Ling-Yu Yang

Therapeutic Effects of Umbilical Cord Blood-Derived Mesenchymal Stem Cell Transplantation in Experimental Lupus Nephritis:

Mesenchymal stem cells (MSCs) have been shown to possess immunomodulatory properties. Systemic lupus erythematosus is an autoimmune disease that results in nephritis and subsequent destruction of renal microstructure. We investigated whether transplantation of human umbilical cord blood-derived MSCs (uMSCs) is useful in alleviating lupus nephritis in a murine model. It was found that uMSCs transplantation significantly delayed the development of proteinuria, decreased anti-dsDNA, alleviated renal injury, and prolonged the life span. There was a trend of decreasing T-helper (Th) 1 cytokines (IFN-γ, IL-2) and proinflammatory cytokines (TNF-α, IL-6, IL-12) and increasing Th2 cytokines (IL-4, IL-10). The in vitro coculture experiments showed that uMSCs only inhibited lymphocytes and splenocytes proliferation but not mesangial cells. Long-term engraftment of uMSCs in the kidney was not observed either. Together, these findings indicated that uMSCs were effective in decreasing renal inflammation and alleviating experimental lupus nephritis by inhibiting lymphocytes, inducing polarization of Th2 cytokines, and inhibition of proinflammatory cytokines production rather than direct engraftment and differentiating into renal tissue. Therapeutic effects demonstrated in this preclinical study support further exploration of the possibility to use uMSCs from mismatched donors in lupus nephritis treatment.

The epidemiology and prognostic factors of mortality in critically ill children with acute kidney injury in Taiwan

The incidence of acute kidney injury (AKI) in critically ill children varies among countries. Here we used claims data from the Taiwanese National Health Insurance program from 2006 to 2010 to investigate the epidemiological features and identify factors that predispose individuals to developing AKI and mortality in critically ill children with AKI. Of 60,338 children in this nationwide cohort, AKI was identified in 850, yielding an average incidence rate of 1.4%. Significant independent risk factors for AKI were the use of extracorporeal membrane oxygenation, mechanical ventilation or vasopressors, intrinsic renal diseases, sepsis, and age more than 1 year. Overall, of the AKI cases, 46.5% were due to sepsis, 36.1% underwent renal replacement therapy, and the mortality rate was 44.2%. Multivariate analysis showed that the use of vasopressors, mechanical ventilation, and hemato-oncological disorders were independent predictors of mortality in AKI patients. Thirty-two of the 474 patients who survived had progression to chronic kidney disease or end-stage renal disease. Thus, although not common, AKI in critically ill children still has a high mortality rate associated with a variety of factors. Long-term close follow-up to prevent progressive chronic kidney disease in survivors of critical illnesses with AKI is mandatory.

Conditioned mesenchymal stem cells attenuate progression of chronic kidney disease through inhibition of epithelial-to-mesenchymal transition and immune modulation

Mesenchymal stem cells (MSCs) have been shown to improve the outcome of acute renal injury models; but whether MSCs can delay renal failure in chronic kidney disease (CKD) remains unclear. In the present study, the were cultured in media containing various concentrations of basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2‐phosphate to investigate whether hepatocyte growth factor (HGF) secretion could be increased by the stimulation of these growth factors. Then, TGF‐β1‐treated renal interstitial fibroblast (NRK‐49F), renal proximal tubular cells (NRK‐52E) and podocytes were co‐cultured with conditioned MSCs in the absence or presence of ascorbic acid 2‐phosphate to quantify the protective effects of conditioned MSCs on renal cells. Moreover, male Sprague‐Dawley rats were treated with 1 × 106 conditioned MSCs immediately after 5/6 nephrectomy and every other week through the tail vein for 14 weeks. It was found that basic fibroblast growth factor, epidermal growth factor and ascorbic acid 2‐phosphate promoted HGF secretion in MSCs. Besides, conditioned MSCs were found to be protective against TGF‐β1 induced epithelial‐to‐mesenchymal transition of NRK‐52E and activation of NRK‐49F cells. Furthermore, conditioned MSCs protected podocytes from TGF‐β1‐induced loss of synaptopodin, fibronectin induction, cell death and apoptosis. Rats transplanted with conditioned human MSCs had a significantly increase in creatinine clearance rate, decrease in glomerulosclerosis, interstitial fibrosis and increase in CD4+CD25+Foxp3+ regulatory T cells counts in splenocytes. Together, our studies indicated that conditioned MSCs preserve renal function by their anti‐fibrotic and anti‐inflammatory effects. Transplantation of conditioned MSCs may be useful in treating CKD.

OUTCOME AND RISK FACTORS FOR MORTALITY IN PEDIATRIC PERITONEAL DIALYSIS

♦ Background: The mortality rate among children requiring renal replacement therapy is higher than in children without end-stage renal disease (ESRD). Some factors, such as hypoalbuminemia, high peritoneal transport rate, age, malnutrition, cardiovascular disease, and recurrent peritonitis, appear to be associated with lower survival in adult peritoneal dialysis patients. Data regarding risk factors of mortality in children with continuous ambulatory peritoneal dialysis (CAPD) are limited. The aims of this study were to analyze the clinical characteristics of patients and investigate if routinely used laboratory and clinical variables are independent risk factors for mortality in children on CAPD. ♦ Methods: We performed a retrospective chart analysis of pediatric ESRD patients on CAPD between January 1997 and September 2008. 29 patients undergoing CAPD for more than 3 months were enrolled. An analysis was performed on clinical and biochemical variables for survivors and nonsurvivors to identify potential risk factors for mortality. ♦ Results: Mean age was 12.18 ± 4.57 years. During the follow-up period, 8 patients transferred to hemodialysis and 13 patients received deceased donor renal transplantation. By the end of the study, 5 patients had died. Actuarial survival rate at 2 and 5 years was 96.55% and 91.19% respectively. The major complication during therapy was peritonitis (1 episode/57.79 patient-months). In the univariate analysis, younger age at initiation of dialysis, presence of comorbid disease, higher peritoneal transport rate, increased protein losses through peritoneal dialysis, high total daily protein loss, hypoalbuminemia, and hypophosphatemia were variables associated with mortality in pediatric CAPD patients. However, in the multivariate analysis, only low serum albumin (b = –2.089, p = 0.006; hazard ratio 8.06, 95% confidence interval 0.028 – 0.546) was independently associated with mortality. ♦ Conclusion: Mortality was low in our pediatric patients receiving CAPD. Hypoalbuminemia showed a significant association with death in CAPD patients.

Epidemiology and Predictors of End-stage Renal Disease in Taiwanese Children With Idiopathic Nephrotic Syndrome

Background The incidence of idiopathic nephrotic syndrome (INS) varies among countries, with Asia reporting a higher incidence in comparison with Western countries. We investigated the epidemiologic features of INS and attempted to identify factors that predispose individuals to develop end-stage renal disease (ESRD). Methods Claims data from the Taiwanese National Health Insurance program from 1996 to 2008 were used to investigate the epidemiologic features and clinical variables of INS (International Classification of Diseases, Ninth Revision, Clinical Modification code, 581) in children younger than 18 years. Results We enrolled 4083 children (male-female ratio, 1.91:1). During the 13 years of observation, annual incidence decreased from 9.91 to 3.36 per 100 000 children. Annual number of hospital admissions progressively decreased during the first 3 years after diagnosis. At 3.14 ± 2.77 years after INS onset, ESRD had developed in 145 (3.6%) children. Independent predictors of ESRD included older age at onset, acute renal failure (ARF), hypertensive encephalopathy, and a histologic subtype with focal segmental glomerulosclerosis (FSGS). Conclusions Pediatric INS in Taiwan was more frequent in boys. Unlike India, the current incidence of pediatric INS in Taiwan is very similar to that reported in Western studies. Older age at disease onset, ARF, hypertensive encephalopathy, and FSGS on biopsy are important predictors of poor renal outcome.

Chronic graft-versus-host disease complicated by nephrotic syndrome

Chronic graft-versus-host disease (cGVHD) is one of the most frequent and serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Nephrotic syndrome (NS) is an uncommon and underrecognized manifestation of cGVHD. We report a patient who developed NS 18 months after allogeneic bone marrow transplantation. The onset of NS was accompanied by active manifestations of cGVHD, and immunosuppressants had not been tapered recently. Renal biopsy revealed membranous nephropathy. The patient failed to improve with three combined immunosuppressants (prednisolone, cyclosporine, and mycophenolate mofetil), but achieved partial remission after intravenous immunoglobulin (IVIG) infusion. Twenty-four months after the diagnosis of NS, the patient was still in hematological remission, with normal serum creatinine level, urinary protein loss of 0.7-1.9 g/day and mild oral mucositis. Our report suggests that NS can be a cGVHD-related immune disorder in HSCT patients. Monitoring of renal parameters, especially proteinuria, is important in cGVHD patients. Our case indicated that post-transplant NS, occurring without history of tapering or following immunosuppressant withdrawal, presents a more severe activity of cGVHD and a relatively severe clinical course. IVIG may modify and control the refractory GVHD-related NS, and can be one of the choices of treatment.

Eosinophilic peritonitis: An unusual manifestation of tuberculous peritonitis in peritoneal dialysis patient

Eosinophilic peritonitis is an uncommon clinical entity with diagnostic considerations separate from those of tuberculous peritonitis. We report a patient on continuous ambulatory peritoneal dialysis (CAPD) with eosinophilic peritonitis resulting from tuberculous peritonitis. Acid-fast stain and mycobacterial culture of peritoneal dialysis effluent were both negative result. In the peritoneal dialysis effluent and blood samples, Mycobacterium tuberculosis was detected by polymerase chain reaction analyses. The initiation of antituberculous therapy resulted in resolution of the eosionphilia in the dialysis effluent. After 14 days of antituberculous therapy, the polymerase chain reaction analyses of tuberculosis were negative for both the blood and peritoneal dialysis effluents. Evaluation of tuberculosis infection is necessary if the CAPD-related peritonitis presents with an unusual and unexplained clinical course. Polymerase chain reaction can play an important role in the diagnosis of tuberculous peritonitis in patients undergoing CAPD.

The Effects of Anti‐TNF‐α Antibody on Hyperprolactinemia‐Related Suppression of hCG‐Induced Testosterone Release in Male Rats

INTRODUCTION Hyperprolactinemia (hyperPRL)-related hypogonadism or suppression of human chorionic gonadotropin (hCG)-induced testosterone (T) release is hypothesized to be mediated by a testicular interstitial macrophage and tumor necrosis factor alpha (TNF-α)-involved blockage. AIM To test if the lower T response after hCG challenge in the hyperPRL rats is reversed by administrating anti-TNF-α antibody (Ab). METHODS HyperPRL was induced by allografting two anterior pituitary (AP) glands per rat. Control rats were grafted with similar amount of cerebral cortex. The testicular interstitial cells (TIC) were isolated from the testis 6 weeks after grafting. TIC was treated with anti-TNF-α Ab with or without hCG. The other groups of rats received intra-testicular or intra-muscular anti-TNF-α Ab 7 days before in vitro study. The TIC isolated from each testis was incubated and T release with or without hCG challenge were measured. MAIN OUTCOME MEASURES Prolactin (PRL) and T were measured by radioimmunoassay. TNF-α was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS When low dose of anti-TNF-α Ab was administered to the TIC incubation, the effects of PRL-related suppression of hCG-stimulated T release were not significant. While a higher dose of anti-TNF-α Ab almost abolished the suppressive effects of PRL to hCG-stimulated T release. Prior intra-testicular or intra-muscular administration of anti-TNF-α Ab reversed the suppressive effects of AP grafting on TICs T release. This was demonstrated in groups with anti-TNF-α Ab injection both 7 and 1 day prior to TIC incubations. CONCLUSIONS The data support the hypothesis that the suppression of hCG-induced T release associated with hyperPRL is through a TNF-α-mediated mechanism to suppress the Leydig cells. The effect of anti-TNF-α Ab is durable for at least 7 days. Besides intra-testicular injection, there might be other ways available for administrating Ab. Anti-TNF-α Ab has a potential therapeutic application on hyperPRL-induced hypogonadism or suppression of hCG-induced T release.

Mixed simulation course increases participants' positive stress coping abilities

Background: Lack of health professional awareness of interprofessional collaborative practice (IPCP) often results in stress and conflicts between team members in the medical system. Our study aimed to compare the effectiveness of mixed simulation‐interprofessional education (IPE) courses to enhance coping strategies for IPCP‐associated stress. Methods: Participants (n = 54) from the disciplines of physicians (n = 12), nurses (n = 28) and pharmacists (n = 14) were enrolled. Over the course of the study period, all participants were asked to complete pre‐course (T1), post‐course (T2) and end‐of‐study (T3) questionnaires for self‐assessment of perceived stress scale (PSS), stress coping preference scale (SCPS), and IPCP proficiency. Results: Basically, physicians felt less IPCP‐associated stress than did nurses and pharmacists. For physicians, nurses and pharmacists, the mean post‐course (T2) PSS scores were significantly lower than pre‐course (T1) PSS scores, which indicated decreased IPCP‐associated stress after mixed simulation‐IPE courses. In comparison with physicians, the greater difference (T2–T1 scores) in the PSS and positive coping SCPS subscales scores were noted among nurses and pharmacists. For nurses and pharmacists, the further improvements in stress coping abilities (PSS scale and positive SCPS subscale) were noted at the end‐of‐study self‐assessment by comparison of post‐course scores with end‐of‐study scores. For IPCP proficiency, all participants gave more positive responses to the specific questions in the end‐of‐study questionnaires. Conclusion: Our study supports the use of mixed simulation‐IPE courses as part of continuing education to enhance positive stress coping strategies.

Peer-assisted learning model enhances clinical clerk's procedural skills

Background: Failure to transfer procedural skills learned in a laboratory to the bedside is commonly due to a lack of peer support/stimulation. A digital platform (Facebook) allows new clinical clerks to share experiences and tips that help augment their procedural skills in a peer‐assisted learning/teaching method. This study aims to investigate the effectiveness of the innovation of using the digital platform to support the transfer of laboratory‐trained procedural skills in the clinical units. Methods: Volunteer clinical clerks (n = 44) were enrolled into the peer‐assisted learning (PAL) group, which was characterized by the peer‐assisted learning of procedural skills during their final 3‐month clinical clerkship block. Other clerks (n = 51) did not join the procedural skills‐specific Facebook group and served as the self‐directed learning regular group. The participants in both the PAL and regular groups completed pre‐ and post‐intervention self‐assessments for general self‐assessed efficiency ratings (GSER) and skills specific self‐assessed efficiency ratings (SSSER) for performing vein puncture, intravenous (IV) catheter and nasogastric (NG) tube insertion. Finally, all clerks received the post‐intervention 3‐station Objective Structured Clinical Skills Examination (OSCE) to test their proficiency for the abovementioned three procedural skills. Results: Higher cumulative numbers of vein punctures, IV catheter insertions and NG tube insertions at the bedside were carried out by the PAL group than the regular group. A greater improvement in GSERs and SSSERs for medical procedures was found in the PAL group than in the regular group. The PAL group obtained higher procedural skills scores in the post‐intervention OSCEs than the regular group. Conclusion: Our study suggested that the implementation of a procedural skill‐specific digital platform effectively helps clerks to transfer laboratory‐trained procedural skills into the clinical units. In comparison with the regular self‐directed learning group, the peer‐assisted learning characteristics of Facebook give additional benefits to the PAL group by enhancing their procedural skills.