Jei-Wen Chang

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.

Evaluation of imaging studies for vesicoureteral reflux in infants with first urinary tract infection.

BACKGROUND Routine imaging studies following first urinary tract infection(UTI) in infancy are clinically used to identify who has vesicoureteral reflux (VUR) and acute pyelonephritis or renal scars. The potential value of these images in avoiding children acquiring renal complication and whether the children benefited from these examinations were not well justified. METHODS Analysis was undertaken of 114 infants (228 renal units) at the time of first documented UTI. All underwent renal ultrasound, voiding cystourethrography (VCUG) and dimercaptosuccinic acid (DMSA) renal scan on admission and repeated follow-up VCUG, DMSA or both after 4-6 months if initial examinations showed abnormal at first time. The VUR on VCUG when UTI and its statistical correlations with both acute and follow-up DMSA renal scan revealing renal scar were calculated. RESULTS Seventeen children (14.9%) had VUR detected by VCUG. Forty-six patients (40.4%) had abnormal findings on acute DMSA renal scans (acute pyelonephritis or renal scars). The sensitivity, specificity, positive prediction rate and negative prediction rates of DMSA for VUR were 63%, 82.6%, 32.7% and 94.3%, respectively. The initial identified VUR versus renal scarring on follow-up DMSA showed little correlation. CONCLUSIONS There is limited effectiveness of routine investigation by VCUG in infants with first confirmed UTI. VCUG may be withheld in a child who presents with first UTI before the age of one year if there has been no demonstrable abnormal DMSA scan.

Amelioration of paraquat-induced pulmonary injury by mesenchymal stem cells.

Acute paraquat (PQ) poisoning induces redox cycle and leads to fatal injury of lung. Clinical management is supportive in nature due to lack of effective antidote, and the mortality is very high. Mesenchymal stem cells (MSCs) process the properties of immunomodulation, anti-inflammatory, and antifibrotic effects and oxidative stress resistance. MSC transplantation may theoretically serve as an antidote in PQ intoxication. In this study, we examined the potential therapeutic effects of MSCs in PQ-induced lung injury. The degree of PQ toxicity in the rat type II pneumocyte cell line, L2, and MSCs was evaluated by examining cell viability, ultrastructural changes, and gene expression. L2 cells treated with 0.5 mM PQ were cocultured in the absence or presence of MSCs. For the in vivo study, adult male SD rats were administered an intraperitoneal injection of PQ (24 mg/kg body weight) and were divided into three groups: group I, control; group II, cyclophosphamide and methylprednisolone; group III, MSC transplantation 6 h after PQ exposure. MSCs were relatively resistant to PQ toxicity. Coculture with MSCs significantly inhibited PQ accumulation in L2 cells and upregulated the expression of antioxidative heme oxygenase 1 and metallothionein 1a genes, reversed epithelial-to-mesenchymal transition, and increased the viability of PQ-exposed L2 cells. Treatment with MSCs resulted in a significant reduction in severity of liver and renal function deterioration, alleviated lung injury, and prolonged the life span of rats. Altogether, our results suggest that MSCs possess antidote-like effect through multifactorial protection mechanism. The results of this preclinical study demonstrate that transplantation of MSCs may be a promising therapy and should be further validated clinically.

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.

Extreme Hypernatremia Combined With Rhabdomyolysis and Acute Renal Failure

Rhabdomyolysis is a life-threatening condition that involves muscle cell destruction. Among its etiologies, severe hypernatremia is a less common cause. We report a teenage girl with congenital central hypoventilation syndrome and hypothalamus dysfunction syndrome who presented with extreme hypernatremia (sodium, 211 mmol/L) with rhabdomyolysis (creatine kinase, 32,850 U/L) and acute renal failure (creatinine, 6.1 mg/dL) following gastroenteritis with 7-kg weight loss. Rhabdomyolysis subsequently led to acute renal failure and hyperkalemia. Acute hemodialysis was initiated on hospital day 3 for hyperkalemia. This resulted in a 13 mmol/L fall in serum sodium in 3 hours despite using a 156 mmol/L sodium bath, but without the development of cerebral edema or neurological defect. This report highlights an unusual cause of rhabdomyolysis in children and the experience of managing such a difficult clinical situation.