Efficacy and safety of tacrolimus in de novo pediatric transplant recipients randomized to receive immediate- or prolonged-release tacrolimus.

BACKGROUND AND AIMS: This multicenter trial compared immediate-release tacrolimus (IR-T) vs prolonged-release tacrolimus (PR-T) in de novo kidney, liver, and heart transplant recipients aged <16 years. Each formulation had similar pharmacokinetic (PK) profiles. Follow-up efficacy and safety results are reported herein. MATERIALS AND METHODS: Patients, randomized 1:1, received once-daily, PR-T or twice-daily, IR-T within 4 days of surgery. After a 4-week PK assessment, patients continued randomized treatment for 48 additional weeks. At Year 1, efficacy assessments included the number of clinical acute rejections, biopsy-confirmed acute rejection (BCAR) episodes (including severity), patient and graft survival, and efficacy failure (composite of death, graft loss, BCAR, or unknown outcome). Adverse events were assessed throughout. RESULTS: The study included 44 children. At Year 1, mean ± standard deviation tacrolimus trough levels were 6.6 ± 2.2 and 5.4 ± 1.6 ng/mL, and there were 2 and 7 acute rejection episodes in the PR-T and IR-T groups, respectively. No cases of graft loss or death were reported during the study. The overall efficacy failure rate was 18.2% (PR-T n = 1; IR-T n = 7). CONCLUSIONS: In pediatric de novo solid organ recipients, the low incidence of BCAR and low efficacy failure rate suggest that PR-T-based immunosuppression is effective and well tolerated to 1-year post-transplantation.

5-ASA induced interstitial nephritis in patients with inflammatory bowel disease: a systematic review.

BACKGROUND: Acute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis. METHODS: Embase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: "inflammatory bowel disease", "interstitial nephritis" and "aminosalicylates". Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed. RESULTS: Forty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12-48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5-5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure. CONCLUSIONS: AIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387.

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.

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.

Heparanase activity is dysregulated in children with steroid-sensitive nephrotic syndrome.

BACKGROUND: Immune cells express heparanase, an endoglycosidase, able to degrade heparan sulfate glycosaminoglycan (HSGAG) in the glomerular capillary wall (GCW) and potentially induce proteinuria. The aim of this study was to determine whether dysregulated heparanase expression is associated with the heavy proteinuria of childhood steroid-sensitive nephrotic syndrome (SSNS). METHODS: Plasma and urinary heparanase activity and peripheral blood mononuclear cell (PBMC) mRNA heparanase levels [real-time polymerase chain reaction (PCR)] were measured in children with SSNS in relapse and remission. Plasma and urinary heparanase activity was determined in adult patients with nephrotic syndrome and in age- and gender-matched controls. RESULTS: Plasma heparanase activity was reduced in SSNS with relapse (811.2 units) compared to remission (1147.96 units) (P= 0.003) and control subjects (1390.51 units) (P < 0.001). In adult nephrotic syndrome, plasma heparanase activity was significantly lower in patients compared to controls. However, there was no difference between remission and relapse states. In children, urinary heparanase activity/urinary creatinine ratio was highest in SSNS relapse (14.26 units/mg) compared with remission (7.43 units/mg) (P= 0.016) and controls (2.29) (P < 0.001). However, PBMC heparanase mRNA expression was not different between these three groups. In adult nephrotic syndrome, urinary heparanase activity/urinary creatinine levels were lower in both remission and relapse compared to controls and there was no difference between remission and relapse states. CONCLUSION: In childhood SSNS, there is a qualitative and quantitative difference in urinary heparanase activity expression that is not paralleled in adult nephrotic syndrome. These data suggest that dysregulated heparanase expression may play a significant role in the pathogenesis of SSNS, possibly through an abnormality in post-translational control of latent heparanase activation.