A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children.

BACKGROUND: Acute kidney injury (AKI) increases the morbidity of critically ill children. Thus, it is necessary to identify better renal biomarkers to follow the outcome of these patients. This prospective case-control study explored the clinical value of a urinary biomarker profile comprised of neutrophil gelatinase lipocalin (uNGAL), fibroblast growth factor-2 (uFGF-2), and epidermal growth factor (uEGF) to follow these patients. METHODS: Urine samples were collected from 21 healthy children, and 39 critically ill children (mean age 7.5 years ± 6.97 SD) admitted to a pediatric intensive care unit with sepsis or requiring extra corporeal membrane oxygenation (ECMO). uNGAL, uFGF-2, and uEGF levels were measured using ELISA kits during the first 24 h of admission to PICU, at peak of illness, and upon resolution of the critical illness. RESULTS: On admission, the uNGAL and uFGF-2 levels were increased, and the uEGF levels were decreased, in critically ill children with AKI (n = 19) compared to those without AKI (n = 20), and healthy controls. A biomarker score using the combined cut-off values of uNGAL, uFGF-2, and uEGF (AUC = 0.90) showed the highest specificity to identify children with AKI, relative to each biomarker alone. uNGAL and uFGF-2 on admission showed high sensitivity and specificity to predict mortality (AUC = 0.82). CONCLUSIONS: The biomarker profile comprised of uNGAL, uFGF-2, and uEGF increased the specificity to detect AKI in critically ill children, when compared to each biomarker used alone. uNGAL and uFGF-2 may also predict the risk of death. Further validation of these findings in a large sample size is warranted.

Role of circulating fibroblast growth factor-2 in lipopolysaccharide-induced acute kidney injury in mice.

Fibroblast growth factor-2 (FGF-2) is an angiogenic growth factor involved in renal growth and regeneration. Previous studies in rodents revealed that single intrarenal injections of FGF-2 improved the outcome of acute kidney injury (AKI). Septic children usually show elevated plasma levels of FGF-2, and are at risk of developing AKI. However, the role of circulating FGF-2 in the pathogenesis of AKI is not well understood. We have developed a mouse model to determine how FGF-2 released into the circulation modulates the outcome of AKI induced by lipopolysaccharide (LPS). Young FVB/N mice were infected with adenoviruses carrying a secreted form of human FGF-2 or control LacZ vectors. Subsequently, when the circulating levels of FGF-2 were similar to those seen in septic children, mice were injected with a non-lethal dose of LPS or control buffer. All mice injected with LPS developed hypotension and AKI, from which they recovered after 5 days. FGF-2 did not improve the outcome of AKI, and induced more significant renal proliferative and apoptotic changes during the recovery phase. These findings suggest that circulating FGF-2 may not necessarily prevent the development or improve the outcome of AKI. Moreover, the renal accumulation of FGF-2 might cause further renal damage.

Serum uric acid is associated with high blood pressure in pediatric hemodialysis patients.

Serum uric acid (UA) is positively associated with hypertension (HTN). HTN is common in pediatric patients receiving hemodialysis (HD) and peritoneal dialysis (PD). We assessed the relationship between UA and BP in 63 pediatric dialysis patients by measuring pre-treatment UA levels and BP in HD patients and in-center UA levels and blood pressure (BP) in PD patients. UA levels were similar in both groups [6.8 ± 0.2 (HD) vs. 6.5 ± 0.3 (PD), p = 0.6]. Pre-treatment systolic BP percentile was associated with a high UA level [91.9 ± 2.3 (>6.0 mg/dL) vs. 79.3 ± 5.8 mm Hg (≤6.0 mg/dL), p = 0.01] in HD patients only. There was a negative relationship between UA and dialysis vintage (r = -0.31, p = 0.01). In both groups, there was no relationship between UA and Kt/V. In HD patients, fluid overload was unrelated to UA level [4.2 ± 0.6% (≤6.0 mg/dL) vs. 4.3 ± 0.3% (>6.0 mg/dL), p = 0.9]. Moreover, pre-HD treatment systolic BP percentile correlated with UA (beta 0.36, p = 0.02) independent of volume. UA levels were higher in patients receiving anti-hypertensive medications [6.3 ± 0.2 (No Meds] vs 7.0 ± 0.2 (BP Meds) mg/dL, p= 0.01]. Finally, there was no relationship between serum UA and normalized protein catabolic rate (r = 0.14; p = 0.4). In summary, serum UA impacts BP in pediatric HD patients, independent of volume, nutritional and weight status.

Anti-erythropoietin antibodies followed by endogenous erythropoietin production in a dialysis patient.

We present a case of a young girl with end-stage renal disease secondary to anti-glomerular basement membrane disease who was receiving maintenance peritoneal dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO) antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia. Initially, the patient required intermittent red blood cell transfusions. After immunosuppressive therapy had been initiated with corticosteroids and cyclosporine, the EPO antibody levels decreased precipitously, associated with an increased level of endogenous EPO production. For the following 6 months, the patient maintained adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.

A urinary biomarker profile for children with HIV-associated renal diseases.

Human immunodeficiency virus (HIV)-infected children are at risk of developing several types of renal diseases, including HIV-associated nephropathy (HIVAN), which is usually seen during late stages of infection in children with a high viral load. This disease is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global-focal segmental glomerulosclerosis combined with microcystic transformation of the renal tubules. Because HIVAN can have an insidious clinical onset, renal biopsy is the only definitive way of establishing a diagnosis. Given the risk of performing this procedure in HIV-infected children with other AIDS-defining illness, we sought to identify informative biomarkers such as growth factors in the urine of 55 HIV-infected children that might be predictive of the extent and activity of the renal lesions characteristic of HIVAN. We found that the levels of epidermal growth factor were lower in the urine of children with renal disease, whereas levels of fibroblast growth factor-2 and metalloproteinase-2 were higher as compared with those levels in infected children without renal disease. Similar changes were observed in HIV-Tg26 mice correlating with the progression of renal disease in this model of HIVAN. Our findings suggest that this urinary growth factor profile may be useful in facilitating the diagnosis of HIV-infected children at risk of developing HIVAN when interpreted in the appropriate clinical setting.