Ginevri F.,Instituto G Gaslini |
Nocera A.,S Martino Instituto Nazionale Per La Ricerca Sul Cancro |
Comoli P.,Pediatric Hematology Oncology |
Innocente A.,Transplantation Immunology |
And 14 more authors.
American Journal of Transplantation | Year: 2012
The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
Kocaoglu M.,Near East University |
Gok F.,Pediatric Nephrology
Diagnostic and Interventional Radiology | Year: 2015
Several vascular abnormalities related with urinary system such as crossing accessory renal vessels, retroiliac ureters, retrocaval ureters, posterior nutcracker syndrome, and ovarian vein syndrome may be responsible for urinary collecting system obstruction. Split-bolus magnetic resonance urography (MRU) using contrast material as two separate bolus injections provides superior demonstration of the collecting system and obstructing vascular anomalies simultaneously and enables accurate preoperative radiologic diagnosis. In this pictorial review we aimed to outline the split-bolus MRU technique in children, list the coexisting congenital collecting system and vascular abnormalities, and exhibit the split-bolus MRU appearances of concurrent urinary collecting system and vascular abnormalities. © Turkish Society of Radiology 2015.
PubMed | Pediatric Nephrology., Pediatric Nephrology, University of Cologne, University of Texas Southwestern Medical Center and Nephrology and.
Type: Journal Article | Journal: Journal of the American Society of Nephrology : JASN | Year: 2016
Hypercalciuria is a major risk factor for nephrolithiasis. We previously reported that Uromodulin (UMOD) protects against nephrolithiasis by upregulating the renal calcium channel TRPV5. This channel is crucial for calcium reabsorption in the distal convoluted tubule (DCT). Recently, mutations in the gene encoding Mucin-1 (MUC1) were found to cause autosomal dominant tubulointerstitial kidney disease, the same disease caused by UMOD mutations. Because of the similarities between UMOD and MUC1 regarding associated disease phenotype, protein structure, and function as a cellular barrier, we examined whether urinary MUC1 also enhances TRPV5 channel activity and protects against nephrolithiasis. We established a semiquantitative assay for detecting MUC1 in human urine and found that, compared with controls (n=12), patients (n=12) with hypercalciuric nephrolithiasis had significantly decreased levels of urinary MUC1. Immunofluorescence showed MUC1 in the thick ascending limb, DCT, and collecting duct. Applying whole-cell patch-clamp recording of HEK cells, we found that wild-type but not disease mutant MUC1 increased TRPV5 activity by impairing dynamin-2- and caveolin-1-mediated endocytosis of TRPV5. Coimmunoprecipitation confirmed a physical interaction between TRPV5 and MUC1. However, MUC1 did not increase the activity of N-glycan-deficient TRPV5. MUC1 is characterized by variable number tandem repeats (VNTRs) that bind the lectin galectin-3; galectin-3 siRNA but not galectin-1 siRNA prevented MUC1-induced upregulation of TRPV5 activity. Additionally, MUC1 lacking VNTRs did not increase TRPV5 activity. Our results suggest that MUC1 forms a lattice with the N-glycan of TRPV5 via galectin-3, which impairs TRPV5 endocytosis and increases urinary calcium reabsorption.
News Article | December 7, 2016
When it came time to blow out his candles on his 14th birthday, Estefano Reano had only one wish: a new heart. Just 40 minutes later, the Pediatric Heart Transplant team at Joe DiMaggio Children’s Hospital surprised his family with a phone call that made his wish come true making the Weston teen the hospital’s 30th heart transplant recipient. “He was playing at home, when we got the phone call telling us there was a heart for Estefano,” said Alfonso Ospino, the teen’s stepfather. “I went to my wife with phone in hand with the news and then turned around and said to our son ‘get ready there is another gift waiting for you.'” Today, he is the living legacy of a donor family who gave this pediatric heart transplant patient with a gift of a new life with his family, physicians and medical staff and in time to go home for the holidays. Emotions were high at a press conference on Tuesday at the Conine Clubhouse, located adjacent to JDCH, where Estefano and his family were reunited with the heart transplant team. They came to express their gratitude and give moving tributes and heartfelt testimonials urging the community to become organ donors. “I am so happy to be here and I am so thankful to everyone,” said Estefano. “I want to do many things like travel and I want to one day run a sanctuary for endangered animals. I thank the family for giving someone like me a second chance to live the life that I always wanted.” “I prayed and have been grateful to be able to care for my son at home with the help of these doctors,” said Roxana Fergusson, the teen’s mom – “I know there are many children who do not have that opportunity and must live and wait for their hearts in a hospital room. Most importantly we pray for the family who donated, and I thank them for giving us this gift because I know now that my son has the heart of an angel because of them.” Members of the transplant team spoke about Estefano’s condition that led to his need for a heart transplant and the technological advances that allow children to wait longer than previously possible. According to the team of doctors at JDCH, every child’s unique conditions presents a unique situation and complexity. In the case of Estefano, he was born with a structural heart condition known as single ventricle heart defect, a condition where the heart is not using all four chambers of the heart to function normally. Estefano underwent five open heart surgeries since the age of 2. While the surgeries allowed his heart to function better and sustain. The surgeries worked for a few years until he began to further grow. A few years ago, his heart began to fail and the team assessed the need to put him on the transplant list. “Estefano waited over two years for his heart,” said Maryanne R. K. Chrisant, M.D., Director, Pediatric Cardiac Transplant, Heart Failure & Cardiomyopathy at JDCH. “He and his family realize that receiving a heart transplant is a second chance for Estefano to lead a more normal life. Estefano is looking forward to returning to school, going out to play athletics and being outside with his friends. His successful course and future dreams coincide with our 30th transplant celebration.” “As a pediatric heart transplant team here at Joe DiMaggio we have had the privilege to care for 30 children and provide them with an opportunity for a new life, and that is truly an amazing and humbling feeling,” said Frank Scholl, M.D. Surgical Director of Heart Transplantation at JDCH. “At this time of this great joy, we need to remember to thank our donor families who have given the ultimate gift to another human being, we could simply not do this without them.” A video of the surgeons and nurses singing Happy Birthday inside the operating room after a successful surgery spread rapidly after it was posted on the Joe DiMaggio Children’s Hospital Facebook page. The Pediatric Heart Transplant program at JDCH opened on December 10, 2010, when approval at the federal level from UNOS (United Network for Organ Sharing) was granted. The approval of the program was the culmination of years of strategic planning, including the formation of a pediatric cardiac transplant team with the right mix of expertise and compassion. Five days after program approval, the hospital’s first pediatric heart transplant was performed by the expert cardiac transplant team. In 1992, Joe DiMaggio himself helped Memorial Healthcare System celebrate the opening of the first Joe DiMaggio Children’s Hospital. Today’s 224-bed hospital opened in 2011 and offers a safe, compassionate and nurturing environment for young patients and their families. With more than 600 board-certified physicians on staff, the hospital’s broad range of pediatric specialties includes: Heart Institute, Center for Cancer and Blood Disorders, Cleft and Craniofacial Center, Cystic Fibrosis and Pulmonary Center, Emergency Department and Trauma Center, Endocrinology, General and Thoracic Surgery, Orthopedics, Pediatric Nephrology and Hypertension Program; Pediatric Intensive Care Unit, Wasie Neonatal Intensive Care Unit, [U18] Sports Medicine, Outpatient Services and Inpatient/Outpatient Rehabilitation Program.
News Article | November 28, 2016
The message on the shirt Naida Revelo wore in her first 5K run made it clear what motivated the grandmother to take on the physical challenge: “Joe D’s Saved My Grandson’s Life.” Revelo was among the more than 6,000 people who participated in the 2016 Tour de Broward, with each having their own reasons for cycling, running, or walking. A similar number is expected again in 2017, each of them united by a desire to support Joe DiMaggio Children’s Hospital, the region’s largest pediatric facility serving Broward, Palm Beach, and northern Miami-Dade counties. The same facility that has impacted many lives. “This is an opportunity for the South Florida community to assist our efforts to provide safe, high quality, cost-effective, patient and family-centered care,” said Memorial Healthcare System President & CEO Aurelio M. Fernandez, III, FACHE. “We want everyone in our community to get involved.” The event – which takes place Sunday, February 26, at Miramar Regional Park – has raised more than $2.5 million in its previous seven years for Joe DiMaggio Children's Hospital, a facility that provides care regardless of one’s ability to pay. Sponsored by ANF Group, Tour de Broward consists of 50 and 100K bicycle rides, a 5K timed run, 3K walk, and the “Power of Play Kid Zone,” a sports-themed, fun area for children 13 or younger. The 100K ride starts at 7:00 a.m., run at 8:00 am and walk at 9:00 a.m. Pre-registration and day-of registration fees range from $15-$50, depending on the event and sign-up date. Participants can register in advance at http://www.tourdebroward.com or at the park on the day of the event. Pre-registration takes place until noon Saturday, February 25. For runners and riders there is an additional fundraising commitment, however, some exceptions apply. Please refer to Event Information on the Tour de Broward website at http://www.tourdebroward.com. Due to construction at the park, all participant and volunteer parking will be held on the grounds of Memorial Hospital Miramar, 1901 SW 172 Ave., Miramar, Florida. There will be no parking permitted at the park. Shuttles will be provided. To learn about sponsorship opportunities, call (954) 265-7241. For general information about the event, call (954) 905-5633. In 1992, Joe DiMaggio himself helped Memorial Healthcare System celebrate the opening of the first Joe DiMaggio Children’s Hospital. Today’s 224-bed hospital opened in 2011 and offers a safe, compassionate and nurturing environment for young patients and their families. With more than 600 board-certified physicians on staff, the hospital’s broad range of pediatric specialties includes: Heart Institute, Center for Cancer and Blood Disorders, Cleft and Craniofacial Center, Cystic Fibrosis and Pulmonary Center, Emergency Department and Trauma Center, Endocrinology, General and Thoracic Surgery, Orthopedics, Pediatric Nephrology and Hypertension Program; Pediatric Intensive Care Unit, Wasie Neonatal Intensive Care Unit, [U18] Sports Medicine, Outpatient Services and Inpatient/Outpatient Rehabilitation Program.
Zaloszyc A.,University of Strasbourg |
Schaefer B.,University of Heidelberg |
Schaefer F.,University of Heidelberg |
Krid S.,Pediatric Nephrology |
And 4 more authors.
Pediatric Nephrology | Year: 2013
Background: Hypertension is frequent in chronic hemodialyzed patients and usually treated by reducing extracellular fluid. Probing dry weight only based on a clinical evaluation may be hazardous, especially in case of volume independent hypertension. Methods: We performed a 1-year retrospective study in three pediatric centers to define the relation between blood pressure (BP) and hydration status, assessed by whole-body bioimpedance spectroscopy (BIS). We analyzed 463 concomitant measurements of BP, relative overhydration (rel.OH), and plasma sodium (Napl) in 23 children (mean age 13.9 ± 5.1 years). Results: Pre-dialytic under-hydration (rel.OH < -7 %) was present in 5.4 % of the sessions, out of which 24 % showed hypertension. Normohydration (rel.OH -7 - +7 %) was observed in 62.4 % of the sessions, 45.3 % of them revealed hypertension. Moderate OH (rel.OH +7 - +15 %) was present in 21 % of the sessions, 47.4 % of them showed normal BP. In 11.2 % of the sessions, severe overhydration (rel.OH > +15 %) was assessed, however, the majority (73 %) showed normal BP. Patient-specific Napl setpoint could not be described. Mean dialysate sodium concentration was higher than mean Napl. Conclusions: Hypertension is not always related to overhydration. Therefore, BIS should restrict the practice of "probing dry weight" in hypertensive children. Moreover, sodium dialytic balance needs to be considered to improve BP management. © 2013 IPNA.
PubMed | Institute of Medical Biometry and Informatics, Pediatric Nephrology, University of Strasbourg and Center for Pediatric and Adolescent Medicine
Type: Journal Article | Journal: Pediatric nephrology (Berlin, Germany) | Year: 2016
Modern hemodialysis (HD) machines are able to measure ionic dialysance online and thereby continuously monitor Kt/V. The accuracy of measurement depends on the input of the correct urea distribution volume (V), available from anthropometric equations and body composition monitoring (BCM). The latter method, however, has not been validated in children.We compared V determined by BCM to that calculated using four different anthropometric formulas (Morgenstern, Mellits and Cheek, Hume-Weyers and Watson equations) in 23 pediatric HD patients. We also compared online Kt/V using BCM-derived V with the Kt/V calculated from pre- and post-dialytic urea concentrations using the single-pool second-generation Daugirdas equation.The V calculated by the Morgenstern equation was similar to that derived by BCM, with a mean difference of -0.7% (95% limits of agreement -11.7 to 10.3%). In contrast, the V calculated by the other equations was 5.4, 6.2 and 18%, respectively higher than the BCM-derived V. The mean difference between Kt/V calculated using the Daugirdas equation and online Kt/V determination based on BCM-derived V data was 0.10 (95% limits of agreement -0.50 to 0.70%).In our pediatric HD patients the V measured by BCM was in agreement with that calculated using the Morgenstern equation, which is the only equation which has been validated to date in children on dialysis. Online determination of Kt/V using a BCM-derived V largely agreed with that calculated by the Daugirdas equation. We therefore conclude that the former approach is suitable for frequent online assessment of dialytic small solute clearance.
News Article | November 19, 2016
SAN DIEGO, Nov. 19, 2016 (GLOBE NEWSWIRE) -- Retrophin, Inc. (NASDAQ:RTRX) today announced additional results from the Phase 2 DUET study of sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS), a rare kidney disorder without an FDA-approved pharmacologic treatment that often leads to end-stage renal disease. These new findings are being presented today in the late-breaking High-Impact Clinical Trials oral session at the American Society of Nephrology (ASN) Kidney Week 2016 in Chicago. “The prevalence of FSGS is on the rise and without an approved therapy, many patients diagnosed with the disorder face a progressive decline and the high likelihood of end-stage renal disease,” said Howard Trachtman, MD, Professor of Pediatrics; Director, Division of Pediatric Nephrology, NYU School of Medicine, NYU Langone Medical Center. “These findings from the DUET study underscore the potential of sparsentan as a first-in-class treatment for FSGS.” As announced in September, top-line data from DUET showed the sparsentan treatment group achieved statistical significance in the study’s primary efficacy endpoint, reduction of proteinuria. These results showed a greater than two-fold reduction of proteinuria compared to irbesartan, after an eight-week, double-blind treatment period. An analysis of the secondary endpoint presented today showed that a significantly greater proportion of patients receiving sparsentan achieved modified partial remission of proteinuria, compared to irbesartan-treated patients. Modified partial remission, defined as proteinuria levels of less than or equal to 1.5 g/g and greater than 40 percent reduction of proteinuria from baseline, is associated with long-term preservation of renal function in FSGS. In addition, four patients receiving sparsentan achieved complete remission, compared to zero irbesartan-treated patients. Also presented today was a post-hoc, intention-to-treat (ITT) analysis showing that the sparsentan treatment group again demonstrated a greater than two-fold reduction of proteinuria, compared to irbesartan. Further analysis of the safety database from the initial eight-week, double-blind treatment period presented today showed sparsentan was generally safe and well-tolerated. “These new results add to the growing body of evidence from the DUET study, reinforcing our confidence that sparsentan may represent a significant advancement in the treatment of FSGS,” said Stephen Aselage, chief executive officer of Retrophin. “We thank the DUET investigators for their diligence, as well as the patients and their families for their commitment to finding new and better treatment options for FSGS.” New findings from the DUET study presented at ASN Kidney Week include: The DUET study is an international, randomized, double-blind, Phase 2 clinical trial assessing the safety and efficacy of sparsentan in 109 patients with primary focal segmental glomerulosclerosis (FSGS), of which 96 qualified for the evaluable efficacy database. The primary endpoint is the reduction of proteinuria, as compared to irbesartan, which is part of a class of drugs used to manage FSGS in the absence of an FDA-approved pharmacologic treatment. After a two-week washout period, patients were randomized to receive daily oral doses of 200 mg, 400 mg, and 800 mg of sparsentan or 300 mg of irbesartan. After completing an initial eight weeks of randomized treatment, all patients were eligible to receive sparsentan as part of the study’s open-label extension. Focal segmental glomerulosclerosis, or FSGS, is a rare disorder without an FDA-approved pharmacologic treatment option that is estimated to affect up to 40,000 patients in the U.S. with similar prevalence in Europe. The disorder is defined by progressive scarring of the kidney and often leads to end-stage renal disease. FSGS is characterized by proteinuria, where protein is found in the urine due to a breakdown of the normal filtration mechanism in the kidney. Other common symptoms include swelling in parts of the body known as edema, as well as low blood albumin levels, abnormal lipid profiles, and hypertension. Reduction in proteinuria is widely regarded to be beneficial in the treatment of FSGS, and may be associated with a decreased risk of progression to end-stage renal disease. Achieving modified partial remission of proteinuria, defined as proteinuria levels of less than or equal to 1.5 g/g and greater than 40 percent reduction of proteinuria from baseline, is associated with long-term preservation of renal function in patients with FSGS. In the absence of an FDA-approved pharmacologic treatment, patients with FSGS are currently managed with angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcineurin inhibitors, and steroids. Sparsentan could be the first FDA-approved pharmacologic treatment for focal segmental glomerulosclerosis, or FSGS, a rare kidney disorder that often leads to end-stage renal disease. Sparsentan’s dual mechanism of action combines angiotensin receptor blockade with endothelin receptor type A blockade. In several forms of chronic kidney disease, endothelin receptor blockade has been shown to have an additive beneficial effect on proteinuria in combination with renin-angiotensin blockade via angiotensin receptor blockade or angiotensin converting enzyme inhibitors. The Phase 2 DUET study of sparsentan met the primary efficacy endpoint for the combined treatment group, demonstrating a greater than two-fold reduction of proteinuria compared to irbesartan, after the eight-week, double-blind treatment period. The Company is working with the FDA to determine the most expeditious path forward to advance the development of sparsentan towards approval. In 2015, the FDA and European Commission each granted sparsentan orphan drug designation for the treatment of FSGS. Retrophin is a fully integrated biopharmaceutical company dedicated to delivering life-changing therapies to people living with rare diseases who have few, if any, treatment options. The Company’s approach centers on its pipeline featuring clinical-stage assets targeting rare diseases with significant unmet medical needs, including sparsentan for focal segmental glomerulosclerosis (FSGS), a disorder characterized by progressive scarring of the kidney often leading to end-stage renal disease, and RE-024 for pantothenate kinase-associated neurodegeneration (PKAN), a life-threatening neurological disorder that typically begins in early childhood. Research exploring the potential of early-stage assets in several rare diseases is also underway. Retrophin’s R&D efforts are supported by revenues from the Company’s commercial products Thiola®, Cholbam®, and Chenodal®. This press release contains “forward-looking statements” as that term is defined in the Private Securities Litigation Reform Act of 1995. In addition, expressions of our strategies, intentions or plans are also forward-looking statements. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are risks and uncertainties associated with the Company’s business and finances in general, as well as risks and uncertainties associated with the Company’s research, preclinical, and clinical-stage pipeline. Specifically, the Company faces the risk that additional clinical trials will be required for regulatory approvals, risk that additional clinical trials, if any, will fail to demonstrate that sparsentan is safe or effective, and risk that the sparsentan program will be delayed for regulatory or other reasons. You are cautioned not to place undue reliance on these forward-looking statements as there are important factors that could cause actual results to differ materially from those in forward-looking statements, many of which are beyond our control. The Company undertakes no obligation to publicly update forward-looking statements, whether as a result of new information, future events, or otherwise. Investors are referred to the full discussion of risks and uncertainties as included in the Company’s filings with the Securities and Exchange Commission.
Krid S.,Pediatric Nephrology |
Roumenina L.T.,French Institute of Health and Medical Research |
Roumenina L.T.,University of Paris Descartes |
Beury D.,Laboratoire dImmunologie |
And 6 more authors.
American Journal of Transplantation | Year: 2012
We report the first observation of successful kidney transplantation under pre-emptive eculizumab treatment in a 7-year-old boy with atypical hemolytic uremic syndrome (aHUS) and a known hybrid CFH/CFHR1 gene, who was dependent on plasma therapy during the 3-year dialysis period. The hybrid CFH/CFHR1 protein has an altered C3b/C3d binding, is incapable to protect cells from complement attack and is directly implicated in aHUS pathogenesis. There was no evidence of recurrence during the first 16-month follow-up period. We conclude that eculizumab alone, without plasma therapy (plasma infusion and/or plasma exchange), is sufficient to prevent recurrence of aHUS and to maintain long-term graft function. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
PubMed | Pediatric Hepatology, Pediatric Nephrology and Laboratory of Immunology
Type: Journal Article | Journal: Pediatric nephrology (Berlin, Germany) | Year: 2016
Rational options for the treatment of end-stage renal disease (ESRD) due to atypical hemolytic uremic syndrome (aHUS) in children are still open to discussion. In the case of human complement factor H (CFH) deficiency, the choice is either kidney transplantation in combination with eculizumab, a humanized anti-C5 monoclonal antibody, or a combined liver-kidney transplantation.A child with a homozygous CFH deficiency underwent a successful liver-kidney transplantation. CFH levels normalized within days. After 6years of follow-up, the graft function (Cockroft clearance 100ml minThe results of this long-term follow-up confirm that combined liver-kidney transplantation remains a reasonable option in patients with ESRD due to aHUS when an identified genetic abnormality of the C3 convertase regulator synthesized in the liver has been identified.