[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.

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.

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.

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.

MRI and proton spectroscopy in Lowe syndrome.

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. We report two patients with typical intracranial lesions on MRI. The proton spectroscopy study of the periventricular white matter showed a moderate elevation of the signal at 3.56 ppm in the patient with cystic lesions. This resonance is usually assigned to myo-inositol and interpreted as a glial marker. In our patient it could also represent a true accumulation inside the cysts of phosphatidylinositol 4,5-biphosphate which is not degraded in patients with Lowe syndrome.

Simultaneous occurrence of the haemolytic uraemic syndrome and acute post-infectious glomerulonephritis.

We report on two children, a 12-year-old boy and a 6-year-old girl, with simultaneous occurrence of clinical and laboratory features consistent with both diarrhoea-negative haemolytic uraemic syndrome (D-HUS) and acute post-infectious glomerulonephritis (APGN). Both presented with acute renal insufficiency, hypertension and oedema. Laboratory evaluation revealed micro-angiopathic anaemia with burr cells, thrombocytopenia, elevated lactic dehydrogenase and low complement C3. Urinalysis showed marked proteinuria and haematuria. Renal biopsy was characteristic of APGN, but not of HUS. The outcome was good in both children. Conclusion. The simultaneous occurrence of diarrhoea-negative haemolytic uraemic syndrome and acute post-infectious glomerulonephritis is rare. The outcome is generally good as is expected in the latter condition in contrast to the former.

Randomised controlled trial of three day versus 10 day intravenous antibiotics in acute pyelonephritis: effect on renal scarring.

BACKGROUND: Acute pyelonephritis often leaves children with permanent renal scarring. AIMS: To compare the prevalence of scarring following initial treatment with antibiotics administered intravenously for 10 or three days. METHODS: In a prospective two centre trial, 220 patients aged 3 months to 16 years with positive urine culture and acute renal lesions on initial DMSA scintigraphy, were randomly assigned to receive intravenous ceftriaxone (50 mg/kg once daily) for 10 or three days, followed by oral cefixime (4 mg/kg twice daily) to complete a 15 day course. After three months, scintigraphy was repeated in order to diagnose renal scars. RESULTS: Renal scarring developed in 33% of the 110 children in the 10 day intravenous group and 36% of the 110 children in the three day group. Children older than 1 year had more renal scarring than infants (42% (54/129) and 24% (22/91), respectively). After adjustment for age, sex, duration of fever before treatment, degree of inflammation, presence of vesicoureteric reflux, and the patients' recruitment centres, there was no significant difference between the two treatments on renal scarring. During follow up, 15 children had recurrence of urinary infection with no significant difference between the two treatment groups. CONCLUSION: In children with acute pyelonephritis, initial intravenous treatment for 10 days, compared with three days, does not significantly reduce the development of renal scarring.

Ingested pins causing perforation.

We report two children who underwent endoscopic removal of ingested foreign bodies which had perforated the stomach, one of which had migrated into the thorax.

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.

[Pediatric kidney transplantation and living donors--invaluable by virtue of necessity]. / Pädiatrische Nierentransplantation und Lebendspende--aus der Not eine Tugend.

UNLABELLED: Renal transplantation is the treatment of choice for paediatric patients with end-stage renal failure. Living donor transplantation (LDT) has become an important therapeutic option due to the shortage of cadaver donors and increasingly long waiting times. METHODS: Between 1992 and 1999, a total of 48 paediatric and adolescent patients underwent renal transplantation in Zurich. Of these, 21 patients (44%) received a kidney from a living related donor. 11 patients had been dialysed before LDT over a period of 0.2-5.7 years (median 0.6), and 10 were transplanted preemptively. Triple immunosuppression consisted of cyclosporine A, azathioprine or mycophenolate mofetil (MMF; since 1998), and prednisone. The observation period was 0.5-7.3 years (median 2). RESULTS: Recipients were 2-18 (median 10.5) years old at transplantation. One third had either a congenital malformation, an inherited disease, or an acquired disorder. One patient died of an associated cardiac disease at 4 months with functioning graft, and one functional graft loss occurred after 2.8 years. 9 patients were switched from cyclosporine to tacrolimus, 7 for biopsy-proven rejection and 2 for cosmetic reasons (hypertrichosis). No antibody preparations were used. Median glomerular filtration rate (51Cr-EDTA), measured after one year in 11 donor/recipients, was 64 (55-95) and 54 (32-82) ml/min/1.73 m2, respectively. The most recent estimated renal function (Schwartz formula) of 19 functioning grafts was 37-79 ml/min/1.73 m2 (median 63). Median body height of 16 patients with no associated extrarenal disease was -0.9 SDS (standard deviation score); the remaining 3--with serious extra-renal disease--were considerably growth retarded. Main complications were reversible rejection episodes in 19 (90%), arterial hypertension (16), CMV disease (2) and asymptomatic CMV infection (3), pyelonephritis (3), and recurrence of the primary renal disease, seizures, diabetes mellitus and non-compliance (one each). Actuarial patient and graft survival (Kaplan-Meier) after 3 years was 95 and 83% respectively. This was not statistically different from the cadaveric donor group (n = 27) with 100 and 80% survival respectively. Overall rehabilitation was excellent. The donors were 12 mothers, 8 fathers and one grandmother aged 31 to 50 (median 39) years; none of them experienced serious postoperative problems. CONCLUSIONS: The paediatric transplantation programme would no longer be feasible in Switzerland without LDT. The results are very encouraging; preemptive transplantation makes it possible to avoid dialysis in half of the patients. The risk for the donor is small, and careful evaluation without putting pressure on the family is essential.

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.

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.

[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.

[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.

Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations.

We investigated 17 children with nephrotic syndrome (NS) of early onset (14 aged < 1 year) and rapid progression to end-stage renal disease for the presence of mutations in the Wilms' tumor suppressor gene WT1 on chromosome 11. In eight children (7 genotypic males) an association with Wilms' tumor and/or ambiguous genitalia (Denys-Drash syndrome) was observed. In these eight and two additional female patients with NS only constitutional missense mutations in the WT1 gene were detected; four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described). Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases. End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients. A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female). From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype. No mutation of the WT1 gene was found in seven other children with isolated congenital or infantile NS with or without DMS who appeared to have a slower progression than the first group. It is proposed that patients with early onset, rapidly progressive NS and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms' tumor.

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.

Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie.

Joubert syndrome type B (JSB) is a developmental disorder of the nephronophthisis (NPH) complex with multiple organ involvement, including NPH, coloboma of the eye, aplasia of the cerebellar vermis, and the facultative symptoms of psychomotor retardation, polydactyly, and neonatal tachypnea. In isolated autosomal recessive NPH type 1 (NPH1), homozygous deletions have been described as causative in more than 80% of patients. Since different combinations of the extrarenal symptoms with NPH occur in JSB, a contiguous gene deletion syndrome in the NPH1 genetic region would seem a highly likely cause for JSB. We therefore examined 11 families with JSB for the presence of extended deletions at the NPH1 locus. Genomic DNA was examined using four consecutive polymerase chain reaction (PCR) markers that are deleted in NPH1 and three PCR makers flanking the NPH1 deletion. In all seven markers examined, there was no homozygous deletion detected in any of the 11 JSB families studied. Since these markers saturate the NPH1 deletion region at high density, this finding excludes the presence of large homozygous deletions of the NPH1 region in these JSB families, making it unlikely that deletions of the NPH1 region are a primary cause for JSB.

Familial progressive tubulo-interstitial nephropathy and cholestatic liver disease -- a newly recognized entity?

UNLABELLED: We describe two siblings (female and male) with progressive tubulo-interstitial nephropathy and cholestatic liver disease. The main characteristics were progressive renal failure and elevated liver enzymes (AST, ALT and gamma-GT). Dialysis was started at the age of 1.9 and 6.5 years, respectively. Renal histology disclosed sclerosed glomeruli and atrophic tubules; the interstitium was fibrotic and infiltrated by lymphocytes. Endoscopic retrograde cholangiopancreatography revealed segmental irregularities and narrowing of the intrahepatic bile ducts, consistent with early primary sclerosing cholangitis. Liver histology showed enlarged portal triads, mild proliferation and inflammation of bile ducts, and fibrosis. At 5.9 years the girl underwent a successful renal transplantation whereas the boy is still on dialysis. CONCLUSION: The association of progressive tubulointerstitial nephropathy and cholestatic liver disease, consistent with early primary sclerosing cholangitis, constitutes a distinct autosomal recessive entity.