J.A.E. van Wijk

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

BACKGROUND AND OBJECTIVESnIntrauterine growth restriction (IUGR) and prematurity are associated with a low nephron endowment. It can therefore be expected that neonates who are born premature and/or after IUGR have a lower GFR. Measurement of GFR in neonates is difficult, but the clearance of amikacin has been proven to be a reliable marker. We hypothesized that amikacin clearance is lower after IUGR or premature birth as a marker of low nephron endowment.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnAmikacin clearance was retrospectively analyzed in 161 neonates who received amikacin within the first 24 h of life. Using the MW/Pharm computer program, a population one-compartment model was calculated. The mean population pharmacokinetic parameters were individualized for each patient according to the maximum a posteriori Bayesian fitting method and provided the amikacin clearance.nnnRESULTSnOur results show that birth weight z score and gestational age are correlated with the clearance of amikacin (partial correlation coefficient 0.159, P = 0.046, and 0.396, P < 0.001, respectively), after correction for other factors.nnnCONCLUSIONSnWe conclude that renal clearance on the first day of life is lower in neonates with a lower gestational age and/or birth weight z score. This indicates that both prematurity and IUGR impair GFR on the first day of life.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10‐14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370‐kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein‐altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370‐kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

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·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·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.ResumenLa restricción del crecimiento intrauterino (RCIU) afecta al desarrollo renal y reduce el número de nefronas, pero hay pocos datos respecto de la función renal a largo plazo. Se estudia en este trabajo el efecto de la restricción del crecimiento intrauterino sobre la función renal en ratas viejas. La restricción del crecimiento intrauterino se indujo mediante ligado bilateral de las arterias uterinas en ratas Wistar preñadas y se estudió la función renal en los hijos a la edad de 18 meses (ratas RCIU). En ejemplares RCIU macho, la velocidad de filtración glomerular se reduce significativamente respecto de los controles y en las hembras, se incrementa la excreción proteica urinaria respecto de las ratas control. En todos los casos, RCIU y control, se observa una marcada proteinuria, que es significativamente mayor en los machos que en las hembras, sin que haya diferencias entre los grupos. La reabsorción tubular de fosfato es menor en las hembras, sin diferencias en los grupos experimentales. Los resultados indican que la restricción del crecimiento intrauterino afecta a la función renal en la rata.

Acceptability of liquid Human growth hormone (hGH) [Norditropin SimpleXx®] in adults and children with GH deficiency and children with chronic renal disease

ObjectiveHuman 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 investigatedDesign and patientsAn 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 cartridgesMain outcome measures and resultsThe 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 cartridgesConclusionsThe 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

Discrepant Results of Serum Creatinine and Cystatin C in a Urological Patient

A 3-month-old boy was seen for routine follow-up at the pediatric nephrology outpatient clinic. He had been diagnosed as having Sotos syndrome manifesting with craniofacial dysmorphism, feeding difficulties, pulmonary artery stenosis, and atrial septal defect, as well as complex urological abnormalities. He had bilateral hydronephrosis with megaureter and grade V vesicoureteral reflux to the left and grade I to the right kidney. At the age of 6 weeks, static renal scintigraphy using DMSA (99mTc-dimercaptosuccinic acid) to assess renal morphology, structure, and function had demonstrated almost symmetrical kidney function (split kidney function left 44% vs right 56%) without cortical scarring.nnWhile his baseline serum creatinine had been 40 μmol/L (0.45 mg/dL), a sudden rise to 69 μmol/L (0.79 mg/dL) was noted. Urinary tract infection was ruled out, as was dehydration. On renal ultrasound, dilation of the right collecting system and ureter had increased significantly and a novel fluid collection at the upper pole was noted, which prompted an MRI study (Fig. 1). In addition to serum creatinine, cystatin C measurement was ordered and was within the reference interval for age (1.13 mg/L).nnnnFig. 1. Abdominal MRI.nBilateral hydronephrosis and fluid collection at right upper pole (asterisk).nnnnCreatinine, the most commonly used endogenous marker of glomerular filtration rate (GFR),4 has in recent years been supplemented by cystatin C. In fact, todays most reliable equations for estimating GFR both in adults (1) and in children (2) make use of a combination of the 2. Still, in certain conditions the 2 markers can give very discordant findings, which may be diagnostic, as in the case presented here. Discordant findings may occur …

Bartter syndrome type III and congenital anomalies of the kidney and urinary tract: an antenatal presentation.

Bartter syndrome encompasses a variety of inheritable renal tubular transport disorders characterized by hypokalemia and hypochloremic metabolic alkalosis. Bartter syndrome Type III is caused by genetic alterations in the chloride channel kidney B (CLCNKB) gene and often presents in the first 2 years of life, known as classic Bartter syndrome. However, in rare cases Bartter syndrome Type III has an antenatal presentation with polyhydramnios, premature delivery and severe dehydration in the first weeks of life. Associations between congenital anomalies of the kidney and urinary tract and Bartter syndrome are extremely rare. This case report presents a girl with Bartter syndrome Type III due to a homozygous CLCNKB mutation and bilateral congenital anomalies of the kidney and urinary tract. In addition, we describe the antenatal presentation as well as its perinatal management.

Laag geboortegewicht: consequenties voor de nier?

SummaryIn recent years, a relation has been shown between low birth weight and a higher risk of diseases in adult life, particularly hypertension, cardiovascular diseases and type 2 diabetes. Causal factor could be intrauterine growth retardation, which interferes with the development and function of organs (called programming).Human and animal studies show that programming of the kidney leads to a reduced number of nephrons. In order to compensate, there is hyperfiltration in remnant nephrons, leading to glomerular and systemic hypertension and glomerulosclerosis, with renal failure as endpoint. Oligonephronia makes the kidneys more vulnerable: in case of accessory renal disease, prognosis seems to deteriorate with low birth weight.The renin-angiotensin system (ras) appears to play an important role based on its influence on renal hemodynamics, which is altered when associated with low birth weight. Animal studies suggest the ras as means for pharmacological manipulation of the low birth weight consequences. However, more data is needed before coming to clinical implications.SamenvattingDe laatste jaren is er bewijs geleverd voor een relatie tussen een laag geboortegewicht en een toegenomen risico op aandoeningen op latere leeftijd, zoals hypertensie, hart- en vaatziekten en diabetes mellitus type II. Oorzakelijk dient gedacht te worden aan intra-uteriene groeivertraging, hetgeen interfereert met de aanleg en functie van organen (herprogrammering genoemd).Uit onderzoek bij de mens en diverse proefdiermodellen blijkt herprogrammering van de nier voor een afgenomen hoeveelheid nefronen te zorgen. Ter compensatie treedt er in de aanwezige nefronen hyperfiltratie op, leidend tot glomerulaire en systemische hypertensie en glomerulosclerose, met als eindpunt nierinsufficiëntie. Door het verminderde aantal nefronen zijn de nieren kwetsbaarder; in het geval van bijkomende renale aandoeningen lijkt de prognose slechter te zijn bij een laag geboortegewicht.De rol van het renine-angiotensine-systeem (ras) is belangrijk gezien de invloed ervan op de renale hemodynamiek, die veranderd is bij een laag geboortegewicht. Uit proefdieronderzoek lijkt het ras een aangrijpingspunt te bieden voor medicamenteuze manipulatie van de gevolgen van een laag geboortegewicht. Aanvullende gegevens zijn echter noodzakelijk om tot klinische implicaties te komen.

15 Nieren en urinewegen

In de algemene praktijk komen urineweginfecties bij kinderen vaak voor. Anatomische en functionele oorzaken liggen hieraan ten grondslag. Vooral bij jonge kinderen verlopen de infecties vaak aspecifiek en zijn ze moeilijk vast te stellen. Toch kan aanzienlijke nierschade worden aangericht omdat het nierweefsel op die leeftijd erg kwetsbaar is. Glomerulaire aandoeningen hebben meestal een immunologische achtergrond, kunnen langere tijd onopgemerkt blijven en zo de nierfunctie bedreigen. Beide soorten aandoeningen worden hieronder beschreven.

Acute nierinsufficiëntie op basis van een tubulo-interstitiële nefritis en uveïtis: TINU-syndroom

SamenvattingEen twaalfjarig meisje werd gezien in verband met een acute nierinsufficiëntie, polyurie, normale bloeddruk en met name renaal-tubulaire functiestoornissen. De verdenking op een tubulo-interstitiële nefritis werd bevestigd door middel van een nierbiopt. Bij verder onderzoek bleek zij ook een uveïtis posterior te hebben. Door middel van bloedonderzoek konden andere auto-immuunaandoeningen worden uitgesloten en de diagnose tubulo-interstitiële nefritis met uveïtis (TINU-syndroom) worden gesteld. De uveïtis werd behandeld met lokale corticosteroïden met snel resultaat. Er werd daarnaast gestart met systemische corticosteroïden. Hierop volgde binnen een maand herstel van de nierfunctie, wat kenmerkend is voor dit ziektebeeld.SummaryA twelve year-old girl presented with acute renal failure, polyuria, normal blood pressure and renal-tubular dysfunction. Tubulo-interstitial nephritis was suspected and confirmed by renal biopsy. On ophthalmological examination, a posterior uveitis was found. Autoimmune diseases presenting with the association of nephritis and uveitis were excluded. Therefore a diagnosis of tubulo-interstitial nephritis with uveitis (TINU syndrome) was made. The patient was treated with topical and systemic corticosteroids. Both the uveitis and the nephritis responded quickly to this therapy, which is characteristic for TINU.

Verkleving van de labia minora

SamenvattingVerkleving van de kleine schaamlippen (labia minora) komt vaak voor bij prepuberale meisjes met name tussen de 13 en 23 maanden. De labia minora zijn mediaan met elkaar gefuseerd. Meestal blijft de verkleving asymptomatisch en in 80% van de gevallen verdwijnt de verkleving spontaan binnen een jaar. De verkleving kan leiden tot stasis van urine waardoor een bacteriurie kan optreden. De meest voorkomende klachten van labiaverklevingen zijn urineweginfecties, vaginale pijn of jeuk en urineretentie. De oorzaak van de verkleving is waarschijnlijk multifactorieel waarbij hypo-oestrogeniteit een belangrijke rol speelt. De meest gebruikte therapie is oestrogeenhoudende zalf. Deze crème moet een- tot tweemaal daags gedurende enkele weken op de verkleving worden aangebracht. Het succespercentage van deze behandeling ligt tussen de 50 en 100%. Een andere optie met vergelijkbaar succes is betamethasoncrème. Alleen in uitzonderlijke gevallen is operatief klieven geïndiceerd.SummaryLabial adhesions appear frequently in prepubertal girls. It is most common in girls aged 13 till 23 months. The labia minora are fused in the midline. Most girls are asymptomatic and in 80% the adhesions disappear within one year. The adhesion can lead to stasis of urine which in turn can lead to bacteruria. Urinary tract infections, vaginal pain or itching and acute urine retention can be the presenting complaint. The cause of labial adhesions is not completely known but the low estrogen levels are most likely involved. The most used treatment is topical estrogen. This is used once or twice daily for several weeks. The success rate ranges from 50 to 100%. Another option is bethamethasone cream with similar success rates. The operative treatment (cleavage of adhesion) is only indicated in exceptional cases.