Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients.

BACKGROUND: Fibroblast growth factor 23 (FGF23) and endothelium-related biomarkers have been related to AKI in critically-ill patients. Also, FGF23 is associated with endothelial dysfunction. In this study, we investigated if elevated FGF23 association with severe AKI is mediated by several endothelial/glycocalyx-related biomarkers. METHODS: Prospective cohort study with critically-ill patients. Blood samples were collected within the first 24 h after ICU admission. Severe AKI (defined according to KDIGO stage 2/3) was the analyzed outcome. RESULTS: 265 patients were enrolled and 82 (30.9%) developed severe AKI-defined according to KDIGO stage 2/3. Blood samples to biomarkers measurement were collected within the first 24 h after ICU admission. After adjustment for several variables, FGF23, vascular cell adhesion protein 1 (VCAM-1), angiopoietin 2 (AGPT2), syndecan-1 and intercellular adhesion molecule-1 (ICAM-1) were associated with severe AKI. The individual indirect effects of VCAM-1, AGPT2 and syndecan-1 explained 23%, 31%, and 32% of the total observed effect of FGF23 on severe AKI, respectively. ICAM-1 showed no statistically significant mediation. When all three endothelium-related biomarkers were included in a directed acyclic graph (DAG), the Bayesian network learning suggested the following causal association pathway FGF-23 → syndecan-1 → VCAM-1 → AGPT2 → severe AKI. CONCLUSIONS: The association between FGF23 and AKI are mediated by endothelium-related biomarkers, mainly VCAM-1, AGPT2 and syndecan-1. Moreover, the statistical models show that syndecan-1, a biomarker of endothelial glycocalyx dysfunction, seems to be the initial mediator between FGF23 and severe AKI.

Angiopoietin-2 as a predictor of acute kidney injury in critically ill patients and association with ARDS.

BACKGROUND AND OBJECTIVE: Angiopoietin-2 (AGPT2) has been proposed as a key mediator of organ dysfunction, mainly in acute respiratory distress syndrome (ARDS). It has also been associated with acute kidney injury (AKI). We aimed to investigate the role of AGPT2 in patients with and without ARDS. METHODS: In a cohort study with critically ill patients, AGPT1 and AGPT2 were assayed in plasma collected within the first 24 h after admission to intensive care unit (ICU). Severe AKI and the need for dialysis were outcome measures from comparative analysis with clinical characteristics useful for AKI risk stratification. RESULTS: Among 283 patients (50.2% males), 109 (38.5%) had ARDS. AGPT2 levels at admission were higher in patients with ARDS. Although overall AGPT2 and AGPT2/AGPT1 levels were associated with severe AKI, this association was not significant in patients without ARDS; however, it remained strongly significant in ARDS patients. In patients without ARDS, AGPT2 showed only a weak discriminatory capacity to predict severe AKI (area under the curve (AUC): 0.64 vs 0.81 in the ARDS group). The continuous net reclassification improvement (NRI) in the ARDS group resulting from AGPT2 inclusion was 64.1% (P < 0.001) and the integrated discrimination improvement (IDI) index was 0.057 (P = 0.003). There was no significant difference in NRI in the no-ARDS group. CONCLUSION: AGPT2 and AGPT2/AGPT1 ratio are associated with severe AKI and there was only a need of renal replacement therapy (RRT) in patients with or at risk of ARDS, not in other critically ill patients. Adding AGPT2 to a clinical model resulted in a significant improvement in the capacity to predict severe AKI specifically in ARDS patients.

Urinary Syndecan-1 and acute kidney injury after pediatric cardiac surgery.

INTRODUCTION: Acute kidney injury (AKI) is a common occurrence after pediatric cardiac surgery. Plasma syndecan-1 is a biomarker of endothelial glycocalyx damage and it is associated with AKI. Syndecan-1 is also expressed in renal tubular cells but there is no study evaluating urinary syndecan-1 in predicting AKI. METHODS: Prospective cohort study with 86 patients ≤18 years submitted to cardiac surgery at one reference institution. Postoperative urinary syndecan-1 was collected within the first 2 h after cardiac surgery. Severe AKI - defined according to KDIGO as stage 2 or 3 - doubling of serum creatinine from the preoperative value or need for dialysis during hospitalization was the main outcome. Analyses were adjusted for clinical cofounders. RESULTS: Postoperative urinary syndecan-1 levels were higher in patients with severe AKI and even after adjustment for several clinical variables; the fourth quartile was significantly associated with severe AKI. The AUC-ROC for postoperative urinary syndecan-1 showed good discriminatory capacity (AUC-ROC = 0.793). The addition of urinary syndecan-1 improved the discrimination capacity of a clinical model (0.78 to 0.84). It also improved risk prediction, as measured by net reclassification improvement (NRI). CONCLUSION: Urinary syndecan-1 predicts severe AKI after pediatric cardiac surgery. Moreover, it appears to add capacity to predict severe AKI into a clinical model.

Renal Evaluation in Common Variable Immunodeficiency.

INTRODUCTION: Common variable immunodeficiency (CVID) comprises a heterogeneous group of disorders characterized by impaired antibody production. Kidney involvement in CVID is described in isolated and sporadic case reports. The objective of this study was to study the renal function pattern in CVID patients through glomerular and tubular function tests. METHODS: Study of 12 patients with CVID diagnosis and 12 healthy control individuals. Glomerular filtration rate (GFR), fractional excretion of sodium (FENa+ ) and potassium (FEK+ ), urinary concentration, and acidification capacity were measured. In addition, microalbuminuria and urinary monocyte chemoattractant protein-1 (MCP-1) were evaluated as markers of selectivity of the glomerular barrier and inflammation, respectively. RESULTS: In relation to glomerular markers, all CVID patients had normal GFR (>90 mL/min/1.73 m2), and microalbuminuria and urinary MCP-1 levels were also similar to those of controls. Interestingly, CVID patients had reduced urinary concentration capacity, as demonstrated by lower U/POsm ratio, when compared to controls. Also, while all control subjects achieved a urinary pH less than 5.3, no CVID patients showed a decrease in urinary pH to such levels in response to acid loading with CaCl2, characterizing impaired urinary acidification capacity. CONCLUSION: Patients showed a trend towards an elevated prevalence of tubular dysfunction, mainly related to urinary acidification and concentration capacities.

Quantitative Renal Echogenicity as a Tool for Diagnosis of Advanced Chronic Kidney Disease in Patients with Glomerulopathies and no Liver Disease.

BACKGROUND/AIMS: Glomerulopathy patients are prone to developing transitory reduced glomerular filtration rate (GFR), which can be difficult to differentiate from irreversible chronic kidney disease (CKD). Renal ultrasound can be useful, but differently from renal length, quantitative renal echogenicity has not been formerly evaluated regarding its capacity to identify irreversible advanced CKD. METHODS: A prospective study was performed, where quantitative renal echogenicity was performed during renal biopsy in patients with suspected glomerular disease (n=197). Quantitative echogenicity was measured as the inverse of the ratio between the mean pixel densities of the renal cortex and adjacent liver using ScionImage software. Patients were followed during a six-months period to ascertain irreversible advanced CKD. Quantitative renal echogenicity and histopathology parameters discriminatory capacity were compared regarding their capacity to detect advanced and irreversible CKD - estimated GFR less than 30mL/min/1.73m2 confirmed after a six-month follow-up. RESULTS: At renal biopsy, the mean eGFR was 53.9±33.6 mL/min/1.73m2 and 63 (32.0%) patients had an eGFR less than 30 mL/min/1.73m2. Mean kidney/liver echogenicity ratio was 1.06±0.19 and it was inversely correlated with eGFR at follow-up (r=-0.684, p<0.001). Multivariate analysis was performed to create a histopathology index that correctly identifies irreversible advanced CKD. Renal echogenicity discriminatory capacity to identify irreversible advanced CKD was 0.793 (0.719 -0.867), similar to the histopathology index. Elevated renal echogenicity with best discriminatory capacity was a kidney/liver ratio greater than 1.15. This cutoff had a predictive positive value of 92% in patients with eGFR less than 30mL/min/1.73m2. CONCLUSION: Quantitative renal echogenicity can be a useful tool in patients with glomerular disease and normal kidney size (>8cm) to identify those patients with irreversible advanced CKD.

Syndecan-1 improves severe acute kidney injury prediction after pediatric cardiac surgery.

OBJECTIVE: Acute kidney injury is a common occurrence after pediatric cardiac surgery and is associated with adverse patient outcomes. Syndecan-1 is a biomarker of endothelial glycocalyx damage, and its early increment after surgery can be associated with acute kidney injury. METHODS: We performed a prospective cohort study with 289 patients aged less than 18 years who underwent cardiac surgery at 1 reference institution. Postoperative plasma syndecan-1 was collected within the first 2 hours after cardiac surgery. Severe acute kidney injury, defined according to Kidney Disease: Improving Global Outcomes stage 2 or 3, doubling of serum creatinine from the preoperative value, or need for dialysis during hospitalization, was the main outcome. Analyses were adjusted for clinical variables and "renal angina index" components (early decrease in estimated creatinine clearance from baseline and increase in percent of intensive care unit fluid overload on the first postoperative day). RESULTS: Plasma syndecan-1 levels measured early in the postoperative period were independently associated with severe acute kidney injury. The accuracy of postoperative syndecan-1 for the diagnosis of severe acute kidney injury was moderate (area under the curve receiver operating characteristic, 0.77; 95% confidence interval, 0.68-0.85). The addition of syndecan-1 improved the discrimination capacity of a clinical model from 0.80 to 0.86 (P = .004) and improved risk prediction, as measured by net reclassification improvement and integrated discrimination improvement. Postoperative sundecan-1 levels also were independently associated with longer length of intensive care unit and hospital stay. CONCLUSIONS: Postoperative plasma syndecan-1 is associated with subsequent severe acute kidney injury and poor outcomes among children undergoing cardiac surgery. It may be useful to identify patients who are at increased risk for acute kidney injury after cardiac surgery.

Glycocalyx injury in adults with nephrotic syndrome: Association with endothelial function.

BACKGROUND: Glomerulopathy is a group of diseases that affect mainly young adults. Endothelial dysfunction, atherosclerosis, and increased cardiac mortality can complicate the evolution of such patients. However, there is no study evaluating endothelial glycocalyx in this pathology. METHODS: This cross-sectional study included 49 patients with untreated primary nephrotic syndrome that were otherwise healthy. In addition to routine laboratory measurements, syndecan-1, intercellular adhesion molecule-1 (ICAM-1), and e-selectin were measured. Moreover, flow-mediated dilation (FMD) was used as the main endothelial function surrogate. RESULTS: Of the 49 patients with nephrotic syndrome, 25 (51.0%) were females. The mean age of patients was 39.0±12.1y. FMD was reduced in nephrotic patients in comparison with controls (3.7±1.7 vs. 6.6±1.1%, p<0.001). Nephrotic patients had higher levels of ICAM-1 (616.6±219.7 vs. 356.9±102.0ng/ml, p<0.001) and syndecan-1 (180.3±64.1 vs. 28.2±9.8ng/ml, p<0.001). No significant difference was observed regarding e-selectin (129.9±54.2 vs. 120.2±61.5ng/ml, p=0.489). After adjusting for age and glomerular filtration rate, syndecan-1 was significantly associated with 24-h urinary protein excretion, LDL-cholesterol, HDL-cholesterol, and triglycerides. While age, LDL-cholesterol, and 24-h urinary protein excretion were associated with FMD in the multivariate analysis, when syndecan-1, ICAM-1, and e-selectin were added to the model, only syndecan-1 was independently associated with FMD. CONCLUSIONS: We demonstrated that syndecan-1, a marker of endothelial glycocalyx damage, is increased in patients with nephrotic syndrome and near-normal renal function. Moreover, we determined its association with nephrotic syndrome features and suggest it can have a role in the endothelial dysfunction of these patients.