Hagen Staude

An Outbreak of Shiga Toxin–Producing Escherichia coli O104:H4 Hemolytic Uremic Syndrome in Germany: Presentation and Short-term Outcome in Children

BACKGROUND In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. METHODS Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. RESULTS Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 [74%]) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. CONCLUSIONS E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin-producing E. coli HUS.

Three-Year Growth Hormone Treatment in Short Children with X-Linked Hypophosphatemic Rickets: Effects on Linear Growth and Body Disproportion

CONTEXT Children with X-linked hypophosphatemic rickets (XLH) are prone to progressive disproportionate stunting despite oral phosphate and vitamin D treatment. OBJECTIVE Our objective was to analyze the effects of GH treatment on stature and lengths of linear body segments in short children with XLH. DESIGN, SETTINGS, AND PATIENTS A 3-yr randomized controlled open-label GH study in short prepubertal children with XLH (n = 16) on phosphate and calcitriol treatment was conducted. A cohort of XLH patients (n = 76) on conservative treatment served as an XLH reference population. MAIN OUTCOME MEASURES Changes in SD scores (SDS) of stature and linear body segments, i.e. sitting height, leg and arm length, and sitting height index (i.e. ratio between sitting height and stature) were the main outcome measures. RESULTS XLH patients presented at time of enrollment with significant impairments of stature (-3.3 SDS) and linear body segments compared with healthy children. Leg length (-3.8 SDS) was most impaired, whereas sitting height (-1.7 SDS) was best preserved. The markedly elevated mean sitting height index (+3.3 SDS) reflected severe body disproportion. GH resulted in a sustained increase in linear growth (stature, +1.1 SDS; sitting height, +1.3 SDS; leg length, +0.8 SDS; arm length, +1.1 SDS; each P < 0.05 vs. baseline), whereas no significant changes were observed in controls. Mean height SDS at 3 yr did not significantly differ between groups. Sitting height index remained stable in both the GH-treated patients and in study controls but increased further in the XLH-reference population. CONCLUSIONS The 3-yr GH treatment improved linear growth without progression of body disproportion in short children with XLH.

Clinical and Molecular Characterization of Patients with Heterozygous Mutations in Wilms Tumor Suppressor Gene 1

BACKGROUND AND OBJECTIVES The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. RESULTS Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. CONCLUSIONS Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4+CD45RA−Foxp3− and Foxp3low effector T cells from children with LN correlates with increased frequencies of IL-17–producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17–producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3–activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

BACKGROUND AND OBJECTIVES Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

Serum fetuin-A and vitamin D in children with mild-to-severe chronic kidney disease: a cross-sectional study

BACKGROUND Fetuin-A and vitamin D are significant correlates of cardiovascular morbidity in paediatric chronic kidney disease (CKD) patients. It is thus far unknown, whether or not serum fetuin-A is affected by the vitamin D status or treatment with vitamin D preparations in these patients. METHODS In a cross-sectional study, serum concentrations of fetuin-A, 25-hydroxyvitamin D(3) (25OHD) and 1,25-dihydroxyvitamin D(3) (calcitriol) levels were determined in 112 paediatric patients with mild-to-severe CKD (Stages 1-5) and after renal transplantation. A25OHD supplementation and/or calcitriol treatment were given in 64% of the patients. RESULTS Fetuin-A levels were clearly reduced in dialysis patients but were comparable to healthy controls in those with moderate CKD and after transplantation. Although 64 and 46% of all patients received 25OHD and/or calcitriol treatment, 48 and 20% of patients were 25OHD and/or calcitriol deficient, respectively. Within the whole patient cohort, fetuin-A correlated with serum calcium and yearly weight-related 25OHD dosage (each P < 0.01) but not with the vitamin D status per se. Multiple regression analysis revealed the need for dialysis treatment and cumulative 25OHD dosage as independent predictors of fetuin-A concentrations (model r(2) = 0.17). In dialysis patients, fetuin-A was inversely correlated with serum C-reactive protein but positively correlated with cumulative calcitriol dosage and serum parathormone (each P < 0.01). CONCLUSIONS Fetuin-A levels are clearly reduced in children on dialysis but not in those with moderate CKD and after transplantation. Besides the degree of microinflammation, the cumulative intake of 25OHD and calcitriol are significantly correlated to fetuin-A in these patients. The impact of vitamin D treatment appears to be at least partly mediated by serum calcium.

Intermediate Follow-up of Pediatric Patients With Hemolytic Uremic Syndrome During the 2011 Outbreak Caused by E. coli O104:H4

Background. In 2011 Escherichia coli O104:H4 caused an outbreak with >800 cases of hemolytic uremic syndrome (HUS) in Germany, including 90 children. Data on the intermediate outcome in children after HUS due to E. coli O104:H4 have been lacking. Methods. Follow-up data were gathered retrospectively from the medical records of patients who had been included in the German Pediatric HUS Registry during the 2011 outbreak. Results. Seventy-two of the 89 (81%) patients were included after a median follow-up of 3.0 (0.9-4.7) years. Hypertension and proteinuria were present in 19% and 28% of these patients, respectively. Of 4 patients with chronic kidney disease (CKD) > stage 2 at short-term follow-up, 1 had a normalized estimated glomerular filtration rate, and 3 (4%) had persistent CKD > stage 2. In 1 of these patients, CKD improved from stage 4 to 3; 1 who had CKD stage 5 at presentation received kidney transplantation; and 1 patient required further hemodialysis during follow-up. One patient (1.4%) still had major neurological symptoms at the latest follow-up. Dialysis during the acute phase (P = .01), dialysis duration (P = .01), and the duration of oligo-/anuria (P = .005) were associated with the development of renal sequelae. Patients treated with eculizumab (n = 11) and/or plasmapheresis (n = 13) during the acute phase of HUS had comparable outcomes. Conclusions. The overall outcome of pediatric patients after HUS due to E. coli O104:H4 was equivalent to previous reports on HUS due to other types of Shiga toxin-producing E. coli (STEC). Regular follow-up visits in patients are recommended after STEC-HUS.

Transitional Care and Adherence of Adolescents and Young Adults After Kidney Transplantation in Germany and Austria: A Binational Observatory Census Within the TRANSNephro Trial

AbstractTransition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure.We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012.Most centers (73%) confirmed agreements on the transition procedure. Patients’ age at transfer was subject to regulation in 73% (18 years). Median age at transition was 18.3 years (16.5–36.7). Median serum creatinine increased from 123 to 132 &mgr;mol/L over the 12 month observation period before transfer (P = 0.002). A total of 25/119 patients showed increased creatinine ≥20% just before transfer. Biopsy proven rejection was found in 10/119 patients. Three patients lost their graft due to chronic graft nephropathy.Mean coefficient of variation (CoV%) of immunosuppression levels was 0.20 ± 0.1. Increased creatinine levels ≥20% just before transfer were less frequently seen in patients with CoV < 0.20 (P = 0.007).The majority of pediatric nephrology centers have internal agreements on transitional care. More than half of the patients had CoV of immunosuppression trough levels consistent with good adherence. Although, 20% of the patients showed increase in serum creatinine close to transfer.

Exhaled volatile substances mirror clinical conditions in pediatric chronic kidney disease

Monitoring metabolic adaptation to chronic kidney disease (CKD) early in the time course of the disease is challenging. As a non-invasive technique, analysis of exhaled breath profiles is especially attractive in children. Up to now, no reports on breath profiles in this patient cohort are available. 116 pediatric subjects suffering from mild-to-moderate CKD (n = 48) or having a functional renal transplant KTx (n = 8) and healthy controls (n = 60) matched for age and sex were investigated. Non-invasive quantitative analysis of exhaled breath profiles by means of a highly sensitive online mass spectrometric technique (PTR-ToF) was used. CKD stage, the underlying renal disease (HUS; glomerular diseases; abnormalities of kidney and urinary tract or polycystic kidney disease) and the presence of a functional renal transplant were considered as classifiers. Exhaled volatile organic compound (VOC) patterns differed between CKD/ KTx patients and healthy children. Amounts of ammonia, ethanol, isoprene, pentanal and heptanal were higher in patients compared to healthy controls (556, 146, 70.5, 9.3, and 5.4 ppbV vs. 284, 82.4, 49.6, 5.30, and 2.78 ppbV). Methylamine concentrations were lower in the patient group (6.5 vs 10.1 ppbV). These concentration differences were most pronounced in HUS and kidney transplanted patients. When patients were grouped with respect to degree of renal failure these differences could still be detected. Ammonia accumulated already in CKD stage 1, whereas alterations of isoprene (linked to cholesterol metabolism), pentanal and heptanal (linked to oxidative stress) concentrations were detectable in the breath of patients with CKD stage 2 to 4. Only weak associations between serum creatinine and exhaled VOCs were noted. Non-invasive breath testing may help to understand basic mechanisms and metabolic adaptation accompanying progression of CKD. Our results support the current notion that metabolic adaptation occurs early during the time course of CKD.

Reduced serum fetuin-A in nephrotic children: a consequence of proteinuria?

Background: The extracellular protein fetuin-A is a potent soluble inhibitor of calcification, and its deficiency has been associated with vascular calcification in dialysis patients. In proteinuric patients, significant urinary losses of fetuin-A may cause low serum fetuin-A levels. Methods: In a cross-sectional study, urinary/serum concentrations of fetuin-A were investigated in proteinuric children with glomerular diseases and preserved renal function (n = 58) in comparison to healthy controls (n = 246). Results: Mean fetuin-A serum concentrations were clearly reduced in children with nephrotic syndrome (0.25 ± 0.14 g/l, p < 0.001), slightly reduced in children with large proteinuria (0.39 ± 0.15 g/l, p < 0.05), and comparable to controls in those with mild proteinuria (0.45 ± 0.14 vs. 0.46 ± 0.12 g/l). Fetuin-A was positively correlated with serum protein (r = 0.58), albumin (r = 0.57), and calcium (r = 0.64), but negatively correlated with proteinuria (r = –0.41), albuminuria (r = –0.46), and urinary fetuin-A excretion (r = –0.48; each p < 0.001). The fractional excretion of fetuin-A was significantly associated with the degree of proteinuria and serum fetuin-A levels. However, the urinary loss of fetuin-A and albumin in nephrotic children differed by three orders of magnitude and the mean fractional excretion of fetuin-A was only 1/10 of that of albumin (0.016 ± 0.029 vs. 0.162 ± 0.403%; p < 0.001). Conclusions: Fetuin-A is clearly reduced in children with nephrotic syndrome and associated with the degree of hypoalbuminemia. This is due to urinary fetuin-A loss and/or reduced hepatic synthesis. Persistent fetuin-A deficiency may have an impact on cardiovascular morbidity in nephrotic children.