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Seasonal blood pressure (BP) variation is mostly found between the summer and winter months. Guidelines for diagnosis and treatment of hypertension in children have not considered this variation until recently. This review aims to present an overview of seasonal BP variation in childhood along with potential underlying pathophysiological mechanisms and long-term implications as well as conclusions for future studies. In pediatric cohorts, seven studies investigated seasonal changes in BP. These changes amount to 3.4-5.9 mmHg (or 0.5-1.5 mmHg per - 1 °C difference in environmental temperature) in systolic BP with a peak in fall or winter. Potential mechanisms and mediators of seasonal BP variation include sympathetic activation of the nervous system with an increase of urinary and plasma norepinephrine levels in the winter season. Additionally, the physical activity among children and adolescents was inversely correlated with BP levels. Temperature sensitivity of BP and pediatric BP levels predict future systolic BP and target-organ damage. Therefore, cardiovascular events may even be long-term complications of seasonal BP variation in pediatric hypertensive patients. Overall, these data strongly suggest an important effect of ambient temperature on BP in children. Additional studies in pediatric cohorts are needed to define how best to incorporate such variation into clinical practice., Author(s): Niels Ziegelasch [sup.1] , Mandy Vogel [sup.1] [sup.2] , Werner Siekmeyer [sup.1] , Heiko Billing [sup.1] , Ingo Dähnert [sup.3] , Wieland Kiess [sup.1] [sup.2] [sup.4] Author Affiliations: (1) [...]

Background Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). Methods Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. Results The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. Conclusion Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment., Author(s): Verena Klämbt [sup.1] , Charlotte Gimpel [sup.2] , Martin Bald [sup.3] , Christopher Gerken [sup.4] , Heiko Billing [sup.5] , Sebastian Loos [sup.6] , Matthias Hansen [sup.7] , Jens [...]

Author(s): Verena Klämbt [sup.1] , Charlotte Gimpel [sup.2] , Martin Bald [sup.3] , Christopher Gerken [sup.4] , Heiko Billing [sup.5] , Sebastian Loos [sup.6] , Matthias Hansen [sup.7] , Jens [...]

Background Endothelial cell injury plays a key role in the pathogenesis of lupus nephritis (LN) and atherosclerosis. The aim of this study was to identify factors involved in the process of endothelial damage in children and adolescents with LN. Methods We evaluated the relationship between plasma vascular endothelial growth factor (VEGF), its soluble receptors sVEGFR-1 and sVEGFR-2 and markers of endothelial inflammation and injury (angiopoietin-2 and thrombomodulin, respectively) in 23 children and adolescents with LN (active LN, n=14; inactive LN, n =9; mean age 15 years) and 20 healthy controls (HC; mean age 12 years). Results VEGF, sVEGFR-1, angiopoietin-2 and thrombomodulin levels were significantly higher in children and adolescents with active LN thaninpatientsinremission or HC. In active LN, however, VEGF was inversely relatedtosVEGFR-1 (r=-0.802,p Conclusions sVEGFR-1 may play an important role in promoting endothelial damage in children and adolescents with active LN and could possibly be used to monitor disease severity. Keywords Endothelial injury * Lupus nephritis * SLEDAI-2 K * Soluble VEGF receptors * Vascular endothelial growth factor, Introduction Endothelial cell injury is a characteristic feature of lupus nephritis (LN) [1, 2]. Increased endothelial cell apoptosis [3], endothelial dysfunction and inflammation [4-6], all of which are frequently present [...]

Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, RANTES), complement (Bb, C1q, C3d-CIC, C5a) and endothelial cell activation (sVCAM-1) in children with LN (n=22, mean age 14.8 ± 4.7 years), nephrotic syndrome (n = 13) and age-matched healthy controls (n=20) to define parameters that correlate with LN activity. Complement fragments of the alternative (Bb, p=0.0004) classical (C3d-CIC, p Keywords Anti-C1q antibodies * B cell activating factor * C1q * Complement activation products * Lupus nephritis * Soluble VCAM-1 * RANTES, Introduction Childhood lupus nephritis (LN) remains a significant diagnostic and therapeutic challenge due to its complex etiopathogenesis, heterogeneous presentation, and unpredictable course. A complex interplay between abnormally activated B and [...]

Children with X-linked hypophosphatemic rickets (XLH) are prone to severe stunting. A multicenter mixed-longitudinal study was conducted to assess age-related stature, sitting height, arm and leg length in XLH patients on continuous treatment with phosphate and calcitriol. Mean standard deviation scores (SDS) for all body dimensions were markedly reduced and differed significantly among each other at the initial and subsequent evaluations (baseline: stature -2.48 SDS; sitting height -0.99 SDS; arm length -1.81 SDS; leg length -2.90 SDS; each p < 0.001). A strong association between stature and leg length ([r.sup.2] = 0.87, p < 0.001) was noted. Leg length SDS decreased progressively during childhood (2-9 years) and adolescence (12-15 years; each p < 0.001). Sitting height SDS increased significantly during late childhood, indicating uncoupled growth of the legs and trunk and resulting in an ever increasing sitting height index (i.e. ratio of sitting height to stature; age 2 years 2.0 SDS; age 10 years 3.3 SDS; p < 0.001) that was associated with the degree of stunting ([r.sup.2] = 0.314, p < 0.001). Mean serum phosphate levels were positively associated with stature and leg length, but negatively with sitting height index. Based on these results, we can conclude that growth of the legs and trunk is uncoupled in XLH and related to serum phosphate levels. Keywords Anthropometry * Disproportion * Linear growth * Puberty * X-linked hypophosphatemic rickets, Introduction X-linked hypophosphatemic rickets (XLH, MIM #307800) is an inherited disorder of phosphate homeostasis characterized by short stature, rickets, osteomalacia, hypophosphatemia, aberrant phosphate reabsorption, and suppressed 1 a-hydroxylation of 25(OH) [...]

Byline: Heiko Billing (1), Dominik Muller (1), Rainer Ruf (2), Anne Lichtenberger (2), Friedhelm Hildebrandt (2), Christian August (3), Uwe Querfeld (1), Dieter Haffner (1) Keywords: Focal segmental glomerulosclerosis; Podocin; NPHS2 gene; Proteinuria; Nephrotic syndrome Abstract: Mutations in the NPHS2 gene encoding podocin are associated with steroid-resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal transplantation (RTx). A 4-year-old girl with infantile SRNS was started on peritoneal dialysis because of end-stage renal disease due to FSGS. Mutational screening of the patient and her parents revealed a novel single nucleotide deletion in exon 8 of the NHPS2 gene (948delT), for which the patient was homozygous and her parents confirmed heterozygous asymptomatic carriers. At the age of 4.5 years the patient received a renal graft from her mother. On day 7 after RTx, the patient developed progressive proteinuria (urine protein/creatinine ratio 2.4 g/g), which responded within 1 week to prednisone pulse therapy, an increased cyclosporin A dosage, and ramipril therapy. The patient has maintained stable graft function and no further recurrence of proteinuria has been observed. In conclusion, patients with SRNS due to NPHS2 mutations are not protected from recurrence of proteinuria after RTx. The quick response to increased immunosuppression in our patient suggests an immune-mediated pathomechanism for recurrence of proteinuria. Author Affiliation: (1) Department of Pediatric Nephrology, Charite Hospital, Augustenburger Platz 1, 13353 Berlin, Germany (2) Department of Pediatrics, University of Michigan, Ann Arbor, USA (3) Institute of Pathology, University of Munster, Germany Article History: Registration Date: 23/12/2003 Received Date: 30/09/2003 Accepted Date: 08/12/2003 Online Date: 10/03/2004

Purpose: Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN)., Methods: The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow cytometry. Intracellular expression of IL-17 and INF-γ was assessed after stimulation with anti-CD3 and anti-CD28. Serum concentrations of IP10, CCL2, TGF-β, IL-17, and IL-23 were measured by ELISA. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index 2000 update (SLEDAI-2K)., Results: Children with active LN displayed increased frequencies of effector memory CD4(+)CD45RO(+)CCR7(-) and terminal differentiated CD4(+)CD45RA(+)CCR7(-) T cells and reduced naive CD4(+)CD45RA(+)CCR7(+) T cells compared to those with inactive LN or HC. Circulating CD4(+)CXCR3(+) and CD4(+)CCR2(+) T cells correlated inversely with the renal SLEDAI-2K, whereas IP10 and CCL2 showed a positive correlation. Reduced CD4(+)Foxp3(+) T cells and serum TFG-β levels in active LN were associated with high serum IL-17 and IL-23 levels and correlated inversely with the renal SLEDAI-2K (r = -0.5855, p = 0.0013 and r = -0.6246, p = 0.0005, respectively), whereas IL-17 and IL-23 correlated positively (r = 0.5516, p = 0.0029 and r = 0.6116, p = 0.0007, respectively). Expansion of Th17 and Th1/Th17 cells in children with LN was significantly greater than in HC (p = 0.0304 and p = 0.0067, respectively)., Conclusion: Children with active LN display high levels of pro-inflammatory cytokines associated with an increase in effector T cells and reduction of regulatory T cells. Therapeutic regulation of the aberrant cytokine profile might specifically interrupt pathogenic mechanisms.