[Measles epidemic in a highly developed country: low mortality, high morbidity and extensive costs]. / Masernepidemie in der Zentralschweiz 2006-2009: Hohe Morbidität und Kosten.

BACKGROUND: Vaccination with 2 doses of > 95% of the population is necessary to eliminate measles. In Switzerland and especially in the central part, vaccine coverage is low (2006: 65%). This led 2006-2009 to a measles epidemic with thousands of cases and high costs. One death was noted in a formerly healthy 12 year old girl. PATIENTS AND METHODS: All measles cases, either hospitalized or reported to the authority, in the canton Lucerne between 2006 and 2009 were included. Course, complications, immunization rates and costs of the hospitalized children were analyzed. RESULTS: A total of 1 041 cases of measles were recorded; 758 (73%) were children < 16 years of age. 56 (6%) of the patients were admitted to hospital; half of them were children (n=26, admission rate 3.4%). Main complications were pneumonia with oxygen requirement (n=19), bacterial infections of the base of the skull (n=2) and acute measles encephalitis (n=3). One child each developed acute appendicitis and diabetes mellitus type 1. No death was noted. Median hospitalisation costs were 18 780 CHF. The surveillance system was incomplete: Every third admitted child was not reported to the authority. CONCLUSION: Due to low vaccine coverage measles still account for epidemics with high morbidity and extensive costs. Instant reporting of all cases is crucial for disease control. Early identification of persons at risk allows timely immunization. Switzerland will remain of central importance to eliminate measles in Europe by 2015.

Favorable long-term outcome of nephrotic syndrome after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The development of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (HS-CT) is a rare complication with few long-term outcome data. PATIENTS: Clinical course and long-term outcome of three adult patients and one child with NS after HSCT (total number of transplants n = 533) are presented. RESULTS: The median age at onset of NS was 35 years (range 15 - 56), occurring at a median of 17 months (range 11 - 21) after HSCT. Discontinuation of cyclosporine A (CSA) prior to onset of NS was a consistent feature and occurred a median of 6 months (range 2 - 10 months) prior to the development of NS. The histopathological lesion was membranous nephropathy (n = 3) and membranoproliferative glomerulonephritis Type 1 (n = 1). History of acute or concomitant clinically apparent chronic graft versus host disease (GVHD) was present in all cases except the pediatric patient who had abundant DR-activated cytotoxic T cells without evidence of viral reactivation. Long-term immunosuppression for 11 - 36 months with steroids (n = 1), combined steroids and CSA (n = 2) or CSA alone in steroid-refractory NS (n = 1) resulted in sustained remission of the NS in all patients (12 months - 8 years off immunosuppression). CONCLUSION: NS after HSCT seems to be etiologically related to subclinical or overt chronic GVHD, which flares up after discontinuation of CSA. However, resumption of immunosuppression can reverse NS as well as GVHD and induce favorable sustained long-term remission.

Multi-exon deletions of the PKHD1 gene cause autosomal recessive polycystic kidney disease (ARPKD).

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, a large gene spanning 470 kb of genomic DNA. So far, only micromutations in the 66 exons encoding the longest open reading frame (ORF) have been described, and account for about 80% of mutations. OBJECTIVE: To test the hypothesis that gross genomic rearrangements and mutations in alternatively spliced exons contribute to a subset of the remaining disease alleles. METHODS: Using DHPLC for alternatively spliced exons and quantitative real time polymerase chain reaction to detect genomic imbalances, 58 ARPKD patients were screened, of whom 55 were known to harbour one PKHD1 point mutation in the longest ORF. RESULTS: Three different heterozygous PKHD1 deletions and several single nucleotide changes in alternatively spliced exons were identified. The detected partial gene deletions are most likely pathogenic, while a potential biological function of the alterations identified in alternatively spliced exons must await the definition of transcripts containing alternative exons and their predicted reading frames. CONCLUSIONS: Gross PKHD1 deletions account for a detectable proportion of ARPKD cases. Screening for major genomic PKHD1 rearrangements will further improve mutation analysis in ARPKD.

Antenatal oligohydramnios of renal origin: postnatal therapeutic and prognostic challenges.

Urinary tract anomalies (UTA) including polycystic kidney disease nowadays can be detected antenatally by ultrasound. The concomitant presence of oligohydramnios has been regarded as a severe risk factor for renal dysfunction and pulmonary hypoplasia, although clinical data after birth are scarce. We report the postnatal course and long-term follow-up of 10 infants with oligohydramnios due to congenital UTA from two pediatric nephrology centers. The underlying final diagnoses were autosomal-recessive polycystic kidney disease (ARPKD, n = 2), familial tubular dysgenesis (n = 2) and bilateral renal hypoplasia (n = 6) including 3 children with posterior urethral valves. Two children died in the neonatal period while 8 children are currently alive at a median age of 2.5 (range 1.1-10) years. In the postnatal period, respiratory failure necessitating mechanical ventilation occurred in 7 infants (including the 2 non-survivors). All surviving children had chronic renal failure, which could be managed conservatively in 6 children (median GFR 45 (range 15-53) ml/min/1.73 m2) while 2 reached end-stage renal disease; one undergoing preemptive kidney transplantation and one peritoneal dialysis. Seven of 8 children reached normal developmental milestones. In conclusion, the presence of antenatal oligohydramnios in infants with UTA does not always carry a poor prognosis. The high incidence of perinatal complications, the complexity of underlying causes and the prevalence of postnatal chronic renal dysfunction calls for a multidisciplinary approach in the management of these children.

Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisis.

Joubert syndrome (JS) is an autosomal recessive disorder, consisting of mental retardation, cerebellar vermis aplasia, an irregular breathing pattern, and retinal degeneration. Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS. However, missense mutations in a new ciliary gene (RPGRIP1L) were found in type B patients. We analyzed a cohort of 56 patients with JS type B who were negative for mutations in three (AHI1, NPHP1, and CEP290/NPHP6) of the four genes previously linked to the syndrome. The 26 exons encoding RPGRIP1L were analyzed by means of PCR amplification, CEL I endonuclease digestion, and subsequent sequencing. Using this approach, four different mutations in the RPGRIP1L gene in five different families were identified and three were found to be novel mutations. Additionally, we verified that missense mutations are responsible for JS type B and cluster in exon 15 of the RPGRIP1L gene. Our studies confirm that a T615P mutation represents the most common mutation in the RPGRIP1L gene causing disease in about 8-10% of JS type B patients negative for NPHP1, NPHP6, or AHI1 mutations.

Outcome of fetal renal pelvic dilatation diagnosed during the third trimester.

OBJECTIVES: The aim of this study was to evaluate renal function and the need for postnatal treatment--antibiotic therapy and/or surgery--in relation to the grade of fetal renal pelvic dilatation (RPD) found on third-trimester ultrasound examination. METHODS: The retrospective study included 78 children, born between 1995 and 2000, with 115 dilated fetal renal pelvic units. The children were allocated to three groups based on pelvic anteroposterior diameter (APD) detected on third-trimester ultrasound: APDs of 7-9.9 mm, 10-14.9 mm and > or = 15 mm were classified as mild dilatation, moderate hydronephrosis and severe hydronephrosis, respectively. Renal function was assessed by scintigraphy. RESULTS: None of the 20 children with mild dilatation experienced a urinary tract infection (UTI) or underwent surgery; two had associated renal or urinary tract abnormalities. In contrast, five out of 22 (23%) children with moderate hydronephrosis and 23 out of 36 (64%) with severe hydronephrosis had either a UTI or required surgery (P < 0.001); associated abnormalities were also more common (6 out of 22 and 15 out of 36, respectively). There was no significant correlation between the grade of antenatal RPD and postnatal ipsilateral renal function. CONCLUSIONS: The need for postnatal treatment increased significantly with the grade of antenatal RPD. Children with antenatal mild dilatation were discharged early from follow-up whereas those with moderate and severe fetal hydronephrosis needed close follow-up by a multidisciplinary team.

Morphology of original and transplanted thymuses in severe combined immunodeficiency.

Twenty-six patients with severe combined immunodeficiency (SCID) were examined. In 20 cases no defect of the biochemical pathways was found; 6 cases showed a deficiency in adenosine deaminase (ADA) activity. In 19 cases histological sections of the thymus were available. In 3 cases, in addition to the original thymuses, transplanted thymic allografts were microscopically examined. The thymus in SCID without abnormality of the ADA pathway showed a uniform dysplastic pattern with only moderate variations related to mode of inheritance and length of survival. The thymus in SCID with ADA deficiency displayed a heterogeneous pattern ranging from almost normal to a completely dysplastic structure, whereas the transplanted thymic allografts presented either a normal or a dysplastic appearance. The morphology of the thymus is not pathognomonic of any given biochemical defect, clinical course, or type of SCID. SCID with apparently normal biochemical pathways probably results from a variety of pathogenetic mechanisms.

Heparin-induced thrombocytopenia type II on hemodialysis: switch to danaparoid.

We report two pediatric patients with end-stage renal failure who developed heparin-induced thrombocytopenia type II (HIT II) on hemodialysis (HD). Both developed acute respiratory distress and chest pain within 30 min of initiating the 5th HD session. The platelets dropped during HD from 168 to 38x10(9)/l and from 248 to 109x10(9)/l, respectively. Marked clots were observed in the dialyzers. Substitution of heparin with the low molecular weight heparin dalteparin had no effect. Switching from anticoagulation to the heparinoid danaparoid resulted in immediate disappearance of all adverse effects, and further long-term HD was uneventful. HIT II was diagnosed clinically; heparin-induced platelet activation test (HIPA) and serum IgG, IgA, and IgM to heparin-platelet factor 4 complexes (HPF4) were both negative. We conclude that HIT II may occur in children on HD. HIT II is essentially a clinical diagnosis, as HIPA and antibodies to HPF4 are not always positive. Once HIT II is suspected, heparin (and low-molecular-weight heparins) should be stopped immediately. Long-term anticoagulation with danaparoid is a valuable option for patients on HD.

Salivary excretion of endogenous proteins in nephrotic syndrome in children.

Size and charge selectivity of capillary permeability in the salivary glands of nephrotic children were investigated by measuring salivary excretion of endogenous plasma proteins of different size and charge. We examined 10 children with steroid-sensitive nephrotic syndrome (SSNS) in relapse and subsequent remission, 11 with steroid-resistant nephrotic syndrome, and 11 healthy children (controls). Albumin [mol. wt. 66 kilodaltons (kDa), isoelectric point (pI) 4.9] was measured by radio-immunoassay, transferrin (mol. wt. 77 kDa, pI 5.9) and immunoglobulins IgG1 (mol. wt. 150 kDa, pI 7-9) and IgG4 (mol. wt. 150 kDa, pI < 6) by enzyme-linked immunoabsorbent assay. In saliva, no significant differences were found between the four groups of children for any of the four proteins. Also, the saliva/plasma ratios of the four proteins were not different among the four groups. From these data, we conclude that in subjects with SSNS in relapse, neither size nor charge selectivity of salivary gland capillary permeability are affected.

Heterogeneity of atypical haemolytic uraemic syndromes.

Atypical, non-diarrhoea associated haemolytic uraemic syndrome (D-HUS) is a heterogeneous disorder with a generally poor outcome, although this view has now been questioned. The clinical and laboratory features of 23 children with D-HUS, representing a third of all patients with HUS seen during the last 26 years, were examined. The median age was 4.9 years (range 3 days-13.8 years). Twenty one children (91%) survived the initial phase. All patients except six infants aged < 18 months required dialysis (74%). Hypertension (43%), cardiomyopathy (43%), and cerebral convulsions (48%) were common. Nineteen (83%) children were followed up for a median period of 5.5 years (range 0.5-23.4). Only five (26%) patients, among them four infants, recovered completely. Six (32%) patients had one to 10 recurrences, including two siblings with neonatal onset, and eight (42%) developed end stage renal failure. Five children underwent cadaveric renal transplantation, with recurrence and subsequent graft failure in two. Four children died, resulting in an overall mortality of 26%. Atypical HUS is heterogeneous with regard to epidemiology, pathophysiology, and outcome. Children with a recurrent, familial, or neonatal course have worse outcomes; in contrast, infants not requiring dialysis in the acute phase have a better prognosis.

Bladder control a consequence of maturation: evidence after renal transplantation.

This report contains case studies on three children with early end-stage renal failure due to renal malformation or nephrotic syndrome, but without bladder involvement. All patients became anuric in the second year of life, before having obtained bladder control. They underwent successful cadaveric renal transplantation, having been anuric for almost 2 to 4 years. When the bladder catheter was removed 5 days after transplantation, all three children asked for the urine potty without ever having been prompted. Three weeks after transplantation, all three children achieved complete bladder control during the day, and two of them also at night. These observations add further evidence to the notion that the development of bladder control is a consequence of maturation and not of training.

[Glomerulopathy in Denys-Drash syndrome. Case report of a model disease]. / Glomerulopathie beim Denys-Drash-Syndrom. Kasuistik einer Modellkrankheit.

About 10% of all nephroblastomas (Wilms' tumor) present as part of malformation syndromes. The Denys-Drash syndrome (DDS) comprises pseudohermaphroditism, glomerulopathy and, early, often bilateral Wilms' tumors. A nephrectomy was performed in a 4-month-old girl because of a Wilms' tumor. Two months later, low serum albumin levels and proteinuria had developed. A biopsy from the remaining kidney showed a glomerulopathy which could also be seen in the nephrectomy specimen. The morphology was highly characteristic: the innermost layer of the kidney cortex exhibited augmentation of the mesangial matrix only; the intermediate layer showed severe sclerosis of glomeruli with deposition of fibrillary material; and the subcapsular layer revealed very small glomeruli and atrophic tubuli. Fifteen months later, peritoneal dialysis was necessary and due to the high risk of tumor development in the remaining kidney, a nephrectomy was performed. Molecular analysis revealed a point mutation within exon 9 of the WT1 gene (394 ARG-->TRP), which was homozygous in the tumor and heterozygous within renal parenchyma. The DDS is caused by a mutation in the WT1 gene on chromosome 11p13 which occurs during oogenesis or spermiogenesis. The WT1 gene is highly expressed during the development of the genitalia and the kidney; damage in one allele only causes the malformation syndrome. Loss of the second allele of the WT1 gene constitutes the second step of tumorigenesis. The appearance of Wilms' tumors derived from cells homozygous for the mutation reveals the function of the WT1 gene as a tumor suppressor gene.

[Small patients--big costs: the economic aspects of treating young children with renal failure]. / Kleine Patienten--grosse Kosten: ökonomische Aspekte der Behandlung niereninsuffizienter Kleinkinder.

Since 1985, 20 children have been followed with early onset of chronic renal failure (plasma creatinine > 120 mumol/l in first year of life). So far, 10 and 7 patients underwent peritoneal dialysis and renal transplantation, respectively. The aim of this study was to assess the overall costs. The recorded costs comprised both the direct costs of dialysis and transplantation, and the costs of all medical and psychosocial measures. The annual median costs of conservative treatment, peritoneal dialysis, the year of transplantation, and follow-up after transplantation amounted to 30,000, 93,000, 130,000 and 28,000 Swiss francs, respectively. The youngest patients caused the highest expenses. The active treatment permitted not only survival, but--in most patients--also a normal cognitive and psychosocial development.

Urinary oxalate excretion in urolithiasis and nephrocalcinosis.

AIMS: To investigate urinary oxalate excretion in children with urolithiasis and/or nephrocalcinosis and to classify hyperoxaluria (HyOx). METHODS: A total of 106 patients were screened. In those in whom the oxalate: creatinine ratio was increased, 24 hour urinary oxalate excretion was measured. Liver biopsy and/or genomic analysis was performed if primary hyperoxaluria (PH) was suspected. Stool specimens were examined for Oxalobacter formigenes in HyOx not related to PH type 1 or 2 (PH1, PH2) and in controls. RESULTS: A total of 21 patients screened had HyOx (>0.5 mmol/24 h per 1.73 m(2)); they were classified into five groups. Eleven had PH (PH1 in nine and neither PH1 nor PH2 in two). Six had secondary HyOx: two enteric and four dietary. Four could not be classified. Seven patients had concomitant hypercalciuria. Only one of 12 patients was colonised with O formigenes compared to six of 13 controls. CONCLUSIONS: HyOx is an important risk factor for urolithiasis and nephrocalcinosis in children, and can coexist with hypercalciuria. A novel type of PH is proposed. Absence of O formigenes may contribute to HyOx not related to PH1.

Alternative treatment to corticosteroids in steroid sensitive idiopathic nephrotic syndrome.

A review was undertaken of the use of alternative immunosuppressive treatment in addition to corticosteroids in a cohort of 429 children with steroid sensitive nephrotic syndrome (SSNS) treated between 1980 and 1994. Two hundred and twenty two children (52%) received at least one course of alternative treatment, 98 (23%) two, and 43 (10%) three. Cyclophosphamide was administered to 196 children (46%); in 181 it was the first course of alternative treatment and in 104 (57%) of those it was also the last ('final course'). Levamisole was given to 56 children (13%) and cyclosporin to 53 (12%). Fifteen children in whom cyclosporin failed were treated with chlorambucil. A few patients received azathioprine or vincristine. Ten children developed secondary steroid resistance, of whom five progressed to chronic renal failure. Acute complications included reversible renal failure, septicaemia, peritonitis, convulsions, and cerebral thrombosis. There were three deaths. It is concluded that half of the referred children with SSNS were deemed to require at least one course of alternative immunosuppressive treatment, and that side effects of the treatment and complications of SSNS are infrequent but occasionally fatal.

[New faces, forgotten diseases:border medical examination of asylum seekers' children 1990-1991]. / Neue Gesichter, vergessene Krankheiten: grenzsanitarische Untersuchungen von Asylbewerberkindern 1990-1991.

Hitherto there has been no epidemiologic basis for the extent of initial medical examination (IME) of children of refugees. In Switzerland little data is published on the incidence of diseases among refugees; in particular information on their children is scarce. We report the results of IME in these children in the Canton of Zürich from 1 July 1990 to 30 June 1991. The Federal Refugees Office assigned 1487 children to the Canton of Zürich. 920 children (61.9%) were registered, 259 (17.4%) at Zürich Children's Hospital and 661 with local physicians (44.5%). The current IME included a tuberculin skin test only, with additional hepatitis B screening of children from high risk countries. At the Zürich Children's Hospital the IME was extended: every child was examined clinically and a history was taken. The findings in the children examined at the Zürich Children's Hospital were as follows: 171 (66%) were healthy. 5 children (2%) had tuberculosis, 2 (0.8%) vitamin D deficiency rickets, 5 (2%) had iron deficiency anemia, 9 had hepatitis B (all recovered), 25 (9.7%) had various skin diseases and in 51 a variety of diseases of differing clinical significance were diagnosed. The local physicians found a similar incidence of tuberculosis, vitamin D deficiency rickets, iron deficiency anemia and skin diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term low-dose cyclosporin A in steroid dependent nephrotic syndrome of childhood.

Therapy of steroid-dependent idiopathic nephrotic syndrome is often unsatisfactory. Since 1986 we have treated nine children (six male and three female), aged 3-16 years, with cyclosporin A (CsA) during 2.0-5.2 (median 3.1) years. All had minimal change disease on renal biopsy and had previously received cyclophosphamide. Mean daily dosage of CsA was 4.1 mg/kg (range 2.7-5.8) and mean whole blood trough level was 220 ng/ml (range 141-271). The relapse rate decreased from 3.4/patient year before CsA to 0.55 on CsA. Discontinuation of CsA or reduction below 2 mg/kg daily was always followed by a relapse. The overall relapse rate, including the period with very low-dose CsA, was 0.95/patient year. Four patients required additional low-dose alternate-day prednisone. Repeat renal biopsy showed minimal change disease in eight patients and focal segmental glomerulosclerosis in one; CsA-toxicity was mild in two and moderate in one. The latter was the only patient with slightly reduced glomerular filtration rate. Two boys with delayed puberty spontaneously matured and reached expected final height. We conclude that long-term low-dose CsA is very effective and steroid-sparing. Its use is justified in selected patients, particularly in those with numerous relapses and in male patients before and during puberty, as long as renal function and CsA-toxicity are carefully monitored.

Charge and size selectivity of proteinuria in children with idiopathic nephrotic syndrome.

Experimental studies have pointed to charge selectivity as an important determinant of glomerular permeability to macromolecules. Loss of glomerular basement membrane (GBM) polyanion has been proposed as a cause of the selective proteinuria in minimal change nephrotic syndrome (MCNS). However, the presence of less-anionic albumin in urine than plasma from MCNS and focal and segmental glomerulosclerosis (FSGS) patients has been interpreted both as evidence for partial maintenance of charge selectivity and for involvement of other pathogenic mechanisms. The exact role of charge selectivity in the pathogenesis of nephrotic proteinuria remains controversial. We have examined the clearance of endogenous proteins of differing size and charge in children with idiopathic nephrotic syndrome (NS). Chromatofocusing was used to determine the isoelectric points (pIs) of albumins in paired plasma and urine samples from patients with FSGS (n = 6) and MCNS (n = 6). Charge selectivity was assessed by comparing the pIs of the fractions with the highest albumin concentration (model pI) in plasma and urine. The difference between the modal pIs was defined as the delta modal pI. Charge selectivity was also assessed from the albumin/transferrin and IgG4/IgG1 clearance ratios; size selectivity from the IgG1/albumin and IgG1/transferrin as well as the IgG4/albumin and IgG4/transferrin clearances. In children with FSGS, the mean (+/-SD) delta modal pI was -0.05 +/- 0.16, and in MCNS -0.05 +/- 0.11. Neither value differed significantly from zero. The albumin/transferrin clearance ratio showed no significant difference between FSGS and MCNS, but the IgG4/IgG1 clearance ratio was significantly higher in MCNS (P < 0.05). Size selectivity was significantly reduced in FSGS compared with MCNS (for IgG1/transferrin P < 0.01 and for IgG1/albumin P < 0.05). For IgG4/transferrin and IgG4/albumin, P was < 0.05. In conclusion, there was no evidence for residual charge selectivity in idiopathic NS associated with either MCNS or FSGS during nephrotic-range proteinuria. There was a significant loss of GBM size selectivity in children with FSGS with heavy proteinuria compared with children with MCNS with heavy proteinuria.

Pyelonephritis and vesicoureteral reflux after renal transplantation in young children.

PURPOSE: We assessed morbidity and risk factors of pyelonephritis in children after renal transplantation. MATERIALS AND METHODS: Between 1986 and 1995, 41 children underwent transplantation and all who had documented pyelonephritis were evaluated. RESULTS: Six children who underwent transplantation before age 7 years had 1 to 3 episodes of pyelonephritis with significant renal dysfunction and vesicoureteral reflux into the grafted system. An antireflux reimplantation procedure in 5 children was complicated by temporary functional obstruction in 3. No further infection occurred after correction of vesicoureteral reflux. After a median of 4.5 years post-transplantation all patients have a functioning graft. CONCLUSIONS: After renal transplantation vesicoureteral reflux and young recipient age are major risk factors for pyelonephritis with subsequent graft dysfunction.