医学最新文献

Background: Ambulatory hypertension is associated with elevated left ventricular mass index (LVMI), cardiac dysfunction, and increased arterial stiffness in adolescents. Whether the addition of measures of BP variability improves the prediction of subclinical cardiovascular target organ damage (TOD) over mean BP measures is not known.

Methods: We assessed clinic and ambulatory BP (ABP), anthropometrics, and TOD in 397 adolescents. ABP means standard deviation (SD), BP, and heart rate (HR) dipping were calculated; coefficients of variability (CV) were calculated (SD/mean) to assess ABP variabilities. Measures of TOD included LVMI, left ventricular hypertrophy (LVH), LV systolic shortening, LV diastolic function (e'/a'), and pulse wave velocity. General linear models were used to determine if increased ABP variability measures were significant determinants of TOD in models containing mean ABP percentiles, age, sex, race/ethnicity, BMI z-score, and HR.

Results: Mean participant age was 15.6 ± 1.7 years (63% white, 59% male) with mean casual BP 122.6/71.6 mmHg ±12.4/10.5, and mean awake systolic ABP 124.2/72.0 ± 11.3/7.7 mmHg. In linear models, increased awake CV-DBP and HR dipping were significant determinants of LVMI. CV-HR was an independent determinant of diastolic (e'/a') but not systolic dysfunction. Using logistic regression, the combination of awake and asleep diastolic ABP variability and awake systolic ABP percentile improved the prediction of LVH.

Conclusions: Consideration of ABP variability in addition to ABP percentile may aid in identifying adolescents at risk for LVH.

Membranous-like glomerulopathy with masked IgG-kappa deposits (MGMID) is a rare entity described primarily among young females with previously diagnosed autoimmune diseases. We present a 12-year-old female with systemic juvenile idiopathic arthritis (sJIA) with persistent non-nephrotic range proteinuria despite normal kidney function. She underwent two kidney biopsies with the second ultimately confirming her diagnosis. The initial biopsy was suggestive of mild C3 glomerulonephritis (C3GN). She was started on an angiotensin-converting enzyme inhibitor (ACE-I) without improvement. Proteinuria progressed to the nephrotic range, prompting initiation of high-dose steroids followed by a steroid taper. Mycophenolate was added during steroid weaning due to ongoing proteinuria. Despite full-dose mycophenolate and ACE-I therapy, a repeat biopsy was performed due to lack of response and revealed MGMID. She remains on full-dose mycophenolate and lisinopril with significant improvement in her proteinuria.

Background: Vesicoureteral reflux (VUR) is a common pediatric urological condition associated with kidney scarring, which can lead to hypertension, proteinuria, and chronic kidney disease. Current diagnostic methods, such as 99mTc-dimercaptosuccinic acid (DMSA) scans, are costly, involve radiation, and fail to detect early fibrosis. Urinary periostin, an extracellular matrix protein upregulated in kidney fibrosis, holds promise as a non-invasive biomarker for kidney scarring in VUR patients. This study aimed to evaluate urinary periostin as a biomarker for kidney scarring in children with VUR and compare its diagnostic performance with DMSA scans.

Methods: This prospective case-control study enrolled 60 children (35 males and 25 females) aged between 1 and 140 months (with mean (SD) of 43.7 (34.45)) with VUR (30 with kidney scarring [Scar+] and 30 without [Scar-]). Urinary periostin levels were measured via ELISA and corrected with urine creatinine. DMSA scans confirmed scarring. Receiver operating characteristic (ROC) analysis assessed periostin's diagnostic accuracy, and logistic regression identified predictors of scarring.

Results: Urinary periostin levels were significantly higher in Scar+ patients (27.4 ± 6.64 ng/mL) than in Scar- patients (18.1 ± 4.63 ng/mL, p < 0.001). ROC analysis yielded an area under the curve of 0.869, with a 21.5 ng/mL cutoff showing 80.0% sensitivity and 76.6% specificity. Periostin (OR 1.44, p < 0.001) was the only independent predictor of scarring. Periostin levels correlated with VUR grade (r = 0.63, p < 0.001).

Conclusions: Urinary periostin is a highly sensitive and specific non-invasive biomarker for detecting kidney scarring in VUR, potentially reducing reliance on DMSA scans.

Background: To evaluate the incidence and potential predisposing factors for the development of acute kidney injury (AKI) in asphyxiated neonates undergoing hypothermic treatment.

Methods: This retrospective study was conducted at the Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy. All neonates above 34 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with hypothermia, weighing more than 1800 g, admitted from January 1, 2013 to December 31, 2022, were included. AKI was defined according to the neonatal KDIGO classification.

Results: A total of 75 neonates were enrolled, including 13 (17%) with severe HIE. The incidence of AKI was 35%, with 62% of cases identified as a reduction in diuresis, 27% as changes in creatinine and oliguria, and only 11% as isolated creatinine elevation. The rate of AKI was significantly higher in infants with severe HIE (p < 0.001). The development of AKI added significantly (aOR = 41.2, p = 0.007) to the probability of death, even after adjusting for severe HIE. Infants who developed AKI required more inotropes, had higher rates of hyponatremia (serum sodium < 125 mEq/L), and were less likely to normalize lactate levels within 24 h of birth.

Conclusions: In asphyxiated newborns, reduced kidney perfusion can cause kidney impairment in nearly 40% of those undergoing treatment. Enhancing the detection of AKI is crucial for improving patient outcomes. We recommend proactive monitoring of lactate trends, urinary output, and serum sodium levels to enable early interventions that protect kidney function and improve outcomes for these vulnerable infants.

Background: Urinary extravasation (UE) in patients with posterior urethral valves (PUV), in the form of urinomas or urinary ascites, is thought to represent a pop-off mechanism. Previous literature has proposed a kidney protective mechanism, although this remains controversial. Here, we performed a matched comparison to assess the effect of UE on kidney outcomes.

Methods: We retrospectively reviewed our PUV database, including all patients diagnosed < 3 months of age with at least 1-year follow-up. We collected demographics, management, vesicoureteral reflux (VUR) status, and kidney function parameters. UE was defined as postnatal urinoma or urinary ascites. We performed both unadjusted and propensity-matched comparisons of patients with and without UE. Matching was used to balance age, diversion status, urinary tract infection history, presence of VUR, and nadir creatinine. The primary outcomes were 1-, 3-, and 5-year kidney outcomes.

Results: Of the 138 patients meeting inclusion criteria, 27 (20%) had UE (23 urinoma, 4 urinary ascites). The median age at presentation was 5 days. Six patients (26%) required percutaneous drainage, and the median time to resolution was 21 days. Patients with UE had significantly higher initial creatinine levels but no difference in nadir values. Of those with available data, 18 (18%) and 10 (14%) had chronic kidney disease (CKD) at 3 and 5 years. Overall, there was no difference in 3- and 5-year rates of CKD between patients with and without a history of UE.

Conclusions: In a matched comparison, UE was not associated with long-term adverse or beneficial effects on kidney function. This study provides further evidence that the presence of UE may not be a relevant prognostic factor in children with PUV.

Background: Pediatric chronic kidney disease (CKD) causes significantly impaired health-related quality of life (hrQOL) and caregiver burden, but no studies focus specifically on autosomal recessive polycystic kidney disease (ARPKD).

Methods: This prospective case-control study assessed hrQOL (using PedsQL®ESRD) and screened for psychosocial problems (strength and difficulties questionnaire (SDQ)) in 43 children with ARPKD. Fifty-eight caregivers reported on the disease's impact on family (FaBel) and their own QOL (Ulm inventory of parental caregiver QOL (ULQIE)). As controls, we questioned 36 matched healthy children and 57 parents under similar pandemic restrictions and used published historical controls (healthy and with advanced CKD).

Results: Patients were aged 9.0 ± 4.8 years with CKD stage G1-4 (45%), on dialysis (14%) or after kidney transplantation (26%). Nine patients had developmental delay secondary to medical complications. PedsQL®ESRD total scores correlated significantly to kidney function, but could not capture liver-specific symptoms. All 4 measures showed significant differences between treatment modalities with best scores in patients during CKD stages G1-4 and worst on dialysis, except SDQ, which was worst after transplantation. The most significant extra-renal risk factor for all 4 scores was developmental delay of the child. SDQ scores were elevated in contemporary vs. historical controls, but even further in ARPKD especially for peer relationship problems.

Conclusion: In summary, ARPKD causes significantly impaired hrQOL, psychosocial problems and caregiver burden, which were equal to, if not greater than, that of controls with more advanced kidney failure. Treatment modality and developmental delay were the most important risk factors.

Trial registration: Trial registered 06/2020 DRKS S00021059.

Chimeric antigen receptor (CAR)-modified T cells have garnered substantial attention due to their clinical success, culminating in six Food and Drug Administration-approved therapies for hematological malignancies. Notably, CD19-specific CAR T cell therapies have achieved remarkable clinical efficacy in treating B-cell malignancies, but these profound and durable responses are not observed in CAR T therapies targeting other indications, particularly solid tumors. Key design elements of CAR constructs - namely, antigen binding affinity and spacer length - play critical roles in determining T cell effector function and overall therapeutic effectiveness. Refining CAR designs may enhance T cell functionality, extend clinical application, and potentially apply CAR T cell therapies across a wider array of malignancies. In this study, affinity variant and spacer variant CARs targeting BCMA and DLL3 tumor antigens were evaluated using in vitro measurements of antigen-binding properties and effector function. Each panel of CARs spanned 2-3 logs of antigen binding affinity (BCMA: 181 pM KD to 74 nM KD, DLL3: 417 pM to 407 nM). Additionally, CAR T cells were challenged with tumor spheroids composed of BCMA⁺ H929 and DLL3⁺ SHP77 tumor cells. We show that for both tumor models, higher affinity CARs (KD stronger than approximately 100 nM) paired with an intermediate length spacer (IgG1 Fc, CH2-CH3, 230AA) elicited the strongest levels of tumor killing, CAR⁺ T cell expansion, and proinflammatory cytokine production. These CARs displayed the strongest cellular affinity when measured in a conjugation assay, suggesting a relationship between cellular affinity and T cell functional performance. This study highlights the critical role of CAR design in enhancing T cell functionality, demonstrating that high-affinity CARs combined with intermediate-length spacers yield superior performance in targeting BCMA and DLL3 antigens. This study provides a framework for rational CAR design, informing strategies to broaden the clinical utility of CAR T-cell therapies beyond hematologic cancers.