ABSTRACT
PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT). METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs). RESULTS: In approximately 5% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development. CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.
Subject(s)
DNA Copy Number Variations , Exome Sequencing/methods , Genetic Predisposition to Disease/genetics , Urogenital Abnormalities/diagnosis , Vesico-Ureteral Reflux/diagnosis , Adolescent , Child , Child, Preschool , Female , Forkhead Transcription Factors/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Humans , Infant , Intracellular Signaling Peptides and Proteins/genetics , Male , Nuclear Proteins/genetics , PAX2 Transcription Factor/genetics , Pedigree , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatases/genetics , Repressor Proteins/genetics , Urogenital Abnormalities/genetics , Vesico-Ureteral Reflux/genetics , Young AdultABSTRACT
Minimizing IS to reduce side effects without compromising long-term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two-drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan-Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log-rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre-emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three-drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy-proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two-drug maintenance regimen had no adverse effect on long-term transplant outcome and had low malignancy and infection rates.
Subject(s)
Immunosuppression Therapy/methods , Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Renal Insufficiency/surgery , Adolescent , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Biopsy , Child , Cyclosporine/administration & dosage , Cyclosporine/therapeutic use , Daclizumab , Drug Therapy, Combination , Female , Follow-Up Studies , Graft Survival , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Kaplan-Meier Estimate , Male , Multivariate Analysis , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/therapeutic use , Prednisone/administration & dosage , Prednisone/therapeutic use , Proportional Hazards Models , Retrospective Studies , Tacrolimus/administration & dosage , Tacrolimus/therapeutic use , Time Factors , Treatment Outcome , Young AdultABSTRACT
Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult patients with chronic kidney disease (CKD). This randomized, open-label, crossover study was conducted to determine the pharmacokinetic profile of darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of age with CKD were randomized and received a single 0.5 micro g/kg dose of darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a 14- to 16-day washout period, patients received an identical dose of darbepoetin alfa by the alternate route. After IV administration, the mean clearance of darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h. After SC administration, absorption was rate limiting, with a mean terminal half-life of 42.8 h and a mean bioavailability of 54%. Comparison of these results with those from a previous study of darbepoetin alfa in adult patients indicated that the disposition of darbepoetin alfa administered IV or SC is similar in adult and pediatric patients, although absorption may be slightly more rapid in pediatric patients after SC dosing. The mean terminal half-life of darbepoetin alfa in this study was approximately two- to fourfold longer than that previously reported for epoetin in pediatric patients.
Subject(s)
Erythropoietin/analogs & derivatives , Erythropoietin/pharmacokinetics , Kidney Failure, Chronic/metabolism , Adolescent , Adult , Area Under Curve , Biological Availability , Child , Child, Preschool , Cross-Over Studies , Darbepoetin alfa , Enzyme-Linked Immunosorbent Assay , Female , Half-Life , Humans , Infant , Injections, Intravenous , Injections, Subcutaneous , Male , Renal DialysisABSTRACT
BACKGROUND: Transplantation is the optimal therapy for pediatric end-stage renal disease (ESRD) patients, but in a subset of patients with peritoneal membrane failure, failed transplants or poor social situations, chronic hemodialysis (HD) remains the only option. Long-term survival of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) in pediatric patients has not been well described. METHODS: We studied the survival of permanent vascular access in 34 pediatric ESRD patients treated with chronic HD at our institution between 1/1/89 and 12/1/95 and followed to 12/31/2000. RESULTS: Twenty-four AVFs and 28 AVGs were created in 19 and 23 patients, respectively. Mean age and weight at insertion were 15.1 years (range 7.1 to 20.9) and 46 kg (18 to 81) for AVFs and 13.3 years (3.8 to 21.1) and 41.5 kg (10.5 to 145) for AVGs. Fifteen patients weighed <35 kg at the time of access creation (7 AVFs in 5 patients, 14 AVGs in 13 patients). Excluding primary failures, one-year, three-year and five-year patency rates for AVFs (74%, 59%, 59%) and AVGs (96%, 69%, 40%) were not significantly different. Patency did not correlate with patient weight or age at access creation. Primary access failure occurred more often (P < 0.01) in AVFs (8/24) compared to AVGs (1/28). Access thrombosis, stenosis and infection occurred more frequently in AVG (P = 0.02). CONCLUSIONS: Both AVF and AVG function well even in small pediatric patients and have survival rates equivalent to adult series and longer than cuffed venous catheters in pediatric patients. Both AVFs and AVGs are preferable for long-term HD access in pediatrics.
