Activation of transforming growth factor-β(1 )and early atherosclerosis in systemic lupus erythematosus

The efficiency of activating latent transforming growth factor (TGF)-β(1 )in systemic lupus erythematosus (SLE) may control the balance between inflammation and fibrosis, modulating the disease phenotype. To test this hypothesis we studied the ability to activate TGF-β(1 )in SLE patients and control individuals within the context of inflammatory disease activity, cumulative organ damage and early atherosclerosis. An Activation Index (AI) for TGF-β(1 )was determined for 32 patients with SLE and 33 age-matched and sex-matched control individuals by quantifying the increase in active TGF-β(1 )under controlled standard conditions. Apoptosis in peripheral blood mononuclear cells was determined by fluorescence-activated cell sorting. Carotid artery intima-media thickness was measured using standard Doppler ultrasound. These measures were compared between patients and control individuals. In an analysis conducted in patients, we assessed the associations of these measures with SLE phenotype, including early atherosclerosis. Both intima-media thickness and TGF-β(1 )AI for SLE patients were within the normal range. There was a significant inverse association between TGF-β(1 )AI and levels of apoptosis in peripheral blood mononuclear cells after 24 hours in culture for both SLE patients and control individuals. Only in SLE patients was there a significant negative correlation between TGF-β(1 )AI and low-density lipoprotein cholesterol (r = -0.404; P = 0.022) and between TGF-β(1 )AI and carotid artery intima-media thickness (r = -0.587; P = 0.0004). A low AI was associated with irreversible damage (SLICC [Systemic Lupus International Collaborating Clinics] Damage Index ≥1) and was inversely correlated with disease duration. Intima-media thickness was significantly linked to total cholesterol (r = 0.371; P = 0.037). To conclude, in SLE low normal TGF-β(1 )activation was linked with increased lymphocyte apoptosis, irreversible organ damage, disease duration, calculated low-density lipoprotein levels and increased carotid IMT, and may contribute to the development of early atherosclerosis

A modified in vivo flow variation technique of microdialysis for sampling uremic toxins in the subcutaneous interstitial compartment

&lt;i&gt;Background:&lt;/i&gt; Uremic toxins are typically measured in plasma and little is known of their interstitial concentrations. We undertook experiments to validate a microdialysis technique for simultaneous recovery of small and large uremic toxins in the subcutaneous interstitial fluid (ISF). &lt;i&gt;Methods:&lt;/i&gt; Microdialysis catheters were inserted into the subcutaneous interstitium of 8 subjects (controls and uremic patients) and perfused using two different solutions at incremental flow rates to determine analyte recovery and ISF concentrations of urea and protein. &lt;i&gt;Results:&lt;/i&gt; 10% dextran-40 perfusate allowed the determination of interstitial concentrations of urea and protein reliably, by virtue of the exponential decay of their concentrations in the microdialysate with incremental flow rates (R&lt;sup&gt;2&lt;/sup&gt; = 0.63–0.99). Interstitial and plasma urea correlated well (r = 0.95), as did interstitial urea from distant anatomical sites (r = 0.96). &lt;i&gt;Conclusion:&lt;/i&gt; Cutaneous microdialysis with dextran-40 allows measurement of small and large molecule concentrations in ISF, creating an opportunity to characterize ISF in uremia.</jats:p

Towards a biomarker panel for the assessment of AKI in children receiving intensive care

BACKGROUND: Critically ill children and neonates are at high risk of developing acute kidney injury (AKI). AKI is associated with short- and long-term renal impairment and increased mortality. Current methods of diagnosing AKI rely on measurements of serum creatinine, which is a late and insensitive marker. Few studies to date have assessed AKI biomarkers in a heterogeneous patient cohort. METHODS: We conducted a prospective feasibility study in a paediatric intensive care setting over a 6-month period to describe the relationship between AKI (defined according to pRIFLE criteria) and new AKI biomarkers. RESULTS: In total, 49 patients between the ages of 16 days and 15 years were recruited for measurement of plasma cystatin C (Cys-C) and neutrophil gelatinase-associated lipocalin (pNGAL) concentrations, as well as for urinary kidney injury molecule-1 (KIM-1) and urinary NGAL (uNGAL) concentrations. Almost one-half (49 %) of the patient cohort experienced an AKI episode, and Cys-C and pNGAL were the strongest candidates for the detection of AKI. Our data suggest that the widely used estimated baseline creatinine clearance value of 120 mL/min/1.73 m(2) underestimates actual baseline function in patients admitted to paediatric intensive care units. CONCLUSIONS: This investigation demonstrates the feasibility of new AKI biomarker testing in a mixed patient cohort and provides novel biomarker profiling for further evaluation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00467-015-3089-3) contains supplementary material, which is available to authorized users

rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial.

BACKGROUND: Extended criteria donor (ECD) and donation after circulatory death (DCD) kidneys are at increased risk of delayed graft function (DGF). Experimental evidence suggests that erythropoietin (EPO) attenuates renal damage in acute kidney injury. This study piloted the administration of high dose recombinant human EPO-beta at implantation of ECD and DCD kidneys, and evaluated biomarkers of kidney injury post-transplant. METHODS: Forty patients were randomly assigned to receive either rhEPO-b (100,000 iu) (n = 19 in the intervention group, as 1 patient was un-transplantable post randomisation), or placebo (n = 20) in this, double blind, placebo-controlled trial at Manchester Royal Infirmary from August 2007 to June 2009. Participants received either an ECD (n = 17) or DCD (n = 22) kidney. Adverse events, renal function, haematopoietic markers, and rejections were recorded out to 90 days post-transplant. Biomarkers of kidney injury (neutrophil gelatinase-associated lipocalin, Kidney Injury Molecule-1 and IL-18) were measured in blood and urine during the first post-operative week. RESULTS: The incidence of DGF (53% vs 55%) (RR = 1.0; CI = 0.5-1.6; p = 0.93) and slow graft function (SGF) (32% vs 25%) (RR = 1.1; CI = 0.5-1.9; p = 0.73) respectively, serum creatinine, eGFR, haemoglobin and haematocrit, blood pressure, and acute rejection were similar in the 2 study arms. High dose rhEPO-b had little effect on the temporal profiles of the biomarkers. CONCLUSIONS: High dose rhEPO-b appears to be safe and well tolerated in the early post- transplant period in this study, but has little effect on delayed or slow graft function in recipients of kidneys from DCD and ECD donors. Comparing the profiles of biomarkers of kidney injury (NGAL, IL-18 and KIM-1) showed little difference between the rhEPO-b treated and placebo groups. A meta-analysis of five trials yielded an overall estimate of the RR for DGF of 0.89 (CI = 0.73; 1.07), a modest effect favouring EPO but not a significant difference. A definitive trial based on this estimate would require 1000-2500 patients per arm for populations with base DGF rates of 50-30% and 90% power. Such a trial is clearly unfeasible. TRIAL REGISTRATION: EudraCT Number 2006-005373-22 ISRCTN ISRCTN85447324 registered 19/08/09