Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in diabetic tubulopathy.

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.

Therapeutic perspective: evolving evidence of nonsteroidal mineralocorticoid receptor antagonists in diabetic kidney disease.

Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been investigated as treatments for DKD. However, these drugs do not prevent overactivation of the mineralocorticoid receptor (MR). Studies have shown a correlation between MR hyperactivation, renal injury, and DKD. Finerenone, a novel and selective nonsteroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for the treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for the treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve the treatment of DKD is needed.

Catheter-related superior vena cava obstruction: A rare cause of chylothorax in maintenance hemodialysis patients.

With the extensive use of dialysis catheters in patients undergoing hemodialysis, superior vena cava (SVC) syndrome has gradually attracted attention in recent years. Chylothorax caused by SVC syndrome is rarely reported. In this paper, we report a case of chylothorax secondary to superior vena cava obstruction (SVCO) in a maintenance hemodialysis patient after multiple dialysis catheter placements. Relieving the SVCO through intravascular intervention could effectively treat chylothorax. In the past fourteen months, no recurrence of symptoms has been observed.

Effects of different potassium-lowering regimens on acute hyperkalemia in hemodialysis patients: a real-world, retrospective study.

BACKGROUND: Hyperkalemia is a common and potentially life-threatening electrolyte disorder in maintenance hemodialysis (MHD) patients. This study aimed to evaluate the efficacy and safety of potassium-lowering regimens during treatment of acute hyperkalemia in MHD patients. METHODS: This retrospective real-world study (RWS) was conducted among 139 MHD patients. They were given different potassium-lowering regimens, viz. the insulin and glucose (IG) intravenous administration group (IG, 46 patients), the sodium polystyrene sulfonate group (SPS, 33 patients), the sodium zirconium cyclosilicate group (SZC, 38 patients), the IG + SZC group (22 patients). The primary efficacy end point was the rate of serum potassium decline at 2 h. The rates of adverse events were also compared. RESULTS: At 2 h, the mean ± SE change of serum potassium level was - 0.71 ± 0.32 mmol per liter (mmol/L) in IG group, - 0.43 ± 0.38 mmol/L in SPS group, - 0.64 ± 0.36 mmol/L in SZC group, - 1.43 ± 0.38 mmol/L in IG + SZC group (P < 0.01). The serum potassium level in IG + SZC group decreased more than that in the other three groups (P < 0.01), while the serum potassium level in SPS group decreased less than that in the other three groups (P < 0.05). There was no significant difference on the decrease of the serum potassium level between IG group and the SZC group (P = 0.374). The IG group and the IG + SZC group had higher rates of symptomatic hypoglycemia. The SPS group had significant decreases of serum calcium and serum magnesium after treatment. CONCLUSIONS: Among MHD patients with acute hyperkalemia, SZC had similar potassium-lowering efficacy with IG intravenous administration at 2 h and superior on convenience and side-effects.

Mitochondrial dysfunction in diabetic tubulopathy.

Diabetic kidney disease (DKD) is a devastating microvascular complication associated with diabetes mellitus. Recently, the major focus of glomerular lesions of DKD has partly shifted to diabetic tubulopathy because of renal insufficiency and prognosis of patients is closely related to tubular atrophy and interstitial fibrosis. Indeed, the proximal tubule enriching in mitochondria for its high energy demand and dependence on aerobic metabolism has given us pause to focus primarily on the mitochondria-centric view of early diabetic tubulopathy. Multiple studies suggest that diabetes condition directly damages renal tubules, resulting in mitochondria dysfunction, including decreased bioenergetics, overproduction of mitochondrial reactive oxygen species (mtROSs), defective mitophagy and dynamics disturbances, which in turn trigger a series of metabolic abnormalities. However, the precise mechanism underlying mitochondrial dysfunction of renal tubules is still in its infancy. Understanding tubulointerstitial's pathobiology would facilitate the search for new biomarkers of DKD. In this Review, we summarize the current literature and postulate that the potential effects of mitochondrial dysfunction may accelerate initiation of early-stage diabetic tubulopathy, as well as their potential therapeutic strategies.

Central Venous Disease Increases the Risk of Microbial Colonization in Hemodialysis Catheters.

Objectives: Tunneled-cuffed catheters (TCCs) are widely used in maintenance hemodialysis patients. However, microbial colonization in catheters increases the likelihood of developing various complications, such as catheter-related infection (CRI), catheter failure, hospitalization, and death. Identification of the risk factors related to microorganism colonization may help us reduce the incidence of these adverse events. Therefore, a retrospective analysis of patients who underwent TCC removal was conducted. Methods: From a pool of 389 adult patients, 145 were selected for inclusion in the study. None of the patients met the diagnostic criteria for CRI within 30 days before recruitment. The right internal jugular vein was the unique route evaluated. The catheter removal procedure was guided by digital subtraction angiography. Catheter tips were collected for culture. Biochemical and clinical parameters were collected at the time of catheter removal. Results: The average age of this cohort was 55.46 ± 17.25 years. A total of 45/145 (31.03%) patients were verified to have a positive catheter culture. The proportions of gram-positive bacteria, gram-negative bacteria, and fungi were 57.8, 28.9, and 13.3%, respectively. History of CRI [odds ratio (OR) = 2.44, 95% confidence interval (CI) 1.09 to 5.49], fibrin sheath (OR = 2.93, 95% CI 1.39-6.19), white blood cell (WBC) count ≥5.9 × 109/l (OR = 2.31, 95% CI 1.12-4.77), moderate (OR = 4.87, 95% CI 1.61-14.78) or severe central venous stenosis (CVS) (OR = 4.74, 95% CI 1.16-19.38), and central venous thrombosis (CVT) (OR = 3.41, 95% CI 1.51-7.69) were associated with a significantly increased incidence of microbial colonization in a univariate analysis. Central venous disease (CVD) elevated the risk of microbial colonization, with an OR of 3.37 (1.47-7.71, P = 0.004). A multivariate analysis showed that both CVS and CVT were strongly associated with catheter microbial colonization, with ORs of 3.06 (1.20-7.78, P = 0.019) and 4.13 (1.21-14.05, P = 0.023), respectively. As the extent of stenosis increased, the relative risk of catheter microbial colonization also increased. In patients with moderate and severe stenosis, a sustained and significant increase in OR from 5.13 to 5.77 was observed. Conclusions: An elevated WBC count and CVD can put hemodialysis patients with TCCs at a higher risk of microbial colonization, even if these patients do not have the relevant symptoms of infection. Avoiding indwelling catheters is still the primary method for preventing CRI.

Permissive effect of GSK3ß on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease.

Renal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3ß is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3ß overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-ß1 treatment augmented GSK3ß expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3ß inhibitors or by ectopic expression of a dominant-negative mutant of GSK3ß but reinforced in cells expressing the constitutively active mutant of GSK3ß. Mechanistically, GSK3ß suppressed, whereas inhibiting GSK3ß facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-ß1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3ß in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3ß is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

Triptolide potentiates the cytoskeleton-stabilizing activity of cyclosporine A in glomerular podocytes via a GSK3ß dependent mechanism.

Tripterygium wilfordii Hook F. (TwHF) is a traditional Chinese herb and has a broad spectrum of biological functions including immunosuppression and anti-inflammatory effects. When used in combination with other standard of care medications, such as glucocorticoids and calcineurin inhibitors like cyclosporine A, for treating glomerular diseases, TwHF demonstrates a remarkable dose-sparing effect, the molecular mechanism for which remains largely unknown. In an in vitro model of podocytopathy elicited by a diabetic milieu, triptolide, the major active component of TwHF, at low doses, potentiated the beneficial effect of cyclosporine A, and protected podocytes against diabetic milieu-elicited injury, mitigated cytoskeleton derangement, and preserved podocyte filtration barrier function, entailing a synergistic cytoskeleton-preserving and podocyte protective effect of triptolide and cyclosporine A. Mechanistically, inhibitory phosphorylation of GSK3ß, a key molecule recently implicated as a convergence point of podocytopathic pathways, is likely required for the synergistic effect of triptolide and cyclosporine A on podocyte protection, because the synergistic effect was largely blunted in cells expressing the constitutively active GSK3ß. Ergo, a synergistic podocyte cytoskeleton-stabilizing mechanism seems to underlie the cyclosporine A-sparing effect of triptolide in glomerulopathies. Combined triptolide and cyclosporine A therapy at reduced doses may be an invaluable regimen for treating diabetic nephropathy.

Glycogen synthase kinase 3ß hyperactivity in urinary exfoliated cells predicts progression of diabetic kidney disease.

Burgeoning evidence points to glycogen synthase kinase (GSK)3ß as a key player in diverse kidney diseases. However, as a pivotal transducer of the insulin signaling pathway, the role of GSK3ß in diabetic kidney disease remains uncertain. In db/db mice, renal expression of total and activated GSK3ß was increasingly elevated. This preceded the development of diabetic kidney disease, and correlated with the progression of signs of diabetic kidney injury, including albuminuria and extracellular matrix accumulation in glomeruli and tubulointerstitia. In vitro, exposure of glomerular podocytes, mesangial cells, and renal tubular cells to a diabetic milieu induced GSK3ß overexpression and hyperactivity, which seem essential and sufficient for eliciting diabetic cellular damages in kidney cells, because the cytopathic effect of the diabetic milieu was mitigated by GSK3ß knockdown, but was mimicked by ectopic expression of constitutively active GSK3ß even in the normal milieu. In consistency, kidney biopsy specimens procured from patients with varying stages of diabetic nephropathy revealed an amplified expression of total and activated GSK3ß in glomeruli and renal tubules, associated with the severity of diabetic nephropathy. Moreover, in retrospective cohorts of type 2 diabetic patients that were followed for over five years, the relative activity of GSK3ß in banked urinary exfoliated cells represented an independent risk factor for development or progression of renal impairment. Furthermore, receiver operating characteristic curve analysis demonstrated that GSK3ß activity in urinary exfoliated cells provided much better power than albuminuria in discriminating diabetic patients with progressive renal impairment from those with stable kidney function. Thus, renal expression and activity of GSK3ß are amplified in experimental and clinical diabetic nephropathy. Hence, GSK3ß in urinary exfoliated cells may serve as a novel biomarker for predicting diabetic kidney disease progression.

The geriatric nutritional risk index may predict healthcare costs and health transitions during hemodialysis in China.

BACKGROUND AND OBJECTIVES: The aim of the present study was to retrospectively analyze the relationship between the Geriatric Nutritional Risk Index (GNRI) at baseline and healthcare costs of three-month as well as the risk of quality-of-life score at the 6-month follow-up for Chinese hemodialysis patients. METHODS AND STUDY DESIGN: One hundred patients who had been on maintenance hemodialysis were enrolled in this study. The general characteristics, laboratory test results and GNRI of the patients at baseline were recorded. The healthcare costs and quality-of-life scores were determined at the follow-up examination. RESULTS: Patients were divided into two groups according to their median GNRI at baseline: a lower GNRI group (GNRI <86.4) and a higher GNRI group (GNRI >86.4). The patients in the lower GNRI group exhibited reduced hemoglobin (74.7±13.1 g/dL vs 82.3±15.2 g/dL, p<0.05) and albumin (27.4±3.3 g/L vs 34.5±4.0 g/L, p<0.05) as well as reduced body weight (62.7±9.5 kg vs 68.0±9.2 kg, p<0.05) at baseline. The medication cost at follow-up was higher in the lower GNRI group (RMB 3,238±1,534 vs RMB 2,378±1,048, p<0.05). And a lower GNRI at baseline was associated with increased future medication costs and worse health in hemodialysis patients. CONCLUSIONS: The present study suggests that a lower GNRI in hemodialysis patients may be associated with an increased risk of higher future healthcare costs as well as worse health.

A Retrospective Study of Preferable Alternative Route to Right Internal Jugular Vein for Placing Tunneled Dialysis Catheters: Right External Jugular Vein versus Left Internal Jugular Vein.

BACKGROUND: Right internal jugular vein (IJV) is a preferred access route for tunneled (cuffed) dialysis catheters (TDCs), and both right external jugular vein (EJV) and left IJV are alternative routes for patients in case the right IJV isn't available for TDC placement. This retrospective study aimed to determine if a disparity exists between the two alternative routes in hemodialysis patients in terms of outcomes of TDCs. METHODS: 49 hemodialysis patients who required TDCs through right EJV (n = 21) or left IJV (n = 28) as long-term vascular access were included in this study. The primary end point was cumulative catheter patency. Secondary end points include primary catheter patency, proportion of patients that never required urokinase and incidence of catheter-related bloodstream infections (CRBSI). RESULTS: A total of 20,870 catheter-days were evaluated and the median was 384 (interquartile range, 262-605) catheter-days. Fewer catheters were removed in the right EJV group than in the left IJV group (P = 0.007). Mean cumulative catheter patency was higher in the right EJV group compared with the left IJV group (P = 0.031). There was no significant difference between the two groups in the incidence of CRBSI, primary catheter patency or proportion of patients that never required urokinase use. Total indwell time of antecedent catheters was identified as an independent risk factor for cumulative catheter patency by Cox regression hazards test with an HR of 2.212 (95% CI, 1.363-3.588; p = 0.001). CONCLUSIONS: Right EJV might be superior to left IJV as an alternative insertion route for TDC placement in hemodialysis patients whose right IJVs are unavailable.

Epidemiology of haemodialysis catheter complications: a survey of 865 dialysis patients from 14 haemodialysis centres in Henan province in China.

OBJECTIVES: To investigate the incidence rates and risk factors for catheter-related complications in different districts and populations in Henan Province in China. DESIGN: Cross-sectional. SETTING: Fourteen hospitals in Henan Province. PARTICIPANTS: 865 patients with renal dysfunction undergoing dialysis using catheters between October 2013 and October 2014. MAIN OUTCOME MEASURES: The main outcome measures were complications, risk factors and patient characteristics. Catheter-related complications included catheter-related infection (catheter exit-site infection, catheter tunnel infection and catheter-related bloodstream infection), catheter dysfunction (thrombosis, catheter malposition or kinking, and fibrin shell formation) and central vein stenosis. RESULTS: The overall incidence rate was 7.74/1000 catheter-days, affecting 38.61% of all patients, for catheter infections, 10.58/1000 catheter-days, affecting 56.65% of all patients, for catheter dysfunction, and 0.68/1000 catheter-days, affecting 8.79% of all patients, for central vein stenosis. Multivariate analysis showed that increased age, diabetes, primary educational level or below, rural residence, lack of a nephropathy visit before dialysis and pre-established permanent vascular access, not taking oral drugs to prevent catheter thrombus, lower serum albumin levels and higher ferritin levels were independently associated with catheter infections. Rural residence, not taking oral drugs to prevent thrombus, lack of an imaging examination after catheter insertion, non-tunnel catheter type, lack of medical insurance, lack of nephropathy visit before dialysis and pre-established permanent vascular access, left-sided catheter position, access via the femoral vein and lower haemoglobin level were independently associated with catheter dysfunction. Diabetes, lack of nephropathy visit before dialysis and pre-established permanent vascular access, lack of oral drugs to prevent catheter thrombus, left-sided catheter location and higher number of catheter insertions, were independently associated with central vein stenosis. CONCLUSIONS: The rate of catheter-related complications was high in patients with end-stage renal disease in Henan Province. Our finding suggest that strategies should be implemented to decrease complication rates.

Cuffed-tunneled hemodialysis catheter survival and complications in pediatric patients: a single-center data analysis in China.

This study aims to evaluate the outcome and complications of cuffed-tunneled catheters in pediatric patients. Between January 2010 and December 2013, 16 pediatric patients with end-stage renal disease (ESRD) were included. 21 cuffed-tunneled hemodialysis catheters were inserted in patients for long-term hemodialysis access. No serious complications were observed in all patients receiving catheter insertion operation, except one with hemopneumothorax. Median survival time was 413.5 days, with rate being 67.5% in the first year, 51.5% in the second year and 43.6% in the third year. Among attempted catheter insertions, 21 (100%) achieved successful vascular access with 13 (61.9%) being remained for the required period and 8 (38.1%) being removed due to death, intractable blood or tunnel infections, catheter thrombosis or malposition. The overall rate of catheter-related infections, thrombosis and malposition was 7.3, 23.4 and 3.4 episodes/1000 catheter days, respectively. Cuffed-tunneled hemodialysis catheters could be effectively used for maintenance of hemodialysis vascular access for pediatric patients with ESRD. Various surveillance measures should be taken to ensure cuffed-tunneled catheters' long-term patency.

Effect of peritoneal dialysis on expression of vascular endothelial growth factor, basic fibroblast growth factor and endostatin of the peritoneum in peritoneal dialysis patients.

AIM: The aim of this study is to investigate the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin (ES) in human peritoneum and investigate the relationship between them and peritoneum neoangiogensis in the patients with uraemia and peritoneal dialysis (PD). METHODS: Peritoneal biopsies were obtained from normal subjects (n = 8), uraemic predialysis patients (n = 12) and PD patients (n = 10). The mRNA expression of VEGF, bFGF and ES in peritoneal tissues were measured through real-time polymerase chain reaction. The protein expression of VEGF, bFGF and ES in peritoneal tissues were determined through western blot. Microvessel density (MVD) of peritoneal tissue was assessed using immunohistochemistry with CD34 monoclonal antibody. RESULTS: The mRNA and protein of VEGF, bFGF and ES were expressed in all peritoneal samples. Compared with the normal control group, the mRNA and protein expression of VEGF and bFGF in peritoneal tissues were all significantly upregulated in the uraemic predialysis and PD group (all P < 0.05). Compared with the normal control group, the protein expression of ES were significantly upregulated in the uraemic predialysis and PD group (all (P < 0.05), but the mRNA expression of ES did not have obvious differences in the uraemic predialysis and PD group as compared to the normal control group (P > 0.05). MVD of peritoneal tissue were increased in the uraemic predialysis and PD group compared with the normal group (all P < 0.05). A significant positive correlation was found between VEGF mRNA expression and MVD, bFGF mRNA expression and MVD. CONCLUSION: The mRNA expression of VEGF and bFGF, the protein expression of VEGF, bFGF, and ES and microvessel density (MVD) are increased both in the uraemic predialysis and PD patients. These results show that uraemia circumstances and non-physiological compatibility of peritoneal dialysis solution might increase VEGF, bFGF and ES expression and MVD, which might participate in the increment of the peritoneum neoangiogensis and ultrafiltration failure in PD patients.

Effects of recombinant human endostatin on peritoneal angiogenesis in peritoneal dialysis rats.

AIM: To investigate the effects of recombinant human endostatin (Endostar) on peritoneum angiogenesis in a model of dialysate exposure in rats. METHODS: Forty male Sprague-Dawley rats were randomized to five groups: normal (group 1); uraemia (group 2); 4.25% peritoneal dialysate (PD) uraemic (group 3); uraemia + PD + recombinant human endostatin 10 mg/kg PD (group 4); and uraemia + PD + recombinant human endostatin 40 mg/kg PD (group 5). The uraemic rats model was established by 5/6 nephrectomy. Endostatin was administrated by s.c. injection every other day, over 28 days. After 28 days of PD fluid exposure, immunohistochemistry and reverse transcript polymerase chain reaction were used to detect protein and mRNA expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in each group. Microvessel density (MVD) was measured by immunohistochemistry. RESULTS: Compared with group 1, the mRNA and protein expressions of VEGF and bFGF were significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in groups 4 and 5 (P < 0.05). Compared with group 4, the mRNA and protein expressions of VEGF and bFGF were significantly downregulated in group 5 (P < 0.05). Compared with group 1, MVD was significantly upregulated in groups 2 and 3 (P < 0.05). Compared with group 3, MVD was significantly downregulated in groups 4 and 5 (P < 0.05). CONCLUSION: Endostar can effectively inhibit rat peritoneum neoangiogenesis and the effect was dose-dependent.