[Fetal and neonatal kidney function. Implications for fetal urinary tract abnormalities]. / Die fetale und neonatale Nierenfunktion. Implikationen für angeborene Harntraktanomalien.

High-resolution sonography provides the opportunity for prenatal detection of fetal anomalies of the urinary tract. In view of various options of prenatal urinary diversion to alleviate obstruction, it has become a scientific goal to measure fetal renal function and to determine the prognosis of urinary tract malformations. The article outlines the accumulated knowledge of the development of fetal renal function and the diagnostic possibilities offered by sonography and by laboratory test with focus on the chemistry of the amniotic fluid. Taking into consideration the high risks of prenatal intervention, these findings are discussed as to their relevance for the clinical management of pregnancies complicated by fetal urinary tract abnormalities. Lastly, criteria are proposed for the decision making in clinical practice.

Necrotizing sarcoid granulomatosis: a rarity in childhood.

Necrotizing sarcoid granulomatosis (NSG) is characterized by pulmonary nodular infiltrates, a typical histology, and a benign clinical course. The etiology and pathogenesis of the disease are still unknown. In childhood, it is extremely rare, with only three reported cases so far. Here we report on an 8-year-old girl, who to our knowledge is the youngest reported patient with NSG. The girl presented with shortness of breath and a sore throat. Chest X-ray and computed tomography (CT) scan revealed multiple nodular opacities of the lung. The symptoms and radiological findings disappeared within 6 months without any treatment. The diagnosis was based on the typical signs and symptoms of NSG and on the exclusion of other diseases. As abnormal immunological findings such as the lack of specific diphtheria antibodies in spite of vaccination against diphtheria were present, we suggest that immunologic mechanisms could play an etiologic role in the pathogenesis of NSG. In addition, the ratio of CD4+/CD8+ T-cells in the peripheral blood was significantly reduced, whereas the CD4+/CD8+ T-cell ratio in the immunohistochemical staining of the lung tissue was elevated. Since this compartmentalization is a typical finding in sarcoidosis, it supports the theory that NSG may represent a variant of sarcoidosis. However, because some characteristics of NSG are uncommon in typical sarcoidosis, NSG may also be an entity in its own right.

Streptococcus pyogenes meningitis: report of a case and review of the literature.

UNLABELLED: Streptococcus pyogenes is a very uncommon cause of bacterial meningitis beyond the neonatal period. A case report and a review of the recent literature is presented. We report on a previously healthy 7-year-old boy who developed S. pyogenes meningitis following a 2-day history of otitis media. A CT scan revealed right-sided mastoiditis as a possible focus of infection. The patient was treated with penicillin G for 14 days. The clinical course was uneventful, and the recovered without sequelae. By means of the polymerase chain reaction, the presence of streptococcal pyrogenic exotoxin (SPE) B and SPE C, but not SPE A genes was discovered from the bacterial DNA. CONCLUSION: Streptococcus pyogenes is a rare cause of bacterial meningitis but has to be considered as the causative pathogen beyond the neonatal period.

Cyclosporin-A-induced effects on the free Ca2+ concentration in LLC-PK1-cells and their mechanisms.

Here we have examined the effects of Cyclosporin A (CyA) on the free intracellular Ca2+ concentration ([Ca2+]i) of LLC-PK1/PKE20 cells to evaluate mechanisms of CyA nephrotoxicity using Fura-2 microspectrofluorometry or digital fluorescence video imaging. The CyA-associated changes were compared to the effects of tacrolimus (Tac), a structurally unrelated immunosuppressant with similar cellular pathways which also causes nephrotoxicity. CyA (EC50(: 1 nmol/l, n=16) and Tac (EC50: 1 nmol/l, n=5) caused a concentration-dependent increase of [Ca2+]i which was substantially attenuated by reducing the external Ca2+ concentration (10(-6) mol/l). Similarly Cyclosporin H, a non-immunosuppressive analogue of CyA, stimulated a Ca2+ influx. Nicardipine (10(-6) mol/l) reduced the CyA- and the Tac-induced Ca2+ influx to 52+/-16% (n=10) and 13+/-10% (n=13) of control respectively. Diltiazem and verapamil (10(-6) mol/l) were also effective, but flufenamate (10(-4) mol/l), Gd3+ (10(-5) mol/l) and La3+ (10(-5) mol/l) were not. In the absence of extracellular Ca2+ CyA led to a small but significant [Ca2+]i increase, indicating additional release from internal stores. Depletion of inositol-1,4,5-trisphosphate-(InsP3-) sensitive Ca2+ stores by extracellular ATP (10(4) mol/l) in low-Ca2+ solution completely suppressed the CyA-induced [Ca2+]i rise. CyA had no effect on the cellular InsP3 concentration. Furthermore, inhibition of phospholipase-Cbeta (PLCbeta) by U73122 (2x10(-5) mol/l) did not alter the CyA-stimulated [Ca2+]i rise. A direct effect of CyA on InsP3-sensitive Ca2+ stores, the InsP3 receptor, the Ca2+ content of the stores or involvement of additional stores is assumed. Incubation with CyA for 1, 12 and 24 h enhanced the rise in [Ca2+]i peak induced by ATP, arginine vasopressin (AVP) and angiotensin II. In summary, CyA stimulated a [Ca2+]i increase in LLC-PK1 cells through Ca2+ release from InsP3-sensitive stores and Ca2+ influx via a nicardipine-sensitive pathway. The CyA-mediated [Ca2+]i increase is independent of PLCbeta activity and InsP3 metabolism. CyA caused long-term enhancement of the agonist-induced rise in [Ca2+]i. The effects of CyA on Ca2+ signaling appear to be independent of its immunosuppressive action.

Focal dermal hypoplasia (Goltz-Gorlin syndrome) associated with obstructive papillomatosis of the larynx and hypopharynx.

A 14-year-old girl with focal dermal hypoplasia (Goltz-Gorlin-syndrome) presented with dysphagia, hoarseness, inspiratory stridor, intermittent dry cough and a 10% weight loss. Endoscopy showed that these symptoms were caused by papillomatosis of the hypopharynx and the larynx. The papillomatous masses were resected subtotally by endoscopic laser treatment. Residual papillomas were left in the subglottic space but tracheotomy could be avoided. Complete clinical recovery with adequate weight gain as well as, resolution of dyspnoe and dysphagia resulted after the intervention. Histological examination did not show morphological signs of human papilloma virus as an etiological agent.

Luminal ATP induces K+ secretion via a P2Y2 receptor in rat distal colonic mucosa.

We have previously investigated, in studies of rat distal colonic mucosa, the effect of ATP added to the basolateral side on ion transport and [Ca2+]i. It was demonstrated that ATP acts via a P2Y1 receptor to increase [Ca2+]i and NaCl secretion. In the present study we investigated the effect of luminally added nucleotides (ATP, UTP) on transepithelial voltage (Vte) and resistance (Rte) in Ussing chamber experiments on rat distal colonic mucosa. Both nucleotides induced a rapid and transient (within 30 s) change of Vte to lumen-positive values (resting Vte: -2+/-1 mV; peak Vte after 100 micromol/l ATP: +2.4+/-1.1 mV) and a decrease of Rte from 89. 9+/-10.3 to 83.8+/-9.1 Omegacm2 (n=10). Similar values were obtained with luminal UTP (n=15). The estimated EC50 values for both nucleotides were approximately 6 micromol/l. The ATP-induced Vte effect was nearly completely sensitive to Ba2+. Addition of the K+ channel blocker Ba2+ (1 mmol/l) to the luminal solution reversibly inhibited 77+/-4% (n=5) of the ATP-induced Vte effect. Experiments to identify the respective P2 receptor subtype revealed the following rank order of potency at 500 micromol/l agonist: UTP>/=ATP>>2-methylthio-ATP=ADP>>adenosine> AMP>beta, gamma-methylene-ATP (n=5). This closely resembles the published rank order for the P2Y2 receptor. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique P2Y2 receptor-specific mRNA was detected in total RNA extracted from isolated crypts. In summary these data indicate that luminal ATP and UTP act via a P2Y2 receptor in the luminal membrane of colonic mucosa to elicit a transient K+ secretion.

Acute bilateral renal vein thrombosis complicating Netherton syndrome.

UNLABELLED: A 1-year old male infant suffering from Netherton syndrome with severe generalized erythroderma presented with acute renal failure due to bilateral renal vein thrombosis (RVT) after a short episode of enteritis. The imperceptible fluid loss through the skin and the additional enteric water loss had led to decompensation of the delicate fluid balance and had resulted in RVT as a sequel of haemoconcentration. Reperfusion of the left kidney could be achieved by treatment with urokinase and heparin. Prophylactic oral anticoagulation was instituted for several weeks. CONCLUSION: In severe Netherton disease meticulous surveillance of the fluid balance is important and aggressive treatment is indicated in case of additional fluid loss.

Coagulation changes associated with the hemolytic uremic syndrome.

The hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, acute renal failure, and thrombocytopenia. The pathological correlate is thrombotic microangiopathy of glomerular capillaries and arterioles in the kidneys and almost every other organ. The presence of platelet thrombi without extensive soluble coagulation system activation is a constant feature of HUS and thrombotic thrombocytopenic purpura (TTP). Damage to the endothelial cell seems to be a central event in the pathogenesis of HUS and TTP, resulting in loss of fibrinolytic properties and subsequent thrombotic occlusion of the microvasculature. According to earlier and recent studies, a variety of hemostatic alterations have been described. Among the many findings, low platelet counts, increased von Willebrand's factor (vWF), and normal fibrinogen are almost invariably observed. The dubious long-term outcome, even of postdiarrheal HUS, which is believed to have a more favorable prognosis than HUS of other etiopathogenic origin, necessitates further investigation of the pathophysiology of thrombotic microangiopathy and meticulous reevaluation of treatment strategies aimed at interfering with the process of thrombosis early in the disease course. The intention of this article is to highlight findings possibly relevant for disease management and to give an overview of the putative pathomechanisms involved.

Capacitative Ca2+ entry (CCE) induced by luminal and basolateral ATP in polarised MDCK-C7 cells is restricted to the basolateral membrane.

In previous studies we have characterised various properties of capacitative Ca2+ entry (CCE) in different epithelia. After Ca2+ store depletion with PLC/InsP3-coupled agonists or by inhibition of store Ca2+ uptake, with for example thapsigargin, Ca2+ influx is activated. This leads to a sustained cellular response (e.g. NaCl secretion). In the present study, we have investigated CCE in polarised MDCK-C7 cells grown on permeable supports in a chamber allowing for separate luminal and basolateral perfusion. The transepithelial resistance (Rte) and voltage (Vte) were measured simultaneously to verify the tightness of the epithelial monolayers. MDCK-C7 cells grew to very tight monolayers (Rto > 3000 omega.cm2). Apical ATP (100 mumol/l) led to a biphasic [Ca2+]i increase. Removal of apical Ca2+ in the continuous presence of ATP did not reduce the stimulated plateau. However, removal of Ca2+ from the basolateral side rapidly and completely interrupted the [Ca2+]i plateau to below basal values ([Ca2+]i decrease during plateau phase after removal of basolateral Ca2+ = 213 +/- 15 nmol/l, n = 9). Furthermore, MDCK-C7 responded to basolateral ATP (100 mumol/l) with a biphasic [Ca2+]i transient. Again the plateau phase of the ATP-induced [Ca2+]i effect was fully dependent on the presence of basolateral but not apical Ca2+ ([Ca2+]i decrease during plateau phase after removal of basolateral Ca2+ = 196 +/- 5 nmol/l, n = 10). Receptor-independent depletion of cytosolic Ca2+ stores with thapsigargin from both sides led to a rise in [Ca2+]i, which was also exclusively dependent on the presence of basolateral Ca2+ (n = 8). These data indicate that MDCK-C7 cells express luminal and basolateral P2-receptors coupled to PLC/InsP3/Ca2+. ATP applied from both sides induced a sustained [Ca2+]i plateau which was due to transmembrane Ca2+ influx. The ATP- and thapsigargin-induced Ca2+ influx pathway was exclusively located in the basolateral membrane.

Hemolytic uremic syndromes in childhood.

The hemolytic uremic syndrome (HUS) comprises hemolytic anemia, acute renal failure, and thrombocytopenia. It is the most frequent cause of acute renal failure in childhood. Ninety percent of the patients have a diarrheal prodrome, and are referred to as having typical HUS. Approximately 10% exhibit the so-called atypical HUS. Typical HUS is caused by shigatoxin-producing Escherichia coli. The toxin, bound to the globotriosyl ceramide cell receptor and internalized, interferes with protein synthesis, predominantly of endothelial cells. The main target is the kidney, but nearly every organ system can be involved. The most common extrarenal involvement is damage to the central nervous system. The central event is probably an insult to the endothelial cell with consecutive loss of antithrombogenic properties. The von Willebrand factor, activation of platelets via platelet-activating factor, other growth factors (e.g., interleukins 1, 6, 8), nitric oxide, lipopolysaccharides, activated polymorphonucleated neutrophils, and the metabolites of the arachidonic acid cascade (e.g., prostaglandin I2) are believed to be involved in the pathogenic cascade. Controlled therapeutic trials with heparin, dipyridamole, aspirin, and urokinase have not been associated with improved outcome. Antibiotics have not yielded any benefit. Plasma infusions and plasma exchange appear to be efficacious, and are justified in cases of atypical HUS and thrombotic thrombocytopenic purpura. Binding of the toxin to the intestinal lumen, and thereby inhibition of enteral reabsorption, is under investigation.

Postexercise albuminuria in children with different duration of type-1 diabetes mellitus.

About 30% of diabetic patients develop progressive renal failure. We studied albumin, IgG, and transferrin excretion during exercise in diabetic children without signs of nephropathy to investigate proteinuria under these conditions: 39 patients with insulin-dependent diabetes mellitus and 21 healthy children undertook a bicycle exercise test. Albuminuria measured by nephelometry was calculated as the albumin excretion rate (AER) and albumin-to-creatinine ratio before and after exercise. The diabetic group was divided into three subgroups according to disease duration (DI < 5 years, DII 5-10 years, DIII > 10 years). No significant difference in metabolic control (hemoglobin A1c was detected between the diabetic groups (median hemoglobin A1c: DI 7.2%, DII 7.6%, DIII 8.6%). There was no increase in AER in the healthy children after exercise. Before exercise the diabetic groups had an AER similar to controls. No significant increase in albuminuria after exercise was seen in group DI. Both groups with a disease duration of more than 5 years had a significant increase in albuminuria [median before/after: DII 7.8/16.7 (P < 0.05), DIII 0/57.9 (P < 0.05) micrograms/min per 1.73 m2). Of these patients, 43% also had a measurable urinary excretion of IgG and transferrin, indicating structural glomerular damage. There was no correlation of albuminuria and parameters of metabolic control or renal function. We conclude that in diabetic children an exercise test unveils albuminuria in certain patients, while their AER may be normal at rest.

Subureteral collagen injection versus antireflux surgery in primary vesico-ureteral reflux grade III.

UNLABELLED: Endoscopic subureteral collagen injection (SCIN) was performed in 24 girls and 5 boys (mean/range: 3.2/0.7-12.2 years) with primary grade III vesicoureteral reflux. Clinical outcome was compared to 20 girls and 6 boys treated by antireflux surgery (mean/range: 3.0/0.2-9.4 years). forty-one ureters were treated by endoscopy, 37 by surgery. Patients were followed for 12 months. SCIN was not associated with severe persistent complications. No reflux was detected immediately after SCIN. After 6 months recurrent grade II reflux was present in 1 (4%) surgically treated patient and in 12/29 (41%) patients treated by collagen injection. This corresponded to a recurrence rate of 1/37 (3%) of ureters following surgery and 15/41 (37%) following SCIN. 8/15 refluxing ureters after collagen showed decreased reflux grade (two grade I, six grade II). After 12 months 24/26 (92%) patients with antireflux surgery remained free of urinary tract infections as compared to 25/29 (86%) children following endoscopy. Following SCIN, 4/29 (14%) patients required secondary antireflux surgery because of recurrent urinary tract infections. CONCLUSION: On the basis of this study endoscopic SCIN appears to be safe in children. It is less effective than surgery with regard to elimination of primary grade II reflux. However, clinical success rate is comparable to surgery with regard to the frequency of recurrent urinary tract infections after the procedure. This may be due to the reduction of refluxing urine volume in those patients who showed recurrence of reflux after collagen injection.

Urinary excretion of adenosine deaminase binding protein in neonates treated with tobramycin.

The potential tubulotoxicity of tobramycin and cefotaxim were assessed in neonates by measuring the urinary level of adenosine deaminase binding protein (ABP) and urinary alpha 1-microglobulin and beta 2-microglobulin. In a prospective study, 33 neonates who received tobramycin and cefotaxim for suspected neonatal sepsis were compared with 48 untreated newborns during the first 10 days of life. The urinary concentrations of ABP and its excretion rates, corrected for body weight and body surface area, were significantly increased from the 1st day of treatment. Urinary alpha 1-microglobulin and beta 2-microglobulin were not elevated under tobramycin and cefotaxim during the first 2 days of treatment. We conclude that ABP may be a sensitive marker for the detection of proximal renal tubular injury during tobramycin and cefotaxim treatments of neonates. The increase in urinary ABP which occurs before an elevation of urinary alpha 1-microglobulin and beta 2-microglobulin may reflect earlier structural than functional alterations. However, since none of the treated infants had signs of electrolyte disorders or glomerular dysfunction, the clinical relevance of ABP measurement should be reevaluated.

Prostanoids in paediatric kidney diseases.

Prostanoids belong to the growing family of eicosanoids, which are all derived from arachidonic acid. Prostanoids act as modulators and mediators in a large spectrum of physiological and pathophysiological processes within the kidney. On the one hand, the potent vasoconstrictor and platelet-aggregating thromboxane (TX) A2 is involved in the pathophysiology of a variety of glomerular diseases, such as haemolytic-uraemic syndrome and immune-mediated glomerulopathies. Prostaglandin (PG) E2, on the other hand, interferes with tubular electrolyte and water handling. Clinical data support the hypothesis that this member of the prostanoid family contributes to the pathophysiology of Bartter's syndrome, hyperprostaglandin E syndrome, idiopathic hypercalciuria and renal diabetes insipidus. Both prostanoids, TXA2 and PGE2, are involved in the pathophysiology of obstructive uropathies. The physiological and protective role of renal vasodilator prostanoids (PGI2 and PGE2) has been studied during treatment with non-steroidal anti-inflammatory drugs. Part of the pharmacological effects of frusemide and converting enzyme inhibitors is mediated by PGI2 and PGE2. The role of renal prostanoids in cyclosporine toxicity is still equivocal. Future investigations on the physiological and pathophysiological role of renal prostanoids will have to consider the multiple interactions between prostanoids on the one hand, and classical hormones and other mediators (e.g. cytokines) on the other hand.

Evaluation of local renal function in newborn infants under tobramycin therapy.

Aminoglycosides (AG) provided for less than 5 days to newborn infants do not produce a marked disturbance of glomerular filtration rate (creatinine clearance) or tubular sodium handling (fractional sodium excretion). However, transient disturbances of proximal tubular cell functions can be noted: the excretion of N-acetylglucosaminidase, a lysosomal enzyme, is elevated, and mature not premature infants show a decreased tubular reabsorption of low-molecular-weight proteins during AG treatment. Preliminary investigations show an increased excretion of villin, a structural protein of proximal tubular cells, and a decreased secretion of Tamm-Horsfall protein by the cells of ascending limb of Henle and early distal tubule.

[Fulminant autoimmune cold-type hemolysis with marked elevation of monothermic cold agglutinins. Successful therapy with membrane plasmapheresis]. / Foudroyant verlaufende Autoimmunhämolyse vom Kältetyp mit ausgeprägter Vermehrung von monothermischen Kälteagglutininen: Erfolgreiche Therapie mit Membranplasmapherese.

Autoimmune hemolytic anemia associated with cold autoantibodies is rare in infancy. In a 7 months old infant with severe hemolysis, a hemoglobin of 5.9 g/dl and a cold agglutinin titer of 1:8000, even the transfusion of warmed, packed red cells (37 degrees C) lead to hemolysis. Hemoglobin fell to 2.8 g/dl despite prevention of exposure to cold, parenteral steroids and immunoglobulins. Cold agglutinin titer fell to 1:8 after plasma separation. Subsequent transfusion did not lead to hemolysis and permanent remission was achieved.

Hypertension after renal transplantation in patients treated with cyclosporin and azathioprine.

The incidence of hypertension was sought in 102 children who had undergone renal transplantation. Fifty five were being treated with cyclosporin and 47 with azathioprine, and they were followed up for a maximum of five years. After one year 35 of those receiving cyclosporin (64%) and 34 of those receiving azathioprine (72%) were hypertensive; after five years the figures were 5/6 (83%) and 25/35 (71%), respectively. Recipients of grafts from living related donors had a lower incidence of hypertension than recipients of cadaveric grafts. The incidence of hypertension was higher in patients with acquired original kidney disease than in children with congenital or familial diseases. In both groups creatinine clearance and the frequency of acute rejection episodes did not differ between normotensive and hypertensive patients. When the lowest concentrations of cyclosporin in whole blood were more than 400 ng/ml the incidence of hypertension one year after transplantation was higher. The incidence of hypertension after renal transplantation in children is higher than that reported in adults. Acquired original disease, transplantation of cadaveric grafts, and nephrotoxicity of cyclosporin are all contributory factors.