Gaurav Kapur

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Treatment of Severe Edema in Children with Nephrotic Syndrome with Diuretics Alone — A Prospective Study

BACKGROUND AND OBJECTIVE Severe edema in children with nephrotic syndrome (NS) may be associated with volume contraction (VC) or volume expansion (VE). Usually, severe edema in children is treated with intravenous (IV) albumin and diuretics, which is appropriate for VC patients. However, in VE patients, this can precipitate fluid overload. The objective of this study was to evaluate treatment of severe edema in NS with diuretics alone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Thirty NS patients with severe edema were enrolled in this prospective study in two phases. VC was diagnosed based on fractional excretion of sodium (FeNa) <1%. VC patients received IV albumin and furosemide. VE patients received IV furosemide and oral spironolactone. On the basis of phase 1 observations, FeNa <0.2% identified VC in 20 phase 2 patients. RESULTS All phase 1 patients had FeNa <1%. Phase 1 patients when reanalyzed based on a FeNa cutoff of 0.2%; it was noted that VC patients had higher BUN, BUN/creatinine ratio, urine osmolality, and lower FeNa and urine sodium compared with VE patients. Similar results were observed in phase 2. VC patients had significantly higher renin, aldosterone, and antidiuretic hormone levels. In phase 2, 11 VE patients received diuretics alone and 9 VC patients received albumin and furosemide. There was no difference in hospital stay and weight loss in VC and VE groups after treatment. CONCLUSIONS FeNa is useful in distinguishing VC versus VE in NS children with severe edema. The use of diuretics alone in VE patients is safe and effective.

Effectiveness of a Multidisciplinary Clinic in Managing Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Long-term outcome of patients with chronic kidney disease (CKD) correlates with adequacy of predialysis care. This is best provided in a multidisciplinary clinic that integrates the services of a nephrologist with other staff. There is limited data about such clinics in children. The Childrens Hospital of Michigan established a Chronic Renal Insufficiency (CRI) clinic in 2002 to provide comprehensive care to children with CKD. These children receive care from a nephrologist, nurse clinician, transplant coordinator, dietician, social worker, and psychologist. The objective of the study was to compare outcome variables between patients from the CRI clinic and a general nephrology clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective chart review of 44 patients with CKD stages 2 to 4, who were managed in the general nephrology clinic (1996-2001, n = 20) or the CRI clinic (2002-2007, n = 24) for 1 yr before starting renal replacement therapy (RRT). Laboratory parameters, growth, and dialysis access type at time of RRT were compared between the two cohorts. RESULTS At RRT, patients from the CRI clinic had better hemoglobin, lower parathyroid hormone and calcium phosphorus product than patients followed in the general nephrology clinic. More patients from the general nephrology clinic had an unplanned initiation of dialysis compared with patients from the CRI clinic (50% versus 10.5%, P < 0.05). CONCLUSIONS This indicates that children followed in a multidisciplinary clinic have better outcome variables and are more likely to achieve K/DOQI targets at initiation of dialysis. They are better prepared for dialysis with electively planned catheter insertion or functioning arteriovenous grafts/fistulae.

Secondary hypertension in overweight and stage 1 hypertensive children: a Midwest Pediatric Nephrology Consortium report.

J Clin Hypertens (Greenwich). 2010;12:34–39. ©2009 Wiley Periodicals, Inc.

Dimercaptosuccinic acid (DMSA) renal scan in the evaluation of hypertension in children

Renal scarring is known to be associated with hypertension. The primary objective of this study was to investigate the prevalence of renal scarring in children referred to our clinic with hypertension. The secondary objective was to compare renal ultrasound (US) examination with dimercaptosuccinic acid (DMSA) renal scan in diagnosing renal scars in these patients. The study included 159 patients who underwent DMSA renal scan as well as renal US for the evaluation of hypertension of unknown etiology. Thirty-three (21%) patients were found to have renal scars; their demographic details, including mean age and gender distribution, were not significantly different from those without renal scars. In comparison with the DMSA renal scan, sensitivity and specificity of renal US in diagnosing renal scars were 36% and 94%, respectively. In our study, in which the prevalence of scarring was 21%, this gave positive predictive and negative predictive values of 63% and 85%, respectively. In conclusion, our study indicates that renal scarring is present in 21% of otherwise healthy children who are evaluated for newly diagnosed hypertension, and renal US is not a sensitive imaging modality to rule out renal scarring.

Catch-up growth in children with late-diagnosed coeliac disease

Anthropometric parameters and catch-up growth were prospectively evaluated in fifty late-diagnosed children with coeliac disease aged 2.25-10 years after 1-4 years of adhering to a strict gluten-free diet (GFD). The anthropometric parameters were expressed as Z scores relative to National Centre for Health Statistics standards using Epi Info 2000 (weight-for-height Z score (WHZ) and height-for-age Z score (HAZ)). Catch-up growth was evaluated by repeated measures. ANOVA, overall significance by an F test and pair-wise comparisons for estimated marginal means using the least significant difference. At the time of enrolment, no significant difference was observed in WHZ and HAZ between children diagnosed before (group 1) or after (group 2) 4 years of age. On follow-up, HAZ was significantly higher in group 1 after the first and third years of the GFD (P=0.04 and 0.02, respectively), with a non-significant increase after completing 4 years of the GFD (P=0.22). Feeding the GFD resulted in an overall significant (F=3.99, P=0.011) increase in HAZ up to 4 years of follow-up. However, the catch-up in height was incomplete, with stunting in sixteen (55.4%) of twenty-nine children after 3 years and in seven (46.6%) of fifteen children after 4 years on the GFD. Pair-wise comparisons demonstrated a linear catch-up growth during the initial follow-up on GFD. Treatment with the GFD did not result in an overall significant increase in WHZ up to 4 years of follow-up (F=1.01, P=0.42). Our results suggest that, in children with late-diagnosed coeliac disease, treatment with a GFD leads to a normalisation of body mass and a significant but incomplete recovery in HAZ during 4 years of follow-up.

Serum prolactin in celiac disease.

Serum prolactin levels (SPL) were estimated in patients with celiac disease (CD), diagnosed as per ESPGAN criteria, on unrestricted gluten containing diet (group 1), as well as those consuming a gluten-free diet (GFD) (group 2). Forty-one children with CD, with 20 cases in group 1 (mean age 5.67 +/- 2.14, range 2.5-10.5 years) and 21 cases in group 2 (mean duration of follow-up 2 years, range 1-4 years), and 41 age- and sex-matched controls were studied. Hyperprolactinemia was defined as serum prolactin > 18 ng/ml in males and > 24 ng/ml in females. Upper gastrointestinal endoscopic biopsy was performed in both study groups for initial and follow-up evaluation. Hyperprolactinemia was detected in all the patients of group 1 and one patient of group 2 who had severe villous atrophy. The SPL in group 1 (mean 48.3 +/- 17.4; range 20-90 ng/ml) and group 2 (mean 18.3 +/- 6.9, range 10-39 ng/ml) was significantly higher compared with the controls (mean 9.3 +/- 4.5; range 2.4-20 ng/ml; p < 0.001). Among the patients with CD, mean SPL in group 1 was significantly higher than in group 2 (p < 0.001). In group 1, there was a positive correlation between SPL and duration of symptoms (p = 0.006, r = 0.768) and age of diagnosis (p < 0.001, r = 0.842). A positive correlation also existed in group 2 between SPL and degree of villous atrophy (p < 0.001, r = 0.71) and lamina propria infiltrate (p < 0.001, r = 0.568). Our results suggest that SPL has a significant correlation with activity of CD. Therefore serum prolactin estimation may provide an additional marker of disease activity in CD and may be a more viable option economically.

Iron supplementation in children with Celiac Disease

Objective : To evaluate the effect of iron supplementation, in addition to gluten free diet (GFD), on hematological profile of children with Celiac Disease (CD).Methods : Children diagnosed as CD as per modified ESPGAN criteria were prospectively evaluated for their hematological profile at the time of their enrolment and after consuming GFD for at least one year. The results were compared with age and sex matched controls. Evaluation of hematological profile included hemoglobin estimation, complete blood counts, peripheral blood smear examination, serum iron, total iron binding capacity (TIBC), and serum ferritin estimation. All the enrolled cases were given iron supplementation in addition to exclusion of gluten from their diet. Repeat intestinal biopsy was performed in all the cases after completing 1 year on GFD.Results : Twenty one children (mean age 6.67 years, range 4 2–11 years) diagnosed as CD who completed at least one year of regular follow up on GFD (mean 1.5 years, range 1 2–2 years) were analysed for their hematological profile at the time of enrolment and after consuming GFD and iron supplementation. At the time of enrolment all the children had hemoglobin level <11 gm%, 78% had microcytic hypochromic anemia and 22% had dimorphic anemia, with lower mean MCV, MCH and serum ferritin levels, and a significantly higher mean TIBC as compared to controls (p <0.001). In the follow up evaluation of these cases on GFD, mean hemoglobin levels were comparable with controls but the cases continued to have lower mean MCV, MCH serum ferritin levels (p <0.05) and higher mean TIBC (p <0.05). Seven children had mild anemia. Serum ferritin levels showed a negative correlation with the grade of villous atrophy and lamina propria infiltrate.Conclusion : Our results suggest that iron deficiency anemia (IDA) is commonly associated with CD and iron deficiency state continues for a longer time even after excluding gluten from the diet and iron supplementation. Apart from offering them GFD rich in iron, early detection and treatment of IDA and prophylactic iron folic acid supplementation will go a long way to optimize their mental and psychomotor functions.

Childhood posterior reversible encephalopathy syndrome: Magnetic resonance imaging findings with emphasis on increased leptomeningeal FLAIR signal

Purpose Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiologic syndrome characterized clinically by headache, seizures, and altered sensorium and radiological changes which are usually reversible. The purpose of this study was to describe the spectrum of magnetic resonance imaging (MRI) findings in childhood PRES, to determine the common etiologies for childhood PRES, and to have an insight into the pathophysiology of PRES. Methods The MRI results of 20 clinically diagnosed cases of PRES between July 2011 and June 2013 were reviewed. The final diagnosis of PRES was based on the clinical presentation and the MRI features at the time of presentation, which resolved on the follow-up imaging. The medical records of the patients were reviewed to determine the underlying medical disease. Results Eight out of the 20 patients included in the study were on cyclosporine or tacrolimus based immunosuppressant therapy for kidney transplant. Four patients had severe hypertension at presentation. The most common MRI finding was high T2-fluid-attenuated inversion recovery (FLAIR) signal in the cortex and subcortical white matter of both cerebral hemispheres, particularly in the parietal and occipital lobes (n = 16). The second most common MRI finding was increased leptomeningeal FLAIR signal (n = 7). Out of seven patients with leptomeningeal signal, five demonstrated leptomeningeal enhancement as well. Four out of these seven patients had no other parenchymal findings. Conclusion Childhood PRES is commonly seen in the setting of immunosuppressant therapy for kidney transplant, severe hypertension and cancer treatment. There was high incidence of increased leptomeningeal FLAIR signal and leptomeningeal enhancement in our study. It supports the current theory of endothelial injury with increased microvascular permeability as the potential pathophysiology of PRES. Also, absence of elevated blood pressure in majority of the patients in our study supports the theory of direct endothelial injury by some agents leading to vasogenic edema.

Hypoxia decreases podocyte expression of slit diaphragm proteins.

Background Chronic hypoxia contributes to progressive tubulointerstitial injury and, consequently, renal failure. However, the effect of hypoxia on glomerular podocytes, which are integral to the slit diaphragm complex and responsible for selectivity of the glomerular filtration barrier, has not been completely determined. Methods Conditionally immortalized mouse podocyte cells were exposed to hypoxic (1% O2) or normoxic (room air) conditions for 24, 48, or 72 hours, after which cell viability was determined by MTT assay. Cells were stained with podocin and phalloidin to determine podocin and intracellular actin distribution. Expression of synaptopodin, CD2-associated protein (CD2AP), NcK, transforming growth factor-β1 (TGF-β1), hypoxia-inducible factor (HIF-1α) were evaluated by real-time polymerase chain reaction. Results Podocytes exposed to hypoxia had significantly reduced viability at 48 (87%) and 72 hours (66%). There was disarrangement of intracellular filament actin by phalloidin staining, a 30% weaker fluorescence intensity by podocin staining, significantly reduced expression of synaptopodin (12%), CD2AP (42%), NcK (38%), and increased expression of TGF-β1 and P-ERK after hypoxia treatment. Conclusion Podocyte exposure to hypoxia leads to reduced viability and SD protein expression, which may explain persistent and/or increasing proteinuria in patients with progressive renal failure. Increased expression of TGF-β1 and P-ERK is associated with apoptosis and fibrosis, which could be the link between hypoxia and glomerular injury.