Glomerular Filtration Rate Measured Based on Iomeprol Clearance Assessed at CT Urography in Living Kidney Donor Candidates.

Background Estimating glomerular filtration rate (GFR) from serum creatinine can be inaccurate, and current procedures for measuring GFR are time-consuming and cumbersome. Purpose To develop a method for measuring GFR based on iomeprol clearance assessed at CT urography in kidney donor candidates and compare this with iohexol clearance (reference standard for measuring GFR). Materials and Methods This cross-sectional retrospective study included data from kidney donor candidates who underwent both iohexol clearance and CT urography between July 2016 and October 2022. CT-measured GFR was calculated as the iomeprol excretion rate in the urinary system between arterial and excretory phases (Hounsfield units times milliliters per minute) divided by a surrogate for serum iomeprol concentration in the aorta at the midpoint (in Hounsfield units). Performance of CT-measured GFR was assessed with use of mean bias (mean difference between CT-measured GFR and iohexol clearance), precision (the distance between quartile 1 and quartile 3 of the bias [quartile 3 minus quartile 1], with a small value indicating high precision), and accuracy (percentage of CT-measured GFR values falling within 10%, 20%, and 30% of iohexol clearance values). Intraobserver agreement was assessed for 30 randomly selected individuals with the Lin concordance correlation coefficient. Results A total of 75 kidney donor candidates were included (mean age, 51 years ± 13 [SD]; 45 female). The CT-measured GFR was unbiased (1.1 mL/min/1.73 m2 [95% CI: -1.9, 4.1]) and highly precise (16.2 mL/min/1.73 m2 [quartiles 1 to 3, -6.6 to 9.6]). The accuracy of CT-measured GFR within 10%, 20%, and 30% was 61.3% (95% CI: 50.3, 72.4), 88.0% (95% CI: 80.7, 95.4), and 100%, respectively. Concordance between CT-based GFR measurements taken 2 months apart was almost perfect (correlation coefficient, 0.99 [95% CI: 0.98, 0.99]). Conclusion In living kidney donors, GFR measured based on iomeprol clearance assessed at CT urography showed good agreement with GFR measured based on iohexol clearance. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Davenport in this issue.

Glucose pattern in children with classical congenital adrenal hyperplasia: evidence from continuous glucose monitoring.

BACKGROUND: While the risk for hypoglycemia during acute illness is well described in children with classical congenital adrenal hyperplasia (CAH), there is little evidence for the prevalence of asymptomatic hypoglycemia and the daily glucose patterns in CAH. Herein, we explored the daytime glucose profile of children with classical CAH. METHODS: We conducted an observational study in 11 children (6 female; age 3.1 years [1.4, 5.1]; body mass index 17.3 kg/m2 [15.6, 17.9]) with a genetic diagnosis of classical CAH receiving hydrocortisone and fludrocortisone replacement therapy. Participants underwent 2 14-day continuous glucose monitoring (CGM) sessions and an inpatient 24 h series cortisol and adrenocorticotropic hormone (ACTH) measures. Data were analyzed for 3 daytime lags (7 Am-4 Pm, 4 Pm-10pm, 10 Pm-7 Am) corresponding to the hydrocortisone dosing period with cortisol and ACTH measured before the hydrocortisone dose. RESULTS: Eleven participants completed at least 1 CGM session, and 7 out of 11 underwent both the CGM session and the cortisol/ACTH serial measures. In the whole cohort, the percentage of time of sensor glucose values <70 mg/dL was higher during the 10 Pm-7 Am and the 7 Am-4 Pm time slots than in the late afternoon period (17% [7, 54] and 15% [6.8, 24] vs 2% [1.1, 16.7] during the periods 7 Am-4 Pm and 4 Pm-10 Pm, respectively [P = .006 and P = .003]). Nighttime hypoglycemia was mostly spent below the 65 mg/dL (10.9% [4.1, 34]). The glycemic pattern paralleled the nadir of daily cortisol at 7 Am (10.3±4.4 µg/dL). A greater percentage of time in hypoglycemia was associated with lower cortisol concentration at 7 Am and 10 Pm (P < .001 and P = .005). CONCLUSIONS: Continuous glucose monitoring demonstrated a disrupted daily glucose pattern in children with CAH, paralleled by a lower cortisol concentration. CLINICALTRIALS.GOV REGISTRATION: NCT04322435.

Whole-body vibration may not affect bone mineral density and bone turnover in persons with chronic spinal cord injury: A preliminary study.

CONTEXT: Spinal-cord injury (SCI) induces bone loss and dramatically increases the risk of fracture. OBJECTIVES: Determine the effects of whole-body vibration (WBV) on areal bone mineral density (aBMD), whole body composition and bone biological parameters in individuals with chronic-state SCI. DESIGN: Randomized study. SETTING: Centre Neurologique PROPARA. PARTICIPANTS: Fourteen subjects were randomly assigned to a WBV or a control group. INTERVENTIONS: WBV (20-45 min, 30-45 Hz, 0.5 g) was performed in verticalized persons twice weekly for 6 months. OUTCOME MEASURES: aBMD was measured by DXA at baseline and 6 months and bone biological parameters at baseline, 1, 3 and 6 months. RESULTS: No significant aBMD change was found in either the WBV or control group after 6 months of follow-up. Similarly, periostin, sclerostin and bone turnover markers remained relatively stable throughout follow-up and no difference in variation was observed within-group and between groups. Except for whole-body fat mass, which showed a significant decrease in the WBV group compared to controls, no difference in changes was observed, whatever the localization for fat and lean body mass. CONCLUSIONS: During the chronic phase, aBMD and bone remodeling reach a new steady state. However, the DXA technique and the bone markers, including sclerostin and periostin, both of which reflect bone cell activity influenced by mechanical strain, showed that the bone tissue of individuals with SCI was insensitive to 6 months of WBV training at the study dose. Nevertheless, results of this preliminary study that was underpowered need to be confirmed and other modalities of WBV may be more effective in improving aBMD of this population. TRIALS REGISTRATION: N°IDRCB:2011-A00224-37.

Effect of Nutritional Deprivation after Sleeve Gastrectomy on Bone Mass, Periostin, Sclerostin and Semaphorin 4D: A Two-Year Longitudinal Study.

Bariatric surgery induces bone loss, but the exact mechanisms by which this process occurs are not fully known. The aims of this 2-year longitudinal study were to (i) investigate the changes in areal bone mineral density (aBMD) and bone turnover markers following sleeve gastrectomy (SG) and (ii) determine the parameters associated with the aBMD variations. Bone turnover markers, sclerostin, periostin and semaphorin 4D were assessed before and 1, 12 and 24 months after SG, and aBMD was determined by DXA at baseline and after 12 and 24 months in 83 patients with obesity. Bone turnover increased from 1 month, peaked at 12 months and remained elevated at 24 months. Periostin and sclerostin presented only modest increases at 1 month, whereas semaphorin 4D showed increases only at 12 and 24 months. A significant aBMD decrease was observed only at total hip regions at 12 and 24 months. This demineralisation was mainly related to body weight loss. In summary, reduced aBMD was observed after SG in the hip region (mechanical-loading bone sites) due to an increase in bone turnover in favour of bone resorption. Periostin, sclerostin and semaphorin 4D levels varied after SG, showing different time lags, but contrary to weight loss, these biological parameters did not seem to be directly implicated in the skeletal deterioration.

Identifying patient-related predictors of permanent growth hormone deficiency.

Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.

Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels.

BACKGROUND: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). OBJECTIVE: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. PATIENTS AND METHODS: Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. RESULTS: We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P = .008 and .016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. CONCLUSIONS: Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing.

Long-term treatment with teduglutide: a 48-week open-label single-center clinical trial in children with short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) is the main cause of intestinal failure in children. OBJECTIVES: This single-center study evaluated the safety and efficacy of teduglutide in pediatric patients with SBS-associated intestinal failure (SBS-IF). METHODS: Children with SBS followed at our center with ≥2 y on parenteral nutrition (PN) and with small bowel length <80 cm who had reached a plateau were consecutively included in the study. At baseline, participants underwent a clinical assessment including a 3-d stool balance analysis, which was repeated at the end of the study. Teduglutide was administered subcutaneously 0.05 mg/kg/d for 48 wk. PN dependence was expressed as the PN dependency index (PNDI), which is the ratio PN non-protein energy intake/REE. Safety endpoints included treatment-emergent adverse events and growth parameters. RESULTS: Median age at inclusion was 9.4 y (range: 5-16). The median residual SB length was 26 cm (IQR: 12-40). At baseline, the median PNDI was 94% (IQR: 74-119), (median PN intake: 38.9 calories/kg/d, IQR: 26.1-48.6). At week 24, 24 (96%) children experienced a reduction of >20% of PN requirements with a median PNDI = 50% (IQR: 38-81), (PN intake: 23.5 calories/kg/d IQR: 14.6-26.2), P < 0.01. At week 48, 8 children (32%) were weaned completely off PN. Plasma citrulline increased from 14 µmol/L (IQR: 8-21) at baseline to 29 µmol/L (IQR: 17-54) at week 48 (P < 0.001). Weight, height, and BMI z-scores remained stable. The median total energy absorption rate increased from 59% (IQR: 46-76) at baseline to 73% (IQR: 58-81) at week 48 (P = 0.0222). Fasting and postprandial endogenous GLP-2 concentrations increased at weeks 24 and 48 compared with baseline. Mild abdominal pain at the early phase of treatment, stoma changes, and redness at the injection site were commonly reported. CONCLUSIONS: Increased intestinal absorption and PN dependency reduction were observed with teduglutide treatment in children with SBS-IF. TRIAL REGISTRATION: ClinicalTrials.gov NCT03562130. https://clinicaltrials.gov/ct2/show/NCT03562130?term=NCT03562130&draw=2&rank=1.

Assessment of Puberty and Hypothalamic-Pituitary-Gonadal Axis Function After Childhood Brain Tumor Treatment.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: To describe hypothalamic-pituitary-gonadal axis (HPGA) function in patients treated in childhood for a primary brain tumor more than 5 years earlier, in order to identify risk factors for HPGA impairment. METHODS: We retrospectively included 204 patients diagnosed with a primary brain tumor before 18 years of age and monitored at the pediatric endocrinology unit of the Necker Enfants-Malades University Hospital (Paris, France) between January 2010 and December 2015. Patients with pituitary adenoma or untreated glioma were excluded. RESULTS: Among patients with suprasellar glioma not treated by radiotherapy, the prevalence of advanced puberty was 65% overall and 70% when the diagnosis occurred before 5 years of age. Medulloblastoma chemotherapy caused gonadal toxicity in 70% of all patients and in 87.5% of those younger than 5 years at diagnosis. In the group with craniopharyngioma, 70% of patients had hypogonadotropic hypogonadism, which was consistently accompanied by growth hormone deficiency. CONCLUSION: Tumor type, location, and treatment were the risk main factors for HPGA impairment. Awareness that onset can be delayed is essential to guide information of parents and patients, patient monitoring, and timely hormone replacement therapy.

GH and Childhood-onset Craniopharyngioma: When to Initiate GH Replacement Therapy?

CONTEXT: Craniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma. OBJECTIVE: To evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence). METHODS: Retrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (<12-month group), among which 29 patients were treated between 6 and 12 months (6-12 month group). The main outcome was the risk of tumor new event (progression of residual tumor or tumor recurrence after complete resection) after primary treatment in the >12-month group and in the <12 month or in the 6- to 12-month group patients. RESULTS: In the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the <12-month group. The 2- and 5-year event-free survivals were the same in the 6- to 12-month group (72.4%; 95% CI, 52.4-85.1). By log-rank test, the event-free survival was not different between groups (P = .98 and P = .91).The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment. CONCLUSIONS: No association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone.

Like other secreted peptides, nascent parathyroid hormone (PTH) is synthesized with a pre- and a pro-sequence (25 and 6 amino acids, respectively). These precursor segments are sequentially removed in parathyroid cells before packaging into secretory granules. Three patients from two unrelated families who presented during infancy with symptomatic hypocalcemia were found to have a homozygous serine (S) to proline (P) change affecting the first amino acid of the mature PTH. Unexpectedly, biological activity of synthetic [P1]PTH(1-34) was indistinguishable from that of unmodified [S1]PTH(1-34). However, in contrast to conditioned medium from COS-7 cells expressing prepro[S1]PTH(1-84), medium from cells expressing prepro[P1]PTH(1-84) failed to stimulate cAMP production despite similar PTH levels when measured by an intact assay that detects PTH(1-84) and large amino-terminally truncated fragments thereof. Analysis of the secreted, but inactive PTH variant led to the identification of pro[P1]PTH(-6 to +84). Synthetic pro[P1]PTH(-6 to +34) and pro[S1]PTH(-6 to +34) had much less bioactivity than the corresponding PTH(1-34) analogs. Unlike pro[S1]PTH(-6 to +34), pro[P1]PTH(-6 to +34) was resistant to cleavage by furin suggesting that the amino acid variant impairs preproPTH processing. Consistent with this conclusion, plasma of patients with the homozygous P1 mutation had elevated proPTH levels, as determined with an in-house assay specific for pro[P1]PTH(-6 to +84). In fact, a large fraction of PTH detected by the commercial intact assay represented the secreted pro[P1]PTH. In contrast, two commercial biointact assays that use antibodies directed against the first few amino acid residues of PTH(1-84) for capture or detection failed to detect pro[P1]PTH.

Analysis of a pitfall in congenital adrenal hyperplasia newborn screening: evidence of maternal use of corticoids detected on dried blood spot.

Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

Gonadotropins as novel active partners in vascular diseases: Insight from angiogenic properties and thrombotic potential of endothelial colony-forming cells.

BACKGROUND: The impact of estrogen and testosterone on atherosclerotic cardiovascular disease is well known, but the role of the gonadotropins follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) to some extent remain less studied. OBJECTIVES: To explore the angiogenic potential of gonadotropins on endothelial colony-forming cells (ECFCs). METHODS: We examined the effects of various doses of gonadotropins on ECFCs obtained from cord blood by assessing colony number, proliferation, migration, and sprouting ability. Moreover, we studied thrombin generation in ECFCs exposed to gonadotropins by performing a thrombin generation assay. Finally, we determined the levels of circulating gonadotropins in 30 men, to exclude the effect of estrogen, with lower extremity arterial disease (LEAD), in comparison with age- and sex-matched controls. RESULTS: Exposure to FSH, LH, or PRL resulted in an increase in ECFC migration but showed no effect on proliferation or ECFC commitment from cord blood mononuclear cells. Using a three-dimensional fibrin gel assay, we showed that ECFC sprouting was significantly enhanced by gonadotropins. Exposure to FSH also increased the thrombin generation of ECFCs exposed to FSH. Finally, FSH and LH levels in men with LEAD were higher than those in controls. CONCLUSION: Gonadotropins increase ECFC-related angiogenesis and may be involved in thrombin generation in cardiovascular disease. Gonadotropins may act as biomarkers; moreover, we hypothesize that gonadotropin-blocking strategies may be a novel interesting therapeutic approach in atherosclerotic cardiovascular disease.

Hormone Immunoassay Interference: A 2021 Update.

Immunoassays are powerful qualitative and quantitative analytical techniques. Since the first description of an immunoassay method in 1959, advances have been made in assay designs and analytical characteristics, opening the door for their widespread implementation in clinical laboratories. Clinical endocrinology is closely linked to laboratory medicine because hormone quantification is important for the diagnosis, treatment, and prognosis of endocrine disorders. Several interferences in immunoassays have been identified through the years; although some are no longer encountered in daily practice, cross-reaction, heterophile antibodies, biotin, and anti-analyte antibodies still cause problems. Newer interferences are also emerging with the development of new therapies. The interfering substance may be exogenous (e.g., a drug or substance absorbed by the patient) or endogenous (e.g., antibodies produced by the patient), and the bias caused by interference can be positive or negative. The consequences of interference can be deleterious when clinicians consider erroneous results to establish a diagnosis, leading to unnecessary explorations or inappropriate treatments. Clinical laboratories and manufacturers continue to investigate methods for the detection, elimination, and prevention of interferences. However, no system is completely devoid of such incidents. In this review, we focus on the analytical interferences encountered in daily practice and possible solutions for their detection or elimination.

High Prevalence of Early Endocrine Disorders After Childhood Brain Tumors in a Large Cohort.

CONTEXT: Endocrine complications are common in pediatric brain tumor patients. OBJECTIVE: We aimed to describe the endocrine follow-up of patients with primary brain tumors. METHODS: This is a noninterventional observational study based on data collection from medical records of 221 patients followed at a Pediatric Endocrinology Department. RESULTS: Median age at diagnosis was 6.7 years (range, 0-15.9), median follow-up 6.7 years (0.3-26.6), 48.9% female. Main tumor types were medulloblastoma (37.6%), craniopharyngioma (29.0%), and glioma (20.4%). By anatomic location, 48% were suprasellar (SS) and 52% non-suprasellar (NSS). Growth hormone deficiency (GHD) prevalence was similar in both groups (SS: 83.0%, NSS: 76.5%; P = 0.338), appearing at median 1.8 years (-0.8 to 12.4) after diagnosis; postradiotherapy GHD appeared median 1.6 years after radiotherapy (0.2-10.7). Hypothyroidism was more prevalent in SS (76.4%), than NSS (33.9%) (P < 0.001), as well as ACTH deficiency (SS: 69.8%, NSS: 6.1%; P < 0.001). Early puberty was similar in SS (16%) and NSS (12.2%). Hypogonadotropic hypogonadism was predominant in SS (63.1%) vs NSS (1.3%), P < 0.001, and postchemotherapy gonadal toxicity in NSS (29.6%) vs SS (2.8%), P < 0.001. Adult height was lower for NSS compared to target height (-1.0 SD, P < 0.0001) and to SS patients (P < 0.0001). Thyroid nodules were found in 13/45 patients (28.8%), including 4 cancers (4.8-11.5 years after radiotherapy). Last follow-up visit BMI was higher in both groups (P = 0.0001), and obesity incidence was higher for SS (46.2%) than NSS (17.4%). CONCLUSION: We found a high incidence of early-onset endocrine disorders. An endocrine consultation and nutritional evaluation should be mandatory for all patients with a brain tumor, especially when the tumor is suprasellar or after hypothalamus/pituitary irradiation.

Deciphering the Prognostic and Predictive Value of Urinary CXCL10 in Kidney Recipients With BK Virus Reactivation.

BK virus (BKV) replication increases urinary chemokine C-X-C motif ligand 10 (uCXCL10) levels in kidney transplant recipients (KTRs). Here, we investigated uCXCL10 levels across different stages of BKV replication as a prognostic and predictive marker for functional decline in KTRs after BKV-DNAemia. uCXCL10 was assessed in a cross-sectional study (474 paired urine/blood/biopsy samples and a longitudinal study (1,184 samples from 60 KTRs with BKV-DNAemia). uCXCL10 levels gradually increased with urine (P-value < 0.0001) and blood BKV viral load (P < 0.05) but were similar in the viruria and no BKV groups (P > 0.99). In viremic patients, uCXCL10 at biopsy was associated with graft functional decline [HR = 1.65, 95% CI (1.08-2.51), P = 0.02], irrespective of baseline eGFR, blood viral load, or BKVN diagnosis. uCXL10/cr (threshold: 12.86 ng/mmol) discriminated patients with a low risk of graft function decline from high-risk patients (P = 0.01). In the longitudinal study, the uCXCL10 and BKV-DNAemia trajectories were superimposable. Stratification using the same uCXCL10/cr threshold at first viremia predicted the subsequent inflammatory response, assessed by time-adjusted uCXCL10/cr AUC (P < 0.001), and graft functional decline (P = 0.03). In KTRs, uCXCL10 increases in BKV-DNAemia but not in isolated viruria. uCXCL10/cr is a prognostic biomarker of eGFR decrease, and a 12.86 ng/ml threshold predicts higher inflammatory burdens and poor renal outcomes.

Ustekinumab Serum Trough Levels May Identify Suboptimal Responders to Ustekinumab in Crohn's Disease.

INTRODUCTION: The aim of this study was to evaluate the association between serum ustekinumab (UST) trough levels and response to induction and maintenance UST treatment in refractory Crohn's Disease (CD) patients. METHODS: We performed a prospective study including CD patients who received UST from September 2015 to January 2017. Patients received 90 mg of UST subcutaneously at weeks 0, 4, and 12, then every 8 weeks. Two cohorts of patients were analyzed: an induction cohort and a maintenance cohort. We evaluated clinical, biological, and imaging/endoscopic response to UST treatment. UST trough levels and anti-UST antibodies were dosed at weeks 12 and 28 in the induction cohort, and at a single time point in the maintenance cohort. RESULTS: Forty-nine patients were enrolled in the maintenance cohort. Mean concentrations of UST were 1.88 ± 1.40 µg/mL. UST trough levels were not significantly different in patients with or without clinical, biological, or imaging/endoscopic responses to UST treatment (p > 0.11). Twenty-three consecutive patients were included in the induction cohort. At week 12, mean UST concentrations were 1.45 ± 1.15 µg/mL. Patients with a biological response to UST treatment had significant higher serum UST trough concentration (median 1.72 µg/mL) than non-responders (median 0.56 µg/mL, p = 0.02). A UST trough level ≥ 1.10 µg/mL at week 12 was associated with a biological response to UST treatment at 6 months. CONCLUSION: UST trough levels were associated with a biological response at the end of the induction phase. In patients with low levels of UST, optimization treatment may be necessary to obtain a sustained response.

Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite® reagents.

BACKGROUND: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite® reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material. METHODS: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID-free children and adolescents. Reference intervals were calculated for previously published age groups (6-12 months, 12-18 months, 18 months-2 years, 2-3 years, 3-4 years, 4-6 years, 6-9 years, 9-12 years and 12-18 years), according to the Clinical and Laboratory Standards Institute's C28-A3c protocol. RESULTS: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender-specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration. CONCLUSIONS: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite® immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals.