UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). METHODS: We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. RESULTS: Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission-brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. CONCLUSIONS: OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.

Identifying critically ill children at high risk of acute kidney injury and renal replacement therapy.

Acute kidney injury (AKI), a common complication in paediatric intensive care units (PICU), is associated with increased morbidity and mortality. In this single centre, prospective, observational cohort study, neutrophil gelatinase-associated lipocalin in urine (uNGAL) and plasma (pNGAL) and renal angina index (RAI), and combinations of these markers, were assessed for their ability to predict severe (stage 2 or 3) AKI in children and young people admitted to PICU. In PICU children and young people had initial and serial uNGAL and pNGAL measurements, RAI calculation on day 1, and collection of clinical data, including serum creatinine measurements. Primary outcomes were severe AKI and renal replacement therapy (RRT). Secondary outcomes were length of stay, hospital acquired infection and mortality. The area under the Receiver Operating Characteristic (ROC) curves and Youden index was used to determine biomarker performance and identify optimum cut-off values. Of 657 children recruited, 104 met criteria for severe AKI (15∙8%) and 47 (7∙2%) required RRT. Severe AKI was associated with increased length of stay, hospital acquired infection, and mortality. The area under the curve (AUC) for severe AKI prediction for Day 1 uNGAL, Day 1 pNGAL and RAI were 0.75 (95% Confidence Interval [CI] 0∙69, 0∙81), 0∙64 (95% CI 0∙56, 0∙72), and 0.73 (95% CI 0∙65, 0∙80) respectively. The optimal combination of measures was RAI and day 1 uNGAL, giving an AUC of 0∙80 for severe AKI prediction (95% CI 0∙71, 0∙88). In this heterogenous PICU cohort, urine or plasma NGAL in isolation had poorer prediction accuracy for severe AKI than in previously reported homogeneous populations. However, when combined together with RAI, they produced good prediction for severe AKI.

Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study.

BACKGROUND: In juvenile-onset systemic lupus erythematosus (JSLE), renal involvement (lupus nephritis) is frequently seen and can result in long-term morbidity. This prospective longitudinal study aimed to identify the utility of standard and/or novel biomarkers for monitoring and predicting lupus nephritis in a real world setting. METHODS: Using an unselected JSLE cohort, urine samples were collected during routine clinical review. Protein concentrations of urinary monocyte chemo-attractant protein 1 (uMCP1) and neutrophil gelatinase-associated lipocalin (uNGAL) were analysed along with standard disease activity markers, and were compared with current and subsequent disease activity. RESULTS: JSLE patients (n = 64; median age 14.1 years) were seen at 3 (interquartile range: 2-5) clinical reviews over 364 (182-532) days. Multivariate analysis demonstrated uMCP1 and serum C3 as independent variables (p < 0.001) for active renal disease at the time of the current review. uMCP1 was an excellent predictor of improved renal disease over time (AUC: 0.81; p = 0.013). uNGAL was a good predictor of worsened renal disease activity (AUC 0.76; p = 0.04) over time. CONCLUSION: Biomarkers (uMCP1, serum C3) can indicate current renal involvement in JSLE, whilst uMCP1 and uNGAL are able to predict subsequent renal disease activity changes. Moving towards biomarker-led monitoring may improve the renal outcome for our patients.

Henoch schonlein purpura--a 5-year review and proposed pathway.

Henoch Schonlein Purpura (HSP) is the commonest systemic vasculitis of childhood typically presenting with a palpable purpuric rash and frequently involving the renal system. We are the first group to clinically assess, critically analyse and subsequently revise a nurse led monitoring pathway for this condition.A cohort of 102 children presenting with HSP to a secondary/tertiary level UK paediatric hospital over a five year period, were monitored using a nurse led care pathway. Using this cohort, the incidence (6.21 cases per 100,000 children per year) and natural disease course of HSP nephritis (46% initial renal inflammation; 9% subsequent renal referral; 1% renal biopsy and immunosuppression) was determined. Older patients were at higher risk of requiring a renal referral (renal referral 12.3 (8.4-13.5) years vs. normal outcome 6.0 (3.7-8.5) years; p<0.01). A normal urinalysis on day 7 had a 97% (confidence interval 90 to 99%) negative predictive value in predicting a normal renal outcome.Using this data and existing literature base, The Alder Hey Henoch Schonlein Purpura Pathway was developed, a revised pathway for the screening of poor renal outcome in HSP. This is based on a six-month monitoring period for all patients presenting with HSP, which importantly prioritises patients according to the urine findings on day 7 and thus intensively monitors those at higher risk of developing nephritis. The pathway could be easily adapted for use in different settings and resources.The introduction of a standardised pathway for the monitoring of HSP will facilitate the implementation of disease registries to further our understanding of the condition and permit future clinical trials.

Abnormal urinary steroid profiles in four hypertensive obese children.

BACKGROUND: There is a poorly understood association between obesity and hypertension. We demonstrated abnormalities of adrenal androgen and cortisol metabolites in four hypertensive obese children. PATIENTS: Four males (aged 10 to 15 years) were evaluated for systolic blood pressures consistently above the 99.6th percentile. All were overweight with BMI ranging from 27-35. Clinical examinations, renal ultrasound and DMSA scans were normal. Plasma electrolytes, renin, aldosterone, cortisol, testosterone, ACTH and TSH were normal. 24-Hour urinary steroid profiles showed a generalised excess of adrenal androgen and cortisol metabolites in all cases. Relevant recognised disorders of adrenal androgen and cortisol metabolism were excluded. CONCLUSION: There is no clinical condition explaining these abnormal urinary steroid profiles. These results support previous findings and provide new data on abnormal urinary adrenal androgen excretion in obese hypertensive patients. Further studies may determine the relationship between obesity, hypertension and the observed abnormalities of urinary steroid excretion.

Peritoneal dialysis for chronic renal failure in a patient with methylmalonic acidaemia.

Chronic renal failure is a common complication of methylmalonic acidaemia (MMA). It is usually managed with haemodialysis and renal transplantation. We report the use of continuous cycling peritoneal dialysis (CCPD) for 20 months in a paediatric patient with chronic renal failure due to MMA. This procedure resulted in the elimination of 950 micromol methylmalonate (MM) per day and a fall in the plasma MM concentration from 3.9 to 0.74 mmol/l. As a result of this treatment, the frequency at which this patient was hospitalised was markedly reduced prior to a successful renal transplantation.

Multicentre prospective randomised trial of tacrolimus, azathioprine and prednisolone with or without basiliximab: two-year follow-up data.

A total of 192 children and adolescents undergoing renal transplantation were randomly chosen to receive tacrolimus, azathioprine and corticosteroids (TAS, n = 93) or tacrolimus, azathioprine, corticosteroids and two doses of basiliximab (TAS + B, n = 99). Six-month outcome data have previously been reported; this manuscript reports the 2-year data. Complete 2-year data were available on 164 (85.4%) of the original 192 patients. There was a single death in the TAS arm. Kaplan-Meier estimates of survival free of graft loss at 2 years were 94.9% in the TAS + B arm and 89.6% in the TAS arm [hazard ratio (HR) 0.52; 95% confidence interval (CI) 0.17 to 1.54, P = 0.23]. Estimates of survival free from rejection at 2 years were 75.2% in the TAS + B arm and 68.7% in the TAS arm (HR 0.81; 95% CI 0.46 to 1.40, P = 0.44). The mean estimated glomerular filtration rate (GFR) at 2 years, was 65.8 ml/min per 1.73 m(2) body surface area in the TAS arm and 66.7 ml/min per 1.73 m(2) in the TAS + B arm (P = 0.78). Blood pressure and cholesterol levels were similar in the two arms, and there was no evidence of a difference in the incidence of infection or malignancy. These data provide further evidence of a lack of benefit associated with the addition of basiliximab to a TAS regimen for European paediatric renal transplant recipients at low immunological risk.

Using non-steroidal anti-inflammatory drugs (NSAIDs) in volume depleted children can precipitate acute renal failure.

Non-steroidal anti-inflammatory drugs (NSAIDs) are increasingly popular in hospital medicine and general practice and are readily available over the counter. The vast majority of healthy children who ingest therapeutic doses of NSAIDs for a limited duration tolerate them without any significant adverse effects. However, the risk of renal toxicity is potentially increased in situations where there is stimulation of the renin-angiotensin system such as with volume depletion or in pre-existing chronic renal disease. We describe four cases which illustrate this complication occurring in a children's hospital. We have not proven cause and effect, but further research is needed to define the true risk of the potential renal complications of NSAIDs in patients at risk of dehydration.

Intravenous iron treatment in paediatric chronic kidney disease patients not on erythropoietin.

Intravenous (i.v.) iron treatment reduces erythropoietin (EPO) dose in paediatric haemodialysis patients. The efficacy in paediatric nonhaemodialysis patients is less well established. i.v. iron is routinely given in our institution to these patients, including some who have not started EPO. The effect of this strategy was examined. Patients with chronic kidney disease (CKD) or peritoneal dialysis (PD) not on EPO were identified. Case notes were reviewed for haemoglobin (Hb), red cell and iron indices for 6 months before and at least 3 months after i.v. iron. Five patients were identified. Mean age was 13.3 years and mean i.v. iron (Venofer) dose = 3.1 mg/kg. Median number of doses = 7 (range 3-10). Hb increased significantly after i.v. iron from 11.4 +/- 0.7 to 12.8 +/- 1.3 g/dl (p = 0.02). Mean cell volume increased from 87.7+/-3.4 to 90.1 +/- 3.7 fl (p = 0.01), and mean cell Hb remained unchanged: 29.2 +/- 1.2 to 29.7 +/- 1.0 pg (p = 0.12). Absolute and percentage reticulocyte count remained unchanged. There was no change in iron indices: ferritin 55.1 +/- 31.3 to 97.3 +/- 46.5 ng/ml (p = 0.3), iron 18.9 +/- 6.9 to 18.1 +/- 4.2 micromol/l (p = 0.7), transferrin 1.9 +/- 1.6 to 2.0 +/- 0.1 g/l (p = 1.0), transferrin saturation 35.7 +/- 8.1 to 40.3 +/- 18.0% (p = 0.5). i.v. iron slightly improved Hb levels in five paediatric CKD and PD patients not receiving EPO. This strategy may delay the need for EPO treatment and deserves further evaluation.

Using NSAID in volume depleted children can precipitate acute renal failure.

Non-steroidal anti-inflammatory drugs (NSAID) are increasingly popular in hospital medicine and general practice and are readily available over the counter. The vast majority of healthy children who ingest therapeutic doses of NSAID for a limited duration tolerate them without any significant adverse effects. However, the risk of renal toxicity is potentially increased in situations where there is stimulation of the renin-angiotensin system such as with volume depletion or in pre-existing chronic renal disease. We describe four cases which illustrate this complication occurring in a children's hospital. We have not proven cause and effect, but further research is needed to define the true risk of the potential renal complications of NSAID in patients at risk of dehydration.