Analytical Solutions of a Two-Compartment Model Based on the Volume-Average Theory for Blood Toxin Concentration during and after Dialysis.

Accurate prediction of blood toxin concentration during and after dialysis will greatly contribute to the determination of dialysis treatment conditions. Conventional models, namely single-compartment model and two-compartment model, have advantages and disadvantages in terms of accuracy and practical application. In this study, we attempted to derive the mathematical model that predicts blood toxin concentrations during and after dialysis, which has both accuracy and practicality. To propose the accurate model, a new two-compartment model was mathematically derived by adapting volume-averaging theory to the mass transfer around peripheral tissues. Subsequently, to propose a practical model for predicting the blood toxin concentration during dialysis, an analytical solution expressed as algebraic expression was derived by adopting variable transformation. Furthermore, the other analytical solution that predicts rebound phenomena after dialysis was also derived through similar steps. The comparisons with the clinical data revealed that the proposed analytical solutions can reproduce the behavior of the measured blood urea concentration during and after dialysis. The analytical solutions proposed as algebraic expressions will allow a doctor to estimate the blood toxin concentration of a patient during and after dialysis. The proposed analytical solutions may be useful to consider the treatment conditions for dialysis, including the rebound phenomenon.

Evaluating the need for and effect of percutaneous transluminal angioplasty on arteriovenous fistulas by using total recirculation rate per dialysis session ("clearance gap").

The functioning of an arteriovenous fistula (AVF) used for vascular access during hemodialysis has been assessed mainly by dilution methods. Although these techniques indicate the immediate recirculation rate, the results obtained may not correlate with Kt/V. In contrast, the clearance gap (CL-Gap) method provides the total recirculation rate per dialysis session and correlates well with Kt/V. We assessed the correlation between Kt/V and CL-Gap as well as the change in radial artery (RA) blood flow speed in the fistula before percutaneous transluminal angioplasty (PTA) in 45 patients undergoing continuous hemodialysis. The dialysis dose during the determination of CL-Gap was 1.2 to 1.4 Kt/V. Patients with a 10% elevation or more than a 10% relative increase in CL-Gap underwent PTA (n = 45), and the values obtained for Kt/V and CL-Gap before PTA were compared with those obtained immediately afterward. The mean RA blood flow speed improved significantly (from 52.9 to 97.5cm/sec) after PTA, as did Kt/V (1.07 to 1.30) and CL-Gap (14.1% to -0.2%). A significant correlation between these differences was apparent (r = -0.436 and p = 0.003). These findings suggest that calculating CL-Gap may be useful for determining when PTA is required and for assessing the effectiveness of PTA, toward obtaining better dialysis.

Impacts of icodextrin on integrin-mediated wound healing of peritoneal mesothelial cells.

AIMS: Exposure to glucose and its metabolites in peritoneal dialysis fluid (PDF) results in structural alterations of the peritoneal membrane. Icodextrin-containing PDF eliminates glucose and reduces deterioration of peritoneal membrane function, but direct effects of icodextrin molecules on peritoneal mesothelial cells have yet to be elucidated. We compared the impacts of icodextrin itself with those of glucose under PDF-free conditions on wound healing processes of injured mesothelial cell monolayers, focusing on integrin-mediated cell adhesion mechanisms. MAIN METHODS: Regeneration processes of the peritoneal mesothelial cell monolayer were investigated employing an in vitro wound healing assay of cultured rat peritoneal mesothelial cells treated with icodextrin powder- or glucose-dissolved culture medium without PDF, as well as icodextrin- or glucose-containing PDF. The effects of icodextrin on integrin-mediated cell adhesions were examined by immunocytochemistry and Western blotting against focal adhesion kinase (FAK). KEY FINDINGS: Cell migration over fibronectin was inhibited in conventional glucose-containing PDF, while icodextrin-containing PDF exerted no significant inhibitory effects. Culture medium containing 1.5% glucose without PDF also inhibited wound healing of mesothelial cells, while 7.5% icodextrin-dissolved culture medium without PDF had no inhibitory effects. Glucose suppressed cell motility by inhibiting tyrosine phosphorylation of FAK, formation of focal adhesions, and cell spreading, while icodextrin had no effects on any of these mesothelial cell functions. SIGNIFICANCE: Our results demonstrate icodextrin to have no adverse effects on wound healing processes of peritoneal mesothelial cells. Preservation of integrin-mediated cell adhesion might be one of the molecular mechanisms accounting for the superior biocompatibility of icodextrin-containing PDF.

Minimal change nephrotic syndrome in a patient with strongyloidiasis.

Strongyloidiasis, a chronic infection caused by the intestinal parasite Strongyloides stercoralis, is prevalent in the Nansei Islands of Japan. Here, we report our findings on a case of strongyloidiasis complicated with steroid-resistant minimal change nephrotic syndrome in a 69-year-old male resident of Fukuoka Prefecture who had lived in Yakushima, one of the Nansei Islands, until age 15. In October 2006, he developed proteinuria and edema, and was diagnosed with minimal change nephrotic syndrome on the basis of the renal biopsy findings. Following treatment with prednisolone, the level of proteinuria decreased to 0.29 g/day by day 35. However, 5 days later (day 40), the patient developed persistent watery diarrhea and vomiting, leading to dehydration and malnutrition. Pneumonia and bacterial meningitis subsequently developed (day 146); filarial (infectious-type) and rhabditiform (noninfectious-type) S. stercoralis larvae were detected for the first time in the patient's sputum, gastric juice, feces, and urine. Although treatment with ivermectin was started immediately and the parasitosis responded to the treatment, the patient died of sepsis. Consequently, although strongyloidiasis is a rare infection except in endemic regions, it is essential to consider the possibility of this disease and begin treatment early for patients who have lived in endemic areas and who complain of unexplained diarrhea during steroid-induced or other immunosuppression.

An integrin-activating peptide, PHSRN, ameliorates inhibitory effects of conventional peritoneal dialysis fluids on peritoneal wound healing.

BACKGROUND: Bioincompatible peritoneal dialysis fluids (PDFs) cause pathological changes in the peritoneal membrane, related to membrane dysfunction and progressive peritoneal fibrosis. We investigated the effects of Pro-His-Ser-Arg-Asn (PHSRN) peptide, one of the fibronectin cell-binding domains that activates integrins and reinforces wound healing, on peritoneal remodelling in a rat peritoneal injury model undergoing peritoneal dialysis. METHODS: The peritoneal mesothelial monolayer was removed by a stripping procedure in rats receiving conventional high glucose-containing PDF supplemented with or without PHSRN or control His-Ser-Pro-Asn-Hrg (HSPNR) peptides. Effects of PHSRN on cell motility and signalling molecules were examined in cultured rat peritoneal mesothelial cells (RPMCs) and normal rat kidney fibroblasts (NRKs). RESULTS: The cytokeratin- and HBME-1-positive mesothelial cell monolayer was selectively removed by the procedure. By day 6, HBME-1-positive cells had regenerated to 53.3 +/- 6.5% of the peritoneal surface in the control group. Regeneration of the mesothelial layer was delayed in the PDF group (35.2 +/- 10.2%, P < 0.05), but PHSRN reversed the effects of PDF (51.7 +/- 9.6%, P < 0.05). PDF treatment increased thickening of granulomatous submesothelial tissue and numbers of ED1-, CD31- and alpha-smooth muscle actin-positive cells, but PHSRN ameliorated these effects. HSPNR had no effects on mesothelial regeneration or peritoneal wound healing. PHSRN, but not HSPNR, recovered glucose-induced inhibition of cell motility and phosphorylation of focal adhesion kinase and its downstream p130(Cas) in RPMCs and NRKs. CONCLUSIONS: These results suggest that PHSRN has beneficial effects on peritoneal regeneration by reducing the inhibitory effects of conventional PDF on integrin-mediated wound healing.

A case report of steroid-resistant antineutrophil cytoplasmic antibody-related vasculitis successfully treated by mizoribine in a hemodialysis patient.

Mizoribine (MZR) has shown to be effective against antineutrophil cytoplasmic antibody (ANCA)-related vasculitis; however, no reports have described the successful treatment of steroid-resistant ANCA-related vasculitis with MZR in patients with renal insufficiency requiring hemodialysis. We herein report the case of a 39-year-old man undergoing hemodialysis in whom MZR successfully lowered the myeloperoxidase (MPO)-ANCA titer accompanied by remission of interstitial pneumonia, together with the pharmacokinetics of MZR. The patient developed severe renal insufficiency and interstitial pneumonia, and was started on hemodialysis. Although prednisolone was administered followed by azathioprine, the MPO-ANCA level and interstitial pneumonia showed insufficient improvement. Azathioprine was replaced by MZR and the administered dose of MZR was determined by measuring serum concentrations of MZR at the start of the dialysis session; this was because we confirmed that MZR could only be removed via dialysis, and that the serum concentration of MZR was maintained until the next dialysis session. The maintenance dose was finally set at MZR 75 mg after each dialysis. Subsequently, the ANCA titer decreased and interstitial pneumonia resolved without any MZR-related side effects. This case demonstrates that MZR is safe and effective, even in patients with steroid-resistant ANCA-related vasculitis undergoing hemodialysis, and can be monitored by measuring serum concentrations of MZR.

Fluvastatin attenuates IGF-1-induced ERK1/2 activation and cell proliferation by mevalonic acid depletion in human mesangial cells.

AIMS: Insulin-like growth factor (IGF)-1 is a major mitogenic growth factor for mesangial cells (MCs). Statins slow the progression of chronic kidney disease by affecting inflammatory cell signaling pathways, in addition to improving lipid profile, however, no studies have investigated the effects of fluvastatin on mitogen-activated protein (MAP) kinase activity or MC proliferation in kidney cells. We investigated the effects of fluvastatin on IGF-1-induced activation of intracellular signal pathways and MC proliferation, and examined the inhibitory mechanisms of fluvastatin. MAIN METHODS: Western blotting and cell proliferation assay were used. KEY FINDINGS: IGF-1 induced phosphorylation of extracellular-related kinase (ERK)1/2, MAP or ERK kinase (MEK)1/2, and Akt, expression of cyclin D1, and MC proliferation in cultured human MCs. Fluvastatin or PD98059, an MEK1 inhibitor, completely abolished IGF-1-induced MEK1/2 and ERK1/2 phosphorylation and MC proliferation, whereas inhibition of Akt had no effect on MC proliferation. Mevalonic acid prevented fluvastatin inhibition of IGF-1-induced MEK1/2 and ERK1/2 phosphorylation, cyclin D1 expression, and MC proliferation. SIGNIFICANCE: Fluvastatin inhibits IGF-1-induced activation of the MAP kinase pathway and MC proliferation by mevalonic acid depletion, and might have renoprotective effects by inhibiting IGF-1-mediated MC proliferation.

Electromagnetic interference with a bipolar pacemaker by an induction heating (IH) rice cooker.

Electromagnetic fields may interfere with normal pacemaker function. Despite new device designs and bipolar leads, electromagnetic interference (EMI) remains a concern when pacemaker recipients are exposed to various household appliances. We report the observation of EMI by an induction heating (IH) rice cooker in a patient with sick sinus syndrome who was the recipient of a bipolar dual chamber-pacing system. Stored electrograms revealed episodes of inappropriate ventricular pacing, all coinciding with the opening of an IH rice cooker. Recipients of implantable medical devices must be warned to handle IH rice cookers with caution.

Synergistic induction of monocyte chemoattractant protein-1 by integrins and platelet-derived growth factor via focal adhesion kinase in mesangial cells.

BACKGROUND: Growth factors, extracellular matrix and its receptor integrins are upregulated in various glomerular diseases. We investigated the mechanism of collaboration between integrins and platelet-derived growth factor (PDGF) in focal adhesion kinase (FAK)- and extracellular signal-related kinase (ERK)1/2-mediated signal pathways that lead to monocyte chemoattractant protein (MCP)-1 expression in cultured rat mesangial cells (MCs). METHODS: Serum-starved MCs were plated on fibronectin- or polylysine-coated plates with or without PDGF, and examined for phosphorylation of ERK1/2, mitogen-activated protein or ERK kinase (MEK)1/2 and FAK by western blotting, and for expression of MCP-1 mRNA and protein by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The effects of dominant-negative FAK on MCP-1 expression were examined. RESULTS: Cell adhesion to fibronectin increased phosphorylation of FAK, MEK1/2 and ERK1/2, and induced MCP-1 mRNA and protein expression. PDGF increased phosphorylation of FAK, MEK1/2 and ERK1/2 even without cell adhesion to fibronectin, and induced MCP-1 mRNA and protein expression. PDGF with integrin activation by fibronectin synergistically increased phosphorylation of FAK, MEK1/2 and ERK1/2, and expression of MCP-1 mRNA and protein. Dominant-negative FAK attenuated fibronectin enhancement of PDGF-induced ERK1/2 phosphorylation and MCP-1 expression, indicating involvement of FAK in this signalling. CONCLUSIONS: Our results suggest the cooperative role of integrin and PDGF receptor in activation of the ERK pathway possibly via FAK in MCs. The synergistic activation of integrin and PDGF signalling may play an important role in the progression of glomerular diseases through the induction of MCP-1.

Infective tricuspid valve endocarditis due to abscess of an endogenous arteriovenous fistula in a chronic hemodialysis patient.

Patients on chronic hemodialysis are at high risk for endocarditis due to prosthetic access devices. Right-sided endocarditis without any predisposing factors is rare in dialysis patients. A 76-year-old female, who had chronic renal failure had been treated by hemodialysis and had a permanent pacemaker implanted, was admitted to our hospital with a high fever and lumbago after abscess formation at an autogenous arteriovenous fistula for hemodialysis. Methicillin Resistant Staphylococcus Aureus was identified by blood culture examination. Echocardiography revealed vegetation attached to the tricuspid valve. Chest X-ray and perfusion lung scintigraphy showed pulmonary infarction, perhaps due to vegetation-derived emboli. Computed tomography also showed pyogenic spondylitis in L4 and L5. Repeated vascular punctures even of autogenous grafts expose dialysis patients to bacteremia and imply a higher risk of infectious endocarditis.

Development of proximal calciphylaxis with penile involvement after parathyroidectomy in a patient on hemodialysis.

Elevated parathyroid hormone (PTH) levels and hyperphosphatemia are thought to be associated with the development of calciphylaxis. We report a patient on hemodialysis who developed proximal calciphylaxis with consistently low PTH levels after parathyroidectomy. A 31-year-old man was admitted to our hospital because of abdominal skin ulcerations. Calciphylaxis spread to the penis, and simultaneous progressive lung calcification was evident on chest X-ray, suggestive of pulmonary calciphylaxis on 99mTc-methylene disphosphonate scintigraphy. The patient died of respiratory failure despite intensive treatment including hyperbaric oxygen therapy. This is the first report of a patient on hemodialysis who developed calciphylaxis involving the penis after parathyroidectomy.

Integrins induce expression of monocyte chemoattractant protein-1 via focal adhesion kinase in mesangial cells.

BACKGROUND: Integrins are major adhesion receptors that not only regulate cytoskeletal organization, but also trigger a variety of intracellular signal transduction pathways. We examined the effects of increased extracellular matrix (ECM) accumulation on monocyte chemoattractant protein-1 (MCP-1) expression, which is known to play an important role in the progression of various glomerular diseases. METHODS: MCP-1 mRNA and protein expression in cultured rat mesangial cells (MC) attached to ECM proteins were examined by reverse transcription (RT)-polymerase chain reaction (PCR) and Western blotting, respectively. Phosphorylation of focal adhesion kinase (FAK) was measured by Western blotting. Effects of wild-type and dominant-negative FAK on MCP-1 expression were examined by a transient transfection assay. RESULTS: Cell adhesion to fibronectin-induced phosphorylation of FAK and MCP-1 mRNA expression in time- and dose-dependent manners followed by increased MCP-1 protein expression. All integrin-interacting substrates (laminin and types I, III, and IV collagens) also increased levels of FAK phosphorylation and MCP-1 expression, whereas nonspecific adhesive substrates (polylysine and concanavalin A) had no significant effects. Overexpression of wild-type FAK increased phosphorylation of FAK and expression of MCP-1 mRNA and protein, whereas transfection of dominant-negative FAK abolished adhesion-induced MCP-1 expression. Adhesion-induced expression of MCP-1 mRNA was inhibited by genistein and tosyl phenylalanyl chloromethylketone (TPCK), suggesting that tyrosine kinases [e.g., FAK, and nuclear factor kappa B (NF-kappa B)] are necessary in this signaling. CONCLUSION: Our results indicate that integrin-mediated cell adhesion to the ECM can induce MCP-1 expression through activation of FAK, and suggest a role for altered ECM deposition in the progression of glomerular diseases by affecting gene expression.

High glucose levels inhibit focal adhesion kinase-mediated wound healing of rat peritoneal mesothelial cells.

BACKGROUND: The peritoneum is progressively denuded of its mesothelial cell monolayer in patients on continuous ambulatory peritoneal dialysis (CAPD). These alterations of the mesothelium cause membrane dysfunction and progressive peritoneal fibrosis. Integrins regulate cell motility and play an important role in wound healing. We investigated the effects of high glucose on the regeneration process of the peritoneal mesothelial cell monolayer using cultured rat peritoneal mesothelial cells (RPMC). METHODS: The effects of glucose or mannitol on the regeneration of RPMC and formation of focal adhesions were examined by in vitro wound healing assay and immunocytochemistry, respectively. Activities of focal adhesion kinase (FAK) and its downstream p130Cas were examined by Western blotting. Effects of wild-type and dominant-negative FAK on RPMC migration were examined by a transient transfection assay. RESULTS: Cell migration over fibronectin (FN) was clearly inhibited in culture media containing high glucose (28 to 140 mmol/L). RPMC formed focal adhesions on FN in the presence of a regular glucose concentration (5.6 mmol/L); however, tyrosine phosphorylation of FAK and p130Cas and formation of focal adhesions observed by FAK and vinculin staining were substantially inhibited by high glucose. Mannitol also induced significant inhibitory effects, but these were milder than those of glucose. Transfection of dominant-negative FAK inhibited cell migration in a regular glucose concentration, whereas overexpression of wild-type FAK abrogated glucose-induced inhibition of cell migration. CONCLUSIONS: Our results demonstrate that high glucose concentrations as well as high osmolarity inhibit FAK-mediated migration of mesothelial cells, and suggest that dialysates containing high glucose concentrations may cause peritoneal damage by inhibiting wound healing of the mesothelial cell monolayer.

Adrenomedullin inhibits pressure-induced mesangial MCP-1 expression through activation of protein kinase A.

BACKGROUND: In glomerular hypertension, monocyte chemoattractant protein-1 (MCP-1) has been implicated in glomerulosclerosis progression. High-pressure load and stretch on mesangial cells (MC) are two major effects of increased glomerular pressure. We previously reported that pressure per se could induce MCP-1 expression in cultured MC, suggesting the involvement of glomerular hypertension in renal disease progression through MCP-1 expression in MC. We also showed that adrenomedullin (AM) inhibited pressure-induced MC proliferation; however, it is not clear whether AM alters pressure-induced mesangial MCP-1 expression. In this study, we examined the effect of AM on pressure-induced MCP-1 expression in cultured rat MC and the mechanism of such action. Using compressed helium, pressure was applied to MC placed in a sealed chamber. AM inhibited pressure-induced MCP-1 mRNA expression, measured by reverse transcribed-polymerase chain reaction (RT-PCR), in a dose-dependent manner. This inhibition was in parallel to an increase in cellular cyclic AMP (cAMP) levels evoked by AM. The effects of forskolin and dibutyryl cAMP mimicked those of AM. Protein kinase A (PKA) inhibitor H-89 significantly weakened the effects of AM. AM significantly reduced the pressure-induced increase in MCP-1 protein in supernatants of cultured MC, measured by enzyme-linked immunosorbent assay (ELISA). Our results suggested that AM inhibits pressure-induced mesangial MCP-1 expression through PKA activation.

Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease.

BACKGROUND: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. PATIENTS AND METHODS: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. RESULTS: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = -0.756, p < 0.0001). CONCLUSIONS: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.