ω-3 Polyunsaturated Fatty Acids Improve the Blood-Brain-Barrier Integrity in Contrast-Induced Blood-Brain-Barrier Injury in Uremic Mice.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood-brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia-reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

Leucine-enriched amino acid supplementation and exercise to prevent sarcopenia in patients on hemodialysis: a single-arm pilot study.

Background: Sarcopenia, which is strongly associated with mortality and quality of life, occurs in up to 40% of hemodialysis patients. Here, we investigated the preventive effects of leucine-enriched amino acid supplementation and resistance exercise in non-sarcopenic hemodialysis patients, and characterized the biochemical and immunophenotypic profiles of those who benefited from the intervention. Methods: Twenty-two patients on maintenance hemodialysis at our hospital were enrolled in this single center, prospective, single-arm pilot trial. For the first 12 weeks, the subjects were administered a total of 6 g of leucine per day. Three grams were supplied via capsules, and the remaining three grams were provided via beverages containing macro- and micro- nutrients, such as 10 µg of vitamin D and 290 mg of calcium. The supplements were not provided for the next 12 weeks. Muscle mass, grip strength, and physical performance were measured using the bioimpedance analyzer (BIA), handgrip strength (HGS), and short physical performance battery (SPPB) protocols, respectively, at baseline, 12 weeks, and 24 weeks. In addition, serum biochemistry, immunophenotype of peripheral blood mononuclear cells, and nutritional status was assessed at the three time points. Those who showed 5% or more improvement in parameters were defined as responders, otherwise, as non-responders (ClinicalTrials.gov identification number: NCT04927208). Results: Twenty-one out of twenty-two patients (95.4%) showed improvement in at least one or more parameters among muscle mass, grip strength, and physical performance. After 12 weeks of intervention, skeletal muscle index was increased in 14 patients (63.6%), and grip strength was improved in 7 patients (31.8%). Baseline grip strength lower than 35.0 kg was the strongest predictor of improvement in grip strength (AUC 0.933 from ROC curve). Grip strength showed a significant increase in females than males (7.6 ± 8.2 vs. -1.6 ± 7.2%, p = 0.03), in age over 60 than under 60 (5.3 ± 6.2 vs. -1.4 ± 9.1%, p = 0.04), and in higher (≥95%) than lower (<95%) exercise compliance (6.8 ± 7.7 vs. -3.2 ± 6.4%, p = 0.004). In SPPB study, gait speed and sit-to-stand time was improved in 13 patients (59.1%) and 14 patients (63.6%), respectively. Baseline hemoglobin lower than 10.5 g/dl and hematocrit lower than 30.8% were predictor of improvement in the sit-to-stand time (AUC 0.862 and 0.848, respectively). Serum biochemistry results showed that, compared to non-responders, responders in muscle mass had lower baseline monocyte fraction (8.4 ± 1.9 vs. 6.9 ± 1.1%, p = 0.03), and responders in grip strength had lower baseline total protein (6.7 ± 0.4 vs. 6.4 ± 0.3 g/dL, p = 0.04). Immunophenotypic analysis found that the intervention tended to increase the naïve/memory CD8+ T cell ratio (from 1.2 ± 0.8 to 1.4 ± 1.1, p = 0.07). Conclusion: Leucine-enriched amino acid supplementation and resistance exercise induced significant improvement in muscle mass, strength, and physical function in subpopulation of the non-sarcopenic hemodialysis patients. Those who benefited from the intervention were old-age females with lower baseline grip strength or lower hemoglobin or hematocrit, and who have good exercise compliance. Therefore, we propose that the intervention will help to prevent sarcopenia in selected patients on maintenance hemodialysis.

Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice.

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia.

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.

Safety and efficacy of PG102P for the control of pruritus in patients undergoing hemodialysis (SNUG trial): study protocol for a randomized controlled trial.

BACKGROUND: Pruritus in patients undergoing hemodialysis is a highly prevalent complication that affects quality of life. Several medications are currently used for the treatment of uremic pruritus, but these are not satisfactory. PG102P, which is prepared from Actinidia arguta, has an immune-modulating effect on pruritus. This trial is designed to assess the antipruritic effect of PG102P compared with placebo. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial will include 80 patients undergoing hemodialysis. The patients will be randomized in a 1:1 ratio to a treatment group (PG102P 1.5 g/day) or a control group (placebo). The treatment will last for 8 weeks, followed by a 2-week observational period. During the observational period, all of the patients will maintain the antipruritic treatment previously used. The primary endpoint will be measured as the difference in visual analog scale between the groups before and after treatment. Secondary outcomes include serum levels of total immunoglobulin E, eosinophil cationic protein, potassium, calcium, phosphorus, intact parathyroid hormone, and blood eosinophil count between weeks 0 and 8. Kidney Disease and Quality of Life and Beck's Depression Inventory questionnaires will be conducted. Safety assessments and any adverse events that occur will also be evaluated. DISCUSSION: The SNUG is a clinical study that aims to investigate the antipruritic effect of PG102P to ameliorate itching in patients undergoing hemodialysis. TRIAL REGISTRATION: Clinical Trials.gov, NCT03576235. Registered on 4 July 2018.

High Endogenous Accumulation of ω-3 Polyunsaturated Fatty Acids Protect against Ischemia-Reperfusion Renal Injury through AMPK-Mediated Autophagy in Fat-1 Mice.

Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). Fat-1 transgenic mice produce ω3-Polyunsaturated fatty acids (ω3-PUFAs) from ω6-Polyunsaturated fatty acids (ω6-PUFAs) without a dietary ω3-PUFAs supplement, leading to a high accumulation of omega-3 in various tissues. ω3-PUFAs show protective effects against various renal injuries and it has recently been reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated its associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI and renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7; lower amounts of p62; and, higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more adenosine monophosphate-activated protein kinase (AMPK) activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

Comparison of treatment delay associated with tunneled hemodialysis catheter placement between interventionists.

BACKGROUND/AIMS: Fragmented care in nephrology can cause treatment delays. Nephrologists are qualified to perform vascular access-related procedures because they understand the pathophysiology of renal disease and perform physical examination for vascular access. We compared treatment delays associated with tunneled hemodialysis catheter (TDC) placement between interventional radiologists and nephrologists. METHODS: We collected data by radiologists from January 1, 2011 through December 31, 2011 and by nephrologists from since July 1, 2012 through June 30, 2013. We compared the duration from the hemodialysis decision to TDC placement (D-P duration) and hemodialysis initiation (D-H duration), catheter success and the complication rate, and the frequency and the usage time of non-tunneled hemodialysis catheters (NDCs) before TDC placement. RESULTS: The study analyzed 483 placed TDCs: 280 TDCs placed by radiologists and 203 by nephrologists. The D-P durations were 319 minutes (interquartile range [IQR], 180 to 1,057) in the radiologist group and 140 minutes (IQR, 0 to 792) in the nephrologist group. Additionally, the D-H durations were 415 minutes (IQR,260 to 1,091) and 275 minutes (IQR, 123 to 598), respectively. These differences were statistically significant (p = 0.00). The TDC success rate (95.3% vs. 94.5%, respectively; p = 0.32) and complication rate (16.2% vs. 11%, respectively; p = 0.11) did not differ between the groups. The frequency (24.5 vs. 26%, respectively; p = 0.72) and the usage time of NDC (8,451 vs. 8,416 minutes, respectively; p = 0.91) before TDC placement were not statistically significant. CONCLUSIONS: Trained interventional nephrologists could perform TDC placement safely, minimizing treatment delays.

Severe hypernatremia by excessive bamboo salt ingestion in healthy young woman.

Severe hypernatremia is an important electrolyte disorder that has serious effects. The patient had no medical history. A. 20-year-old ingested bamboo salt for digestion and weight reduction according to the folk remedies posted on an internet website. She presented with vomiting and diarrhea over ten times per day. Her initial serum sodium concentration was 174mEq/L. Her symptoms improved rapidly with hypotonic saline infusion. She recovered completely without any sequelae in three days. Severe hypernatremia in a normal young adult with clear consciousness and normal renal function has not been reported in Korea yet. So we report a case of severe hypernatremia by excessive bamboo salt ingestion in healthy young woman.

Hyperammonemia in a patient with late-onset ornithine carbamoyltransferase deficiency.

Ornithine carbamoyltransferase (OTC) deficiency is a urea cycle disorder that causes the accumulation of ammonia, which can lead to encephalopathy. Adults presenting with hyperammonemia who are subsequently diagnosed with urea cycle disorders are rare. Herein, we report a case of a late-onset OTC deficient patient who was successfully treated with arginine, benzoate and hemodialysis. A 59-yr-old man was admitted to our hospital with progressive lethargy and confusion. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. A plasma amino acid and urine organic acid analysis revealed OTC deficiency. Despite the administration of a lactulose enema, the patient's serum ammonia level increased and he remained confused, leading us to initiate acute hemodialysis. After treatment with arginine, sodium benzoate and hemodialysis, the patient's serum ammonia level stabilized and his mental status returned to normal.