Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN).

Multinational studies have reported monogenic etiologies in 25%-30% of children with steroid-resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi-gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one-third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1-14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8-11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co-existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent.

Patient- and parent proxy-reported outcome measures for life participation in children with chronic kidney disease: a systematic review.

BACKGROUND: The burden of chronic kidney disease (CKD) and its treatment may severely limit the ability of children with CKD to do daily tasks and participate in family, school, sporting and recreational activities. Life participation is critically important to affected children and their families; however, the appropriateness and validity of available measures used to assess this outcome are uncertain. The aim of this study was to identify the characteristics, content and psychometric properties of existing measures for life participation used in children with CKD. METHODS: We searched MEDLINE, Embase, PsychINFO, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Kidney and Transplant register to August 2019 for all studies that used a measure to report life participation in children with CKD. For each measure, we extracted and analyzed the characteristics, dimensions of life participation and psychometric properties. RESULTS: From 128 studies, we identified 63 different measures used to assess life participation in children with CKD. Twenty-five (40%) of the measures were patient reported, 7 (11%) were parent proxy reported and 31 (49%) had both self and parent proxy reports available. Twenty-two were used in one study only. The Pediatric Quality of Life Inventory version 4.0 generic module was used most frequently in 62 (48%) studies. Seven (11%) were designed to assess ability to participate in life, with 56 (89%) designed to assess other constructs (e.g. quality of life) with a subscale or selected questions on life participation. Across all measures, the three most frequent activities specified were social activities with friends and/or family, leisure activities and self-care activities. Validation data in the pediatric CKD population were available for only 19 (30%) measures. CONCLUSIONS: Life participation is inconsistently measured in children with CKD and the measures used vary in their characteristics, content and validity. Validation data supporting these measures in this population are often incomplete and are sparse. A meaningful and validated measure for life participation in children with CKD is needed.

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

RATIONALE & OBJECTIVE: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD. STUDY DESIGN: An online 2-round Delphi survey in English, French, and Hindi languages. SETTINGS & PARTICIPANTS: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale. ANALYTICAL APPROACH: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically. RESULTS: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals. LIMITATIONS: Most participants completed the survey in English. CONCLUSIONS: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6-dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6-treated patient-derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children.

BACKGROUND: About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non-corticosteroid immunosuppressive medications prolong periods of remission, they have significant potential adverse effects. Currently, there is no consensus about the most appropriate second-line agent in children who are steroid sensitive, but who continue to relapse. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013. OBJECTIVES: To evaluate the benefits and harms of non-corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non-corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility, risk of bias of the included studies and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE. MAIN RESULTS: We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty-seven and 27 studies were at low risk of incomplete and selective reporting respectively. Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29). Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence). Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence). Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on-treatment period (low certainty evidence). Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence). AUTHORS' CONCLUSIONS: New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid-dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long-term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.

Both the rituximab dose and maintenance immunosuppression in steroid-dependent/frequently-relapsing nephrotic syndrome have important effects on outcomes.

Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children.

BACKGROUND: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, response to these agents is limited so newer agents are being assessed for efficacy. This is an update of a review first published in 2004 and updated in 2006, 2010 and 2016. OBJECTIVES: To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). Studies, which enrolled children and adults but in which paediatric data could not be separated from adult data, were also included. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, results were expressed as mean difference (MD) and 95% CI. Data were pooled using the random effects model. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: Twenty-five studies (1063 participants) were included. Fourteen studies were at low risk of bias for sequence generation and allocation concealment. Five and 19 studies were at low risk of performance and detection bias. Fourteen, 14 and 13 studies were at low risk of attrition bias, reporting bias and other bias respectively. Cyclosporin compared with placebo or no treatment may increase the number of participants who achieve complete remission (4 studies, 74 participants: RR 3.50, 95% CI 1.09 to 11.20) or complete or partial remission (4 studies, 74 children: RR 3.15, 95% CI 1.04 to 9.57) by 6 months (low certainty evidence). It is uncertain whether cyclosporin increases the likelihood of worsening hypertension or reduces the likelihood of end-stage kidney disease (very low certainty evidence). CNI compared with IV cyclophosphamide (CPA) may increase the number of participants with complete or partial remission at 3 to 6 months (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13) (low certainty evidence) and probably reduces the number with treatment failure (non response, serious infection, persistently elevated creatinine (1 study, 124 participants: RR 0.32, 95% CI 0.18 to 0.58) (moderate certainty evidence) with little or no increase in serious infections (1 study, 131 participants: RR 0.49, 95% CI 0.16 to 1.56) (moderate certainty evidence). Tacrolimus compared with cyclosporin may make little or no difference to the number who achieve complete or partial remission (2 studies, 58 participants: RR 1.05, 95% CI 0.87 to 1.25) (low certainty evidence) or in the number with worsening hypertension (2 studies, 58 participants: RR 0.41, 95% CI 0.08 to 2.15) (low certainty evidence). Cyclosporin compared with mycophenolate mofetil (MMF) and dexamethasone probably makes little or no difference to the number who achieve complete or partial remission (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) (moderate certainty evidence) and makes little or no difference to the number dying (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) or with 50% reduction in glomerular filtration rate (GFR) (1 study, 138 participants: RR 2.29, 95% CI 0.46 to 11.41) (low certainty evidence). Among children, who have achieved complete remission, tacrolimus compared with MMF may increase the number of children who maintain complete or partial response for 12 months (1 study, 60 children: RR 2.01, 95% CI 1.32 to 3.07) (low certainty evidence). Oral CPA with prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (2 studies, 84 children: RR 1.06, 95% CI 0.61 to 1.87) (low certainty evidence). IV CPA compared with oral CPA (2 studies, 61 children: RR 1.58, 95% CI 0.65 to 3.85) and IV compared with oral CPA plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96) may make little or no difference to the number who achieve complete remission (low certainty evidence). It is uncertain whether rituximab and cyclosporin compared with cyclosporin increases the likelihood of remission because the certainty of the evidence is very low. It is uncertain whether adalimumab or galactose compared with conservative therapy increases the likelihood of remission because the certainty of the evidence is very low. Two studies reported that ACEi may reduce proteinuria in children with SRNS. One study reported that the dual angiotensin II and endothelin Type A receptor antagonist, sparsentan, may reduce proteinuria more effectively than the angiotensin receptor blocker, irbesartan. AUTHORS' CONCLUSIONS: To date RCTs have demonstrated that CNIs may increase the likelihood of complete or partial remission compared with placebo/no treatment or CPA. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.

Persistent Dengue Infection in an Immunosuppressed Patient Reveals the Roles of Humoral and Cellular Immune Responses in Virus Clearance.

Detailed understanding of the roles of humoral and cellular immune responses in sterilizing dengue virus (DENV) infection in humans is required to inform effective vaccine development. We report an unusual case of persistent DENV infection in a lymphopenic renal transplant recipient who was therapeutically immunosuppressed to prevent organ rejection. Following resolution of symptomatic dengue, this patient remained positive for DENV3 RNA in the blood for 4 months and viruric up to 9 months post-infection despite demonstrable levels of serum neutralizing antibodies throughout this period. Full resolution of DENV infection instead coincided with recovery of CD8+ T cell counts during reversal from lymphopenia. Taken collectively, our observations suggest a role for cellular immunity in sterilizing DENV infection in humans. Any dengue vaccine should thus be able to induce both humoral and cellular immunity that respectively prevent symptomatic infection and enable effective viral clearance.

ADPedKD: A Global Online Platform on the Management of Children With ADPKD.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of renal failure. For several decades, ADPKD was regarded as an adult-onset disease. In the past decade, it has become more widely appreciated that the disease course begins in childhood. However, evidence-based guidelines on how to manage and approach children diagnosed with or at risk of ADPKD are lacking. Also, scoring systems to stratify patients into risk categories have been established only for adults. Overall, there are insufficient data on the clinical course during childhood. We therefore initiated the global ADPedKD project to establish a large international pediatric ADPKD cohort for deep characterization. METHODS: Global ADPedKD is an international multicenter observational study focusing on childhood-diagnosed ADPKD. This collaborative project is based on interoperable Web-based databases, comprising 7 regional and independent but uniformly organized chapters, namely Africa, Asia, Australia, Europe, North America, South America, and the United Kingdom. In the database, a detailed basic data questionnaire, including genetics, is used in combination with data entry from follow-up visits, to provide both retrospective and prospective longitudinal data on clinical, radiologic, and laboratory findings, as well as therapeutic interventions. DISCUSSION: The global ADPedKD initiative aims to characterize in detail the most extensive international pediatric ADPKD cohort reported to date, providing evidence for the development of unified diagnostic, follow-up, and treatment recommendations regarding modifiable disease factors. Moreover, this registry will serve as a platform for the development of clinical and/or biochemical markers predicting the risk of early and progressive disease.

MeSsAGe risk score: tool for renal biopsy decision in steroid-dependent nephrotic syndrome.

BACKGROUND: A lack of consensus exists as to the timing of kidney biopsy in children with steroid-dependent nephrotic syndrome (SDNS) where minimal change disease (MCD) predominates. This study aimed at examining the applicability of a biomarker-assisted risk score model to select SDNS patients at high risk of focal segmental glomerulosclerosis (FSGS) for biopsy. METHODS: Fifty-five patients with SDNS and biopsy-proven MCD (n = 40) or FSGS (n = 15) were studied. A risk score model was developed with variables consisting of age, sex, eGFR, suPAR levels and percentage of CD8+ memory T cells. Following multivariate regression analysis, total risk score was calculated as sum of the products of odds ratios and corresponding variables. Predictive cut-off point was determined using receiver operator characteristics (ROC) curve analysis. RESULTS: Plasma suPAR levels in FSGS patients were significantly higher, while percentage of CD45RO+CD8+CD3+ was significantly lower than in MCD patients and controls. ROC analysis suggests the risk score model with threshold score of 16.7 (AUC 0.84, 95% CI 0.72-0.96) was a good predictor of FSGS on biopsy. The 100% PPV cut-off was >24.0, while the 100% NPV was <13.3. CONCLUSION: A suPAR and CD8+ memory T cell percentage-based risk score model was developed to stratify SDNS patients for biopsy and for predicting FSGS.

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS.

BACKGROUND AND OBJECTIVES: Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m(2)) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab. RESULTS: Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154(+)CD4(+)CD3(+) subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%±28.1% versus 78.9%±16.4%; P=0.03). IFN-γ(+)CD3(+) and IL-2(+)CD3(+) were similarly decreased in responders compared with nonresponders (0.6%±0.8% versus 7.5%±6.1%; P=0.003 and 0.2%±0.5% versus 4.0%±4.7%; P<0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154(+)CD4(+)CD3(+), 74.8%±17.2%; IFN-γ(+)CD3(+), 7.1%±7.7%; and IL-2(+)CD3(+), 7.9%±10.9%; P<0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154(+)CD4(+)CD3(+) <83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-γ(+)CD3(+)<2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2(+)CD3(+)<0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response. CONCLUSIONS: We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

Recurrent white thrombi formation in hemodialysis tubing: a case report.

BACKGROUND: While the appearance of red clots in the dialyzer is a common phenomenon in every hemodialysis unit, the occurrence of white thrombi in the tubing is relatively rare. CASE PRESENTATION: We describe an adolescent male with recurrent white thrombi formation in the hemodialysis tubing. This patient had chronic renal failure from focal segmental glomerulosclerosis, but was no longer nephrotic at the time of the thrombi formation. He had a history of recurrent thrombosis of his vascular access. However, no pro-thrombotic risk factors could be identified. White particulate matter, measuring 1 to 3mm in size, and adherent to the arterial and venous blood tubing lines was found during the rinse back of a hemodialysis session. This was associated with a 60% decrease in his platelet count. Light microscopic examination of the deposits revealed the presence of platelet aggregates. He subsequently developed thrombosis of his arteriovenous graft six hours later. The white thrombi recurred at the next dialysis session, as well as six months later. These episodes occurred regardless of the type of dialysis machine or tubing, and appeared to resolve with an increase in heparin dose. CONCLUSION: Recurrent white thrombi formation can occur in the hemodialysis tubing of a patient with no identifiable pro-thrombotic factors. The white thrombi may be a harbinger of arteriovenous graft thrombosis and may be prevented by an increase in heparin dose.

Use of HF20 membrane in critically ill unstable low-body-weight infants on inotropic support.

BACKGROUND: Initiating continuous renal replacement therapy (CRRT) in infants exposes them to the dual hemodynamic challenges of high circuit extracorporeal volumes and potential membrane reactions, in the case of acrylonitrile AN69 membranes. The use of the new Prismaflex HF20 membrane in hemodynamically unstable low-body-weight infants on inotropic support has not been reported. TREATMENT: We describe the use of the HF20 (Gambro Lundia AB, Lund, Sweden) membrane in four low-body-weight infants (2.3 to 5.4 kg) with multi-organ dysfunction syndrome who were critically ill in the Pediatric Intensive Care Unit (PICU), hemodynamically unstable, and on inotropes. We were able to achieve target volume loss in all infants without compromising their hemodynamic status. Mean arterial pressures were maintained between 39 and 57 mmHg. The relatively low circuit volume of the HF20 set (60 ml) obviated the need for blood prime in the majority; however, when blood prime was required, there was no adverse reaction with the polyarylethersulfone (PAES) membrane. Solute clearance in these small infants was efficient with correction of metabolic acidosis and electrolyte abnormalities. Excellent circuit lifespan (56.3 ± 32.3 h) was observed. CONCLUSIONS: CRRT using the HF20 membrane is safe and hemodynamically well tolerated in high-risk, unstable low-body-weight infants with cardiac dysfunction on multiple inotropes.

Outbreak of acute norovirus gastroenteritis in a military facility in Singapore: a public health perspective.

INTRODUCTION: Norovirus gastrointestinal disease (GID) outbreaks occur frequently in closed settings, with high attack rates. On October 16, 2008, a norovirus GID outbreak occurred at a Singapore military camp. This study describes the epidemiological investigations conducted to determine the cause of outbreak and the efficacy of the public health measures implemented. METHODS: Epidemiologic investigations included a case-control study of exposure to different food items and an environmental exposure survey. Stool samplings of patients and food handlers for common pathogens, and microbiologic testing of food and water samples were performed. Inspection of dining facilities and health screening of all food-handlers were also conducted. RESULTS: A total of 156 GID cases were reported on October 15-31, 2008. 24 (15.4%) personnel were positive for norovirus. The predominant symptoms were diarrhoea (76.3%) and abdominal pain (69.2%). There was no clinical correlation between any food item and the affected personnel. Testing of food and water samples, dining facility inspections and health screening of food handlers showed satisfactory results. The environmental exposure survey indicated possible transmission due to environmental contamination by vomitus in common areas. Comprehensive environmental decontamination was performed with hypochlorite solution, and personal hygiene measures were enforced. The outbreak lasted 17 days, with a decline in cases post intervention. CONCLUSION: Timely notification and prompt response can curtail disease transmission. Swift implementation of public health measures, such as emphasis on personal hygiene, isolation of affected cases and comprehensive disinfection of the environment, effectively stopped norovirus transmission and may be adapted for future GID outbreaks.