Urinary Ratio Research Articles

Physiologically based pharmacokinetic (PBPK) modeling of the role of CYP2D6 polymorphism for metabolic phenotyping with dextromethorphan.

The cytochrome P450 2D6 (CYP2D6) is a key xenobiotic-metabolizing enzyme involved in the clearance of many drugs. Genetic polymorphisms in CYP2D6 contribute to the large inter-individual variability in drug metabolism and could affect metabolic phenotyping of CYP2D6 probe substances such as dextromethorphan (DXM). To study this question, we (i) established an extensive pharmacokinetics dataset for DXM; and (ii) developed and validated a physiologically based pharmacokinetic (PBPK) model of DXM and its metabolites dextrorphan (DXO) and dextrorphan O-glucuronide (DXO-Glu) based on the data. Drug-gene interactions (DGI) were introduced by accounting for changes in CYP2D6 enzyme kinetics depending on activity score (AS), which in combination with AS for individual polymorphisms allowed us to model CYP2D6 gene variants. Variability in CYP3A4 and CYP2D6 activity was modeled based on in vitro data from human liver microsomes. Model predictions are in very good agreement with pharmacokinetics data for CYP2D6 polymorphisms, CYP2D6 activity as described by the AS system, and CYP2D6 metabolic phenotypes (UM, EM, IM, PM). The model was applied to investigate the genotype-phenotype association and the role of CYP2D6 polymorphisms for metabolic phenotyping using the urinary cumulative metabolic ratio (UCMR), DXM/(DXO + DXO-Glu). The effect of parameters on UCMR was studied via sensitivity analysis. Model predictions indicate very good robustness against the intervention protocol (i.e. application form, dosing amount, dissolution rate, and sampling time) and good robustness against physiological variation. The model is capable of estimating the UCMR dispersion within and across populations depending on activity scores. Moreover, the distribution of UCMR and the risk of genotype-phenotype mismatch could be estimated for populations with known CYP2D6 genotype frequencies. The model can be applied for individual prediction of UCMR and metabolic phenotype based on CYP2D6 genotype. Both, model and database are freely available for reuse.

Evaluation of Urinary Calcium–Creatinine Ratio for Early Prediction of Preeclampsia

Background: Preeclampsia (PE) is one of the most important hypertensive disorders in pregnancy. It is one of the fatal complications with significant mortality and morbidity. Incidence of preeclampsia is around 5-10% of all pregnancies, and in developing countries like Bangladesh it is around 4-18%. Objective: The objective of this study was to determine the efficacy of urinary calcium-creatinine ratio in a spot urine sample for early prediction of preeclampsia in pregnant women. Methods: It's a cross sectional type of analytical study, done in the department of Obstetrics & Gynaecology, Sir Salimuilah Medical College Mitford Hospital, Dhaka. After fulfilling inclusion and exclusion criteria total 100 pregnant women with risk factors of preeclampsia were enrolled as the study population. Results: Among different parameters serum calcium concentration of normal pregnancy and preeclampsia group varied significantly (p<0.05). Women with preeclampsia showed reduced excretion of calcium in comparison to normal pregnant women when spot urinary calcium concentration was evaluated. In this study comparison of spot urinary calcium-creatinine ratio in normal pregnant woman and in preeclamptic women was done and the result was highly significant (p <0.001). Conclusion: This study is intended to identify at risk patients and put selection criteria for primary prevention to reduce morbidity and mortality in patients of preeclampsia. It showed lower urinary calcium excretion and calcium-creatinine ratio in preeclamptic women than normotensive pregnant women. Therefore, a single random urinary calcium-creatinine may be an effective tool for the early diagnosis of preeclampsia.

Poppy Seed Consumption May Be Associated with Codeine-Only Urine Drug Test Results.

Consumption of poppy seed-containing food products can result in opiate-positive urine drug test results and may pose challenges in distinguishing poppy seed consumption from opiate administration. In this context, guidance has suggested that codeine concentrations exceeding 300 ng/mL coupled with morphine-to-codeine ratios <2 are indicative of codeine consumption and, therefore, exclude poppy seed consumption as a legitimate explanation for the test result. In recent years, we performed independent medical examinations of three individuals who produced codeine-positive/morphine-negative (300 ng/mL) forensic urine drug test results but denied codeine administration, attributing their test results to the consumption of specific poppy seed-containing food products. In the present study, 11 participants consumed one of the 10 unique poppy seed-containing food products, including the three implicated food products. Six of 33 non-baseline urine samples (18%)-representing three food products-were positive for codeine and negative for morphine at 300 ng/mL cut-offs (and therefore featured morphine-to-codeine ratios <2). This study adds to a small literature indicating that consumption of poppy seed-containing food products cannot reliably be distinguished from codeine administration based on previously published urinary opiate concentrations and ratios. An important caveat is that in none of these cases did maximum urinary codeine concentrations exceed 1,300 µg/g creatinine.

Study the Correlation of Urinary Calcium-Creatinine Ratio as a Predictor of Pre-Eclampsia

Study the Correlation of Urinary Calcium-Creatinine Ratio as a Predictor of Pre-Eclampsia

Pharmacokinetics, safety, and tolerability of sodium phenylacetate and sodium benzoate in healthy Japanese volunteers: A phase I, single-center, open-label study

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.

Effect of divalent and trivalent metal ions on artificial membrane permeation of fluoroquinolones.

The purpose of the present study was to evaluate the predictability of PAMPA for the effect of metal ions on the bioavailability of fluoroquinolones (FQ). Eleven FQs and seven metal ions were employed in this study. The PAMPA membrane consisted of a 10 % soybean lecithin (SL) - decane solution. A drug solution in MES buffer with or without a metal ion (added as a chloride salt) was added to the donor compartment. In the absence of metal ions, FQ showed relatively high permeability (> 5 × 10-6 cm/sec) in SL-PAMPA despite their hydrophilic and zwitterionic properties. As the PAMPA permeability ratio with/without metal ions became smaller, the urinary excretion and AUC ratios tended to be smaller, suggesting that SL-PAMPA is a suitable in vitro model to evaluate the potential effect of metal ions on the bioavailability of FQ. However, the reduction in AUC and urinary excretion was overestimated for low solubility metal ion formulations (dried aluminum hydroxide gel and La2(CO3)3・8H2O). In such cases, the dissolution of the metal ion formulations and the permeation of FQs should be simultaneously evaluated.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population

Belimumab improved kidney outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the United States and the European Union. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup. Prespecified subgroup analysis of BLISS-LN, a phase 3, placebo-controlled, randomized 104-week trial. Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy. Patients were administered intravenous belimumab 10mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1,000mg each, could be administered during induction. The primary end point was primary efficacy renal response (PERR; ie, urinary protein-creatinine ratio≤0.7g/g, estimated glomerular filtration rate no more than 20% below preflare value or≥60mL/min/1.73m2, and no treatment failure) at week 104. Key secondary end points included complete renal response (CRR; urinary protein-creatinine ratio<0.5g/g, estimated glomerular filtration rate no more than 10% below preflare value or≥90mL/min/1.73m2, and no treatment failure) at week 104; PERR at week 52; time to kidney-related event or death; and safety. PERR and CRR were analyzed using a logistic regression model, and time to a kidney-related event or death was analyzed using a Cox proportional hazards regression model. 142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab, n=74; placebo, n=68). At week 104, more belimumab than placebo patients achieved PERR (53% vs 37%; OR, 1.76 [95% CI, 0.88-3.51]) and CRR (35% vs 25%; OR, 1.73 [95% CI, 0.80-3.74]). At week 52, more belimumab than placebo patients achieved PERR (62% vs 37%; OR, 2.74 [95% CI, 1.33-5.64]). Belimumab reduced the risk of a kidney-related event or death compared with placebo at any time (HR, 0.37 [95% CI, 0.15-0.91]). Safety was similar across treatment groups. Small sample size and lack of formal significance testing. Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian subgroup with LN. This study was funded by GSK (GSK study no. BEL114054). Registered at ClinicalTrials.gov with study number NCT01639339.

Correlation of Urinary Protein Creatinine Ratio Versus Urinary Tract Infection in Assessment of Severity of Pre-Eclampsia

Correlation of Urinary Protein Creatinine Ratio Versus Urinary Tract Infection in Assessment of Severity of Pre-Eclampsia

Urinary Levels of miR-491-5p and miR-592 as Potential Diagnostic Biomarkers in Female Aging Patients with OAB: A Pilot Study

Women with overactive bladder syndrome (OAB) have a lower urinary ratio of nerve growth factor (NGF) to its precursor (proNGF) compared to healthy controls. MicroRNAs related to NGF and proNGF metabolism and to their receptors may be present in urine and may possess diagnostic value. Urine and blood samples from 20 control and 20 OAB women (50–80 years) were obtained, together with validated questionnaires and other clinical parameters. The relative expression of urinary microRNAs was measured with RT-qPCR. MiR-491-5p, which negatively controls the translation of the matrix metalloproteinase-9 (MMP-9), the main enzyme degrading NGF, was significantly decreased in OAB. Similarly, miR-592, which represses p75NTR receptor synthesis, was down-regulated in OAB. Age, renal function and insulin resistance did not affect these results. ROC curves confirmed the high sensitivity of miR-491-5p and miR-592 for diagnosis. On the other hand, miRNAs involved in the expression of proNGF, of survival receptor TrkA and of markers of nerve integrity were similar between groups. The detection of miR-491-5p and miR-592 in urine could be a useful and non-invasive tool for the diagnosis of OAB syndrome in aging women.

Correlation between Insulin Resistance and Microalbuminuria Creatinine Ratio in Postmenopausal Women.

Objective To study the relationship between insulin resistance and urinary microalbumin creatinine ratio in postmenopausal women. Methods The selected research group comprised 104 postmenopausal women with type 2 diabetes who were admitted to the Department of Endocrinology in the green card center at the First Affiliated Hospital of Hainan Medical University between 2017 and 2019 inclusive. Ninety-eight postmenopausal women with the normal blood glucose metabolism hospitalized in the same period were used as the control group. The age, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, fasting blood glucose, fasting insulin (FINS), glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), and urinary albumin-creatinine ratio (UACR) were analyzed. The insulin resistance index (HOMR-IR) was calculated, and the correlation between IR and UACR was analyzed. Results Levels of HOMA-IR, SBP, HbA1c, HDL-C, LDL-C, TC, TG, FPG, FINS, and UACR in the study group were higher than those in the control group, and a significant difference was found between the groups (P < 0.05). The level of DBP in the study group was lower than that in the control group, and the difference was statistically significant (P < 0.05). Pearson correlation analysis showed that UACR was positively correlated with HOMA-IR and HbA1c (r = 0.254, r = 0.565, P < 0.01). Multiple linear stepwise regression analysis further showed that HOMA-IR and age were positively correlated with UACR (P < 0.05). Conclusion There is a correlation between IR and UACR in postmenopausal women. IR is an independent risk factor for UACR.

A longitudinal study of cytochrome P450 2D6 (CYP2D6) activity during adolescence.

CYP2D6 substrates are among the most highly prescribed medications in teenagers and also commonly associated with serious adverse events. To investigate the relative contributions of genetic variation, growth, and development on CYP2D6 activity during puberty, healthy children and adolescents 7–15 years of age at enrollment participated in a longitudinal phenotyping study involving administration of 0.3 mg/kg dextromethorphan (DM) and 4‐h urine collection every 6 months for 3 years (7 total visits). At each visit, height, weight, and sexual maturity were recorded, and CYP2D6 activity was determined as the urinary molar ratio of DM to its metabolite dextrorphan (DX). A total of 188 participants completed at least one visit, and 102 completed all seven study visits. Following univariate analysis, only CYP2D6 activity score (p < 0.001), urinary pH (p < 0.001), weight (p = 0.018), and attention‐deficit/hyperactivity disorder (ADHD) diagnosis (p < 0.001) were significantly correlated with log(DM/DX). Results of linear mixed model analysis with random intercept, random slope covariance structure revealed that CYP2D6 activity score had the strongest effect on log(DM/DX), with model‐estimated average log(DM/DX) being 3.8 SDs higher for poor metabolizers than for patients with activity score 3. A moderate effect on log(DM/DX) was observed for sex, and smaller effects were observed for ADHD diagnosis and urinary pH. The log(DM/DX) did not change meaningfully with age or pubertal development. CYP2D6 genotype remains the single, largest determinant of variability in CYP2D6 activity during puberty. Incorporation of genotype‐based dosing guidelines should be considered for CYP2D6 substrates given the prevalent use of these agents in this pediatric age group.

CX3CL1-induced CD16+ monocytes extravasation in myeloperoxidase-ANCA-associated vasculitis correlates with renal damage.

BackgroundMonocytes are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Monocyte/macrophages are the dominant infiltrating cells in the glomeruli of patients with myeloperoxidase-AAV (MPO-AAV). However, how human monocyte subsets extravasate to the kidney in MPO-AAV with renal damage is unclear.Methods30 MPO-AAV patients with renal damage and 22 healthy controls were enrolled in this study. Monocyte subsets and monocyte-related chemokines in the blood and kidneys of MPO-AAV patients were detected. The chemoattractant activity of the CX3CL1-CX3CR1 axis on CD16+ monocytes was observed. The effect of MPO-ANCA on the migration of CD16+ monocytes to human glomerular endothelial cells (HGECs) was detected by flow cytometry and transwell migration assay.ResultsCompared with controls, CD16+ monocytes were significantly decreased in the blood and increased in the glomeruli of MPO-AAV patients with renal damage. The level of CX3CL1, but not CCL2, was significantly increased in the plasma of MPO-AAV patients. CX3CL1 co-localized with glomerular endothelial cells in MPO-AAV patients with renal damage. Moreover, we initially found that MPO-ANCA promotes an increase of the chemokine CX3CL1 on HGECs, imposing recruitment on CD16+ monocytes. Finally, the percentage of CD16+ monocytes in the blood was found to be positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with urinary protein creatinine ratio in MPO-AAV patients with renal damage. Furthermore, the urinary protein creatinine ratio was positively correlated with the infiltrating of CD14+ and CD16+ cells in the kidneys.ConclusionEnhanced extravasation of CD16+ monocytes to the kidney via the CX3CL1-CX3CR1 axis may be involved in renal damage in MPO-AAV.

Metabolomic analysis of equine urine to determine route of altrenogest administration

Distinguish allowed oral administration of altrenogest from the illegal intramuscular route. Androgenic anabolic steroids (AAS) are some of the most common illegal compounds used in the sporting industry. Altrenogest, also known as allyltrenbolone, is a steroidal progestin that is used to suppress oestrus in female horses. The use of this substance results in more manageable mares for training and competition alongside male horses, while also improving the workplace safety of riders and handlers. In response to the detection of low levels of steroid impurities contained in commercially available altrenogest products, Rule LR44A was introduced by Racing NSW in June 2018 (Gestal MFV. Racing NSW, ed. Vol LR44A. 2018). This prohibited the use of injectable altrenogest and allows orally administered altrenogest outside of one clear day of racing. This research focused on a qualitative investigation of phase II metabolites in mares impacted by the administration of altrenogest, and to differentiate the allowed oral administration from the illegal intramuscular route. A complementary targeted/non-targeted metabolomic approach was used to monitor urinary levels of androgens, corticosteroids and progestins, as both phase I (unconjugated) and phase II (sulfate and glucuronide conjugates) metabolites where possible. Samples obtained from a ten-mare administration study using a crossover-design, conducted by Charles Sturt University with ethics approval (A19050), was analysed involving both oral and intramuscular administration of altrenogest. The collection period spanned from pre-administration to 21 days post-administration, totalling 32 samples. A steroid sulfate analysis method was adapted from C. Fitzgerald et al (2021) to collect the intact sulfated steroids present in the sample without the use of hydrolysis. Data was acquired using a Shimadzu (Kyoto, Japan) 9030 UHPLC-QTOF-MS instrument. Data analysis used a combination of MSDial (version 4.80), Microsoft Excel (version 16.58), RStudio (version 2021.09.2) and Jupyter Notebook (version 6.3.0). The quantification of steroid impurities was performed using enzyme hydrolysis and liquid-liquid extraction prior to LC-MS/MS analysis using a Shimadzu Nexera UHPLC coupled to an 8060 triple-quadrupole MS. An initial investigation of the data showed larger LOWESS normalised intensity of altrenogest in injected samples when compared to oral administration samples. LOWESS utilises a locally weighted scatterplot smoothing program to normalise intensity data. The absence of some phase II conjugates in injected samples indicated reduced reliance on hepatic metabolism. The urinary ratio of altrenogest to altrenogest sulfate (A/AS) displayed up-regulation within the first 24 h of oral administration, suggesting it to be a putative biomarker for further investigation. The urinary A/AS ratio demonstrated the potential to distinguish between oral and injected altrenogest in racehorses.

Short- and Long-Term Progression of Kidney Involvement in Systemic Lupus Erythematosus Patients with Low-Grade Proteinuria.

Lupus nephritis remains a common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current guidelines recommend performing a kidney biopsy at a urine protein-creatinine ratio of ≥0.5 g/g. However, cross-sectional studies reported a high prevalence of active histologic lupus nephritis lesions, and even chronic irreversible scarring, in patients with low-grade proteinuria. This study was initiated to assess disease progression in patients with SLE and low-grade proteinuria to identify risk factors for progression to overt proteinuria suggestive of clinical lupus nephritis. Patients with SLE who had an incident urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g without known lupus nephritis were identified from the Einstein Rheumatic Disease Registry. Patients who developed a random urinary protein-creatinine ratio of ≥0.5 g/g with or without biopsy during the follow-up period were defined as "progressors." Patients who progressed to a urinary protein-creatinine ratio of ≥0.5 g/g within 2 years of developing a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g were defined as "fast progressors," a subgroup expected to benefit most from early biopsies and therapeutic interventions. Among 151 eligible patients with SLE and low-grade proteinuria at study entry, 76 (50%) progressed to a urinary protein-creatinine ratio of ≥0.5 g/g, of which 44 underwent a clinically indicated biopsy. The median (interquartile range) time from a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g to progression was 1.2 (0.3-3.0) years. Of the 20 biopsies performed in the first 2 years, 16 specimens showed active, treatable lupus nephritis. Low complement and shorter SLE duration at low-grade proteinuria onset were associated with progression to overt proteinuria across different analyses. Other associated factors included hypertension, diabetes mellitus, younger age, and the presence of hematuria. In this longitudinal cohort of patients with SLE and low-grade proteinuria at study entry, over half progressed to a urinary protein-creatinine ratio of ≥0.5 g/g in a short time period.

A CASE SERIES ON HYPERCALCEMIA

Hypercalcemia in adults arises from a myriad of underlying causes. Etiology of hypercalcemia varies from causes like Vitamin D toxicity to hyperparathyroidism, hyperthyroidism, chronic kidney disease, granulomatous diseases, and malignant diseases .Though not an uncommon metabolic problem, hypercalcemia can easily be missed due to the diverse clinical presentations. Primary hyperparathyroidism and malignancy are the most common causes, accounting for 90% of the cases. Clinical manifestation varies depending on the ionized calcium levels. Symptoms manifest when calcium levels exceed 12 mg/dl. We report four different cases that illustrate the need for a focused workup of hypercalcemia. Routine hypercalcemia workup includes serum Parathormone (PTH), Vitamin D, ionized calcium, phosphorus, magnesium, alkaline phosphatase levels, renal functions, and urinary calcium-creatinine ratio. Prognosis depends on the cause of hypercalcemia. The clinical diagnosis needs a high index of suspicion. Denitive management requires focused workup for etiological diagnosis and treatment of underlying cause. Treatment for hypercalcemia is required in all symptomatic patients or if the calcium level exceeds more than 15 mg/dL, even if asymptomatic. Immediate management includes restoring intravascular volume and promoting diuresis. Calcitonin, Bisphosphonates and steroids play a role in medical management. For patient's refractory to medical treatment, hemodialysis is required.

A cohort study on use of the spot urine calcium-creatinine ratio for prediction of antepartum preeclampsia among high-risk pregnant women in Delta State, Nigeria

Background/Aim: Preeclampsia is a multisystemic disorder, which significantly contributes to maternal and fetal morbidity and mortality, especially in developing countries where it accounts for about one-third of maternal mortality cases. Predicting its occurrence will reveal a sizeable population of pregnant women who will undoubtedly benefit from prevention. The ideal screening marker for the disease is still being investigated. The urine calcium-creatinine ratio (CCR) is an inexpensive, simple, and easily assayed biomarker. This study determined the accuracy of the spot urinary calcium-creatinine ratio in predicting the occurrence of preeclampsia.&#x0D; Methods: This was a prospective cohort study conducted in Delta State, which involved four healthcare facilities in Nigeria. A total of 138 pregnant women between 8 and 18 weeks gestation were recruited. Urine samples were obtained at 18 weeks to assay their CCR, and patients were followed up weekly for blood pressure measurement and dipstick urinalysis until delivery.&#x0D; Results: The mean spot urine CCR in this study was 0.225 (0.101). It was significantly lower in women who developed preeclampsia compared to normotensive women (P &lt; 0.001). Multiple logistics regression analysis showed that the association between urine CCR and occurrence of preeclampsia was statistically significant. At a receiver operating characteristic cutoff of ≤ 0.1065, CCR had a sensitivity of 75%, specificity of 91.3%, positive predictive value (PPV) of 35.3%, and negative predictive value (NPV) of 98.3%. The low PPV of 35.3% can be explained by the low prevalence of preeclampsia (5.78%) in the study population.&#x0D; Conclusion: In conclusion, the poor PPV of the urine CCR was due to the low prevalence of preeclampsia in the study. However, in considering all women at risk, urine CCR may be a good prognostic marker when the illness prevalence is substantial.

Investigation of buprenorphine-related deaths using urinary metabolite concentrations.

Quantitative analysis of postmortem urine, instead of blood, for buprenorphine and metabolites may provide additional evidence for the diagnosis of fatal buprenorphine poisoning. In this study, 247 autopsy urine samples, previously testing positive for buprenorphine or norbuprenorphine, were quantitatively reanalysed with a recently developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for unconjugated buprenorphine (BUP), norbuprenorphine (NBUP), naloxone (NAL), and their respective conjugated metabolites, buprenorphine glucuronide (BUPG), norbuprenorphine glucuronide (NBUPG), and naloxone glucuronide (NALG). The cases were divided, according to medical examiners' decision, to buprenorphine poisonings and other causes of death. The groups were compared for urinary concentrations and metabolite concentration ratios of the six analytes. All median concentrations were higher in the buprenorphine poisoning group. The median concentration of BUPG was significantly higher and the median metabolite ratios NBUP/BUP, NBUPG/BUPG, and NBUPtotal/BUPtotal were significantly lower in poisonings than in other causes of death. Naloxone-related concentrations and ratios were not significantly different between the groups.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial

Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. Phase 3, open-label, single-arm trial. Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate≤45 mL/min/1.73 m2 (if age≥12 months) or increased serum creatinine level (if age<12 months), and POx≥20 μmol/L at screening, including patients with or without systemic oxalosis. Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. All patients (N= 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI,-15.2% to 81.8%) in cohort A (n= 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n= 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. Single-arm study without placebo control. Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. Alnylam Pharmaceuticals. Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Predictive significance of joint plasma fibrinogen and urinary alpha-1 microglobulin-creatinine ratio in patients with diabetic kidney disease.

Although many biomarkers have high diagnostic and predictive power for diabetic kidney disease (DKD), less studies were performed for the predictive assessment in DKD and its progression with combined blood and urinary biomarkers. This study aims to explore the predictive significance of joint plasma fibrinogen (FIB) concentration and urinary alpha-1 microglobulin-creatinine (α1-MG/CR) ratio in DKD. A total of 234 patients with type 2 diabetes were enrolled, and their clinical and laboratory data were retrospectively assessed. A ROC curve analysis was performed to evaluate the power of plasma FIB and urinary α1-MG/CR ratio for identifying DKD and advanced DKD, respectively. The predictive power for DKD and advanced DKD was analyzed by regression analysis. Plasma FIB and urinary α1-MG/CR levels were higher in patients with DKD than with pure T2D (p<0.001). The multivariate-adjusted odds ratios (ORs) were 5.047 (95%CI: 2.276-10.720) and 2.192 (95%CI: 1.539-3.122) (p<0.001) for FIB and α1-MG/CR as continuous variables for DKD prediction, respectively. The optimal cut-off values were 3.21 g/L and 2.11mg/mmol for identifying DKD, and 5.58 g/L and 11.07 mg/mmol for advanced DKD from ROC curves. At these cut-off values, the sensitivity and specificity of joint FIB and α1-MG/CR were 0.95 and 0.92 for identifying DKD, and 0.62 and 0.67 for identifying advanced DKD, respectively. The area under curve was 0.972 (95%CI: 0.948-0.995) (p<0.001) and 0.611, 95%CI: 0.488-0.734) (p>0.05). The multivariate-adjusted ORs for joint FIB and α1-MG/CR at the cut-off values were 214.500 (95%CI: 58.054-792.536) and 3.252 (95%CI: 1.040-10.175) (p<0.05), respectively. The present study suggests that joint plasma FIB concentration and urinary α1-MG/CR ratio can be used as a powerful predictor for general DKD, but it is less predictive for advanced DKD.

Genomic DNA Methylation in Diabetic Chronic Complications in Patients With Type 2 Diabetes Mellitus.

AimTo explore the relationship between genomic DNA methylation and diabetic chronic complications.Methods299 patients with type 2 diabetes mellitus (T2DM) hospitalized in the Second Affiliated Hospital of Soochow University were enrolled. We divided the patients into different complications groups and corresponding non-complication groups. Clinical and biochemical parameters were compared between the two groups. The level of genomic DNA methylation in leukocytes was determined by high-performance liquid chromatography-tandem mass spectrometry.Results(1) Age, duration of diabetes, creatinine (Cr), blood urea nitrogen (BUN), genomic DNA methylation, 24- hour urine total protein (24-hUTP), and intima-media thickness (IMT) were significantly higher in the carotid plaque (CP) group. Waist-to-hip ratio (WHR), body mass index (BMI), estimated glomerular- filtration rate (eGFR), and albumin (Alb) were significantly lower in the CP group. Gender, age and BMI were the influencing factors of CP. (2) Age, duration, Cr, BUN, urinary microalbumin creatinine ratio (UACR), systolic blood pressure (SBP), TCSS, and 24- hUTP were significantly higher in the diabetic retinopathy (DR) group. eGFR, 2h postprandial C- peptide, and Alb were lower in the DR group. Age, duration, Cr, Alb, SBP, and the presence of DN were the influencing factors of DR. (3) Age, duration, HbA1c, BUN, TCSS, SBP, and IMT(R) were significantly higher in the diabetic nephropathy (DN) group. 2h postprandial C-peptide, and Alb were lower in the DN group. HbA1c, BUN, DR, and HBP were the influencing factors of DN. (4) Age, duration, total cholesterol (TC), low-density lipoprotein (LDL-C), triglyceride (TG), Cr, BUN, uric acid (UA), and SBP were significantly higher in the diabetic peripheral neuropathy (DPN) group. The level of genomic DNA methylation and eGFR were significantly lower in the DPN group. Age, duration, LDL-C, UA, the presence of DR, and the genomic DNA methylation level were the influencing factors for DPN. Incorporating the level of genomic DNA methylation into the prediction model could improve the ability to predict DPN on the basis of conventional risk factors.ConclusionLow level of genomic DNA methylation is a relatively specific risk factor for DPN in patients with T2DM and not a contributing factor to the other chronic complications.