Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients.

X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and acquired renal phosphate wasting were analyzed. Eighty XLH patients, including 29 children, were included. Genetic testing, performed in 78.8% of patients, showed a PHEX mutation in 96.8%. Median (range) Z-score for height was - 2.5 (- 5.5; 1.0) in adults and - 1.4 (- 3.7; 1.0) in children. Many patients were overweight or obese: 64.3% of adults and 37.0% of children. All children received XLH-related medication e.g., active vitamin D, phosphate supplementation or burosumab, while 8 adults used no medication. Lower age at start of XLH-related treatment was associated with higher height at inclusion. Hearing loss was reported in 6.9% of children and 31.4% of adults. Knee deformities were observed in 75.0% of all patients and osteoarthritis in 51.0% of adult patients. Nephrocalcinosis was observed in 62.1% of children and 33.3% of adults. Earlier start of XLH-related treatment was associated with higher risk of nephrocalcinosis and detection at younger age. Hyperparathyroidism longer than six months was reported in 37.9% of children and 35.3% of adults. This nationwide study confirms the high prevalence of adiposity, hearing loss, bone deformities, osteoarthritis, nephrocalcinosis and hyperparathyroidism in Dutch XLH patients. Early start of XLH-related treatment appears to be beneficial for longitudinal growth but may increase development of nephrocalcinosis.

Kidney Blow Out Due to Inguinal Herniation of the Ureter in an Infant.

Ureteroinguinal herniation is a rare event, usually diagnosed during the surgical repair of inguinal hernias. Here, we describe the first case of a kidney blow out due to this condition in a male infant.

Pyuria is absent during urinary tract infections in neutropenic patients.

To investigate the diagnostic significance of a normal urine sediment in the work-up for fever of unknown origin in neutropenia. Urinary tract infection was defined as ≥10(5) urinary pathogens in the absence of another focus. Pyuria was found in only 1/23 neutropenic episodes compared to 21/31 in controls (P < 0.0001).

[A boy with cyclic vomiting and an alleged furosemide allergy on the basis of a subpelvic stenosis]. / Een jongen met cyclisch braken en een vermeende furosemideallergie op basis van een subpelviene stenose.

An 8-year-old boy, known with a Diamond-Blackfan anaemia, was admitted to the hospital because of frequent vomiting since 3 days and loin pain. In previous years, he had been admitted several times for the same complaints but no cause had been identified. Ultrasound examination of the abdomen performed at admittance showed dilatation of the left renal pelvis. A renal scintigraphy was discussed with the mother, and she refused the injection of furosemide, because her son was allegedly allergic to furosemide: previous furosemide treatments during blood transfusions for his anaemia had always resulted in stomach-ache and vomiting, which may be attributed, however, to an acute dilatation of the renal pelvis due to the diuretic effect of furosemide. Scintigraphy without furosemide showed a significant obstruction and asymmetric renal function, so a pyeloplasty was performed after which he has been symptom-free. In patients with cyclic vomiting, an intermittent uretero-pelvic junction obstruction should be considered and can only be ruled out when ultrasound during the complaints and renal scintigraphy under adequate hydration and after furosemide are normal.

[From gene to disease; Dent's disease caused by abnormalities in the CLCN5 and OCRL1 genes]. / Van gen naar ziekte; de ziekte van Dent veroorzaakt door afwijkingen in CLCN5- en OCRL1-genen.

Dent's disease is an X-linked disorder, characterized by generalized proximal tubular dysfunction, nephrolithiasis, nephrocalcinosis and the development ofend-stage renal disease, generally occurring after the age of thirty. In the majority of cases, the disease is caused by mutations in the CLCN5-gene. The pathogenesis of the disease has not yet been clarified. Defective recycling of multi-ligand proximal tubular receptors megalin and cubilin is considered responsible for the defective reabsorption of low molecular weight proteins, albumin, hormones and vitamins. Treatment with thiazide diuretics to diminish the hypercalciuria in combination with citrate supplements might prevent renal stone formation and deterioration of renal function. In the laboratory ofDNA diagnostics in the Radboud University Nijmegen Medical Centre, the molecular analysis of the CLCN5-gene in patients suspected with this disease is performed.

[Schimke's immuno-osseous dysplasia as an explanation for the rare combination of disproportionately short stature and the nephrotic syndrome]. / Immuno-ossale dysplasie van Schimke als zeldzame oorzaak van de combinatie van kleine lichaamslengte en nefrotisch syndroom.

A 10-year-old Turkish boy with consanguineous parents was presented with a disproportionately short stature and a nephrotic syndrome. The mild form of Schimke's immuno-osseous dysplasia was diagnosed as the common cause. This rare, autosomal recessive osteochondrodysplasia is characterised by spondyloepiphyseal dysplasia, facial dysmorphism, T-cell immunodeficiency and progressive renal failure due to focal segmental glomerulosclerosis. In Schimke's immuno-osseous dysplasia, a severe early-onset form and a milder later-onset form can be distinguished on the basis of the clinical course. The patient was treated by fluid and salt restriction, enalapril and later also losartan, which led to a decrease in the proteinuria and an increase in serum albumin concentration. Two years later, the renal function was still normal.

Therapeutic approach to Candida bezoar in children.

INTRODUCTION: Candida bezoar (CB) is a rare finding in neonates and infants with candiduria, presenting as necrotic debris with proliferating mycelia in the collecting system of the kidney. If initial antifungal medical treatment does not result in clearance of candiduria and disappearance of CB on ultrasound in dilated kidneys, invasive interventions like insertion of nephrostomy tubes (NT) or surgical interventions to drain the kidney are sometimes advocated(.). However, NT placement can be a technical challenge, especially in pre- and dysmature neonates, and NT displacement or obstruction by the CB can lead to suboptimal treatment. Identification of those children who will benefit from invasive renal drainage is important. OBJECTIVE: This study evaluates the management of patients with CB in three tertiary referral hospitals to determine criteria for intervention. MATERIALS AND METHODS: A retrospective multicenter chart analysis was conducted of children with candiduria and ultrasonographic demonstration of CB (diagnosed between March 1995 and August 2012). The indication for invasive renal drainage (if performed) and subsequent clinical outcome, serum creatinine levels and ultrasound findings were assessed. RESULTS: A total of 12 children were included, two of which were premature neonates. Eight children had congenital urogenital anomalies. One older child with acute myeloid leukemia had CB during chemotherapy and one ex-premature developed CB following cerebral candidiasis. All children received systemic antifungal medication; in seven children invasive treatment was added. Indications for invasive treatment were clinical deterioration, progressive renal dilation, pyonephrosis, rising creatinine levels and persistence of CB. Two underwent a Y-cutaneous ureterostomy and nephrostomy tubes were inserted in five children. Percutaneous renal drainage by nephrostomy led to complications in 3 of 6 procedures. In all patients, irrespective of therapeutic modality, follow-up ultrasound demonstrated no de novo changes. No additional parenchymal defects or deterioration of split renal function were seen on DMSA or MAG-3 scan. DISCUSSION: In the literature renal drainage is suggested in case of complete obstruction. However dilatation is a frequent finding in children as part of the congenital renal anomaly and does not necessarily mean that there is obstruction of the urinary tract. Even in children without candida infections the diagnosis of obstruction is not straightforward, while the results of a MAG 3 scan can be obscured by compromised kidney function, parenchymal bacterial infiltration and neonatal immaturity of the kidney. If candiduria and CB persist despite intensive medical treatment, intensive consultation is required before renal drainage, because NT insertion might be a surgical challenge. Complications such as displacement of the NT, urinoma development, or NT obstruction can occur and was seen in three of six procedures. Premature neonates seem to be more prone to complications due to their small anatomical proportions, requiring medical equipment with small diameters prone to displacement and obstruction. Some studies describe successful pharmaceutical management in the majority of patients with CB. Other studies describe unilateral surgical intervention in children with bilateral CB where unilateral drainage did not influence overall renal outcome. This is in line with our results. A limitation of the present study is its retrospective design. In this population, the motivation for invasive renal drainage or conservative management was not well documented in all cases, and was mainly based on clinical and diagnostic parameters like creatinine levels and radiographic findings. CONCLUSION: Renal drainage should be considered in selected cases after failure of systemic antifungal treatment. Inserting and maintaining a nephrostomy tube in young children is associated with a high rate of complications; conservative treatment is likely to be sufficient in the majority of patients with candiduria and CB.

Response to diphtheria and tetanus booster vaccination in pediatric renal transplant recipients.

BACKGROUND: Although inactivated vaccines are recommended for immunocompromized patients, efficacy and safety of diphtheria and tetanus immunization in renal transplant recipients have received little attention so far. The aim of the study was to investigate the response to a standard diphtheria and tetanus booster vaccination in pediatric renal transplant recipients. METHODS: Forty-two children, median age 13.2 years (range, 7.8-18.9 years) with complete primary immunization 9.2 years (0.9-15.4 years) before transplantation were enrolled. Immunosuppression consisted of cyclosporine plus prednisolone in 15 (36%), cyclosporine, azathioprine, and prednisolone in 24 (57%), and tacrolimus plus prednisolone in 3 (7%). Antibodies were measured by enzyme-linked immunosorbent assay before and 1, 6, and 12 months after vaccination. RESULTS: Before vaccination, protective antibody concentrations exceeding 0.1 IU/ml against diphtheria were found in 16 children (38%). Thirty-eight (90%) had protective antibody concentrations against tetanus. After booster immunization, the protection rate against diphtheria rose to 95% at 1 month with a decline to 93% at 6 and 76% at 12 months. Protection against tetanus was complete after vaccination and persisted over the observation. Antibody concentrations were comparable to those reported for healthy children. Statistical analysis showed no influence of allograft function, immunosuppressive regimen, previous cytotoxic therapy, or time between primary immunization and end-stage renal failure on antibody response. Immunization was well tolerated and kidney function remained unaffected in patients with stable allograft function. CONCLUSIONS: Diphtheria and tetanus vaccination can be performed effectively and safely in renal transplant recipients as generally recommended.

The beta2-microglobulin/cystatin C ratio--a potential marker of post-transplant lymphoproliferative disease.

BACKGROUND: As a consequence of more intensified immunosuppression, post-transplant lymphoproliferative disease (PTLD) is increasingly observed in patients after solid-organ transplantation. Beta2-microglobulin, a low-molecular weight protein (MW 11.8 kDa), is produced by all nucleated cells as part of the HLA complex. Its serum concentration is directly correlated with prognosis in patients with lymphatic neoplasms. Like other low-molecular weight proteins, beta2-microglobulin is eliminated by glomerular filtration. This complicates its use as a tumor marker in renal insufficiency. Cystatin C, a low-molecular weight protein of 13.3 kDa, is a new marker of kidney function largely unaffected by extrarenal disease. We, therefore, sought to assess the potential of the beta2-microglobulin/cystatin C ratio (beta2M/Cys) as a marker of lymphoproliferation. PATIENTS AND METHODS: Beta2M/Cys was determined by particle-enhanced immunonephelometry in sera from 132 children with different degrees of renal insufficiency, 5 of whom had lymphoproliferative disease. Renal function was assessed using the Schwartz formula. RESULTS: Beta2M/Cys was constant between 1.2 and 2.4 mg/mg for Schwartz GFR > or = 40 ml/min x 1.73 m2. With lower GFR, beta2M/Cys rose progressively, maximum values being found in the hemodialysis patients (4.85-11.73). Healthy renal transplant recipients had beta2M/Cys comparable to controls. With acute lymphoproliferative disease, all but one patient had significantly elevated beta2M/Cys between 2.68 and 3.68 mg/mg, which returned to normal in remission (1.67-2.35 mg/mg). The sensitivity of a beta2M/Cys ratio > 2.4 mg/mg for the detection of PTLD was 80%, the specificity 100%, positive predictive value 100%, negative predictive value 90%. CONCLUSION: The beta2-microglobulin/cystatin C ratio is a promising parameter of lymphoproliferation in patients with normal or mildly impaired renal function.

Cystatin C and creatinine after successful kidney transplantation in children.

BACKGROUND: Serum creatinine is commonly used for the monitoring of allograft function following renal transplantation (RTX). Due to lower muscle mass, creatinine production rate is reduced in children, thus decreasing its sensitivity for the detection of allograft dysfunction. In children, the serum concentration of cystatin C, a low molecular weight protein of 13.3 kDa, reflects glomerular filtration rate independent of age, height and body composition. We, therefore, sought to assess the potential of cystatin C as a marker of allograft function in children. METHODS: Cystatin C and creatinine were measured in parallel at least daily in 24 children (14 boys, 10 girls; mean age 10.5+/-5.1 years) during hospitalization after successful RTX. Cystatin was determined immunoturbidimetrically, creatinine enzymatically. RESULTS: Within one hour after RTX, cystatin C (mean+/-SE) almost halved from 6.69+/-0.45 mg/l to 3.69+/-0.38 mg/l while creatinine declined from 862 +/-65.4 to 633+/-62.9 micromol/l. Following a nadir of 1.82+/-0.18 mg/l on day 2, there was a secondary increase in cystatin C concentrations to 2.69+/-0.35 mg/l on day 10. Creatinine concentrations continued to decline until day 9 reaching 80.5+/-13.1 micromol/l. Day-to-day variation at steady-state was comparable. In the course of 9 acute rejection episodes, both parameters rose in parallel, the increase in creatinine concentration being much greater. CONCLUSION: Cystatin C was an early indicator of allograft function following successful RTX in children. It did not prove superior to creatinine for the recognition of acute allograft dysfunction, however.

Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls.

Cystinuria is a hereditary disorder of cystine and dibasic amino acid transport across the luminal membrane of renal tubules and intestine, resulting in recurrent nephrolithiasis. While mutations in the SLC3A1 gene cause type I cystinuria, patients with non-type I cystinuria carry mutations in the SLC7A9 gene. Both gene products form the renal amino acid transporter rBAT/b0,+AT affected in cystinuria. In the present study a total of 59 patients with different ethnic background were screened for sequence variations in SLC7A9, out of these 32 were of German origin. For determination of allele frequencies of detected polymorphisms, 58 healthy German controls were investigated. Molecular-genetic analysis was performed using single-strand conformation polymorphism analysis, restriction assays and sequencing. Allele frequencies were analyzed statistically for the detected polymorphisms. In addition to the 6 already known variants we identified 7 new polymorphisms. Statistical analyses showed a significantly different distribution of alleles between German patients and German controls in case of the polymorphisms c. 147C>T (exon 2), c.386C>T (exon 3), IVS3+22T>G, c.584C>T (exon 4), c.610T>C (exon 4), c.692C>T (exon 5), c.852C>A (exon 6) and c.872C>T (exon 6). In summary, our results show that cystinuria is a complex disease which is not only caused by mutations in SLC7A9 and SLC3A1, but also influenced by other modifying factors such as variants in SLC7A9.

Long-term outcome of kidney function after twin-twin transfusion syndrome treated by intrauterine laser coagulation.

Twin-twin transfusion syndrome (TTTS) is caused by unbalanced shunting of blood between monochorionic twins. It is well known that chronic hypotension and hypovolemia may cause renal insufficiency in the donor twin. The long-term outcome of kidney function after TTTS has not previously been delineated in the literature, however. The aim of this study was to evaluate the long-term outcome of kidney function in children after intrauterine laser treatment for severe TTTS. Eighteen surviving twin pairs after intrauterine laser treatment for TTTS were involved in the study. Their gestational age at birth was 29-39 weeks, their median birth weight was 2050 g, and their median age at evaluation was 3 years 1 month, range 1 year 9 months to 4 years 5 months. Serum creatinine, cystatin C, and beta 2-microglobulin, sodium, potassium, and phosphate excretion, and urine albumin and alpha-1-microglobulin were measured. Creatinine clearance was calculated by use of the Schwartz formula. The laboratory findings for all 36 children were within normal limits. There were no significant differences between donors and recipients. Despite severe alteration of renal function before the laser treatment (anuria-polyuria) no long-term impairment of renal function could be detected in any of the 18 twin pairs.

[Facial paralysis in a 2 1/2-year-old girl due to herpes zoster oticus. Results of the reactivation of a chickenpox infection in infancy]. / Fazialisparese bei einem 2 1/2 jährigen Mädchen infolge eines Zoster oticus. Folge der Reaktivierung einer Windpockeninfektion im Säuglingsalter.

A case of herpes zoster oticus in a 2 1/2 year-old girl with a history of varicella at the age of 4 months is reported. Peripheral facial palsy was the prominent clinical symptom. Following treatment with Acyclovir 15 mg/kg/day i.v. for 7 days a complete remission was noted. Course, treatment and prognosis of zoster oticus are discussed, as well as the increased incidence of herpes zoster in children who had varicella before the age of 1 year.

Post-renal transplant erythrocytosis in a child.

We report the case of a 7-year-old boy who developed severe erythrocytosis 4 months after successful kidney transplantation, with a well-functioning graft. When the haematocrit rose above 60%, phlebotomy had to be performed once to twice a week in order to keep the haematocrit below 50%. A 3-month course of theophylline therapy did not influence the erythrocytosis significantly. There were 5 further patients with erythrocytosis out of 186 children who had undergone kidney transplantation at our centre.