Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and ...transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on
,
and
genes in Chilean pediatric kidney recipients using TAC and MPA.
A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years Q1-Q3 4.5-11.6 years and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The
polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while
-24G > A,
-275T > A, and
-2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C
), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C
/D), and area under the curve in 12 h normalized by dose requirements (AUC
/D).
The frequencies of the variant alleles
,
,
, and
were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC
/TAC-D were 1.6-fold higher in
patients than in
carriers (
and
). When analyzing patients with steroid withdrawal,
patients had 1.7-fold higher AUC
/TAC-D than the other genotypes. Patients carrying the
genotype had higher TAC-C
, lower TAC-D and higher TAC-C
/D, consistently in a 6-months follow-up. Creatinine clearance was stable during the follow-up, regardless of the genotype. No significant differences between
and
genotypes were observed in MPA-C
, MPA-D or MPA-C
/D. However, patients carrying the
allele had lower AUC
/MPA-D than those carrying the
ancestral allele.
These results support that
and
genotyping in pediatric recipients might be useful and advisable to guide TAC and MPA dosing and monitoring in children that undergo kidney transplantation.
ABSTRACT
Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with ...glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC‐induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC‐induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC‐induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan‐FGFR antagonist (PD173074), a C‐terminal FGF23 peptide (FGF23180‐205) which blocks the binding of FGF23 to the FGFR‐Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC‐treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC‐induced growth impairment in children.
This prospective, comparative trial investigated the impact on mean change in height standard deviation score (SDS), acute rejection rate, and renal function of early steroid withdrawal in 96 ...recipients with 5 years of follow-up. Recipients under basiliximab induction and steroid withdrawal (SW: TAC/MMF;
n
= 55) were compared with a matched steroid control group (SC: TAC/MMF/STEROID,
n
= 41). SW received steroids until Day 6, SC decreased to 10 mg/m
2
within 2 months post-transplant. Five years after SW, the longitudinal growth (SDS) gain was 1.4 ± 0.4 vs. 1.1 ± 0.3 for SC group (
p
< 0.02). Height benefits in prepubertal and pubertal status in both groups were demonstrated in the delta growth trends (mixed model;
p
< 0.01). Biopsy-proven acute rejection in SW was 11% and 17.5%, SC (
p
: ns). Mean eGFR (ml/min/1.73 m
2
) at 5 years post-transplant was SW 80.6 ± 27.8 vs. 82.6 ± 25.1 for SC (
p
: ns). The death-censored graft survival rate at 1 and 5 years was 99 and 90% for SW; 98 and 96% for SC (
p
= ns). PTLD incidence in SW 3.3 vs. 2.5% in SC (
p
: ns). Five years post-transplant, early steroid withdrawal showed positive impacts on growth, stable renal function without increased acute rejection risk, and PTLD incidence.
This paper contributes to scholarship on the political ecology of drinking water, water commodification, and its social and environmental effects by looking at Chile’s Rural Drinking Water (Agua ...Potable Rural or APR) program. The APR program was created in 1964 to deliver drinking water to rural populations. I explore the actions a group of people undertake to secure drinking water in rural Northern Chile, an area experiencing a decade-long drought. I map how their efforts in securing drinking water coordinate with those of others at different institutional levels. This research relies on Dorothy Smith’s Institutional Ethnography (IE), a bottom-up feminist sociology explaining how the social world is organised through the active work of people whose doings are coordinated through texts, language, and discourse. Using methodological devices such as the construction of ‘facts’ and ‘ideological codes’ this research shows how the categories of ‘water rights’, and ‘vulnerability’ are essential in ruling differential access to drinking water. The research unpacks the social organisation of ‘community water management’ which although discursively based on mutual aid and solidarity, is part of the larger neoliberal institution governing access to water in the country. This research expands knowledge about the institutional mechanisms preventing rural people from accessing a basic human right, going beyond the naming of phenomena as ‘commodification’ or ‘neoliberalisation’ to explaining how these are organised and implemented, through texts and people’s work, with detrimental effects for communities and their environments.
•Institutional Ethnography shows how differential water access occurs.•‘Water rights’ based on ideology benefit transnational companies and Chile's elite.•Drinking water denied to ‘(non)vulnerable’ people when living in rural Chile.•Chile's Constitution and Water Code prevent access to drinking water.•International institutions should listen to people before endorsing policies.
The short half-life of erythropoietin (rHuEPO) leads to repeated fluctuations in hemoglobin levels and the need for frequent administration. Continuous erythropoietin receptor activator (CERA) ...therapy has been approved for once or twice a month in adult dialysis patients. To evaluate the efficacy and safety of CERA therapy in the management of anemia in pediatric peritoneal dialysis (PD) stable PD children under twice-a-week EPO were converted to a subcutaneous CERA, scheduled every 2 weeks. The follow-up was 6 months. The primary efficacy parameter was hemoglobin > 11 g/dL. The exclusion criteria were ferritin <100 ng/ml and Hb saturation <20%. Sixteen children, aged 9.75 ± 3.6 years, including 11 boys, participated in the study. Mean Hb level at month 0 was 10.8 ± 1.9 g/dL. A decrease in hemoglobin to 10.38 ± 1 g/dL at month 2 was observed. The CERA dose was increased from 0.86 ± 0.33 to 1.67 ± 0.4 μg/kg at month 3. The target Hb level was reached by the 3rd month. The Hb level and CERA dose were 12.2 ± 1.2 and 1.6 ± 0.67 μg/kg respectively at the end of the study. No adverse events were observed during the protocol. CERA is an effective and safe therapy for maintaining hemoglobin levels when administered twice, up to once a month, in PD children. Doses required to reach target Hb were higher than published experiences in adult populations.
Purpose
The purpose of this paper is to problematise the idea of “at-home ethnography” and to expand knowledge about insider/outsider distinctions by using insights from institutional ethnography ...(IE). It also examines the strengths and challenges of “returning” researchers recognising their unique position in overcoming these binaries.
Design/methodology/approach
IE is the method the researcher used to explore community-based water management in rural Chile. The researcher is interested in learning from rural drinking water organisations to understand the way in which their knowledge is organised. The data presented derived from field notes of participant observation and the researcher’s diary.
Findings
The notion of “at-home ethnography” fell short when reflecting on the researcher’s positions and experiences in the field. This is especially true when researchers return to their countries to carry out fieldwork. The negotiation of boundaries, codes and feelings requires the researcher to appreciate the complex relationships surrounding ethnographic work, in order to explore how community-based water management is done in the local setting, without forgetting where the setting is embedded.
Originality/value
Unique insights are offered into the advantages and tensions of conducting fieldwork “at home” when the researcher has lived “abroad” for an extended time. A critique and contribution to “at-home ethnography” is offered from an IE perspective.
INTRODUCTIONMycophenolic acid (MPA) is among the drugs used to achieve effective immunosuppression in kid ney transplantation (KT), which is characterized by complex pharmacokinetics and high intra- ...and interindividual variability. Monitoring the trough concentration level (C0) of MPA for dosage ad justments is considered controversial, mainly due to its low correlation with the area under the curve (AUC). OBJECTIVETo correlate the C0 and AUC of MPA in pediatric patients with KT. PATIENTS AND METHODProspective study carried out in 54 KT patients under treatment with MPA. Linear regressions and correlations were performed between ABC and C0. Multiple comparisons group analysis was performed according to post-transplant time and the two oral presentations of MPA. RESULTSThe plasma level that best correlates with AUC was C0 (r2 = 0.52). There was a significant group of patients with subtherapeutic levels (36.6% of all measurements). It was also determined that the C0 must be between 1.42 and 4.55 µg/ml for the AUC to be within the therapeutic range. It was shown that the correlation between C0 and AUC improves after three months post-transplantation and is even better when administering mycophenolate mofetil. CONCLUSIONThe use of C0 is recom mended to adjust the dose of MPA in pediatric patients with KT, especially in those with more than 3 months post-transplantation. For patients with early KT or complex clinical pictures, monitoring using ABC is recommended.
Nephrotic syndrome (NS) in children has been associated with a systemic circulating permeability factor. Therefore, once peritoneal dialysis (PD) has been started, peritoneal protein losses should be ...higher in the nephrotic than in the non-nephrotic population.
We compared peritoneal protein losses in children with and without NS on PD.
Our retrospective 4-year study analyzed Hispanic patients with NS under PD. Data at dialysis entry and 6 months later were compared. Nutritional support was given according to recommended dietary allowances and recommendations from the Kidney Disease Outcomes Quality Initiative. Clinical and biochemical data were obtained, and 24-hour dialysate and urine samples were collected to measure protein losses. Dialysis dose (Kt/V), daily protein intake (DPI), normalized protein equivalent of nitrogen appearance (nPNA), peritoneal equilibration test (PET), and peritonitis rate were determined. All measurements took place at least 4 weeks after resolution of a peritonitis episode. All patients received automated PD using a HomeChoice PD System cycler (Baxter Healthcare Corporation, Deerfield, IL, USA), with an exchange volume of 1100 mL/m(2) and a dextrose concentration of 1.5% - 2.5%. A control group of non-NS children on PD matched by age and sex were also studied. Data are reported as mean ± standard deviation. Differences between groups were calculated using the Mann-Whitney U-test, and p < 0.05 was considered significant.
Each study group consisted of 10 patients NS patients: 4 boys, mean age of 7.3 ± 4.1 years; control patients: 6 boys, mean age of 7.2 ± 4.7 years (p = nonsignificant). In the group with NS, 8 patients were diagnosed by biopsy as having focal segmental glomerulosclerosis, and 2 as having minimal-change disease. At study entry, patients with NS had hourly urinary protein losses of 398 ± 313 mg/m(2) and daily peritoneal protein losses of 3.4 ± 1.9 g/m(2), compared with 29.9 ± 31 mg/m(2) and 1.5 ± 1.1 g/m(2) respectively in the control group (p < 0.05). The same statistical difference was found 6 months later. We observed no statistical differences in PET results, daily exchange volume, and mean dextrose concentration of dialysate. Similarly, no significant between-group differences were observed for Kt/V, DPI, nPNA, and biochemical parameters.
Hispanic children with NS on PD show higher peritoneal protein losses than do their control counterparts. Such differences could be secondary to increased peritoneal permeability caused by a systemic permeability factor.
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