Off-label, off-limits? Parental awareness and attitudes towards off-label use in paediatrics

Off-label drug use in paediatrics is associated with an increased risk of adverse drug reactions. Any risk–benefit analysis has to be based on value judgments that should include parents' views. However, nothing is known so far about the parents' perspective on this critical issue. Therefore, a quantitative survey with parents of healthy and chronically ill children was carried out (n = 94). Knowledge about the practise of off-label use is generally poor in both groups. Surprisingly, this is also true for the parents of children with chronic disease. Nine percent of the parents of chronically ill children and 20% of the parents of healthy children would refuse treatment with an off-label drug. Parents who have poor knowledge about the practise of off-label use tend to refuse to volunteer their child for study participation. Therefore, the information of parents on the off-label use of drugs is important to meet ethical standards and to increase the parents' acceptance of medical studies with children

Working Towards a Treat-to-Target Protocol in Juvenile Proliferative Lupus Nephritis - A Survey of Pediatric Rheumatologists and Nephrologists in Germany and Austria.

BackgroundTo describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN.MethodsSurvey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Pediatric Nephrology (GPN) on diagnostics and (concomitant) therapy of LN.ResultsFifty-eight physicians completed the survey. Overall, there was a considerable heterogeneity regarding the suggested diagnostics and management of juvenile proliferative LN. Increased urinary protein excretion, either assessed by 24 h urine collection or spot urine (protein-creatinine ratio), and reduced estimated glomerular filtration rate were specified as important parameters for indication of kidney biopsy to diagnose proliferative LN and monitoring of therapy. Corticosteroids were generally proposed for induction and maintenance therapy, most often in conjunction with either mycophenolate mofetil (MMF) or cyclophosphamide (CP) as steroid-sparing immunosuppressants. MMF was clearly preferred over CP for induction therapy of LN class III, whereas CP and MMF were equally proposed for LN class IV. MMF was most often recommended for maintenance therapy in conjunction with oral corticosteroids and continued for at least 3 years and 1 year, respectively, after remission. Hydroxychloroquine was widely accepted as a concomitant measure followed by renin-angiotensin system inhibitors in cases of arterial hypertension and/or proteinuria.ConclusionThe majority of pediatric rheumatologists and nephrologists in Germany and Austria propose the use of corticosteroids, most often in combination with either MMF or CP, for treatment of proliferative LN in children. The considerable heterogeneity of responses supports the need for a treat-to-target protocol for juvenile proliferative LN between pediatric rheumatologists and nephrologists

Kidney Injury by Variants in the <i>COL4A5</i> Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases

STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis

<p>CDK10/CycM is a protein kinase deficient in STAR (toe Syndactyly, Telecanthus and Anogenital and Renal malformations) syndrome, which results from mutations in the X-linked <i>FAM58A</i> gene encoding Cyclin M. The biological functions of CDK10/CycM and etiology of STAR syndrome are poorly understood. Here, we report that deficiency of CDK10/Cyclin M promotes assembly and elongation of primary cilia. We establish that this reflects a key role for CDK10/Cyclin M in regulation of actin network organization, which is known to govern ciliogenesis. In an unbiased screen, we identified the RhoA-associated kinase PKN2 as a CDK10/CycM phosphorylation substrate. We establish that PKN2 is a bone fide regulator of ciliogenesis, acting in a similar manner to CDK10/CycM. We discovered that CDK10/Cyclin M binds and phosphorylates PKN2 on threonines 121 and 124, within PKN2′s core RhoA-binding domain. Furthermore, we demonstrate that deficiencies in CDK10/CycM or PKN2, or expression of a non-phosphorylatable version of PKN2, destabilize both the RhoA protein and the actin network architecture. Importantly, we established that ectopic expression of RhoA is sufficient to override the induction of ciliogenesis resulting from CDK10/CycM knockdown, indicating that RhoA regulation is critical for CDK10/CycM's negative effect on ciliogenesis. Finally, we show that kidney sections from a STAR patient display dilated renal tubules and abnormal, elongated cilia. Altogether, these results reveal CDK10/CycM as a key regulator of actin dynamics and a suppressor of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling. Moreover, they suggest that STAR syndrome is a ciliopathy.</p

HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German Multicenter HNF1B Childhood Registry

Background HNF1B gene mutations are an important cause of bilateral (cystic) dysplasia in children, complicated by chronic renal insufficiency. The clinical variability, the absence of genotype-phenotype correlations, and limited long-term data render counseling of affected families difficult. Methods Longitudinal data of 62 children probands with genetically proven HNF1B nephropathy was obtained in a multicenter approach. Genetic family cascade screening was performed in 30/62 cases. Results Eighty-seven percent of patients had bilateral dysplasia, 74% visible bilateral, and 16% unilateral renal cysts at the end of observation. Cyst development was non-progressive in 72% with a mean glomerular filtration rate (GFR) loss of -0.33 ml/min/1.73m(2) per year (8.9). In patients with an increase in cyst number, the annual GFR reduction was -2.8 ml/min/1.73m(2) (+/- 13.2), in the total cohort -1.0 ml/min/1.73m(2) (+/- 10.3). A subset of HNF1B patients differs from this group and develops end stage renal disease (ESRD) at very early ages < 2 years. Hyperuricemia (37%) was a frequent finding at young age (median 1 year), whereas hypomagnesemia (24%), elevated liver enzymes (21%), and hyperglycemia (8%) showed an increased incidence in the teenaged child. Genetic analysis revealed no genotype-phenotype correlations but a significant parent-of-origin effect with a preponderance of 81% of maternal inheritance in dominant cases. Conclusions In most children, HNF1B nephropathy has a non-progressive course of cyst development and a slow-progressive course of kidney function. A subgroup of patients developed ESRD at very young age < 2 years requiring special medical attention. The parent-of-origin effect suggests an influence of epigenetic modifiers in HNF1B disease

Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets