Rituximab-to-vaccine interval on SARS-CoV-2 immunogenicity in children: The potential role of prior natural infection.

BACKGROUND: Treatment with anti-CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA-based COVID-19 vaccines in children aged 5-18 years undergoing rituximab treatment compared to healthy matched children. METHODS: Between 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5-18 years under rituximab treatment who had received two mRNA-based SARS-CoV-2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS-CoV-2 infection. Blood samples were collected at day 60 (±30) and day 270 (±90) after the second vaccination. RESULTS: The rituximab-treated group exhibited significantly lower levels of antibodies specific to the anti-receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein than healthy controls at 60 (±30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p = .008). However, patients with a rituximab-to-vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti-N antibody levels) had a high level of anti-RBD antibodies. CONCLUSION: A past infection with SARS-CoV-2 may induce anti-RBD-specific memory B cells that can be re-activated by SARS-CoV-2 vaccination, even after rituximab-induced B-cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS-CoV-2 infection.

[Rare causes of Hypophosphatemia: diagnostic approach]. / Hypophosphatémies de causes rares : approche diagnostique.

Hypophosphatemia is common and may be overlooked due to its asymptomatic nature or non-specific symptoms. Two main mechanisms are at its origin: a shift towards the intracellular sector and an increase in urinary phosphate excretion. A measurement of the urinary phosphate reabsorption threshold allows a diagnostic orientation. Alongside common forms of parathyroid hormone-dependent hypophosphatemia, one should not ignore rare FGF23-mediated forms, in particular X-linked hypophosphatemic rickets. The treatment, above all etiological, also includes the administration of phosphate and, in the event of an excess of FGF23, supplementation with calcitriol. In cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets, the use of burosumab, an anti-FGF23 antibody, must be considered.

L'hypophosphatémie est fréquente. Pourtant, elle peut parfois être méconnue de par son caractère asymptomatique ou ses symptômes non spécifiques. Deux grands mécanismes sont à son origine : un shift vers le secteur intracellulaire et une augmentation de l'excrétion urinaire de phosphate. Une mesure du seuil de réabsorption urinaire de phosphate permet une orientation diagnostique. À côté de formes communes d'hypophosphatémies parathormone-dépendantes, il ne faut pas méconnaître des formes rares FGF23 médiées, en particulier le rachitisme hypophosphatémique lié à l'X. Le traitement, avant tout étiologique comporte aussi l'administration de phosphate et lors d'un excès de FGF23, une supplémentation en calcitriol. En cas d'ostéomalacie oncogénique et de rachitisme hypophosphatémique lié à l'X, l'emploi de burosumab, anticorps anti-FGF23, doit être considéré.

[Management of genetic renal disorders: local experience and importance of the network]. / Prise en charge des maladies rénales génétiques : expérience locale et importance du réseau.

In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.

Dans le domaine des maladies rénales, la rareté est fréquente. Chez l'enfant, 60 % des maladies touchant les reins sont rares et les malformations de l'axe urinaire sont prépondérantes. Chez l'adulte, près de 22 % des pathologies qui mènent à la maladie rénale terminale sont rares et incluent les glomérulonéphrites et les maladies génétiques. La rareté de ces pathologies fait que les compétences médicales peuvent être difficiles à trouver et l'expérience locale insuffisante. Ainsi, seule la mise en réseau des données, des ressources et des compétences peut permettre d'améliorer la prise en charge de ces patients. Le CHUV et les HUG ont mis en place des consultations spécialisées pour les maladies rénales rares. Elles s'inscrivent dans un réseau national et international.

Antibody-mediated rejection after kidney transplantation in children; therapy challenges and future potential treatments.

Antibody-mediated rejection (AMR) remains one of the most critical problems in renal transplantation, with a significant impact on patient and graft survival. In the United States, no treatment has received FDA approval jet. Studies about treatments of AMR remain controversial, limited by the absence of a gold standard and the difficulty in creating large, multi-center studies. These limitations emerge even more in pediatric transplantation because of the limited number of pediatric studies and the occasional use of some therapies with unknown and poorly documented side effects. The lack of recommendations and the unsharp definition of different forms of AMR contribute to the challenging management of the therapy by pediatric nephrologists. In an attempt to help clinicians involved in the care of renal transplanted children affected by an AMR, we rely on the latest recommendations of the Transplantation Society (TTS) for the classification and treatment of AMR to describe treatments available today and potential new treatments with a particular focus on the pediatric population.

Serum NGAL, BNP, PTH, and albumin do not improve glomerular filtration rate estimating formulas in children.

Glomerular filtration rate (GFR) is difficult to measure, and estimating formulas are notorious for lacking precision. This study aims to assess if the inclusion of additional biomarkers improves the performance of eGFR formulas. A hundred and sixteen children with renal diseases were enrolled. Data for age, weight, height, inulin clearance (iGFR), serum creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), parathyroid hormone (PTH), albumin, and brain natriuretic peptide (BNP) were collected. These variables were added to the revised and combined (serum creatinine and cystatin C) Schwartz formulas, and the quadratic and combined quadratic formulas. We calculated the adjusted r-square (r2) in relation to iGFR and tested the improvement in variance explained by means of the likelihood ratio test. The combined Schwartz and the combined quadratic formulas yielded best results with an r2 of 0.676 and 0.730, respectively. The addition of BNP and PTH to the combined Schwartz and quadratic formulas improved the variance slightly. NGAL and albumin failed to improve the prediction of GFR further. These study results also confirm that the addition of cystatin C improves the performance of estimating GFR formulas, in particular the Schwartz formula.Conclusion: The addition of serum NGAL, BNP, PTH, and albumin to the combined Schwartz and quadratic formulas for estimating GFR did not improve GFR prediction in our population. What is Known: • Estimating glomerular filtration rate (GFR) formulas include serum creatinine and/or cystatin C but lack precision when compared to measured GFR. • The serum concentrations of some biological parameters such as neutrophil gelatinase-associated lipocalin (NGAL), parathyroid hormone (PTH), albumin, and brain natriuretic peptide (BNP) vary with the level of renal function. What is New: • The addition of BNP and PTH to the combined quadratic formula improved its performance only slightly. NGAL and albumin failed to improve the prediction of GFR further.

Results in the ESPN/ERA-EDTA Registry suggest disparities in access to kidney transplantation but little variation in graft survival of children across Europe.

One of the main objectives of the European health policy framework is to ensure equitable access to high-quality health services across Europe. Here we examined country-specific kidney transplantation and graft failure rates in children and explore their country- and patient-level determinants. Patients under 20 years of age initiating kidney replacement therapy from January 2007 through December 2015 in 37 European countries participating in the ESPN/ERA-EDTA Registry were included in the analyses. Countries were categorized as low-, middle-, and high-income based on gross domestic product. At five years of follow-up, 4326 of 6909 children on kidney replacement therapy received their first kidney transplant. Overall median time from kidney replacement therapy start to first kidney transplantation was 1.4 (inter quartile range 0.3-4.3) years. The five-year kidney transplantation probability was 48.8% (95% confidence interval: 45.9-51.7%) in low-income, 76.3% (72.8-79.5%) in middle-income and 92.3% (91.0-93.4%) in high-income countries and was strongly associated with macro-economic factors. Gross domestic product alone explained 67% of the international variation in transplantation rates. Compared with high-income countries, kidney transplantation was 76% less likely to be performed in low-income and 58% less likely in middle-income countries. Overall five-year graft survival in Europe was 88% and showed little variation across countries. Thus, despite large disparities transplantation access across Europe, graft failure rates were relatively similar. Hence, graft survival in low-risk transplant recipients from lower-income countries seems as good as graft survival among all (low-, medium-, and high-risk) graft recipients from high-income countries.

Variables of interest to predict glomerular filtration rate in preterm newborns in the first days of life.

BACKGROUND: Measurement of neonatal renal function is challenging, and accurate, easy-to-use markers to estimate glomerular filtration rate (eGFR) are lacking. This study aimed to evaluate principal determinants of GFR in neonates and develop a predictive equation. METHODS: GFR was measured, using single injection inulin clearance, at median day 3 of life in 48 newborns. Associations of clearance with height, gestational age, weight, creatinine, and cystatin C were explored and a multivariable model to estimate GFR developed. We also evaluated preexisting GFR equations (Schwartz, Zappitelli, combined Zappitelli). RESULTS: Forty-four clearances were measured, 36 very preterm neonates (28-32 weeks); 5 extremely preterm (< 28 weeks), and 3 term newborns. No patient presented acute renal insufficiency. Median inulin clearance in preterm infants was 18.83 ml/min/1.73 m2 (IQ 15.29; 24.99). Inulin clearance correlated with weight (ρ 0.74), gestational age (ρ 0.72), height (ρ 0.49), and creatinine (ρ - 0.42), but not cystatin C. In the multivariable model, predicted GFR equation was 2.32* (weight (g))0.64/(creatinine (mcmol/l))0.62. Mean error in predicting clearance was - 0.8 ml/min/1.73 m2 (- 3.0-1.4) ranging from - 14.9 to 13.3 ml/min/1.73 m2. Mean prediction error with Zappitelli and combined Zappitelli equations were 28.5 ml/min/1.73 m2 (95% CI 24.6-32.3) and 28.3 ml/min/1.73 m2 (95% CI 24.9-31.7), respectively, and 2 ml/min/1.73 m2 (95% CI - 0.6-4.6) for Schwartz equation. CONCLUSIONS: Weight and gestational age are crucial determinants of GFR in neonates. The Zappitelli models were not validated in our population. Our predictive model and Schwartz models performed better. Our model should be evaluated in another preterm population, particularly in those presenting renal insufficiency.

Renal follow-up in pediatrician practice after discharge from neonatology units: about a survey.

There is growing evidences of long-term renal and cardiovascular consequences of prematurity, intra-uterine growth restriction, and neonatal acute kidney injury (AKI). We performed an online survey to describe current pediatric management in this population, sent to 148 ambulatory pediatricians in Geneva. Among the 40% of pediatricians who completed the survey, 43% modify their blood pressure measurement practice in case of neonatal acute kidney injury, 24% and 19% in a context of prematurity or intra-uterine growth restriction, respectively. Twenty-five percent provide information about cardiovascular risk factors or catch up growth. In case of prematurity or intra-uterine growth restriction, renal tests (ultrasound, serum creatinine, micro albuminuria) or referral to nephrologist were realized by less than 5% of the pediatricians. For neonatal acute kidney injury, renal tests, and referral to specialists are performed by 30 and 60% of pediatricians, respectively. When prematurity or intra-uterine growth restriction was associated with abnormal blood pressure or abnormal renal tests, the referral to the specialist reached 80%.Conclusion: Ambulatory renal and cardio-vascular follow-up in case of neonatal medical history can be enhanced, with necessity to raise awareness and to edict guidelines available to pediatricians. What is Known: • There is a compelling evidence of long-term renal and cardiovascular consequences of prematurity and low birth weight. • Specific cardiovascular and renal follow-up guidelines, coming from professional organizations, are currently not available for these patients. What is New: • Pediatricians in ambulatory setting do not adapt their renal and cardiovascular follow-up in case of neonatal medical history. • There is a necessity to raise awareness about these long-term consequences among pediatricians and to edict guidelines available to them.

Spot urine samples to estimate 24-hour urinary calcium excretion in school-age children.

Urinary calcium/creatinine ratio (UCa/Cr) on a single spot urine sample is frequently used in children to evaluate calciuria, but its accuracy to estimate 24-h urinary calcium excretion (24hUCa) has not been properly assessed. We analyzed the correlation between UCa/Cr in various spot samples and 24hUCa among healthy children. A 24-h urine specimen and three spot urine samples (evening, first, and second morning) were collected in a convenience sample of children aged 6 to 16 years (n = 101). Measured 24hUCa was compared with UCa/Cr in each of the three spot samples. The ability of UCa/Cr to discriminate between children with and without hypercalciuria (calciuria > 4 mg/kg/24 h, 1 mmol/kg/24 h) and optimal timing of the spot sample were determined. Eighty-five children completed an adequate 24-h urine collection. Pearson correlation coefficients between the UCa/Cr on the spot sample and 24hUCa were 0.64, 0.71, and 0.52 for the evening, first, and second morning spot samples, respectively. Areas under the ROC curve were 0.90, 0.82, and 0.75, respectively, for the corresponding spot samples.Conclusion: The relatively strong correlation between 24hUCa and UCa/Cr in evening and first morning spot urine samples suggests that these spots could be preferred in clinical practice.Trial registration: ClinicalTrials.gov , NCT02900261, date of trial registration 14 September 2016. What is Known: •Urinary calcium/creatinine ratio on a single spot urine sample is frequently used as a proxy for 24-h urinary calcium excretion. •Correlation of these indicators, including the best timing for spot urine sampling, has not been properly assessed. What is New: •Relatively strong correlations were found between the calcium/creatinine ratio on a single spot urine sample and 24-h urinary calcium excretion in healthy children. •Evening and first morning spot samples had the highest correlation.

[Vitamin D deficiency and rickets : screening and treatment, practical aspects for clinicians]. / Carence en vitamine D et rachitisme : dépistage et traitement, aspects pratiques pour le clinicien.

Vitamin D deficiency is increasing in Switzerland. If cases of rickets are scarce, pediatricians are often dealing with patients presenting vitamin D deficiency. The increase in vitamin D deficiency is certainly due to modification of life habits in recent decades. Clinical presentation varies according to age and severity of deficit. Treatments differ based on the level of vitamin D deficiency and symptoms. Vitamin D deficiency rickets is the most common cause of rickets and is predominantly seen in patients with risks factors They are other types of rickets like pseudo-vitamin D deficiency and hypophosphatemic rickets that the clinician needs to recognize. In which situation should the clinician suspect vitamin D deficiency or rickets ? Different types of rickets and practical aspects of treatment are reviewed in this article.

Le déficit en vitamine D est en augmentation en Suisse. Si les cas de rachitisme restent peu fréquents, les pédiatres sont souvent confrontés à un déficit en vitamine D. Cette augmentation est en lien avec les changements des habitudes de vie sur les dernières décennies. Le déficit en vitamine D se présente sous plusieurs formes et le traitement varie en fonction du degré du déficit et des symptômes. Le rachitisme carentiel est la forme la plus fréquente de rachitisme et concerne principalement les populations avec des facteurs de risque. Le diagnostic différentiel comprend le rachitisme pseudo-carentiel et le rachitisme hypophosphatémique. Quand et chez qui le praticien doit-il suspecter un déficit en vitamine D ou un rachitisme ? Le diagnostic différentiel et les aspects pratiques du traitement sont présentés dans cet article.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Balancing competing needs in kidney transplantation: does an allocation system prioritizing children affect the renal transplant function?

Children often merit priority in access to deceased donor kidneys by organ-sharing organizations. We report the impact of the new Swiss Organ Allocation System (SOAS) introduced in 2007, offering all kidney allografts from deceased donors <60 years preferentially to children. The retrospective cohort study included all paediatric transplant patients (<20 years of age) before (n = 19) and after (n = 32) the new SOAS (from 2001 to 2014). Estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio (UPC), need for antihypertensive medication, waiting times to kidney transplantation (KTX), number of pre-emptive transplantations and rejections, and the proportion of living donor transplants were considered as outcome parameters. Patients after the new SOAS had significantly better eGFRs 2 years after KTX (Mean Difference, MD = 25.7 ml/min/1.73 m2 , P = 0.025), lower UPC ratios (Median Difference, MeD = -14.5 g/mol, P = 0.004), decreased waiting times to KTX (MeD = -97 days, P = 0.021) and a higher proportion of pre-emptive transplantations (Odds Ratio = 9.4, 95% CI = 1.1-80.3, P = 0.018), while the need for antihypertensive medication, number of rejections and living donor transplantations remained stable. The new SOAS is associated with improved short-term clinical outcomes and more rapid access to KTX. Despite lacking long-term research, the study results should encourage other policy makers to adopt the SOAS approach.

[Genetic kidney diseases: new perspectives on diagnosis]. / Maladies génétiques rénales: perspectives diagnostiques.

Suspected renal inherited disorders are regularly evaluated in nephrology consultations both in adults and children. A positive family history and/or a typical phenotype should lead to genetic investigations. A confirmatory diagnosis integrated in a multidisciplinary genetic counseling approach gives patient guidance for further pregnancy. It also allows physician to better stratify disease risk and indicates treatment in some cases. The time to diagnosis and costs have been dramatically reduced thanks to next generation sequencing in several cases of complex inherited nephrologic syndromes.

Effect of glucocorticoids on growth and bone mineral density in children with nephrotic syndrome.

UNLABELLED: Glucocorticosteroids (GCs) are the first-line treatment for idiopathic nephrotic syndrome (NS), but prolonged administration interferes with growth and bone mineralization. We conducted a retrospective study to analyze the long-term impact of prednisone on growth and bone mineral density (BMD) in children with NS. Data from children with NS followed during almost 10 years were analyzed. Height and spine BMD values were converted to Z-scores (standard deviation [SD]). The mean cumulative dose of GCs received was calculated and correlated to patient's growth and spine BMD using linear regression and subgroup analysis. We included 30 patients diagnosed at 3.7 years old (interquartile range (IQR) 2.6-4.8) and followed over 9.8 years (IQR 6.6-11.7). The one half of NS patients was steroid sensitive and one half dependent or resistant. The median cumulative dose of GCs received was 0.27 mg/kg/day (IQR 0.18-0.35). Growth and spine BMD were both negatively associated with the cumulative dose of GCs (P=0.001 and P=0.037, respectively). Final height Z-scores were significantly lower in patients receiving >0.2 mg/kg/day GCs (P=0.001). No difference was observed in spine BMD between subgroups. CONCLUSION: Increasing doses of GCs were significantly associated with lower height and BMD Z-scores. A significant effect on growth was observed with cutoff doses above 0.2 mg/kg/day.

Evaluation and predictive factors of renal function progression using cystatin C and creatinine in neonates born with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) is a main cause leading to endstage renal disease (ESRD) during childhood occurring at a frequency of 1 in every 500 pregnancies. No early predictive markers of long-term renal function (RF) are validated in these neonates. The aim of this study was to compare CysC and creatinine (creat) as markers of RF from birth to 2 years and to identify factors of RF progression. METHODS: The 56 patients included in this study were followed for a median of 235 days (137 - 739). Repeated measures of CysC and creat during 2 years of RF evaluation were taken in 28 patients. Changes in RF with age were analyzed. Potential risk factors for RF progression were analyzed for: type of kidney disease (KD), bilateralism of KD, prenatal pelvic dilatation, reflux and initial relative RF (RRF) asymmetry obtained by scan. RESULTS: With age, a rapid decrease of CysC (16.3%, p < 0.001), and creat (68.6%, p < 0.001) was observed at 1 month. Between 1 month and 1 year, CysC decreased 4% per month (p < 0.001) and creatinine stabilized (+ 1.9%/m, p = 0.11). After 1 year, both CysC and creat stabilized. In the multivariate model, CysC significantly increased in patients with bilateralism (p = 0.004) or asymmetric RRF (p = 0.03). Creat was not significant. CONCLUSION: CysC was a better marker than creat to follow RF in neonates with CAKUT. Using CysC, bilateralism, and RRF asymmetry were significantly associated with RF progression.

[Quadratic formula: a new pediatric advance for glomerular filtration rate estimation]. / Pédiatrie 1. Formule Quadratique: une nouveauté pédiatrique et pratique pour estimer le taux de filtration glomérulaire.

A new formula for glomerular filtration rate estimation in pediatric population from 2 to 18 years has been developed by the University Unit of Pediatric Nephrology. This Quadratic formula, accessible online, allows pediatricians to adjust drug dosage and/or follow-up renal function more precisely and in an easy manner.

Urinary low-molecular-weight protein excretion in pediatric idiopathic nephrotic syndrome.

BACKGROUND: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic nephrotic syndrome (INS). We have evaluated the reliability of urinary neutrophil-gelatinase-associated lipocalin (uNGAL), urinary alpha1-microglobulin (uα1M) and urinary N-acetyl-beta-D-glucosaminidase (ußNAG) as markers for differentiating MCD from FSGS. We have also evaluated whether these proteins are associated to INS relapses or to glomerular filtration rate (GFR). METHODS: The patient cohort comprised 35 children with MCD and nine with FSGS; 19 healthy age-matched children were included in the study as controls. Of the 35 patients, 28 were in remission (21 MCD, 7 FSGS) and 16 were in relapse (14 MCD, 2 FSGS). The prognostic accuracies of these proteins were assessed by receiver operating characteristic (ROC) curve analyses. RESULTS: The level of uNGAL, indexed or not to urinary creatinine (uCreat), was significantly different between children with INS and healthy children (p = 0.02), between healthy children and those with FSGS (p = 0.007) and between children with MCD and those with FSGS (p = 0.01). It was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cut-off value of 17 ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 0.77 and specificity of 0.78. ußNAG was not significantly different in patients with MCD and those with FSGS (p = 0.86). Only uα1M, indexed or not to uCreat, was significantly (p < 0.001) higher for patients in relapse compared to those in remission. CONCLUSIONS: Our results indicate that in our patient cohort uNGAL was a reliable biomarker for differentiating MCD from FSGS independently of proteinuria or GFR levels.

Early urine output monitoring in very preterm infants to predict in-hospital neonatal outcomes: a bicentric retrospective cohort study.

OBJECTIVE: To evaluate whether urine output (UO), rarely assessed in the literature, is associated with relevant neonatal outcomes in very preterm infants, and which UO threshold may be the most clinically relevant. DESIGN: Retrospective cohort study. SETTING: Two Level IV neonatal intensive care units. PATIENTS: Very preterm infants born between 240/7 and 296/7 weeks of gestation documented with eight UO measurements per day between postnatal day 1 and day 7. MAIN OUTCOME MEASURES: Composite outcome defined as death before discharge, or moderate to severe bronchopulmonary dysplasia, or severe brain lesions. The association between this outcome and UO was studied using several UO thresholds. RESULTS: Among 532 infants studied, UO <1.0 mL/kg/hour for at least 24 consecutive hours was measured in 55/532 (10%) infants and the primary outcome was recorded in 25 patients. The association between a UO threshold <1.0 mL/kg/hour and the primary outcome was found marginally significant (crude OR 1.80, 95% CI 1.02 to 3.16, p=0.04). The primary outcome was recorded in 112/242 (46%) patients with a UO <2.0 mL/kg/hour and only 64/290 (22%) patients with a UO ≥2.0 mL/kg/hour (p<0.001). This UO threshold was found significantly associated with the primary outcome (crude OR 3.1, 95% CI 2.1 to 4.7, p<0.001), an association confirmed using a multivariate logistic regression model including baseline covariates (adjusted OR 3.7, 95% CI 2.2 to 6.4, p<0.001). CONCLUSION: A UO <2 mL/kg/hour over 24 hours between postnatal day 1 and day 7 strongly predicts neonatal mortality or severe morbidities in very preterm infants.

Is Cystatin C a promising marker of renal function, at birth, in neonates prenatally diagnosed with congenital kidney anomalies?

BACKGROUND: Despite the increased prenatal diagnosis of congenital abnormalities of the kidney and urinary tract (CAKUT), no reliable renal marker for glomerular filtration rate (GFR) has been validated yet in neonates. Cystatin C (CysC) is specific to the neonate and is proposed as a sensitive marker for this population. The aims of the study were first to define a reference interval in our center of CysC at birth in normal term babies and assess CysC as a marker of GFR in a group of term neonates prenatally diagnosed with CAKUT compared to controls. METHODS: One hundred normal term neonates (control group) and 33 neonates with kidney malformation (KM) had the CysC levels in their cord blood measured. A reference interval for CysC in controls was calculated using non-parametric methods. CysC from controls was compared first to the whole group of neonates with KM, then with KM group divided in infants (n = 20) with unilateral kidney malformation (UKM) and those (n = 13) with bilateral kidney malformation (BKM). A multivariable analysis was performed to assess the difference in CysC between the groups with adjustment on other factors. The ability of CysC to discriminate neonates with BKM from the controls was assessed by a non-parametric receiver-operated characteristics (ROC) curve. RESULTS: In the control group, the CysC reference interval was [1.54-2.64] mg/L with a median (M) CysC of 2.02 IQR [1.86-2.23]. In the neonates with KM, M CysC was 1.98 IQR [1.79-2.34]; 1.88 IQR [1.76-2.01] in the UKM group and 2.52 IQR [2.16-2.71] in BKM group. Using a multivariate regression analyses, CysC was significantly increased (P < 0.001) in BKM compared to controls with an increment of CysC of 24.5%, and independent from gender, weight and size. The ROC curve analyses, comparing BKM versus controls with a chosen cut-off for CysC of 2.34, showed a sensitivity of 69% and a specificity of 86%. CONCLUSIONS: Comparing CysC with a reference interval of CysC validated in our center, we showed a significant increase of CysC in neonates presenting BKM compared to controls and those with UKM.

Third-party mesenchymal stromal cell infusion is associated with a decrease in thrombotic microangiopathy symptoms observed post-hematopoietic stem cell transplantation.

TA-TMA is a pathology that occurs after allogenic HSC transplantation with an incidence of 4-13%, and represents one of the most severe vascular damage related with this therapy. We report here the case of a nine-yr-old girl suffering from a severe refractory aplastic anemia who received an unrelated, 9/10 HLA-matched HSC. Soon after transplantation, the patient developed a graft-versus-host disease (GvHD), a TA-TMA, and renal insufficiency. These pathologies remained refractory to the various treatments undertaken and required several hospitalizations in the intensive care unit. On day 106 post-HSC transfusion, after several episodes of intensive care, the patient was infused with mismatched, third-party MSCs. Schizocyte levels rapidly decreased after MSC infusion, and two wk later, most biological parameters returned to normal. Erythrocyte and thrombocyte transfusions were discontinued, and the patient remained stable for 10 wk. Thereafter, TA-TMA symptoms, viral reactivation, pleural and cardiac effusions reappeared and lead to the death of the patient. Our observations suggest that allogenic MSC infusion may decrease the symptoms of TA-TMA, but further investigation is required to determine how and when MSC should be infused to develop a long-lasting protective effect.