Marianne Wigger

Strict blood-pressure control and progression of renal failure in children.

BACKGROUND Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

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.

DEAP-HUS: deficiency of CFHR plasma proteins and autoantibody-positive form of hemolytic uremic syndrome.

DEAP-HUS [Deficiency of CFHR (complement factor H-related) plasma proteins and Autoantibody Positive form of Hemolytic Uremic Syndrome] represents a novel subtype of hemolytic uremic syndrome (HUS) with unique characteristics. It affects children and requires special clinical attention in terms of diagnosis and therapy. DEAP-HUS and other atypical forms of HUS share common features, such as microangiopathic hemolytic anemia, acute renal failure, and thrombocytopenia. However, DEAP-HUS has the unique combination of an acquired factor in the form of autoantibodies to the complement inhibitor Factor H and a genetic factor which, in most cases, is the chromosomal deletion of a 84-kbp fragment within human chromosome 1 that results in the absence of the CFHR1 and CFHR3 proteins in plasma. Special attention is required to diagnose and treat DEAP-HUS patients. Most patients show a favorable response to the reduction of autoantibody titers by either plasma therapy, steroid treatment, and/or immunosuppression. In addition, in those DEAP-HUS patients with end-stage renal disease, the reduction of autoantibody titers prior to transplantation is expected to prevent post-transplant disease recurrence by aiming for full complement control at the endothelial cell surface in order to minimize adverse complement and immune reactions.

Epidemiology and Morbidity of Epstein-Barr Virus Infection in Pediatric Renal Transplant Recipients: A Multicenter, Prospective Study

BACKGROUND The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. METHODS In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationship between EBV load, EBV serology, and EBV-related morbidity (posttransplant lymphoproliferative disease [PTLD] or symptomatic EBV infection, defined as flu-like symptoms or infectious mononucleosis). RESULTS EBV primary infection occurred in 27 of 43 (63%) seronegative patients and reactivation/reinfection in 28 of 63 (44%) seropositive patients. There was no association between the degree or duration of EBV load and EBV-related morbidity: The vast majority (17 of 18 [94%]) of patients with a high, persistent EBV load remained PTLD-free throughout a follow-up of 5.0 ± 1.3 years, while 2 of 3 (66%) patients with EBV-related PTLD exhibited only a low EBV load beforehand. Eight of 18 (44%) patients with a high, persistent EBV load remained asymptomatic during a follow-up of 5.3 ± 2.9 years. Multivariate analysis identified the EBV high-risk (D(+)/R(-)) serostatus (odds ratio [OR], 7.07; P < .05), the presence of human leukocyte antigen (HLA)-DR7 (OR, 5.65; P < .05), and the intensity of the immunosuppressive therapy (OR, 1.53; P < .01) as independent risk factors for the development of a symptomatic EBV infection. CONCLUSIONS Presence of EBV high-risk seroconstellation, HLA-DR7, and intensity of immunosuppressive therapy are significant risk factors for a symptomatic EBV infection, whereas there is no close association between the degree or duration of EBV load and EBV-related morbidity. Clinical Trials Registration. NCT00963248.

Assessment of the cardiovascular system in pediatric chronic kidney disease: a pilot study

Long-term survival of children and adolescents with chronic kidney disease (CKD) is mainly limited by cardiovascular disease. Pediatric CKD patients (n = 26) on conservative treatment, dialysis and after renal transplantation were compared with healthy controls (n = 24) with respect to cardiovascular status. Mean baseline diameter of the brachial artery was significantly higher, and mean flow-mediated vasodilation (FMD) was significantly reduced, in CKD patients. CKD patients showed significantly increased left ventricular mass index, blood pressure (BP) values and age-related values of mean carotid intima-media thickness [intima-media thickness–standard deviation score (IMT-SDS)] compared with those of controls. Approximately 60% of patients presented with impaired FMD (≤ 5.79%), which was significantly associated with intima-media thickening, although only three patients (12%) presented with both, impaired FMD and increased age-related IMT. The latter was significantly associated with higher values for day-time BP. In contrast, duration and degree of CKD, mode of renal replacement therapy, homocysteine levels and concomitant medication showed no association with cardiovascular status. The majority of our pediatric CKD patients showed reduced endothelial function, which may have preceded the development of carotid arteriopathy. Therefore, routine assessment of FMD may be a useful tool to identify CKD patients at risk of progressive cardiovascular morbidity.

Estimated one-yr glomerular filtration rate is an excellent predictor of long-term graft survival in pediatric first kidney transplants

Abstract:  Acute rejection episodes following pediatric renal transplantation have been progressively reduced by recent immunosuppressive regimens. Nevertheless, grafts continue to fail over time and surrogate parameters for long‐term RGS are lacking. We investigated post‐transplant renal function within the first yr as an independent predictor of long‐term RGS in 104 pediatric first kidney transplant recipients (mean age 11.1 ± 3.9 yr; mean follow‐up 8.3 ± 3.5 yr) transplanted between January 1989 and December 2000. GFR was assessed by use of the Schwartz formula at 30 days and six and 12 months after transplantation, respectively. Patients were further stratified at all times according to GFR: (i) GFR<45 mL/min/1.73 m2, (ii) GFR 45–80 mL/min/1.73 m2, and (iii) GFR>80 mL/min/1.73 m2. Cox regression analysis including factors potentially influencing long‐term RGS, e.g., age, gender, transplant yr, HLA‐mismatch, underlying renal disease, clinical acute rejection, absolute GFR as well as the change in GFR within the first yr was performed. Graft failure occurred in 24 out of 104 patients (23%) 6.2 yr (mean) after transplantation corresponding to a cumulative five‐yr graft survival of 87.5%. GFRs at 30 days and six and 12 months were significantly associated with long‐term RGS in the univariate cox regression analysis (GFR at 30 days, p = 0.045; GFR at six months, p = 0.004; GFR at 12 months, p < 0.001). None of the other variables were significant parameters of correlation. Multivariate cox analysis revealed a GFR below 45 mL/min/1.73 m2 at 12 months after transplantation as the only independent predictor of long‐term RGS (hazard ratio 55.9, 95% CI 5.29–591, p = 0.001). GFR at 12 months post‐transplant is an excellent surrogate parameter for long‐term RGS in children. This parameter might be useful as a primary end‐point in short‐term pediatric clinical trials.

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.

Effect of alcohol consumption on the liver detoxication capacity as measured by [13C]methacetin- and [methyl-13C]methionine-breath tests

The aim of this study was to investigate the hepatic microsomal and mitochondrial functions by using the 13CO2-breath test in healthy subjects either before or after the consumption of red wine. Fourteen adults received [13C]methacetin and [methyl-13C]methionine together with a standardised dinner. Expired air samples were taken over 6 h. After a wash-out period, the subjects consumed 0.4 ml ethanol/kg/day together with dinner over a 10-day period. Thereafter, 13C-tracer administration was repeated under identical conditions. The 13CO2-enrichments were measured by isotope ratio mass spectrometry. The mean cumulative percentage 13C-dose recovery (CPDR) after administration of [13C]methacetin and [methyl-13C]methionine either without or with red wine consumption amounted to 38.2±6.3 vs. 36.3±6.7% (p=0.363) and 9.5±3.3 vs. 8.8±2.5% (p=0.47), respectively. Moderate alcohol consumption does not induce significant short-term changes of the microsomal and the mitochondrial functions of the human liver in healthy subjects.

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.

Metabolic Effects of HAY's Diet

Abstract The aim of the study was, to evaluate the metabolic effect of HAYs diet on protein turnover, fat oxidation, respiratory quotient, body fat and weight loss. Twelve healthy adults received an individually regular diet and thereafter a corresponding isocaloric and isonitrogenous 10-day HAY-diet. Protein turnover and 13C-fat oxidation were investigated after administration of [15N]glycine and an [U-13C]algae lipid mixture. The 15N and 13C enrichment in urine and breath were measured by isotope ratio mass spectrometry. The respiratory quotient was measured by indirect calorimetry. Body fat, total body water and lean body mass were estimated by bio-electric impedance analysis. HAYs diet led to a significantly higher 13C-fat oxidation (15.4 vs. 22.0% P < 0.01), corresponding to a lower respiratory quotient (0.88 vs. 0.81; P < 0.01), whereas the protein turnover remained constant in both diets (3.06 vs. 3.05 g/kg/day). HAYs diet did not reduce total body water, lean body mass, body fat and body weight (72.2 vs. 71.4 kg).