ABSTRACT
BACKGROUND: Alemtuzumab has been used in off-label studies of solid organ transplantation. METHODS: We analyzed the first 42 pediatric consecutive living donor kidney transplantations under alemtuzumab pretreatment with tacrolimus monotherapy and subsequent spaced weaning. We focused especially on the causes of recipient death and graft loss and the characteristics of rejection. RESULTS: Laparoscopic live-donor nephrectomy was associated with no mortality and no delayed graft function. The actuarial 1, 2, 3, and 4 years patient and graft survivals were 97.6% and 97.6%, 93.5% and 85.4%, 93.5% and 85.4%, and 93.5% and 85.4%, respectively. The incidence of cumulative acute cellular rejection (ACR) at 1, 2, 3, and 4 years was 0%, 2.4%, 4.8%, and 4.8%, respectively. The mean serum creatinine (mg/dL) and glomerular filtration rate (mL/min/1.73 m) at 1, 2, and 3 years were 0.8+/-0.4 and 94.0+/-36.8, 0.9+/-0.4 and 79.6+/-31.9, and 0.9+/-0.4 and 95.0+/-21.7, respectively. Two (4.7%) recipients had ACR, and both Banff 1a ACRs were steroid sensitive. No patients had antibody-mediated rejection. Weaning to spaced dose (qod or less) tacrolimus monotherapy was attempted in 16 (38%) and was successful in 12 (26%) patients. All patients are currently steroid free. There was no tissue invasive cytomegalovirus disease or infection, no BK/polyoma viral nephropathy, and no posttransplant proliferative disease. CONCLUSION: This experience confirms the 4-year safety and efficacy of this approach in pediatric recipients.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/therapeutic use , Kidney Transplantation/immunology , Living Donors , Tacrolimus/therapeutic use , Adult , Alemtuzumab , Antibodies, Monoclonal, Humanized , Child , Creatinine/blood , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/epidemiology , Histocompatibility Testing , Humans , Immunosuppressive Agents/therapeutic use , Kidney Diseases/classification , Kidney Diseases/surgery , Kidney Transplantation/mortality , Male , Reoperation/statistics & numerical data , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVE: Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. STUDY DESIGN: Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. RESULTS: Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 +/- 0.35 mg/dL and creatinine clearance was 90.8 +/- 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. CONCLUSION: The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients.
Subject(s)
Antilymphocyte Serum/therapeutic use , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , T-Lymphocytes/immunology , Tacrolimus/therapeutic use , Adolescent , Alemtuzumab , Antibiotic Prophylaxis , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/administration & dosage , Antibodies, Neoplasm/therapeutic use , Child , Child, Preschool , Creatinine/blood , Graft Rejection , Graft Survival , Humans , Immunosuppressive Agents/administration & dosage , Infant , Sirolimus/administration & dosage , Sirolimus/therapeutic use , Survival Analysis , T-Lymphocytes/drug effects , Tacrolimus/administration & dosageABSTRACT
BK virus (BKV) infections after renal transplantation are increasingly recognized. Development of immune monitoring strategies against BKV requires definition of antigenic epitopes. Hence, T cells from HLA-A02-positive healthy subjects and kidney transplant recipients were stimulated by BKV lysate pulsed on mature autologous dendritic cells and screened against four different T antigen peptides or against BKV lysate. IFN-gamma production was measured by ELISPOT assays. The peptide BKV362-371 (MLTERFNHIL) was naturally processed and recognized by five of six healthy subjects (39 +/- 11 IFN-gamma spots/100,000 cells) and five of seven kidney transplant recipients (21 +/- 12 IFN-gamma spots). Less frequent and weaker CD8+ T-cell responses were detected against three other peptides. Thus, BKV large T antigen is a target for CD8+ T-cell immunity. T-antigen-specific T-cytotoxic cells circulate in healthy blood donors, implying that transient expression of T antigen presumably occurs at sites of viral latency and helps maintain a constant pool of circulating CD8+ T memory cells.
Subject(s)
Antigens, Polyomavirus Transforming/blood , BK Virus/immunology , CD8-Positive T-Lymphocytes/immunology , Kidney Transplantation/immunology , Adult , Amino Acid Sequence , Antigens, Viral, Tumor/blood , Female , Humans , Immunologic Memory , Interferon-gamma/analysis , Male , Middle Aged , Molecular Sequence Data , Monitoring, Immunologic , Peptides/immunology , Polyomavirus Infections/diagnosis , Tumor Virus Infections/diagnosisABSTRACT
Congenital anomalies of kidney and urinary tract (CAKUT), including vesico-ureteric reflux (VUR), are major causes of ESRD in childhood. Herein is reported evidence for a locus on 13q33q34 associated with CAKUT. Deletion mapping of chromosome 13q was performed in four children with CAKUT using 31 microsatellite markers on peripheral blood genomic DNA that was obtained from the patients and their parents. mRNA expression of the positional candidate genes was compared with sequences in electronic databases in silico and also studied in adult and fetal mouse kidneys using reverse transcription-PCR. The children (three girls; age range 5 to 17 yr) had varying severity of developmental delay and other organ system involvement. The spectrum of CAKUT included high-grade VUR (n = 2), renal dysplasia (n = 2), and hydronephrosis (n = 1). Both the children with VUR had evidence of renal failure with one of them developing ESRD. Deletion mapping identified a 7-Mb critical region flanked by markers D13S1311 and D13S285. There are 33 genes (12 known; 21 computer predicted) in this region. In silico expression studies showed matches for 14 of these genes in the kidneys and 10 in the bladder expressed sequenced tags databases. Mouse kidney studies showed that of the 24 genes examined, several had variable expression through the different stages of renal development, whereas five of the genes were not expressed at all. Herein is reported a new locus on chromosome 13q33q34 that can be associated with VUR with several genes showing mRNA expression patterns that suggest their potential for involvement in renal/urinary tract developmental anomalies.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Kidney/abnormalities , Vesico-Ureteral Reflux/genetics , Adolescent , Animals , Base Sequence , Child, Preschool , DNA/genetics , Female , Gene Expression Profiling , Gene Expression Regulation, Developmental , Genetic Markers , Humans , Karyotyping , Mice , Mice, Mutant Strains , Urinary Tract/abnormalitiesABSTRACT
Nephrotic syndrome (NS) is a pathological entity characterized by massive proteinuria and has diverse etiology. Although it is one of the most common renal diseases in children, the etiological factors responsible for idiopathic NS/FSGS remain largely unknown. Previous studies had implicated a variety of factors including genetic factors, although NS is generally regarded as a sporadic disease. Familial cases of NS have however been reported periodically, and both autosomal dominant and recessive forms have been identified. Studies of familial NS/FSGS have led to the discovery of several genes that are expressed in podocytes and are associated with proteinuria. These discoveries have shifted the focus from glomerular basement membrane (GBM) to recognition of the central role of podocytes in maintaining glomerular perm selectivity and pathogenesis of NS/FSGS. Associations with various genes (NPHS1, ACTN4, NPHS2, WT-1) and linkage to several chromosomal regions (such as 19q13, 11q21, 11q24) have been reported in patients with familial NS/FSGS.
Subject(s)
Nephrotic Syndrome/genetics , Child , Humans , Kidney Glomerulus/anatomy & histology , Nephrotic Syndrome/pathology , PodocytesABSTRACT
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) and congenital anomalies of kidney and urinary tract (CAKUT) are major causes of renal dysfunction in children. Although a few patients with 13q deletion have been previously reported with renal anomalies, the association of SRNS with 13q has not been reported and critical regions associated with CAKUT have not been identified. We present the results of deletion mapping studies to identify the critical regions. METHODS: Cytogenetic and deletion mapping studies were performed on DNA obtained from peripheral blood of two children with renal anomalies and interstitial deletion of 13q as well as their parents. Twenty eight microsatellite markers with a spacing of 1-8 Mb (1-3 cM) were utilized. RESULTS: The patients (both males, 5 and 10 years old) had varying severity of developmental delay and other neurologic disorders. The renal involvement included hydronephrosis, ureterocele, renal dysplasia, and mesangioproliferative SRNS. Our studies imply existence of at least two critical regions in the 13q area that are linked to CAKUT. The first is a 7 Mb region defined by markers D13S776 and D13S891 shared by both patients. The second is a much larger region extending at least 33 Mb above D13S776 seen in one patient with severe renal malformations and SRNS. CONCLUSION: We report an association of chromosome 13q with CAKUT as well as SRNS. Our studies suggest the presence of more than one gene in this region that is likely to be involved in renal development and function.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 13 , Kidney/abnormalities , Nephrotic Syndrome/drug therapy , Nephrotic Syndrome/genetics , Steroids/therapeutic use , Urinary Tract/abnormalities , Abnormalities, Multiple/pathology , Child , Child, Preschool , Chromosome Mapping , Cytogenetic Analysis , Drug Resistance , Gene Deletion , Humans , Karyotyping , Kidney/diagnostic imaging , Kidney/pathology , Male , Nephrotic Syndrome/pathology , Ultrasonography , Urinary Tract/diagnostic imaging , UrographyABSTRACT
The glomerular structural factors associated with progression of congenital nephrotic syndrome of Finnish type (CNF) are incompletely understood. We studied glomerular volume and the proportion of various glomerular subtypes in seven CNF patients (aged 4 months to 3 years). Glomerular tubular connections (GTC) were analyzed in two patients early and late in the disease spectrum (creatinine 0.2 and 2.8 mg/dl, respectively). The proportions of "normal" glomeruli decreased (r=-0.91, P=0.003) and microcystic glomeruli increased (r=0.85, P=0.015), while the fetal and sclerosed glomeruli remained stable (r=0.073 and 0.08 respectively, P=NS for both) with age. The "normal" glomeruli were larger in CNF than in six age-matched minimal change nephrotic patients (P=0.009). GTC analyses in the mild disease showed that 75% of the 12 "normal" glomeruli had normal tubules, and 25% were atubular or were attached to atrophic tubules, while 88% of the 12 fetal glomeruli were either atubular or were attached to atrophic tubules. In the advanced disease, 67% of 12 "normal" glomeruli had normal tubules, and 33% were atubular or atrophic, while none of the fetal or microcystic glomeruli had "normal tubules". Thus atubular glomeruli may play an important role in disease progression in CNF, as it is associated with a progressive decrease in hypertrophied "normal" glomeruli and an increase in largely atubular microcystic glomeruli.