Increased susceptibility to structural acute kidney injury in a mouse model of presymptomatic cardiomyopathy.

The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant α-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 vs. wild type 0.65 ± 0.16 mg/dl, P < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ml, P < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the Ren1 gene, marked overexpression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice vs. 2.01 ± 0.58 mg/dl in wild type, P < 0.05), urine NGAL (9,198.79 ± 3,799.52 in transgenic mice vs. 3,252.94 ± 2,420.36 ng/ml in wild type, P < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, P < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, P < 0.05), and TdT-mediated dUTP nick-end labeling (TUNEL)-positive nuclei (10.1 ± 2.1 in the transgenic group vs. 5.7 ± 1.6 per 100 cells counted in wild type, P < 0.01). Our findings indicate functional renal impairment, urinary biomarker elevations, and induction of renin gene and protein expression in the kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury.

A Novel Biomarker Panel to Identify Steroid Resistance in Childhood Idiopathic Nephrotic Syndrome.

Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Response to initial treatment with corticosteroids is an indicator of prognosis, as resistant patients often present more progressive disease. In this cross-sectional pilot study, we set out to discover a panel of noninvasive biomarkers that could distinguish steroid-resistant nephrotic syndrome (SRNS) from steroid-sensitive nephrotic syndrome (SSNS). Information gleaned from such a panel could yield more individualized treatment plans and prevent unnecessary steroid exposure in patients unlikely to respond. Urine was collected from 50 pediatric patients diagnosed with idiopathic NS at Cincinnati Children's Hospital Medical Center. Isobaric tags for relative and absolute quantitation (iTRAQ) was used to discover 13 proteins that were differentially expressed in SSNS vs SRNS in a small 5 × 5 discovery cohort. Suitable assays were found for 9 of the 13 markers identified by iTRAQ and were used in a 25 SRNS × 25 SSNS validation cohort. Vitamin D-binding protein (VDBP), alpha-1 acid glycoprotein 1 (AGP1), alpha-1 acid glycoprotein 2 (AGP2), alpha-1-B glycoprotein (A1BG), fetuin-A, prealbumin, thyroxine-binding globulin and hemopexin, and alpha-2 macroglobulin were measured and combined with urine neutrophil gelatinase-associated lipocalin (NGAL), which had been previously shown to distinguish patients with SRNS. Urinary VDBP, prealbumin, NGAL, fetuin-A, and AGP2 were found to be significantly elevated in SRNS using univariate analysis, with area under the receiver operating characteristic curves (AUCs) ranging from 0.65 to 0.81. Multivariate analysis revealed a panel of all 10 markers that yielded an AUC of 0.92 for identification of SRNS. A subset of 5 markers (including VDBP, NGAL, fetuin-A, prealbumin, and AGP2) showed significant associations with SRNS and yielded an AUC of 0.85.

Urinary Vitamin D-Binding Protein as a Biomarker of Steroid-Resistant Nephrotic Syndrome.

BACKGROUND: Idiopathic nephrotic syndrome (NS) is one of the most common glomerular disorders of childhood and is associated with increased urinary vitamin D-binding protein (uVDBP) excretion. We tested the hypothesis that uVDBP represents a biomarker to differentiate steroid-resistant nephrotic syndrome (SRNS) from the more benign forms of steroid-sensitive nephrotic syndrome (SSNS). METHODS: This cross-sectional study included children with SRNS (n = 24), SSNS (n = 28), and normal controls (n = 5). Urine and clinical data were collected from patients. Measurements of uVDBP were performed with a commercially available ELISA kit and normalized to urine creatinine. RESULTS: Concentrations of uVDBP were significantly higher (P < 0.001) in patients with SRNS (13,659 ng/mL, interquartile range [IQR] 477-22,979) than in patients with SSNS (94 ng/mL, IQR 53-202) and normal controls (23 ng/mL, IQR 22-99, P = 0.002). Significance did not change when the results were corrected for urine creatinine. uVDBP was significantly negatively correlated with estimated glomerular filtration rate (eGFR; R = -0.76, P = 0.03). However, uVDBP was still markedly elevated in patients with SRNS with eGFR >100 mL/minute/1.73 m(2). There was a positive correlation between microalbuminuria (MALB/Cr) and uVDBP (R = 0.67, P < 0.001). However, uVDBP displayed a much higher discriminatory ability for distinguishing SRNS than MALB/Cr (area under the curve = 0.92 vs 0.67, respectively). An uVDBP cutoff of 362 ng/mL yielded the optimal sensitivity (80%) and specificity (83%) to distinguish SRNS from SSNS. CONCLUSIONS: In this preliminary study, uVDBP represents a noninvasive biomarker that could distinguish SRNS from the more benign SSNS with high discriminatory power.

Burkitt lymphoma in a child with atopic dermatitis and a 7-year history of regular topical tacrolimus use.

We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.