elecsys, the Siemens Healthineers Atellica®IM, and the Fujirebio Lumipulse® NfL assays. Passing-Bablok regression analyses were performed to assess the correlation and bias between methods. Additionally, the distribution of NfL concentrations for each assay was assessed in three disease groups: amyotrophic lateral sclerosis (ALS) upon initial diagnosis, ALS treated, and multiple sclerosis (MS). RESULTS: The R2 between assays were all ≥ 0.95, however, significant proportional bias was observed between some assays. In particular, the Roche Elecsys assay NfL concentrations were significantly lower (∼85 %) when compared against the other three assays. The four assays were comparable with regards to the percentage of patients that were identified as having an elevated NfL result in the various clinical groups: ALS initial diagnoses (83-94 %), ALS untreated (93-100 %), and MS (8-18 %). CONCLUSIONS: This is the first study describing a head-to-head comparison of four automated NfL immunoassays. We demonstrate that there is a strong correlation between assays but a lack of standardization which is evident by the bias observed between some of the evaluated methods. These analytical differences will be important to consider when using NfL as a biomarker of neurodegeneration.

Performance of the Lumipulse plasma Aß42/40 and pTau181 immunoassays in the detection of amyloid pathology.

INTRODUCTION: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aß) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET). METHODS: Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aß42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP-MS) assay for plasma Aß42/40 was also evaluated. Amyloid-PET status was the outcome measure. RESULTS: Lumipulse and IP-MS Aß42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid-PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aß42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aß42/40 and pTau181 did not significantly improve performance over Aß42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71). DISCUSSION: The Lumipulse Aß42/40 assay showed similar performance to the IP-MS Aß42/40 assay for detection of an abnormal amyloid-PET; and both assays performed better than the two p-tau181 immunoassays. The Simoa Aß42/Aß40 assay was the least accurate at predicting an abnormal amyloid-PET status. Highlights: Lumipulse plasma Aß42/Aß40 AUC for abnormal amyloid-PET detection was 0.81.This performance was comparable to previously reported IP-MS and higher than Simoa.Performance of Alzheimer's disease blood biomarkers varies between assays.

Lack of observed interference by therapeutic monoclonal antibodies in select commonly utilized immunoassays.

BACKGROUND: Therapeutic monoclonal antibodies (tmabs) have been hypothesized to interfere with immunoassay measurements, although studies investigating this potential new class of interference are lacking. This study evaluated the effects of tmabs used in cancers ipilimumab (Bristol Myers Squibb), nivolumab (Bristol Myers Squibb), pembrolizumab (Merck) and autoimmune disorders adalimumab (AbbVie), infliximab (Janssen) and vedolizumab (Takeda) in common immunoassays used in the clinical laboratory. METHODS: Residual sera from 10 randomly chosen patients were split into two tubes and spiked with same volume (approximately 5 % final volume) of either saline (control) or 6 tmabs (final concentration of 100 µg/mL each). Concentrations from sixteen analytes in 19 different assays were assessed: TSH (Roche and Beckman), free thyroxine (Roche and Siemens), cortisol (Beckman), Cancer Antigens (CA): CA19-9 (Beckman), CA15-3 (Roche), CA125 (Roche), and CA27.29 (Siemens), carcinoembryonic antigen (Beckman), alpha-fetoprotein (Beckman), thyroglobulin (Beckman) and thyroglobulin antibodies (Beckman), thyroid peroxidase antibody (Beckman), beta-human chorionic gonadotropin (Roche and Beckman), total prostate-specific antigen (Roche), parathyroid hormone (Roche) and antinuclear antibodies IgG (Werfen). The tmab spiked residual sera were compared with matched saline spiked sera and percent error was assessed against allowable total error defined from biological variation or CLIA limits. RESULTS: None of the tested immunoassays were affected by the presence of the tmabs, in samples within or outside assay reference intervals. The median % error among all immunoassays ranged between -2.0% (for TSH) to 2.7% (for TPO Ab assay). CONCLUSION: These findings demonstrate no detectable tmab interference for the assessed immunoassays using spiked preparations of the tmabs in residual human sera. The findings are limited to the tmabs and immunoassays studied here.

Postsurgical utility of copeptin for the prediction of postoperative arginine vasopressin deficiency.

OBJECTIVE: Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors' aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD. METHODS: Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10-30 hours of extubation). Patients were evaluated for the development of AVD. RESULTS: One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8-67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing's disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027). CONCLUSIONS: In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Establishment of a Labile Bound Copper Reference Interval in a Healthy Population via an Inductively Coupled Plasma Mass Spectrometry Dual Filtration-Based Assay.

CONTEXT.­: Clinical testing for Wilson disease (WD) is potentially challenging. Measuring the fraction of labile bound copper (LBC) to total copper may be a promising alternative diagnostic tool with better sensitivity and specificity than some current biomarker approaches. A dual filtration-based inductively coupled mass spectrometry (ICP-MS) assay to measure LBC in serum was developed. OBJECTIVE.­: To establish a reference interval for LBC and LBC to total copper (LBC fraction) in a healthy adult population, and to examine associations between total copper, LBC, and LBC fraction with age, sex, menopausal status, hormone replacement therapy, and supplement use. DESIGN.­: Serum samples were collected from healthy male (n = 110) and female (n = 104) patients between the ages of 19 and 80 years. Total copper and LBC were analyzed using ICP-MS. Results were used to calculate the LBC fraction. Reference intervals were calculated for the 2.5th and 97.5th percentiles for both LBC and LBC fraction. RESULTS.­: The reference intervals for LBC were determined to be 13 to 105 ng/mL and 12 to 107 ng/mL for female and male patients, respectively. The reference intervals for the LBC fraction were 1.0% to 8.1% and 1.2% to 10.5% for female and male patients, respectively. No significant associations were found regarding age, menopausal status, hormone replacement therapy, or vitamin and supplement use. CONCLUSIONS.­: Sex-specific reference intervals have now been established for LBC and LBC fraction. These data in conjunction with further testing of WD populations can be used to assess the sensitivity and specificity of LBC fraction in screening, monitoring, and diagnosis.

Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders.

OBJECTIVE: Evaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions. METHODS: Intact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported. RESULTS: iFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001). CONCLUSIONS: This study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.

Detection of Cadmium and Lead in Kidney Stones. Associations with Patient Demographics, Stone Composition, and Smoking.

BACKGROUND: Kidney stones are a highly prevalent disease worldwide. Additionally, both environmental and occupational exposure to Pb and Cd continue to be prevalent globally and can result in renal toxicity. The objective of this study was to examine the potential presence of Pb and Cd in kidney stones, and to assess for correlation with demographic factors including smoking, gender, age, and kidney stone matrix composition. METHODS: Patient kidney stones (n = 96) were analyzed using Fourier transform infrared spectroscopy to identify the stone constituents. Cd and Pb concentrations (µg/g) were determined by inductively coupled plasma mass spectrometry. Cd and Pb concentrations were correlated using bivariable and multivariable statistical analysis with demographic factors (age, gender, smoking status), and kidney stone composition. RESULTS: Kidney stone Cd (median 0.092 µg/g, range 0.014 to 2.46) and Pb concentrations (median 0.95 µg/g, range 0.060 to 15.4) were moderately correlated (r = 0.56, P < 0.0001). Cd concentrations were positively associated with patient history of smoking, patient age, and calcium oxalate monohydrate levels while negatively associated with struvite and uric acid/uric acid dihydrate. Pb concentrations were positively associated with females and apatite levels while negatively associated with uric acid/uric acid dihydrate. After holding constant other stone type composition levels, smoking status, and age, both Pb and Cd were positively associated with apatite and negatively associated with uric acid/uric acid dihydrate, struvite, and calcium carbonate. CONCLUSIONS: Cd and Pb kidney stone concentrations are associated with specific kidney stone types. Cd and Pb kidney stone concentrations are both associated with smoking.

The effect of burosumab on intact and C-terminal FGF23 measurements.

OBJECTIVE: To investigate the effect of CRYSVITA® (burosumab-twza) on FGF23 measurements in an intact and a C-terminal immunoassay. METHODS: An intact serum FGF23 (MedFrontier) and a C-terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4-11.3 µg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post-burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurements RESULTS: Spiking burosumab (1.4-11.3 µg/ml) into sample pools resulted in a dose-dependent negative analytical interference on intact FGF23 measurements and no significant interference for C-terminal FGF23 measurements. However, more than a 500-fold median increase (post- vs. pre-burosumab administration) in in vivo FGF23 concentrations were observed by both assays. CONCLUSIONS: Therapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C-terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C-terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results. SUMMARY: This article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C-terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

Comparison of intact protein and digested peptide techniques for high throughput proteotyping of ApoE.

INTRODUCTION: Apolipoprotein E (ApoE) genotyping has been shown to have diagnostic value in the evaluation of cardiovascular diseases and neurodegenerative disorders such as Alzheimer's disease. Although genetic testing is well established for this application, liquid chromatography-mass spectrometry (LC-MS) has the potential to provide a high throughput, low-cost alternative for ApoE evaluation. METHODS: Serum samples were analyzed by peptide, intact protein, and genomic techniques. For peptide analysis, samples were digested with trypsin followed by liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) using a high-throughput multichannel LC system coupled to a Sciex 7500 mass spectrometer. For intact protein analysis, ApoE was immuno-purified using a monoclonal antibody immobilized on magnetic beads followed by high-resolution LC-MS analysis using an Exploris 480. DNA was extracted and evaluated using Sanger sequencing as a reference method. RESULTS AND DISCUSSION: The peptide measurement method produced one discrepant result when compared to genomic sequencing (out of 38 sequenced samples), whereas the intact protein analysis followed by deconvolution resulted in two discrepant results and when the intact protein data was processed with chromatographic integration there were three discrepant results. Therefore, the intact protein method proved slightly less accurate, required longer analysis time, and is substantially more costly, while providing only a 30 min improvement in sample preparation time. CONCLUSIONS: With current MS technology clinical laboratories appear to be better served to utilize trypsin digest sample preparation and LC-MS/MS as opposed to high-resolution LC-MS intact protein analysis techniques for evaluation of ApoE proteotype. Peptide analysis methods are capable of producing accurate results with high throughput and minimal cost.

Thyroglobulin Assay Interferences: Clinical Usefulness of Mass-Spectrometry Methods.

Context: Thyroglobulin autoantibodies (TgAbs) affect thyroglobulin immunometric assays (TgIMAs), causing falsely low results. Conversely, heterophilic antibodies (HAs) may cause falsely elevated results. Thyroglobulin (Tg) measurements by mass spectrometry (MS) resist antibody interference. The most effective use of TgIMA/TgMS in the evaluation of Tg remains unclear. Objective: The objective of this work was to study the usefulness of TgMS vs TgIMA in the presence of Tg measurement interference by HA and TgAb. Methods: In 163 thyroid cancer patients, Tg was postoperatively measured by TgIMA and TgMS. When TgIMA was elevated and TgMS undetectable, HA was assessed by serial dilution and pretreatment with HA blocking reagent. TgIMA and TgMS were compared in TgAb-positive patients with well-characterized clinical status. Results: 6 out of 45 cases with TgIMA >1 ng/mL had undetectable TgMS. HA interference was confirmed by serial dilution and HA blocking reagent addition. In TgAb-positive cases, TgIMA and TgMS were highly correlated (R2 = 0.86). In patients with structural disease and TgAb, TgIMA and TgMS were detectable in 6/19 patients, and 9/19 cases, respectively. The TgMS concentration range in the 3 discrepant cases ranged from 0.5 to 2.0 ng/mL. Hence, the presence of TgAb was associated with inappropriately reduced Tg concentrations with both TgIMA and TgMS. Conclusion: HA cause falsely elevated TgIMA with undetectable TgMS with significant frequency. TgMS can be used to rule out HA interference. Albeit resistant to TgAb in vitro, TgMS detects little Tg in patients with TgAb and structural disease. Hence, TgAb may reduce Tg concentrations in vivo. The implication is that no assay design may be able to overcome this problem. TgMS may not detect structural disease in TgAb-positive patients.

Different glucose analyzers report different glucose concentration values in term newborns.

Background: The American Academy of Pediatrics and Pediatric Endocrine Society neonatal hypoglycemia guidelines based their glucose concentration treatment thresholds on studies that predominantly used Beckman and Yellow Springs Glucose Oxidase Analyzers. Currently, a majority (76%) of U.S. hospital laboratories utilizing glucose oxidase methodology use Vitros® Glucose Analyzers. However, a bias of ~+5% between glucose concentrations from Beckman vs. Vitros Glucose Analyzers has been reported; this could have a clinically significant effect when using published guideline treatment thresholds. Methods: To determine if there is similar instrument bias between Beckman and Vitros Analyzers in reported glucose concentrations from term newborns, we compared plasma glucose concentrations measured within the first 3 h after birth by Beckman vs. Vitros Analyzers in a total of 1,987 newborns (Beckman n = 904, Vitros n = 1,083). Data were fit using nonlinear cubic spline models between collection time and glucose concentration. Results: The non-linear patterns of initial glucose concentrations (during the first 3 h after birth) as measured by Beckman and Vitros Analyzers paralleled each other with no overlap of the fit spline curve 95% confidence intervals, with an approximate +5 mg/dL constant bias. Additionally, in method comparison studies performed in the Chemistry Laboratory on adult samples, there was a +4.2-7.4 mg/dL measured glucose bias for the Beckman vs. Vitros Analyzer. Conclusion: Glucose concentrations from term, appropriate size for gestational age newborns were about 5 mg/dL higher when measured by Beckman vs. Vitros Analyzers. Perhaps, concentrations of 45 mg/dL reported from Beckman Analyzers may be equivalent to 40 mg/dL from Vitros Analyzers. When managing neonatal hypoglycemia, it is important to know which analyzer was used and whether adjusting for potential instrument bias is necessary when following published guidelines.

Plasma neurofilament light chain (NfL) reference interval determination in an Age-stratified cognitively unimpaired cohort.

BACKGROUND AND AIMS: Neurofilament light chain (NfL) is an emerging biomarker of neurodegenerative disease progression. As plasma NfL increases with age, characterization of NfL concentrations in an age-stratified cognitively unimpaired population was assessed. MATERIALS AND METHODS: EDTA-plasma samples were measured using the Simoa® NF-light™ Advantage Kit assay. One-sided reference intervals were established from 1100 cognitive normal individuals (588 male, 512 female) aged 20 to 95 years. Of those, 927 samples were obtained from the Mayo Clinic Study of Aging cohort (age > 50 years), and the remainder (age < 50 years) were obtained from individuals without known neurological conditions. All samples were from individuals without known chronic kidney disease, stroke or myocardial infarction, and a body mass index < 30 kg/m2. RESULTS: The 97.5th percentile limits for the following age ranges (in years) were (pg/mL): 20 s: ≤8.4, 30 s: ≤11.4, 40 s: ≤15.4, 50 s: ≤20.8, 60 s: ≤28.0, 70 s: ≤37.9, 80+: ≤51.2. Sex had no significant effect on reference intervals. Observed NfL concentrations increased at a rate of 3.1 % per year of age. CONCLUSIONS: Characterization of the rate of NfL concentration increase and decade-wide reference intervals from a neurologically well-characterized patient population will aid in interpretation of NfL during the clinical evaluation of a potential neurodegenerative disease.

Assessment of gadolinium and iodine concentrations in kidney stones and correlation with contrast agent exposure, stone matrix composition, and patient demographic factors.

BACKGROUND: Gadolinium-based contrast agents (GBCAs) and Iodinated contrast media are widely utilized to increase medical imaging sensitivity. With predominant renal elimination, the potential for the incorporation of contrast agent derived gadolinium and iodine into kidney stones remains largely uncharacterized. The study objective was to measure gadolinium and iodine concentrations within kidney stones. Observed elemental concentrations were correlated with prior contrast agent administration, kidney stone composition, age, gender, and smoking status. METHODS: Kidney stones from 96 patients were analyzed by Fourier Transform Infrared Spectroscopy to determine stone composition. Residual kidney stone material was digested and analyzed by Inductively Coupled Plasma Mass Spectrometry to determine gadolinium and iodine concentrations. Univariable and multivariable lognormal linear regression were performed to study the relationship between kidney stone element concentrations and contrast agent administration, kidney stone composition, age, gender, and smoking status. RESULTS: Median iodine and gadolinium stone concentrations were 6.4 (range 0.6-3997) and 0.1 (range ≤0.013-113.5) µg/g respectively. Elevated gadolinium was strongly associated with GBCA history with a hazard rate of 2.20 (95 % CI 1.14-3.25 P < 0.001). Gadolinium was positively associated with smoking, as well as stones comprised of apatite and calcium oxalate. Iodine concentrations were negatively associated with uric acid stones. CONCLUSION: Gadolinium, but not iodine, concentrations in kidney stones was strongly correlated with contrast exposure history. Stone matrix composition and demographic factors, particularly smoking, can influence observed kidney stone elemental concentrations. Additional studies are needed to determine if exposure to gadolinium and iodine promote the formation of stone matrix and/or reflect exposure history.

Development of a PTHrP chemiluminescent immunoassay to assess humoral hypercalcemia of malignancy.

BACKGROUND: Parathyroid hormone related peptide (PTHrP) measurements are helpful in the evaluation and management of individuals suspected of humoral hypercalcemia of malignancy (HHM). AIM: To develop a chemiluminescent assay for PTHrP quantitation, establish reference intervals, and evaluate its clinical performance. METHOD: PTHrP 1-86 was measured using a polyclonal rabbit antibody (capture) and an acridinium ester labeled goat polyclonal antibody for chemiluminescent detection. RESULTS: Assay imprecision was < 9% (intra-assay) and < 15% (inter-assay). The analytical measuring range was 0.16-50.5 pmol/L. No significant cross-reactivity was observed for PTH (1-84), PTHrP (107-139), and PTHrP (1-36); whereas PTHrP (38-94) showed 8.3% cross-reactivity. Comparison with the pre-existing Mayo assay showed a positive bias: new assay = 2.24 (pre-existing assay)-0.30 and r2 = 0.96. The reference interval was ≤ 0.7 pmol/L, however, a cut-off of ≤ 4.2 pmol/L yielded increased specificity (98%). Comparison of patients with HHM versus those without HHM resulted in an area under the ROC curve of 0.99. A significant inverse relationship between eGFR and PTHrP was observed (r = 0.738). PTHrP concentrations in patients with Chronic Kidney Disease (CKD) were ≤ 4.2 pmol/L. CONCLUSION: This assay is specific for PTHrP 1-86. A clinical decision limit of 4.2 pmol/L was sensitive and specific for patients with HHM.