Priyanka Khandelwal

Association of early postnatal growth trajectory with body composition in term low birth weight infants.

Growth acceleration or catch-up growth (CUG) in early infancy is a plausible risk factor for later obesity and cardiovascular disease. We postulate that this risk may be mediated by an adverse programming of body composition by CUG in early infancy. The study was aimed at evaluating the association between the pattern of gain in weight and length of term low birth weight (LBW) infants from birth to 6 months, with fat mass percent (FM%) at 6 months. Term healthy singleton LBW infants were enrolled. Babys weight and length z-scores were measured at birth and three follow-up visits. Body composition was measured by dual-energy absorptiometry at last visit. A total of 54 babies (28 boys) were enrolled. The mean birth weight and gestation were 2175±180 g and 37.6±0.6 weeks. Follow-up visits were at 1.4±0.0, 3.0±0.3 and 7.2±0.8 months. The proportion of babies who showed CUG [increase in weight for age z-score (∆WAZ)>0.67] from birth to 1.4, 3.0 and 7.2 months was 29.6, 26.4 and 48.5%, respectively. The mean FM% at 7.2 months was 16.6±7.8%. Infants with greater ∆WAZ from birth to 3 and 7.2 months had significantly greater FM% at 7.2 months after adjusting for current age, size and gender. Infants with early CUG (<1.4 months) had higher FM% than infants with no CUG. We conclude that earlier and greater increment in WAZ is positively associated with FM%.

Outcomes of renal transplant in patients with anti-complement factor H antibody-associated hemolytic uremic syndrome.

Atypical HUS associated with anti‐CFH autoantibodies is an uncommon illness associated with high risk of progression to end‐stage renal disease. Disease relapses after transplantation, observed in one‐third cases, often lead to graft loss. We report four patients with anti‐CFH antibody‐associated HUS who underwent renal transplantation 16–62 months from initial presentation. Two patients each received organs from deceased and living‐related donors. Anti‐CFH antibody titers were monitored during the illness and following transplantation. All patients received two doses of IV rituximab before or after transplantation; three patient each received 1–2 g/kg of IV immunoglobulin or underwent 2–5 sessions of plasma exchanges. The use of therapeutic plasma exchange, IV immunoglobulin, and rituximab in two cases enabled two‐third reduction in anti‐CFH antibody titers before transplantation. At 5‐ to 26‐month follow‐up, all patients showed satisfactory graft function without recurrence of HUS. This is the first report of patients with anti‐CFH antibody‐associated HUS who underwent living‐related renal transplantation. Clearance of anti‐CFH antibody by therapeutic plasma exchange and adjuvant immunosuppression aimed at decreasing antibody levels may enable successful transplantation and recurrence‐free survival.

Characterization of genetic predisposition and autoantibody profile in atypical haemolytic-uraemic syndrome

We previously reported that Indian paediatric patients with atypical haemolytic–uraemic syndrome (aHUS) showed high frequencies of anti‐complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH‐related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3–/–). We now report that Indian paediatric aHUS patients without anti‐FH autoantibodies also showed modestly higher frequencies of the FHR1/3–/– genotype. Further, when we characterized epitope specificities and binding avidities of anti‐FH autoantibodies in aHUS patients, most anti‐FH autoantibodies were directed towards the FH cell‐surface anchoring polyanionic binding site‐containing C‐terminal short conservative regions (SCRs) 17–20 with higher binding avidities than for native FH. FH SCR17–20‐binding anti‐FH autoantibodies also bound the other cell‐surface anchoring polyanionic binding site‐containing region FH SCR5–8, at lower binding avidities. Anti‐FH autoantibody avidities correlated with antibody titres. These anti‐FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3–/– genotype. Our data suggest a complex matrix of interactions between FHR1‐FHR3 deletion, immunomodulation and anti‐FH autoantibodies in the aetiopathogenesis of aHUS.

Mutations in membrane cofactor protein (CD46) gene in Indian children with hemolytic uremic syndrome

Abstract Background Mutations in the CD46 gene account for an important proportion of patients with atypical hemolytic uremic syndrome (aHUS) who characteristically show multiple relapses, no response to plasma exchange and low recurrence risk in allograft. We screened for mutations in CD46 in patients with and without circulating anti-factor H (FH) antibodies–associated aHUS. Methods We estimated CD46 surface expression by flow cytometry and sequenced the CD46 gene in 23 and 56 patients with and without circulating anti-FH antibodies, respectively. Human Splicing Finder and PolyPhen2 were used for in silico prediction of pathogenicity. Results Two novel and three known (c.286 +2T > G, c.104G > A and c.565T > G) mutations in CD46 were found in nine (11.4%) patients; one patient had a variant of unknown significance and two patients presented during the first year of life. Novel intronic (c.1127 + 46C > G) and exonic (c.911C > T) mutations are proposed to activate cryptic splicing sites or alter protein conformation. Markedly reduced CD46 surface expression was found in homozygous states in five patients. Conclusion Patients with mutations in CD46 present at all ages, including the first year of life. Mutations in intron 2, (c.286 +2T > G) may be a potential hot spot in Indian children. Flow cytometry for CD46 expression is a satisfactory screening tool enabling early diagnosis.