Pharmacovigilance of nephrotoxic drugs in neonates:the Pottel method for acute kidney injury detection in ELBW neonates

Background: Extremely low birth weight (ELBW) neonates (birth weight ≤ 1000 g) are at high risk to develop drug-induced acute kidney injury (AKI). However, we lack a pragmatic detection tool to capture their time-dependent (patho)physiologic serum creatinine (Scr) patterns. Pottel et al. suggested rescaling Scr by dividing Scr with the mean Scr value of the age- and sex-specific reference population. We explored if this Pottel method can detect drug-related nephrotoxicity in ELBW neonates. Methods: A previously reported dataset on Scr changes in ELBW neonates exposed to ibuprofen, amikacin, or vancomycin was updated to calculate Pottel scores for every available Scr value in the first 28 postnatal days. We hereby used previously published postnatal age-specific 50th centile values in an ELBW population. Linear mixed models were applied, analyzing Pottel scores as response variable and continuous time (day), drug exposure, and interaction thereof in the explanatory model. Results: Serum creatinine (n = 3231) observations in 201 ELBW neonates were collected. A statistically significant rise of Pottel scores was observed with ibuprofen starting from postnatal day 4. In addition, a cumulative effect of treatment with mean Pottel scores on day 0 of 1.020 and on day 3 during treatment of 1.106 (95% CI 1.068–1.145, p &lt; 0.001) was observed, corrected for effect of antibiotics. Antibiotic administrations showed a small but statistically significant difference up to postnatal day 5. Conclusions: As rescaled Scr biomarker, the Pottel method showed a clear association with ibuprofen-exposed ELBW neonates, suggesting its applicability as a pragmatic bedside alternative tool to assess nephrotoxicity. Graphical abstract: (Figure presented.)</p

Glomerular Filtration Rate in Former Extreme Low Birth Weight Infants over the Full Pediatric Age Range: A Pooled Analysis

Various cohort studies document a lower glomerular filtration rate (GFR) in former extremely low birth weight (ELBW, <1000 g) neonates throughout childhood when compared to term controls. The current aim is to pool these studies to describe the GFR pattern over the pediatric age range. To do so, we conducted a systematic review on studies reporting on GFR measurements in former ELBW cases while GFR data of healthy age-matched controls included in these studies were co-collected. Based on 248 hits, 6 case-control and 3 cohort studies were identified, with 444 GFR measurements in 380 former ELBW cases (median age 5.3-20.7 years). The majority were small (17-78 cases) single center studies, with heterogeneity in GFR measurement (inulin, cystatin C or creatinine estimated GFR formulae) tools. Despite this, the median GFR (mL/min/1.73 m2) within case-control studies was consistently lower (-13%, range -8% to -25%) in cases, so that a relevant minority (15-30%) has a eGFR<90 mL/min/1.73 m2). Consequently, this pooled analysis describes a consistent pattern of reduced eGFR in former ELBW cases throughout childhood. Research should focus on perinatal risk factors for impaired GFR and long-term outcome, but is hampered by single center cohorts, study size and heterogeneity of GFR assessment tools

Paired measurement of urinary creatinine in neonates based on a Jaffe and an enzymatic IDMS-traceable assay

BACKGROUND: Urinary creatinine can be quantified by Jaffe or enzymatic assays and is commonly used as denominator of urinary excretion of electrolytes or protein. Paired analysis in pediatric and adult samples documented inter-assay differences (up to 80%). We verified the interchangeability of two IDMS-traceable assays (Jaffe and enzymatic) for neonatal urine and report on neonatal urinary creatinine values using these IDMS-traceable methods. METHODS: Creatinine was measured in 84 neonatal urine samples from 46 neonates by an IDMS traceable Jaffe and enzymatic assay (Roche Diagnostics, Cobas c702 module). Creatinine values, differences in urinary creatinine and clinical characteristics were described and covariates of between assay difference were explored (Wilcoxon, Bland-Altman, correlation, multiple regression). RESULTS: Median Jaffe and enzymatic urinary creatinine concentrations were 9.25 (range 3.7-42.2) and 9.15 (range 3.8-42.9) mg/dL respectively, resulting in a median difference of 0.08 (SD 0.6, range −2.4 to 0.96) mg/dL. In a multiple regression model, urinary enzymatic creatinine concentration (r = 0.45) and postnatal age (r = −0.59) remained independent variables of the difference between both assays (r(2) adj = 0.45). CONCLUSIONS: The tested IDMS-traceable assays showed interchangeable in heterogeneous neonatal urine samples. Using these assays, neonatal urinary creatinine showed 5–20 fold lower values than those observed in children or adults with a significant negative correlation with postnatal age

The importance of genetic testing in adolescent-onset steroid-resistant nephrotic syndrome - Case report

Approximately 10-20% of children and 40% of adults with idiopathic nephrotic syndrome are steroid resistant and progress to end-stage renal disease requiring dialysis or renal transplantation. In these cases, renal histology typically shows focal segmental glomerulosclerosis. Mutations in NPHS1, NPHS2, WT1, CD2AP and ACTN4 genes located on different chromosomes, expressed by glomerular podocytes, have been identified in patients with steroid-resistant nephrotic syndrome. The authors report two cases of adolescent-onset steroid-resistant nephrotic syndrome. Both cases had similar clinical and histopathological manifestations, with different prognosis and evolution due to different mechanisms leading to proteinuria: an acquired and a genetic form. The first case, a 16 year old girl presented the onset of the disease with massive, generalized edema, secondary hypothyroidism and high blood pressure. Evolution was favorable under cyclosporine therapy. The second case, a 13-years-old adolescent girl, presented an insidious onset of the disease with mild edema. Genetic testing revealed a mutation in the WT1 gene. The patient developed end-stage kidney failure eight months after the onset of the disease and following kidney transplant had a favorable evolution. Histological examination of the renal biopsy specimen showed focal segmental glomerulosclerosis in both cases. Conclusions: Genetic forms of nephrotic syndrome do not respond to immunosuppressive therapy and may progress to end-stage renal disease, but after kidney transplantation relapse is not expected, in contrast to the immune form. The early genetic diagnosis in steroid-resistant nephrotic syndrome is time-consuming, but is important for proper clinical management of the patients, prognosis and genetic counseling of the families

Oxidative stress in autosomal dominant polycystic kidney disease: player and/or early predictor for disease progression?

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and kidney enlargement ultimately leading to end-stage renal disease. ADPKD also causes extrarenal manifestations, including endothelial dysfunction and hypertension. Both of these complications are linked with reduced nitric oxide levels related to excessive oxidative stress (OS). OS, defined as disturbances in the prooxidant/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen and nitrogen free radicals. Next to endothelial dysfunction and hypertension, there is cumulative evidence that OS occurs in the early stages of ADPKD. In the current review, we aim to summarize the cardiovascular complications and the relevance of OS in ADPKD and, more specifically, in the early stages of the disease. First, we will briefly introduce the link between ADPKD and the early cardiovascular complications including hypertension. Secondly, we will describe the potential role of OS in the early stages of ADPKD and its possible importance beyond the chronic kidney disease (CKD) effect. Finally, we will discuss some pharmacological agents capable of reducing reactive oxygen species and OS, which might represent potential treatment targets for ADPKD

Treatment of steroid-resistant pediatric nephrotic syndrome

Children who suffer from steroid-resistant nephrotic syndrome (SRNS) require aggressive treatment to achieve remission. When intravenous high-dose methylprednisolone fails, calcineurin inhibitors, such as cyclosporine and tacrolimus, are used as the first line of treatment. A significant number of patients with SRNS progress to end-stage renal disease if remission is not achieved. For these children, renal replacement therapy can also be problematic; peritoneal dialysis may be accompanied by significant protein loss through the peritoneal membrane, and kidney allograft transplantation may be complicated by recurrence of SRNS. Plasmapheresis and rituximab were initially used for treatment of recurrent SRNS after transplantation; these are now under consideration as rescue therapies for refractory SRNS. Although the prognosis of SRNS is complicated and unfavorable, intensive treatment in the early stages of the disease may achieve remission in more than half of the patients. Therefore, timely referral of pediatric SRNS patients to pediatric nephrology specialists for histological and genetic diagnosis and treatment is highly recommended

Novel Human Podocyte Cell Model Carrying G2/G2 APOL1 High-Risk Genotype

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