Application of lipid apheresis in acute lipogenic pancreatitis.

INTRODUCTION: Recently, the incidence of hypertriglyceridemia-associated pancreatitis(HTG-AP) has been increasing. The pathogenesis of lipogenic pancreatitis is not fully understood.This study aimed to retrospectively analyze the laboratory data, clinical manifestations, and prognosis of patients with lipid-derived pancreatitis who received lipid purification,to explore whether lipid purification is a better treatment for acute hyperlipidemic pancreatitis . METHODS: In this study, we enrolled five subjects diagnosed with HTG-AP at the Second Xiangya Hospital of Central South University between 2021 and 2022. We collected demographic data, medical histories, clinical manifestations, and laboratory data. All patients received routine therapy. Blood lipid purification was conducted using the double filtration plasmapheresis (DFPP) method. Plasma was separated from blood cells and purified to remove cholesterol, triglycerides, and low-density lipoprotein (LDL). SPSS was used for statistical analyses. RESULTS: Following a single lipoprotein apheresis (LA) treatment, significant improvements in serum lipid levels were observed. Three patients achieved triglyceride levels below 5.65mmol/L within 24 hours, while the remaining two patients experienced reductions of 82% and 78%, respectively. The average triglyceride level decreased from 36.82 to 7.27mmol/L, representing an 80% reduction from baseline. Total cholesterol decreased by 59% on average, and LDL levels decreased by 69%. Statistically significant differences were observed in triglyceride and cholesterol levels before and after treatment. Four patients exhibited increased HDL levels post-treatment, while one patient showed a decrease. The average HDL/TC level was 21% higher after treatment. CONCLUSION: LA in HTG-AP effectively improves clinical symptoms, rapidly lowers lipid levels, and achieves good therapeutic outcomes.

Lipophagy: A Potential Therapeutic Target for Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and one of the main causes of end-stage renal disease (ESRD). There are many factors causing the progression of DN. Lipid metabolism disorder is a common clinical manifestation of DN, and ectopic renal lipid deposition was recently proposed as a key factor promoting the development of DN. Lipophagy is a newly discovered type of selective autophagy that can remove excessive lipids in cells to maintain lipid homeostasis. Recently, abnormalities in lipophagy have also been implicated in the progression of DN. Here, we discuss the formation of lipid droplets, describe lipophagy and its key regulatory signals, summarize the current research progress of lipophay in DN, and finally propose that lipophagy may be a potential target for the treatment of DN.

Adipose-Renal Axis in Diabetic Nephropathy.

Long-term diabetes can lead to renal injury known as diabetic nephropathy (DN), which is a major cause of end-stage renal disease (ESRD). However, its pathogenesis has not been well explained. Adipose tissue is recognized as an important energy storage device for the body. Interestingly, many studies have shown that adipose tissue can also act as an endocrine organ by secreting a variety of adipokines to maintain homeostasis. Here, we summarize some of the adipokines that have been identified so far to, more specifically, emphasize their role in DN progression and propose that the "adipose-renal axis" may be a potential target for treating DN.

Dynamic serum albumin and outcome of peritoneal dialysis patients: A retrospective study in China.

Introduction: Serum albumin levels at a single time point have been shown to predict mortality in peritoneal dialysis (PD) patients. However, we believe that the dynamic change in albumin after PD may be more significant. In this study, we investigated the relationship between dynamic serum albumin and the clinical outcome of patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Methods: The participants in this study enrolled 586 patients who underwent CAPD at the peritoneal dialysis center of Second Xiangya Hospital in China. We retrospectively reviewed medical records from January 1, 2010, to December 31, 2019. Baseline serum albumin (Alb), time-averaged albumin level (TA-ALB) and serum albumin reach rate (SR: defined as the percentage of serum albumin measurements that reached ≥ 35 g/L) were applied as the predictor variables. All-cause mortality and cardiovascular mortality were used as the outcome variables. Hazard function of all-cause mortality and cardiovascular mortality in the study participants were examined by using Cox proportional hazard regression models. Results: Age (HR = 1.03, 95% CI 1.00-1.05), cardiovascular disease (HR = 1.80, 95% CI 1.07-3.03) and TA-ALB (HR = 0.92, 95% CI 0.85-0.99) were independent risk factors for all-cause mortality in PD patients. Patients with TA-ALB of <33 g/L (HR = 2.33, 95% CI 1.17-4.62) exhibited a higher risk for all-cause mortality than those with TA-ALB ≥ 36 g/L. Stratified SR showed a similar trend. Patients with a <25% SR exhibited a significantly increased risk for all-cause mortality (HR = 2.72, 95% CI, 1.24-5.96) by fully adjusted analysis. However, neither TA-ALB nor SR were associated with the risk of cardiovascular mortality after adjusted analysis. Conclusion: This study demonstrated that age, cardiovascular disease, and TA-ALB were independent risk factors for all-cause mortality in PD patients. TA-ALB and SR can better predict the prognosis of PD patients than baseline Alb. Dynamic changes in Alb are more clinically significant than baseline Alb in predicting mortality risk.

Melatonin alleviates renal injury by activating mitophagy in diabetic nephropathy.

Diabetic nephropathy (DN) causes serious renal tubule and interstitial damage, but effective prevention and treatment measures are lacking. Abnormal mitophagy may be involved in the progression of DN, but its upstream and downstream regulatory mechanisms remain unclear. Melatonin, a pineal hormone associated with circadian rhythms, is involved in regulating mitochondrial homeostasis. Here, we demonstrated abnormal mitophagy in the kidneys of DN mice or high glucose (HG)-treated HK-2 cells, which was accompanied by increased oxidative stress and inflammation. At the same time, the melatonin treatment alleviated kidney damage. After mitochondrial isolation, we found that melatonin promoted AMPK phosphorylation and accelerated the translocation of PINK1 and Parkin to the mitochondria, thereby activating mitophagy, reducing oxidative stress, and inhibiting inflammation. Interestingly, the renal protective effect of melatonin can be partially blocked by downregulation of PINK1 and inhibition of AMPK. Our studies demonstrated for the first time that melatonin plays a protective role in DN through the AMPK-PINK1-mitophagy pathway.

LncRNA MALAT1 Aggravates Renal Tubular Injury via Activating LIN28A and the Nox4/AMPK/mTOR Signaling Axis in Diabetic Nephropathy.

Background: Diabetic nephropathy (DN) is a serious complication among patients with diabetes. Elucidating its pathogenesis is crucial for identifying novel biomarkers and therapeutic targets for DN. Methods: DN tissues were harvested for examining MALAT1, LIN28A and Nox4. Human kidney-2 (HK-2) cells were treated with high glucose (HG) for establishing a cell model of DN. Cell viability was examined by MTT assay. HG-induced cell apoptosis and secretion of TNF-α and IL-6 were analyzed by TUNEL and ELISA assays, respectively. RIP and RNA pull-down assays were applied to analyze the interaction between MALAT1, LIN28A and Nox4 in HK-2 and human embryonic kidney 293T (HEK-293T) cells. A rat model of DN was established to determine the role of MALAT1 in DN in vivo. Results: MALAT1, LIN28A and Nox4 were upregulated in DN tissues and HG-treated HK-2 cells. Overexpression of MALAT1, LIN28A or Nox4 reduced cell viability and enhanced cell apoptosis, ROS generation and secretion of inflammatory cytokines in HG-treated HK-2 cells, whereas knockdown of MALAT1, LIN28A or Nox4 exerted opposite effects. Furthermore, MALAT1 directly interacted with LIN28A. Moreover, MALAT1 facilitated the interaction between LIN28A and Nox4 to increase Nox4 stability. Knockdown of Nox4 relieved HG-induced injury by suppressing the AMPK/mTOR signaling in HK-2 cells. Knockdown of MALAT1 alleviated renal tubular epithelial injury by suppressing LIN28A and the Nox4/AMPK/TOR signaling in DN. Conclusion: MALAT1 activates the AMPK/mTOR signaling via interacting with LIN28A to stabilize Nox4 mRNA, thereby aggravating high glucose-induced renal tubular epithelial injury. Our findings provide potential therapeutic targets for DN.

Gasdermin D is involved in switching from apoptosis to pyroptosis in TLR4-mediated renal tubular epithelial cells injury in diabetic kidney disease.

BACKGROUND: Toll-like receptor 4 (TLR4) mediated pathway plays a pivotal role in promoting tubulointerstitial inflammation and contributes to the progression in type 2 diabetic kidney disease (T2DKD). As the first identified key pyroptosis executor, gasdermin D (GSDMD) is activated by caspases and might be the key protein to switch apoptosis to pyroptosis. It remains unclear that role of TLR4 on canonical pyroptosis pathway, and whether GSDMD is involved in switching from apoptosis to pyroptosis in the TLR4-related tubular injury in T2DKD. METHODS: Immunohistochemistry staining was used to detect the expression of pyroptosis-related proteins in renal tissues of T2DKD patients. T2DKD models was induced in TLR4 knockout (TLR4-/-) mice through a high-fat diet combined with streptozotocin. Pyroptosis (caspase-1, GSDMD, interleukin 18(IL-18), interleukin 1ß(IL-1ß)) and apoptosis levels (caspase-3, Bax and Bcl-2) were detected by Western blot. HK-2 cells were cultured under high-glucose (HG) conditions as an in vitro model and then challenged with a TLR4-specific antagonist (TAK-242). GSDMD small interfering RNA (siRNA) and overexpression plasmid were transfected into HK-2 cells to down- or up-regulate GSDMD. The pyroptosis and apoptosis rates were determined by flow cytometry. RESULTS: The expression levels of caspase-1, GSDMD, IL-18 and IL-1ß were increased in renal biopsy tissues of T2DKD patients and GSDMD expression was positively correlated with tubular injury. Silencing GSDMD attenuated HG-induced IL-18, IL-1ß, FN and α-SMA, and reduced pyroptotic cells rate in HK-2 cells. Up-regulation of GSDMD inhibited HG-induced expression of Bax and cleaved caspase-3 and reduced apoptosis rate. TLR4 knockout alleviated tubular injury and interstitial macrophages infiltration, improved impaired renal dysfunction, and decreased the expressions of active N-terminal of GSDMD(GSDMD-N), cleaved caspase-1(cl-caspase-1) and cleaved caspase-3(cl-caspase-3) in T2DKD mice. TLR4 inhibition reduced HG-induced pyroptosis and apoptosis level in HK-2 cells, while GSDMD up-regulation increased pyroptosis rate and decreased apoptosis rate. CONCLUSIONS: TLR4 could exacerbate tubular injury and fibrosis via GSDMD-mediated canonical pyroptosis pathway in T2DKD. Activation of GSDMD could inhibit apoptosis and activate pyroptosis, which may involve the potential switch mechanism between TLR4-mediated pyroptosis and apoptosis in T2DKD.

Oxalate crystal-related acute renal injury caused by orlistat: A case report. / å¥¥åˆ©å¸ä»–è‡´è‰é ¸ç›ç»“æ™¶ç›¸å ³æ€¥æ€§è‚¾æŸä¼¤1例.

We reported a case of oxalate crystal-related acute kidney injury caused by orlistat. The patient was admitted for nephrotic syndrome and acute kidney injury. The pathomorphological assessment of renal biopsy showed intratubular oxalate crystals. The patient reported that she had taken orlistat regularly to loss weight for more than a year. This patient had a habit of drinking vegetable soup and strong herbal tea daily. Orlistat, an intestinal lipase inhibitor, may cause secondary hyperoxaluria, that is, intestinal hyperoxaluria. Dietary habits could be a common precipitating factor for orlistat-relevant hyperoxaluria. It was comprehensively considered to be oxalate crystal-related acute renal injury, and the patient's renal function recovered gradually after drug withdrawal. Clinicians should pay attention to screening drug-related acute kidney injury including orlistat when observing patients with unexplained acute kidney injury, and renal biopsy should be performed if necessary. It is also important to warn people who take the orlistat for weight loss about the side effects of this drug so as to adjust the eating habits.

Microbiology and Outcome of Peritoneal Dialysis-Related Peritonitis in Elderly Patients: A Retrospective Study in China.

Objective: The number of elderly patients on peritoneal dialysis (PD) has rapidly increased in the past few decades. We sought to explore the microbiology and outcomes of peritonitis in elderly PD patients compared with younger PD patients. Methods: We conducted a retrospective study to analyze the clinical characteristics, causative organism distribution, and outcome of all PD patients who developed peritonitis between September 1, 2014 and December 31, 2020, from Second Xiangya Hospital, Central South University, China. Patients who experienced peritonitis were separated into elderly and younger groups. The elderly was defined as ≥ 65 years old at the initiation of PD. Results: Among 1,200 patients, 64(33.9%) in elderly (n = 189) and 215 (21.3%) in younger (n = 1,011) developed at least one episode of peritonitis. A total of 394 episodes of peritonitis occurred in 279 patients. Of these, 88 episodes occurred in 64 elderly patients, and 306 episodes occurred in 215 younger patients. Gram-positive bacteria were the main causative organisms in elderly and younger patients (43.2% and 38.0%, respectively). Staphylococcus and Escherichia coli were the most common gram-positive and gram-negative bacteria, respectively. Fungal peritonitis in elderly patients was higher compared with younger patients (χ2 = 6.55, P = 0.01). Moreover, Acinetobacter baumannii (χ 2=9.25, P = 0.002) and polymicrobial peritonitis (χ 2 = 6.41, P = 0.01) in elderly patients were also significantly higher than that in younger patients. Additionally, elderly PD patients had higher peritonitis-related mortality than younger patients (χ 2 = 12.521, P = 0.000), though there was no significant difference in catheter removal between the two groups. Kaplan-Meier analysis showed that cumulative survival was significantly lower in elderly patients than younger patients (log rank = 7.867, p = 0.005), but similar technical survival in both groups (log rank = 0.036, p = 0.849). Conclusions: This retrospective study demonstrated that elderly PD patients were more likely to develop Acinetobacter baumannii, fungal and polymicrobial peritonitis than younger PD patients. In addition, peritonitis-related mortality was significantly higher in elderly patients, whereas peritonitis-related catheter removal was comparable between elderly and younger PD patients. Understanding microbiology and outcome in elderly patients will help to reduce the incidence of PD-associated peritonitis and improve the quality of life.

Digital Spatial Profiling of Individual Glomeruli From Patients With Anti-Neutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis.

We previously showed that the rupture of Bowman's capsule (BC) promotes the progression of crescentic glomerulonephritis by enhancing the entry of CD8+ T cells into the glomeruli. In the present study, we utilized digital spatial profiling to simultaneously profile the altered abundances of the messenger RNA (mRNA) transcripts and proteins in the glomerular and periglomerular areas of four biopsy samples of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis (ANCA-GN) and two biopsy specimens of minimal change disease (MCD) controls. The paraffin-embedded biopsy samples were stained with collagen IV, CD45, and SYTO 13 to distinguish the glomeruli with periglomerular infiltration but intact BC, with focal BC rupture, and with extensive rupture of BC and glomeruli without crescent formation and leukocytic infiltration in ANCA-GN. By assessing multiple discrete glomerular areas, we found that the transcript expression levels of the secreted phosphoprotein-1 and its receptor CD44 were upregulated significantly in the glomeruli with more severe ruptures of BC, and their expression levels correlated positively with the fibrotic markers. We also found that both alternative and classic complement pathways were activated in the glomeruli from patients with ANCA-GN. Furthermore, M1 macrophages were involved mostly in the early stage of BC rupture, while M2 macrophages were involved in the late stage and may contribute to the fibrosis process of the crescents. Finally, loss of glomerular cells in ANCA-GN was likely mediated by apoptosis. Our results show that digital spatial profiling allows the comparative analysis of the mRNA and protein profiles in individual glomeruli affected differently by the disease process and the identification of potential novel mechanisms in ANCA-GN.

A Systematic Review and Meta-Analysis: Hyponatremia Predicted All-Cause and Cardiovascular Mortality in Dialysis Population.

BACKGROUND: Hyponatremia is one of the most common disorders of electrolytes. Some research studies reported that hyponatremia was closely associated with mortality in patients with dialysis. However, this viewpoint remains controversial. OBJECTIVE: We aimed to do a systematic review and meta-analysis to assess the influence of hyponatremia on mortality in patients with dialysis. METHODS: We identified the eligible studies that investigated the association between hyponatremia and mortality risk in patients under dialysis by searching systematically a series of databases including PubMed, Embase, Cochrane, Web of science, and Ovid from January 2011 to June 2020. Adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) were pooled. RESULTS: From 1,116 records identified, 12 studies including prospective and retrospective cohort studies met our inclusion criteria. We found hyponatremia both at baseline (HR: 1.50 and 95% CI: 1.41-1.59) and in time-varying (HR: 1.63 and 95% CI: 1.44-1.84) were significantly correlated to all-cause mortality after multivariable adjusted. By the subgroup analysis, the same results were presented in hemodialysis (HR: 1.48 and 95% CI: 1.38-1.59) or peritoneal dialysis patients (HR: 1.52 and 95% CI: 1.37-1.70). We also observed that lower serum sodium was independently associated with cardiovascular death. CONCLUSIONS: Hyponatremia was independently associated with all-cause and cardiovascular mortality, and it might predict adverse outcomes of patients under dialysis.

The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response.

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.

A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin.

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

Mitochondria-Targeted Peptide SS31 Attenuates Renal Tubulointerstitial Injury via Inhibiting Mitochondrial Fission in Diabetic Mice.

OBJECTIVE: Renal tubular injury is an early characteristic of diabetic nephropathy (DN) that is related to mitochondrial dysfunction. In this study, we explore the effects and mechanisms of mitochondria-targeted peptide SS31 on renal tubulointerstitial injury in DN. METHOD: 40 C57BL/6 mice were randomly divided into control group, STZ group, STZ+SS31 group, and STZ+normal saline group. SS31 was intraperitoneally injected to the mice every other day for 24 weeks. Renal lesions and the expression of Drp1, Mfn1, Bcl-2, Bax, Caspase1, IL-1ß, and FN were detected. In in vitro studies, HK-2 cells were incubated with different concentrations of D-glucose (5, 30 mM) or combined with SS31 and Drp1 inhibitor Midivi1. Mitochondrial ROS, membrane potential, and morphology have been detected to evaluate the mitochondrial function. RESULTS: Compared with diabetic mice, the levels of serum creatinine and microalbuminuria were significantly decreased in the SS31 group. Renal tubulointerstitial fibrosis, oxidative stress, and apoptosis were observed in diabetic mice, while the pathological changes were reduced in the SS31-treatment group. SS31 could decrease the expression of Drp1, Bax, Caspase1, IL-1ß, and FN in the renal tissue of diabetic mice, while increasing the expression of Mfn1. Additionally, mitochondria exhibit focal enlargement and crista swelling in renal tubular cells of diabetic mice, while SS31 treatment could partially block these changes. An in vitro study showed that pretreatment with SS31 or Drp1 inhibitor Mdivi1 could restore the level of mitochondrial ROS, the membrane potential levels, and the expressions of Drp1, Bax, Caspase1, IL-1ß, and FN in HK-2 cells under high-glucose conditions. CONCLUSION: SS31 protected renal tubulointerstitial injury in diabetic mice through a decrease in mitochondrial fragmentation via suppressing the expression of Drp1 and increasing the expression of Mfn1.

Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice.

Na+/H+ exchanger isoform 3 (NHE3) contributes to Na+/bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phosphoenolpyruvate carboxykinase) in proximal tubules and H+ and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na+-glucose cotransporter (SGLT)2 and higher SGLT1 expression, indicating a downward tubular shift in Na+ and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.

Aeromonas sobria peritonitis in a peritoneal dialysis (PD) patient: a case report and review of the literature.

BACKGROUND: Peritonitis is a common cause of catheter removal and mortality in the patient undergoing peritoneal dialysis (PD). Various pathogenic organisms have been identified as the etiology of PD-related peritonitis, among which Aeromonas sobria is a rare one. Several studies have indicated that Aeromonas sobria might be of particular clinical significance because of its enterotoxin production. We here present a case of peritonitis due to Aeromonas sobria in a PD patient and review of the related literature. CASE PRESENTATION: A 37-year-old man with chronic renal failure who was secondary to chronic glomerulonephritis had been on PD for approximately 6 months without any episode of peritonitis. In July 2015, he was admitted to the hospital for fever, vomiting, abdominal pain, diarrhea and cloudy dialysate several hours after eating stinky tofu. The peritoneal effluent culture yielded Aeromonas sobria. The patient was given intraperitoneal amikacin and intravenous levofloxacin for 10 days. And the patient's symptoms such as diarrhea, abdominal pain were relieved and the cloudy effluent turned to be clear. Unfortunately, peritoneal dialysis catheter was blocked because of fibrin clot formation in the setting of inflammation, and finally it was removed. CONCLUSIONS: Aeromonas species are rare causes of PD-related peritonitis, however they should not be ignored. Clinicians should be aware of monitoring the hygiene protocol and retraining patients at regular intervals, especially for such rare cases.

Knockout of Na+-glucose cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase NOS1 in the macula densa and glomerular hyperfiltration.

Na+-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa (MD) sensing of an increase in luminal glucose, which increases nitric oxide (NO) synthase 1 (MD-NOS1)-mediated NO formation and potentially glomerular filtratrion rate (GFR). Here, the contribution of SGLT1 was tested by gene knockout (-/-) in type 1 diabetic Akita mice. A low-glucose diet was used to prevent intestinal malabsorption in Sglt1-/- mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in Sglt1-/- versus littermate wild-type Akita mice (480 vs. 550 mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic Sglt1-/- mice, associated with similar hyperglycemia versus wild-type mice (350 vs. 385 mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in nondiabetic mice. During SGLT2 inhibition in Akita mice, Sglt1-/- mice had likewise reduced blood glucose (200 vs. 300 mg/dl), associated with lesser MD-NOS1 expression, GFR, kidney weight, glomerular size, and albuminuria. Absence of Sglt1 in Akita mice increased systolic blood pressure, associated with suppressed renal renin mRNA expression. This may reflect fluid retention due to blunted hyperfiltration. SGLT2 inhibition prevented the blood pressure increase in Sglt1-/- Akita mice, possibly due to additive glucosuric/diuretic effects. The data indicate that SGLT1 contributes to diabetic hyperfiltration and limits diabetic hypertension. Potential mechanisms include its role in glucose-driven upregulation of MD-NOS1 expression. This pathway may increase GFR to maintain volume balance when enhanced MD glucose delivery indicates upstream saturation of SGLTs and thus hyperreabsorption.

The Kidney Specific Protein myo-Inositol Oxygenase, a Potential Biomarker for Diabetic Nephropathy.

BACKGROUND/AIMS: Renal tubular injury plays an important role in the progression of diabetic nephropathy (DN). However, there is a lack of specific biomarkers for tubular damage in incipient DN. We have evaluated the role of myo-inositol oxygenase (MIOX) in the tubular injury of DN, but whether it could serve as a new biomarker for the early diagnosis of DN is unclear. METHODS: Ninety patients with type 2 diabetes mellitus (T2DM) were divided into normoalbuminuria, microalbuminuria and macroalbuminuria groups. Fifteen patients from the last group were pathologically diagnosed as type 2 DN (T2DN), and fifteen patients with minimal change disease served as a control group. The expression of MIOX and silent information regulator 1 (Sirt1) in renal biopsies was determined by immunohistochemistry (IHC), and serum/urine MIOX, Sirt1, KIM-1 and NGAL were measured using enzyme-linked immunosorbent assays (ELISAs). Spearman's correlation and multiple regression analyses were carried out for statistical analyses. RESULTS: Compared with the controls, MIOX expression was significantly increased in the renal tissues of T2DN patients, and was positively correlated with tubulointerstitial lesions and renal ROS production but inversely correlated with Sirt1 expression. In addition, the serum and urine MIOX were significantly increased and gradually elevated with the increasing of UACR. Interestingly, elevated MIOX levels in serum and urine were found in diabetic patients without early signs of glomerular damage (normoalbuminuric group). Further multivariate regression analysis showed that sMIOX and uMIOX correlated significantly with HbA1c, serum creatinine and logUACR, respectively. CONCLUSION: These data indicate that increased MIOX expression in the kidney contributes to tubular damage in DN. The concentration of MIOX in the serum and urine may serve as a new biomarker for the early diagnosis of DN.

Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin.

The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg·kg-1 ·day-1) in Oat3-/- mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.