Drug-induced renal Fanconi syndrome

A number of therapeutic drugs are toxic to the kidney proximal tubule (PT) and can cause the renal Fanconi syndrome (FS). The most frequently implicated drugs are cisplatin, ifosfamide, tenofovir, sodium valproate and aminoglycoside antibiotics, and the new oral iron chelator deferasirox has also recently been associated with FS. The incidence of full or partial FS is almost certainly under-estimated due to a lack of appropriate systematic studies, variations in definitions of tubular dysfunction and under-reporting of adverse events. The clinical features of FS are amino aciduria, low molecular weight proteinuria, hypophosphataemia, metabolic acidosis and glycosuria. The most serious complications are bone demineralization from urinary phosphate wasting and progressive decline in kidney function. Commonly used tests for kidney function such as estimated glomerular filtration rate and urine albumin/creatinine ratio are not sensitive markers of PT toxicity; patients at risk should thus be monitored with more appropriate tests, and drugs should be stopped or reduced in dose if toxicity occurs. Substantial recovery of PT function can occur after withdrawal of therapy, but this can take months and chronic damage may persist in some case

Renal pericytes: regulators of medullary blood flow

Regulation of medullary blood flow (MBF) is essential in maintaining normal kidney function. Blood flow to the medulla is supplied by the descending vasa recta (DVR), which arise from the efferent arterioles of juxtamedullary glomeruli. DVR are composed of a continuous endothelium, intercalated with smooth muscle-like cells called pericytes. Pericytes have been shown to alter the diameter of isolated and in situ DVR in response to vasoactive stimuli that are transmitted via a network of autocrine and paracrine signalling pathways. Vasoactive stimuli can be released by neighbouring tubular epithelial, endothelial, red blood cells and neuronal cells in response to changes in NaCl transport and oxygen tension. The experimentally described sensitivity of pericytes to these stimuli strongly suggests their leading role in the phenomenon of MBF autoregulation. Because the debate on autoregulation of MBF fervently continues, we discuss the evidence favouring a physiological role for pericytes in the regulation of MBF and describe their potential role in tubulo-vascular cross-talk in this region of the kidney. Our review also considers current methods used to explore pericyte activity and function in the renal medulla

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

A monolithic common-collector front-end optical preamplifier

A monolithic transimpedance preamplifier has been developed having a common-collector cascode configuration with shunt feedback, using an advanced bipolar IC process. The measured sensitivity was -35.0 dBm at 140 Mbit/s for an error rate of 10-9and a p-in photodiode responsivity of 0.5 A/

Bartter's and Gitelman's syndromes: Their relationship to the actions of loop and thiazide diuretics

The wider recognition of inherited Bartter’s and Bartter’s-like syndromes, especially Gitelman’s, has come largely as a result of the advances in, and application of, molecular genetics. By exploiting pre-existing renal cell models of ion transport, specifically for sodium and potassium, the known mechanisms and sites of action of loop and thiazide diuretics and the similarity of their chronic effects to these syndromes, it was possible for geneticists to take a candidate gene approach. This was initially successful but, when not all cases could be explained on this basis, it forced a more detailed clinical appraisal and better phenotyping, resulting in the discovery of novel genes involved in controlling renal sodium, potassium and chloride transport, and new insights into renal tubular physiology. This is a good example of one form of ‘translational research’, the message being the importance of our ability to link (in this instance) basic renal physiology and pharmacology, with clinical nephrology and genetics.The wider recognition of inherited Bartter's and Bartter's-like syndromes, especially Gitelman's, has come largely as a result of the advances in, and application of, molecular genetics. By exploiting pre-existing renal cell models of ion transport, specifically for sodium and potassium, the known mechanisms and sites of action of loop and thiazide diuretics and the similarity of their chronic effects to these syndromes, it was possible for geneticists to take a candidate gene approach. This was initially successful but, when not all cases could be explained on this basis, it forced a more detailed clinical appraisal and better phenotyping, resulting in the discovery of novel genes involved in controlling renal sodium, potassium and chloride transport, and new insights into renal tubular physiology. This is a good example of one form of 'translational research', the message being the importance of our ability to link (in this instance) basic renal physiology and pharmacology, with clinical nephrology and genetics. © 2006 Elsevier Ltd. All rights reserved

Pathophysiology and management of hypokalemia: a clinical perspective

Potassium (K(+)) ions are the predominant intracellular cations. K(+) homeostasis depends on external balance (dietary intake [typically 100 mmol per day] versus excretion [95% via the kidney; 5% via the colon]) and internal balance (the distribution of K(+) between intracellular and extracellular fluid compartments). The uneven distribution of K(+) across cell membranes means that a mere 1% shift in its distribution can cause a 50% change in plasma K(+) concentration. Hormonal mechanisms (involving insulin, beta-adrenergic agonists and aldosterone) modulate K(+) distribution by promoting rapid transfer of K(+) across the plasma membrane. Extrarenal K(+) losses from the body are usually small, but can be marked in individuals with chronic diarrhea, severe burns or prolonged sweating. Under normal circumstances, the kidney's distal nephron secretes K(+) and determines final urinary excretion. In patients with hypokalemia (plasma K(+) concentration <3.5 mmol/l), after the exclusion of extrarenal causes, alterations in sodium ion delivery to the distal nephron, mineralocorticoid status, or a specific inherited or acquired defect in distal nephron function (each of which affects distal nephron K(+) secretion), should be considered. Clinical management of hypokalemia should establish the underlying cause and alleviate the primary disorder. This Review aims to inform clinicians about the pathophysiology and appropriate treatment for hypokalemia

Conventional and confocal epi-reflection and fluorescence microscopy of the rat kidney in vivo

To visualize superficial and accessible renal tubule cells functioning in situ and to relate what we can 'see' to what we know of their function from more invasive in vivo or less direct in vitro studies means applying and adapting recent advances in epifluorescence and confocal microscopy to improve image resolution and to combine this with the use of fluorescent labels to monitor the handling of specific molecules by the proximal and distal renal tubule cells in vivo. Doing this in living tissue is novel, especially in the kidney. Application of confocal microscopy to the imaging of living tissue, as opposed to isolated cells, has not been widely reported. The kidney surface has been imaged before using the confocal microscope and in preliminary studies we have extended this by using a different confocal system with and without fluorescence. While the studies published up to now have been morphological, comparing standard renal (structural) histology of surface glomeruli and renal tubules with the corresponding in vivo confocal images, more dynamic, real-time studies have been limited. Individual red blood cells can be seen flowing around the peritubule capillary network and nucleated white blood cells can also be distinguished. Tubule cells, endothelial cells, the proximal tubule cell brush border and cell mitochondria can be visualized. Filtration and secretion can be observed, and the early and late parts of the proximal tubule distinguished, and the distal tubule recognized. Localization of fluorescently labeled insulin to the luminal brush border and progressive uptake of label and distribution within proximal tubule cells toward the basolateral (blood side) membrane can be demonstrated. The possibility of monitoring hemodynamic changes and tracking the filtration, uptake, secretion and absorption of fluorescently tagged molecules, as well as intracellular fluorescence, e.g. calcium or pH is an exciting prospect and is ripe for detailed exploration