REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study- protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study.

INTRODUCTION: Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable. METHODS AND ANALYSIS: The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period. ETHICS AND DISSEMINATION: This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants. TRIAL REGISTRATION NUMBER: NTR5670, EudraCT no 2016-002430-76.

Pyuria is absent during urinary tract infections in neutropenic patients.

To investigate the diagnostic significance of a normal urine sediment in the work-up for fever of unknown origin in neutropenia. Urinary tract infection was defined as ≥10(5) urinary pathogens in the absence of another focus. Pyuria was found in only 1/23 neutropenic episodes compared to 21/31 in controls (P < 0.0001).

[A boy with cyclic vomiting and an alleged furosemide allergy on the basis of a subpelvic stenosis]. / Een jongen met cyclisch braken en een vermeende furosemideallergie op basis van een subpelviene stenose.

An 8-year-old boy, known with a Diamond-Blackfan anaemia, was admitted to the hospital because of frequent vomiting since 3 days and loin pain. In previous years, he had been admitted several times for the same complaints but no cause had been identified. Ultrasound examination of the abdomen performed at admittance showed dilatation of the left renal pelvis. A renal scintigraphy was discussed with the mother, and she refused the injection of furosemide, because her son was allegedly allergic to furosemide: previous furosemide treatments during blood transfusions for his anaemia had always resulted in stomach-ache and vomiting, which may be attributed, however, to an acute dilatation of the renal pelvis due to the diuretic effect of furosemide. Scintigraphy without furosemide showed a significant obstruction and asymmetric renal function, so a pyeloplasty was performed after which he has been symptom-free. In patients with cyclic vomiting, an intermittent uretero-pelvic junction obstruction should be considered and can only be ruled out when ultrasound during the complaints and renal scintigraphy under adequate hydration and after furosemide are normal.

Weekend versus working day: differences in telemetric blood pressure in male Wistar rats.

Blood pressure (BP) is a frequently monitored parameter in research. Various methods are used to obtain BP values in animal models, but telemetry is the method of choice because it allows for continuous monitoring in conscious and freely moving animals. However, factors due to the animal facility, like activities and sound, can still influence measurements. We, therefore, retrospectively compared BP values in adult male Wistar rats during working hours with values from non-working days. Telemetry devices were implanted according to standard protocol. Values were obtained at the age of 6 and 12 months during working hours (Friday 10:00-16:00 h, lights on 06:00-18:00 h) and compared with data from the average of Saturday 10:00-16:00 h and Sunday 10:00-16:00 h, representing non-working days. Data were available from 12 and 7 rats at 6 months and 12 months of age respectively. Relative differences in heart rate, spontaneous locomotor activity, systolic and diastolic BP were 2.2% (P<0.001), 32.9% (P<0.05), 3.2% (P<0.05) and 3.7% (P<0.05), respectively, with no differences between the age groups. We have shown a significant and important difference between BP values obtained during working hours and non-working days using telemetry in adult male Wistar rats. This phenomenon has implications for the interpretation of BP measurements in animals.

Influence of intrauterine growth restriction on renal function in the adult rat.

Intrauterine growth restriction (IUGR) has been shown to influence renal development and lead to fewer nephrons. Data on long term renal function after IUGR are limited. We studied the effect on renal function of IUGR in aging rats. IUGR was induced using a model of bilateral uterine artery ligation in pregnant Wistar rats. Renal function was studied at the age of 18 months. In male IUGR rats, estimated glomerular filtration rate was significantly decreased compared to male control rats [1.1 (SD 0.3) 1.7 (SD 0.3) ml x min(-1), p<0.05]. Female IUGR rats showed an increased urinary protein excretion compared with female control rats [84 (SD 73) vs. 12 (SD 13) mg x 24h(-1), p<0.01]. All male rats showed heavy proteinuria (p<0.01 vs. female rats from same experimental group), with no significant differences between the groups. Tubular reabsorption of phosphorus was lower in females, but showed no differences between the experimental groups. In conclusion, IUGR impairs renal function in the rat. It is suggested that a low nephron endowment leads to proteinuria as a sign of glomerular damage, and ends with a decrease in glomerular filtration rate as a sign of glomerular loss.

[Schimke's immuno-osseous dysplasia as an explanation for the rare combination of disproportionately short stature and the nephrotic syndrome]. / Immuno-ossale dysplasie van Schimke als zeldzame oorzaak van de combinatie van kleine lichaamslengte en nefrotisch syndroom.

A 10-year-old Turkish boy with consanguineous parents was presented with a disproportionately short stature and a nephrotic syndrome. The mild form of Schimke's immuno-osseous dysplasia was diagnosed as the common cause. This rare, autosomal recessive osteochondrodysplasia is characterised by spondyloepiphyseal dysplasia, facial dysmorphism, T-cell immunodeficiency and progressive renal failure due to focal segmental glomerulosclerosis. In Schimke's immuno-osseous dysplasia, a severe early-onset form and a milder later-onset form can be distinguished on the basis of the clinical course. The patient was treated by fluid and salt restriction, enalapril and later also losartan, which led to a decrease in the proteinuria and an increase in serum albumin concentration. Two years later, the renal function was still normal.

Craniopagus: the Suriname-Amsterdam conjunction.

OBJECTS: A case of a Suriname female occipito-parietal to occipito-parieto-temporal craniopagus twins is described. The girls were transferred to the VU University Medical Center (VUmc) in Amsterdam, the Netherlands, for further diagnostics and to analyze whether surgical separation was feasible and ethically justifiable. The multifactorial aspects of different treatment options are discussed. METHODS: The twins underwent multiple investigations by a multidisciplinary team. Advanced imaging techniques with 3D-CT scan, MRI and MRA scans, image fusion techniques and, most importantly, cerebral angiography with balloon occlusion tests were performed. CONCLUSIONS: Because of a shared venous ring, with preferential drainage to the left child, and which endovascular balloon occlusion showed could not be separated, surgical separation of the twins with a fair chance of survival without additional neurological damage and with prospects of a good quality of life was regarded as impossible. In accordance with the parents' wishes, the twins were not separated and offered optimal integral conservative treatment.

Approach for defining endogenous reference genes in gene expression experiments.

The quantification of gene expression by real-time polymerase chain reaction (PCR) has revolutionized the field of gene expression analysis. Due to its sensitivity and flexibility it is becoming the method of choice for many investigators. However, good normalization protocols still have to be implemented to facilitate data exchange and comparison. We have designed primers for 10 unrelated genes and developed a simple protocol to detect genes with stable expression that are suitable for use as endogenous reference genes for further use in the normalization of gene expression data obtained by real-time PCR. Using this protocol, we were able to identify human proteosome subunit Y as a reliable endogenous reference gene for human umbilical vein endothelial cells treated for up to 18 h with TNFalpha, IL-4, or IFNgamma and for B cells isolated from healthy controls and patients suffering from IgA nephropathy. Other optional endogenous reference genes that can be considered are phosphomannomutase (PPMM) and actin for endothelial cells and glyceraldehyde-3-phosphate dehydrogenase and PPMM for B cells.

Acceptability of Liquid Human Growth Hormone (hGH) [Norditropin Simple Xx®] in Adults and Children with GH Deficiency and Children with Chronic Renal Disease.

OBJECTIVE: Human growth hormone (GH) is well established as a treatment for growth hormone deficiency. Recently, a new liquid GH formulation (Norditropin SimpleXx®) has become available that does not require reconstitution before subcutaneous self-administration with a new delivery system (NordiPen™) and an optional auto-injector (NordiPenmate™). In this study the acceptability and tolerability of and compliance with the liquid formulation were investigated DESIGN AND PATIENTS: An open 6-week multicentre trial in 53 patients, including adults and children, was performed in The Netherlands. Acceptability and tolerability of the liquid GH formulation were assessed by questionnaires and compliance by both questionnaires and re-collection of GH cartridges MAIN OUTCOME MEASURES AND RESULTS: The mean daily dosage of GH was 0.24 mg/m2 (0.03 to 0.82 mg/m2) in adults and 1.13 mg/m2 (0.65 to 1.77 mg/m2) in children. Most patients (91% of adults and 89% of children) preferred to continue on the new GH formulation rather than the previously used formulation. This was mainly due to the easier and less time-consuming procedure and the good tolerance of the drug. Self-reported compliance also improved, but this could not be proven due to poor return of study cartridges CONCLUSIONS: The use of the liquid GH formulation Norditropin SimpleXx® with the NordiPen™ device and optional use of the NordiPenmate™ device was well accepted by both adults and children. This was mainly due to the avoidance of reconstitution and the ease of handling of the injection device.