Pharmacokinetics of rituximab in a pediatric patient with therapy-resistant nephrotic syndrome

Background

Rituximab (RTX) has recently been introduced as a second-line therapy for nephrotic syndrome in children. Studies show that RTX given during the nephrotic state may be less effective than treatment during a non-nephrotic state, possibly due to loss of RTX in the urine.

Case-Diagnosis/Treatment

We describe a 10-year-old boy with steroid-resistant nephrotic syndrome (SRNS) treated with RTX during a phase of active non-selective proteinuria. The serum half-life of RTX in this patient was less than 1 day compared to 20 days in patients without protein losses. Urinary clearance was at least 25 %, compared to approximately 0 % in control patients. However, RTX loss in the urine, as well as in pleural effusion and ascites, only partly explains the rapid drop in the serum RTX concentration of this patient.

Conclusions

Serum half-life of RTX can be extremely short, partly due to excessive urinary losses in therapy-resistant nephrotic syndrome with non-selective proteinuria, as seen in our patient. These findings may help to explain the poor results of RTX treatment in patients with active proteinuria.

     

Etiology and epidemiology of end-stage renal disease in Dutch children 1987–2001

In this retrospective study 351 children (<16.0 years) with end-stage renal disease (ESRD) accepted for renal replacement therapy (RRT) in the four Dutch pediatric centers were analyzed for the period 1987–2001. The data were compared with a previous study performed in 1979–1986. Eighty patients were of non-Dutch origin. An annual ESRD incidence of 5.8 patients per million of the child population (p.m.c.p.) was calculated, without significant changes with time. The final prevalence in Dutch children under 15 years of ESRD was 38.7 p.m.c.p. The most frequent primary renal disease leading to ESRD was urethral valves, with a significant increase vs. the previous observation period (14% vs. 6%). The distribution of primary renal diseases was similar in patients of non-Dutch origin and in Dutch patients. Peritoneal dialysis was the most frequent dialysis procedure initially applied (62% vs. 26% in the earlier observation period). Thirteen percent of all first transplantations (n=278) were pre-emptive and 19% from living donors. Five-year graft survival after a living-donor and a cadaver graft was 80% and 73%, respectively. Overall patient survival after 10 years on RRT was 94%.     

Point-of-care creatinine testing in children at risk for sudden deterioration of renal function.

BACKGROUND: Point-of-care testing for creatinine blood concentrations may be useful in predicting the onset of recurrent conditions threatening renal function in children at home. Our aim was to evaluate two point-of-care systems for creatinine testing vs. an automated creatinine assay. METHODS: Twenty patients aged between 2 months and 17 years were randomly selected. Capillary blood specimens were taken for two point-of-care tests (Reflotron and i-STAT), and the results were compared to the routine enzymatic creatinine assay on a Hitachi 912 analyser using material collected simultaneously. RESULTS: The mean difference in creatinine concentration between the Reflotron and the Hitachi 912 and i-STAT and Hitachi 912 test was -16 and 4 micromol/L, respectively. The slope of the Passing-Bablok method comparison was 0.95 (95% CI 0.87-1.06) and 0.96 (95% CI 0.90-1.00) for the Reflotron and i-STAT test, respectively. CONCLUSIONS: The blood creatinine concentrations measured using the Reflotron and the i-STAT device correlated well with those from the routine assay, especially in the concentration range up to 500 micromol/L. Both systems are good options for point-of-care creatinine testing in capillary blood. However, the i-STAT seems the better option for monitoring at home given its greater ease of use.     

The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase

Recent studies have established ciliary dysfunction as the underlying cause of a broad range of multi-organ phenotypes, known as 'ciliopathies'. Ciliopathy-associated proteins have a common site of action in the cilium, however, their overall importance for ciliary function differs, as implied by the extreme variability in ciliopathy phenotypes. The aim of this study was to gain more insight in the function of two ciliopathy-associated protein homologs, RPGR interacting protein 1 (RPGRIP1) and RPGRIP1-like protein (RPGRIP1L). Mutations in RPGRIP1 lead to the eye-restricted disease Leber congenital amaurosis, while mutations in RPGRIP1L are causative for Joubert and Meckel syndrome, which affect multiple organs and are at the severe end of the ciliopathy spectrum. Using tandem affinity purification in combination with mass spectrometry, we identified Nek4 serine/threonine kinase as a prominent component of both the RPGRIP1- as well as the RPGRIP1L-associated protein complex. In ciliated cells, this kinase localized to basal bodies, while in ciliated organs, the kinase was predominantly detected at the ciliary rootlet. Down-regulation of NEK4 in ciliated cells led to a significant decrease in cilium assembly, pointing to a role for Nek4 in cilium dynamics. We now hypothesize that RPGRIP1 and RPGRIP1L function as cilium-specific scaffolds that recruit a Nek4 signaling network which regulates cilium stability. Our data are in line with previously established roles in the cilium of other members of the Nek protein family and define NEK4 as a ciliopathy candidate gene.     

Risk of emotional disorder in offspring of depressed parents: gender differences in the effect of a second emotionally affected parent

In offspring of depressed parents a second parent with emotional problems is likely to increase risk of emotional disorder. This effect may however differ between sons and daughters and between offspring of depressed fathers and offspring of depressed mothers. In adolescent and young-adult offspring of parents with major depressive disorder, this study examined the effects of a second affected parent, offspring gender, gender of the depressed parent and their interactions on risk of depression and anxiety disorder. We found that daughters had a higher risk of depression and anxiety than sons and that offspring of depressed mothers had a higher risk of anxiety than offspring of depressed fathers. In addition to these main effects, we found an interaction between parent and offspring gender inasmuch that sons of depressed fathers had the lowest risk of depression and anxiety relative to the other groups. A second affected parent tended to increase risk of depression and significantly increased risk of anxiety. However, this effect of a second affected parent on offspring anxiety was most prominent in daughters when the second affected parent was the father, whereas risk in sons did not increase if the father was affected as well. Our results indicate that paternal and maternal depression similarly and additively increase daughters' risk of emotional disorder, but that sons' risk only increases with maternal depression. Intergenerational transmission of emotional disorder seems strongest when the female gender is involved, either in the form of a daughter or a depressed mother.     

Cardiac Surgery with Cardiopulmonary Bypass in Low-Weight or Preterm Neonates: A Retrospective Study Analyzing Early Outcome

Background: Most outcome studies in congenital cardiac surgery for “low weight” neonates include patients undergoing surgery without cardiopulmonary bypass (CPB). The primary objective of our study was to identify risk factors for in-hospital mortality in neonates weighing less than 3 Kg and undergoing surgery with CPB. In addition, we compared the effect of early surgery with CPB (before 37W-gestational age (GA)) for congenital heart disease to delayed surgery until a corrected GA of 37 weeks in an attempt to promote weight gain. Methods: Retrospective single-center study including all patients operated between 1997 and 2017. Uni- and multivariable analysis were used to analyze outcome. Results: 143 patients were included. The median weight was 2.7 Kg and 49 (34.3%) weighted <2.5 Kg. 80% of the patients were Risk stratification STAT categories ≥3. 114 patients (80%) were operated without delay (usual timing, median age 9 days), whereas 29 patients (20%) entered a delayed strategy (median age 30 days). In-hospital mortality was 21.7%. By multivariate analysis, dysmaturity, preoperative positive ventilation, post-operative ECMO requirement or resuscitation, and any residual lesion were predictors of in-hospital death. In-hospital mortality in the usual timing group and the delayed group were 21.1% and 24.1%, respectively (p = 0.71). In-hospital mortality for neonates operated prior to 37W-GA (n = 10) was 27.3%. Conclusions: Predictors of in-hospital mortality in neonates less 3 Kg requiring CPB surgery did not differ from those unveiled in other contemporary studies. Our data demonstrates that a strategy of delaying surgery in selected patients resulted in similar clinical outcome.     

Autologous in vivo adipose tissue engineering in hyaluronan-based gels--a pilot study

BACKGROUND: There is a major clinical need for strategies for adequately reconstructing the soft tissue defects found after deep burns, tumor resection, or trauma. A promising solution is adipose tissue engineering with preadipocytes, stem-cell derived precursors of the adipose tissue, implanted within biomaterials. This pilot study evaluated hyaluronan gels mixed with autologous undifferentiated preadipocytes in a pig model for their potency to generate new fat. MATERIALS AND METHODS: Preadipocytes were isolated from intra-abdominal pig fat by collagenase digestion, plated on fibronectin-coated culture dishes in Dulbecco's modified Eagle medium/Ham's F12 (Biochrom, Berlin, Germany) combined with 10% pig serum, expanded, and mixed with hyaluronan gel. Two types of gels with varying degrees of amidation of the carboxyl groups were tested (HYADD3, HYADD4). Cell-loaded gels and unseeded controls were injected subcutaneously into the ears of three pigs, explanted at 6 wk, and analyzed histologically. RESULTS: Both cell-loaded specimens were detected macroscopically. They demonstrated a slight volume effect with limited stability after 6 wk. Unloaded HYADD3 and HYADD4 controls could not be identified at the time of explantation. Histology of HYADD3 revealed islets of mature adipocytes and vessels embedded in fat tissue surrounded by gel. In contrast, no fat formation was found in HYADD4 gels when implanted in the ear. CONCLUSIONS: Histological findings demonstrate that HYADD3 is a promising gel for generating adipose tissue. Even though HYADD3 might be a potential material for the reconstruction of small tissue defects, the question remains as to whether the adipose tissue within the gel is attributable to preadipocyte maturation or ingrowth from neighboring tissue.