Sleep enhances reconsolidation-based strengthening of visuospatial memories.

Consolidated memories can be returned to a labile state upon reactivation. The re-stabilization of reactivated memories, or reconsolidation, can allow for change in previously established memories. Given the role of sleep in the initial consolidation of memories, sleep may be important for reconsolidation as well. However, effects of sleep on reconsolidation and specific aspects of sleep that may contribute are unclear. Here, participants learned 30 picture-location pairs. After overnight sleep, initial consolidation was tested. Following either one day (Experiment 1) or one week (Experiment 2), participants were tested again to reactivate their memory and then learned 30 novel picture-location pairs. Control groups (Experiment 1) received no reactivation prior to new learning. Twelve hours later, after daytime wakefulness or overnight sleep, participants completed a final memory test. Sleep participants underwent polysomnography between reactivation and final tests. In Experiment 1, reactivation led to preservation of memory compared to no reactivation. Sleep was associated with less post-reactivation memory decline than waking, with memory preservation positively related to time spent in non-rapid-eye movement sleep. In Experiment 2, sleep was associated with greater post-reactivation memory improvement than waking, with improvement positively related to sigma activity. These results suggest sleep enhances reconsolidation-based strengthening of episodic memories.

Kisspeptin Overcomes GnRH Neuronal Suppression Secondary to Hyperprolactinemia in Humans.

CONTEXT: Hyperprolactinemia suppresses gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) pulses. The hypothalamic neuropeptide kisspeptin potently stimulates the secretion of GnRH. The effects of exogenous kisspeptin administration on GnRH pulse generation in the setting of hyperprolactinemia have not previously been explored. OBJECTIVE: This work aimed to examine the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in women with hyperprolactinemia. METHODS: Women with hyperprolactinemia (n = 11) participated in two 12-hour visits. Before study visits, participants underwent washout of dopamine agonist and/or combined oral contraceptive. Frequent blood sampling was performed (1 sample was collected every 10 minutes). Visit 1 involved no intervention, to examine baseline LH pulsatility. During visit 2, kisspeptin 112-121 (0.24 nmol/kg) was administered every 1 hour, for 10 hours. At hour 11, one intravenous bolus of GnRH (75 ng/kg) was administered. RESULTS: Repetitive intravenous bolus kisspeptin administration increased the total number of LH pulses in the setting of hyperprolactinemia. The interpulse interval declined during the same time frames. LH pulse amplitude did not change, but the mean LH rose. In 6 participants with progesterone levels suggestive of an anovulatory state, mean LH and estradiol levels increased significantly at visit 2. In the entire cohort, follicle-stimulating hormone and prolactin levels did not change significantly across the 2 visits. A total of 73% of subjects exhibited an LH pulse within 30 minutes of first kisspeptin dose. CONCLUSION: Kisspeptin is capable of stimulating hypothalamic GnRH-induced LH pulses in the setting of hyperprolactinemia.

Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion.

Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1-/- females corrected overtime, hyperaldosteronism persisted at 14 months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing's syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.

Uric Acid and Acute Kidney Injury in the Critically Ill.

RATIONALE & OBJECTIVE: Uric acid is excreted by the kidney and accumulates in acute kidney injury (AKI). Whether higher plasma uric acid level predisposes to AKI or its complications is not known. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 2 independent cohorts of critically ill patients: (1) 208 patients without AKI admitted to the intensive care unit (ICU) at Brigham & Women's Hospital between October 2008 and December 2016; and (2) 250 participants with AKI requiring renal replacement therapy (RRT) who had not yet initiated RRT enrolled in the Acute Renal Failure Trial Network (ATN) Study. EXPOSURE: Plasma uric acid level upon ICU admission and before RRT initiation in the ICU and ATN Study cohorts, respectively. OUTCOMES: Incident AKI and 60-day mortality in the ICU and ATN Study cohorts, respectively. ANALYTICAL APPROACH: Logistic regression models were used to test the association of plasma uric acid level with incident AKI and 60-day mortality. RESULTS: In the ICU cohort, median plasma uric acid level was 4.7 (interquartile range [IQR], 3.6-6.4) mg/dL, and 40 patients (19.2%) developed AKI. Higher plasma uric acid levels associated with incident AKI, but this association was confounded by serum creatinine level and was not significant after multivariable adjustment (adjusted OR per doubling of uric acid, 1.50; 95% CI, 0.80-2.81). In the ATN Study cohort, median plasma uric acid level was 11.1 (IQR, 8.6-14.2) mg/dL, and 125 participants (50.0%) died within 60 days. There was no statistically significant association between plasma uric acid levels and 60-day mortality in either unadjusted models or after multivariable adjustment for demographic, severity-of-illness, and kidney-specific covariates (adjusted OR per doubling of uric acid, 1.15; 95% CI, 0.71-1.86). LIMITATIONS: Heterogeneity of ICU patients. CONCLUSIONS: Plasma uric acid levels upon ICU admission or before RRT initiation are not independently associated with adverse clinical outcomes in critically ill patients.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

Non-tunneled versus tunneled dialysis catheters for acute kidney injury requiring renal replacement therapy: a prospective cohort study.

BACKGROUND: Acute kidney injury requiring renal replacement therapy (AKI-RRT) is associated with high morbidity, mortality and resource utilization. The type of vascular access placed for AKI-RRT is an important decision, for which there is a lack of evidence-based guidelines. METHODS: We conducted a prospective cohort study over a 16-month period with 154 patients initiated on AKI-RRT via either a non-tunneled dialysis catheter (NTDC) or a tunneled dialysis catheter (TDC) at an academic hospital. We compared differences in renal replacement delivery and mechanical and infectious outcomes between NTDCs and TDCs. RESULTS: Patients who received TDCs had significantly better RRT delivery, both with continuous venovenous hemofiltration (CVVH) and intermittent hemodialysis (IHD), compared to patients who received NTDCs; these findings were confirmed after multivariable adjustment for AKI-specific disease severity score, history of chronic kidney disease, renal consult team, and AKI cause. In CVVH and IHD, the median venous and arterial blood flow pressures were significantly higher with TDCs compared to NTDCs (p < 0.001). Additionally for CVVH, the median number of interruptions per catheter was higher with NTDCs compared to TDCs (Rate Ratio (RR) 2.7; p < 0.001), and for IHD, a higher median blood flow was seen with TDCs (p < 0.001). There were a significantly higher number of mechanical complications with NTDCs (RR 13.6 p = 0.001). No significant difference was observed between TDCs and NTDCs for positive blood cultures per catheter. CONCLUSIONS: Compared to NTDCs, TDCs for patients with AKI-RRT had improved RRT delivery and fewer mechanical complications. Initial TDC placement for AKI-RRT should be considered when not clinically contraindicated given the potential for improved RRT delivery and outcomes.

Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness.

Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort (n=131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients.