Lipoprotein modulation of proteinuric renal injury.

High-density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain to renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, and apoAI mimetic (L-4F), and the in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis, and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25+) mice, which express human CD25 on podocytes. Podocyte injury was induced by using immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25+:apoE-/- mice, was generated by mating apoE-deficient (apoE-/-) mice with NEP25+ mice. Animals received L-4F or control vehicle. Renal function, podocyte injury, and atherosclerosis were assessed. PAN reduced podocyte viability, migration, and increased ROS production, all significantly lessened by apoAI, HDL, and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/signal transducers and activators of transcription 3. In NEP25+ mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25+:apoE-/- mice had more atherosclerosis than non-proteinuric apoE-/- mice, and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL, and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be a novel candidate to lessen podocyte damage and its complications.

Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism.

BACKGROUND: Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism. METHODS: LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDLCKD and HDLCont, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1ß), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist. RESULTS: There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HDCKD was significantly less effective than HDLCont in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDLCKD increased macrophage cytokine response (TNF-α, MCP-1, IL-1ß, and NF-κB) versus HDLCont. The heightened cytokine response to HDLCKD was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2. CONCLUSIONS: Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDLCKD. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDLCKD. However, LXR agonism actually increases the pro-inflammatory effects of HDLCKD through activation of TLRs and ERK1/2 pathways.

Upregulation of prolactin receptor in proximal tubular cells was induced in cardiac dysfunction model mice.

BACKGROUND: In order to clarify the interaction between cardiac dysfunction and sodium homeostasis in the kidney, we used a murine model of cardiac dysfunction and investigated the effect on sodium transporters in renal tubular cells. METHODS: Cardiac function was deteriorated by abdominal aortic banding, and the gene expression of sodium transporters in the kidneys was evaluated by real-time RT-PCR and compared with that in the kidneys of control mice. RESULTS: Gene expression of all three variants of the murine prolactin receptor was enhanced by aortic banding. Upregulated prolactin receptor was distributed in the proximal tubular cells of the pars recta in the deep inner cortex and the outer stripe of the outer medulla. Prolactin has been reported to be a natriuretic hormone that inhibits proximal tubular Na(+)/K(+)-ATPase activity, resulting in reduced sodium reabsorption and the acceleration of natriuresis. Inhibition of endogenous prolactin secretion by bromocriptine administration decreased the urine sodium excretion in both aortic banding and control mice. On the other hand, excess exogenous prolactin administration enhanced urine potassium excretion in aortic banding mice. Furthermore, a high-sodium diet accelerated urinary sodium excretion, which was also significantly decreased by inhibition of endogenous prolactin secretion in aortic banding mice. CONCLUSION: We reported that the prolactin receptor was upregulated by aortic banding treatment. Prolactin-prolactin receptor interaction in the proximal tubular cells of the pars recta should involve a different mechanism of kaliuresis other than inhibition of Na(+)/K(+)-ATPase.

Exercise instruction during haemodialysis treatment after changes to the insurance regime: a nationwide questionnaire survey in Japan.

In April 2022, an additional medical fee for exercise instruction during haemodialysis treatment was approved for insurance claims in Japan. We conducted a questionnaire survey to investigate the current situation regarding exercise therapy during haemodialysis treatment after this change. Questionnaires were mailed to 4257 haemodialysis facilities, almost all the haemodialysis facilities in Japan, on January 31, 2023. In total, 1657 facilities responded, of which 550 (33%) provided exercise instruction during haemodialysis treatment, and 65% of these claimed the new fee. Of the 550 facilities that had claimed the fee at the time of survey, 245 (55%) started exercise instruction in April 2022 or later. Exercise instruction focused on resistance training (81%) and aerobic exercise (62%) for 20-30 min (66%) three times a week (80%). The instructors included physicians in 45% of facilities, nurses in 74%, and physical therapists in 36%. Efficacy was evaluated in 76% of the facilities providing instruction, mainly by assessing change in muscle strength (49%). Overall, 39% of facilities had experienced some adverse events, but none were life-threatening. In conclusion, after the change in the insurance regime, exercise instruction during haemodialysis treatment has become more popular, and more patients on haemodialysis are undergoing exercise therapy.

Fatal acute portal vein thrombosis associated with hepatic cysts in a patient with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) often involves polycystic liver disease (PLD). In severe cases, PLD can develop various complications. However, fatal acute portal vein thrombosis (APVT) associated with PLD has not been reported. A 64-year-old male reported mild consciousness disorder. He had been under maintenance hemodialysis for end-stage renal disease due to ADPKD with PLD. Because of recurring hepatic cyst infections, he had sustained high levels of C-reactive protein. Regarding the mild consciousness disorder, a diagnosis of hepatic encephalopathy was made based on an elevation of serum ammonia without any other abnormal liver function tests. Several days after his admission, hepatobiliary enzymes elevated, and acute liver failure progressed. Enhanced abdominal computed tomography suggested the possibility of complete occlusion of the portal vein by a thrombus. Based on an absence of obvious portosystemic collaterals, a diagnosis of APVT was made. The patient died 19 days after admission. Patients with PLD with repeated cystic infections have been seen to develop liver failure, and APVT formation may be one cause of the rapid progression of fatal liver failure. In conclusion, this is the first paper to report on the involvement of APVT in patients with PLD.

Integrin α1/ß1 and α2/ß1 as a receptor for IgA1 in human glomerular mesangial cells in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of IgA1 and galactose-deficient IgA1 is expected to play a pathogenic role. However, the identity of the receptor for IgA1 is still controversial. Hence, the aim of this study was to explore the receptor for galactose-deficient IgA1. Human monoclonal IgA1 was treated with exoglycosidase and FITC-conjugated control, asialo- and agalactosyl-IgA1 was used as a probe to detect the receptor in cultured human mesangial cells. Tumor necrosis factor-α or transforming growth factor-ß1 treatment accelerated IgA1-binding on mesangial cells, and these effects were diminished by the addition of dexamethasone, whereas these changes were not dependent on galactose-deficiency of IgA1. According to comprehensive gene expression analysis, we focused on integrin ß1. Pre-treatment by Mn(2+), which activates integrin by changing its structure, enhanced the binding of IgA1 in cultured mesangial cells. Furthermore, pre-incubation with collagens specifically enhanced binding of IgA1 in the cultured human mesangial cells without activation by Mn(2+). Collagen type IV distributed in the mesangial region of the glomeruli as well as Bowman's capsule and tubular basal membrane in IgAN patients, and the IgA1 with collagen type IV induced proliferative signals on mesangial cells by phosphorylating extracellular signal-regulated kinase more effectively than the IgA1 alone. Immunoprecipitation assay revealed the binding of IgA1 and integrin α1/ß1 and α2/ß1 heterodimer and down-regulation of integrin α1, α2 and ß1 expression in human mesangial cells induced by each specific small interfering RNA diminished the ability to bind IgA1 probe. Integrin α1/ß1 and α2/ß1 would be a candidate receptor for IgA1.

Dialysis disequilibrium syndrome induced by neoplastic meningitis in a patient receiving maintenance hemodialysis.

BACKGROUND: Dialysis disequilibrium syndrome is characterized by neurological symptoms resulting from cerebral edema, which occurs as a consequence of hemodialysis. Dialysis disequilibrium syndrome most often occurs in patients who have just started hemodialysis, during hemodialysis, or soon after hemodialysis; although it may also occur in patients who are under maintenance hemodialysis with pre-existing neurological disease. CASE PRESENTATION: A 70-year-old woman, who had been receiving maintenance hemodialysis for one year, was diagnosed with ovarian cancer by ascites cytological examination. Two years later, she reported severe headache and nausea during hemodialysis and was diagnosed with dialysis disequilibrium syndrome. Although brain images revealed mild hydrocephalus without any mass lesions, poorly differentiated adenocarcinoma cells were detected in her cerebrospinal fluid. These findings indicated that DDS was induced by neoplastic meningitis due to ovarian cancer metastasis. CONCLUSION: Neoplastic meningitis should be considered and excluded in hemodialysis patients with dialysis disequilibrium syndrome and malignancy by cytological examination of the cerebrospinal fluid even if cerebral imaging shows no obvious lesions. This is the first reported case of dialysis disequilibrium syndrome induced by neoplastic meningitis in a patient receiving maintenance hemodialysis.

Pro-inflammatory HDL in women with obesity and nonalcoholic steatohepatitis.

BACKGROUND: Individuals with non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), are at increased risk for cardiovascular events, independent of traditional risk factors. Limited data on pro-inflammatory high density lipoprotein (HDL) in NASH exists in the literature. We hypothesized that HDL from individuals with NASH would be more pro-inflammatory than HDL from individuals without NASH. METHODS: Study participants were individuals with obesity who had undergone bariatric surgery with wedge liver biopsy. Using HDL isolated from serum obtained from study participants at the time of surgery, HDL-elicited macrophage cytokine expression (TNF-α, IL-1ß, and IL-6) from THP-1 macrophages, HDL-associated receptor expression (ABCA1 and ABCG1) from apolipoprotein E deficient (apo E-/-) mouse peritoneal macrophages, and isolevuglandin (isoLG) modified HDL were measured. RESULTS: 11 women with NASH and 15 women without NASH were included in the study. Both TNF-α (P = 0.032) and IL-1ß (P = 0.029) were significantly more expressed by THP-1 macrophages exposed to HDL from women with NASH compared to women without NASH. ABCA1 and ABCG1 expression by apo E-/- mouse peritoneal macrophages was not significantly different when exposed to HDL from either women with NASH or women without NASH. IsoLG-modified HDL isolated from the serum of women with NASH trended higher than women without NASH. CONCLUSION: Our study suggests a more pro-inflammatory HDL in women with obesity and NASH compared to women with obesity and without NASH.

IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD.

BACKGROUND AND OBJECTIVES: Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL function in CKD is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a post hoc analysis of two randomized, clinical trials, IL-1 trap in participants with GFR 15-59 ml/min per 1.73 m2 (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-α, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons. RESULTS: The mean age of the participants was 60±13 years, 72% (n=33) were men, and 39% (n=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF-α by 15% (P=0.05) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-like receptor protein 3 by 16% (P=0.01) and 25% (P=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (P<0.001) and 12% in the placebo arm in study B (P=0.004). Net cholesterol efflux capacity was not affected by either intervention. CONCLUSIONS: IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.

Crowned Dens Syndrome as an Initial Manifestation of Crystalline Deposition Disease.

An 88-year-old woman presented with fever and acute posterior neck pain. A CT scan revealed calcification of the transverse ligament and crown-like calcification around the odontoid process. According to the clinical and radiological findings, she was diagnosed with crowned dens syndrome (CDS). Her symptoms drastically improved following treatment with oral nonsteroidal anti-inflammatory medication. An X-ray of her wrist, elbow, shoulder and knee joints showed asymptomatic calcium deposits, suggesting underlying crystalline deposition disease. CDS may occur as the initial presentation of crystalline deposition disease. The measurement of procalcitonin and an X-ray survey of the major joints may be helpful for the diagnosis of CDS.