Efforts to establish an animal model of Fanconi syndrome after ifosfamide administration to rats.

About 10% of children develop Fanconi syndrome (FS) a few months after ifosfamide (IFO) treatment. To establish an animal model, IFO was injected as 4 or 5 treatment courses (TCs, once daily for 3 consecutive days), to adult female rats (AF, 8 mg 100 g(-1) body wt, 4 TCs), to young female rats (YF, 8 mg 100 g(-1) body wt, 5 TCs) and to male rats (M, 6 mg 100 g(-1) body wt, 4 TCs). In the adult female rats, polyuria with electrolyte and albumin wasting occurred acutely, 2 days after the first treatment course. After the third treatment course, 30% of the rats died, but survivors showed a reduced excretion of electrolytes and glucose. The body weight increase was significantly diminished in adult female and male rats by about 25% or 70%, respectively. Up to 5 months after 5 TCs in young female rats, 15% of the animals died but the survivors did not show any sign of renal failure. In males, 28% of the rats died and in surviving animals the excretion of electrolytes, proteins and glucose as well as GFR were reduced 7 weeks after the last treatment course. There were no pathomorphological changes in kidney and liver. Determination of renal and hepatic cytochrome P450 activities indicated that results of adult female and male rats could be caused by starving, known as a common side effect of IFO, and not by its nephrotoxicity. Altogether, it was not possible to establish a model of a Fanconi syndrome persisting after cessation of IFO treatment in our rat strain, whereas acute, FS-like IFO effects on the kidney could be shown.

[Urinary tract infections in infants and children -- a consensus on diagnostic, therapy and prophylaxis]. / Harnwegsinfektionen im Säuglings- und Kindesalter. Konsensusempfehlungen zu Diagnostik, Therapie und Prophylaxe.

Urinary 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.

The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect.

Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20-30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Clinical data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicoureteral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.

Two-hour postdose concentration: a reliable marker for cyclosporine exposure in adolescents with stable renal transplants.

In pediatric renal transplant recipients, most patients receive maintenance treatment with cyclosporine (CsA) and mycophenolate mofetil (MMF). Until now, the 2-hour postdose CsA target level for combined maintenance treatment with MMF has not been defined. This prospective pilot study evaluated the pharmacokinetics of CsA under the influence of MMF to determine a reliable single CsA concentration time that correlates with the area under the curve (AUC(0-6h)) estimates for adolescents who were additionally treated with MMF during the late posttransplant period. The study included 13 adolescents (mean posttransplantation time, 3.5 +/- 2.55 years) with stable renal transplant function (S-Crea 121 +/- 40 micromol/L). CsA pharmacokinetic absorption profiles over a 6-hour dose interval (n = 26) were evaluated for the optimal single peak concentration using the CsA concentrations predose (C0) and at 1, 2, 3, 4, and 6 hours postdose (C1-6). Whereas C2 (mean 743.2 +/- 221.8 ng/mL) was the single point with the closest correlation to AUC(0-6h) (r2 = 0.86; P < .001), C0 (mean 120.5 +/- 35.2 ng/mL) showed the weakest correlation (r2 = 0.61, P = .002). C2 appears to be an accurate predictor of CsA exposure in adolescent kidney transplant recipients under maintenance immunosuppression in combination with MMF. Average values achieved with current dosing practices cluster around the target C2 ranges recommended for adults. The data provide a foundation for initiation of prospective clinical trials to assess the long-term risk for chronic allograft dysfunction among pediatric stable renal transplant patients in combination protocols.

Renal function in long-term survivors of stem cell transplantation in childhood. A prospective trial.

The aim of this prospective study was to assess glomerular and tubular renal function before, and 1 and 2 years after hematological stem cell therapy (HSCT) in children and adolescents. 137 consecutive patients undergoing HSCT, for malignant diseases, were included in a prospective trial. Forty-four patients were followed for up to 1 year after HSCT and 36 for up to 2 years, without relapse. Ninety healthy school children were used as a control group. The following parameters were investigated: inulin clearance (GFR), urinary excretion of albumin, alpha1-microglobulin (alpha1-MG), calcium, beta-N-acetylglucosaminidase (beta-NAG) and Tamm-Horsfall protein (THP), tubular phosphate reabsorption (TP/Cl(cr)) and percent reabsorption of amino acids (TAA). Significantly lower GFR was found 1 and 2 years after HSCT but within the normal range in the period before HSCT. There was no correlation between GFR within the first month after HSCT and long-term outcome of GFR. Tubular dysfunction was found in 14-45% of patients 1 and 2 years after HSCT depending on the parameter investigated. Pathological values 1 and 2 years after HSCT were found for alpha1-MG excretion in 40% and 39%, respectively, for TP/Cl(cr) in 44% and 45%, for beta-NAG in 26% and 19%. Median TP/Cl(cr) was significantly lower 2 years after HSCT than before. TAA was mildly impaired in 7/14 patients before, in 5/29 one and in 9/29 2 years after HSCT, but median TAA was within normal range at all times. The median excretion of albumin, THP and calcium was within the normal range at all investigations. No influence of ifosfamide pre-treatment on the severity of tubulopathy was found. The investigation of tubular renal function should be part of a long-term follow-up in children after HSCT.

Ambulatory blood pressure monitoring in children with unilateral multicystic dysplastic kidney.

UNLABELLED: Multicystic dysplastic kidney (MCDK) is one of the most common congenital renal anomalies. Arterial hypertension is a potential complication of MCDK. Blood pressure (BP) has so far been measured only casually and the frequency of hypertension has been estimated to be between 0%-8%. Ambulatory blood pressure monitoring (ABPM) provides more precise information on BP than the casual BP measurement. The aim of this study was to investigate the BP profile in children with MCDK using ABPM. A group of 25 children (16 girls), with a mean age of 7.8 years (range 3.8-17.7 years) were investigated. ABPM was performed using the oscillometric SpaceLabs 90207 device. Hypertension was defined as mean systolic and/or diastolic BP during the day and/or in the night exceeding 95th percentile for ABPM. Five (20%) children showed hypertension, two of them had combined daytime and night-time hypertension and three had isolated nocturnal hypertension, although daytime BP was between the 90th-95th percentile in two of them. Children with ultrasonographical and/or laboratory signs of contralateral kidney abnormalities showed a higher incidence of hypertension than those without abnormalities (two of four versus 3 of 21). The mean night-time systolic and diastolic BP of children with MCDK was significantly higher than in healthy children (+ 0.50 and + 0.54 SDS, respectively, P = 0.012 and 0.03, respectively). Three of the hypertensive children were already nephrectomised. All five hypertensive children showed ultrasonographical and/or laboratory signs of contralateral kidney abnormalities. Hypertensive children had significantly higher microalbuminuria than normotensive children (6.9 +/- 3.2 mg/mmol creatinine versus 1.8 +/- 0.7, P = 0.03). The nocturnal BP fall (dip) was attenuated in five children, only one of whom was hypertensive. CONCLUSION: Arterial hypertension in children with multicystic dysplastic kidney is seen more often if based on ambulatory blood pressure monitoring than on casual blood pressure recordings. The main risk factor for developing hypertension is contralateral kidney damage. Ambulatory blood pressure monitoring should be performed in children with multicystic dysplastic kidney, especially in those with contralateral kidney abnormalities.

Nephrocalcinosis in children: a retrospective survey. Members of the Arbeitsgemeinschaft für pädiatrische Nephrologie.

We carried out a retrospective survey on 152 children and adolescents with nephrocalcinosis (NC) in 22 German centers of pediatric nephrology. Etiology, clinical manifestations, growth and development, sonographic appearance of NC and renal function were analyzed. The median age at the time of diagnosis was 3.3 (range 0.1-21) years and the median duration of follow-up was 4.1 years. In 34% of children NC was associated with idiopathic hypercalciuria (IHC) and in 32% with various hereditary tubular disorders. In 9% NC was observed subsequent to prophylactic bolus administration of vitamin D in infancy. A positive family history was found in 36%. Clinical manifestations were mainly failure to thrive during the 1st year of life (46%), psychomotor/mental retardation (28%) and urinary tract infection (34%). In 14% nephrolithiasis was associated. During the follow-up the proportion of patients with the most severe degree of NC (stages 2b or 3) increased from 40% to 55% and that of hypercalciuria decreased from 79% to 52%. Body height was <2 standard deviation scores (SDS) of normal in 41% at the time of diagnosis and in 32% at the last observation; the increase in relative height was significant only for IHC. Glomerular filtration rate (GFR) and urinary concentration capacity changed only slightly with time. At the last investigation GFR was <50 ml/min/1.73 m2 in 6% and concentration capacity <800 mosmol/kg in 48% of patients. The degree of NC was negatively correlated with GFR and concentration capacity.

Contrast-enhanced sonography of vesicoureterorenal reflux in children: preliminary results.

OBJECTIVE: The aim of our study was to evaluate contrast-enhanced sonography as an alternative to radiographic voiding cystourethrography in the detection of vesicoureteral reflux. SUBJECTS AND METHODS: A total of 46 children, ranging in age from 3 weeks to 14 years (median: 4 years, 6 months) with 92 ureterorenal units were investigated for reflux using radiographic voiding cystourethrography and contrast-enhanced sonography in one session. After sonography of the urinary tract, the bladder was filled with saline solution via a catheter. Later, a contrast-enhancing agent was instilled and sonography was repeated. Documentation was done using S-VHS video and a laser camera. Reflux was diagnosed when microbubbles were observed in the ureter or in the renal pelvis. In addition, conventional voiding cystourethrography was performed. Patients without micturition during either sonography or radiographic examination were excluded (eight ureterorenal units). RESULTS: The findings obtained by contrast-enhanced sonography and voiding cystourethrography were concordant in 78 ureterorenal units (92.9%). No reflux was detected in 67 units (79.8%) by either method. With voiding cystourethrography as the standard of reference, the sensitivity of contrast-enhanced sonography was 91.7%; the specificity, 93.1%; and the accuracy, 92.9%. The positive predictive value was 68.8%, and the negative predictive value was 98.5%. CONCLUSION: Contrast-enhanced sonography is highly sensitive for the detection of vesicoureteral reflux. Therefore, it may reduce the number of radiographic investigations.

Kidney growth and renal function in unilateral multicystic dysplastic kidney disease.

The natural history of multicystic dysplastic kidney (MCDK) is not well established. We analyzed kidney growth and renal function in 33 children with prenatally diagnosed unilateral MCDK in a long-term study. The mean observation period was 4.9 years with a range of 1-11.6 years. Abnormalities of the contralateral kidney were found in 10 of 33 patients (30%): ureteropelvic junction obstruction (5), ureterovesical junction obstruction (2), and vesicoureteral reflux (3). In 6 children the dysplastic kidney had been removed. Complete involution was observed in 48% and a decrease of size in 33% of 27 dysplastic kidneys. At the time of last examination, 27 of 29 children showed a volume of the contralateral kidney above the normal range (>145%). Hypertrophy of the contralateral kidney, defined as kidney length above 2 standard deviation scores (SDS), was seen in 24% of 33 children at birth, thus showing that hypertrophy of the contralateral kidney starts in utero and continues throughout childhood. The extent of contralateral hypertrophy was independent of associated abnormalities in this study. Mean creatinine was increased in the whole group (mean +1.13 SDS). Calculated creatinine clearance in 21 patients over 2 years was within normal limits, with a median of 102 ml/min per 1.73 m2 (range 84-143). Based on the results of this and previous studies, nephrectomy cannot be recommended in typical cases, but a regular follow-up of these patients seems necessary.

Clinical features of unilateral multicystic renal dysplasia in children.

UNLABELLED: A clinical study of 204 patients with unilateral multicystic renal dysplasia referred to 30 nephrology departments was undertaken to assess the frequency of complications in children who underwent nephrectomy (n = 40) versus those who were treated conservatively (n = 164). Six patients required antihypertensive treatment, 30 (13% of girls, 17% of boys) had at least one episode of urinary tract infection. The number of clinical complications did not differ in patients who underwent nephrectomy in comparison to those who did not. The dysplastic kidney decreased in size in 65% of kidneys with repeated ultrasound values; no change occurred in 16%, while an increase in maximal diameter was observed in 19%. Contralateral kidney length of more than 2 standard deviation scores (SDS) was seen in 30% of patients. There is evidence for a slight impairment of renal function in the whole study group given by a median of serum creatinine level of 0.63 SDS in all patients available for analysis. Among those 35 patients with contralateral anomalies (mainly obstructive changes and vesico-ureteral reflux), all 3 patients with contralateral changes suggestive of hypoplasia and 22% with obstruction, but only 1/7 (14%) with reflux showed elevated serum creatinine level >2 SDS. CONCLUSION: Renal function seems to be slightly impaired in patients with unilateral multicystic renal dysplasia. The apparent tendency to regression of the dysplastic kidney and no difference in the number of complications justify a conservative management rather than operative intervention.

Complete recovery of renal function in a Wilms' tumor patient after acute renal failure caused by autologous bone marrow transplantation (ABMT).

An autologous bone marrow transplantation (ABMT) was carried out on a 4-year-old boy following the second pulmonary relapse of a nephroblastoma. Glomerular and tubular function of the remaining kidney before ABMT was normal. Etoposide, carboplatin, and melphalan were used in the conditioning regimen. The patient developed acute renal failure (ARF), and hemodialysis was required for 3 weeks. The situation was further complicated by his requiring mechanical ventilation for 12 days. Today, the patient is in good general health and in stable remission 32 months after bone marrow transplantation. This report shows that even serious tubular and glomerular dysfunction may be completely reversible in children. The background for high-dose chemotherapy with ABMT or stem cell rescue is discussed.

Renal function after conditioning therapy for bone marrow transplantation in childhood.

The knowledge of renal function in the course of BMT is poor. We prospectively investigated glomerular and tubular function in 42 children who underwent BMT because of malignancy. Seventeen children were transplanted autologously. Investigations were performed before and immediately after the conditioning regimen. Inulin and creatinine clearance, albuminuria, urine excretion of alpha 1-microglobulin, beta-N-acetylglucosaminidase, alanine-aminopeptidase, intestinal alkaline phosphatase, and Tamm-Horsfall-Protein as well as sodium- and phosphatreabsorption were measured. The patients were classified regarding use of total body irradiation (tTBI) in the conditioning regimen. BEFORE CR: Glomerular filtration rate (GFR) was not influenced by the underlying diagnosis or previous treatment. Mean GFR was elevated compared with the reference group. Microalbuminuria was elevated in 15% of patients, and mean levels were higher than in the reference group. Proximal tubular dysfunction was indicated by an elevated excretion of alpha 1-MG in 54%, of beta-NAG in 66%, of AAP in 40%, and of IAP in 47%. Fractional sodium excretion was abnormal in 21%, phosphate reabsorption in 5% and THP-excretion in 7% of the patients. AFTER CR: Creatinine clearance was not affected by CR. After CR alpha 1-MG, beta-NAG, FENa, AAP, and IAP were increased compared with values before CR. TP/Clcr was decreased. Excretion of THP was not altered by CR. In patients without fTBI there was a greater increase in alpha 1-MG excretion and decrease in phosphate reabsorption after CR compared with patients conditioned with fTBI. We conclude that significant proximal tubular dysfunction is present in about 50-60% of patients before and in nearly all alter CR. Distal tubular function was less severely affected. Severity of nephrotoxicity after CR did not correlate with pre-existing abnormalities.

Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the major hereditary nephropathies in children predominantly presenting in early childhood. The clinical picture is variable but there is a fatal outcome in many cases. We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes. Linkage was confirmed using six adjacent microsatellite markers and the highest lod score of 7.42 was obtained with D6S272 at theta = 0.00. Our findings should lead to more accurate forms of prenatal diagnosis than those currently available using ultrasound.

[Follow-up and prognosis of pyelonephritis in infancy]. / Verlauf und Prognose der Pyelonephritis im Säuglingsalter.

128 infants between 1 and 18 months, 80 girls and 48 boys suffering from their first pyelonephritis (PN), were investigated and followed up over 2.9 +/- 2.2 years (mean +/- SD). 20 children showed urinary tract obstructions. In 49 of 108 cases (45%) with nonobstructive PN a vesico-uretero-renal reflux (VUR) was found and surgically corrected in 13 cases. In 36 patients (52 renal units) the VUR disappeared in most cases under medical management within 3 years. Recurrences of urinary tract infections (UTI) were found in the same frequency in children with and without reflux (28%), but those with VUR showed significantly more PN. 22 of 108 patients with nonobstructive PN (20%) developed renal scars, 39% of children with reflux (mostly VUR III. or IV. degree), 5% of those without reflux. In more than half of these cases renal scars were found already after the first PN. We conclude that a reduction of the risk of renal damage and an improvement of the prognosis can achieved by the following measures: 1. early detection of obstruction by pre- or postnatal sonographic screening, 2. early and exact diagnosis of PN and antibiotic therapy without delay. PN has to be excluded in all infants with unclear fever. 3. In all infants with PN a voiding cystography should be performed. In children with VUR, long-term chemoprophylaxis is necessary to avoid recurrence of PN.

[Urinary tract infection in childhood--an overview. 2. Therapy]. / Die Harnweginfektion im Kindesalter--eine Ubersicht. 2. Therapie.

The prevention of pyelonephritic scarring is the main aim of the treatment of urinary tract infections (UTI) in children. Therefore, an early diagnosis and an immediate and effective antibiotic therapy of acute pyelonephritis is necessary, especially in the first years of life. Furthermore, recurrences of UTI should be prevented in children at high risk of developing renal scarring (vesicoureteric reflux, obstruction of the urinary tract, injured kidneys, bladder dysfunction). In the present paper recommendations are given for antibiotic therapy of acute UTI, antibacterial prophylaxis of reinfections and treatment of bladder dysfunctions.

[Urinary tract infection in childhood--a review. 1: Diagnosis]. / Die Harnweginfektion im Kindesalter--eine Ubersicht. Teil 1: Diagnostik.

Urinary tract infections (UTI) are common in childhood. About 10% of children with UTI develop renal scars. Main risk factors for development of pyelonephritic scarring are obstructive malformations, vesicoureteric reflux, young age and delayed or insufficient therapy. Thus, in infants with fever one should always think of pyelonephritis. The most important objective in the management of children with UTI is the prevention of kidney damage. An early and correct diagnosis is necessary. The localisation of UTI and search for risk factors by imaging diagnostic techniques is the basis for specific therapy and follow-up. The present paper gives recommendations for the diagnostic procedure in children with UTI.

Nephrocalcinosis, hypercalciuria and elevated serum levels of 1,25-dihydroxyvitamin D in children. Possible link to vitamin D toxicity.

Ten children age 1 1/2 to 14 years, had bilateral nephrocalcinosis and hypercalciuria, but normal serum calcium (Ca) and phosphate (P) concentrations. Patients with hypercalciuria were divided into absorptive (n = 4) and renal (n = 6) subgroups, and in the latter four patients had a primary Ca-leak and two had a P-leak. All the children had received intermittent high dose vitamin D prophylaxis during infancy. At the time of investigation all had normal serum levels of 25-hydroxyvitamin D, yet all but one had elevated values of 1,25-(OH)2D. Although the hypercalciuria was indistinguishable from the various known forms of idiopathic hypercalciuria, the previous clinical course and the pattern of bone mineral homeostasis suggest that both clinical features, namely nephrocalcinosis and hypercalciuria were related to vitamin D toxicity through various pathogenetic pathways.