Abstract
Background and Aims
Response to calcineurin inhibitors (CNI) is associated with a significant improvement in long-term kidney survival of children with non-genetic steroid resistant ...nephrotic syndrome (SRNS). On the contrary, these agents are considered non-efficacious in monogenic SRNS and are contraindicated according to the latest International Pediatric Nephrology Association (IPNA) Clinical Practice Recommendations for SRNS. However, there is evidence suggesting that remission with CNI therapy in this subgroup of children with SRNS is possible, but no studies to date have assessed this question in a systematic way. We aimed to study the incidence of response to CNI in children with monogenic SRNS, factors predictive of remission and the effect of treatment on kidney survival.
Method
Retrospective cohort study of children 0–18 years with genetically confirmed SRNS treated with a CNI for at least 3 months. Demographic, clinical, genetic, biochemical, histopathologic and treatment data were collected at various time points; at clinical diagnosis, 6, 12, 24 months from CNI onset, and last available follow-up. Pathogenicity of all reported variants was assessed by a dedicated geneticist according to the American College of Medical Genetics guidelines and only patients with a pathogenic genotype were included in the analysis1. Patients were classified according to their response to CNI as complete, partial or non-responders based on the IPNA Clinical Practice Recommendations for SRNS2.
Results
141 patients from 37 international paediatric nephrology centers were included in the study. At 6 months from CNI initiation and at last visit, 27.6% and 22.5%, respectively, demonstrated either complete or partial response (“at least partial response”). Median observation time between CNI initiation and last visit was 42.1 months (IQR 20.1–65.6) and was comparable between patients with no response and at least partial response (42.3 vs 41.6 months; P>0.05). No serious adverse effects mandating treatment discontinuation were reported. Children demonstrating at least partial response at 6 months had a lower risk of progression to kidney failure at last visit versus non-responders (hazard ratio 95%CI 0.25, 0.10–0.62; P = 0.003). Subgroup analysis of patients with a follow-up of at least 2 years revealed similar results with a hazard ratio of 0.35 (95%CI 0.14–0.91; P = 0.03). Of the various clinical, biochemical, genetic, histopathologic and treatment parameters tested in a multivariable logistic regression model only higher serum albumin at CNI onset was associated with higher likelihood of response at 6 months (odds ratio 95% CI 1.16, 1.08–1.24; P < 0.001).
Conclusion
Our findings suggest that CNI use could be considered in monogenic SRNS and that achievement of response in this setting can alter an otherwise dismal long-term kidney outcome.
Corticosteroid-related toxicity in children with steroid-sensitive nephrotic syndrome is primarily related to the cumulative dose of prednisone. To optimize treatment of relapses, we conducted the ...PROPINE study, a multicentric, open-label, randomized, superiority trial. Seventy-eight relapsing children aged 3-17 years who had not received steroid-sparing medications during the previous 12 months were randomized to receive, from day five after remission, either 18 doses of 40 mg/m2 of prednisone on alternate days (short arm), or the same cumulative dose tapered over double the time (long arm). Patients were monitored with an ad-hoc smartphone application, allowing daily reporting. The primary outcome was the six-month relapse rate at which time, 23/40 and 16/38 patients had relapsed in the long and short arms, respectively (no significant difference). Additionally, 40/78 patients were also enrolled in a secondary crossover study and were allocated to the opposite arm. Altogether, at six months, the relapse rate was 32/40 and 28/40 in the long and short arms, respectively (no significant difference). A post-hoc analysis excluding 30 patients treated with low-dose prednisone maintenance therapy failed to show significant differences between the two arms. No differences in adverse events, blood pressure and weight gain were observed. Thus, our data do not support the prescription of prolonged tapering schedules for relapses of steroid-sensitive nephrotic syndrome in children.
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Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II ...region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
Gaucher disease (GD) is an autosomal recessive lysosomal storage disease characterized by the deficient activity of beta-glucocerebrosidase (GBA). GBA deficiency results in the accumulation of ...glucosylceramide in different organs, causing tissue damage. Typical GD features are spleno-hepatomegaly, peripheral blood cytopenias (mostly thrombocytopenia and/or anemia), growth retardation, bone involvement, gammopathies, increased risk of malignancies and, in some patients, neurological manifestations.
Since symptoms are non-specific, the diagnosis can be delayed for years or missed.
Enzyme replacement therapy (ERT) with recombinant β-glucocerebrosidase is safe and effective in preventing and/or reversing many clinical manifestations. However, if the diagnosis is delayed for years, major complications cannot be reversed.
A useful screening method for GD is based on measuring enzyme activity on a Dried Blood Spot (DBS), while the gold standard test is still considered GBA activity in cellular homogenates.
A pediatric algorithm has been proposed to promote timely diagnosis and early access to ERT (Di Rocco M et Al, Ped Blood & Cancer 2014;61:1905-09).
Since pediatric patients with splenomegaly and cytopenias are usually referred to pediatric hematologists, we have designed the GAU-PED study to evaluate the prevalence of GD among children referred to the haematology paediatric units and selected according to the above mentioned diagnostic algorithm. Here, we report a preliminary analysis of GAU-PED trial at 18 months after the start of the enrolment.
The GAU-PED study involves 53 centers in the context of the AIEOP Study Group, the Italian clinical research consortium in paediatric hematology and oncology.
Patients (1-18 years old) referring to the pediatric hematology and oncology units for spleno-w/wo hepatomegaly and cytopenia (thrombocytopenia and/or anaemia), where other causes of splenomegaly has been excluded, are tested for GBA activity though a DBS sample. Only patients with DBS showing a GBA activity below normal values are recalled to confirm GBA enzyme deficiency using the gold standard GBA analysis in cell omogenate. For every tested patient, clinical information are also collected.
During the first 18 months of accrual, a total of 47 DBS have been collected from 18 centers, after parental consent. DBS values under 5 pmol/punch(1)/h(1)were found in 19/47 patients (40%). These patients have been recalled for the conventional enzymatic test. The diagnosis of GD has been confirmed in 5/19 (26%) DBS positive patients. In all 5 patients the genetic analysis has been consistent with GD.
Overall, in the tested population, the prevalence of GD is 10.6% (95% CI, 4 - 24%) equal to 5/47 enrolled patients.
Three patients were females and 2 males. The mean age at diagnosis was 8.4 years (range 2 - 13 years). The median time from the initial clinical presentation and the diagnosis has been 12 months (range 6-120 months), while the mean time between the DBS test and the diagnosis has been 4.8 months (range 3 - 6 months). ERT has been started in all GD patients. The clinical characteristics of the 5 patients with GD are summarized in Table 1.
CONCLUSION/SUMMARY: Our preliminary results support the use of DBS as screening test for GD in a selected population of children with splenomegaly and/or thrombocytopenia considered at increased risk for the disease. The use of an appropriate diagnostic algorithm is useful to increase awareness of GD among pediatric hematologists and to shorten the time to diagnosis. Taking in consideration the long life expectancy of pediatric GD patients, the early diagnosis will have a strong impact on health and quality of life.
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No relevant conflicts of interest to declare.
Children requiring kidney replacement therapy experience high burden of cardiovascular (CV) disease leading to increased mortality. Intima-media thickness (IMT) indicating atherosclerosis is a ...validated surrogate marker for future CV events.
We investigated the effect of different treatment modalities (dialysis, preemptive kidney transplantation (KTx), late KTx after dialysis) on IMT by multivariable linear mixed-effect modeling. Patients were enrolled in a prospective cohort study.
A total of 261 analyzed children had a mean follow-up of 3 y. Children after preemptive and late KTx had lower levels of IMT when compared with dialysis. Using an interaction term, a significant progression of IMT over time was seen during dialysis (β = 0.0053 mm/y, P = 0.004). IMT before the start of therapy was the most influential determinant in all models. Low IMT was associated with maintenance steroid treatment after preemptive KTx. High IMT on dialysis was associated with higher systolic blood pressure, lower body mass index, lower serum albumin, and lower bicarbonate.
IMT remained rather stable in children several years after KTx. In contrast, children on dialysis had higher IMT values, which increased over time. In these children, blood pressure control, calorie and protein intake, and acid-base homeostasis seem important. Taken together, children might profit from early transplantation to limit accumulation of CV risk.
Purpose
Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their ...efficacy and side effects have been reported. To date, there is no way to predict patients’ resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity.
Methods
The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients.
Results
Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (
p
= 0.022; OR = 4.3, 95%CI = 1.2–25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (
p
= 0.010; OR = 0.12, 95%CI = 9.2 × 10
−3
–6.7 × 10
−1
). Significant results were confirmed in the entire cohort.
Conclusions
Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.
Background
Subjects with a congenital solitary kidney (CSK) are believed to be at risk of hypertension due to their low number of nephrons. However, as CSK is a congenital abnormality of the kidney ...or urinary tract (CAKUT), subtle dysplastic changes contributing to hypertension cannot be excluded.
Methods
We retrospectively compared office blood pressure (OBP) and ambulatory blood pressure monitoring (ABPM) between two groups of children with CAKUT, aged 6–18 years: Group A with a CSK and Group B with two kidneys. All had normal renal parenchyma on scintigraphy and normal renal function. OBP and mean systolic and diastolic 24-h, daytime and nighttime ambulatory BP records were analyzed. The distribution of OBP and APBM as continuous values and the prevalence of hypertension (ambulatory/severe ambulatory or masked hypertension) in the two groups were compared.
Results
There were 81 patients in Group A and 45 in Group B. Median OBP standard deviation scores were normal in both groups, without significant differences. Median ABPM standard deviation scores, although normal, were significantly higher in Group A and the prevalence of hypertension was higher (ambulatory/severe ambulatory or masked) (33.3 vs. 13.3%,
p
= 0.019), mainly because of the greater occurrence of masked hypertension.
Conclusions
Our data show that a CSK per se can be associated with an increased risk of hypertension from the pediatric age. Therefore, ABPM, which has proved valuable in the screening of hypertension, is warranted in children with a CSK, even if laboratory and imaging assessment is otherwise normal.
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