Safety and infectious outcomes in pediatric kidney transplant recipients after COVID-19 vaccination: A pediatric nephrology research consortium study.

BACKGROUND: Adult kidney transplant recipients (KTRs) fully vaccinated against COVID-19 have substantial morbidity and mortality related to SARS-CoV-2 infection compared with the general population. However, little is known regarding the safety and efficacy of the COVID-19 vaccination series in pediatric KTRs. METHODS: A multicenter, retrospective observational study was performed across nine pediatric transplantation centers. Eligible KTRs fully vaccinated against COVID-19 were enrolled and data were collected pertaining to SARS-CoV-2 infection incidence and severity, graft outcomes and post-vaccination safety profile, as well as overall patient survival. RESULTS: A total of 247 patients were included in this investigation with a median age at transplantation of 11 years (IQR 5-15). SARS-CoV-2 infection was observed in 30/110 (27.27%) of fully vaccinated patients, tested post-transplant, within the defined follow-up period. Of these patients, 6/30 (18.18%) required hospitalization and 3/30 (12.12%) required reduction in immunosuppression, with no reported deaths. De novo donor-specific antibodies (DSAs) were found in 8/86 (9.30%) of DSA-tested patients with two experiencing rejection and subsequent graft loss. The overall incidence of rejection and graft loss among the total cohort was 11/247 (4.45%) and 6/247 (3.64%), respectively. A 100% patient survival was observed. CONCLUSIONS: Observationally, infectious outcomes of SARS-CoV-2 in fully vaccinated pediatric KTRs are excellent, with a low incidence of infection requiring hospitalization and no associated deaths. Though de novo DSAs were observed, there was minimal graft rejection and graft loss reported in the total cohort.

Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium.

BACKGROUND: Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS: Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS: We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS: In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.

Nocturnal blood pressure dipping, blood pressure variability, and cognitive function in early and middle-aged adults.

Higher nighttime blood pressure (BP), less BP dipping, and higher BP variability have been linked with worse cognitive function in the elderly. The goal of this study is to explore whether this relationship already exists in early and middle adulthood. We further examined whether ethnic differences between African Americans and European Americans in BP parameters can explain ethnic differences in cognitive function. 24-h ambulatory BP monitoring and cognitive function were obtained from 390 participants (average age: 37.2 years with a range of 25-50; 54.9% African Americans; 63.6% females). We observed that higher nighttime BP, decreased dipping, and higher variability were significantly associated with lower scores on the Picture Sequence Memory Test. Significant negative associations between variability and overall composite scores were also observed. No significant associations between average 24-h or daytime BP and cognitive function were observed. Ethnic differences in nighttime diastolic pressures and dipping can explain 6.81% to 10.8% of the ethnicity difference in the score of the Picture Sequence Memory Test (ps < .05). This study suggests that the associations of nighttime BP, dipping, and variability with cognitive function already exist in young and middle-aged adults. Ethnic differences in nighttime BP and dipping can at least partially explain ethnic differences in cognitive function. The stronger association of these parameters with cognitive function than daytime or average BP in this age range raises the importance of using ambulatory BP monitoring for more precise detection of abnormal BP patterns in young adulthood.

Age, sex and race distribution of accelerometer-derived sleep variability in US school-aged children and adults.

Sleep variability (e.g. intra-individual variabilities in sleep duration or sleep timing, social jetlag, and catch-up sleep) is an important factor impacting health and mortality. However, limited information is available on the distribution of these sleep parameters across the human life span. We aimed to provide distribution of sleep variability related parameters across lifespan by sex and race in a national representative sample from the U.S. population. The study included 9981 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, who had 4-7 days of valid 24-h accelerometer recording with at least one day obtained during weekend (Friday or Saturday night). Of the study participants, 43% showed ≥ 60 min sleep duration standard deviation (SD), 51% experienced ≥ 60 min catch-up sleep, 20% showed ≥ 60 min sleep midpoint SD, and 43% experienced ≥ 60 min social jetlag. American youth and young adults averaged greater sleep variability compared to other age groups. Non-Hispanic Blacks showed greater sleep variability in all parameters compared to other racial groups. There was a main effect of sex on sleep midpoint SD and social jetlag with males averaging slightly more than females. Our study provides important observations on sleep variability parameters of residents of the United States by using objectively measured sleep patterns and will provide unique insights for personalized advice on sleep hygiene.

Day-to-day deviations in sleep parameters and biological aging: Findings from the NHANES 2011-2014.

OBJECTIVES: The majority of the previous research has focused on the impact of average sleep parameters on longevity. In this study, we aimed to investigate the associations of day-to-day deviations in sleep parameters with biological ages among 6052 adults participating in the 2011-2014 waves of the US National Health and Nutrition Examination Survey. METHODS: Sleep parameters, including sleep duration, efficiency, midpoint, and day-to-day deviations in sleep parameters, including standard deviation of sleep duration (sleep variability), standard deviation of sleep midpoint (sleep irregularity), catch-up sleep, and social jetlag, were obtained from 4 to 7 days of 24-h accelerometer recording. We used physiological data to compute measurements of biological aging according to 3 published algorithms: PhenoAge, Klemera-Doubal method Biological Age, and homeostatic dysregulation. RESULTS: After adjustment of multiple covariates, we observed that all parameters of day-to-day deviations in sleep were significantly associated with biological aging with larger sleep variability, larger sleep irregularity, more catch-up sleep, and more social jetlag linked with more advanced biological aging. The significant associations of sleep irregularity, catch-up sleep, and social jetlag with biological aging indices remained even after adjustment for sleep duration, efficiency, and midpoint. CONCLUSION: In this study, we found that day-to-day deviations in sleep parameters are independently associated with biological aging in US general population. Since day-to-day deviation in sleep is a modifiable behavioral factor, our finding suggests that intervention aiming at increasing regularity in sleep patterns may be a novel approach for extending a healthy life span.

Age, sex and race distribution of accelerometer-derived sleep variability in US school-aged children and adults.

Background: Sleep variability (e.g. intra-individual variabilities in sleep duration or sleep timing, social jetlag, and catch-up sleep) is an important factor impacting health and mortality. However, limited information is available on the distribution of these sleep parameters across the human life span. We aimed to provide distribution of sleep variability related parameters across lifespan by sex and race in a national representative sample from the U.S. population. Methods: The study included 9,799 participants 6 years and older from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, who had at least 3 days of valid sleep parameters with at least one day obtained during weekend (Friday or Saturday night). These were calculated from 7-day 24-h accelerometer recordings. Results: Of the study participants, 43% showed ≥ 60 minutes sleep duration standard deviation (SD), 51% experienced ≥ 60 minutes catch-up sleep, 20% showed ≥ 60 minutes midpoint of sleep SD, and 43% experienced ≥ 60 minutes social jetlag. American youth and young adults averaged greater sleep variability compared to other age groups. Non-Hispanic Blacks showed greater sleep variability in all parameters compared to other racial groups. There was a main effect of sex on sleep midpoint SD and social jetlag with males averaging slightly more than females. Conclusion: Our study provides important observations on sleep irregularity parameters of residents of the United States by using objectively measured sleep patterns and will provide unique insights for personalized advice on sleep hygiene.

Routine Diaper Change Alters Kidney Oxygenation in Premature Infants: A Non-A Priori Analysis.

BACKGROUND: Reduction in oxygen delivery to developing kidneys of premature infants may be an important source for acute kidney injury in premature infants. PURPOSE: To describe changes in continuous kidney oxygenation (RrSO 2 ) measures before, during, and after routine diaper changes. METHODS: Non-a priori analysis of a prospective cohort that received continuous measurement of RrSO 2 with near-infrared spectroscopy (NIRS) over the first 14 days of life demonstrating acute RrSO 2 drops surrounding diaper changes. RESULTS: In total, 26 of 38 (68%) infants (≤1800 g) from our cohort exhibited acute drops in RrSO 2 that temporally correlated with diaper changes. Mean (SD) RrSO 2 baseline prior to each diaper change event was 71.1 (13.2), dropped to 59.3 (11.6) during diaper change, and recovered to 73.3 (13.2). There was a significant difference between means when comparing baseline to diaper change ( P < .001; 95% CI, 9.9 to 13.8) and diaper change to recovery ( P < .001; 95% CI, -16.9 to -11.2). The mean decrease in RrSO 2 during diaper change averaged 12 points (17%) below 15-minute RrSO 2 mean prior to diaper change, with quick recovery to prediaper change levels. No decreases in SpO 2 , blood pressure, or heart rate were documented during the intermittent kidney hypoxic events. IMPLICATIONS FOR PRACTICE AND RESEARCH: Routine diaper changes in preterm infants may increase the risk for acute reductions in RrSO 2 as measured by NIRS; however, the impact on kidney health remains unknown. Larger prospective cohort studies assessing kidney function and outcomes related to this phenomenon are needed.

Late-Onset Hyponatremia in Premature Infants.

Late-onset hyponatremia (LOH) frequently affects premature infants 2 or more weeks of age due to inadequate sodium intake and excessive kidney loss. Late-onset hyponatremia typically occurs in infants who are physiologically stable and is defined as serum sodium of 132 mEq/L or less or between 133 and 135 mEq/L if receiving sodium supplementation. Recent evidence suggests that spot urine sodium levels may improve the recognition of LOH, as low levels of excreted urine reflect a total body sodium deficit and negative balance. Untreated LOH may result in poor somatic growth, neurodevelopmental delay, higher incidence of bronchopulmonary dysplasia, and more severe retinopathy of prematurity. The primary prevention of LOH is to maintain serum sodium between 135 and 145 mEq/L; however, there are currently no formal protocols guiding sodium supplementation. The purpose of this article is to present on overview of LOH pathophysiology and its effect on somatic growth, neurodevelopment outcomes, and other related sequelae. We further discuss general management strategies and describe a protocol for sodium supplementation that is presently undergoing an evaluation for effectiveness.

Dual diagnosis of autosomal dominant polycystic kidney disease and sickle cell disease in a teenage male.

BACKGROUND: Sickle cell disease (SCD) and autosomal dominant polycystic kidney disease (ADPKD) are relatively common genetic conditions with considerable overlap in clinical presentation. In addition to similarities between the signs and symptoms in sickle cell nephropathy and ADPKD, more than half of SCD patients have kidney cysts. The co-occurrence of these two diseases has not been previously reported in the literature. CASE DIAGNOSIS/TREATMENT: A 16-year-old Black male with SCD had bilateral kidney enlargement and multiple simple cysts on ultrasound. Although kidney cysts are significantly more common in individuals affected with SCD, genetic testing with a broad kidney gene panel was performed to explore the possible presence of another underlying genetic cause of his cysts, in addition to SCD. A dual diagnosis of SCD and ADPKD was made following the identification of two copies of the common pathogenic sickle cell HBB variant (c.20A > T, p.Glu7Val) and a pathogenic missense variant in PKD1 (c.8311G > A, p.Glu2771Lys). CONCLUSIONS: SCD and ADPKD differ in pathophysiological mechanisms and treatment regimens. As such, it will be paramount for this teenager to be closely monitored for signs of diminished kidney function and to be co-managed as he transitions to adult care to ensure proper treatment and management. Early identification of individuals with both SCD and a co-occurring condition is crucial to ensuring proper clinical management. Furthermore, identifying and reporting additional patients with SCD and ADPKD dual diagnoses will help us to understand the co-occurring disease course and optimal treatments.

Blunted rest-activity circadian rhythm increases the risk of all-cause, cardiovascular disease and cancer mortality in US adults.

To examine whether rest-activity circadian rhythm parameters can predict all-cause, cardiovascular disease and cancer mortality in a general adult population of the US. We further compared the mortality predictive performance of these parameters with that of traditional risk factors. This study included 7,252 adults from US National Health and Nutrition Examination Surveys (NHANES) 2011-2014, who had wrist accelerometer data obtained at baseline and follow-up status linked to the National Death Index records (2011-2019). During a median of 81 months (interquartile range, 69-94 months) of follow-up, 674 (9.3%) deaths occurred. There were inverse associations between relative amplitude (RA) and all-cause mortality, cardiovascular disease and cancer mortality with increased quartiles RA associated with lower mortality risk (all P < 0.05). The Hazard Ratios ranged from 0.61 to 0.79. Furthermore, RA outperformed all the tested traditional predictors of all-cause mortality with the exception of age. This study suggests that participants with blunted rest-activity circadian rhythms had a higher risk of all-cause, cardiovascular disease and cancer mortality. Future studies will be needed to test whether interventions that regulate rest-activity circadian activity rhythms will improve health outcomes.

Outcomes of granulocyte colony-stimulating factor use in pediatric kidney transplant recipients: A Pediatric Nephrology Research Consortium study.

BACKGROUND: Neutropenia is common in the first year after pediatric kidney transplant and is associated with an increased risk of infection, allograft loss, and death. Granulocyte colony-stimulating factor (G-CSF) increases neutrophil production, but its use in pediatric solid organ transplant recipients remains largely undescribed. METHODS: We performed a multicenter retrospective cohort study of children with neutropenia within the first 180 days after kidney transplant. Multivariable linear regression and Poisson regression were used to assess duration of neutropenia and incidence of hospitalization, infection, and rejection. RESULTS: Of 341 neutropenic patients, 83 received G-CSF during their first episode of neutropenia. Median dose of G-CSF was 5 mcg/kg for 3 (IQR 2-7) doses. G-CSF use was associated with transplant center, induction immunosuppression, steroid-free maintenance immunosuppression, hospitalization, and decreases in mycophenolate mofetil, valganciclovir, and trimethoprim-sulfamethoxazole dosing. Absolute neutrophil count nadir was also significantly lower among those treated with G-CSF. G-CSF use was not associated with a shorter duration of neutropenia (p = .313) and was associated with a higher rate of neutropenia relapse (p = .002) in adjusted analysis. G-CSF use was associated with a decreased risk of hospitalization (aIRR 0.25 (95%CI 0.12-0.53) p < .001) but there was no association with incidence of bacterial infection or rejection within 90 days of neutropenic episode. CONCLUSION: G-CSF use for neutropenia in pediatric kidney transplant recipients did not shorten the overall duration of neutropenia but was associated with lower risk of hospitalization. Prospective studies are needed to determine which patients may benefit from G-CSF treatment.

Renal Oxygenation (rSO 2 ) Population Parameter Estimates in Premature Infants Routinely Monitored With Near-Infrared Spectroscopy.

BACKGROUND: Currently, reference ranges for renal oxygenation measured by near-infrared spectroscopy (NIRS) in preterm infants beyond the first days of life are lacking, especially those born prior to 29 weeks' gestation. Population estimates of renal oxygenation (rSO 2 ) levels among preterm infants over time have yet to be established, leading to reluctance in clinical application. PURPOSE: To characterize the distribution and estimate population parameters for renal oxygenation measured by NIRS during the first 14 days of life among preterm infants. METHODS: We prospectively observed rSO 2 trends of 37 infants before 34 weeks' gestation and 1800-g or less birth weight for the first 14 days of life. Analyses included distribution fit tests, ordinary least squares (OLS) regression, and t tests. RESULTS: Average daily rSO 2 variation steadily increased with 42% difference through the first 14 days of life. For all infants, renal rSO 2 means peaked during the first 3 days of life and plateaued around 7 days. Daily rSO 2 slopes were significantly lower among males and infants 29 weeks' or less gestation. IMPLICATIONS FOR PRACTICE: Renal rSO 2 during the first 14 days of life reflects normal extrauterine transition reaching stabilization around 7 days of life. Gestational age, birth weight, and gender may predict the early trajectory of rSO 2 patterns. Population estimates provide parameters for renal rSO 2 that may indicate early-onset tissue hypoxia when acute or significant drops from baseline occur. IMPLICATIONS FOR RESEARCH: We present a framework to guide future research using renal NIRS technology in preterm infants to determine deviations from expected trends that may precede renal injury.

Effect of renal denervation on urine angiotensinogen excretion in prenatally programmed rats.

Prenatal programming results in an increase in blood pressure in adult offspring. We have shown that compared to control adult offspring whose mothers were fed a 20% protein diet, programmed adults whose mothers were fed a 6% protein diet during the last half of pregnancy have an increase in renal sympathetic nerve activity and urinary angiotensinogen/creatinine levels. We hypothesized that the increase in urinary angiotensinogen was mediated by renal sympathetic nerve activity in programmed rats. In this study performed in 3 month old rats, renal denervation resulted in normalization of blood pressure in the 6% programmed group (150 ± 3 Hg in 6% sham vs. 121 ± 4 Hg in 6% denervated, P < 0.001), and a reduction in blood pressure in the 20% group (126 ± 2 Hg 20% sham vs. 113 ± 4 Hg 20% denervated (P < 0.05). We confirm that the intrarenal renin-angiotensin system assessed by urinary angiotensinogen/creatinine is upregulated in offspring of rats fed a 6% protein diet rats compared to 20% controls. To determine if sympathetic nerve activity was mediating the increase in urinary angiotensinogen in programmed rats, we compared denervated to sham-operated control and programmed rats. Renal denervation had no effect on urinary angiotensinogen/creatinine ratio in the 20% group and no effect on the increased urinary angiotensinogen/creatinine ratio found in programmed rats. This study demonstrates that the increase in urinary angiotensinogen in programmed rats is not mediated by renal sympathetic nerve activity.

Transient enalapril attenuates the reduction in glomerular filtration rate in prenatally programmed rats.

A maternal low-protein diet has been shown to program hypertension and a reduction in glomerular filtration rate in adult offspring. This study examined the effect of continuous administration of enalapril in the drinking water and transient administration of enalapril administered from 21 to 42 days of age on blood pressure and glomerular filtration rate (GFR) in male rats whose mothers were fed a 20% protein diet (control) or a 6% protein diet (programmed) during the last half of pregnancy. After birth all rats were fed a 20% protein diet. Programmed rats (maternal 6% protein diet) were hypertensive at 15 months of age compared to control rats and both continuous and transient administration of enalapril had no effect on blood pressure on control offspring, but normalized the blood pressure of programmed offspring. GFR was 3.2 ± 0.1 mL/min in the control group and 1.7 ± 0.1 mL/min in the programmed rats at 17 months of age (P < 0.001). The GFR was 3.0 ± 0.1 mL/min in the control and 2.7 ± 0.1 mL/min in the programmed group that received continuous enalapril in their drinking water showing that enalapril can prevent the decrease in GFR in programmed rats. Transient administration of enalapril had no effect on GFR in the control group (3.2 ± 0.1 mL/min) and prevented the decrease in GFR in the programmed group (2.9 ± 0.1 mL/min). In conclusion, transient exposure to enalapril for 3 weeks after weaning can prevent the hypertension and decrease in GFR in prenatal programmed rats.

Transient Exposure of Enalapril Normalizes Prenatal Programming of Hypertension and Urinary Angiotensinogen Excretion.

Maternal low protein diet programs offspring to develop hypertension as adults. Transient exposure to angiotensin converting enzyme inhibitors or angiotensin II receptor blockers can result in improvement in hypertension. Male rats whose mothers received a low protein diet during the last half of pregnancy were given either vehicle, continuous enalapril (CE) in their drinking water or were given transient enalapril exposure (TE) after weaning at 21 days of age. The TE group had enalapril in their drinking water for 21 days starting from day 21 of life. All rats were studied at 6 months of age. Vehicle treated rats whose mothers were fed a low protein diet were hypertensive, had albuminuria, and demonstrated upregulation of the intrarenal renin-angiotensin system as evidenced by higher urinary angiotensinogen and urinary angiotensin II levels. In low protein rats both continuous and transient exposure to enalapril normalized blood pressure, urinary angiotensinogen and urinary angiotensin II levels at 6 months of age, but only continuous administration of enalapril decreased urinary albumin excretion. These data support the importance of the intrarenal renin-angiotensin system in mediating hypertension in programmed rats and transient exposure to enalapril can reprogram the hypertension and dysregulation of the intrarenal renin-angiotensin system.