Rolf Beetz

Muscarinic Acetylcholine Receptor M3 Mutation Causes Urinary Bladder Disease and a Prune-Belly-like Syndrome.

Urinary bladder malformations associated with bladder outlet obstruction are a frequent cause of progressive renal failure in children. We here describe a muscarinic acetylcholine receptor M3 (CHRM3) (1q41-q44) homozygous frameshift mutation in familial congenital bladder malformation associated with a prune-belly-like syndrome, defining an isolated gene defect underlying this sometimes devastating disease. CHRM3 encodes the M3 muscarinic acetylcholine receptor, which we show is present in developing renal epithelia and bladder muscle. These observations may imply that M3 has a role beyond its known contribution to detrusor contractions. This Mendelian disease caused by a muscarinic acetylcholine receptor mutation strikingly phenocopies Chrm3 null mutant mice.

Late-Onset Manifestation of Antenatal Bartter Syndrome as a Result of Residual Function of the Mutated Renal Na+-K+-2Cl− Co-Transporter

Genetic defects of the Na+-K+-2Cl- (NKCC2) sodium potassium chloride co-transporter result in severe, prenatal-onset renal salt wasting accompanied by polyhydramnios, prematurity, and life-threatening hypovolemia of the neonate (antenatal Bartter syndrome or hyperprostaglandin E syndrome). Herein are described two brothers who presented with hyperuricemia, mild metabolic alkalosis, low serum potassium levels, and bilateral medullary nephrocalcinosis at the ages of 13 and 15 yr. Impaired function of sodium chloride reabsorption along the thick ascending limb of Henles loop was deduced from a reduced increase in diuresis and urinary chloride excretion upon application of furosemide. Molecular genetic analysis revealed that the brothers were compound heterozygotes for mutations in the SLC12A1 gene coding for the NKCC2 co-transporter. Functional analysis of the mutated rat NKCC2 protein by tracer-flux assays after heterologous expression in Xenopus oocytes revealed significant residual transport activity of the NKCC2 p.F177Y mutant construct in contrast to no activity of the NKCC2-D918fs frameshift mutant construct. However, coexpression of the two mutants was not significantly different from that of NKCC2-F177Y alone or wild type. Membrane expression of NKCC2-F177Y as determined by luminometric surface quantification was not significantly different from wild-type protein, pointing to an intrinsic partial transport defect caused by the p.F177Y mutation. The partial function of NKCC2-F177Y, which is not negatively affected by NKCC2-D918fs, therefore explains a mild and late-onset phenotype and for the first time establishes a mild phenotype-associated SLC12A1 gene mutation.

Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first three decades of life. Identification of single-gene mutations that cause CAKUT permits the first insights into related disease mechanisms. However, for most cases the underlying defect remains elusive. We identified a kindred with an autosomal-dominant form of CAKUT with predominant ureteropelvic junction obstruction. By whole exome sequencing, we identified a heterozygous truncating mutation (c.1010delG) of T-Box transcription factor 18 (TBX18) in seven affected members of the large kindred. A screen of additional families with CAKUT identified three families harboring two heterozygous TBX18 mutations (c.1570C>T and c.487A>G). TBX18 is essential for developmental specification of the ureteric mesenchyme and ureteric smooth muscle cells. We found that all three TBX18 altered proteins still dimerized with the wild-type protein but had prolonged protein half life and exhibited reduced transcriptional repression activity compared to wild-type TBX18. The p.Lys163Glu substitution altered an amino acid residue critical for TBX18-DNA interaction, resulting in impaired TBX18-DNA binding. These data indicate that dominant-negative TBX18 mutations cause human CAKUT by interference with TBX18 transcriptional repression, thus implicating ureter smooth muscle cell development in the pathogenesis of human CAKUT.

Three-Year Growth Hormone Treatment in Short Children with X-Linked Hypophosphatemic Rickets: Effects on Linear Growth and Body Disproportion

CONTEXT Children with X-linked hypophosphatemic rickets (XLH) are prone to progressive disproportionate stunting despite oral phosphate and vitamin D treatment. OBJECTIVE Our objective was to analyze the effects of GH treatment on stature and lengths of linear body segments in short children with XLH. DESIGN, SETTINGS, AND PATIENTS A 3-yr randomized controlled open-label GH study in short prepubertal children with XLH (n = 16) on phosphate and calcitriol treatment was conducted. A cohort of XLH patients (n = 76) on conservative treatment served as an XLH reference population. MAIN OUTCOME MEASURES Changes in SD scores (SDS) of stature and linear body segments, i.e. sitting height, leg and arm length, and sitting height index (i.e. ratio between sitting height and stature) were the main outcome measures. RESULTS XLH patients presented at time of enrollment with significant impairments of stature (-3.3 SDS) and linear body segments compared with healthy children. Leg length (-3.8 SDS) was most impaired, whereas sitting height (-1.7 SDS) was best preserved. The markedly elevated mean sitting height index (+3.3 SDS) reflected severe body disproportion. GH resulted in a sustained increase in linear growth (stature, +1.1 SDS; sitting height, +1.3 SDS; leg length, +0.8 SDS; arm length, +1.1 SDS; each P < 0.05 vs. baseline), whereas no significant changes were observed in controls. Mean height SDS at 3 yr did not significantly differ between groups. Sitting height index remained stable in both the GH-treated patients and in study controls but increased further in the XLH-reference population. CONCLUSIONS The 3-yr GH treatment improved linear growth without progression of body disproportion in short children with XLH.

[Urinary tract infections in infants and children -- a consensus on diagnostic, therapy and prophylaxis].

ZusammenfassungIm Säuglings- und Kindesalter gehören Harnwegsinfektionen (HWI) zu den häufigsten bakteriellen Infektionskrankheiten. Die frühzeitige Diagnose einer Pyelonephritis und die rasche, kalkulierte antibakterielle Therapie sind entscheidend für die Prognose. Die weiterführende Diagnostik dient der Früherkennung von Nieren- und Harnwegsfehlbildungen sowie Blasenfunktionsstörungen als Risikofaktoren rezidivierender HWI.In der Diagnostik, Therapie und Prophylaxe kindlicher HWI begegnen sich Kinderärzte, Urologen und Infektiologen. Ziel der vorliegenden Empfehlung ist es, ein gemeinsames Konzept zu erstellen, das dem behandelnden Arzt eine Hilfe für sein Handeln gibt und die interdisziplinäre Zusammenarbeit erleichtert.AbstractUrinary tract infections (UTI) are among the most common bacterial infections in infants and children. The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition.Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.

Harnwegsinfektionen im Säuglings- und Kindesalter

ZusammenfassungIm Säuglings- und Kindesalter gehören Harnwegsinfektionen (HWI) zu den häufigsten bakteriellen Infektionskrankheiten. Die frühzeitige Diagnose einer Pyelonephritis und die rasche, kalkulierte antibakterielle Therapie sind entscheidend für die Prognose. Die weiterführende Diagnostik dient der Früherkennung von Nieren- und Harnwegsfehlbildungen sowie Blasenfunktionsstörungen als Risikofaktoren rezidivierender HWI.In der Diagnostik, Therapie und Prophylaxe kindlicher HWI begegnen sich Kinderärzte, Urologen und Infektiologen. Ziel der vorliegenden Empfehlung ist es, ein gemeinsames Konzept zu erstellen, das dem behandelnden Arzt eine Hilfe für sein Handeln gibt und die interdisziplinäre Zusammenarbeit erleichtert.AbstractUrinary tract infections (UTI) are among the most common bacterial infections in infants and children. The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition.Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.

Harnwegsinfektionen im Säuglings- und Kindesalter@@@Urinary tract infections in infants and children – a consensus on diagnostic, therapy and prophylaxis: Konsensusempfehlungen zu Diagnostik, Therapie und Prophylaxe

ZusammenfassungIm Säuglings- und Kindesalter gehören Harnwegsinfektionen (HWI) zu den häufigsten bakteriellen Infektionskrankheiten. Die frühzeitige Diagnose einer Pyelonephritis und die rasche, kalkulierte antibakterielle Therapie sind entscheidend für die Prognose. Die weiterführende Diagnostik dient der Früherkennung von Nieren- und Harnwegsfehlbildungen sowie Blasenfunktionsstörungen als Risikofaktoren rezidivierender HWI.In der Diagnostik, Therapie und Prophylaxe kindlicher HWI begegnen sich Kinderärzte, Urologen und Infektiologen. Ziel der vorliegenden Empfehlung ist es, ein gemeinsames Konzept zu erstellen, das dem behandelnden Arzt eine Hilfe für sein Handeln gibt und die interdisziplinäre Zusammenarbeit erleichtert.AbstractUrinary tract infections (UTI) are among the most common bacterial infections in infants and children. The early diagnosis of a pyelonephritis and its rapid, calculated antibacterial therapy are decisive for the prognosis. Urogenital anomalies, renal damage and bladder dysfunction may influence the risk of recurrences of UTI and pyelonephritic scarring. Diagnostic strategies therefore should focus on their early recognition.Pediatricians, urologists and infectiologists are cooperating in diagnostic, therapy and prophylaxis of UTI. The aim of the interdisciplinary consensus presented was to work out a concept which may help to manage childhood UTI in daily practice.

Prospective analysis of long-term renal function in survivors of childhood Wilms tumor

BackgroundConsidering the improved outcome, a better understanding of the late effects in Wilms tumor survivors (WT-S) is needed. This study was aimed at evaluating renal function and determining the prevalence of clinical and subclinical renal dysfunction in a cohort of WT-S using a multimodal diagnostic approach.MethodsThirty-seven WT-S were included in this prospective cross-sectional single center study. To evaluate renal function, glomerular filtration rate (GFR) and urinary protein excretion were assessed. Additionally, kidney sonomorphology and blood pressure were analyzed.ResultsAll examined WT-S (mean age 28.7 years, mean follow-up 24.8 years) had been treated with a combination of surgery and chemotherapy; 59.5% had received adjuvant radiotherapy. Impaired glomerular renal function was detected in a considerable proportion of WT-S, with age-adjusted cystatin-based GFR estimation below age norm in 55.9%. A lower cystatin-based estimated GFR (eGFR) correlated with longer follow-up time and higher irradiation dose. In 5 patients (13.5%) albuminuria was identified. Analysis of sonomorphology detected compensatory contralateral renal hypertrophy in 83.3% of WT-S. Chronic kidney disease (CKD) ≥ stage II was present in 55.9% of WT-S. Blood pressure measurements revealed arterial hypertension in 15 (40.5%) WT-S (newly diagnosed n=10). In 24.3% both CKD ≥ stage II and arterial hypertension were determined.ConclusionEven though WT-S are believed to carry a low risk for end-stage renal disease, in this study, a remarkable number of WT-S presented with previously unidentified subclinical signs of renal function impairment and secondary morbidity. Therefore, it is important to continue regular follow-up, especially after transition into adulthood.

Blasenfunktionsstörungen durch Meningomyelozele

Bei den meisten Erkrankungen spielt die Zeit eine wichtige Rolle. So ist es auch bei der Meningomyelozele — genauer gesagt bei der Blasenfunktionsstörung, die sie auslösen kann. Deren Typ kann sich im Laufe der Zeit ändern. Das beeinflusst den Zeitpunkt diagnostischer und therapeutischer Maßnahmen.