Optimal Timing of Serum Creatinine Measurement for KDPI Scoring to Predict Postoperative Renal Function in Deceased Donor Kidney Transplantation.

INTRODUCTION: The widely employed Kidney Donor Profile Index (KDPI) scoring system, designed for assessing deceased donors (DD), plays a pivotal role in predicting graft function post kidney transplantation (KT). Given the dynamic nature of renal function, including serum creatinine (sCr), in managing DDs, it remains uncertain optimal timing to use KDPI for assessing postoperative graft function. METHODS: In this retrospective review, we assessed 246 DDs who were managed within a donor management program from January 2010 to December 2021. We collected sCr values for KDPI scoring at admission, peak, and last measurements before KT. Recipient data included occurrence of slow graft function (SGF), delayed graft function (DGF), and glomerular filtration rate (GFR) at one-year post-transplantation (1 Y). Using Receiver Operating Characteristic (ROC) and Pearson correlation analyses, we explored correlations of KDPI score (admission, peak, last) with graft function (SGF, DGF, GFR 1 Y). RESULTS: The average age of DDs and recipients was 49.78 ± 13.37 and 52.54 ± 10.49 years, respectively, with mean KDPI values at admission, peak, and last measurements of 62.36 ± 25.44, 66.94 ± 24.73, and 63.75 ± 25.80. After transplantation, SGF was observed in 81 recipients (32.9%) and DGF in 32 (13.0%). For SGF, the Area Under the Curve (AUC) from ROC analysis were 0.684 (95% CI, 0.615-0.753; P < .001) at admission, 0.691 (0.623-0.759; P < .001) at peak, and 0.697 (0.630-0.765; P < .001) at the last measurement. In predicting DGF, the corresponding AUC values were 0.746 (0.661-0.831; P < .001) at admission, 0.724 (0.637-0.810; P < .001) at peak, and 0.721 (0.643-0.809; P < .001) at the last. Moreover, KDPI scores at all time points-admission, peak, and last-moderately correlated with GFR 1 Y (R = -0.426, -0.423, -0.417). CONCLUSION: KDPI measurements at all time points, particularly admission, would be more effective in predicting DGF in DDKT.

Metabolomic profiling in kidney cells treated with a sodium glucose-cotransporter 2 inhibitor.

We aimed to determine the metabolomic profile of kidney cells under high glucose conditions and following sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment. Targeted metabolomics using the Absolute IDQ-p180 kit was applied to quantify metabolites in kidney cells stimulated with high glucose (25 and 50 mM) and treated with SGLT2 inhibitor, dapagliflozin (2 µM). Primary cultured human tubular epithelial cells and podocytes were used to identify the metabolomic profile in high glucose conditions following dapagliflozin treatment. The levels of asparagine, PC ae C34:1, and PC ae C36:2 were elevated in tubular epithelial cells stimulated with 50 mM glucose and were significantly decreased after 2 µM dapagliflozin treatment. The level of PC aa C32:0 was significantly decreased after 50 mM glucose treatment compared with the control, and its level was significantly increased after dapagliflozin treatment in podocytes. The metabolism of glutathione, asparagine and proline was significantly changed in tubular epithelial cells under high-glucose stimulation. And the pathway analysis showed that aminoacyl-tRNA biosynthesis, arginine and proline metabolism, glutathione metabolism, valine, leucine and isoleucine biosynthesis, phenylalanine, tyrosine, and tryptophan biosynthesis, beta-alanine metabolism, phenylalanine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, glycine, serine and threonine metabolism were altered in tubular epithelial cells after dapagliflozin treatment following 50 mM glucose compared to those treated with 50 mM glucose.

A Case Report of MPO-ANCA-Associated Vasculitis Following Heterologous mRNA1273 COVID-19 Booster Vaccination.

Despite that clinical trials have been examining the safety profile of coronavirus disease 2019 (COVID-19) vaccines, there are concerns about long-term side effects as the number of vaccinations increases. Herein, we report a case of new-onset renal-limited anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis after booster vaccination with the mRNA 1273 (Moderna) vaccine. A 72-year-old woman with no specific past history, and who had a normal renal function, developed ANCA-associated vasculitis following heterologous booster with mRNA1273 (Moderna) vaccine. After a kidney biopsy, she was diagnosed with ANCA-associated pauci-immune crescentic glomerulonephritis. Her renal function and constitutional symptoms have been improved with treatment with plasmapheresis, intravenous cyclophosphamide and steroid pulse therapy (intravenous 500 mg of methylprednisolone sodium succinate for 3 days) followed by a reduced steroid regimen.

Lower response to denosumab in diabetes patients on hemodialysis.

INTRODUCTION: The incidence of fractures is much higher in patients with chronic kidney disease, especially those on hemodialysis (HD). Denosumab is known to treat osteoporosis. However, no exact guideline exists for treatment with denosumab in patients, especially those with diabetes. This study analyzed the effect of denosumab in HD patients with or without diabetes. MATERIALS AND METHODS: Dual-energy X-ray absorptiometry was performed in 89 HD patients: 42 were diagnosed with osteoporosis. 33 patients were treated with denosumab. An observational retrospective analysis was conducted in 25 HD patients whose follow-up biomarkers were measured at 6 months after denosumab treatment. FINDINGS: Bone mineral density (BMD) of lumbar spine (LS) and femur neck (FN) were largely improved (+3.40% and 4.96%, respectively) 1 year after the treatment. The T-scores were also improved. Both bone turnover markers were significantly decreased 6 months after treatment; the levels of C-terminal telopeptide (CTX) and bone-specific alkaline phosphatase (bsALP) were decreased by -1.04 ± 1.24 ng/mL (p < 0.001) and -35.72 ± 36.07 IU/L (p < 0.001), respectively. The response was significantly different between the diabetes and non-diabetes group. The increase in LS BMD was significantly lower in the diabetes group than in the non-diabetes group (0.02 ± 0.03 vs. 0.07 ± 0.02, p = 0.02). Decrease in CTX, but not in bsALP, was also lower in the diabetes group compared to the non-diabetes group (-0.58 ± 0.70 vs. -1.55 ± 1.12, p = 0.03). Pretreatment with calcium and calcitriol prevented symptomatic hypocalcemia except in 1 case. CONCLUSION: Denosumab improved bone density and osteoclastic activity in HD patients, with a lower response in patients with diabetes.

Pulse Pressure Variation is a Valuable Marker for Predicting Fluid Responsiveness in Brain-Dead Donors.

PURPOSE: Hemodynamic management in brain-dead donors (BDDs) is challenging due to hemodynamic instabilities. We compared functional parameters with traditional parameters for hemodynamic monitoring in BDDs. MATERIALS AND METHODS: Seventeen BDDs with a positive balance of >500 mL for 8 hours were included. Functional hemodynamic monitoring, including pulse pressure variation (PPV), stroke volume variation (SVV), cardiac output, and systemic vascular resistance index (SVRI) was performed in the setting of tidal volume of 6 mL/kg to 8 mL/kg and minimal positive end-expiratory pressure of 5 cm to 8 cm H2O. Responders were defined by a cardiac output increase of >15% after fluid therapy. RESULTS: Among the 17 BDDs (mean age, 46.80±13.91 years), 15 were male. Seven responders out of 17 (41.1%) had a significantly higher PPV (22.8±8.4 vs 13.4±5.9%, P = .038) and serum albumin level (3.2±0.6 vs 2.6±0.5 g/L, P = .040) at baseline than nonresponders. However, other hemodynamic markers such as SVV and SVRI were similar between groups. Traditional markers of volume status, such as heart rate, central venous pressure, hemoglobin, and serum uric acid level were also similar between the 2 groups. Hemodynamic markers including PPV, SVV, and SVRI were significantly reduced in responders. CONCLUSIONS: PPV was the most valuable hemodynamic marker for predicting volume responsiveness in BDDs.

Fumarate modulates phospholipase A2 receptor autoimmunity-induced podocyte injury in membranous nephropathy.

Downstream mechanisms that lead to podocyte injury following phospholipase A2 receptor (PLA2R) autoimmunity remain elusive. To help define this we compared urinary metabolomic profiles of patients with PLA2R-associated membranous nephropathy (MN) at the time of kidney biopsy with those of patients with minimal change disease (MCD) and to healthy individuals. Among the metabolites differentially expressed in patients with PLA2R-associated MN compared to healthy individuals, fumarate was the only significant differentially expressed metabolite in PLA2R-associated MN compared to MCD [fold-difference vs. healthy controls and vs. MCD: 1.76 and 1.60, respectively]. High urinary fumarate levels could predict the composite outcome of PLA2R-associated MN. Fumarate hydratase, which hydrolyzes fumarate, colocalized with podocalyxin, and its expression was lower in glomerular sections from patients with PLA2R-associated MN than in those from healthy individuals, patients with non-PLA2R-associated MN or MCD. Podocytes stimulated with IgG purified from serum with a high anti-PLA2R titer (MN-IgG) decreased expression of fumarate hydratase and increased fumarate levels. These changes were coupled to alterations in the expression of molecules involved in the phenotypic profile of podocytes (WT1, ZO-1, Snail, and fibronectin), an increase in albumin flux across the podocyte layer and the production of reactive oxygen species in podocytes. However, overexpression of fumarate hydratase ameliorated these alterations. Furthermore, knockdown of fumarate hydratase exhibited synergistic effects with MN-IgG treatment. Thus, fumarate may promote changes in the phenotypic profiles of podocytes after the development of PLA2R autoimmunity. These findings suggest that fumarate could serve as a potential target for the treatment of PLA2R-associated MN.

Cardiovascular risk of nonsteroidal anti-inflammatory drugs in dialysis patients: a nationwide population-based study.

BACKGROUND: Given the cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs), it is essential to identify the relationship between NSAIDs and cardiovascular outcomes in dialysis patients who have elevated cardiovascular risk. METHODS: A case-crossover study was conducted to assess the association of NSAIDs with major adverse cardiac and cerebrovascular events (MACCEs) and mortality using the Korean Health Insurance dataset. The case period was defined as 1-30 days prior to the event date and the control periods were defined as 61-90 days and 91-120 days prior to the event date. RESULTS: There were 3433 and 8524 incident dialysis patients who experienced MACCEs and mortality, respectively, after exposure to NSAIDs within 120 days before each event. NSAIDs significantly increased the risk of MACCEs {adjusted odds ratio [aOR] 1.37 [95% confidence interval (CI) 1.26-1.50]} and mortality [aOR 1.29 (95% CI 1.22-1.36)]. Nonselective NSAIDs, but not selective cyclooxygenase-2 inhibitors, significantly increased the risk of MACCEs and mortality. However, the MACCE and mortality risk did not increase in a dose-dependent manner in the analysis according to the cumulative defined daily dosage of NSAIDs. The incidence of MACCEs in the case period tended to be more common in patients who had recent exposure to NSAIDs than in patients who did not have recent exposure to NSAIDs. CONCLUSIONS: Clinicians should be particularly cautious when prescribing NSAIDs to dialysis patients considering the associations of NSAIDs with cardiovascular outcomes and mortality, which might occur independent of the dose and duration of exposure.

VSIG4 Induces Epithelial-Mesenchymal Transition of Renal Tubular Cells under High-Glucose Conditions.

High glucose-mediated tubular injury contributes to the development and progression of diabetic nephropathy through renal tubulointerstitial fibrosis. V-set immunoglobulin-domain-containing 4 (VSIG4), a B7 family-related protein, is a complement receptor. Although the role of epithelial-mesenchymal transition (EMT) has been reported in several diseases, little is known about its relationship with VSIG4 under diabetic conditions. This study aimed to investigate the role of VSIG4 in human tubule cells stimulated by high glucose (HG, 55 mM). HG upregulated both mRNA and protein levels of VSIG4 in proximal tubule cells (HK-2 cells) and Madin Darby Canine Kidney cells. These upregulations were accompanied by increased expression of mesenchymal markers such as fibronectin, N-cadherin, matrix metalloproteinase 9, and vimentin, and by decreased expression of the epithelial marker, E-cadherin. The siRNA-mediated inhibition of VSIG4 in HK-2 cells restored the dysregulation of EMT in cells. Interestingly, VSIG4 inhibition did not affect the expression of transforming growth factor (TGF)-ß, whereas inhibition of TGF-ß reduced VSIG4 expression, subsequently suppressing fibrosis markers. These findings suggest that VSIG4 plays an important role in mediating renal tubular EMT through the downstream action of HG-induced TGF-ß activation.

Clinical outcomes of prolonged dual antiplatelet therapy after coronary drug-eluting stent implantation in dialysis patients.

BACKGROUND: End-stage renal disease yields susceptibility to both ischemia and bleeding. The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is not established in dialysis patients, who are usually excluded from randomized studies. Since recent studies implied the benefits of prolonged DAPT >12 months in chronic kidney disease, we investigated the effectiveness and safety of prolonged DAPT in dialysis patients with higher cardiovascular risks. METHODS: In this nationwide population-based study, we analyzed dialysis patients who underwent DES implantation from 2008 to 2015. Continued DAPT was compared with discontinued DAPT using landmark analyses, including free-of-event participants at 12 (n = 2246), 15 (n = 1925) and 18 months (n = 1692) after DES implantation. The primary outcome was major adverse cardiovascular events (MACEs): a composite of mortality, nonfatal myocardial infarction, coronary revascularization and stroke. Major bleeding was a safety outcome. Inverse probability of treatment weighting Cox regression was performed. RESULTS: Mean follow-up periods were 278.3-292.4 days, depending on landmarks. Overall, incidences of major bleeding were far lower than those of MACE. Continued DAPT groups showed lower incidences of MACE and higher incidences of major bleeding, compared with discontinued DAPT groups. In Cox analyses, continued DAPT reduced the hazards of MACE at the 12- [hazard ratio (HR) = 0.74, 95% confidence interval (CI) 0.61-0.90; P = 0.003], 15- (HR = 0.78, 95% CI 0.64-0.96; P = 0.019) and 18-month landmarks (HR = 0.79, 95% CI 0.63-0.99; P = 0.041), but without a significant increase in major bleeding at 12 (HR = 1.39, 95% CI 0.90-2.16; P = 0.14), 15 (HR = 1.13, 95% CI 0.75-1.70; P = 0.55) or 18 months (HR = 1.27, 95% CI 0.83-1.95; P = 0.27). CONCLUSIONS: Prolonged DAPT reduced MACE without significantly increasing major bleeding in patients who were event-free at 12 months after DES implantation. In deciding on DAPT duration, prolonged DAPT should be considered in dialysis patients.

A case of successful late steroid withdrawal after ABO-incompatible kidney transplantation.

Few data exist regarding steroid withdrawal in ABO-incompatible (ABO-i) kidney transplantation (KT). Here, we report a case of steroid withdrawal after ABO-i KT. A 46-year-old man diagnosed with Henoch-Schonlein purpura received ABO-i KT from his 42-year-old sister. The recipient and donor blood types were O and AB, respectively. His preoperative ABO antibody titers were anti-A of 1:16 and anti-B of 1:8 in isoagglutinin test. HLA mismatch was 0 and he received a single 325 mg/m2 dose of intravenous (IV) rituximab 4 weeks before KT. Three sessions of plasma exchange were undertaken before KT and low-dose IV immunoglobulin of 0.1 g/kg was administered after plasma exchange. On the day of the operation, ABO antibody titer decreased to anti-A of 1:4 and anti-B of 1:2. Renal function remained stable after KT. The patient wished to stop steroid treatment despite the risk of rejection after withdrawal. Steroid tapering was initiated at 20 months and accomplished at 26 months after KT. At that time, serum creatinine level was 1.13 mg/dL, and anti-A and anti-B titers were 1:8 and 1:2, respectively. No issues were observed after steroid withdrawal. At 48 months after KT, serum creatinine level was 1.21 mg/dL, and anti-A and anti-B antibody titers were 1:32 and 1:2, respectively. Steroid withdrawal in ABO-i KT might be considered in immunologically low-risk patients.

Effect of Cinacalcet in Kidney Transplant Patients With Hyperparathyroidism.

OBJECTIVE: In dialysis patients, cinacalcet could be an effective alternative to parathyroidectomy for treating hyperparathyroidism. In the present study, we aimed to determine the characteristics of subjects with persistent hyperparathyroidism who require parathyroidectomy despite the use of cinacalcet. METHODS: Nine kidney transplant patients (7 men, 2 women; mean age 53.2 [SD, 8.9] years) who had tertiary hyperparathyroidism were reviewed in a single center. Pre- and postcinacalcet levels of calcium, phosphorous, intact parathyroid hormone (iPTH), and renal function were analyzed to evaluate the effect of cinacalcet treatment in these patients. The baseline parameters before cinacalcet treatment were compared in patients who did and did not undergo parathyroidectomy. RESULTS: Cinacalcet reduced serum calcium levels in all patients (11.48 [SD, 0.73] mg/dL to 10.20 [0.70] mg/dL; P = .008). Serum phosphorous levels significantly increased from 2.28 (SD, 0.77) mg/dL to 3.02 (SD, 0.65) mg/dL (P = .03). The iPTH levels in 7 patients decreased, while the mean level remained unchanged in total subjects. The iPTH levels increased even with cinacalcet treatment in 2 patients. In 3 patients, serum calcium levels abruptly increased after cinacalcet withdrawal. Five patients who showed persistent hypercalcemia due to hyperparathyroidism underwent parathyroidectomy. These 5 patients had significantly different characteristics compared with 4 patients who did not undergo parathyroidectomy: hypercalcemia (11.92 [SD, 0.68] mg/dL vs 10.93 [SD, 0.26] mg/dL; P = .02), hypophosphatemia (1.74 [SD, 0.36] mg/dL vs 2.95 [SD, 0.58] mg/dL; P = .03), and hyperparathyroidism (252.2 [SD, 131.4] pg/dL vs 101.5 [SD, 18.4] pg/dL; P = .02). CONCLUSION: Cinacalcet reduced hypercalcemia due to hyperparathyroidism in the transplant patients. However, patients who had pre-existing higher iPTH, hypercalcemia, and hypophosphatemia needed parathyroidectomy. Therefore, cinacalcet could be considered an alternative to parathyroidectomy in selected patients.

The association of tumor necrosis factor superfamily 13 with recurrence of immunoglobulin A nephropathy in living related kidney transplantation.

BACKGROUND: An increasing amount of evidence has demonstrated an association between an increase in the level of tumor necrosis factor superfamily 13 (TNFSF13) and immunoglobulin A nephropathy (IgAN) progression. We aimed to evaluate if the level of pre-transplant serum TNFSF13 is predictive of IgAN recurrence after kidney transplantation. METHODS: This analysis was based on the clinical and laboratory data of 69 patients with IgAN who underwent first kidney transplantation with no evidence of mesangial IgA deposits in zero-time transplantation biopsy. We measured pre-transplant serum TNFSF13, total IgA, and galactose-deficient IgA1 levels. RESULTS: The recurrence rate of IgAN over a median follow-up duration of 5.1 years was 15.9% (11/69 patients), with a mean time to the first recurrence of 1.7 years. The high pre-transplant TNFSF13 level was associated with IgAN recurrence after kidney transplantation among patients who received a graft from a living related donor. CONCLUSIONS: This study highlights association of TNFSF13 levels in recurrent IgAN patients who undergo living related donor transplantation. Further research is needed to clarify mechanisms by which TNFSF13 affects the recurrence of IgA nephropathy.

Epidemiology of continuous renal replacement therapy in Korea: Results from the National Health Insurance Service claims database from 2005 to 2016.

BACKGROUND: Continuous renal replacement therapy (CRRT) is an important treatment modality for severe acute kidney injury. As such, the epidemiology of CRRT in Korea needs further investigation. METHODS: We conducted a nationwide, population-based study analyzing the claims data from National Health Insurance Service of Korea. All index intensive care unit admission cases of CRRT in government-designated tertiary referral hospitals in Korea from 2005 to 2016 were included. Patients with a history of renal replacement therapy or who were under 20 years old were not considered. In addition to baseline and treatment characteristics, patient outcomes, including all-cause mortality and renal survival rates, were investigated. We stratified the study patients according to 3-year time periods and major regions of the nation. RESULTS: We included 37,337 patients who received CRRT in Korea. The overall use of CRRT increased over time, and more than 80% of cases of acute renal replacement therapy were CRRT after 2014. Seoul was the region in which the majority of CRRT (45.0%) was performed. The clinical characteristics of CRRT patients were significantly different among time-intervals and regions. Both all-cause mortality and renal survival rates after CRRT were prominently improved in the recent time periods (P < 0.001). CONCLUSION: CRRT is a widely used treatment strategy for severe acute kidney injury in Korea. The prognosis of CRRT patients has improved compared to the past. This epidemiological study of CRRT in Korea revealed notable trends with regard to time period and geographic region.

BAFF and APRIL expression as an autoimmune signature of membranous nephropathy.

BACKGROUND: Based on the fact that B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have a regulatory role in B cell biology, excessive levels of these cytokines can promote autoimmune pathogenesis. However, the expression and implication remain unresolved in cases of membranous nephropathy (MN). RESULTS: The plasma BAFF levels of the primary MN patients were higher than those of healthy controls but lower than those of secondary MN patients, whereas the APRIL levels were similar between the MN patients and healthy controls. The BAFF levels were higher in relapse cases, whereas the APRIL levels were higher in the patients who did not experience remission compared with the counterpart patients. The ectopic expression of BAFF and APRIL was observed in the glomeruli or circulating B cells of MN patients, and this high expression trend was similar to that of lupus patients. CONCLUSIONS: Expression profile of BAFF and APRIL in MN is similar to that of other autoimmune disease, which affects the kidney outcomes. METHODS: Plasma BAFF and APRIL levels were measured upon kidney biopsy in patients with primary (n = 89) and secondary MN (n = 13), and the results were compared with the levels in healthy controls (n = 111). The kidney outcomes (e.g., remission and relapse) were traced for the median of 3 years. Aberrant expression of the cytokines was evaluated in the kidney and circulating B cells using immunohistochemistry and flow cytometry analyses, respectively.

Efficacy and safety of a balanced salt solution versus a 0.9% saline infusion for the prevention of contrast-induced acute kidney injury (BASIC trial): a study protocol for a randomized controlled trial.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is one of the most common causes of iatrogenic kidney injury and, therefore, its prevention is an important issue. However, whether the administration of 0.9% saline is the optimal prophylaxis method remains uncertain due to its supra-physiologic chloride component. In particular, recent studies suggest that chloride-restricted solutions showed superiority over 0.9% saline in several clinical settings. METHODS/DESIGN: The investigators designed a multicenter randomized controlled trial to compare the efficacy of a balanced salt solution and 0.9% saline in CI-AKI prophylaxis. This study will recruit patients who are scheduled for contrast-enhanced computed tomography (CT) scans with CI-AKI prophylaxis. In this study, participants will be randomized into two study arms; the study group will receive a balanced salt solution, and the control group will receive 0.9% saline. Fluids will be administered as designated in the protocol before and after the CT scan, and an evaluation of baseline clinical status will be performed by obtaining blood and urine samples. During the follow-up visits, the incidence of CI-AKI and long-term outcomes, including the start of renal replacement therapy or all-cause mortality, will be assessed. DISCUSSION: To our knowledge, this study will be the first study assessing the preventive value of a balanced salt solution over 0.9% saline for CI-AKI. If the trial shows that the balanced salt solution is as effective for CI-AKI prophylaxis as 0.9% saline, the use of the balanced salt solution could be promoted due to the reduced possibility of consequent metabolic acidosis compared to 0.9% saline. TRIALS REGISTRATION: ClinicalTrials.gov, ID: NCT02799368 . Registered on 14 June 2016.

Roles of fluid shear stress and retinoic acid in the differentiation of primary cultured human podocytes.

Due to the distinct features that distinguish immortalized podocyte cell lines from their in vivo counterparts, primary cultured human podocytes might be a superior cell model for glomerular disease studies. However, the podocyte de-differentiation that occurs in culture remains an unresolved problem. Here, we present a method to differentiate primary cultured podocytes using retinoic acid (RA) and fluid shear stress (FSS), which mimic the in vivo environment of the glomerulus. RA treatment induced changes in the cell shape of podocytes from a cobblestone-like morphology to an arborized configuration with enhanced mobility. Moreover, the expression of synaptopodin and zonula occludens (ZO)-1 in RA-treated podocytes increased along with Krüppel-like factor 15 (KLF15) expression. Confocal microscopy revealed that RA increased the expression of cytoplasmic synaptopodin, which adopted a filamentous arrangement, and junctional ZO-1 expression, which showed a zipper-like pattern. To elucidate the effect of FSS in addition to RA, the podocytes were cultured in microfluidic devices and assigned to the static, static+RA, FSS, and FSS+RA groups. The FSS+RA group showed increased synaptopodin and ZO-1 expression with prominent spikes on the cell-cell interface. Furthermore, interdigitating processes were only observed in the FSS+RA group. Consistent with these data, the mRNA expression levels of synaptopodin, podocin, WT-1 and ZO-1 were synergistically increased by FSS and RA treatment. Additionally, the heights of the cells were greater in the FSS and FSS+RA groups than in the static groups, suggesting a restoration of the 3D cellular shape. Meanwhile, the expression of KLF15 increased in the RA-treated cells regardless of fluidic condition. Taken together, FSS and RA may contribute through different but additive mechanisms to the differentiation of podocytes. These cells may serve as a useful tool for mechanistic studies and the application of regenerative medicine to the treatment of kidney diseases.

Clozapine Induced Neuroleptic Malignant Syndrome.

Neuroleptic malignant syndrome is a rare, but potentially life-threatening adverse event associated with the use of neuroleptic agents. We describe the case of a 47-year-old schizophrenic woman who was treated with clozapine for years. The patient developed acute renal failure with pulmonary edema, and underwent mechanical ventilation and hemodialysis.