Posttransplant Lymphoproliferative Disorder: Experience from a Pediatric Nephrology Unit in North India.

Posttransplant lymphoproliferative disorder (PTLD) is reported in 1%-3% among pediatric renal allograft recipients. We report the experience of PTLD among pediatric renal allograft recipients at a pediatric nephrology center in North India. Four cases of PTLD were identified from among records of 95 pediatric renal allograft recipients over a period of 21 years. Constitutional and localizing symptoms were present in three patients each. The diagnosis was suggested on positron emission tomography in three patients and confirmed by histopathology in all. Sites affected included tonsils, cervical lymph nodes, duodenum, and para-aortic lymph nodes in one patient each. The lymphocytic infiltrate was polymorphic in three patients and monomorphic in one. Immunostaining suggested B-cell origin in all patients. There was evidence of Epstein-Barr virus infection in only one patient. The patients were successfully managed with reduction of immunosuppression (in all), rituximab (in 3), and excision of affected tissue (in 1). Over a follow-up period of 30-88 months, there were no episodes of disease recurrence or allograft rejection, and renal function was preserved.

Cardiovascular outcomes of Nephrotic syndrome in childhood (CVONS) study: a protocol for prospective cohort study.

BACKGROUND: Nephrotic syndrome (NS) is characterized by dyslipidemia which is a well-known risk factor for atherogenesis. Atherosclerosis in childhood is mostly subclinical and endothelial dysfunction is known to precede this. Evidence for screening for endothelial dysfunction and cardiovascular risk factors and early identification of premature onset of atherosclerosis in childhood NS remains tenuous in the absence of well-designed prospective studies addressing cardiovascular comorbidity in NS. The objective of our study is to examine endothelial dysfunction and short-term cardiovascular outcomes in a carefully phenotyped cohort of patients with Nephrotic syndrome as compared to healthy controls. METHODS: In a multi-centric prospective cohort study, 70 Steroid Resistant NS (SRNS), 70 Steroid Sensitive (SSNS) patients along with 70 Healthy Controls are being recruited. After a baseline assessment of functional and structural status of heart (2D Echocardiography), arteries (Carotid Doppler and Intima Media Thickness measurements) and microcirculation [a combination of 2D Echocardiography, Laser Doppler Flowmetry (LDF) and Brachial Artery Flow mediated dilation (FMD) and Nail Fold Capillaroscopy (NFC)], the patients are being investigated for endothelial dysfunction. Venous blood sample (15 ml) is being collected for routine investigations and assay of biochemical endothelial markers through Flow Cytometry. The patients will be followed up at 12 months and 24 months after the recruitment to look for any change from baseline period. DISCUSSION: This study will able to provide a better understanding of the epidemiology of endothelial dysfunction and associated subclinical cardiovascular co-morbidity in childhood NS. Findings on characterization of prevalence of endothelial dysfunction and subclinical markers may be used to design future randomized controlled trials for evaluating the efficacy of preventive and therapeutic interventions in reducing the incidence of cardiovascular disease.

Fluoride-associated ultrastructural changes and apoptosis in human renal tubule: a pilot study.

The susceptibility of the kidneys to fluoride toxicity can largely be attributed to its anatomy and function. As the filtrate moves along the complex tubular structure of each nephron, it is concentrated in the proximal and distal tubules and collecting duct. It has been frequently observed that the children suffering from renal impairments also have some symptoms of dental and skeletal fluorosis. The findings suggest that fluoride somehow interferes with renal anatomy and physiology, which may lead to renal pathogenesis. The aim of this study was to evaluate the fluoride-associated nephrotoxicity. A total of 156 patients with childhood nephrotic syndrome were screened and it was observed that 32 of them had significantly high levels ( p ≤ 0.05) of fluoride in urine (4.01 ± 1.83 ppm) and serum (0.1 ± 0.013 ppm). On the basis of urinary fluoride concentration, patients were divided into two groups, namely group 1 (G-1) ( n = 32) containing normal urine fluoride (0.61 ± 0.17 ppm) and group 2 (G-2) ( n = 32) having high urine fluoride concentration (4.01 ± 1.83 ppm). Age-matched healthy subjects ( n = 33) having normal levels of urinary fluoride (0.56 ± 0.15 ppm) were included in the study as control (group 0 (G-0)). Kidney biopsies were taken from G-1 and G-2 only, who were subjected to ultrastructural (transmission electron microscopy) and apoptotic (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling) analysis. Various subcellular ultrastructural changes including nuclear disintegration, chromosome condensation, cytoplasmic ground substance lysis, and endoplasmic reticulum blebbing were observed. Increased levels of apoptosis were observed in high fluoride group (G-2) compared to normal fluoride group (G-1). Various degrees of fluoride-associated damages to the architecture of tubular epithelia, such as cell swelling and lysis, cytoplasmic vacuolation, nuclear condensation, apoptosis, and necrosis, were observed.

Acute phase response in lame crossbred dairy cattle.

AIM: The study was undertaken to study acute phase response based on acute phase proteins (APPs) such as C-reactive protein (CRP), haptoglobin (Hp), serum amyloid A (SAA), and fibrinogen in lame crossbred dairy cattle. MATERIALS AND METHODS: Lame animals (n=30) were selected within 3-7 days of being noticed as lame by the farm veterinarian, from a local dairy farm in southeast Ludhiana over a period of 6 months, stratified proportionately with respect to stage of lactation with non-lame healthy cows (n=10). All the cows were otherwise healthy and did not have any other inflammatory problems such as pneumonia, enteritis, mastitis, or any kind of acute uterine inflammation. Blood samples were collected from all the animals; serum and plasma samples were separated and stored at -20°C. The levels of CRP, Hp, and SAA were estimated using Sandwich ELISA, whereas fibrinogen was estimated by heat precipitation method. RESULTS: SAA levels in lame cows were significantly higher (22.19±0.85 µg/ml), approximately 3 times as compared to non-lame cows (8.89±0.72 µg/ml), whereas serum Hp concentration was approximately 20 times higher in the lame cattle (21.71±3.32 mg/dl) as compared to non-lame cows (1.17±0.07 mg/dl). Fibrinogen also increased in the lame cattle (3.97±0.22 g/L) as compared to non-lame group (1.40±0.17 g/L). Serum CRP levels analyzed in the lame cattle for the first time in the present study, and significant high concentration was appreciated in lame cattle (4.41±0.33 mg/L) as compared to non-lame cattle (0.61±0.14 mg/L). Lame cattle were having more of sole hemorrhages, sole ulcers, and white line lesions as compared to non-lame cattle. CONCLUSION: It can be concluded that lame cattle exhibit high levels of APPs including CRP, Hp, SAA, and fibrinogen as compared to non-lame cattle.

Idiopathic collapsing glomerulopathy: A clinicopathologic analysis of 30 cases.

Collapsing glomerulopathy (CG) is a distinct clinicopathologic entity associated with various infections, medications and acute ischemia. There have been few scattered reports of CG from India. This study aimed at evaluating the clinicopathologic features of idiopathic CG in Indian patients with comparison between adult-onset and childhood CG. This study included all cases of idiopathic CG diagnosed over a period of 4 years (2006-2009). Appropriate clinical details and laboratory findings were retrieved. Renal biopsies were reviewed and detailed pathologic features assessed. Statistical analysis was performed to compare various features between adult-onset and childhood CG. Over these 4 years, 30 cases of idiopathic CG were diagnosed. Of these, 11 were children. Childhood CG cases had longer duration of symptoms and lower serum urea and creatinine levels compared with adult patients. In renal histology, tubular atrophy and interstitial fibrosis was frequent in our cases. Pediatric cases of CG showed a higher proportion of segmental glomerulosclerosis. On clinical follow-up, nine of the 30 patients progressed to end-stage renal disease and these included two pediatric patients. Idiopathic CG is a significant cause of renal dysfunction in both pediatric and adult patients. Childhood and adult-onset CG differ in few clinicopathologic features. Early and accurate diagnosis of CG is imperative for appropriate management of these patients.

Revised guidelines on management of antenatal hydronephrosis.

Widespread antenatal screening has resulted in increased detection of anomalies of the kidneys and urinary tract. The present guidelines update the recommendations published in 2000. Antenatal hydronephrosis (ANH) is transient and resolves by the third trimester in almost one-half cases. The presence of oligohydramnios and additional renal or extrarenal anomalies suggests significant pathology. All patients with ANH should undergo postnatal ultrasonography; the intensity of subsequent evaluation depends on anteroposterior diameter (APD) of the renal pelvis and/or Society for Fetal Urology (SFU) grading. Patients with postnatal APD exceeding 10 mm and/or SFU grade 3-4 should be screened for upper or lower urinary tract obstruction and vesicoureteric reflux (VUR). Infants with VUR should receive antibiotic prophylaxis through the first year of life, and their parents counseled regarding the risk of urinary tract infections. The management of patients with pelviureteric junction or vesicoureteric junction obstruction depends on clinical features and results of sequential ultrasonography and radionuclide renography. Surgery is considered in patients with increasing renal pelvic APD and/or an obstructed renogram with differential renal function <35-40% or its subsequent decline. Further studies are necessary to clarify the role of prenatal intervention, frequency of follow-up investigations and indications for surgery in these patients.

Calcineurin inhibitor induced nephrotoxicity in steroid resistant nephrotic syndrome.

Prolonged therapy with calcineurin inhibitors (CNI) is effective in patients with difficult nephrotic syndrome. However, information on prevalence and risk factors for nephrotoxicity in children with steroid-resistant nephrotic syndrome is limited. This retrospective observational study was conducted on 40 patients with steroid-resistant nephrotic syndrome treated with cyclosporine (CyA) (n = 28) or tacrolimus (n = 12) for more than 2 years. Nephrotoxicity was defined by the presence of striped fibrosis involving ≥10% of the interstitium or nodular hyalinosis in more than one arteriole. Ten additional parameters were graded semi-quantitatively. Continuous data are presented as median and interquartile range (IQR). The median (IQR) age at onset of nephrotic syndrome and CNI therapy were 30 (21-45) and 49.5 (40-102.5) months. A second renal biopsy, following 30 (26-35) months of CNI therapy, showed histological toxicity in 10 (25%) patients. Toxicity was seen in 7 and 3 patients receiving CyA and tacrolimus, respectively, and 5 patients each with minimal change and focal segmental glomerulosclerosis. Therapy with CNI was associated with significant increases in scores for global glomerulosclerosis, tubular atrophy, interstitial fibrosis, nonnodular arteriolar hyalinosis (P < -0.001 for all), arteriolar smooth-muscle vacuolization (P = -0.02), juxtaglomerular hyperplasia (P = -0.002), and tubular microcalcinosis (P = -0.06). Risk factors for nephrotoxicity were initial resistance (OR 9; 95% CI 1.0-80.1; P = -0.049); dose of CyA (OR 9.2; 95% CI 1.1-74.6; P = -0.037); duration of heavy proteinuria (OR 1.2; 95% CI 1.0-1.4; P = -0.023); and hypertension during therapy (OR 6; 95% CI 1.3-28.3; P = -0.023). Following prolonged CNI therapy, one in four biopsies show features of toxicity. Prolonged duration of heavy proteinuria, hypertension, initial steroid resistance and high CyA dose predict the occurrence of nephrotoxicity.

Common mutation underlying primary hyperoxaluria type1 in three Indian children.

Primary hyperoxaluria is an autosomal recessive disorder caused by deficiency of alanine-glyoxylate aminotransferase, which is encoded by the AGXT gene. We report three Indian children with primary hyperoxaluria type1 having a common mutation in this gene. All patients had evidence of chronic kidney disease at the time of diagnosis, with subsequent progression to end-stage renal disease. The detection of an identical mutation in the AGXT gene suggests that specific genetic screening for this mutation may be useful when considering the diagnosis of primary hyperoxaluria type1.

Giant cell transformation of podocytes: A unique histological feature associated with cystinosis.

Fanconi's syndrome is an unusual cause of renal insufficiency in pediatric patients. Infantile cystinosis is one of the identifiable and treatable etiologies of Fanconi's syndrome. Early diagnosis of cystinosis permits institution of specific therapy with cysteamine. A 3-year-old girl presented with failure to thrive, polyuria, and polydipsia. She was found to have renal tubular defect with renal dysfunction and bilateral small contracted kidneys. A renal biopsy revealed extensive giant cell transformation of podocytes in the glomeruli with focal tubular atrophy and dilatation. However, no crystals were identified. Subsequent ophthalmoscopic examination revealed fine cystine crystals in the cornea and a diagnosis of cystinosis causing Fanconi's syndrome was made. Polykaryocytic transformation of visceral epithelial cells is an important diagnostic clue of nephropathic cystinosis and should be carefully looked for in renal biopsy from a child with Fanconi's syndrome and renal insufficiency.

Physical growth in children with reflux nephropathy with normal or mildly impaired renal function.

Ten children aged 11 months to 10 years (means 5.7 years) with reflux nephropathy, vesicoureteric reflux (VUR) and normal or mildly impaired renal function having GFR more than 50 ml/min/1.72 m(2), were included in the study. The hematological and biochemical parameters were within normal limits. Height standard deviation score (HZ score) was reduced at entry and, decreased further during follow-up (-2.2 and -2.6 at 0 and 12 months, respectively). Weight for height index (WHI) improved significantly (p=0.0004) during follow-up. The basal and stimulated peak growth hormone levels of these patients were found to be elevated, 18.53 +/- 11.36 microg/L and 34.20 +/- 5.86 microg/L, respectively. The IGF-1 levels were low ranging from 45.00 to 84.40 ng/dl (mean +/- SD 61.54 +/- 10.21 ng/dl) compared to 51.80 to 247.50 ng/dl (mean +/- SD111.20 +/- 70.24 ng/dl) in age and sex matched controls, indicating partial insensitivity to growth hormone.

Outcome of lupus nephritis in Indian children.

We report the clinicopathological features, treatment and outcome of 54 Indian children (14 boys) with biopsy-proven lupus nephritis followed over a 10-year period. The mean age (SD) at onset of disease was 9.6 +/- 2.6 (range 2.5-14.4) years. Twenty-six (48.1%) patients had class IV nephritis, 7 (13.0%) had class V, whereas class I, II and III nephritis were present in 3 (5.6%), 10 (18.5%) and 6 (11.1%) patients, respectively. Hypertension, haematuria and nephrotic range proteinuria were present in 30 (55.6%), 31 (57.4%) and 28 (51.8%) patients, respectively. Compared with all the other classes combined, there were more boys among patients with class IV nephritis, and hypertension, haematuria, nephrotic syndrome and decreased glomerular filtration rate at presentation were more common. The mean duration of follow-up was 3.1 +/- 2.9 years (median 2.5, range 0.2-10.3 years). Of the 39 patients who were followed-up for at least 1 year, 33 (84.6%) were in complete or partial remission, whereas six (15.4%) had no response to therapy. The incidence of serious infection was 1.5 episodes per 10 patient-years. Nine patients died, of whom four had serious infections or septicaemia, and three developed end-stage renal failure (ESRF). The patient survival rate at 3 years and at last follow-up visit was 88% and 83.3%, respectively, whereas the renal survival rates (without ESRF) were 92% and 94.4% respectively. Cox regression analysis showed no relation of gender, age of onset, presence of hypertension, haematuria and proteinuria, estimated glomerular filtration rate, renal histology and response to therapy to the outcome of death or ESRF. We found lower patient survival rate as compared with data from the developed countries but similar to that seen in developing countries. Serious infections were an important cause of mortality besides renal failure.

Are therapeutic stem cells justified in bilateral multicystic kidney disease? A review of literature with insights into the embryology.

Aim was to describe the challenges faced in the management of bilateral multicystic kidney disease (MCKD). A case of antenatally detected bilateral polycystic disease was referred at 28 weeks of gestation. The patient was advised to continue pregnancy till term and be in regular follow-up. Postnatally, the male baby passed urine in normal stream and was diagnosed as bilateral multicystic kidney disease on ultrasonography. He developed symptoms of renal failure. The baby was operated with right pyeloplasty and left pyelostomy, as the left ureter was atretic. The histopathology was consistent with bilateral multicystic kidney disease. Postoperatively, the baby was stable with intermittent episodes of metabolic acidosis that were managed medically and with peritoneal dialysis. Autologous stem cells were injected at the age of 1 year into the aorta at the level of the renal arteries clamping the aorta below. Repeat biopsy at time of stem cell injection showed 5/10 glomeruli showing global sclerosis on right side and 5/15 glomeruli showing global sclerosis on left side. The only improvement seen was in decreased doses of medicines to keep the child metabolically stable. The baby kept struggling but succumbed at the age of 17 months and 15 days. Post mortem bilateral renal biopsies demonstrated presence of primitive renal tubules and blastemal cells that were not demonstrated earlier. Survival for few months in bilateral multicystic kidney disease is thus possible with adequate treatment, the novel use of stem cells in these cases may prove beneficial in future though it is too early to comment further.

Multicentric Castleman's disease in two cases.

Castleman's disease is an atypical lymphoproliferative disorder having two types of presentation--the localized and the multicentric form. The localized form presents as a slowly growing mass with a relatively benign course. Multicentric Castleman's disease has a more aggressive clinical course with diffuse lymph node enlargement and systemic illness. It is rarely seen in childhood and only thirteen cases have been reported in literature. This is the first report of 2 cases from the Indian subcontinent with a maximum follow-up of 44 months one of whom had asplenia.

EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides.

BACKGROUND: There has been a lack of appropriate classification criteria for vasculitis in children. OBJECTIVE: To develop a widely accepted general classification for the vasculitides observed in children and specific and realistic classification criteria for common childhood vasculitides (Henoch-Schönlein purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa (PAN), Wegener's granulomatosis (WG), and Takayasu arteritis (TA)). METHODS: The project was divided into two phases: (1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at least 80% of the participants was defined as consensus. RESULTS: Consensus was reached to base the general working classification for childhood vasculitides on vessel size. The small vessel disease was further subcategorised into "granulomatous" and "non-granulomatous." Final criteria were developed to classify a child as HSP, KD, childhood PAN, WG, or TA, with changes introduced based on paediatric experience. Mandatory criteria were suggested for all diseases except WG. CONCLUSIONS: It is hoped that the suggested criteria will be widely accepted around the world because of the reliable techniques used and the international and multispecialist composition of the expert group involved.

T cell Vbeta repertoires in childhood vasculitides.

Superantigens (SAgs) are potent stimulators of T cells bearing specific Vbeta T cell receptors (TCR) and may play a role in the aetiopathogenesis of systemic vasculitis, although this remains contentious. To investigate the possible aetiological role of SAgs, this study examined peripheral blood T cell Vbeta repertoires in children with systemic vasculitis. FACS analysis of 17 different peripheral blood T cell Vbeta families was performed in 20 healthy control children, 27 disease control children with nonvasculitic inflammatory disease, 25 children with primary systemic vasculitis, six patients with Kawasaki disease (KD) and six patients with Henoch-Schönlein purpura (HSP). There was a significantly increased variance of CD4 Vbeta12 and Vbeta17, and CD8 Vbeta1 in the primary systemic vasculitis group compared to control and disease controls. Moreover, 80% of the primary systemic vasculitis children had one or more CD4 Vbeta expansions or deletions, compared with 30% of controls (P < 0.002), and 37% of the disease controls (P < 0.002). In the KD group, the mean percentage of CD4 Vbeta2 T cells was higher than in controls or disease controls. In the HSP group, there was no consistent skewing of the T cell Vbeta repertoire. We have observed changes in the T cell Vbeta repertoire in children with vasculitis over and above those observed in disease controls. While these data provide impetus for further research into this contentious field, they do not resolve unequivocally the question of the role of SAgs in childhood vasculitic syndromes.

Treatment of focal glomerulosclerosis with pulse steroids and oral cyclophosphamide.

Patients with steroid-resistant nephrotic syndrome often have an unsatisfactory long-term outcome and are at risk of developing chronic renal failure. We prospectively treated 65 children with idiopathic steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) with intravenous pulses of corticosteroids and oral cyclophosphamide. Dexamethasone (5 mg/kg) or methylprednisolone (30 mg/kg) was administered intravenously, initially 6 pulses on alternate days, followed by 4 fortnightly and 8 monthly pulses. Oral cyclophosphamide therapy was given for 12 weeks and tapering doses of prednisolone were administered for 52 weeks. The mean age at treatment was 85.7+/- 44.9 months. Five patients developed serious infections during administration of initial alternate-day pulses and were excluded. Of 59 patients who completed initial alternate-day therapy, 17 had complete and 8 partial remission; 34 (57.6%) patients did not respond to treatment. The median urine protein to creatinine ratio decreased from 10.0 to 0.75 (P<0.005) and serum albumin increased from 1.9 g/dl to 2.4 g/dl (P<0.01). The median duration of follow-up after stopping pulse therapy was 25.6 months. Thirty-four patients were followed for more than 3 years (median 4.5 years). Of these, 22 (64.7%) patients had a favorable outcome; persistent complete remission was seen in 15 patients and steroid-responsive relapses in 7. Seven patients had non- nephrotic-range proteinuria, 2 had nephrotic-range proteinuria, and 3 (8.8%) were in chronic renal failure. There was no significant difference in the short- and long-term outcome of patients with initial (n=28) and late resistance (n=31). The outcome in patients receiving intravenous dexamethasone (n=48) or methylprednisolone (n=11) was also similar. The chief side effects included worsening of height standard deviation score (47.4%), transient hypertension (42.5%), and serious infections (18.5%). We conclude that prolonged treatment with intravenous corticosteroids and oral cyclophosphamide is beneficial in patients with steroid-resistant FSGS. Expensive protocols can be successfully modified and used, depending upon the availability of health resources.