Wang's Forceps-Assisted Percutaneous Insertion and Fixation of Peritoneal Dialysis Catheter.

Percutaneous insertion of peritoneal dialysis catheters is theoretically most preferred by nephrologists because of the advantages of bedside performing, surgery independence, and minimal injury over other procedures of catheter placement such as open surgical dissection or laparoscopic operation. However, blindly placing catheters in the percutaneous procedure brings the risk of catheter malposition or bowel perforation; this largely retarded it's implementation. We had previously developed a novel technique termed "Wang's forceps-assisted catheter insertion and fixation," which had been successfully applied in the open surgical catheter insertion and displaced catheter reposition in our center. In this study, we further explored the possibility of applying the Wang's forceps in the procedure of percutaneous catheter insertion both in porcine model and patients with end stage renal disease (ESRD). A total of three miniature pigs successfully received percutaneous catheter insertion using Seldinger's technique with Wang's forceps assistance. The catheters were all placed in the right position and functioning well in dialysate drainage. This novel method of percutaneous catheter insertion was then performed on 20 ESRD patients. The procedure showed effective time-saving with the average operating time of 29.2 ± 3.53 min and was well tolerated by patients with minimal pain and injury. During a follow-up time of 6 months, no complications of catheter displacement, leakage, or blockade occurred. Our preliminary observation demonstrates that utilization of Wang's forceps in a percutaneous procedure conferred benefits of accurately placing and fixing catheters while preserving the merits of minimal invasion and simple performance.

Collagen type III glomerulopathy: case report and review of the literature
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To summarize the clinical and pathological features of collagen type III glomerulopathy, the present report describes a case of collagen type III glomerulopathy and reviewed more than 60 cases recorded by other groups in English literature over the last few years. A 24-year-old female patient was admitted because of lower limbs edema, without any other discomforts. The lab examination of the patient reported proteinuria (2.42 g/24 h urine), microscopic hematuria, and the serum creatinine was 71 µmol/L. She received renal biopsy. The immunofluorescence staining results showed that collagen type III expression was positive. The electron microscopy examination showed that the mesangial regions were widened, with visible fine fibers in it. The periodic stripes of collagen fibers could be seen on some fine fiber-like substance under a high-magnification microscope, the diameters of the fiber-like substances were 40 - 70 nm. Serum collagen type III N-peptide (PIIIP N-P) was 97.94 ng/mL. After the patient received benazepril 10 mg per day and symptomatic treatments (Chinese drug, Cordyceps Capsules 0.5 g per day), her proteinuria resolved (~ 0.5 g/24 hour urine).

Wang's Forceps-Assisted Catheter Reposition and Fixation: An Easy and Reliable Rescue Method.

Catheter migration and omental wrap are the most common causes of catheter malfunction, which usually result in catheter removal or replacement. The conventional open surgery for catheter reposition has many disadvantages. A new tunnel is needed throughout the procedure of catheter replacement causing more pain and frustration to the patients. Another drawback is that the incidence of catheter migration after conventional catheter reposition surgery is still as high as it was before the procedure. Wang's forceps, an instrument commonly used in our peritoneal dialysis center, is easy and effective in catheter insertion and fixation. Recently, we have successfully used the Wang's forceps to resolve the catheter displacement for 10 patients, including 1 patient who suffered from catheter tip migration 3 times and had undergone conventional catheter rescue by both open surgery and laparoscopy. This new technique was easy and reliable, and the original tunnel was maintained, which reduced pain and risk of infection in the patients. These advantages may grant the Wang's forceps technique favorable over the conventional surgical approach.

Identification of the appropriate fixation site to avoid peritoneal catheter migration based on a mechanical analysis.

AIM: To conduct mechanical analysis on the relationship between abdominal wall fixation point and the displacement of catheter top, and establish the finite element model for the complex forces and conditions that the catheter wears in human abdominal cavity, in order to provide the scientific basis for optimizing the catheter position in abdominal wall fixation method. METHODS: Using the PIPE59 finite elements to divide units, and taking the lower part of catheter, that is, below interior polyester cuff to simulate and compute the displacement formula. RESULTS: The whole model includes a total of 1701 units. Periodic load was used to simulate the dynamic pressure that peritoneal dialysis catheter gets in abdominal cavity. The load direction was perpendicular to the catheter axis. We used pressure amplitude, duration and frequency as the boundary conditions, and adjusted the fixation point of the catheter lower part at the same time, thus calculating the extreme displacement value of the catheter top end with changing parameter conditions. We also did fitted regression on the results and obtained the displacement formula: y = 0.2 × 0.87x (y: the end displacement of peritoneal dialysis catheter, x: the distance between fixation point and the interior polyester cuff), R2: .982. Simulation the catheter maximal displacement on flat surface demonstrated that additional catheter fixation at the site of 9 cm or more below the internal cuff significantly restricted the catheter migration. CONCLUSIONS: The optimal position of fixation point in peritoneal dialysis is about 9 cm away from the interior polyester cuff.

Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production.

Thrombotic microangiopathy (TMA) is a disorder characterized by microvascular occlusion that can lead to thrombocytopenia, hemolytic anemia, and glomerular damage. Complement activation is the central event in most cases of TMA. Primary forms of TMA are caused by mutations in genes encoding components of the complement or regulators of the complement cascade. Recently, we and others have described a genetic form of TMA caused by mutations in the gene diacylglycerol kinase-ε (DGKE) that encodes the lipid kinase DGKε (Lemaire M, Fremeaux-Bacchi V, Schaefer F, Choi MR, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji WZ, Overton JD, Mane SM, Nurnberg G, Altmuller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nurnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Nat Genet 45: 531-536, 2013; Ozaltin F, Li BH, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang CY, Chen P, Lu DM, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. J Am Soc Nephrol 24: 377-384, 2013). DGKε is unrelated to the complement pathway, which suggests that unidentified pathogenic mechanisms independent of complement dysregulation may result in TMA. Studying Dgke knockout mice may help to understand the pathogenesis of this disease, but no glomerular phenotype has been described in these animals so far. Here we report that Dgke null mice present subclinical microscopic anomalies of the glomerular endothelium and basal membrane that worsen with age and develop glomerular capillary occlusion when exposed to nephrotoxic serum. We found that induction of cyclooxygenase-2 and of the proangiogenic prostaglandin E2 are impaired in Dgke null kidneys and are associated with reduced expression of the antithrombotic cell adhesion molecule platelet endothelial cell adhesion molecule-1/CD31 in the glomerular endothelium. Notably, prostaglandin E2 supplementation was able to rescue motility defects of Dgke knockdown cells in vitro and to restore angiogenesis in a test in vivo. Our results unveil an unexpected role of Dgke in the induction of cyclooxygenase-2 and in the regulation of glomerular prostanoids synthesis under stress.

Loss of Glis2/NPHP7 causes kidney epithelial cell senescence and suppresses cyst growth in the Kif3a mouse model of cystic kidney disease.

Enlargement of kidney tubules is a common feature of multiple cystic kidney diseases in humans and mice. However, while some of these pathologies are characterized by cyst expansion and organ enlargement, in others, progressive interstitial fibrosis and kidney atrophy prevail. The Kif3a knockout mouse is an established non-orthologous mouse model of cystic kidney disease. Conditional inactivation of Kif3a in kidney tubular cells results in loss of primary cilia and rapid cyst growth. Conversely, loss of function of the gene GLIS2/NPHP7 causes progressive kidney atrophy, interstitial inflammatory infiltration, and fibrosis. Kif3a null tubular cells have unrestrained proliferation and reduced stabilization of p53 resulting in a loss of cell cycle arrest in the presence of DNA damage. In contrast, loss of Glis2 is associated with activation of checkpoint kinase 1, stabilization of p53, and induction of cell senescence. Interestingly, the cystic phenotype of Kif3a knockout mice is partially rescued by genetic ablation of Glis2 and pharmacological stabilization of p53. Thus, Kif3a is required for cell cycle regulation and the DNA damage response, whereas cell senescence is significantly enhanced in Glis2 null cells. Hence, cell senescence is a central feature in nephronophthisis type 7 and Kif3a is unexpectedly required for efficient DNA damage response and cell cycle arrest.

Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury.

Hedgehog (Hh) is an evolutionary conserved signaling pathway that has important functions in kidney morphogenesis and adult organ maintenance. Recent work has shown that Hh signaling is reactivated in the kidney after injury and is an important mediator of progressive fibrosis. Pericytes and fibroblasts have been proposed to be the principal cells that respond to Hh ligands, and pharmacological attenuation of Hh signaling has been considered as a possible treatment for fibrosis, but the effect of Hh inhibition on tubular epithelial cells after kidney injury has not been reported. Using genetically modified mice in which tubule-derived hedgehog signaling is increased and mice in which this pathway is conditionally suppressed in pericytes that express the proteoglycan neuron glial protein 2 (NG2), we found that suppression of Hh signaling is associated with decreased macrophage infiltration and tubular proliferation but also increased tubular apoptosis, an effect that correlated with the reduction of tubular ß-catenin activity. Collectively, our data suggest a complex function of hedgehog signaling after kidney injury in initiating both reparative and proproliferative, prosurvival processes.

High glucose induces autophagy in podocytes.

Autophagy is a cellular pathway involved in protein and organelle degradation. It is relevant to many types of cellular homeostasis and human diseases. High level of glucose is known to inflict podocyte injury, but little is reported about the relationship between high concentrations of glucose and autophagy in these cells. The present study demonstrates that high glucose promotes autophagy in podocytes. Rapamycin further enhances this effect, but 3-methyadenine inhibits it. The proautophagic effect of high glucose manifested in the form of enhanced podocyte expression of LC3-2 and beclin-1; interestingly, antioxidants such as NAC were found to inhibit high glucose-induced autophagy. High glucose induced the generation of ROS by podocytes in a time-dependent manner. High glucose also enhanced podocyte expression of MnSOD and catalase. These findings indicate that high glucose-induced autophagy is mediated through podocyte ROS generation.

Mild proteinuria in a patient with glomerularlimited intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of non- Hodgkin lymphoma characterized by a disseminated intravascular proliferation of tumor cells in the lumina of small vessels. Although the kidney is one of the target organs of IVLBCL, lymphoma cells that localize only in glomeruli are extremely rare. We report a 55-year-old Chinese patient diagnosed as glomerular-limited IVLBCL by percutaneous renal biopsy. The patient was referred to our institution for further examination of mild proteinuria and anemia without lymphoma symptoms. He had daily urinary excretion of 0.65 g proteins with normal renal function. Percutaneous renal biopsy showed that lymphoid cell accumulation was encircled within the glomerular capillary lumina only in certain glomeruli, resulting in marked obstruction of capillary structure. However, almost all of the peritubular capillary and tubulointerstitium were intact. Immunohistochemical analysis confirmed the diagnosis of intravascular large B-cell lymphoma. Extensive systemic examinations showed no other organ involvement. With these characteristic changes, glomerularlimited IVLBCL were considered as an exceptional renal manifestation of intravascular lymphoma diagnosised by percutaneous renal biopsy.

PFKP Activation Ameliorates Foot Process Fusion in Podocytes in Diabetic Kidney Disease.

Background: Glycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified. Methods: mRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using Pfkp siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed in vitro. The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b (Aldob) siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney. Results: mRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes (Hk1, and Pfkp) and down-regulation of downstream genes of glycolysis (Pkm, and Ldha). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. In vitro, the Pfkp siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB in vitro rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice. Conclusions: These findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.

Epidemiological, Clinical, and Immunological Features of a Cluster of COVID-19-Contracted Hemodialysis Patients.

BACKGROUND: The outbreak of highly contagious coronavirus disease 2019 (COVID-19) has posed a serious threat to human life and health, especially for those with underlying diseases. However, the impact of COVID-19 epidemic on hemodialysis (HD) centers and HD patients has not been reported. METHODS: We reviewed the whole course of the COVID-19 in the HD center of Renmin Hospital, Wuhan University (from January 14, 2020, to March 12, 2020). We compared the clinical manifestation and immune profiles among different patient groups with healthy individuals. RESULTS: Forty-two of 230 HD patients (18.26%) and 4 of 33 medical staff (12.12%) were diagnosed with COVID-19 during the study period. Fifteen HD patients (6.52%), including 10 COVID-19 diagnosed, died. Only 2 deaths of the COVID-19 HD patients were associated with pneumonia/lung failure, others were ascribed to cardiovascular/cerebrovascular diseases or hyperkalemia. Except for 3 patients who were admitted to the intensive care unit for a severe condition (8.11%), including 2 who died, most COVID-19 diagnosed patients presented mild or nonrespiratory symptoms. The flow cytometric analysis of peripheral blood showed that multiple lymphocyte populations in HD patients were significantly decreased. HD patients with COVID-19 even displayed more remarkable reduction of serum inflammatory cytokines than other patients with COVID-19. CONCLUSIONS: Compared with the general population, HD patients and health care professionals are the highly susceptible population and HD centers are high-risk areas during the outbreak. Most HD patients with COVID-19 exhibited mild clinical symptoms and did not progress to severe pneumonia, likely due to the impaired cellular immune function and incapability of mounting cytokine storm. More attention should be paid to prevent cardiovascular events, which may be the collateral impacts of the COVID-19 epidemic on HD patients.

Candesartan attenuates Angiotensin II-induced mesangial cell apoptosis via TLR4/MyD88 pathway.

Angiotensin II (Ang II) can stimulate Toll-like receptor 4 (TLR4) expression in mesangial cells (MCs), but the role of TLR4 in the Ang II-induced apoptosis and the effect of candesartan on TLR4 expression remain unclear. Here, we report that Ang II-induced MC apoptosis in a time-dependent manner and up-regulated TLR4/MyD88 expression, and that the intracellular ROS was subsequently increased. We also show that candesartan attenuated the Ang II-induced MC apoptosis, and that this protective effect was dependent on decreased TLR4/MyD88 expression as well as reduced intracellular ROS formation. Furthermore, Ang II increased the apoptosis inducing factor protein level, while candesartan markedly reduced this increase. These results demonstrate that TLR4/MyD88 pathway was involved in the Ang II promoted MC apoptosis, which was related to TLR4/MyD88 mediated oxidative stress. These data also suggest that candesartan exerted anti-apoptotic effect as an antioxidant by modulating this pathway.

Increased mitochondrial fission of glomerular podocytes in diabetic nephropathy.

AIMS: Previous studies showed that abnormal mitochondrial structure and function were involved in the pathological process of diabetic nephropathy (DN). The dynamic mitochondrial processes, including fusion and fission, maintain the mass and quantity of mitochondria. Podocyte injury is a critical factor in the development and progression of DN. The present study evaluated the mitochondrial fission of podocytes in patients with DN. METHODS: We recruited 31 patients with biopsy-confirmed DN. A quantitative analysis of the mitochondrial morphology was conducted with electron microscopy using a computer-assisted morphometric analysis application to calculate the aspect ratio values. Immunofluorescence assays were used to evaluate protein colocalization in the glomeruli of patients. RESULTS: The urine protein level was significantly increased in DN patients compared to non-DN patients (P < 0.001), and the mitochondria in the podocytes from DN patients were more fragmentated than those from patients without DN. The mitochondrial aspect ratio values were negatively correlated with the proteinuria levels (r = -0.574, P = 0.01), and multiple regression analysis verified that the mitochondrial aspect ratio was significantly and independently associated with the urine protein level (ß = -0.519, P = 0.007). In addition, Drp1, a mitochondrial fission factor, preferentially combines with AKAP1, which is located in the mitochondrial membrane. CONCLUSIONS: In the podocytes of DN patients, mitochondrial fragmentation was increased, and mitochondrial aspect ratio values were correlated with the proteinuria levels. The AKAP1-Drp1 pathway may contribute to mitochondrial fission in the pathogenesis of DN.

Angiotensin II infusion induces nephrin expression changes and podocyte apoptosis.

BACKGROUND/AIM: In in vitro studies, angiotensin (Ang) II has been demonstrated to promote podocyte apoptosis. The present study evaluates the effects of Ang II infusion in rats on podocyte nephrin expression and apoptosis and the molecular mechanisms involved in Ang II-induced proteinuria and mesangial expansion. METHODS: Sprague-Dawley rats were randomly assigned to receive either normal saline or Ang II (400 ng x kg(-1) x min(-1)) by means of a mini-osmotic pump for variable time periods. Systolic blood pressure and urinary protein and albumin excretion rate measurements were carried out on days 7, 14, 21, and 28. The animals were sacrificed on days 14 and 28 and evaluated for serum creatinine, renal pathological changes, podocyte apoptosis, renal nephrin mRNA, and protein expression. RESULTS: The Ang II-infused rats developed hypertension and proteinuria. On day 14, the Ang II-infused rats showed narrowing of the slit diaphragm, an increase in podocyte nephrin mRNA and protein expression, and alterations in its distribution along the foot processes. On day 28, the Ang II-infused rats demonstrated the presence of apoptotic podocytes and decreased nephrin mRNA and protein expression. There was a negative correlation between nephrin expression and the numbers of apoptotic podocytes (r = -0.63, p < 0.05). CONCLUSION: These results suggest that changes in nephrin expression may play a role in the pathogenesis of Ang II-induced podocyte apoptosis.

Catalpol protects mice against renal ischemia/reperfusion injury via suppressing PI3K/Akt-eNOS signaling and inflammation.

Renal ischemia/reperfusion-injury (IRI) is a common disease in clinic, which is also the most common cause of acute kidney failure. Previous investigations has illustrated that catalpol has neuroprotective, anti-inflammatory, and anti-hepatitis virus effects. This study was designed to investigate the protective effect of catalpol on renal IRI mice through suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)-endothelial nitric oxide synthase (eNOS) and against inflammation, and the possible underlying mechanism. Firstly, we used renal IRI model to analyze blood urea nitrogen and serum creatinine levels in renal IRI mice. Next, real-time PCR and western blotting were used to detect the expression of KIM-1 and the expression of PI3K, Akt and eNOS levels in renal IRI, respectively. In addition, activities of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and interleukin-10 (IL-10) in renal IRI mice were measured with respective TNF-α, IL-1ß, IL-6 and IL-10 ELISA kits. Our results showed that catalpol clearly reduced blood urea nitrogen, serum creatinine levels and the expression of KIM-1 in renal IRI mice. Meanwhile, we found that catalpol markedly reduced the expression of PI3K, Akt and eNOS levels in renal IRI group. Suppressing of the PI3K/Akt-eNOS and the TNF-α, IL-1ß, IL-6 and IL-10 activities was involved in the protective effect of catalpol on renal IRI. Collectively, catalpol protected renal IRI via inhibiting PI3K/Akt-eNOS signaling and inflammatory responses.

IgA Nephropathy with Pathologic Features of Membranoproliferative Glomerulonephritis following Burn Injury.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, accounting for approximately 30-40% of patients undergoing renal biopsy in Asia. The characteristic and diagnostic lesion of IgAN is the deposition of glomerular IgA. The morphological lesions observed by light microscopy are extremely variable. A causal relationship between IgAN and burn injury has not been established, and the correlation between them is not clear if they appear at the same time. We have explored the cause of severe proteinuria of a Chinese patient with burns of 2nd or 3rd degree after a gas leakage accident 2 weeks ago. The diffuse proliferative glomerulonephritis of this patient revealed type I membranoproliferative glomerulonephritis-like symptoms. Moreover, this patient showed a sensitive response to prednisone. This case report demonstrates the intrinsic relationship between kidney disease and burn injury, which will facilitate a feasible treatment strategy for proteinuria after burn injury.