Nephron Physiology最新文献

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.

Background: Hyperkalemia is a common medical emergency that may result in serious cardiac arrhythmias. Standard therapy with insulin plus glucose reliably lowers the serum potassium concentration ([K(+)]) but carries the risk of hypoglycemia. This study examined whether an intravenous glucose-only bolus lowers serum [K(+)] in stable, nondiabetic, hyperkalemic patients and compared this intervention with insulin-plus-glucose therapy.

Methods: A randomized, crossover study was conducted in 10 chronic hemodialysis patients who were prone to hyperkalemia. Administration of 10 units of insulin with 100 ml of 50% glucose (50 g) was compared with the administration of 100 ml of 50% glucose only. Serum [K(+)] was measured up to 60 min. Patients were monitored for hypoglycemia and EKG changes.

Results: Baseline serum [K(+)] was 6.01 ± 0.87 and 6.23 ± 1.20 mmol/l in the insulin and glucose-only groups, respectively (p = 0.45). At 60 min, the glucose-only group had a fall in [K(+)] of 0.50 ± 0.31 mmol/l (p < 0.001). In the insulin group, there was a fall of 0.83 ± 0.53 mmol/l at 60 min (p < 0.001) and a lower serum [K(+)] at that time compared to the glucose-only group (5.18 ± 0.76 vs. 5.73 ± 1.12 mmol/l, respectively; p = 0.01). In the glucose-only group, the glucose area under the curve (AUC) was greater and the insulin AUC was smaller. Two patients in the insulin group developed hypoglycemia.

Conclusion: Infusion of a glucose-only bolus caused a clinically significant decrease in serum [K(+)] without any episodes of hypoglycemia.

Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells. Such 'vascular osteoinduction' is characterized by expression of osteogenic transcription factors and triggered by increased phosphate concentrations. A key role in this process is assigned to cellular phosphate transporters, most notably the type III sodium-dependent phosphate transporter Pit1. Pit1 expression is stimulated by mineralocorticoid receptor activation. Therefore, aldosterone participates in the phenotypical transformation of VSMCs. In preclinical models, aldosterone antagonism reduces vascular osteoinduction. Patients with CKD suffer from hyperphosphatemia predisposing to vascular osteogenic transformation, potentially further fostered by concomitant hyperaldosteronism. Clearly, additional research is required to define the role of aldosterone in the regulation of osteogenic signaling and the consecutive vascular calcification in CKD, but more generally also other diseases associated with excessive vascular calcification and even in individuals without overt disease.

Objective: To explore the characteristics of blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) in healthy native kidneys.

Methods: Seventy-nine patients without chronic kidney disease underwent BOLD-MRI with T2* spoiled gradient recalled echo sequences. BOLD images were analyzed using R2*map software to produce an R2* pseudo-color map. Cortical and medullary R2* values were analyzed in both kidneys and in both sexes. Different regional R2* values in the cortex and medulla were also analyzed. Physiological indices including age, height, weight, body mass index, body surface area, and estimated glomerular filtration rate (eGFR) were recorded. Correlations between R2* value and physiological indices were determined.

Results: Renal cortical R2* values were lower than values in the medulla (p < 0.001). Female and male cortical R2* values were also lower than the corresponding values in the medulla (p < 0.001). Renal medullary R2* values in the lower renal pole were lower than values in the middle and upper poles (p = 0.001). Age was positively correlated with R2* values in the medulla (r = 0.32, p = 0.004). eGFR was negatively correlated with both cortical R2* values (r = -0.26, p = 0.02) and medullary R2* values (r = -0.29, p = 0.009).

Conclusions: BOLD-MRI can directly visualize renal oxygenation. There was variation in the oxygenation of different regions of the kidney. Renal cortical and medullary oxygenation in healthy kidneys decreased with patient age. eGFR also decreased with patient age.

Aldosterone is classically associated with the regulation of salt and potassium homeostasis but has also profound effects on acid-base balance. During acidosis, circulating aldosterone levels are increased and the hormone acts in concert with angiotensin II and other factors to stimulate renal acid excretion. Pharmacological blockade of aldosterone action as well as inherited or acquired syndromes of impaired aldosterone release or action impair the renal response to acid loading and cause hyperkalemic renal tubular acidosis. The mineralocorticoid receptor (MR) mediating the genomic effects of aldosterone is expressed in all cells of the distal nephron including all subtypes of intercalated cells. In acid-secretory type A intercalated cells, aldosterone stimulates proton secretion into urine, whereas in non-type A intercalated cells, aldosterone increases the activity of the luminal anion exchanger pendrin stimulating bicarbonate secretion and chloride reabsorption. Aldosterone has also stimulatory effects on proton secretion that may be mediated by a non-genomic pathway. In addition, aldosterone indirectly stimulates renal acid excretion by enhancing sodium reabsorption through the epithelial sodium channel ENaC. Increased sodium reabsorption enhances the lumen-negative transepithelial voltage that facilitates proton secretion by neighboring intercalated cells. This indirect coupling of sodium reabsorption and proton secretion is thought to underlie the fludrocortisone-furosemide test for maximal urinary acidification in patients with suspected distal renal tubular acidosis. In patients with CKD, acidosis-induced aldosterone may contribute to progression of kidney disease. In summary, aldosterone is a powerful regulator of renal acid excretion required for normal acid-base balance.

Major depression (MDE) has metabolic and neuroendocrine correlates, which point to a biological overlap between MDE and cardiovascular diseases. Whereas the hypothalamic-pituitary-adrenocortical axis has long been recognized for its involvement in depression, the focus was mostly on cortisol/corticosterone, whereas aldosterone appears to be the 'forgotten' stress hormone. Part of the reason for this is that the receptors for aldosterone, the mineralocorticoid receptors (MR), were thought to be occupied by glucocorticoids in most parts of the brain. However, recently it turned out that aldosterone acts selectively in relevant mood-regulating brain areas, without competing with cortisol/corticosterone. These areas include the nucleus of the solitary tract (NTS), the amygdala and the paraventricular nucleus of the hypothalamus. These regions are intimately involved in the close relationship between emotional and vegetative symptoms. Genetic analysis supports the role of aldosterone and of MR-related pathways in the pathophysiology of depression. Functional markers for these pathways in animal models as well as in humans are available and allow an indirect assessment of NTS function. They include heart rate variability, baroreceptor reflex sensitivity, blood pressure, salt taste sensitivity and slow-wave sleep. MR activation in the periphery is related to electrolyte regulation. MR overactivity is a risk factor for diabetes mellitus and a trigger of inflammatory processes. These markers can be used not only to assist the development of new treatment compounds, but also for a personalized approach to treat patients with depression and related disorders by individual dose titration with an active medication, which targets this system.

An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum- and glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both the brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new therapeutic options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC.