Low skeletal muscle mass index is independently associated with low bone mineral density in kidney transplant recipients: a retrospective observational cohort study.

BACKGROUND: Osteoporosis and osteopenia are more frequent in patients who have received kidney transplants than in healthy individuals. Although osteoporosis and sarcopenia are closely related, only few studies have considered them in the post-transplantation period. We aimed to investigate the relationship between lower bone mineral density and skeletal muscle in kidney transplant recipients. METHODS: We included 371 patients in the maintenance phase of kidney transplantation (> 6 months after transplantation) followed-up at our institution from January to December 2019. The primary endpoint was the association between bone mineral density and skeletal muscle mass index. As secondary endpoints, in addition to skeletal muscle mass index, we investigated other factors associated with low bone mineral density, including kidney function and 25-hydroxy vitamin D (25(OH)D) concentration. Considering the possibility that factors affecting bone mineral density differ between men and women, we explored these factors separately for both sexes. RESULTS: Of the 371 participants, 243 (65.4%) were men. The median age and time after transplantation were 52 and 14 years, respectively. Univariate analysis showed that age, female sex, time since transplantation, cystatin C-based estimated glomerular filtration rate (eGFRcysC), 25(OH)D, and skeletal muscle mass index were associated with bone mineral density. Multivariate analysis showed associations of bone mineral density with eGFRcysC, 25(OH)D, and skeletal muscle mass index. Multivariate analysis by sex showed significant associations with eGFRcysC, hemoglobin, and skeletal muscle mass index in men and with age, eGFRcysC, albumin, and skeletal muscle mass index in women. Bone mineral density was not associated with history of dialysis prior to transplantation or time since transplantation. CONCLUSIONS: In kidney transplant recipients, an independent association between lower bone mineral density and skeletal muscle mass index was observed in both sexes.

The association of low serum magnesium levels with frailty among hemodialysis patients.

Frailty is common among hemodialysis patients and is associated with mortality and fractures. Hypomagnesemia is also known to be a risk factor for mortality and fractures and has been shown to be significantly associated with muscle performance indexes. However, little is known about the association between hypomagnesemia and frailty. We enrolled 339 outpatients who underwent hemodialysis and assessed frailty using the Clinical Frailty Scale (CFS), a 7-point subjective assessment tool based upon clinical judgment. We examined the association between serum magnesium levels and frailty evaluated using the CFS. The median CFS score was 3 points, and 49 (14.5%) patients had frailty (CFS score ≥ 5). In multiple regression analysis, serum magnesium levels were independently associated with increased CFS scores (ß = - 0.126, P = 0.005) adjusted for age, body mass index, diabetes, cardiovascular diseases, prevalent fractures, serum albumin and C-reactive protein. The adjusted odds ratio for frailty was 2.85 [95% confidence interval (CI) 1.23-6.97, P = 0.014] in the lower serum magnesium group categorized based on the median value. Furthermore, with regard to model discrimination, adding serum magnesium levels to the established risk factors significantly improved net reclassification (0.520, P < 0.001) and integrated discrimination (0.023, P = 0.031). Lower serum magnesium levels may be associated with the severity and definition of frailty independent of well-known risk factors.

The Impact of Liver Chemistries on Respiratory Failure among Hemodialysis Patients with COVID-19 during the Omicron Wave.

Objective Although the coronavirus disease 2019 (COVID-19) Omicron variant causes less severe symptoms than previous variants, early indicators for respiratory failure are needed in hemodialysis patients, who have a higher mortality rate than the general population. Liver chemistries are known to reflect the severity of COVID-19 in the general population. This study explored the early indicators for worsened respiratory failure based on patient characteristics, including liver chemistries. Methods This retrospective study included 117 patients admitted for COVID-19 during the Omicron wave. Respiratory failure was defined as oxygen requirement during treatment. Information on the symptoms and clinical characteristics, including liver chemistries [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)], at admission was collected. Results Thirty-five patients (29.9%) required oxygen supply during treatment. In the multivariate logistic regression analyses, AST [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.00-1.13, p=0.029], ALT (OR 1.09, 95% CI 1.02-1.18, p=0.009), and moderate COVID-19 illness (Model including AST, OR 6.95, 95% CI 2.23-23.17, p<0.001; Model including ALT, OR 7.19, 95% CI 2.21-25.22, p=0.001) were independent predictors for respiratory failure. Based on the cutoff values determined by the receiver operating characteristic curve, higher AST (≥23 IU/L) and ALT levels (≥14 IU/L) were also independently associated with respiratory failure (higher AST: 64.3% vs. 18.8%, OR 3.44, 95% CI 1.08-11.10, p=0.035; higher ALT: 48.8% vs. 19.7%, OR 4.23, 95% CI 1.34-14.52, p=0.013, respectively). Conclusion The measurement of AST and ALT levels at baseline may help predict oxygen requirement in hemodialysis patients with COVID-19.

Non-A Blood Type Is a Risk Factor for Poor Cardio-Cerebrovascular Outcomes in Patients Undergoing Dialysis.

The clinical impact of ABO blood type on cardio-cerebrovascular outcomes in patients undergoing dialysis has not been clarified. A total of 365 hemodialysis patients participated in the current study. The primary endpoint was defined as a composite including cardio-cerebrovascular events and cardio-cerebrovascular death. The primary endpoint was observed in 73 patients during a median follow-up period of 1182 days, including 16/149 (11%) with blood type A, 22/81 (27%) with blood type B, 26/99 (26%) with blood type O, and 9/36 (25%) with blood type AB. At baseline, no difference was found in the echocardiographic parameters. Multivariable Cox regression analyses revealed that blood type (type A vs. non-A type; hazard ratio (HR): 0.46, 95% confidence interval (95% CI): 0.26-0.81, p = 0.007), age (per 10-year increase; HR: 1.47, 95% CI: 1.18-1.84), antiplatelet or anticoagulation therapy (HR: 1.91, 95% CI: 1.07-3.41), LVEF (per 10% increase; HR: 0.78, 95% CI: 0.63-0.96), and LV mass index (per 10 g/m2 increase; HR: 1.07, 95% CI: 1.01-1.13) were the independent determinants of the primary endpoint. Kaplan-Meier curves also showed a higher incidence of the primary endpoint in the non-A type than type A (Log-rank p = 0.001). Dialysis patients with blood type A developed cardio-cerebrovascular events more frequently than non-A type patients.

Recurrent Cerebrovascular Complications under Enzyme Replacement Therapy in a Patient with Fabry Disease on Peritoneal Dialysis.

Fabry disease is an X-linked lysosomal storage disorder due to mutations in the alpha-galactosidase A gene, which leads to the accumulation of globotriaosylceramide in various organs. In Fabry disease with end-stage renal disease (ESRD), cerebrovascular events are lethal, even with enzyme replacement therapy (ERT). However, the utility of biomarkers to evaluate the ERT response is unclear. We herein report a case of recurrent cerebrovascular complications under ERT in a Fabry disease patient, progressing to ESRD on peritoneal dialysis. Further studies are warranted, but Fabry disease patients with ESRD receiving ERT might need careful long-term follow-up in cases with cerebrovascular manifestations.

Effects of bone turnover status on the efficacy and safety of denosumab among haemodialysis patients.

Denosumab is reported to increase bone mineral density (BMD) among haemodialysis patients; however, hypocalcaemia is a serious adverse effect among chronic kidney disease (CKD) patients. Identifying which patients will show greater improvement in BMD is important. We enrolled 84 haemodialysis patients with osteoporosis in our study. 28 patients initiated denosumab treatment between October 2019 and October 2020. We assessed BMD changes and investigated the association between baseline bone turnover marker (BTM) levels and 6-month changes in BMD after denosumab treatment. BMD was increased at 6 months in denosumab-treated patients compared with patients not treated with denosumab (lumbar spine: 5.34% vs. - 0.49%; total hip: 2.43% vs. - 0.47%). Bone-specific alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase-5b (TRACP-5b) at baseline were independently associated with increased BMD in the total hip (BAP: ß = 0.472, p value = 0.004; TRACP-5b: ß = 0.433, p value = 0.008) and lumbar spine (BAP: ß = 0.591, p value = 0.001; TRACP-5b: ß = 0.613, p value = 0.0008). BAP and TRACP-5b were also independent predictors of hypocalcaemic events (OR [95% CI] 1.747 [1.084-4.604] and 1.006 [1.000-1.015], respectively). BTMs may be associated with increased BMD and hypocalcaemic events after denosumab treatment. BTM measurement may be useful for assessing the effect of denosumab on BMD; however, careful monitoring of serum calcium levels is needed.

Lateral spine dual-energy X-ray absorptiometry and the risk of fragility fractures in long-term kidney graft recipients.

BACKGROUND: Although the prevalence of osteoporosis and fractures in the first 6-12 months post-renal transplantation is high, little is known about the utility of bone mineral density (BMD) to predict fractures in long-term kidney graft recipients. Lateral spine dual-energy X-ray absorptiometry (DXA) scanning is a reliable tool for measuring glucocorticoid-induced and age-related bone loss in the elderly population. However, little is known about the utility of lateral spine DXA for patients with chronic kidney diseases. This study aimed to analyze the utility of lateral spine BMD for fragility fractures in long-term kidney graft recipients. METHODS: A total of 357 stable kidney transplant recipients for a minimum of 1 year after kidney transplantation underwent DXA measurements at several sites, including the lateral spine between January 2017 and December 2018. We collected data on new incident fractures from the patients' medical records. RESULTS: The median post-transplantation time at baseline DXA measurement was 12.6 years. During the median follow-up period of 3.5 years, 41 (11.4%) fractures occurred. The lateral spine BMDs were independently associated with fractures (adjusted hazard ratio 0.076; 95% confidence interval 0.012-0.42, p = 0.003). The cumulative incidence rate of fractures was significantly higher in the lower lateral spine BMD group (< 0.471 g/cm2, optimal cut-off value by receiver operating characteristic curve) than in the higher lateral spine BMD group (23.4 vs. 7.4%, adjusted hazard ratio 4.92; 95% confidence interval 2.33-10.74, p < 0.001). CONCLUSION: Lateral lumbar spine BMD can be used to predict the risk of fragility fractures in long-term kidney graft recipients.

Impact of left ventricular hypertrophy on clinical outcomes in patients with dialysis: a single-center study in Japan.

PURPOSE: Left ventricular hypertrophy (LVH) is a well-known risk factor for poor clinical outcomes in patients undergoing dialysis. However, little evidence supports the above notion in Japan, and the influence of subtypes of LVH on prognosis. METHODS: We investigated 367 patients undergoing dialysis who underwent routine echocardiographic examinations between April and September 2018. LVH was defined as any LV mass ≥ 115 g/m2 in men and ≥ 95 g/m2 in women obtained by echocardiography. The primary endpoint was a composite outcome including all-cause death, admission due to heart failure, and ischemic heart event or stroke. LVH was divided into subtype-groups according to eccentric hypertrophy or concentric hypertrophy, and with and without hypertension. RESULTS: LVH was observed in 171 (47%) patients. The primary endpoint was observed in 58 patients (16%) during the median follow-up period of 500 days. Multivariable Cox regression analyses identified four independent risk factors for the primary endpoint: age, pulse rate, serum albumin level, and LV mass index (per 10-g/m2 increase; hazard ratio: 1.12, 95% confidence interval: 1.06-1.18, P < 0.001). Kaplan-Meier analyses demonstrated that patients with LVH had a worse prognosis than those without LVH in terms of the primary endpoint (log-rank P < 0.001). The incidence of the primary outcome was not significantly different between patients with eccentric or concentric hypertrophy, and between LVH patients with and without hypertension. CONCLUSION: Japanese patients with LVH undergoing dialysis had a worse prognosis than those without LVH in terms of the composite clinical endpoint.

Impact of serum magnesium and bone mineral density on systemic fractures in chronic hemodialysis patients.

INTRODUCTION: Bone mineral density (BMD) measured with dual-energy X-ray absorptiometry (DXA) can be used to predict fractures, but its clinical utility has not been fully established in chronic kidney disease (CKD) patients. Magnesium is an essential trace element. Although magnesium is associated with the risk of fractures in non-CKD populations, the relationship is unknown in CKD patients. METHODS: BMD and serum magnesium levels were measured in 358 stable outpatients undergoing maintenance hemodialysis therapy. The primary outcome was fragility fracture. Patients were divided into groups according to the median level of magnesium and the normal threshold value of lumbar spine BMD. RESULTS: During the median follow-up period of 36 months, 36 (10.0%) fractures occurred. The cumulative incidence rates of fractures were 17.6% and 5.2% [adjusted hazard ratio (aHR) 2.31, 95% confidence interval (CI) 1.03-5.17, P = 0.030] in the lower (<2.6 mg/dL) and higher (≥2.6 mg/dL) magnesium (Mg) groups, respectively, and 21.2% and 7.3% (aHR 2.59, 95% CI 1.09-6.16, P = 0.027) in the low- and high-BMD groups, respectively. The lower-Mg and low-BMD group had a 9.21-fold higher risk of fractures (95% CI; 2.35-47.00; P = 0.0010) than the higher-Mg and high-BMD group. Furthermore, adding both magnesium levels and lumbar spine BMD levels to the established risk factors significantly improved the prediction of fractures (C-index: 0.784 to 0.830, p = 0.041). DISCUSSION/CONCLUSIONS: The combination of serum magnesium and lumbar spine BMD can be used for fracture risk stratification and synergistically improves the prediction of fractures in CKD patients.

Hemodialysis Product and Hip Fracture in Hemodialysis Patients: A Nationwide Cohort Study in Japan.

Some have raised concerns that longer and more frequent hemodialysis (HD) would be associated with bone fractures due to excess phosphate removal. We examined the effects of hemodialysis product (HDP) on hip fracture incidence among Japanese HD patients using registry data of the Japanese Society for Dialysis Therapy. During a 1-year study period, 1411 hip fractures occurred among 135 984 patients. After adjusting for demographic and clinical factors, patients with a high HDP did not show a significant risk of hip fracture. Interestingly, patients with polycystic kidney disease had a lower risk of hip fracture. Our findings did not support the hypothesis that patients undergoing longer and more frequent HD would face a higher risk of hip fracture than those undergoing shorter and less frequent HD. Polycystic kidney disease was identified as a new significant factor for hip fracture; relative to glomerulonephritis, this condition was associated with a lower risk of hip fracture.

High Ferritin Level and Malnutrition Predict High Risk of Infection-Related Hospitalization in Incident Dialysis Patients: A Japanese Prospective Cohort Study.

AIMS: The aim of the study was to clarify the relationship between serum ferritin and infectious risks. METHODS: We evaluated all hospital admissions due to infections, clinical biomarkers and nutrition status in 129 incident Japanese dialysis patients during a median follow-up of 38 months. RESULTS: Kaplan-Meier analysis revealed that the period without infections requiring hospitalization was significantly shorter in ferritin > median (82.0 ng/ml) group than in the ferritin < median group (log-rank test 4.44, p = 0.035). High ferritin was associated with significantly increased relative risk of hospitalization for infection (Cox hazard model 1.52, 95% CI 1.06-2.17). The number of hospitalization days was gradually longer in patients with high ferritin levels and malnutrition. CONCLUSION: Although serum ferritin levels were low, and doses of iron administered to dialysis patients in Japan are generally lower than in Western countries, an elevated ferritin level was associated with increased risk of infection, particularly in patients with poor nutritional status.

Rat adipose tissue-derived stem cells attenuate peritoneal injuries in rat zymosan-induced peritonitis accompanied by complement activation.

BACKGROUND AIMS: In patients receiving peritoneal dialysis, fungal or yeast peritonitis has a poor prognosis. In rat peritoneum with mechanical scraping, severe peritonitis can be induced by zymosan, a component of yeast (Zy/scraping peritonitis). Administration of rat adipose tissue-derived stromal cells (ASCs) potentially can improve several tissue injuries. The present study investigated whether rat ASCs could improve peritoneal inflammation in Zy/scraping peritonitis. METHODS: Rat ASCs were injected intraperitoneally on a daily basis in rats with Zy/scraping peritonitis. RESULTS: Peritoneal inflammation accompanied by accumulation of inflammatory cells and complement deposition was suppressed by day 5 after injection of rat ASCs. The peritoneal mesothelial layer in Zy/scraping peritonitis with rat ASC treatment was restored compared with the peritoneal mesothelial layer without rat ASC treatment. Injected rat ASCs co-existed with mesothelial cells in the sub-peritoneal layer. In vitro assays showed increased cellular proliferation of rat mesothelial cells combined with rat ASCs by co-culture assays, confirming that fluid factors from rat ASCs might play some role in facilitating the recovery of rat mesothelial cells. Hepatocyte growth factor was released from rat ASCs, and administration of recombinant hepatocyte growth factor increased rat mesothelial cell proliferation. CONCLUSIONS: Because the peritoneal mesothelium shows strong expression of membrane complement regulators such as Crry, CD55 and CD59, restoration of the mesothelial cell layer by rat ASCs might prevent deposition of complement activation products and ameliorate peritoneal injuries. This study suggests the therapeutic possibilities of intraperitoneal rat ASC injection to suppress peritoneal inflammation by restoring the mesothelial layer and decreasing complement activation in fungal or yeast peritonitis.

Geriatric nutritional risk index accurately predicts cardiovascular mortality in incident hemodialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in end-stage renal disease (ESRD) patients. Protein-energy wasting (PEW) or malnutrition is common in this population, and is associated with increasing risk of mortality. The geriatric nutritional risk index (GNRI) has been developed as a tool to assess the nutritional risk, and is associated with mortality not only in elderly patients but also in ESRD patients. However, whether the GNRI could predict the mortality due to CVD remains unclear in this population. We investigated the prognostic value of GNRI at initiation of hemodialysis (HD) therapy for CVD mortality in a large cohort of ESRD patients. METHODS: Serum albumin, body weight, and height for calculating GNRI were measured in 1568 ESRD patients. Thereafter, the patients were divided into quartiles according to GNRI levels [quartile 1 (Q1): < 84.9; Q2: 85.0-91.1; Q3: 91.2-97.2; and Q4: >97.3], and were followed up for up to 10 years. RESULTS: GNRI levels independently correlated with serum C-reactive-protein levels (ß = -0.126, p < 0.0001). Rates of freedom from CVD mortality for 10 years were 57.9%, 73.3%, 80.8%, and 89.2% in Q1, Q2, Q3, and Q4, respectively (p < 0.0001). The GNRI was an independent predictor of CVD mortality (hazard ratio 3.42, 95% confidence interval 2.05-5.70, p < 0.0001 for Q1 vs. Q4). C-index was also greater in an established CVD risk model with GNRI (0.749) compared to that with albumin (0.730), body mass index (0.732), and alone (0.710). Similar results were observed for all-cause mortality. CONCLUSION: GNRI at initiation of HD therapy could predict CVD mortality with incremental value of the predictability compared to serum albumin and body mass index in ESRD patients.

Palladium-catalyzed Z-selective oxidative amination of ortho-substituted primary anilines with olefins under an open air atmosphere.

The Pd-catalyzed oxidative amination of olefins with primary anilines has been achieved using molecular dioxygen as the sole oxidant. The use of ortho-substituted primary anilines such as ortho-toluidine was the key to the successful development of this reaction, providing the corresponding N-alkenyl substituted anilines in high yields with unusually high levels of Z-selectivity.

Messengers without borders: mediators of systemic inflammatory response in AKI.

The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli.

Low serum cultured adipose tissue-derived stromal cells ameliorate acute kidney injury in rats.

Current studies suggest that mesenchymal stromal cells (MSCs) improve acute kidney injury (AKI) via paracrine/endocrine effects. We established human adipose tissue-derived stromal cells (hASCs) cultured in low (2%) serum (hLASCs), which have great potential of tissue regeneration. The present study was performed to investigate the therapeutic effects of hLASCs on AKI and to clarify the mechanisms involved. In low serum, hASCs proliferated well, while human bone marrow-derived stromal cells (hBMSCs) did not. hLASCs secreted higher levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) than did hASCs cultured in high (20%) serum (hHASCs) or hBMSCs cultured in high serum (hHBMSCs). AKI was induced in nude rats by folic acid, and hLASCs, hHASCs or control medium were administered into the renal subcapsules. hLASCs significantly attenuated acute renal damage, while hHASCs showed far less effect. Furthermore, interstitial fibrosis observed on day 14 was less pronounced in the hLASCs group. Cell tracking experiment showed no evidence of transdifferentiation. Intravenous injection of hLASCs or hHBMSCs or subcapsular injection of hHBMSCs did not ameliorate AKI. Concerning the mechanisms, our in vivo experiments showed that HGF knockdown by siRNA impaired the ability of hLASCs to protect the kidney from acute injury whereas VEGF knockdown did not. In conclusion, hLASCs, but not hHASCs or hHBMSCs, ameliorated AKI via paracrine effects, and HGF is one of the key mediators.

Association of cardiac valvular calcifications and C-reactive protein with cardiovascular mortality in incident hemodialysis patients: a Japanese cohort study.

BACKGROUND: Cardiac valve calcification is seen frequently in patients undergoing dialysis. Serum C-reactive protein (CRP) level also is reported to predict future cardiovascular events. We investigated the association among valve calcification, CRP level, and mortality in patients with end-stage renal disease who were just beginning hemodialysis (HD) therapy. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: 1,290 consecutive patients who just started HD therapy were enrolled and were followed up to 10 years. PREDICTOR: Patients were divided into 3 groups according to number of calcified valves: those without valve calcification, those with calcification in a single (aortic or mitral) valve, and those with calcification in both valves. They also were divided into tertiles according to CRP level. OUTCOMES: Cardiovascular and all-cause mortality. MEASUREMENTS: Echocardiography and CRP measurement were performed within 1 month after beginning HD therapy. RESULTS: During follow-up (median, 51 months), 335 (25.9%) patients died, including 156 (12.1%) of cardiovascular disease. The adjusted HR for cardiovascular mortality was 2.80 (95% CI, 1.63-4.81) for 2 calcifications versus 0 (P < 0.001). Furthermore, the risk of cardiovascular mortality was 3.66-fold higher in patients with calcifications in both valves (highest tertile of CRP) compared with patients without valve calcification (lowest tertile of CRP; P < 0.001). LIMITATIONS: Precise medical treatments or therapeutic interventions were not evaluated. CONCLUSIONS: Valve calcification and elevated CRP levels were not only related to additively increased risk of mortality, but also improved the prediction of mortality in patients with end-stage renal disease who had just begun HD therapy.

Autologous cell therapy for cisplatin-induced acute kidney injury by using non-expanded adipose tissue-derived cells.

BACKGROUND AIMS: Recent studies have demonstrated that cultured mesenchymal stromal cells derived from adipose tissue are useful for regenerative cell therapy. The stromal vascular fraction (SVF) can be obtained readily without culturing and may be clinically applicable. We investigated the therapeutic effects of SVF and used it in the treatment of acute kidney injury (AKI). METHODS: Liposuction aspirates were obtained from healthy donors who had provided written informed consent. We harvested the SVF and determined the growth factor secretion and anti-apoptotic ability with conditioned medium. To investigate the effect of SVF on AKI, cisplatin was injected into rats and SVF was administrated into the subcupsula of the kidney. RESULTS: Both human and rat SVF cells secreted vascular endothelial growth factor-A (VEGF) and hepatocyte growth factor (HGF). Human SVF-conditioned media had an anti-apoptotic effect, which was inhibited by anti-HGF antibody (Ab) but not by anti-VEGF Ab. In vivo, SVF significantly ameliorated renal function, attenuated tubular damage and increased the cortical blood flow speed. In the SVF-treated group, VEGF levels in the cortex and HGF levels in both the cortex and medulla, especially tubules in the medulla, were significantly higher. Immunostaining revealed that SVF cells expressing VEGF and HGF and remained in the subcapsule on day 14. CONCLUSIONS: The present study demonstrates that a subcapsular injection of non-expanded SVF cells ameliorates rat AKI, and that the mechanism probably involves secretion of renoprotective molecules. Administration of human SVF may be clinically applicable and useful as a novel autologous cell therapy against kidney diseases.

A rare case of acute kidney injury associated with autoimmune hemolytic anemia and thrombocytopenia after long-term usage of oxaliplatin.

Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan.

Functional consequences of inhibiting exocytosis of Weibel-Palade bodies in acute renal ischemia.

Exocytosis of Weibel-Palade bodies (WPB) represents a distinct response of endothelial cells to stressors, and local release of WPB contents leads to systemic escalation of this response. We synthesized a glycine-(Nα-Et)lysine-proline-arginine (ITF 1697) peptide that has a potential to inhibit exocytosis of WPB and protect microcirculation. Here, we confirmed an inhibitory effect of ITF 1697 using intravital videoimaging and point-tracking of individual organelles. In an in vivo study, mice were implanted with Alzet osmotic pumps (10 µg ITF 1697·kg(-1)·min(-1) at volume of 1 µl/h) and subjected to renal ischemia (IRI). IRI resulted in marked renal injury and elevation of serum creatinine in mice treated with a vehicle. In contrast, renal injury and elevation of creatinine were significantly ameliorated in mice subjected to IRI and receiving ITF 1697. ITF 1697 prevented a systemic response to IRI: a significant surge in the levels of eotaxin and IL-8 (KC; both components of WPB), IL-1α, IL-1ß, and RANTES was all prevented or blunted by the administration of ITF 1697, whereas the levels of an anti-inflammatory, IL-10, and macrophage inflammatory protein-1α were upregulated in ITF 1697-treated animals. En face staining of aortic endothelial cells showed that WPB were depleted after 40-180 min post-IRI, and this was significantly blunted in aortic preparations obtained from mice treated with ITF 1697. WPB exocytosis contributed to IRI-associated mobilization of endothelial progenitor cells and hematopoietic stem cells, and ITF 1697 blunted their mobilization. Unexpectedly, 1 mo after IRI, mice treated with ITF 1697 showed a significantly more pronounced degree of scarring than nontreated animals. In conclusion, 1) application of ITF 1697 inhibits exocytosis of WPB and IRI; 2) the systemic inflammatory response of IRI is in part due to the exocytosis of WPB and its blockade blunts it; and 3) ITF 1697 improves short-term renal function after IRI, but not the long-term fibrotic complications.