Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

The clinical impact of humoral immunity in pediatric renal transplantation.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

Renal transplantation into a diverted urinary system-is it safe in children?

PURPOSE: Historically surgeons caring for children with urinary diversion for bladder outlet obstruction have routinely performed undiversion before renal transplantation. We hypothesized that patients undergoing transplantation into a diverted system would have outcomes similar to those undergoing transplantation into a normal bladder. We review the outcomes of patients with and without diversion undergoing kidney transplantation at our institution. MATERIALS AND METHODS: We retrospectively studied a cohort of children undergoing renal transplant between 1993 and 2006. Patients whose etiology of end-stage renal disease was either obstructive uropathy or renal dysplasia were included. Patients with less than 5 years of followup were excluded from the analysis. Four groups were assembled, ie controls with renal dysplasia and no history of obstructive uropathy undergoing transplant (group 1), patients with obstructive uropathy not diverted at transplant (group 2), patients with obstructive uropathy diverted at transplant (group 3) and patients with obstructive uropathy augmented before transplant (group 4). The groups were compared for outcomes of frequency of urinary tract infection, renal graft function and graft loss. RESULTS: Of the 80 subjects eligible based on diagnostic criteria 43 had completed 5 years of followup. There was no significant difference between groups based on age (p = 0.508), renal function as measured by glomerular filtration rate (p = 0.526) or creatinine (p = 0.612), or frequency of urinary tract infections (p = 0.083). Only 1 patient in the cohort suffered graft loss. CONCLUSIONS: Based on frequency of urinary tract infection, renal function and graft loss 5 years after transplant, there appears to be no added risk to transplanting a kidney into a diverted system.

Outcomes in pediatric solid-organ transplantation.

LaR Pediatric solid-organ transplantation is an increasingly successful treatment for organ failure. Five- and 10-yr patient survival rates have dramatically improved over the last couple of decades, and currently, over 80% of pediatric patients survive into adolescence and young adulthood. Waiting list mortality has been a concern for liver, heart, and intestinal transplantation, illustrating the importance of transplant as a life-saving therapy. Unfortunately, the success of pediatric transplantation comes at the cost of long-term or late complications that arise as a result of allograft rejection or injury, immunosuppression-related morbidity, or both. As transplant recipients enter adolescence treatment, non-adherence becomes a significant issue, and the medical and psychosocial impacts transition to adulthood not only with regard to healthcare but also in terms of functional outcomes, economic potential, and overall QoL. This review addresses the clinical and psychosocial challenges encountered by pediatric transplant recipients in the current era. A better understanding of pediatric transplant outcomes and adult morbidity and mortality requires further ongoing assessment.

Living-Related Donor Kidney Transplant in a Patient With Single Ventricle and Fontan Circulation.

The hemodynamic profile of the Fontan circulation presents challenges that raise questions about candidacy for organ transplantation. We report a case of a 24-year-old male with double-inlet right ventricle and aortic atresia, who suffered bilateral renal cortical necrosis due to neonatal cardiovascular shock, received a live-donor kidney transplant from his mother at age 17, and has diminished yet stable renal function seven years posttransplant.

Longitudinal relations between obesity and hypertension following pediatric renal transplantation.

Obesity and hypertension frequently complicate renal transplantation (RTxp). The objective was to assess relations among obesity, hypertension, and glucocorticoids in pediatric RTxp recipients. A retrospective cohort study was carried out in 141 RTxp recipients, 2-21 years of age, with >or=12 months of follow-up. Body mass index Z-score (BMI-Z), systolic and diastolic blood pressure Z-scores (SBP-Z and DBP-Z), and medications at 1, 3, 6, and 12 months and annually thereafter were recorded. Quasi-least squares regression analysis was used. The prevalence of obesity (BMI>or=95th percentile) increased from 13% at baseline to >30% from 3 months onward. Greater glucocorticoid exposure (mg/kg/day) was associated with greater increases in BMI-Z (p<0.001). This association was greater in males, younger recipients, and those with lower baseline BMI-Z (all interactions p<0.02). The prevalence of systolic hypertension (SBP>or=95th percentile) was 73% at 1 month and >or=40% at all follow-up visits. Greater glucocorticoid exposure (p<0.001) and increases in BMI-Z (p=0.005) were independent determinants of SBP-Z over time. Cyclosporine (versus tacrolimus) was independently associated with greater SBP-Z and DBP-Z (p=0.001). Sustained obesity and hypertension frequently complicated pediatric RTxp. Obesity was an independent determinant of systolic hypertension. Strategies are needed to prevent obesity and its impact on hypertension, cardiovascular disease, and allograft survival.

Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant.

The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

The Effects of Tacrolimus on T-Cell Proliferation Are Short-Lived: A Pilot Analysis of Immune Function Testing.

BACKGROUND: Optimal immunosuppression after organ transplant should balance the risks of rejection, infection, and malignancy while minimizing barriers to adherence including frequent or time-sensitive dosing. There is currently no reliable immune function assay to directly measure the degree of immunosuppression after transplantation. METHODS: We developed an immune function assay to mea//sure T-cell proliferation after exposure to immunosuppression in vivo. We tested the assay in mice, and then piloted the approach using single time point samples, 11 pediatric kidney transplant recipients prescribed tacrolimus, mycophenolate, and prednisone 6 months to 5 years posttransplant, with no history of rejection, opportunistic infection, or cancer. Twelve healthy adults were controls. RESULTS: We demonstrated that our assay can quantify suppression of murine T-cell proliferation after tacrolimus treatment in vivo. In humans, we found a mean 25% reduction in CD4 and CD8 T-cell proliferation in pediatric renal transplant recipients on triple immunosuppression compared with adult healthy controls, but the pilot results were not statistically significant nor correlated with serum tacrolimus levels. We observed that cell processing and washing reduced the effects of tacrolimus on T-cell proliferation, as did discontinuation of tacrolimus treatment shortly before sampling. CONCLUSIONS: T-cell proliferation is currently not suitable to measure immunosuppression because sample processing diminishes observable effects. Future immune function testing should focus on fresh samples with minimal washing steps. Our results also emphasize the importance of adherence to immunosuppressive treatment, because T-cell proliferation recovered substantially after even brief discontinuation of tacrolimus.

Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare metabolic disorder, characterized by hypophosphatemia, variable degrees of rickets/osteomalacia, and hypercalciuria secondary to increased serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. HHRH is caused by mutations in the SLC34A3 gene, which encodes sodium-phosphate co-transporter type IIc. A 6-1/2-year-old female presented with a history of nephrolithiasis. Her metabolic evaluation revealed increased 24-hour urine calcium excretion with high serum calcium, low intact parathyroid hormone (PTH), and elevated 1,25(OH)2D. In addition, the patient had low to low-normal serum phosphorus with high urine phosphorus. The patient had normal stature; without rachitic or boney deformities or a history of fractures. Genetic analysis of SLC34A3 revealed the patient to be a compound heterozygote for a novel single base pair deletion in exon 12 (c.1304delG) and 30-base pair deletion in intron 6 (g.1440-1469del). The single-base pair mutation causes a frameshift, which results in premature stop codon. The intronic deletion is likely caused by misalignment of the 4-basepair homologous repeats and results in the truncation of an already small intron to 63bp, which would impair proper RNA splicing of the intron. This is the fourth unique intronic deletion identified in patients with HHRH, suggesting the frequent occurrence of sequence misalignments in SLC34A3 and the importance of screening introns in patients with HHRH.

Implementation of a clinical practice guideline for identification of microalbuminuria in the pediatric patient with type 1 diabetes.

Evidence-based practice is a shift in the health care culture from basing decisions on consensus opinion, past practice, and precedent toward the use of rigorous analysis of scientific evidence using outcomes research and clinical evidence to guide clinical decision making. The development of evidence-based clinical practice guidelines (CPG) is critical to guide the assessment and management of children with diabetes. This article provides an overview of the infrastructure and processes that are crucial to providing evidence-based care in a large urban pediatric diabetes center. Development of a CPG to identify microalbuminuria in children with type 1 diabetes is discussed.

Severe combined immunodeficiency resulting from mutations in MTHFD1.

Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

Solid-organ transplantation in childhood: transitioning to adult health care.

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.

Early use of plasmapheresis for recurrent post-transplant FSGS.

Recurrence of focal segmental glomerulosclerosis (FSGS) in an allograft is a challenging clinical situation because it frequently results in graft loss. We report our experience with early use of plasmapheresis in recurrent FSGS. Of the 18 (33%) children with biopsy-proven FSGS (in their native kidneys) transplanted at our institution, 6 had recurrence (elevated urine protein/creatinine ratios) post transplant and were treated with plasmapheresis. Patients who received treatment within 1 day of the recurrence (4/6) went into remission after 5-13 plasmapheresis treatments, within 5-27 days of starting treatment. Patients who did not respond to plasmapheresis (2/6) were treated 7 and 17 days after onset of proteinuria; 1 of these had acute tubular necrosis and acute rejection leading to graft loss and the other developed acute rejections, ongoing proteinuria, and subsequent graft loss. All 4 patients who went into remission have maintained good graft function, 22-53 months post transplant. In our experience early institution of plasmapheresis for recurrent post-transplant proteinuria in FSGS is effective.

Glomeruloesclerosis focal y segmentaria: recurrencia de la proteinuria después del transplante renal / Glomeruloesclerosis focal segmental: recurrence of proteinuria after kidney transplant

La glomerulosclerosis focal y segmentaria (GSFS) es la causa del 7-15 por ciento de todos los niños con síndrome nefrótico idiopático. La mayoría de los pacientes con GSFS son resistentes a los corticosteroides, y aproximadamente el 30 por ciento de ellos progresan a la insuficiencia renal crónica terminal. Hace ya más de 30 años, Hoyer et al. reportaron la recurrencia de la GSFS en el transplante renal. La frecuencia de la recurrencia de la GSFS, de acuerdo al reporte del Estudio Cooperativo (NAPRTCS) y de la Asociación Europea Pediátrica de Diálisis y Transplante (EDTA), es del 20-30 por ciento y se asocia a un índice acelerado de pérdida de injerto. Los factores de riesgos sugeridos en la recurrencia de la GSFS incluyen la menor edad de comienzo de la enfermedad, la evolución rápida a la insuficiencia renal, la proliferación mesangial, el tiempo en dialisis, y el grado de HLA matching con el injerto; sin embargo el valor predictivo de estos factores es incierto. Aunque la etiología de la GSFS recurrente permanece incierta, la existencia de un factor plasmático circulante que altera la permeabilidad de la pared capilar glomerular ha sido implicada, debido a la rapidez de la recurrencia de la proteinuria.

Glomeruloesclerosis focal y segmentaria: recurrencia de la proteinuria después del transplante renal / Glomeruloesclerosis focal segmental: recurrence of proteinuria after kidney transplant

La glomerulosclerosis focal y segmentaria (GSFS) es la causa del 7-15 por ciento de todos los niños con síndrome nefrótico idiopático. La mayoría de los pacientes con GSFS son resistentes a los corticosteroides, y aproximadamente el 30 por ciento de ellos progresan a la insuficiencia renal crónica terminal. Hace ya más de 30 años, Hoyer et al. reportaron la recurrencia de la GSFS en el transplante renal. La frecuencia de la recurrencia de la GSFS, de acuerdo al reporte del Estudio Cooperativo (NAPRTCS) y de la Asociación Europea Pediátrica de Diálisis y Transplante (EDTA), es del 20-30 por ciento y se asocia a un índice acelerado de pérdida de injerto. Los factores de riesgos sugeridos en la recurrencia de la GSFS incluyen la menor edad de comienzo de la enfermedad, la evolución rápida a la insuficiencia renal, la proliferación mesangial, el tiempo en dialisis, y el grado de HLA matching con el injerto; sin embargo el valor predictivo de estos factores es incierto. Aunque la etiología de la GSFS recurrente permanece incierta, la existencia de un factor plasmático circulante que altera la permeabilidad de la pared capilar glomerular ha sido implicada, debido a la rapidez de la recurrencia de la proteinuria.(AU)