Abstract: The factors affecting the urinary excretion of oxalate are critical to the risk of forming calcium oxalate stones. This article reviews the role of dietary and intestinal oxalate in determining the level of oxalate excreted in urine. The amount of oxalate available for absorption throughout the intestine is highly dependent on the state of oxalate (a) in the food ingested, and (b) in the intestinal contents at each section of the intestinal tract since only the soluble form of oxalate can be absorbed. In this respect, the solubility of calcium oxalate (CaOx) under the prevailing conditions is paramount in determining the amount of oxalate available for absorption at any particular site. In turn, the main factors that control how much oxalate is in the soluble form are pH and the concentrations of calcium, magnesium and (indirectly) phosphate. Based on these parameters, a model of the intestine has been constructed which brings together the available evidence on the prevailing concentrations of these various factors at different sites in the intestine after allowing for dietary intake and the concentration of the above ions in intestinal secretions. The model then calculates the likely concentration of oxalate that is in the soluble form at each site and therefore available for passive absorption at that site. The model shows that oxalate is likely to be absorbed in the stomach, although it can be also absorbed in the small intestine, particularly at the distal end (after the absorption of calcium), and in the colon, since, on a normal intake of calcium and phosphate, most of the calcium in the large bowel would be anticipated to be precipitated as calcium phosphate under the prevailing alkaline conditions and high concentration of phosphate. The amount of free oxalate in the colon is also controlled by the presence or absence of Oxalobacter formigenes, an anaerobe that has an obligate requirement for oxalate as a source of energy and cellular carbon.

Abstract: Osteopontin (OPN) is a phosphorylated protein of wide tissue distribution that is found in association with dystrophic calcification including in the organic matrix of kidney stones. It is a strong inhibitor of crystal formation and growth in vitro, but there is still debate regarding its effects upon crystal adhesion to tubular epithelial cells. In this brief review, we will outline the evidence implicating OPN in stone disease with the primary emphasis being on the interaction of OPN with calcium oxalate (CaOx), the major constituent of calcium containing stones. Finally, preliminary data is presented regarding the amounts and features of OPN present in the urine of stone formers and normal individuals.

Abstract: This review compares and contrasts three mathematical models used to describe the flow of urine through the renal tubule and the composition of tubular fluid throughout the length of the nephron. From

Abstract: Objective: Perfusion quantification of tissues is an important goal to evaluate the state of blood supply of an organ. We developed a method to quantify tissue perfusion via color Doppler signal quantification from sonographic videos and applied this to describe renal parenchymal perfusion in healthy kidneys. Method: Color Doppler sonographic videos of renal perfusion from both kidneys of 87 healthy children (age 2 weeks to 16 years) were recorded under defined conditions. Perfusion data (color hue, color area) were measured in a standardized region of interest automatically. Signal intensity was calculated as whole ROIs (regions of interest) mean flow velocity (cm/s) encoded by color Doppler signals during one full heart cycle. Results: Normal signal intensity values are: 1.86 cm/s in the region encompassing central 50% of the renal cortex and 0.56 cm/s in the peripheral 50% of the renal cortex. These differences are significant. Signal intensity of both kidneys did not differ. Conclusion: Signal intensity of cortical tissue in healthy kidneys was quantified noninvasively from color Doppler signal data in an easily accomplishable manner with new measurement software. Normal values for this technique have been calculated. Possible further applications might be all situations, where perfusion changes could be expected like inflammation, renal insufficiency, vascular diseases and tumors.

Abstract: Long-standing interest in the possible role of macromolecules in urolithiasis stems from the observation that all human kidney stones consist of a complex amalgam of mineral and organic material. This review summarises what is currently known or is hypothesised about the influences of urinary macromolecules, especially proteins, on the formation of calcium oxalate crystals, their attachment to renal epithelial cells, and their subsequent destruction within those cells. Although a list is provided of proteins that have either been detected in stones or have been implicated by virtue of their effects on crystallization, only a select handful, which have been intensively studied, have been singled out for individual discussion. The review ends with a speculative discussion of the applicability of current knowledge to the investigation and treatment of urolithiasis.

Abstract: Background/Aims: Increased salt intake and enhanced salt sensitivity are implicated in the pathogenesis of hypertension. The aim of the present study was to investigate whether the

Abstract: Background: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-ĸB (NF-ĸB)

Abstract: Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen, angiogenic factor and enhancer of vascular permeability. Expressed in the epithelial cells of the developing glomerulus and tubular epithelium, VEGF plays an important role in the development and maintenance of the early vasculature of the kidney. Here, we review the available literature regarding the expression and function of VEGF both in the developing and healthy adult kidney. Furthermore, we highlight how VEGF expression is altered in the diseased kidney and how this modulated expression may impact on and reflect underlying functional changes occurring during the disease process. As discussed, many controversial issues remain, particularly concerning the role of VEGF in the diseased kidney. That VEGF has been proposed as a potential future therapeutic target for the management of some renal diseases requires first that the precise role of VEGF in the normal kidney and various renal pathologies be further and more clearly defined.

Abstract: Microorganisms may have a role in the pathogenesis and prevention of kidney stones. The subjects of this review include nanobacteria, Oxalobacter formigenes, and lactic acid bacteria. Not reviewed here is the well-described role of infections of the urinary tract with Proteus species and other urease-producing organisms associated with struvite stone formation. Nanobacteria have been proposed to be very small (0.08-0.5 nm), ubiquitous organisms that could play a role in stone formation. The theory is that nanobacteria can nucleate carbonate apatite on their surfaces and thereby provide the nidus for stone formation. However, their existence remains uncertain and many investigators are openly skeptical. Recent investigations suggest that they are artifacts, and not actually living organisms, but their proponents continue to study them. O. formigenes is an obligate anaerobe which may be important in the prevention of stone formation. Its sole substrate for generation of ATP is oxalate. It may thereby metabolize its human host's dietary oxalate and diminish intestinal absorption and subsequent urinary excretion of oxalate. There is evidence that the organism's absence, perhaps sometimes due to courses of antibiotics, may be a cause of hyperoxaluria and stone formation. In early investigations, patients not colonized with the organism can be recolonized. Urinary oxalate can be diminished by accompanying an oxalate-containing meal with the organism. One study demonstrated that a preparation of lactic acid bacteria successfully reduced urinary oxalate excretion in 6 patients with calcium oxalate stones and hyperoxaluria. The mechanism of this effect is uncertain since these bacteria lacked the gene possessed by O. formigenes which codes for that organism's oxalate uptake mechanism. The author is currently completing a small randomized controlled clinical trial with this preparation in calcium stone-forming patients with idiopathic hyperoxaluria.

Abstract: It is well known that during low diuresis or low effective circulating volume, salt excretion is low. The aim of this study was to find out whether salt excretion, expressed as either urinary sodium c

Abstract: Background: Increased oxidative stress (SOX) has been reported in hemodialyzed (HD) patients, but its influence on CC-chemokine levels remains unknown. Methods: T

Abstract: The pathogenesis of glomerular alterations and proteinuria in corticosteroid-responsive nephrotic syndrome (CRNS) is unknown. As an isoform of plasma hemopexin (Hx) with protease activity may be implicated in this disease, we have studied the inhibition of Hx by ADP and reactivation to its active form by endothelial or mesangial cells in vitro. We hypothesized that these cells might potentially be able to convert the inactivated form of Hx (Hxi) to active Hx (Hxa) in vitro, mediated by cellular ecto-ADPase. Since ecto-ADPase (CD39) is upregulated after stimulation of these cells with lipopolysaccharide (LPS) or certain cytokines, we postulated that this conversion might occur specifically after inflammatory stimulation of these cells. Human endothelial or mesangial cell cultures were incubated overnight with or without LPS (10.0 ng/ml) or TNFalpha (10.0 ng/ml), washed and subsequently incubated with Hxi (1.5 mg/ml) in serum-free conditions (Hxi was prepared by treatment of Hxa with ADP or ADP-beta-S). After 60 min, supernatants were tested for their capacity to alter glomerular extracellular matrix molecules (i.e. ecto-apyrase) in vitro using standard methods, and compared with Hxi that had not been incubated with cells. Supernatants containing Hxa (1.5 mg/ml) served as positive control. The results show significant activity in supernatants with Hxi (prepared using native ADP). However, Hxi inactivated by ADP-beta-S (which is non-hydrolyzable) could not be reactivated after contact with LPS-stimulated or unstimulated cells in vitro. As ecto-ADPase of these cells is upregulated by LPS, we believe that reactivation of Hxi to Hxa is mediated by cellular ecto-ADPase. Although the relevance of this inflammation-mediated activation mechanism of Hx in patients with CRNS requires further experimentation, our preliminary observations suggesting that this mechanism is corticosteroid dependent may support a potential role of Hxa in CRNS.

Abstract: Background/Aims: Lipocalin-type prostaglandin D synthase (L-PGDS), an enzyme converting prostaglandin H2 to prostaglandin D2, occurs particularly in the cardio

Abstract: Background: Gene polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (ATR) had been associated with IgA nephropathy (IgAN)

Abstract: Background: The high level of expression of vascular endothelial growth factor (VEGF) in normal podocyte foot processes suggests that VEGF has an important role in maintaining norma

Abstract: Background: High urinary excretion of lysosomal enzymes is thought to reflect tubulointerstitial damage and is observed both in the acute and chronic phases of various morphological forms of glomerulonephritis (GN). It is related to the degree of proteinuria and secondary interstitial inflammatory process. N-acetyl-β-D-glucosaminidase (NAG) and β-glucuronidase (β-GR) are the most commonly used markers of tubulointerstitial injury. NAG and β-GR are also contained in azurophilic granulations of polymorphonuclear leukocytes (PMNs) and may be released during the activation of PMNs. Aims: The aim of this study was to elucidate the role of PMN degranulation in causing the increase of urinary excretion of lysosomal enzymes that is observed in glomerulonephritis. Material and Methods: We analyzed the urinary excretion of NAG, its B isoenzyme NAG-B, β-GR and leukocyte elastase (EL), in 91 patients with morphologically different primary and secondary glomerulopathies, and in 12 healthy controls. Results: Excretion of NAG, NAG-B and β-GR were statistically significantly higher in all GN patients in comparison to healthy controls. In the whole analyzed GN population significant correlations between amount of proteinuria and excretion of NAG, NAG-B and β-GR were ascertained. In subgroup analysis NAG excretion was significantly correlated with proteinuria in patients with diffuse proliferative GN (PGN), mesangiocapillary GN (MCGN), and minimal change disease (MCD). There was a significant correlation between NAG-B and proteinuria in MCD and PGN patients. There was a significant relationship of β-GR and EL with proteinuria and EL with NAG in the PGN group. Significant relationships between serum creatinine and excretion of EL but not NAG, NAG-B, or β-GR were observed in the whole examined group. Conclusions: Increased urinary excretion of elastase, with concomitant high proteinuria and NAG excretion in patients with proliferative GN may indicate that leukocyte degranulation is an additional source of enzymuria in the primary i.e. glomerular inflammatory process. Significant relationship between EL excretion and serum creatinine may indicate that EL released from PMN may also participate in the secondary i.e. interstitial injury that is decisive in the progression of GN.

Abstract: Objective: The crucial steps involved in the lithogenic process are governed by the macromolecular components of urine, of which proteins play a major role. Structurally abnormal pr

Abstract: Aims: Effects of the blockade of renin-angiotensin system (RAS), by angiotensin-converting enzyme inhibitor (ACEi), type 1 angiotensin II receptor blocker (ARB), or a combination of

Abstract: Background: In chronic renal failure (CRF), a defect in urinary concentrating ability develops gradually as the renal failure progresses. Although several molecular mechanisms associated with renal urinary concentration are reported to be impaired in a rat model for renal failure, the mechanisms underlying residual urinary concentration ability in CRF remain to be elucidated. Methods: Rats that underwent an 8-week recovery period after 5/6 nephrectomy were used as the model for CRF. Urinary concentration was induced by 24-hour water restriction. Plasma osmolality and arginine vasopressin (AVP) were measured from blood sampled by inserting a catheter into the femoral artery before and after the water restriction. AQP2 mRNA expression in the inner medulla was examined by competitive PCR and in situ hybridization, and protein expression, by Western blotting. Rats that underwent sham operation were used as control. Results: Water restriction significantly reduced urine volume and increased urine osmolality in CRF rats, although such changes were much less than those in sham-operated rats. Plasma AVP was elevated at the basal condition, and further elevation was noted after water restriction. AQP2 mRNA signals were significantly intensified by water restriction even in CRF rats, although the increase was limited as in the case of urine osmolality. Western blotting also showed a small but significant enhancement of protein signals in response to water restriction in CRF rats. Conclusions: We noted a weak but significant response of AQP2 expression to dehydration in CRF rats. This response in the collecting duct may be one of the factors contributing to residual urinary concentrating ability in CRF.

Abstract: Background/Aim: Endothelin-converting enzyme (ECE) catalyzes the generation of endothelin-1 (ET-1) from its inactive precursor big-ET-1. Previous studies suggested that the ET-1 sys

Abstract: Background/Aims: Approximately 30% of individuals with diabetes mellitus are susceptible to diabetic nephropathy, whereas ischemic injury uniformly induces renal impairment. As matrix accumulation correlates with progressive renal disease we assessed parameters associated with matrix turnover in response to high glucose ± hypoxia in human cortical fibroblasts (CF). Methods: CF were grown to confluence and exposed to media containing 5 or 25 mmol/l D-glucose for 72 h with or without a superimposed hypoxic insult. Results: High glucose increased cellular protein content (p < 0.05). Combined high glucose and hypoxia induced a further increase in cellular protein content (p < 0.005), suggestive of a synergistic hypertrophic effect. MMP secretion corresponded inversely with changes in TIMP expression. In cell cultures derived from 2/3 of patients, high glucose increased MMP-9 (p < 0.0005) and MMP-2 (p < 0.005) while TIMP-1 was reduced (p = 0.05). In the remaining cell cultures derived from 1/3 of patients, MMP-2 was reduced (p < 0.0001) while TIMP-1 and TIMP-2 were both increased (p < 0.05). In contrast, hypoxia induced uniform reductions in MMP-9 and MMP-2 in both normal and high glucose conditions. High glucose increased the expression of PAI-1 mRNA (p < 0.05) in all patients independent of changes in the MMP-TIMP axis. Conclusions: In summary, variability was observed in the MMP-TIMP axis following exposure to high glucose. In contrast, high glucose uniformly induces PAI-1 expression. Hypoxic insults uniformly reduce matrix breakdown independent of the prevailing glucose conditions.

Abstract: Background/Aims: In chronic renal failure (CRF), zinc deficiency is partially attributed to decreased intestinal zinc absorption, but the mechanism of this decrease in intestinal zi

Abstract: Endemic nephropathy has been linked to exposure of ochratoxin-A (OA) in grains and animal products The underlying events surrounding this form of renal injury are not well known, partly due to the la

Abstract: Aims: To isolate, characterize, and quantify the 23-kD calcium oxalate monohydrate (COM) binding protein in the urine of controls and calcium oxalate stone formers and to study its

Abstract: Background: Angiotensin II infusion into rats causes iron deposition in the kidney, which may augment the pro-proteinuric effects of this octapeptide. We have investigated whether administration of iron mimics the renal damage induced by angiotensin II. Methods: Rats were treated with iron dextran at a total dose of 960 mg/kg either with or without angiotensin II treatment at a dose of 0.7 mg/kg/day for 7 days. Protein expression of ferritin and heme oxygenase-1, an oxidative stress-sensitive gene, was determined by Western blot analysis and immunohistochemistry. Results: Administration of iron dextran did not significantly increase proteinuria or decrease creatinine clearance in the rats with or without angiotensin II treatment. Prussian blue staining showed that iron deposition was observed mainly in the glomerular and medullar regions in the iron dextran-treated rats, but in the tubular epithelial cells in angiotensin II-infused rats. Administration of iron dextran upregulated ferritin, but not heme oxygenase-1. Conclusion: Iron dextran did not enhance or cause the renal dysfunction in the angiotensin II-treated or untreated rats, respectively. The distribution of deposited iron and presumably the type of iron compound administered may be important determinants of the development of renal injury.

Abstract: Aims: To explore the effects of ligustrazine on proteinuria, urinary TxB2 (metabolism of thromboxane A2, TxA2) and 6-keto-PGF1α (metabolism of prostacyclines I2, PG I2), glomerular inducible nitric oxide(NO) synthase (iNOS) mRNA, urinary NO–3/NO–2 (decomposing products of NO) and pathological changes in rats with passive Heymann nephritis (PHN). Methods: A rat PHN model was induced by intravenous injection of rabbit anti-rat renal tubular antigen (Tub-Ag) antiserum, and ligustrazine was given intraperitoneally into PHN rats every 2 days for 1–5 weeks. Then, proteinuria, urinary TxB2 and 6-keto-PGF1α, glomerular iNOS mRNA, and urinary NO–3/NO–2 were measured by sulfosalicylic acid, radioimmunoassay (RIA), Northern blot and nitric acid reductase methods, respectively. Moreover, the damage to the renal tissue of the rats was observed under light and electron microscopy and immunofluorescence (IF). Results: The urinary TxB2 in PHN rats was significantly higher than that in control rats, but the PHN rats treated with ligustrazine had significantly less proteinuria, urinary TxB2 and tissue lesions, and more urinary 6-keto-PGF1α, glomerular iNOS mRNA and urinary NO–2/NO–3 than the PHN rats without the administration of ligustrazine. Conclusion: These data indicate that ligustrazine has inhibitory roles on the glomerular injury of PHN rats, which may associate with modulating the balance of TxA2-PGI2 and elevating synthesis of NO to a certain extent.

Abstract: Aim: While the diuretic action of acute ingestion of alcohol has been studied extensively, the effect of chronic alcohol consumption has received less attention. The aim of the present study was to investigate the effect of chronic alcohol consumption on the balance of water intake and excretion and certain renal functions in rats during a period of 12 months. Animals and Study Design: Male Wistar rats received either alcohol (15% v/v; group A, n = 65) or tap water (group C, n = 35) as drinking fluid. Urine and faeces were collected from 6 rats of each group during 7 days, at monthly intervals. In further experiments, the animals received a low-protein/high-fat diet with and without alcohol. Results: When the rats were fed the standard diet, 24-hour urine excretion was significantly reduced in group A compared with group C. This difference was even more pronounced when the animals were fed the low-protein/high-fat diet. The reduced urine excretion was not due to lower liquid consumption and the pattern of daily excretion of faeces was comparable with that observed for urine excretion. Both sodium and potassium excretion and the diuretic response to an acute water load were significantly reduced in group A compared with group C. The changes in water balance induced by chronic alcohol consumption were reversible within a few days when the rats received water instead of 15% alcohol. Conclusions: Chronic alcohol consumption has an antidiuretic effect in rats. The percentage of total ingested fluid leaving the body as hidden water loss increases after alcohol consumption by up to 25–26% over control values.

Abstract: Background: Angiotensin II type 1 (AT1) receptor antagonists provide end-organ protection and enhance resistance artery relaxation in uremia. The effect of AT1 blockade on conduit artery function in renal failure is unknown. Methods: The influence of 8-week losartan therapy (20 mg/kg/day) on tone of isolated main branch mesenteric arterial rings was studied in 5/6 nephrectomized (NX) rats. Blood and urine chemistry were examined, and AT1 receptors quantified using autoradiography. Results: NX rats showed decreased creatinine clearance without change in blood pressure. Losartan did not influence these variables, although [125I]-Sar1,Ile8-angiotensin II binding to renal AT1 receptors was significantly prevented. Vasoconstriction to endothelin-1 was reduced by losartan in NX and Sham rats. Vasorelaxation to acetylcholine was attenuated in untreated but not in losartan-treated NX rats, and experiments with Ca2+-activated K+ channel blockers suggested that impaired endothelium-mediated response after NX was due to deficient relaxation via K+ channels. Endothelium-independent relaxation to levcromakalim, adenosine triphosphate-sensitive K+ channel agonist, was impaired in untreated but not in losartan-treated NX rats. Conclusion: Losartan reduced conduit artery vasoconstriction to endothelin-1 and augmented vasorelaxation via K+ channels in NX rats, although blood pressure and renal function were unchanged. Therefore, AT1 blockade confers functional benefits to large arteries in renal failure.

Abstract: Background/Aims: Calbindin D28k has been reported to be involved in transcellular calcium transport along the rat distal convoluted tubule (DCT). It has also been shown that adminis