A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity.

BACKGROUND: A urine 'biomarker panel' comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an 'excellent' level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. METHODS: The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). RESULTS: The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. CONCLUSIONS: Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

Prophylactic Ureteric Stents in Renal Transplant Recipients: A Multicenter Randomized Controlled Trial of Early Versus Late Removal.

Prophylactic ureteric stenting in renal transplantation reduces major urological complications; however, morbidity is related to the indwelling duration of a stent. We aimed to determine the optimal duration for stents in this clinical setting. Patients (aged 2-75 years) from six UK hospitals who were undergoing renal transplantation were recruited and randomly assigned to either early stent removal at 5 days (without cystoscopy) or late removal at 6 weeks after transplantation (with cystoscopy). The primary outcome was a composite of stent-related complications defined as pain, visible hematuria, migration, fragmentation, and urinary tract infections (UTIs) within 3 mo of transplantation. Between May 2010 and Nov 2013, we randomly assigned 227 participants, with 205 included in the final analysis of the primary outcome. Stent-related complications were significantly higher in the late versus early stent removal groups (36 of 126 [28.6%] vs. 6 of 79 [7.6%]; p < 0.001). The majority of stent complications consisted of UTIs, with an incidence of 31 of 126 (24.6%) in the late group compared with 6 of 79 (7.6%) in the early group (p = 0.004). We found early stent removal on day 5 significantly reduced stent-related complications and improved quality of life in the first 3 mo after transplantation (ISRCTN09184595).

Increased concentration of plasma TNFR1 and TNFR2 in paediatric lupus nephritis.

BACKGROUND: Juvenile-onset systemic lupus erythematous (JSLE) is a debilitating condition that frequently involves the kidneys (lupus nephritis; LN). Tumour necrosis factor alpha (TNF-α), an important pro-inflammatory cytokine, is expressed locally in the kidney and correlates with LN disease activity. The aim of this study was to ascertain whether soluble receptors for TNF-α (sTNFR1/sTNFR2) are significantly increased in children with LN. METHODS: Plasma samples were collected from JSLE patients at routine review. Concentrations of sTNFR1 and sTNFR2 were measured (median; interquartile range, IQR) using enzyme-linked immunosorbent assay (ELISA) in 25 JSLE patients (seven LN) and 20 healthy controls (HCs). RESULTS: sTNFR2 concentration was significantly increased in JSLE (5149 pg/dl, 3413-8561) compared to HCs (3858 pg/dl, 2254-5165; p = 0.049). sTNFR1 concentration was significantly increased in active LN (n = 7, 1765 pg/dl, IQR 1133-4167) compared to inactive LN (n = 18, 1104 pg/dl, 886-1272; p = 0.018). There was a non-significant increase in sTNFR2 concentration in active LN (9829 pg/dl, 3298-21271) compared to inactive LN (4595 pg/dl, 3345-6993; p = 0.146). sTNFR1 concentration correlated moderately with sTNFR2 (r = 0.66, p < 0.001). sTNFR2 demonstrated strong positive correlations with ESR (r = 0.941, p < 0.01) and anti-dsDNA antibodies (r = 0.998, p = 0.041). Both receptors also positively correlated with creatinine (TNFR1 r = 0.81, p < 0.001; TNFR2 r = 0.50, p = 0.015) and urinary albumin creatinine ratio (TNFR1 r = 0.64, p < 0.01; TNFR2 r = 0.63, p < 0.01). CONCLUSIONS: These data indicate that sTNFR1 and sTNFR2 concentrations are elevated in LN and may reflect renal activity. These results provide basis for further investigation into the pathological pathways underlying LN.

The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE.

BACKGROUND: B cells drive antibody formation and T cell activation. This study aimed to describe the clinical indications, efficacy and adverse events (AEs) for the B-cell depleting agent, rituximab, in a large cohort of children with lupus. METHODS: Prescribing records and the UK JSLE Cohort Study database identified rituximab use. RESULTS: Sixty-three patients received 104 courses of intravenous rituximab over a 10-year period. Patients were aged 12.2 (IQR 9.0-13.9) years at diagnosis and 50 (79%) were female. They had disease for 1.4 (0.2-3.0) years at the time of rituximab. Lupus nephritis was the most common indication (36% of first courses). Clinical biomarkers, 2.5 (1.6-4.3) months after treatment, demonstrated a statistically significant improvement in ESR, C3, C4, creatinine, albumin, haemoglobin, anti-dsDNA titres and urine albumin:creatinine ratio. IgG, IgA and IgM levels decreased (p < 0.01). Oral corticosteroid dose significantly reduced after rituximab (dose before 0.26 (0.09-0.44) mg/kg, after 0.17 (0.09-0.30) mg/kg; p = 0.01)). AEs occurred in 19 (18%) of all courses including; delayed second dose (8%), Ig replacement (2%) and infusion reactions (6%; anaphylaxis 2%). The global BILAG score showed a trend toward improvement (before 4.5 (2.0-9.0), after 3.0 (2.0-5.0); p = 0.16). CONCLUSION: Rituximab improves disease activity in children with lupus and serious AEs are infrequent. Controlled studies are required.

Reversible acute anuric kidney injury after surgical evacuation of perinephric hematomas as a complication of renal transplant biopsies.

Percutaneous renal transplant biopsy is the gold standard investigation to diagnose the cause of renal allograft dysfunction. There are inherent risks to this investigation, despite the procedure becoming safer due to the increased utilization of ultrasound-guided techniques. These biopsy risks can be increased when there is acute rejection present with a swollen transplanted kidney. Subcapsular hematomas are not uncommon after percutaneous renal transplant biopsies, but we describe two cases of post-biopsy subcapsular hematoma which were associated with acute renal allograft dysfunction in pediatric renal transplant recipients who did not have acute rejection.

The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients.

The development of donor-specific HLA antibodies (DSA) is associated with worse renal allograft survival in adult patients. This study assessed the natural history of de novo DSA, and its impact on renal function in pediatric renal transplant recipients (RTR). HLA antibodies were measured prospectively using single-antigen-bead assays at 1, 3, 6 and 12 months posttransplant followed by 12-monthly intervals and during episodes of allograft dysfunction. Of 215 patients with HLA antibody monitoring, 75 (35%) developed DSA at median of 0.25 years posttransplant with a high prevalence of Class II (70%) and HLA-DQ (45%) DSA. DSA resolved in 35 (47%) patients and was associated with earlier detection (median, inter-quartile range 0.14, 0.09-0.33 vs. 0.84, 0.15-2.37 years) and lower mean fluorescence intensity (MFI) (2658, 1573-3819 vs. 7820, 5166-11 990). Overall, DSA positive patients had more rapid GFR decline with a 50% reduction in GFR at mean 5.3 (CI: 4.7-5.8) years versus 6.1 (5.7-6.4) years in DSA negative patients (p = 0.02). GFR decreased by a magnitude of 1 mL/min/1.73 m(2) per log10 increase in Class II DSA MFI (p < 0.01). Using Cox regression, independent factors predicting poorer renal allograft outcome were older age at transplant (hazard ratio 1.1, CI: 1.0-1.2 per year), tubulitis (1.5, 1.3-1.8) and microvasculature injury (2.9, 1.4-5.7). In conclusion, pediatric RTR with de novo DSA and microvasculature injury were at risk of allograft failure.

Performance of the new SLICC classification criteria in childhood systemic lupus erythematosus: a multicentre study.

OBJECTIVES: The Systemic Lupus International Collaborating Clinics (SLICC) group has recently proposed a new set of criteria for the classification of systemic lupus erythematosus (SLE). We aimed to compare the sensitivity and specificity of the new SLICC criteria with those of the American College of Rheumatology (ACR) criteria in our childhood-onset SLE patients. METHODS: Three main paediatric lupus centres from Europe participated in this study. Of these centres, one was predominantly a paediatric nephrology centre (Great Ormond Street Hospital, London, UK), one was predominantly a paediatric rheumatology centre (Istituto Giannina Gaslini, Genoa, Italy), and one was a combined centre taking care of both group of patients (Hacettepe University, Ankara, Turkey). The features present at disease onset in patients with childhood-onset SLE, younger than 18 years of age, seen between January 2000 and December 2012 were retrospectively reviewed. For the evaluation of specificity, patients admitted to each centre between May and December 2012 for conditions other than SLE, in whom ANA was deemed necessary within the diagnostic work-up were included as controls. PASW 18.0 for Windows was used for statistical analyses. RESULTS: Both sets of classification criteria were analysed in 154 childhood SLE patients with a mean age at disease onset of 12.7 years and in 123 controls with a mean age of 8.9 years. The sensitivity and specificity of the ACR criteria were 76.6% and 93.4%, respectively, whereas those of the SLICC criteria were 98.7% and 85.3%, respectively. Four patients out of 5 with haemolytic uraemic syndrome (HUS) and 4 patients out of 8 with juvenile dermatomyositis (JDM) met four of the SLICC criteria, whereas 22 lupus nephritis patients failed to meet four of the ACR criteria. CONCLUSIONS: In our paediatric series, the SLICC criteria showed better sensitivity (p<0.001) and led to fewer misclassifications, but were less specific (p<0.001) than the ACR criteria.

The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe.

BACKGROUND: The results of pediatric renal transplantation have improved markedly in the last decade. However, a number of relevant clinical problems remain, such as organ damage caused by chronic rejection, long-term toxicity of immunosuppressive therapy, difficulty in developing tolerance-inducing protocols, secondary cardiovascular comorbidity, post-transplantation lymphoproliferative disease, suboptimal longitudinal growth, quality of life, adherence to immunosuppressive medication, and structured transition programs to adult care. These unmet clinical needs require intense collaborative and interdisciplinary clinical research. We recently founded the Cooperative European Paediatric Renal TransplAnt INitiative (CERTAIN; www.certain-registry.eu) as a research network and platform built on a novel, web-based registry. RESULTS: The registry's dataset provides essential information on generic kidney transplantation-related topics and also captures pediatric-specific topics, such as growth, physical and psychosocial development, and adherence. Due to its flexibility the system can be used as follows: (1) as a registry capturing a minimal or an extended dataset; (2) as a center and/or country-specific transplantation database; or (3) as a patient-specific electronic transplantation chart. The data can be exported directly from the CERTAIN web application into statistical software packages for scientific analyses. The rights regarding data ownership, evaluation, and publications are regulated in the registry's rules of procedure. Data quality is ensured by automatic software validation and a manual data review process. To avoid redundant data entry, CERTAIN has established interfaces for data change with Eurotransplant, the Collaborative Transplant Study (CTS), and the registry of the European Society of Pediatric Nephrology (ESPN) and European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) (ESPN/ERA-EDTA registry). CERTAIN fulfils all regulatory and ethical requirements of the European Union and Germany, in particular, regarding patients' data privacy and security. CONCLUSION: Using modern information technology, the recently established multinational CERTAIN Registry fills a gap in Europe for collaborative 5 research and quality assurance in the field of pediatric renal transplantation.

Increased serum concentration of sphingosine-1-phosphate in juvenile-onset systemic lupus erythematosus.

PURPOSE: Sphingosine-1-phosphate (S1P) is an active sphingolipid with chemotactic abilities and has been linked to inflammatory mediators and autoimmune disease. The aim of this study was to assess whether children with juvenile-onset systemic lupus erythematosus (JSLE) express increased systemic and/or urinary concentrations of S1P. METHODS: A subgroup of patients participating in the UK JSLE Cohort Study, were invited to participate. Cross sectional serum and urine samples were prospectively collected along with demographic and standard clinical data. Results were compared to a cohort of disease controls (Henoch Schonlein Purpura; HSP) and healthy controls (HC). RESULTS: The median age of JSLE patients (n = 15) was 13.6 years (7.2-16.9 years). The serum concentrations of S1P in JSLE patients (7.4 uM, IQR 6.3-12.3 uM) were statistically significantly increased when compared to patients with HSP (n = 10; 5.2 uM, IQR 4.0-7.9 uM; p = 0.016) and HCs (n = 10; 3.8 uM, IQR 2.1-5.8 uM; p = 0.003). There was a trend towards increased serum S1P concentrations between patients with active lupus nephritis (n = 8; 8.7 uM, IQR 6.2-15.3 uM) compared to lupus non-nephritis (n = 7; 6.6 uM, IQR 6.3-10.6 uM; p = 0.355). No relationship was found between disease activity markers and S1P. Urine S1P concentrations were no different between JSLE patients (56.0 nM, IQR 40.3-96.6 nM) and HCs (58.7 nM, IQR 0-241.9 nM; p = 0.889). CONCLUSIONS: We have demonstrated, for the first time, an increased serum concentration of S1P in a cohort of JSLE patients. These findings highlight a role of S1P in the pathophysiology of JSLE that warrants further investigation.

Bridging the gap: an integrated paediatric to adult clinical service for young adults with kidney failure.

PROBLEM: Transition from paediatric to adult care of young adults with chronic diseases is poorly coordinated, often delayed, and usually managed through a single referral letter. About 35% of young adults lose a successfully functioning kidney transplant within 36 months of transfer from paediatric to adult services. DESIGN: Before and after study of the impact of a new integrated paediatric-adult clinical service for patients with kidney failure. SETTING: Adult renal centre in Oxford and two paediatric renal centres in London. STRATEGIES FOR CHANGE: An integrated paediatric-young adult joint transition clinic and care pathway was established in 2006, in conjunction with a young adult clinical service with regular community based clinics. Previously, young adult transplant recipients were transferred by a single referral letter to an adult renal consultant and managed in a conventional adult clinic. KEY MEASURES FOR IMPROVEMENT: Rates of acute rejection and loss of kidney transplants five years before and five years after the introduction of the integrated young adult care pathway. EFFECTS OF THE CHANGE: Nine young adult kidney transplant recipients were transferred directly to adult care between 2000 and 2006 (group 1). From 2006 to 2010, 12 young adult transplant recipients underwent integrated transition into the new young adult service (group 2). Six transplants were lost in group 1 (67%) compared with no transplant losses in group 2. LESSONS LEARNT: Implementing an integrated transition clinic, coupled with improving young adults' healthcare experience through a young adult clinic, improved patient adherence to regular medication and engagement with healthcare providers, as judged by reduced transplant failure rates. This model may be applicable to other young adult populations with chronic disease transferring to adult healthcare.

Successful renal transplantation in factor H autoantibody associated HUS with CFHR1 and 3 deficiency and CFH variant G2850T.

Factor H (CFH) autoantibodies are associated with atypical hemolytic uremic syndrome (aHUS). Peritransplantation plasma exchange therapy and intensification of immunosuppression, with adjuvant use of anti-CD20 monoclonal antibodies has recently been advocated for cases of CFH-autoantibody associated aHUS. In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His). CFH-autoantibodies were detected 2 weeks prior to transplantation. Disease recurrence was not observed using basiliximab, an IL2-receptor antagonist and high-dose corticosteroids with mycophenolate mofetil. Adjuvant therapies such as Rituximab nor intensification of plasma therapy were employed. Consequently, careful consideration needs to be given to the use of additional immunosuppression in certain cases of CFH-autoantibody associated aHUS. Serial measurement of CFH-autoantibodies is required in the immediate pre- and posttransplantation period to further clarify their role as a factor in the recurrence of aHUS posttransplantation. Furthermore, delineation of the functional significance of CFH-autoantibodies is warranted in individual cases.

Calcineurin-inhibitor free immunosuppression with mycophenolate mofetil and corticosteroids in paediatric renal transplantation improves renal allograft function without increasing acute rejection.

The aim of this study was to determine whether CNIs can be safely withdrawn in paediatric patients with declining renal allograft function receiving MMF and corticosteroids for long-term immunosuppression following renal transplantation. We performed a retrospective review of paediatric renal transplant recipients who received MMF with corticosteroids at least three months after transplantation with or without CNI in a single centre. Thirty-eight children (71% male), mean age 7.2 +/- 3.7 yr received MMF and corticosteroids, with 29 (76%) receiving a CNI. Mean follow-up was 59.2 +/- 42 months post-MMF commencement and 109 +/- 98.8 months post-transplantation. Patient and renal allograft survival were 100% and 94%, respectively. There was a significant improvement in eGFR after MMF introduction both in children on a CNI and those where the CNI was withdrawn, with stabilisation of eGFR after two yr. There was no significant difference in the number of acute rejection episodes prior to or following introduction of MMF between the groups. MMF in combination with corticosteroids is a safe and effective immunosuppressive regimen in paediatric renal transplantation. Complete withdrawal of CNIs after conversion to MMF should be considered in all patients, to preserve renal function as evidenced by improved eGFR.

B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus.

OBJECTIVE: B cell dysregulation is involved in the development of childhood-onset systemic lupus erythematosus (SLE). The safety and efficacy of B cell depletion therapy is evaluated in the the largest series of children to be presented in the literature. METHODS: 19 children (89% female) with SLE, aged 6-16 (median 14) years, treated with rituximab in a single centre were retrospectively reviewed. The British Isles Lupus Assessment Group (BILAG) index and biochemical, haematological and immunological parameters were evaluated before and after treatment, with the primary outcome assessed as normal results. Rituximab therapy was used for acute life- or organ-threatening symptoms or symptoms that had not responded to standard treatment. The range of symptoms included lupus nephritis, cerebral lupus and severe general symptoms. Rituximab 750 mg/m(2) was given intravenously twice, usually within a 2-week period. Patients were followed up for 6-38 (median 20) months. RESULTS: Rapid reduction of SLE disease activity was observed within the first month, represented by a reduction of BILAG scores (14 to 6, p<0.005) and an improvement in renal function (estimated glomerular filtration rate of 54 to 68 ml/min/1.73 m(2), p = 0.07), immunological (complement C3: 0.46 to 0.83 g/l, p = 0.02) and haematological (haemoglobin: 9.7 to 10.3 g/dl, p = 0.04) parameters. No serious side effects were observed, except for herpes zoster in five cases. CONCLUSION: In our cohort of children, rituximab was safe and effective when used in combination with standard immunosuppressive agents. Randomised controlled studies are needed to further evaluate the safety and efficacy of rituximab therapy.

The use of the British Isles Lupus Assessment Group (BILAG) index as a valid tool in assessing disease activity in childhood-onset systemic lupus erythematosus.

OBJECTIVES: The British Isles Lupus Assessment Group (BILAG) index is a standardized systemic lupus erythematosus (SLE) disease activity assessment. The main aim of this study was to correlate the BILAG index with laboratory measures of disease activity in childhood-onset SLE with and without biopsy-proven lupus nephritis. METHOD: Prospective observational comparison study of the BILAG index in 21 SLE patients under 18 yr of age over a 12-month period in a tertiary referral paediatric outpatient clinic. RESULTS: Eleven patients with lupus non-nephritis and 10 patients with lupus nephritis were reviewed. The lupus nephritis patients had significantly (P<0.001) more admissions over a similar time interval since diagnosis. The renal BILAG disease activity scores were significantly greater (P = 0.013) in the lupus nephritis group (range 1-9, median 3.0, compared with 0-3 and 1.0 in the lupus non-nephritis group). The total BILAG scores and patient visual analogue scores (VAS) were higher in the lupus nephritis groups, unlike the lower physician VAS, but these differences were not statistically significant compared with other laboratory indices of disease activity. CONCLUSIONS: The BILAG index is a useful tool in monitoring disease activity in children and adolescents with SLE. The data collected for the BILAG index can be used serially and effectively by different clinicians over time to enable recording of disease status at sequential assessments. The lower patient VAS in the lupus non-nephritis group was not significant and may reflect the patients' own perception of lethargy at times of increased disease activity.

Spontaneous clinical improvement in dense deposit disease.

The clinical course and 3-year follow-up of a female patient aged 11 years who presented with nephrotic syndrome and renal failure is described. The renal biopsy revealed type II membranoproliferative glomerulonephritis or dense deposit disease. She was treated with penicillin prophylaxis, frusemide and captopril, and was not given immunosuppression, anticoagulation or antiplatelet therapy. Despite poor prognostic clinical and pathological features, she had spontaneous resolution of her renal failure and proteinuria, although her proteinuria recurred 17 months post presentation. Her unusual progress, with improvement in her disease activity and normalisation of her glomerular filtration rate, is described.

Hemangioma of the temporal bone in a patient presumed to have Ménière's syndrome.

This case report describes a patient with a facial nerve hemangioma of 8 years' duration that initially caused most of the symptoms of Ménière's syndrome: fullness, sensorineural hearing loss, dizziness, tinnitus, and disruption of balance. The hearing loss was in the high-frequency range (> or = 3,000 Hz); typically, the initial hearing loss in Ménière's syndrome is in the low-frequency range. Mild facial nerve weakness and punctate keratitis due to corneal exposure appeared 8 years later. Contrast-enhanced magnetic resonance imaging and high-resolution computed tomography depicted the lesion and made preoperative diagnosis possible. With meticulous surgical removal of the tumor, which was intertwined with the facial nerve, facial nerve function was preserved.

A cluster of injuries at a water slide in Washington State.

Interviews were conducted with 46 people injured on a newly opened water slide in Washington State during the summer of 1983, and 46 age-matched controls. The injuries included nine concussions and eight spinal fractures. The odds ratio associated with being 10 per cent over ideal body weight, adjusted for age and sex, was 1.6 (95% C.I. 1.1-2.5). Three of eight people with spinal fractures were riding with another person between their legs, compared with two of 38 other injured riders (OR = 10.8, 95% C.I. 1.8-63.5).