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Objective A ketogenic diet or mildly increased ketone body levels are beneficial for diabetic kidney disease (DKD) patients. Our previous study has found that sodium-coupled monocarboxylate transporter 1 (SMCT1), a key enzyme in charge of ketone reabsorption, possesses beneficial effects on the function of renal tubular epithelial cells (TECs) in energy crisis. Our present study is to investigate whether SMCT1 is important in maintaining the physiological function of renal tubular and plays a role in DKD. Methods We tested the expression of SMCT1 in kidney tissues from DKD patients receiving kidney biopsy as well as diabetes mice. We compared the difference of β‐hydroxybutyrate (β-HB) levels in serum, urine and kidney tissues between diabetic mice and control. Using recombinant adeno-associated viral vector containing SMCT1 (encoded by Slc5a8 gene), we tested the effect of SMCT1 upregulation on microalbuminuria as well as its effects on mitochondrial energy metabolism in diabetic mice. Then we investigated the role of SMCT1 and its β-HB reabsorption function in maintaining the physiological function of renal tubular using renal tubule-specific Slc5a8 gene knockout mice. Transcriptomes and proteomics analysis were used to explore the underlying mechanism. Results SMCT1 downregulation was found in DKD patients as well as in diabetic mice. Moreover, diabetic mice had a decreased renal β-HB level compared with control, and SMCT1 upregulation could improve microalbuminuria and mitochondrial energy metabolism. In renal tubule–specific Slc5a8 gene knockout mice, microalbuminuria occurred early at 24 weeks of age, accompanied by ATP shortage and metabolic reprogramming in the kidney; however, supplementation with β-HB precursor substance 1,3-butanediol in food alleviated kidney damage as well as energy metabolic reprogramming. Conclusions Decreased SMCT1 expression and its ketone reabsorption function play an important role in the occurrence of DKD. SMCT1 may be a new promising target in treating DKD. [ABSTRACT FROM AUTHOR]

Proximal tubular damage is an important prognostic determinant in various chronic kidney diseases (CKDs). Currently available diagnostic methods do not allow for early disease detection and are neither efficient. Indoxyl sulfate (IS) is an endogenous metabolite and protein‐bound uremic toxin that is eliminated via renal secretion, but accumulates in plasma during tubular dysfunction. Therefore, it may be suitable as a tubular function marker. To evaluate this, a fast bioanalytical method was developed and validated for IS in various species and a kidney cell line using LC–MS/MS. An isotope‐labeled IS potassium salt as an internal standard and acetonitrile (ACN) as a protein precipitant were used for sample pretreatment. The analyte was separated on a Polaris 3 C18‐A column by gradient elution using 0.1% formic acid in water and ACN, and detected by negative electrospray ionization in selected reaction monitoring mode. The within‐day (≤ 4.0%) and between‐day (≤ 4.3%) precisions and accuracies (97.7 to 107.3%) were within the acceptable range. The analyte showed sufficient stability at all conditions investigated. Finally, applying this assay, significantly higher plasma and lower urine concentrations of IS were observed in mice with diabetic nephropathy with tubular damage, which encourages validation toward its use as a biomarker. [ABSTRACT FROM AUTHOR]

Objective: Schistosoma mansoni infection is considered a public health problem. Glomerular involvement in schistosomiasis is a well-documented complication, especially in hepatosplenic schistosomiasis (HSS). However, renal tubular function is poorly understood. The aim of this study was to investigate, through urinary exosomes, tubular transporters functionally in HSS patients.Methods: Cross-sectional study of 20 HSS patients who had isolated exosomes from urine samples. Protease inhibitor was added in the urine samples who were immediately frozen at -80 °C for further exosomes isolation. After urine had thawed, urinary exosomes were obtained using extensive vortexing, centrifugation and ultracentrifugation steps of urine. Urinary transporters expression from exosomes was evaluated by western blot, including NHE3, AQP2 and NKCC2. Charge amounts for gel electrophoresis were adjusted by urinary creatinine concentration of each patient to avoid urinary concentration bias. All protein expression of HSS patients was relative to healthy controls.Results: The expression of aquaporin-2 (AQP2) was lower in HSS patients than in controls (46.8 ± 40.7 vs. 100 ± 70.2%, P = 0.03) and the expression of the NKCC2 co-transporter was higher (191.7 ± 248.6 vs. 100 ± 43.6%, P = 0.02).Conclusions: The decrease of AQP2 and the increase of NKCC2 expression in HSS patients seem to be involved with the inability of urinary concentration in these patients. These data show renal tubular abnormalities in HSS patients without manifest clinical disease. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate tubular functions of posterior urethral valve patients with preserved glomerular functions. Methods: A total of 25 children (ages 1 - 18) who underwent surgery for PUV and had an estimated glomerular filtration rate ≥ 90 mL/min per 1.73m² on long term follow-up and age-matched 25 healthy controls were enrolled. Blood and urine samples were collected to assess electrolyte reabsorption, proteinuria, enzymuria, urine acidification and concentration. Results: Even though microalbumin/creatinine ratio was higher in the patient group [1.00 (1.98) vs 0.31 (0.34) mg/gr creatinine, P = 0.005] none of the subjects had enzymuria, overt proteinuria or hyperphosphaturia. Serum bicarbonate levels were lower and urinary pH higher in patients than the controls (23.2±2.1 vs. 24.6±1.9 mmol/L, P = 0.028 and 6.24±0.77 vs. 5.60±0.64, P = 0.004); furthermore, patients had lower urinary osmolality and density (525 ± 214 vs. 743 ± 194 mOsm/L, P = 0.001 and 1011 ± 5.0 vs. 1016 ± 6.8, P = 0.005). When patients were compared among themselves according to presence or absence of renal scarring and when patients without renal scars were compared to healthy controls, similar findings persisted. Conclusions: This study showed that during long-term follow-up of posterior urethral valve patients with normal glomerular filtration rates, even though proximal tubular functions do not seem to be impaired, acidification and concentration defects exist indicating distal tubulopathy. [ABSTRACT FROM AUTHOR]

Our study aim was to measure the urinary N-acetyl-β-D-glucosaminidase/creatinine (NAG/UCr) index in epileptic children who received levetiracetam (LEV) treatment at least for 6 months, and compare it to healthy children. Thirty five children with epilepsy were enrolled in this prospective study. NAG was studied using the calorimetric method and NAG levels were expressed in units per liter (U/L) and NAG/UCre levels were determined in U/mmol creatinine. There were no statistically significant differences for the urine NAG and NAG/UCr index before and after LEV treatment in the epileptic group (p>0.05, for each). There were no significant correlations between the serum concentration of LEV and urinary NAG levels (r=0.258, p=0.135) and NAG/UCr levels (r=0.164, p=0.346) before treatment. Our study demonstrated that LEV treatment was safe and did not interfere in renal tubular function in epileptic children. [Med-Science 2016; 5(3.000): 771-5]

Objectives: Clinical and subclinical laboratory evidence of renal proximal tubular dysfunction had been reported in children with epilepsy as an adverse effect of some antiepileptic drugs (AEDs). This study aimed to determine kidney function in adult patients with monosymptomatic epilepsy of unknown etiology and treated with valproate (VPA) or carbamazepine (CBZ). Methods: This study included 60 patients [mean age of 33.97 ± 6.70 years and treated with VPA (n = 24) or CBZ (n = 36) for mean duration of treatment of 6.03 ± 2.81years. Measurements of serum creatinine (sCr), urinary creatinine, creatinine clearance (CrCl) and serum kidney injury molecule 1 (KIM-1), markers of renal dysfunction/injury were done. Results: Compared to controls, patients had higher sCr, KIM-1 and lower CrCl levels. Compared to patients on VPA, those on CBZ had relatively higher KIM-1 and lower CrCl levels. We reported only significant correlations between KIM-1 with sCr (r = 0.324, p = 0.001) and duration of treatment with AEDs (r = 0.301, p = 0.02). Conclusion: Chronic VPA and CBZ therapy may be associated with subclinical renal glomerular and/or proximal tubular dysfunctions or injuries. The treating neurologist have to consider this while selection of AED on start treating patients or modifying the AED for patients at high risk of kidney injury. [ABSTRACT FROM AUTHOR]

Objective To analyze the invention effect of curcumin on chronic urinary tract infection in rats and explore its possible mechanism of action. Methods The experimental animals were randomly divided into three groups, normal, model and curcumin group. Chronic urinary tract infection models were built for model group and curcumin group by injecting coliform fluid into the cavity of bladder. From the first day of modeling, rats in the curcumin group were injected with 150 mg/kg curcumin, while rats in normal group and model group were given no other treatment. The treatment lasted for 14 d. The white blood cell counts in blood and urine, bacterial colony count in urine and renal tubular functional indexes of rats in all groups at day 1, 7, and 14 after treatment were detected. Urine β2-microglobulin (β2-MG), urinary N-acetyl-β-D glucosaminidase (NAG) levels were used to detected the inflammatory cytokines in serum after treatment including the contents of IL-6, IL-8, IL-10 and monocyte chemoattractant protein-1 (MCP-1), and real-time PCR was employed to determine the expression of mRNA of toll-like receptor 2 (TLR-2) and TLR-4 in renal tissues and bladder tissues of all groups after treatment. Results The white blood cell counts at day 1 and 7 after treatment in rats of model group and curcumin group were significantly higher than those of normal group at the same time points, while the white blood cell counts of the curcumin group were significantly lower than those of model group ( P < 0.05). The urine white blood cell counts in rats of model group at day 1, 7 and 14 were all significantly higher than those of normal group at the same time points; those in the curcumin group were significantly lower than those of the model group at day 1, 7 and 14 at the same time points ( P < 0.05). The bacterial colony counts of urine in rats of model group and curcumin group at day 1, 7 and 14 were all significantly higher than those of normal group at the same time points, while the counts of curcumin group were significantly lower than those of model group at the same time points ( P < 0.05). Levels of urine β2-MG, NAG, IL-6, IL-8, IL-10, MCP-1 and expression of TLR2 mRNA and TLR4 mRNA in renal and bladder tissues in rats of model group were significantly higher than those of the normal group, while these variables of the curcumin group were significantly higher than those of the normal group but lower than those of model group ( P < 0.05). Conclusions Curcumin can significantly improve the symptoms of chronic urinary tract infections, protect renal tubular function, and also decline inflammatory responses by influencing the expressions of TLR2 mRNA and TLR4 mRNA so as to exert its curative effect on chronic urinary tract infections. [ABSTRACT FROM AUTHOR]

Background: Given that alterations in systemic hemodynamics have a profound influence on renal function in patients with cirrhosis, it is surprising that circadian variations in blood pressure (BP) and renal electrolyte excretion have scarcely been studied. Our aims were to define the relationship of 24-h ambulatory BP changes with renal tubular function and to determine the influence of endotoxemia on BP and urinary parameters. Methods: Forty healthy controls served as a comparator to 20 cirrhotic patients. They underwent 24-h ambulatory BP monitoring and 24-h urine collection. Results: Subjects with cirrhosis demonstrated significant diurnal variations in urinary excretion of sodium (57.7 mmol/min day versus 87 mmol/min night) and creatinine (826 mg/min day versus 1202 mg/min night). Increasing severity of cirrhosis was associated with a progressive reduction in ambulatory awake systolic (P-trend ¼ 0.015), diastolic (P-trend < 0.001) and mean BP (P-trend < 0.001). In patients with cirrhosis, the magnitude of change in BP from awake to sleep state was blunted for systolic BP (5% reduction, P ¼ 0.039) and pulse rate (2% reduction, P < 0.001). The amplitude of variation in pulse rate was blunted with increasing severity of cirrhosis (controls 6.5, Child-Pugh Class A 5.3, Child B 3.4, Child C 1.2, P ¼ 0.03) and the acrophase was right-shifted with increasing severity of cirrhosis. Compared with sleep state, during the awake state, endotoxin was associated with less sodium excretion and a lower systolic BP. Compared with the awake state, endotoxin was associated with a higher sleeping pulse rate (P < 0.001). Conclusions: Patients with cirrhosis have altered diurnal profiles in renal tubular function and blood pressure that appear to be related to endotoxemia. Determining whether endotoxemia is causally related to these perturbations will require interventional studies. [ABSTRACT FROM AUTHOR]

The kidney function can be assessed by a number of methods. The urinary excretion of enzymes, in particular N-acetyl-β-D-glucosaminidase (NAG), is considered a relatively simple, cheap, fast and non-invasive method in the detection and follow-up of renal tubular function under various conditions. The determination of urinary NAG provides a very sensitive and reliable indicator of renal damage, such as injury or dysfunction due to diabetes mellitus, nephrotic syndrome, inflammation, vesicoureteral reflux, urinary tract infection, hypercalciuria, urolithiasis, nephrocalcinosis, perinatal asphyxia, hypoxia, hypertension, heavy metals poisoning, treatment with aminoglycosides, valproate, or other nephrotoxic drugs. This paper gives an overview of the current use of urinary NAG in the detection of renal injury.

Abstract: The effects of the in vivo administration of baclofen on renal tubular transport and aquaporin-2 (AQP2) expression were evaluated. In conscious animals kept in metabolic cages, baclofen (0.01–1mg/kg, s.c.) induced a dose-dependent increment in the urine flow rate (UFR) and in sodium and potassium excretion, associated with an increased osmolal clearance (Closm), a diminished urine to plasma osmolality ratio (Uosm/Posm) and a decrease in AQP2 expression. The above mentioned baclofen effects on functional parameters were corroborated by using conventional renal clearance techniques. Additionally, this model allowed the detection of a diminution in glucose reabsorption. Some experiments were performed with water-deprived or desmopressin-treated rats kept in metabolic cages. Either water deprivation or desmopressin treatment decreased the UFR and increased the Uosm/Posm. Baclofen did not change the Uosm/Posm or AQP2 expression in desmopressin-treated rats; but it increased the UFR and diminished the Uosm/Posm and AQP2 expression in water-deprived animals. These results indicate that in vivo administration of baclofen promotes alterations in proximal tubular transport, since glucose reabsorption was decreased. The distal tubular function was also affected. The increased Closm indicates an alteration in solute reabsorption at the ascending limb of the Henle's loop. The decreased Uosm/Posm and AQP2 expression in controls and in water-deprived, but not in desmopressin-treated rats, lead us to speculate that some effect of baclofen on endogenous vasopressin availability could be responsible for the impaired urine concentrating ability, more than any disturbance in the responsiveness of the renal cells to the hormone. [Copyright &y& Elsevier]

Abstract: Objectives: Increased urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes at 5-years of follow-up. To further explore UOER in relation to local renal physiological phenomena, we studied renal glomerular and tubular functions in patients with type 2 diabetes and normal or increased UOER. Methods: We performed a cross-sectional study of 40 patients with type 2 diabetes (normal UOER, n=16; increased UOER, n=24) who displayed no signs of cardiovascular disease and 21 healthy control persons. The renal clearance values of [51Cr]ethylenediaminetetraacetic acid ([51Cr]EDTA), lithium, orosomucoid, albumin, and sodium were measured. Results: Patients with type 2 diabetes had normal glomerular filtration rate (GFR) measured by [51Cr]EDTA clearance. The clearance value of orosomucoid was highly increased in patients with increased UOER. The clearance values of albumin were similar in patients with increased UOER and in healthy controls. Investigations of renal tubular function revealed normal and similar levels of lithium clearance and proximal and distal reabsorption of sodium and water. Serum values of orosomucoid were higher in patients with increased UOER than in healthy controls (P<.001), but were still within reference limits, suggesting chronic low-grade inflammation. UOER was associated with increasing values of orosomucoid clearance (P<.0001) independently of serum orosomucoid. Conclusions: Patients with type 2 diabetes and increased UOER had normal GFR and showed no signs of renal glomerular or tubular dysfunction. We therefore hypothesize that increased levels of UOER may be caused by local renal production of orosomucoid due to chronic low-grade inflammation. [Copyright &y& Elsevier]

Objective: Iron deficiency anemia (IDA) resulting from lack of sufficient iron for synthesis of hemoglobin is most common hematologic disease of infancy and childhood. There is little information about the renal function in iron deficiency anemia. The aim of the present study was to examine the renal function in children with iron deficiency anemia. Methods: This case-control study was performed in children with iron deficiency anemia (n=20) and healthy age matched subjects (n=20). Blood and urine samples were obtained for hematological and biochemical investigation. Statistical analysis was performed by unpaired sample t-test and Pearson's correlation coefficient. Findings: Fractional excretion of sodium (FENa+) was significantly higher in children with iron deficiency anemia than control subjects (P=0.006). There was no significant difference in the level of urine specific gravity, calcium/creatinine ratio, β2-microglobulin and creatinine clearance between case and control groups (P>0.05). There was no correlation between FENa and Hb (r=0.13, P=0.57), FENa+ and Fe+2 (r=0.079, P=0.72), FENa+ and TIBC (r=-0.083, P=0.71), FENa+ and ferritin (r=0.039, P=0.86) as well as Hb and β2-microglobulin (r=0.02, P=0.37) in IDA patients. Conclusion: The results showed that FENa+ was higher in children with iron deficiency anemia than in normal subjects. The findings revealed evidence of tubular damage in IDA; this needs confirmation by more investigation. [ABSTRACT FROM AUTHOR]

Renal solute clearances are reduced in ischemic acute kidney injury. However, the mechanisms explaining how solute clearance is impaired have not been clarified. Recently, we reported that cadaveric renal allografts exhibit maldistribution of organic anion transporter 1 (OAT1) in proximal tubule cells after ischemia and reperfusion, resulting in impairment of PAH clearance. In the present study, we characterized renal OAT1 in detail after ischemia-reperfusion using a rat model. We analyzed renal OAT1 using confocal microscopy with a three-dimensional reconstruction of serial optical images, Western blot, and quantitative real-time RT-PCR. OAT1 was distributed to basolateral membranes of proximal tubule cells in controls. With ischemia, OAT1 decreased in basolateral membrane, especially in the lateral membrane domain, and appeared diffusely in cytoplasm. After reperfusion following 60-min ischemia, OAT1 often formed cytoplasmic aggregates. The staining for OAT1 started reappearing in lateral membrane domain 1 h after reperfusion. The basolateral membrane staining was relatively well discernable at 240 h of reperfusion. Of note, a distinct increase in OAT1 expression was noted in vasculature early after ischemia and after reperfusion. The total amount of OAT1 protein expression in the kidney diminished after ischemia-reperfusion in a duration-dependent manner until 72 h, when they began to recover. However, even at 240 h, the amount of OAT1 did not reach control levels. The kidney tissues tended to show a remarkable but transient increase in mRNA expression for OAT1 at 5 min of ischemia. Our findings may provide insights of renal OAT1 in its cellular localization and response during ischemic acute kidney injury and recovery from it. [ABSTRACT FROM AUTHOR]

In β-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies demonstrating proteinuria, aminoaciduria, low urine osmolality, and excess secretion of the tubular damage markers, such as urinary N-acetyl-D-glucosaminidase (UNAG) and β2 microglobulin, in patients with thalassemia. The object of this study was to analyze renal tubular and glomerular function in pediatric patients with β-thalassemia and to correlate the renal findings to iron overload. Thirty-seven patients with β-thalassemia major and 11 with thalassemia intermedia were studied. Twelve children without iron metabolism disorders or renal diseases served as a control group. No difference in blood urea nitrogen (BUN), serum creatinine, creatinine clearance, electrolytes, fractional excretion of sodium and potassium, and tubular phosphorus reabsorption was found. Serum uric acid was equal in the two groups, but its urine excretion was significantly higher in the thalassemic group. UNAG and UNAG to creatinine ratio (UNAG/CR) were elevated in all patients with thalassemia compared with the control group ( p < 0.001) and were directly correlated to the amount of transfused iron but not to actual ferritin level. We found that renal tubular function is impaired in children with β- thalassemia major and intermedia. It is not known whether these functional abnormalities would have any long-term effects on the patients. Further studies are needed, and means of preventing these disturbances should be sought. [ABSTRACT FROM AUTHOR]

Abstract: It is known that organophosphate pesticides and their metabolites are generally eliminated through urine and are likely to affect nephrons. Despite the widespread application of Dichlorvos only limited studies appear to have been done on its toxicity to kidney. Intraperitoneal administration of 400μg/kg Dichlorvos in mice exhibited maximum reduction in total protein concentration of kidney after exposure to 120h (52-fold decrease, t-test, P <0.001). Variations in renal clearance and percent reabsorption of acid phosphatase, alkaline phosphatase and nonspecific esterase enzymes were significant at P <0.01 and at P <0.001 (2-way ANOVA), respectively. Maximum significant increase in renal contents of Na+ and Ca++ was induced by 200μg/kg dose after 120 and 240h exposure (P <0.001), while significantly highest retention of K+ and Cl− ions was caused by 400μg/kg dose after 24 and 72h exposure (P <0.01). Histopathological changes in glomeruli, PCTs, DCTs and CTs along with altered renal tubular function and renal clearance of enzymes and various ions indicate the development of acute renal disturbances under the influence of Dichlorvos. [Copyright &y& Elsevier]

To investigate the relations among total mercury levels in hair, toenail, and urine, together with potential effects of methylmercury intake on renal tubular function, we determined their levels, and urinary N-acetyl-β-d-glucosaminidase activity (NAG) and α 1-microglobulin (AMG) in 59 women free from occupational exposures, and estimated daily mercury intakes from fish and other seafood using a food frequency questionnaire. Mercury levels in the women were in hair, in toenail, and creatinine in urine; and, there were positive correlations among them . The daily mercury intake of was significantly correlated with total mercury levels in hair, toenail, and urine (, 0. 537, and 0. 604, ). Among the women, the NAG and AMG were positively correlated with both the daily mercury intake and mercury levels in hair, toenail, and urine ; and, these relations were almost similar when using multiple regression analysis to adjust for possible confounders such as urinary cadmium ( creatinine) and smoking status. In conclusion, mercury resulting from fish consumption can explain total mercury levels in hair, toenail, and urine to some degree (about 30%), partly through the degradation into the inorganic form, and it may confound the renal tubular effect of other nephrotoxic agents. Also, the following equation may be applicable to the population neither with dental amalgam fillings nor with occupational exposures: [hair mercury (μg/g)]=2. 44×[toenail mercury (μg/g)]. [Copyright &y& Elsevier]

Aim: To assess the effects of anti-epileptic drugs on renal tubular function. Methods: Urinary N-acetyl-β-D-glucosaminidase activity was measured in 114 epileptic children (mean age 5.6 ± 1.1 years) who were undergoing monotherapy with valproate ( n = 46), carbamazepine ( n = 34), lamotrigine ( n = 13) and combined therapy with valproate+carbamazepine ( n = 21). Results: The urinary N-acetyl-β-D-glucosaminidase index of valproate ( P < 0.01), carbamazepine ( P < 0.05) and polytherapy group ( P < 0.01) were significantly elevated when compared with that of the control group. No significant difference in N-acetyl-β-D-glucosaminidase levels was found between the lamotrigine group and the control subjects. We found that the distribution of the N-acetyl-β-D-glucosaminidase values of patients depended significantly on the length of therapy ( P < 0.01). The level of urinary excretion of N-acetyl-β-D-glucosaminidase was significantly higher in the patients who were taking long-term treatment (>10 years) with valproate, carbamazepine and combined therapy than those taking therapy shorter than 10 years ( P < 0.01). The mean serum concentrations of valproate and carbamazepine were 68.7 ± 17.44 µg/mL and 5.41 ± 1.23 µg/mL, respectively. There was a significant correlation between the serum concentration of valproate and urinary N-acetyl-β-D-glucosaminidase levels ( r = 0.44, P < 0.01). There was also a significant correlation between the serum concentration of carbamazepine and N-acetyl-β-D-glucosaminidase excretion ( r = 0.52, P < 0.01). Conclusion: The present study demonstrated that in patients treated with valproate and carbamazepine, an impairment of tubular function can be present, whereas lamotrigine does not cause any significant change. [ABSTRACT FROM AUTHOR]

Aims: To investigate acute and short-term effects of sirolimus (SRL) on glomerulo-tubular function, blood pressure (BP), and renal morphology in the rat. Methods: Male Sprague-Dawley rats, weighing initially 140–180 g were treated with SRL in three series: SRL 0.2, 0.4, or 0.8 mg/kg/day intraperitoneally for up to 28 days after skin allo-transplantation from Lewis donors (to establish a dosage with significant immunosuppressive effect). SRL 0.4 mg/kg intravenously (acute effects). SRL 0.4 mg/kg/day intraperitoneally for 7 days (short-term effects). Inulin, lithium (CLi) and sodium clearance, and intra-arterial BP were measured in conscious catheterized rats. Morphological kidney studies were completed after post-mortem fixation. Results: Maximum immunosuppressive effect was achieved with SRL 0.4 mg/kg/day. SRL acutely increased GFR and CLi, whereas fractional proximal reabsorption (PFR) declined. In the short-term study SRL had opposite effects on GFR and CLi, unaffected proximal tubular reabsorption and PFR, raised BP, diminished food consumption, and slower increase in body weight. Morphological changes were non-specific. Conclusion: In a dosage giving maximum immunosuppressive effect, SRL revealed acute effects on glomerular and proximal tubular function thus indicating increased outflow from the proximal tubules whereas one week of SRL treatment produced a change resembling the known nephrotoxic effects of the calcineurine inhibitors. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Tubulointerstitial nephritis is a less frequently recognized but important complication of systemic lupus erythematosus. We have investigated the cytokine β[sub 2] -microglobulin (β[sub 2] M) and Tamm-Horsfall glycoprotein (THG) excretions in the urine of systemic lupus erythematosus patients to identify indices for evaluation of tubulointerstitial inflammation in lupus nephritis (LN). Daily urine was collected from 15 patients with active LN, from 12 patients with inactive LN, and from 17 normal subjects. The amounts of soluble interleukin (IL) 2 receptor, IL-6, IL-8, β[sub 2] M, and THG in urine were measured. β[sub 2] M and THG were regarded as indicators of proximal and distal renal tubule function, respectively. The urinary excretions of IL-6 and IL-8 were significantly higher in patients with active LN than in those with inactive LN and in normal individuals. The excretion of soluble IL-2 receptor in all three groups of subjects was not significantly different. On the other hand, the excretion of β[sub 2] M in patients with LN was significantly higher than that in normal individuals. The excretion of β[sub 2] M in patients with active or inactive LN was not significantly different. The THG excretion was lower in patients with active LN and tubulointerstitial inflammation as compared with patients with inactive LN or normal individuals. Six patients underwent pulse cyclophosphamide therapy during the course of experiments. Five of them showed a decrease in IL-8 and IL-6 excretions in urine after the treatment. The excretions of β[sub 2] M and THG in urine, in addition to IL-6 and IL-8, can reflect the renal inflammatory activity in patients with lupus tubulointerstitial nephritis as well as in those having lupus glomerulonephritis.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Part I: The side-effects of Sandimmune that have been of most significance clinically are renal dysfunction, renal vascular damage and arterial hypertension. To examine the nature and the origin of such effects, the actions of Sandimmune on the renal tubule, the renal vessels and systemic vessels have been analyzed. To evaluate whether common vasoconstrictory systems may be involved, changes in the renin-angiotensin-aldosterone system and prostaglandin-thromboxane system have been assessed. Comparison between animal and human data obtained in vivo and in vitro shows the actions of Sandimmune on the renal tubule to be modest and involve only a few specific effects. The major action of Sandimmune is on the vessels, vasoconstriction being the major cause of renal dysfunction and also the cause of arterial hypertension. Neither the circulating renin-angiotension-aldosterone system nor the prostaglandin-thromboxane system is clearly responsible for vasoconstriction. Although not itself a vasoconstrictor, Sandimmune seems to modulate the constrictory and dilatory response to other agents in several vascular beds. [ABSTRACT FROM AUTHOR]

Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m. Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure ( r=−0.60; P<0.02), and positively with those in plasma norepinephrine ( r=0.55; P<0.05) and renin ( r=0.62, P<0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure ( r=−0.65; P<0.01), and positively with those in plasma norepinephrine ( r=0.58; P<0.05). 24 h-urinary sodium excretion was significantly ( P<0.001) decreased; it was positively correlated with mean blood pressure ( r=0.51; P<0.05) and inversely with supine plasma renin activity ( r=−0.63; P<0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly ( P<0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine ( P<0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator. [ABSTRACT FROM AUTHOR]

The effects of the prolonged 3-hour and 6-hour controlled hypotension induced by prostaglandin E (PGE) on renal tubular function have been comparatively studied with trimethaphan (TMP; 3-hour hypotensive anesthesia) and enflurane deep anesthesia (6-hour hypotensive anesthesia), using the urine N-acetyl-β-D-glucosaminidase (NAG index) and the serum and urine N-acetyl- β-D-glucosaminidase (fractional clearance of β -m; Fc- β -m) as markers. During 3-hour and 6-hour controlled hypotension PGE , NAG index and Fc- β -m and urine volume could be maintained without remarkable changes. In the group with TPM, NAG index and Fc- β -m significantly increased. The increasing trend was also noted over time in deep anesthesia with enflurane. On 1st postoperative day, Fc- β -m significantly increased in PGE group in both 3-hour and 6-hour hypotensive anesthesia, whereas it restored to normal on 2nd postoperative day. Also, in TMP and enflurane deep anesthesia, Fc- β -m significantly increased on 1st postoperative day. With the latter, significant increase was also observed on 2nd postoperative day. These results suggest that, in 3-hour and 6-hour controlled hypotension induced by PGE , renal tubular function is normally maintained and that it is useful for prolonged controlled hypotensive anesthesia. However, further study is necessary because tubular dysfunction might appear on 1st postoperative day. [ABSTRACT FROM AUTHOR]

Aims: To determine and compare two urinary indices of renal tubular function, N-acetyl-glucosaminidase (NAG) and beta 2-microglobulin (beta 2 M), in healthy term neonates and babies with perinatal asphyxia.Methods: In a prospective case-control study using asphyxiated (n = 35) and normal control (n = 55) infants, urinary NAG and beta 2 M were assayed at 24-48 hours of life, 4-6 days, and 4-6 weeks.Results: NAG and beta 2 M were significantly increased at 24-48 hours and 4-6 days in the asphyxiated infants compared with the controls. Increased NAG values reflect the degree of perinatal asphyxia more than do beta 2 M. Gentamicin also increased NAG excretion, but to a lesser extent than did perinatal asphyxia.Conclusions: NAG (+/- beta 2 M) may be a useful marker of perinatal asphyxia. Urinary NAG concentrations correlate with the severity of perinatal asphyxia. [ABSTRACT FROM AUTHOR]

Recent studies in liver and kidney transplant recipients revealed a nephrotoxic adverse effect of the new macrolide immunosuppressant FK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kg per day was investigated in rats using clearance methods including lithium clearance. In rats given FK-506 or placebo during 1 week the nephrotoxicity of FK-506 was characterized by a slight reduction of inulin clearance. The end proximal delivery as measured by the lithium clearance was decreased by FK-506. In rats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerular filtration rate (GFR) had decreased to 23% of the GFR found in controls (<0.001), while end proximal delivery was only 8% of normal. Renal histopathological investigation showed a slight but statistically significant increase of tubular basophilia and atrophy in FK-506-treated rats. Skin transplantation studies in the same rat strain showed a dose-dependent immunosuppressive effect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressive than 0.2 or 0.4 mg/kg, so it was concluded that the lower doses of FK-506 did not fully exploit the drug's immunosuppressive potential. Thus in a dosage inside the therapeutic range defined from skin transplantations, FK-506 generated a number of toxic effects including a considerable nephrotoxic effect. The FK-506 induced changes in glomerular and tubular function was a close match to the changes found in cyclosporin A nephrotoxicity. The present study suggests that FK-506 nephrotoxicity is caused by constriction of preglomerular vessels. [ABSTRACT FROM PUBLISHER]

Fourteen normotensive patients with chronic glomerulonephritis and well-preserved renal function and thirteen healthy control subjects were studied. Glomerular filtration rate (GFR), proximal and distal absolute and fractional tubular reabsorption (PAR, PFR, DARNa, DFRNa), evaluated by the lithium clearance technique, were determined before and in four 30–60-min periods after intravenous injection of frusemide 0.5 mg/kg body weight (Study 1) and 1.0 mg/kg body weight (Study 2). Plasma concentrations of angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP) and arginine vasopressine (AVP) were measured before, and 60 and 180 min after frusemide. GFR decreased and UNa and FENa increased significantly in patients and controls after frusemide in both studies, but in study 2 GFR decreased significantly more in patients than in controls, and UNa and FENa increased significantly less above baseline in patients compared to controls. PAR, PFR, DARNa, and DFRNa were reduced in patients and controls in both studies. In study 2 the reduction in PAR was significantly (P<0.05) less pronounced in patients (23%) than in controls (43%), whereas DARNa was reduced significantly more (P<0.05) in patients (36%) than in controls (21%). The efficiency of frusemide with regard to renal sodium excretion was significantly reduced in patients compared to controls in both studies. Angiotensin II and aldosterone increased, ANP decreased, and AVP was unchanged in patients and controls in both studies.It is concluded that in comparison to control subjects, patients with chronic glomerulonephritis and well-preserved GFR respond to frusemide with an exaggerated reduction in GFR, a lesser decrease in absolute proximal tubular reabsorption, and a larger reduction in absolute distal tubular reabsorption. Thus, primary glomerular disease with well-preserved glomerular function may be accompanied by a distinctly disturbed tubular function. [ABSTRACT FROM PUBLISHER]

The effect of two different regimens of intravenous infusion of amino acids on glomerular filtration rate (GFR), renal plasma flow (RPF), tubular sodium and water handling judged from the clearance of lithium (CLi), and plasma concentrations of angiotensin II (Ang II), aldosterone (Aldo), arginine vasopressin (AVP), atrial natriuretic peptide (ANP), growth hormone (GH), and glucagon was investigated in healthy humans. In the first protocol (n = 11) the infusion lasted 90 min; both GFR and RPF increased significantly (median increase 7.1% and 9.1% respectively, P<0.05 both). In the second protocol (n = 13) the infusion lasted 30 min; both GFR and RPF tended to increase (median increase 3.5% and 7.4%) but the change did not reach significance. The changes in tubular sodium and water handling were similar in the two protocols. Absolute reabsorption rates in the proximal tubules were unaltered, resulting in an increased output into the distal tubules that was totally compensated for by an increased distal reabsorption. Thus no changes in urinary excretion of sodium and water were observed. Ang II, Aldo, AVP, ANP and GH were unchanged by amino acid infusion, but glucagon increased. It is suggested that the alterations in renal haemodynamics and distal tubular reabsorption may be mediated by glucagon. [ABSTRACT FROM PUBLISHER]

The effects of pinacidil on renal haemodynamics, tubular function evaluated by the lithium clearance technique and the plasma levels of angiotensin II (Ang II), aldosterone (Aldo) and atrial natriuretic peptide (ANP) have been evaluated in 12 healthy volunteers given pinacidil 0.1 mg/kg IV in comparison with a placebo given to 13 different healthy volunteers. Pinacidil induced significant reductions in glomerular filtration rate (−5%), renal plasma flow (−12%), urine output (−35%), urinary sodium excretion (−20%), and the fractional excretion of sodium (−17%) and potassium (−29%). Lithium clearance and proximal and distal absolute and fractional reabsorption of sodium were not significantly changed. Ang II and Aldo were significantly increased (80% and 115%, respectively) and ANP was unchanged. The mean arterial blood pressure was not significantly changed by pinacidil, but the heart rate was increased (22%). It is concluded that bolus IV injection of pinacidil in healthy subjects reduced renal blood flow, urine volume and the urinary excretion of sodium and potassium, whereas segmental tubular function was unchanged. The increase in heart rate and activation of the renin-agiotensin-aldosterone system are most likely to be secondary to stimulation of the sympathetic nervous system caused by the vasodilator effect of pinacidil. [ABSTRACT FROM AUTHOR]

The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 μg·kg bwt were given as an intravenous bolus injection to different groups. P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min. Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner. P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30-60 min after injection of P-ANP. It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man. [ABSTRACT FROM AUTHOR]