Successful Introduction of Human Renovascular Units into the Mammalian Kidney.

BACKGROUND: Cell-based therapies aimed at replenishing renal parenchyma have been proposed as an approach for treating CKD. However, pathogenic mechanisms involved in CKD such as renal hypoxia result in loss of kidney function and limit engraftment and therapeutic effects of renal epithelial progenitors. Jointly administering vessel-forming cells (human mesenchymal stromal cells [MSCs] and endothelial colony-forming cells [ECFCs]) may potentially result in in vivo formation of vascular networks. METHODS: We administered renal tubule-forming cells derived from human adult and fetal kidneys (previously shown to exert a functional effect in CKD mice) into mice, alongside MSCs and ECFCs. We then assessed whether this would result in generation of "renovascular units" comprising both vessels and tubules with potential interaction. RESULTS: Directly injecting vessel-forming cells and renal tubule-forming cells into the subcutaneous and subrenal capsular space resulted in self-organization of donor-derived vascular networks that connected to host vasculature, alongside renal tubules comprising tubular epithelia of different nephron segments. Vessels derived from MSCs and ECFCs augmented in vivo tubulogenesis by the renal tubule-forming cells. In vitro coculture experiments showed that MSCs and ECFCs induced self-renewal and genes associated with mesenchymal-epithelial transition in renal tubule-forming cells, indicating paracrine effects. Notably, after renal injury, renal tubule-forming cells and vessel-forming cells infused into the renal artery did not penetrate the renal vascular network to generate vessels; only administering them into the kidney parenchyma resulted in similar generation of human renovascular units in vivo. CONCLUSIONS: Combined cell therapy of vessel-forming cells and renal tubule-forming cells aimed at alleviating renal hypoxia and enhancing tubulogenesis holds promise as the basis for new renal regenerative therapies.

Restoring the function of a diseased kidney via its microvasculature.

BACKGROUND: Based upon observations which indicate that chronic intrarenal hypoxia and microvascular obliteration play an important role in the pathogenesis of renal scarring and loss of function, the idea is presented that restoration of kidney structure and function by arresting microvascular drop-out and restoring the interstitial capillary network could be a feasible approach to regeneration of a diseased kidney. This paper addresses the reasoning behind this possibility. SUMMARY: A 'unifying vasculogenic hypothesis' is discussed which proposes that, in hypoxic nephrons which retain poorly functioning vascular and epithelial elements, the disease process can be slowed or arrested, and nephrons regenerated, by adoptive transfer of endothelial progenitor cells to restore interstitial and glomerular vascular integrity. It is suggested that no other cell types are required to achieve this end. Improved differentiation, proliferation, and function of surviving nephrons could be achieved by restoring adequate oxygen delivery via this approach. KEY MESSAGES: It is hypothesized that, to regenerate the function of a chronically diseased kidney, it is not plausible to create new nephrons. Restoration of function of surviving nephrons could be achieved by regeneration of the renal microvasculature alone. Based upon observations that have demonstrated the feasibility of adoptive endothelial progenitor cell transfer into the kidney, this hypothesis is worthy of being tested.

Ernest Henry Starling (1866-1927) on the formation and reabsorption of lymph.

Ernest Henry Starling laid the groundwork for our modern understanding of how the interstitial fluid, which he referred to as 'lymph', is regulated. Together with his colleague, William Bayliss, he provided the crucial insight into how fluid is driven out of the capillary to form interstitial fluid. That was to measure (estimate) the capillary pressure in different parts of the circulation and to relate changes in these pressures to altered lymph formation. In addressing how interstitial fluid re-enters the circulation, he was able to show that this occurs not only via the lymphatics, but also by re-entering the capillaries, mediated by the oncotic pressure of the plasma proteins. Starling's discoveries put to rest all notions that the processes of filtration and reabsorption of fluid are mediated by the 'vital activity' of cells. They could be explained entirely on the basis of physic-chemical forces. Based upon his insights from animal experiments, he was able to explain the genesis of edema (dropsy) in a number of disease states, including venous obstruction, cardiac disease and inflammatory conditions.

Ernest Henry Starling (1866-1927) on the glomerular and tubular functions of the kidney.

Around the turn of the 20th century, Ernest Henry Starling (1866-1927) made many fundamental contributions to the understanding of human physiology. With a deep interest in how fluid balance is regulated, he naturally turned to explore the intricacies of kidney function. Early in his career he focused upon the process of glomerular filtration and was able to substantiate the view of Carl Ludwig that this process can be explained entirely upon the basis of hydrostatic and oncotic pressure gradients across the glomerular capillary wall and that the process can be regulated by alterations in the tone of the afferent and efferent arterioles. To explore renal tubular function he employed a heart-lung-kidney model in the dog and was able to infer that certain substances are reabsorbed by the tubules (e.g. sodium chloride) and certain by tubular secretion (e.g. uric acid, indigo carmine dye). By temporarily blocking tubular function using hydrocyanic acid he was able to conclude that secreted substances must be taken up on the peritubular side of the cell and concentrated within the cell to drive the secretory process. Finally, he was able to appreciate that the kidney is an organ which is regulated according to the needs of the organism and that the processes of glomerular filtration, tubular secretion and reabsorption are all subject to regulatory influences, which have evolved to conserve the normal chemical composition of the cells and fluids of the body.

The Transformative Influence of La Varenne's Le Cuisinier Francois (1651) on French Culinary Practice.

The current proliferation of modern cookbooks targeted to the public at large makes it impossible to conceive of there being any that could have had an overriding influence on culinary practice or eating preferences, even at a local level. However, when there was a historical absence of cookbooks for a half-century, as there was in France in the first half of the seventeenth century, it is argued herein that the advent of a single cookbook in 1651, Le Cuisinier Francois by La Varenne, could have had a transformational influence on culinary practice over the ensuing half-century. The book went into more than 50 subsequent editions in the second half of the century. La Varenne stated clearly that his intent was to provide a guide for professional cooks. However, it is hypothesized in this article that the widespread and enduring success of the book was due to its attraction to and acquisition by the general public, including household cooks. This can be ascribed to (i) the fact that there had been no French cookbook describing novel culinary approaches in the preceding 50 years, (ii) La Varenne's concise, uncomplicated, and practical style of presentation of recipes, and (iii) his selection of principal ingredients, which were within the reach of the household cook and which reflected the availability of foods at the time of writing. Furthermore, because Le Cuisinier Francois was laid out according to widely observed religious practices, finding the best options for the appropriate day of the month became an easy task for the user. La Varenne initiated a departure from an earlier style of heavily spiced cooking to one that was based on natural flavors, a limited use of spices, and uncomplicated cooking methods. Thus, rather than assuming that the enduring popularity of the book was due to its widespread use by culinary professionals, it is argued that its style and substance must have imparted a sense of empowerment and confidence in the home cook and that, in these terms, La Varenne's influence on culinary practice was far more widespread and truly transformative, accounting for the remarkable success of Le Cuisinier Francois.

Sense of Smell as the Central Driver of Pavlovian Appetite Behavior in Mammals.

The seminal experiments of Ivan Petrovich Pavlov set the stage for an understanding of the physiological concomitants of appetite and feeding behavior. His findings, from careful and creative experimentation, have been uncontested for over a century. One of Pavlov's most fundamental observations was that activation of salivary, gastric and pancreatic secretions during feeding and sham-feeding, precedes entry of food into the mouth, generating signals to the brain from various sensory pathways. Pavlov referred to this as the "psychic" phase of digestion. However, quite surprisingly, he did not attempt to isolate any single sensory system as the main driver of this phenomenon. Herein we revisit Pavlov's findings and hypothesize that the evolutionarily-important sense of smell is the pathway most-likely determinant of feeding behavior in mammals. Substantial understandings of olfactory receptors and their neural pathways in the central nervous system have emerged over the past decade. Neurogenic signals, working in concert with hormonal inputs are described, illustrating the ways in which sense of smell determines food-seeking and food-preference. Additionally, we describe how sense of smell affects metabolic pathways relevant to energy metabolism, hunger and satiety as well as a broad range of human behaviors, thereby reinforcing its central biological role in mammals. Intriguing possibilities for future research, based upon this hypothesis, are raised.

Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics.

In chronic kidney disease, functional impairment correlates with tubulointerstitial fibrosis characterised by inflammation, accumulation of extracellular matrix, tubular atrophy and rarefaction of peritubular capillaries. Loss of the microvasculature implies a hypoxic milieu and suggested an important role for hypoxia when the "chronic hypoxia hypothesis" was proposed a decade ago as an explanation for the progressive nature of fibrosis. Recent data in man provide evidence of decreased renal oxygenation in chronic kidney disease while more direct support for a causal role comes from data in rodent models showing that the decline in renal oxygenation precedes matrix accumulation, suggesting hypoxia may both initiate and promote the fibrotic response. Indeed, in vitro studies show that hypoxia can induce pro-fibrotic changes in tubulointerstitial cells. Additional postulated roles for hypoxia in chronic kidney disease are the sustaining of the inflammatory response, the recruitment, retention and differentiation towards a pro-fibrotic phenotype of circulating progenitor cells and the alteration of the function of intrinsic stem cell populations. Given that accumulating data suggests that chronic hypoxia is a final common pathway to end-stage renal disease, therapeutic strategies that target hypoxia may be of benefit in retarding progression. Normalisation of microvascular tone, administration of pro-angiogenic factors to restore microvasculature integrity, activation of hypoxia-inducible transcription factors and hypoxia-mediated targeting and mobilisation of progenitor cells are all potential targets for future therapy. The limited success of existing strategies in retarding chronic kidney disease mandates that these new avenues of treatment be explored.

Samuel Johnson's illnesses.

The handwritten note of the post-mortem examination of Dr Samuel Johnson resides in the library of the Royal College of Physicians of London. Headed 'asthma' it suggests that he had only one functioning kidney, probably had hypertension, left ventricular hypertrophy and congestive heart failure. This article describes an imaginary presentation by Dr James Wilson, who did the autopsy, and alludes to Johnson's life, and medical history, including impaired vision and hearing, scrofula, abnormal limb movement, gout, abdominal cramps, melancholia and episodes of 'asthma' which were, more than likely to have been episodes of left ventricular failure. Johnson's personality as a demanding patient who took things into his own hands are described based upon reports from his physicians.

Avicenna (980-1037) on the Role of the Liver in Separating Fluid from the Blood, with Insight into the Process from E.H. Starling (1866-1907) a Millennium Later.

BACKGROUND: A statement was made by Avicenna (980-1037) in his Canon of Medicine that the liver separates fluid from the blood. An explanation for this view has not been considered. METHODS: Since the statement emerged from an existing English translation of the Canon (which was made from a prior Latin edition), an alternative English translation of the first Hebrew edition was made in order to verify the statement and to seek additional insight, which could explain its basis, in fact. DATA SOURCES: The English edition of Avicenna's Canon of Medicine published in 1932, translated from the Latin. First Hebrew edition of Avicenna's Canon of Medicine published in 1491, translated from the Arabic. SUBJECTS: None. DESIGN: The relevant sections of the Hebrew Canon on the origin of the body fluids were translated and compared with the existing English translation. OBSERVATIONS: The fluid generated by the liver is likely to be protein-containing, since it was described as frothy and suggests that it is lymph. The suggestion that the liver needs a watery fluid for its action cannot be explained. Ernest Henry Starling (1866-1907) measured lymph formation, showing it to be driven by physical forces. The liver stood out as being the organ with the largest capacity for lymph formation. The vascular walls within the liver were shown to have a higher permeability to serum proteins than any other source of lymph. DATA ANALYSIS: Data are derived from Starling's publications based on individual experiments. These were not analyzed statistically. RESULTS: The explanation for Avicenna's statement that the liver separates moisture from the blood is most likely to be the discovery by Starling, a millennium later, that the liver is the major source of lymph production. CONCLUSIONS AND IMPLICATIONS: The liver is a major source of lymph. Distortion of the architecture of the liver in cirrhosis and other chronic liver diseases lead to ascites, a condition of lymph overflow from the liver.