Wim van Oeveren

Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes

OBJECTIVE We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS Damage markers were measured in triplicate in fresh morning urine samples and in plasma. RESULTS Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037). CONCLUSIONS Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.

Volume Status and Diuretic Therapy in Systolic Heart Failure and the Detection of Early Abnormalities in Renal and Tubular Function

OBJECTIVES This study sought to determine the pharmacodynamic effect of modulation of volume status by withdrawal and reinstitution of diuretic treatment on markers of renal and tubular function. BACKGROUND Decreased renal perfusion and increased congestion are associated with renal dysfunction in patients with heart failure. METHODS In this study, 30 patients with chronic systolic heart failure in a presumed euvolemic state and on standard oral furosemide therapy (40 to 80 mg) were examined. At baseline, subjects were withdrawn from their loop diuretics. After 72 h, their furosemide regimen was reinstated, and patients were studied again 3 days later. Serum creatinine, atrial and B-type natriuretic peptide, urinary kidney injury molecule (KIM)-1, urinary N-acetyl-beta-D-glucosaminidase (NAG), and serum as well as urinary neutrophil gelatinase-associated lipocalin (NGAL) were determined at various time points. RESULTS Diuretic withdrawal resulted in increases in atrial and B-type natriuretic peptide (both p < 0.05). Serum creatinine was unaffected. Both urinary KIM-1 (p < 0.001) and NAG (p = 0.010) concentrations rose significantly, after diuretic withdrawal, whereas serum and urinary NGAL were not significantly affected. After reinitiation of furosemide, both urinary KIM-1 and NAG concentrations returned to baseline (both p < 0.05), but NGAL values were unaffected. CONCLUSIONS Subclinical changes in volume status by diuretic withdrawal and reinstitution are associated with increases and decreases of markers of tubular dysfunction in stable heart failure. Diuretic therapy may favorably affect renal and tubular function by decreasing congestion.

Cerebral near infrared spectroscopy oximetry in extremely preterm infants : Phase II randomised clinical trial

Objective To determine if it is possible to stabilise the cerebral oxygenation of extremely preterm infants monitored by cerebral near infrared spectroscopy (NIRS) oximetry. Design Phase II randomised, single blinded, parallel clinical trial. Setting Eight tertiary neonatal intensive care units in eight European countries. Participants 166 extremely preterm infants born before 28 weeks of gestation: 86 were randomised to cerebral NIRS monitoring and 80 to blinded NIRS monitoring. The only exclusion criterion was a decision not to provide life support. Interventions Monitoring of cerebral oxygenation using NIRS in combination with a dedicated treatment guideline during the first 72 hours of life (experimental) compared with blinded NIRS oxygenation monitoring with standard care (control). Main outcome measures The primary outcome measure was the time spent outside the target range of 55-85% for cerebral oxygenation multiplied by the mean absolute deviation, expressed in %hours (burden of hypoxia and hyperoxia). One hour with an oxygenation of 50% gives 5%hours of hypoxia. Secondary outcomes were all cause mortality at term equivalent age and a brain injury score assessed by cerebral ultrasonography. Randomisation Allocation sequence 1:1 with block sizes 4 and 6 in random order concealed for the investigators. The allocation was stratified for gestational age (<26 weeks or ≥26 weeks). Blinding Cerebral oxygenation measurements were blinded in the control group. All outcome assessors were blinded to group allocation. Results The 86 infants randomised to the NIRS group had a median burden of hypoxia and hyperoxia of 36.1%hours (interquartile range 9.2-79.5%hours) compared with 81.3 (38.5-181.3) %hours in the control group, a reduction of 58% (95% confidence interval 35% to 73%, P<0.001). In the experimental group the median burden of hypoxia was 16.6 (interquartile range 5.4-68.1) %hours, compared with 53.6 (17.4-171.3) %hours in the control group (P=0.0012). The median burden of hyperoxia was similar between the groups: 1.2 (interquartile range 0.3-9.6) %hours in the experimental group compared with 1.1 (0.1-23.4) %hours in the control group (P=0.98). We found no statistically significant differences between the two groups at term corrected age. No severe adverse reactions were associated with the device. Conclusions Cerebral oxygenation was stabilised in extremely preterm infants using a dedicated treatment guideline in combination with cerebral NIRS monitoring. Trial registration ClinicalTrial.gov NCT01590316.

The value of machine perfusion perfusate biomarkers for predicting kidney transplant outcome

Background. Retrospective evidence suggests that lactate dehydrogenase, aspartate aminotransferase, total glutathione-S-transferase (GST), alanine-aminopeptidase, N-acetyl-&bgr;-d-glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) measured during kidney machine perfusion (MP) could have predictive value for posttransplant outcome. However, these data may be biased due to organ discard based on biomarker measurements, and previous analyses were not adjusted for likely confounding factors. No reliable prospective evidence has been available so far. Nevertheless, some centers already use these biomarkers to aid decisions on accepting or discarding a donor kidney. Methods. From 306 deceased-donor kidneys donated after brain death or controlled cardiac death and included in an international randomized controlled trial, these six biomarkers were measured in the MP perfusate. In this unselected prospective data set, we tested whether concentrations were associated with delayed graft function, primary nonfunction, and graft survival. Multivariate regression models investigated whether the biomarkers remained independent predictors when adjusted for relevant confounding factors. Results. GST, NAG, and H-FABP were independent predictors of delayed graft function but not of primary nonfunction and graft survival. Lactate dehydrogenase, aspartate aminotransferase, and alanine-aminopeptidase had no independent prognostic potential for any of the endpoints. Perfusate biomarker concentrations had no relevant correlation with cold ischemic time or renal vascular resistance on the pump. Conclusions. Increased GST, NAG, or H-FABP concentrations during MP are an indication to adjust posttransplant recipient management. However, this study shows for the first time that perfusate biomarker measurements should not lead to kidney discard.

Association of Urinary Biomarkers With Disease Severity in Patients With Autosomal Dominant Polycystic Kidney Disease: A Cross-sectional Analysis

BACKGROUND Disease monitoring of autosomal dominant polycystic kidney disease (ADPKD) will become more important with potential upcoming therapeutic interventions. Because serum creatinine level is considered of limited use and measurement of effective renal blood flow (ERBF) and total renal volume are time consuming and expensive, there is a need for other biomarkers. We aimed to investigate which urinary markers have increased levels in patients with ADPKD; whether these urinary markers are associated with measured glomerular filtration rate (mGFR), ERBF, and total renal volume; and whether these associations are independent of albuminuria (urine albumin excretion [UAE]). STUDY DESIGN Diagnostic test study. SETTING & PARTICIPANTS 102 patients with ADPKD (Ravine criteria) and 102 age- and sex-matched healthy controls. INDEX TEST 24-hour urinary excretion of glomerular (immunoglobulin G), proximal tubular (kidney injury molecule 1 [KIM-1], N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin [NGAL], and β(2)-microglobulin), and distal tubular (heart-type fatty acid binding protein [H-FABP]) damage markers and inflammatory markers (monocyte chemotactic protein 1 [MCP-1] and macrophage migration inhibitory factor). REFERENCE TEST Disease severity assessed using measures of kidney function (mGFR and ERBF, measured using clearance of iothalamate labeled with iodine 125 and hippuran labeled with iodine 131 during continuous infusion, respectively) and structure (total renal volume, measured using magnetic resonance imaging). OTHER MEASUREMENTS 24-hour UAE. RESULTS In 102 patients with ADPKD (aged 40 ± 11 years; 58% men), levels of all measured urinary biomarkers were increased compared with healthy controls. Excretion of immunoglobulin G and albumin relatively were most increased. ERBF and mGFR values were associated with urinary excretion of β(2)-microglobulin, NGAL, and H-FABP independent of UAE, whereas total renal volume was associated with KIM-1, NGAL, and MCP-1 independent of UAE. LIMITATIONS Cross-sectional, single center. CONCLUSIONS Levels of markers for multiple parts of the nephron are increased in patients with ADPKD. In addition to measurement of UAE, measurement of urinary β(2)-microglobulin, KIM-1, H-FABP, MCP-1, and especially NGAL could be of value for determination of disease severity in patients with ADPKD.

Albuminuria, Proteinuria, and Novel Urine Biomarkers as Predictors of Long-term Allograft Outcomes in Kidney Transplant Recipients

BACKGROUND Proteinuria is an established marker of decreased kidney function after kidney transplant. It recently has been suggested that albuminuria might be a more reliable marker. Although albuminuria often is regarded as a marker of glomerular damage, because chronic renal allograft damage is believed to be predominantly an interstitial process, albuminuria in this case might reflect tubular damage. Accordingly, we investigated the value of albuminuria, proteinuria, and tubular damage markers (KIM-1 [kidney injury molecule 1], NAG [N-acetyl-β-d-glucosaminidase], NGAL [neutrophil gelatinase-associated lipocalin], and H-FABP [heart fatty acid binding protein]) in predicting graft outcome in kidney transplant recipients. STUDY DESIGN Prospective observational cohort study. SETTING & PARTICIPANTS 606 patients visiting our outpatient kidney transplant clinic in 2001-2003 were included and used in the analysis for death-censored graft failure. Median follow-up was 4.7 (25th-75th percentile, 3.8-5.2) years. 577 patients had follow-up longer than 1 year and were included in the analysis for estimated glomerular filtration rate (eGFR) decrease. Median follow-up was 3.2 (25th-75th percentile, 2.7-3.7) years. PREDICTORS Urine protein, albumin, and tubular damage markers in 24-hour urine samples. OUTCOMES Death-censored graft failure and decrease in eGFR. RESULTS There were 42 patients with graft failure; mean eGFR change was -0.46 ± 3.7 (standard deviation) mL/min/1.73 m(2)/y. The area under the receiver operating characteristic curve for death-censored graft failure showed that albuminuria (0.78; 95% CI, 0.59-0.76) was significantly higher than proteinuria (0.67; 95% CI, 0.59-0.76; P = 0.001), NGAL (0.63; 95% CI, 0.52-0.74; P = 0.02), and H-FABP (0.62; 95% CI, 0.53-0.73; P = 0.005) and not significantly different from KIM-1 (0.74; 95% CI, 0.66-0.82) and NAG (0.75; 95% CI, 0.67-0.83). Results were similar for the eGFR decrease outcome. LIMITATIONS Single-center observational study. CONCLUSIONS Measuring albuminuria may provide superior predictions for long-term renal outcomes after kidney transplant than total proteinuria. Additional assessment of urinary excretion of tubular damage markers may have limited value.

The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants

Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting.

Early events in kidney donation: progression of endothelial activation, oxidative stress and tubular injury after brain death.

Cerebral injury leading to brain death (BD) causes major physiologic derangements in potential organ donors, which may result in vascular‐endothelial activation and affect posttransplant graft function. We investigated the kinetic of pro‐coagulatory and pro‐inflammatory endothelial activation and the subsequent oxidative stress and renal tubular injury, early after BD declaration. BD was induced by slowly inflating a balloon‐catheter inserted in the extradural space over a period of 30 min. Rats (n = 30) were sacrificed 0.5, 1, 2 or 4 h after BD‐induction and compared with sham‐controls. This study demonstrates immediate pro‐coagulatory and pro‐inflammatory activation of vascular endothelium after BD in kidney donor rats, proportional with the duration of BD. E‐ and P‐Selectins, Aα/Bβ‐fibrinogen mRNA were abruptly and progressively up‐regulated from 0.5 h BD onwards; P‐Selectin membrane protein expression was increased; fibrinogen was primarily visualized in the peritubular capillaries. Plasma von Willebrand factor was significantly higher after 2 h and 4 h BD. Urine heart‐fatty‐acid‐binding‐protein and N‐acetyl‐glucosaminidase, used as new specific and sensitive markers of proximal and distal tubular damage, were found significantly increased after 0.5 h, with a maximum at 4 h. Unexpectedly, oxidative stress was detectable only late, after the installation of tubular injury, suggesting only a secondary role for hypoxia in triggering these injuries.

Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review

Abstract Chronic kidney disease (CKD), especially in its end stage, is marked by extremely high cardiovascular rates of morbidity and mortality; hemodialysis patients have a five-fold shorter life expectancy than healthy subjects of the same age. In CKD the metabolic products that accumulate in the body are so-called uremic toxins. These include advanced glycation end-products (AGE). AGE levels are markedly increased in CKD patients not only because of impaired excretion but also because of increased production. AGE formation has initially been described as a non-enzymatic reaction between proteins and glucose in the so-called Maillard reaction, but they are also more rapidly formed during oxidative stress and subsequent formation of reactive carbonyl compounds like (methyl)glyoxal. AGE accumulate in tissue where they cross-link with proteins, e.g., collagen, inducing tissue stiffening of blood vessels and skin. They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in CKD. The accumulation of AGE in the skin can be measured non-invasively using autofluorescence. The skin autofluorescence is a strong marker of cardiovascular mortality in CKD. The focus of this review is on the role of tissue and plasma AGE, and of skin autofluorescence as a proxy of tissue AGE accumulation, in the increase in cardiovascular disease in end stage renal disease (ESRD). This review will also present the possibility of reducing the AGE accumulation in ESRD patients using the following five methods: 1) use of low AGE peritoneal dialysis solutions; 2) use of advanced hemodialysis techniques; 3) use of AGE reducing drugs; 4) optimizing the nutrition of hemodialysis patients; and 5) renal transplantation.

Heparin-coated bypass circuits: Effects on inflammatory response in pediatric cardiac operations

BACKGROUND This study was designed to investigate whether clinical signs of the inflammatory response in pediatric cardiac patients are reduced by heparin-coated cardiopulmonary bypass circuits and how this could be explained by differences in the pathophysiologic mechanisms involved. METHODS In a randomized, prospective study 19 patients underwent cardiopulmonary bypass either with Carmeda BioActive Surface bypass circuits (n = 9) or with identical noncoated circuits (control, n = 10). Clinical parameters were recorded during the first 48 hours after the start of operation. Blood samples for determination of terminal complement complex, soluble form of E-selectin, and beta-thromboglobulin were obtained perioperatively up to 24 hours after operation. RESULTS All clinical and inflammatory mediators showed a tendency in favor of the group with heparin-coated circuits. When analyzed on a point-by-point basis there were significant differences in postoperative central body temperature, soluble E-selectin levels, and beta-thromboglobulin levels (all p < 0.05). CONCLUSIONS These data suggest that the use of heparin-coated cardiopulmonary bypass offers clinical benefit and tends to reduce the release of inflammatory mediators.