tion’, implying that most patients ‘should’ receive a particular action. In contrast, level 2 guidelines are essentially ‘suggestions’ and are deemed to be ‘weak’ or discretionary, recognising that management decisions may vary in different clinical contexts. Each recommendation was further graded from A to D by the quality of evidence underpinning them, with grade A referring to a high quality of evidence whilst grade D recognised a ‘very low’ evidence base. The overall strength and quality of the supporting evidence is summarised in table 1 . The guidelines focused on 4 key domains: (1) AKI definition, (2) prevention and treatment of AKI, (3) contrastinduced AKI (CI-AKI) and (4) dialysis interventions for the treatment of AKI. The full summary of clinical practice statements is available at www.kdigo.org, but a few key recommendation statements will be highlighted here.

/pdf/kdigo-clinical-practice-guidelines-for-acute-kidney-injury-27tybolw7l.pdf

KDIGO clinical practice guidelines for acute kidney injury.

Dendrimers are branched, synthetic polymers with layered architectures that show promise in several biomedical applications. By regulating dendrimer synthesis, it is possible to precisely manipulate both their molecular weight and chemical composition, thereby allowing predictable tuning of their biocompatibility and pharmacokinetics. Advances in our understanding of the role of molecular weight and architecture on the in vivo behavior of dendrimers, together with recent progress in the design of biodegradable chemistries, has enabled the application of these branched polymers as anti-viral drugs, tissue repair scaffolds, targeted carriers of chemotherapeutics and optical oxygen sensors. Before such products can reach the market, however, the field must not only address the cost of manufacture and quality control of pharmaceutical-grade materials, but also assess the long-term human and environmental health consequences of dendrimer exposure in vivo.

Designing dendrimers for biological applications.

Many solid tumours show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport. This barrier is an obstacle in tumour treatment, as it results in inefficient uptake of therapeutic agents. There are a number of factors that contribute to increased IFP in the tumour, such as vessel abnormalities, fibrosis and contraction of the interstitial matrix. Lowering the tumour IFP with specific signal-transduction antagonists might be a useful approach to improving anticancer drug efficacy.

High interstitial fluid pressure — an obstacle in cancer therapy

In vivo medical imaging has made great progress due to advances in the engineering of imaging devices and developments in the chemistry of imaging probes Several modalities have been utilized for medical imaging, including X-ray radiography and computed tomography (x-ray CT), radionuclide imaging using single photons and positrons, magnetic resonance imaging (MRI), ultrasonography (US), and optical imaging In order to extract more information from imaging, “contrast agents” have been employed For example, organic iodine compounds have been used in X-ray radiography and computed tomography, superparamagnetic or paramagnetic metals have been used in MRI, and microbubbles have been used in ultrasonography Most of these, however, are non-targeted reagents

Molecular imaging is widely considered the future for medical imaging Molecular imaging has been defined as the in vivo characterization and measurement of biologic process at the cellular and molecular level1, or more broadly as a technique to directly or indirectly monitor and record the spatio-temporal distribution of molecular or cellular processes for biochemical, biologic, diagnostic, or therapeutic application2 Molecular imaging is the logical next step in the evolution of medical imaging after anatomic imaging (eg x-rays) and functional imaging (eg MRI) In order to attain truly targeted imaging of specific molecules which exist in relatively low concentrations in living tissues, the imaging techniques must be highly sensitive Although MRI, US, and x-ray CT are often listed as molecular imaging modalities, in truth, radionuclide and optical imaging are the most practical modalities, for molecular imaging, because of their sensitivity and the specificity for target detection

Radionuclide imaging, including gamma scintigraphy and positron emission tomography (PET), are highly sensitive, quantitative, and offer the potential for whole body scanning However, radionuclide imaging methods have the disadvantages of poor spatial and temporal resolution3 Additionally, they require radioactive compounds which have an intrinsically limited half life, and which expose the patient and practitioner to ionizing radiation and are therefore subject to a variety of stringent safety regulations which limit their repeated use4

Optical imaging, on the other hand, has comparable sensitivity to radionuclide imaging, and can be “targeted” if the emitting fluorophore is conjugated to a targeting ligand3 Optical imaging, by virtue of being “switchable”, can result in very high target to background ratios “Switchable” or activatable optical probes are unique in the field of molecular imaging since these agents can be turned on in specific environments but otherwise remain undetectable This improves the achievable target to background ratios, enabling the detection of small tumors against a dark background5,6 This advantage must be balanced against the lack of quantitation with optical imaging due to unpredictable light scattering and absorption, especially when the object of interest is deep within the tissue Visualization through the skin is limited to superficial tissues such as the breast7-9 or lymph nodes10,11 The fluorescence signal from the bright GFP-expressing tumors can be seen in the deep organ only in the nude mice 12,13 However, optical molecular imaging can also be employed during endoscopy14 or surgery 15,16

/pdf/new-strategies-for-fluorescent-probe-design-in-medical-1mcbc28raf.pdf

New Strategies for Fluorescent Probe Design in Medical Diagnostic Imaging

Acute kidney injury

This review focuses on the intricate properties of the glomerular barrier. Other reviews have focused on podocyte biology, mesangial cells, and the glomerular basement membrane (GBM). However, since all components of the glomerular membrane are important for its function, proteinuria will occur regardless of which layer is affected by disease. We review the properties of endothelial cells and their surface layer, the GBM, and podocytes, discuss various methods of studying glomerular permeability, and analyze data concerning the restriction of solutes by size, charge, and shape. We also review the physical principles of transport across biological or artificial membranes and various theoretical models used to predict the fluxes of solutes and water. The glomerular barrier is highly size and charge selective, in qualitative agreement with the classical studies performed 30 years ago. The small amounts of albumin filtered will be reabsorbed by the megalin-cubulin complex and degraded by the proximal tubular cells. At present, there is no unequivocal evidence for reuptake of intact albumin from urine. The cellular components are the key players in restricting solute transport, while the GBM is responsible for most of the resistance to water flow across the glomerular barrier.

Properties of the Glomerular Barrier and Mechanisms of Proteinuria

In this review we summarized the evidence favoring the concept that the major plasma proteins are passively transported across vascular walls through water-filled pathways by means of convection and diffusion. With regard to solute transport, a majority of microvascular walls seems to show a bimodal size selectivity. This implies the presence of a high frequency of functional small pores, restricting proteins, and an extremely low number of non-size-selective pathways, permitting the passage of macromolecules from blood to tissue, here denoted large pores. We discussed the general behavior of such a heteroporous system. A major consequence of two-pore heteroporosity is that large-solute transport must mainly occur due to convection through large pores at low filtration rates, that is, at normal or even zero lymph flows. Indeed, convection must be the predominating transport mode for most solutes across large pores when the net filtration rate is zero. Under these (transient) conditions, the convective leak of macromolecules across large pores will be counterbalanced by absorption of essentially protein-free fluid through protein-restrictive pores. In a heteroporous membrane, proteins can thus be transported by solvent drag across vascular walls in the absence of a net convection. Normally the steady-state transcapillary fluid flow (lymph flow) is about equally partitioned among small and large pores, which makes lymph essentially a "half and half" mixture of protein-free ultrafiltrate and plasma. With increasing fluid flows, however, the plasma filtrate will be progressively diluted, eventually reaching a protein concentration largely in proportion to the fractional hydraulic conductance accounted for by the large pores (alpha L). Under these high lymph flow conditions, not only the large-pore transport but also the small-pore transport (of smaller macromolecules) will become convective. At low lymph flows, however, the small-pore transport of smaller macromolecules is usually mostly diffusive. An important implication of capillary heteroporosity is that single-pore formalism is inadequate for correctly evaluating the capillary sieving characteristics. With the use of homoporous transport formalism, the "lumped" macromolecular PS and sigma will therefore vary as a function of transcapillary fluid flow (Jv). However, it is approximately correct to use single-pore formalism for conditions when Jv is very high during steady state. Thus, if minimal sieving coefficients can be measured for macromolecules, then these values will accurately reflect (1 - sigma).(ABSTRACT TRUNCATED AT 400 WORDS)

Transport of macromolecules across microvascular walls: the two-pore theory

Computer simulations of peritoneal fluid transport in CAPD.

https://www.kidney-international.org/article/S0085-2538(15)47472-1/pdf

Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products

Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-β activation in podocytes; however, it is not clear how TGF-β signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-β signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.

/pdf/endothelial-mitochondrial-oxidative-stress-determines-4nl523lsyg.pdf

Börje Haraldsson

Papers

Properties of the Glomerular Barrier and Mechanisms of Proteinuria

Transport of macromolecules across microvascular walls: the two-pore theory

Computer simulations of peritoneal fluid transport in CAPD.

Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products

Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis