TOPOGRAPHIC CHANGES IN CHOROIDAL THICKNESS IN AGE-RELATED MACULAR DEGENERATION DURING THE DEVELOPMENT OF ACTIVE CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To evaluate topographic changes in choroidal thickness during development of choroidal neovascularization (CNV) in treatment-naive age-related macular degeneration (AMD) and to test the value of such changes as a predictive tool of CNV development. METHODS: This retrospective cohort included 86 eyes that developed CNV from intermediate AMD, 43 eyes with intermediate AMD, and 36 eyes without AMD. Patients with intermediate AMD underwent spectral domain optical coherence tomography using enhanced depth imaging mode every 6 months until CNV was detected. Choroidal neovascularization was localized to one of the subfields of Early Treatment of Diabetic Retinopathy Study grid on fluorescein angiography. Average choroidal thickness of each subfield was calculated. RESULTS: Choroidal thickness of the subfield where CNV developed at first clinical detection significantly increased compared with that 6 months before (P = 0.000 for central, P = 0.001 for superior parafoveal, P = 0.002 for temporal parafoveal, P = 0.002 for inferior parafoveal, and P = 0.001 for nasal parafoveal subfield). In eight patients who visited unexpectedly 3 months before CNV development in central subfield, choroidal thickness of central subfield increased significantly compared with that 6 months before CNV development (P = 0.001). CONCLUSION: Choroidal neovascularization development accompanied choroidal thickening of the corresponding subfield. Regular measurement of choroidal thickness may assist in prediction of CNV.

RIPK3 causes mitochondrial dysfunction and albuminuria in diabetic podocytopathy through PGAM5-Drp1 signaling.

BACKGROUND: Receptor-interacting protein kinase (RIPK)3 is an essential molecule for necroptosis and its role in kidney fibrosis has been investigated using various kidney injury models. However, the relevance and the underlying mechanisms of RIPK3 to podocyte injury in albuminuric diabetic kidney disease (DKD) remain unclear. Here, we investigated the role of RIPK3 in glomerular injury of DKD. METHODS: We analyzed RIPK3 expression levels in the kidneys of patients with biopsy-proven DKD and animal models of DKD. Additionally, to confirm the clinical significance of circulating RIPK3, RIPK3 was measured by ELISA in plasma obtained from a prospective observational cohort of patients with type 2 diabetes, and estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), which are indicators of renal function, were followed up during the observation period. To investigate the role of RIPK3 in glomerular damage in DKD, we induced a DKD model using a high-fat diet in Ripk3 knockout and wild-type mice. To assess whether mitochondrial dysfunction and albuminuria in DKD take a Ripk3-dependent pathway, we used single-cell RNA sequencing of kidney cortex and immortalized podocytes treated with high glucose or overexpressing RIPK3. RESULTS: RIPK3 expression was increased in podocytes of diabetic glomeruli with increased albuminuria and decreased podocyte numbers. Plasma RIPK3 levels were significantly elevated in albuminuric diabetic patients than in non-diabetic controls (p = 0.002) and non-albuminuric diabetic patients (p = 0.046). The participants in the highest tertile of plasma RIPK3 had a higher incidence of renal progression (hazard ratio [HR] 2.29 [1.05-4.98]) and incident chronic kidney disease (HR 4.08 [1.10-15.13]). Ripk3 knockout improved albuminuria, podocyte loss, and renal ultrastructure in DKD mice. Increased mitochondrial fragmentation, upregulated mitochondrial fission-related proteins such as phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (Drp1), and mitochondrial ROS were decreased in podocytes of Ripk3 knockout DKD mice. In cultured podocytes, RIPK3 inhibition attenuated mitochondrial fission and mitochondrial dysfunction by decreasing p-mixed lineage kinase domain-like protein (MLKL), PGAM5, and p-Drp1 S616 and mitochondrial translocation of Drp1. CONCLUSIONS: The study demonstrates that RIPK3 reflects deterioration of renal function of DKD. In addition, RIPK3 induces diabetic podocytopathy by regulating mitochondrial fission via PGAM5-Drp1 signaling through MLKL. Inhibition of RIPK3 might be a promising therapeutic option for treating DKD.

Muscle Mass Adjusted for Body Weight Is Associated with Significant Liver Fibrosis in Young Adults with Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study from a Korean Military Hospital.

Background: Sarcopenia has been associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to investigate the correlation between liver fibrosis and muscle mass in young adults with NAFLD. Methods: We conducted a retrospective review of 88 Korean soldiers <35 years of age who underwent bioelectrical impedance analysis and liver stiffness measurements. A FibroScan-aspartate aminotransferase score >0.35 was used to determine the presence of liver fibrosis. Results: Among the 88 patients, 38 were classified as having significant fibrosis. In the univariate analysis, muscle mass percentage (MMP), muscle-to-fat ratio (MFR), waist-to-hip ratio (WHR), body mass index, impaired fasting glucose or diabetes mellitus, and alanine transaminase (ALT) level were all significantly associated with fibrosis (P<0.001). After adjusting for ALT level, height, and age, MMP and WHR were associated with fibrosis. Conclusion: In young adults, MMP and MFR were significantly associated with hepatic fibrosis.

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway.

Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-ß, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-ß, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK'872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK'872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK'872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.

Trends in the prevalence of chronic kidney disease, other chronic diseases and health-related behaviors in an adult Korean population: data from the Korean National Health and Nutrition Examination Survey (KNHANES).

BACKGROUND: Chronic kidney disease (CKD) is an increasing public health problem. However, there have been limited data on the trend of CKD prevalence, along with the changes of health-related behaviors and other chronic diseases in an adult Korean population. METHODS: Data from the Korean National Health and Nutrition Examination Survey in 2005 and 2007 were analyzed. The study subjects comprised 8400 participants aged ≥ 20 years with creatinine data. CKD was defined as estimated glomerular filtration rate (GFR) <60 mL/min/1.73m(2). GFR was estimated by the abbreviated Modification of Diet in Renal Disease equation. RESULTS: The CKD prevalence was significantly decreased from 2005 to 2007 (8.8 versus 7.2%; P = 0.010). The prevalence of hypertension was stable but that of diabetes was increased. The proportion of blood pressure (BP) <130/80 mmHg in the whole population, and HbA1c <7% in the diabetic participants was increased from 2005 to 2007. Participants in 2007 walked more than those in 2005. The proportion of current smoking and sodium/energy/protein excess was decreased from 2005 to 2007. In subgroup analysis, only hypertensive participants without diabetes revealed a decreasing trend of CKD. CONCLUSIONS: The CKD prevalence was decreased from 2005 to 2007. Since increased diabetes and improved diabetic control neutralized their impact on CKD, improved BP was the fundamental reason for the decrease. Various health-related behaviors may have indirectly affected the decrease of CKD through their effect in controlling BP and diabetes.

Scheimpflug Topography Oriented Adequate Repositioning of a Misaligned Free Flap after Laser in situ Keratomileusis.

This report describes a case of Scheimpflug topography oriented adequate repositioning of a misaligned thick free flap after laser in situ keratomileusis (LASIK). A 24-year-old patient consulted for irregular astigmatism and disoriented free right eye flap. The patient previously underwent binocular LASIK at a private clinic. During the right eye surgery, the flap was repositioned after laser ablation due to the free flap. The free flap was not repositioned to its original configuration due to insufficient preoperative corneal marking. On examination, the uncorrected visual acuity was 0.4, and refractive power was +2.00 Dsph with -4.25 Dcyl axis 66 in the right eye. Scheimpflug topography revealed irregular right eye astigmatism. The sagittal curvature of topography showed a 40° counterclockwise misalignment of the steep axis of the cornea. The free flap was repositioned by 40° clockwise rotation. After this, the refractive corneal power improved to -1.00 Dsph with -1.00 Dcyl Axis 19 in the right eye. The uncorrected and best-corrected visual acuity improved to 20/30 and 20/25 (x - 0.25Dsph -1.25 Dcyl A20), respectively. This is the first report on free flap repositioning using Scheimpflug topography. As proper flap positioning was compromised because of the free LASIK flap with no preoperative corneal marking, the flap was effectively repositioned using Scheimpflug topography.

Protective effects of klotho on palmitate-induced podocyte injury in diabetic nephropathy.

The anti-aging gene, klotho, has been identified as a multi-functional humoral factor and is implicated in multiple biological processes. However, the effects of klotho on podocyte injury in diabetic nephropathy are poorly understood. Thus, the current study aims to investigate the renoprotective effects of klotho against podocyte injury in diabetic nephropathy. We examined lipid accumulation and klotho expression in the kidneys of diabetic patients and animals. We stimulated cultured mouse podocytes with palmitate to induce lipotoxicity-mediated podocyte injury with or without recombinant klotho. Klotho level was decreased in podocytes of lipid-accumulated obese diabetic kidneys and palmitate-treated mouse podocytes. Palmitate-treated podocytes showed increased apoptosis, intracellular ROS, ER stress, inflammation, and fibrosis, and these were significantly attenuated by klotho administration. Klotho treatment restored palmitate-induced downregulation of the antioxidant molecules, Nrf2, Keap1, and SOD1. Klotho inhibited the phosphorylation of FOXO3a, promoted its nuclear translocation, and then upregulated MnSOD expression. In addition, klotho administration attenuated palmitate-induced cytoskeleton changes, decreased nephrin expression, and increased TRPC6 expression, eventually improving podocyte albumin permeability. These results suggest that klotho administration prevents palmitate-induced functional and morphological podocyte injuries, and this may indicate that klotho is a potential therapeutic agent for the treatment of podocyte injury in obese diabetic nephropathy.

RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death.

Fabry disease is a lysosomal storage disease with an X-linked heritage caused by absent or decreased activity of lysosomal enzymes named alpha-galactosidase A (α-gal A). Among the various manifestations of Fabry disease, Fabry nephropathy significantly affects patients' morbidity and mortality. The cellular mechanisms of kidney damage have not been elusively described. Necroptosis is one of the programmed necrotic cell death pathways and is known to play many important roles in kidney injury. We investigated whether RIPK3, a protein phosphokinase with an important role in necroptosis, played a crucial role in the pathogenesis of Fabry nephropathy both in vitro and in vivo. The cell viability of podocytes decreased after lyso-Gb3 treatment in a dose-dependent manner, with increasing RIPK3 expression. Increased reactive oxygen species (ROS) generation after lyso-Gb3 treatment, which was alleviated by GSK'872 (a RIPK3 inhibitor), suggested a role of oxidative stress via a RIPK3-dependent pathway. Cytoskeleton rearrangement induced by lyso-Gb3 was normalized by the RIPK3 inhibitor. When mice were injected with lyso-Gb3, increased urine albuminuria, decreased podocyte counts in the glomeruli, and effaced foot processes were observed. Our results showed that lyso-Gb3 initiated albuminuria, a clinical manifestation of Fabry nephropathy, by podocyte loss and subsequent foot process effacement. These findings suggest a novel pathway in Fabry nephropathy.

Factors associated with aortic stiffness and its change over time in peritoneal dialysis patients.

BACKGROUND: An increase in aortic stiffness, as reflected by an increase in pulse wave velocity (PWV), is an important predictor of cardiovascular mortality in dialysis patients. Decreased serum concentration of calcification inhibitor, such as fetuin-A, is inversely related to mortality in haemodialysis patients. Our aim is to investigate the factors associated with aortic stiffness and its change over time in peritoneal dialysis (PD) patients. METHODS: As a prospective observational study, we analysed 67 PD patients, aged 50 ± 14 years (mean ± SD) and with dialysis duration of 26 (5-58) months (median, interquartile range). At baseline, age, mean arterial pressure (MAP), left ventricular mass (LVM) index, diabetes, serum albumin, calcium (Ca), phosphorus (P) and intact parathyroid hormone (iPTH), uric acid, total bilirubin, high-sensitivity C-reactive protein (hsCRP), fetuin-A, and residual renal function were included in association analysis with aortic stiffness represented by heart-to-femoral PWV (hfPWV). We also evaluated simple vascular calcification score (SVCS) with plain radiograph of the pelvis and both hands. PWV was measured both at baseline and at 1 year. Change of aortic stiffness was determined by △PWV (difference between 1-year PWV and baseline PWV). Time-averaged concentrations were used to evaluate the relation between biologic markers and changes of aortic stiffness. RESULTS: hfPWV was 1022 ± 276 cm/s at baseline, and hfPWV determined at 1 year was 1069 ± 317 cm/s. Mean serum fetuin-A concentration was 0.34 ± 0.08 g/L. At baseline, aortic PWV positively correlated with age, smoking status, diabetes, MAP, total cholesterol and LDL cholesterol. On the other hand, aortic PWV inversely correlated with fetuin-A, log PTH, haemoglobin and albumin. In a multiple regression model, association of serum fetuin-A (ß = -0.329, P = 0.003) with aortic PWV remained significant, along with age (ß = 0.512, P < 0.001), MAP (ß = 0.215, P = 0.047) and log PTH (ß = -0.269, P = 0.025). At follow-up, △MAP (ß = 0.500, P < 0.001) and time-averaged TG (aTG) (ß = 0.259 P = 0.019) were determinants of △PWV. CONCLUSIONS: For our PD patients, serum fetuin-A was an independent determinant of aortic stiffness, as well as age, MAP and log PTH. Although 1 year is not sufficient to observe the change of aortic stiffness, some patients exhibited >15% increase of PWV during this period. △MAP and aTG were factors affecting the change of PWV. Follow-up over a longer period is necessary to elucidate factors that determine changes of aortic stiffness over time from PD patients.

Changes in inner retinal layer thickness in patients with exudative age-related macular degeneration during treatment with anti-vascular endothelial growth factor.

The aim of this study was to identify any changes that occur in the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) in patients with exudative age-related macular degeneration (AMD) during treatment with anti-vascular endothelial growth factor (VEGF) injections.Patients were enrolled in this retrospective study if they had exudative AMD, had received at least 3 injections of ranibizumab or aflibercept, and had a minimum of 12 months of follow-up. We analyzed the changes in the RNFL and GC-IPL using spectral-domain optical coherence tomography in rescan mode.Fifty-two eyes of 52 patients who had been treated with repeated anti-VEGF injections for exudative AMD were included. At the final visit, there was no significant between-group difference in best-corrected visual acuity or intraocular pressure. There was a significant decrease in central macular thickness in all groups (P < .05). There was a decrease in RNFL thickness that was only statistically significant in the ranibizumab group and when the ranibizumab or aflibercept groups were combined (P = .036 and .044, respectively). The thickness of the GC-IPL layer was significantly decreased in the aflibercept and total group (P = .035 and P = .048, respectively).The thicknesses of the RNFL and GC-IPL decreased in patients with exudative AMD who underwent repeated anti-VEGF injections.

Clinical characteristics of acute renal failure with severe loin pain and patchy renal vasoconstriction.

BACKGROUND: Acute renal failure (ARF) with severe loin pain and patchy renal vasoconstriction (PRV) is a syndrome presenting with sudden loin pain after anaerobic exercise. We aimed to investigate the clinical characteristics and the efficacy of diagnostic imaging studies of patients with this syndrome. METHODS: We retrospectively selected 17 patients with ARF accompanied by loin or abdominal pain who showed multiple patchy wedge-shaped delayed contrast enhancements on a computerized tomography scan. Information about the clinical characteristics, including the nature of pain and combined symptoms, suspected causes, such as exercise, drug or alcohol intake, and renal hypouricemia, and the results of laboratory and imaging tests were gathered. RESULTS: The mean age of patients with episodes of ARF accompanied by loin pain was 23.0±6.5 (range 16-35) years old. Pain was mainly located in the loin (70.6%) or abdominal area (76.5%) and continued for approximately 3.5±4.0 days. Exercise was suspected as a primary cause of disease in 12 (70.6%) patients. Maximal serum creatinine was 5.42±3.16 (1.4-12.1) mg/dL 3.1±1.8 (1-7) days after the onset of pain. The peak level of serum uric acid was 9.41±2.91 (6.0-15.8) mg/dL. All of the patients recovered to near-normal renal function, and one patient showed hypouricemia after recovery. CONCLUSION: ARF with severe loin pain and PRV can present with loin or abdominal pain, even without a history of anaerobic exercise. Careful history taking and appropriate imaging studies are critical in the diagnosis and management of this syndrome.