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Tumors of the urinary system, such as prostate cancer, bladder cancer, and renal cell carcinoma, are among the most prevalent types of tumors. They often remain asymptomatic in their early stages, with some patients experiencing recurrence or metastasis post-surgery, leading to disease progression. Lactate dehydrogenase A (LDHA) plays a crucial role in the glycolysis pathway and is closely associated with anaerobic glycolysis in urinary system tumors. Therefore, a comprehensive investigation into the intricate mechanism of LDHA in these tumors can establish a theoretical foundation for early diagnosis and advanced treatment. This review consolidates the current research and applications of LDHA in urinary system tumors, with the aim of providing researchers with a distinct perspective., (© 2024. The Author(s).)

Cylindrospermopsin (CYN) is a cyanotoxin and a hydrophilic alkaloid of 415 Da. The principal effect of CYN is the inhibition of protein synthesis, and it can damage various organs. Studies have demonstrated that the kidney is the most affected organ. CYN has played roles in at least two poisoning cases, i.e., the mysterious Palm Island disease in Australia and the event at Caruaru in Brazil. Therefore, we aimed to determine how CYN disrupts the renal tissue. Dose-response curves following single intraperitoneal injections of purified CYN (at 0, 16, 32, 64 and 128 μg CYN/kg body weight) were created in 10-week-old male BALB/C mice (n = 4). Renal physiology parameters were analyzed after 7 and 14 days. However, no alterations in the glomerular filtration rate (GFR) or nephrin expression (a crucial protein for glomerular integrity) were observed. We detected low-molecular-weight proteinuria and increased excretions of the tubular enzymes lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) at doses of 16, 32 and 64 μg CYN/kg body weight. Furthermore, we observed increases in the renal interstitial space and collagen deposition that indicated edema and fibrosis. The data seem to indicate that the damage is in the proximal tubule., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Renal ischemia-reperfusion injury is the state of which a tissue experiences injury after a phase of restrictive blood supply and recirculation. Ischemia-reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) in several disease states, including kidney transplantation, sepsis, and hypovolemic shock. The most common methods to evaluate AKI are creatinine clearance, plasma creatinine, blood urea nitrogen, or renal histology. However, currently, there are no precise methods to directly assess renal injury state noninvasively. Hyperpolarized 13 C-pyruvate MRI enables noninvasive accurate quantification of the in vivo conversion of pyruvate to lactate, alanine, and bicarbonate. In the present study, we investigated the in situ alterations of metabolic conversion of pyruvate to lactate, alanine, and bicarbonate in a unilateral I/R-I rat model with 30 min and 60 min of ischemia followed by 24 h of reperfusion. The pyruvate conversion was unaltered compared with sham in the 30 min I/R-I group, while a significant reduced metabolic conversion was found in the postischemic kidney after 60 min of ischemia. This indicates that after 30 min of ischemia, the kidney maintains normal metabolic function in spite of decreased kidney function, whereas the postischemic kidney after 60 min of ischemia show a generally reduced metabolic enzyme activity concomitant with a reduced kidney function. We have confidence that these findings can have a high prognostic value in prediction of kidney injury and the outcome of renal injury., (Copyright © 2017 the American Physiological Society.)

Cinnamomum zeylanicum has strong antioxidant properties and has been presented to have nephroprotective effects. Present work was aimed to study the nephroprotective property of the plant extract through urinary enzymes excretion, to confirm its protective effects and to observe the antibacterial activities of gentamicin in combination with the plant extract. 200mg/kg/day of the plant extracts were administered alone and as co-therapy with gentamicin. Urinary lactate dehydrogenase (LDH) and Urinary alkaline phospatase (ALP) excretions were observed through reagents kits with the help of Power-Lab 300. Antibacterial activities were assessed for gentamicin alone and in combination with the extract. Present study showed that the plant extract have excess quantity of flavonoids, which may responsible for attenuating the excessive excretion of urinary LDH. However, Urinary ALP excretion was found remained same throughout the study period in all experimental groups; might be detected in acute damage. Further, the plant also proved to have no decreasing impact on the antibacterial activities of gentamicin.

The effective diuretic dose of 5-HT3 receptor blocker RU-63 (1 mg/kg) was found in experiments on white rats. It is established that the diuretic and saluretic effects of compound RU-63 increase on the background of impact of the gravitational factor. Compound RU-63 (1 mg/kg, subcutaneously) administered daily under hypergravity conditions (3 g in the direction of centrifugal force toward the kidneys) in animals with model ischemic acute renal failure increased excretory function of kidneys, glomerular filtration rate, and creatininuresis (on average by 180%; p < 0.05), and decreased serum creatinine, urinary excretion of protein, lactate dehydrogenase, and g-glutamyl transferase (on average by 49%; p < 0.05) as compared to the untreated control. Under similar conditions, the diuretic hydrochlorothiazide (in a dose of 20 mg/kg, intragastric) produced a more pronounced creatininuretic action than that of RU-63 (by 358%; p < 0.05).

Presented exploratory pilot study was aimed at evaluation of proteins present in urinary specimens collected from prostate cancer suffering subjects after radical prostatectomy, divided into two experimental cohorts: positive (n=15) and negative (n=15) surgical margins (PSM/NSM). The presence of PSM suggests inadequate cancer clearance and the possible need for additional treatment. Proper identification of these risk-patients is therefore of a paramount importance. Total protein profiles were firstly identified by using SDS-PAGE and compared by using partial least square discrimination analysis (PLS-DA), which revealed differences in molecular weights of 80-99 and 150-235 kDa between the experimental groups. For further identification of proteins, comparative proteomic technologies were employed. Two-dimensional gel electrophoresis with subsequent identification of protein spots by using MALDI-TOF mass fingerprinting revealed differential expression of proteins between NSM/PSM cohorts. Moreover, in PSM group, three uniquely identified proteins (cyclin-dependent kinase 6, galectin-3-binding protein and L-lactate dehydrogenase C chain) were found, which show tight connection with prostate cancer and presence of all of them was previously linked to certain aspects of prostate cancer. These proteins may be associated with the molecular mechanisms of prostate cancer development; hence, their identification may be helpful for the assessment of disease progression risk after radical prostatectomy, but also for possible early diagnosis.

The article examines the possibility of determining the level of lactate dehydrogenase (LD) in biological fluids as a marker of renal dysfunction and energy supply in neonates with asphyxia. Investigation included 200 full-term newborns with disturbance kidney function: 100 infants who had severe asphyxia, and 100--with moderate asphyxia. LD activity was determined by kinetic spectrophotometric method. Determination of the activity of LD in the urine in the early neonatal period it is advisable to use as a non-invasive marker for the diagnosis of renal dysfunction in neonates with asphyxia. The content of LD in the blood serum can be used as one of the early markers of kidney damage in newborns with asphyxia.

The purpose of the present study was to evaluate the nephro-protective potential of N-acetylcysteine against hyperoxaluria-induced renal mitochondrial dysfunction in rats. Nine days dosing of 0.4 % ethylene glycol +1 % ammonium chloride, developed hyperoxaluria in male wistar rats which resulted in renal injury and dysfunction as supported by increased level of urinary lactate dehydrogenase, calcium, and decreased creatinine clearance. Mitochondrial oxidative strain in hyperoxaluric animals was evident by decreased levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, reduced glutathione, and an increased lipid peroxidation. Declined activities of respiratory chain enzymes and tricarboxylic acid cycle enzymes showed mitochondrial dysfunction in hyperoxaluric animals. N-acetylcysteine (50 mg/kg, i.p.), by virtue of its -SH reviving power, was able to increase the glutathione levels and thus decrease the oxidative stress in renal mitochondria. Hence, mitochondrial damage is, evidently, an essential event in ethylene glycol-induced hyperoxaluria and N-acetylcysteine presented itself as a safe and effective remedy in combating nephrolithiasis.

In this prospective study, we comparatively evaluated the accuracy of several biomarkers of acute kidney injury (AKI) on predicting its occurrence after liver transplantation (LT). The parameters evaluated were urinary tubular enzymes (γ-glutamyl transpeptidase [γGT], alkaline phosphatase, and urinary lactate dehydrogenase) and urinary neutrophil gelatinase-associated lipocalin. These parameters were evaluated both as isolated variables and divided by urinary creatinine. Samples were collected by the end of surgery (determination 1) and at 12 to 24 hours after surgery (determination 2). The study endpoint was the development of AKI. The study was performed over a 1-year period, and 61 of 77 patients were enrolled (main exclusion criteria were perioperative death, previous known renal failure, and insufficient data for analysis). Of these 61 patients, AKI was observed in 19 (group 1). The main relevant parameter to predict AKI was the absolute value of urinary γGT at determination 1 (area under the curve, 0.74; specificity, 72.5%; sensitivity, 70.3%; cutoff, 36 U/mL). Urinary neutrophil gelatinase-associated lipocalin was not as accurate; the best predicted value for this parameter was absolute value at D1 with an area under the curve of 0.5 (specificity, 84.2%; sensitivity, 35.7%; cutoff value, 44.6 ng/mL). We concluded that the absolute value of urinary γGT evaluated at the end of LT was the most accurate parameter to predict AKI in our cohort. Urinary enzyme levels must be taken into account in future analysis of this issue., (Copyright © 2014 Elsevier Inc. All rights reserved.)

It was shown that development of the Guerin carcinoma and introduction of cisplatin led to the damage of the kidneys of rats that was confirmed by a relative increase of weight, proteinuria, change of gamma-glutamyl transpeptidase and lactate dehydrogenase activity in the urea and tissue homogenates of the kidneys, by a decrease of relative reabsorption and glomerular filtration. Introduction of nanoliposomal forms of the rhenium cluster compounds led to normalization of above mentioned diagnostic indexes and to reduction of the toxic cisplatin influence that was confirmed by biochemical and morphological investigations.

Increasing intracellular calcium ion concentration in the cytoplasm is the starting point in the activation of cell death. Regulation of these pathological processes in various organs and tissues is possible using agents from the group of calcium antagonists. This study was aimed at assessing the level of urinary excretion of two enzymes, lactate dehydrogenase (LDH, EC 1.1.1.27) and y-glutamyltransferase (GGT, EC 2.3.2.2), calcium antagonists in an experimental model of nephrolithiasis and finding ways to pharmacological protection of the kidneys. It established that the use of calcium antagonists can reduce the excretion of LDH by 20% and the excretion of GGT by more than 40%.

Experiments performed on 23 male rats, were divided into 2 groups. Animals in the control received group 1% solution of ethylene glycol (EG) as a drink during 6 weeks. In the test group, EG was also introduced for 6 weeks, and meloxicam was administered in a dose of 2.5 mg/kg from the 4th week. Every 7 days, daily urine was analyzed for the concentrations of oxalate, phosphate, and calcium and for the activity of urothelium injury marker enzymes includng lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and N-acetyl-beta-D-glucose aminidase (NAG). In addition, sections of the rats kidney were used to detect calcium deposits by histochemical Van Koss method. The treatment of experimental nephrolithiasis by meloxicame led to simplification of pathology, as indicated by a significant reduction in the urine oxalate and calcium concentrations and a pronounced decrease in the activity of all marker enzymes (LDH, GGT, NAG).This was confirmed by morphological studies, which detected very significant reduction in both number and size of calcium deposits.

Objective: This study aims to investigate the protection of procyanidins and lycopene from the renal damage induced by mercuric chloride., Methods: Rats were treated with either procyanidins or lycopene 2h before HgCl(2) subcutaneously injection, once daily treatment for 2 successive days., Results: In comparison with HgCl(2) group, markers of renal function such as blood urea nitrogen in serum and urinary protein were decreased to (18.45±11.63) mmol/L and (15.93±9.36) mmol/L, (4.54±0.78) g/(g·Cr) and (4.40±1.12) g/(g·Cr). N-acetyl-beta-D-glucosaminidase, lactate dehydrogenase, alkaline phosphatase in urine were depressed to (125.49±11.68) U/(g·Cr), (103.73±21.79) U/(g·Cr), (101.99±12.28) U/(g·Cr), and (113.19±23.74) U/(g·Cr), (71.14±21.80) U/(g·Cr), (73.64±21.51) U/(g·Cr) in procyanidins and lycopene groups. Indicators of oxidative stress, for example, Glutathion was reduced to (45.58±9.89) μmol/(g·pro) and (45.33±5.90) μmol/(g·pro), and antioxidant enzymes such as superoxide dismutase, glutathione-peroxidase were enhanced to (43.07±10.97) U/(mg·pro) and (39.94±6.04) U/(mg·pro), (83.85±18.48) U/(mg·pro), and (85.62±12.68) U/(mg·pro). Malondialdehyde was lowered to (0.95±0.12) (μmol/g·pro) and (1.03±0.12) μmol/(g·pro) in procyanidins and lycopene groups. ROS generation was decreased by 27.63% and 16.40% and apoptosis was also decreased in procyanidins and lycopene groups respectively. Pathological changes were much better as well., Conclusion: Procyanidins and Lycopene play some protective role against mercury kidney damage., (Copyright © 2011 The Editorial Board of Biomedical and Environmental Sciences. Published by Elsevier B.V. All rights reserved.)

Tubular enzymes (TE) are early markers of acute kidney injury (AKI), but their value for liver transplant (LT) recipients is unknown. We sought to evaluate the usefulness of TE to predict AKI after LT. We enrolled Thirty-nine adult patients without AKI who had been admitted to the Intensive Care Unit (ICU). AKI was diagnosed according to the Acute Kidney Injury Network criteria. Of these patients, 23 had received orthotopic LT and 16 controls had been admitted for other conditions. Urinary lactate dehydrogenase (LDH), alkaline phosphatase (AF) and γ-glutamyl transpeptidase (γ-GT) measured on days 1 and 3 of the ICU stay were normalized to urinary creatinine concentrations. AKI was diagnosed in 14 patients: 8 in the LT group and 6 in the control group. In the LT group, on the first day of the patients' stay in the ICU, urinary LDH (P = .032), AF (P = .022), and γ-GT (P = .002) were significantly higher among those who developed AKI; these elevations preceded those of serum creatinine. In forward receiver-operating characteristic (ROC) plot analysis, the areas under the ROC curves were 0.8, 0.86, and 0.92 for LDH, AF, and γ-GT, respectively. We concluded that TE determined early after LT are a helpful predictors of AKI., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Since nephrotoxicity affects the development of drug candidates, it is important to detect their toxicity at an early stage of drug development. In this study, we measured twelve urinary nephrotoxic biomarkers [total protein, albumin, kidney injury molecule-1 (KIM-1), clusterin, beta2-microglobulin, cystatin-c, alpha-glutathione S-transferase, mu-glutathione S-transferase, N-acetyl-beta-d-glucosaminidase, lactate dehydrogenase (LDH), aspartate aminotransferase and neutrophil gelatinase-associated lipocalin (NGAL)] and two conventional blood nephrotoxic biomarkers (creatinine and blood urea nitrogen) in rat models treated intravenously with puromycin aminonucleoside (PAN) or cisplatin (CDDP), which are known to induce glomerular injury or proximal tubular injury, respectively, and evaluated their usefulness by receiver operating characteristic analysis. In the PAN-treated rats, urinary albumin and (NGAL) were dramatically increased, which were thought to be caused by the dysfunction of proximal tubule in addition to glomerular injury. Conversely, based on its early and time-dependent increase, its large magnitude of alteration and its high accuracy and sensitivity of detection, (KIM-1) in urine appeared to be the best biomarker for detection of CDDP-induced proximal tubular injury. Moreover, (LDH) was considered useful for broad detection of damaged nephrons, because of its broad distribution along the nephron. Therefore, combinatorial measurement of these biomarkers may be a powerful tool for highly effective screening of nephrotoxicity.

Cadmium (Cd) is a nephrotoxic industrial and environmental pollutant that causes a generalized dysfunction of the proximal tubule. Kim-1 is a transmembrane glycoprotein that is normally not detectable in non-injured kidney, but is up-regulated and shed into the urine during the early stages of Cd-induced proximal tubule injury. The objective of the present study was to examine the relationship between the Cd-induced increase in Kim-1 expression and the onset of necrotic and apoptotic cell death in the proximal tubule. Adult male Sprague-Dawley rats were treated with 0.6 mg (5.36 micromol) Cd/kg, subcutaneously, 5 days per week for up to 12 weeks. Urine samples were analyzed for levels of Kim-1 and the enzymatic markers of cell death, lactate dehydrogenase (LDH) and alpha-glutathione-S-transferase (alpha-GST). In addition, necrotic cells were specifically labeled by perfusing the kidneys in situ with ethidium homodimer using a procedure that has been recently developed and validated in the Prozialeck laboratory. Cryosections of the kidneys were also processed for the immunofluorescent visualization of Kim-1 and the identification of apoptotic cells by TUNEL labeling. Results showed that significant levels of Kim-1 began to appear in the urine after 6 weeks of Cd treatment, whereas the levels of total protein, alpha-GST and LDH were not increased until 8-12 weeks. Results of immunofluorescence labeling studies showed that after 6 weeks and 12 weeks, Kim-1 was expressed in the epithelial cells of the proximal tubule, but that there was no increase in the number of necrotic cells, and only a modest increase in the number of apoptotic cells at 12 weeks. These results indicate that the Cd-induced increase in Kim-1 expression occurs before the onset of necrosis and at a point where there is only a modest level of apoptosis in the proximal tubule.

Lactate dehydrogenase activity, crystallogenic and initiator characteristics of biological substrates were evaluated by enzymological and crystalloscopic analysis of rat serum and urine. Changes in these characteristics of biological media in combined thermal injury were shown. This approach is effective for evaluation of the metabolic status in rats with experimental burn disease.

Although aminoglycosides antibiotics are used in children and adult commonly, they have serious side effects such as nephrotoxicity and ototoxicity. In clinical practice, for renal function, the levels of serum creatinine and blood urea nitrogen routinely are measured. Since these parameters have limitations such as unreliability, insensitivity, and nonspecificity, the rapid assessment of renal function based on these patients is very important. Increase in N-acetyl-beta-D-glucosaminidase (NAG), a hydrolytic lysosomal enzyme, suggests proximal tubular cell damage. In this study, 32 children aged 2 months through 2 years, treated with gentamicin and amikacin for suspected infections at the pediatric ward of Alborz hospital from September 2006 to February 2007, were enrolled. Serum and fresh urine before and after drug infusion were obtained on the 1st, 3rd, and 5th days of antibiotic treatment. Serum urea and creatinine with urinary creatinine, albumin, NAG, lactate dehydrogenase (LDH) and alkaline phosphatase (AP) activity were then determined. A statistically significant increase in urinary NAG, LDH, and AP on 5th day was found compared with before gentamicin administration (P < 0.001, P < 0.01, P < 0.05, respectively). The urinary NAG activity may be a useful indicator of renal injury in children treated with aminoglycosides drugs compared with other routine clinical indicators.

Background: Lysosomal enzymuria is usually considered to be a non-specific marker of renal injury, but little is known about lysosomal enzyme excretion in renal proximal tubular cell disorders such as the renal Fanconi syndrome (FS). We examined excretion of two lysosomal enzymes and the cation-independent mannose-6-phosphate receptor (CI-MPR) in patients with inherited FS., Methods: The lysosomal enzyme cathepsin D was measured by ELISA and isolated by pepstatin-agarose affinity chromatography; N-acetyl-beta-d-glucosaminidase (NAG) was assayed colorimetrically, as was the cytosolic enzyme lactate dehydrogenase (LDH). Cathepsin D, procathepsin D and CI-MPR were also detected by western blotting. No patient had a serum creatinine concentration >170 micromol/L. Soluble CI-MPR, isolated from fetal calf serum and bound to agarose, was used to probe cathepsin D for mannose-6-phosphate (M6P)., Results: Increased excretion of cathepsin D (mean = 44-fold) and NAG (mean = 12-fold) was found in FS patients: Dent's disease (n = 5), cystinosis (n = 4), Lowe syndrome (n = 3) and 'autosomal dominant idiopathic FS' (ADIF) (n = 2). Increased cathepsin D excretion was confirmed by western blotting; excretion of procathepsin D and LDH was not increased. When compared with control subjects, CI-MPR excretion was also increased in FS (n = 6). Thus, significantly increased excretion of lysosomal enzymes and CI-MPR was found in all cases of FS examined. Cathepsin D binding to CI-MPR-agarose was inhibited by M6P., Conclusions: We conclude that underlying gene defects in FS may disrupt normal membrane trafficking of CI-MPR, leading to mistrafficking of lysosomal enzymes via a default pathway from the Golgi to the apical surface of proximal tubule cells rather than to lysosomes. Lysosomal enzymes are then secreted into the tubular fluid and excreted in the urine. This contrasts with the widely held view that cell necrosis is the cause of lysosomal enzymuria in renal disease. Moreover, cathepsin D in FS urine is M6P-tagged.

Purpose: Extracorporeal shockwave lithotripsy (SWL) is one of the most common treatments for urinary stones. Despite technological improvements, it may cause side effects varying from minor reversible microscopic damage to severe large renal hematomas. The aim of our experimental study is to assess the efficacy of inosine in avoidance of acute renal damage after SWL., Materials and Methods: We used 25 Wistar rats that had previously had left nephrectomy. The rats were divided into three groups: group A consisted of 10 rats undergoing renal SWL; group B consisted of 10 rats that received adjunctive treatment with IP injection of inosine 40 minutes before SWL; and group C consisted of 5 rats that served as controls. N-acetylglucosaminidase (NAG) and lactate dehydrogenase (LDH) concentrations were evaluated 24 hours before and 24 hours after SWL. All the rats were subsequently sacrificed (4 rats in group A and 4 in group B at 48 hours post-SWL, and the remaining rats were sacrificed 30 days post-SWL). Renal tissue was submitted to histologic and electron microscopic examination to assess early and late alterations., Results: NAG and LDH values were significantly increased after SWL in group A (P<0.001), while no significant NAG and LDH differences were detected in group B (P<0.16). Early histologic examination revealed a considerable amount of cellular degeneration in group A with ultrastructural vacuolization and disruption of lysosomal membranes; the tubular features and cellular structures appeared to be well preserved in group B. No late histologic alterations were evident in any of the specimens., Conclusions: Inosine is helpful and protective in the prevention of early microscopic damage to renal parenchyma due to SWL.

We studied activity of lactate dehydrogenase (LDG) in blood serum and urine of males and females with renal carcinoma as well as in healthy controls in various age groups for specification of LDG role for early diagnosis of the disease. We examined 101 patients with renal carcinoma (males 65.3%, females 34.7%, age 20-80 years, histological verification 98%) and 119 controls matched by gender, age and residence. LDG activity was determined by kinetic UV-test with a special kit. Statistic significance of the results was estimated using such indices as relative risk, confidence interval, two-sample t-test with various variances. Blood LDG was higher more often in 50--59 year old males and females, but differences with the control were not significant. Statistically significant elevation of LDG level in urine in males and insignificant one in females were observed. We believe that LDG activity test as an additional test for early diagnosis of renal carcinoma is justified both in males and females.

The activity of lactate dehydrogenase (LDG), malate dehydrogenase (MDG), concentrations of lactic acid and lipid peroxidation (LPO) products in the blood serum and urine were estimated in 119 patients with acute pyelonephritis (70 cases of serous and 49 cases of purulent). The results of the study showed that acute pyelonephritis patients have activated anaerobic glycolysis. Ischemia leads to accumulation of lactic acid, activation of LPO. Significant differences between the groups of patients reflect strong influence of renaltissue ischemia on activity of systemic metabolic processes and metabolism in renal parenchyma. Standard infusion therapy was given to 30 patients with acute purulent pyelonephritis. 19 patients received solution of succinic acid reamberin. On day 4 of reamberin therapy plasma and urine activity of LDG and MDG attenuated, lactic acid concentration decreased, content of dienic conjugates was close to normal. Patients on reamberin treatment exhibited earlier relief of endogenic intoxication and improvement of blood count. Thus, succinic acid drugs reduce renal ischemia, improve a course of postoperative period in patients with acute purulent pyelonephritis.

Background: Measurement of urinary enzymes facilitates early detection of acute renal impairment. Since in the case of vancomycin-induced nephrotoxicity, there are different findings for the enzyme N-acetyl-beta-D-glucosaminidase (NAG) in various studies, we decided to measure 3 other important urinary enzymes -- gamma-glutamyl-transferase (GGT), alanine aminopeptidase (AAP) and lactate dehydrogenase (LDH) -- in nephrotoxic rats., Methods: Male rats were given intraperitoneal injections of vancomycin (VAN) in doses of 50, 100, 200 and 400 mg/kg or normal saline every 12 hours for 7 days. After the 14th injection, the animals were placed in metabolic cages to collect urine samples., Results: All animals receiving 400 mg/kg VAN died before completion of treatment course. The nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were in tubules, resembling acute tubular necrosis. GGT, AAP and LDH activity was measured in urine and corrected by dividing it by urinary creatinine (Cr) concentration. LDH activity showed a dose-dependent increase, while GGT and AAP activity decreased in the 200 mg/kg treated group, but only GGT showed a significant difference with controls. Serum urea and Cr and kidney weights were increased and animals' weights were decreased significantly in the 200 mg/kg VAN group compared with other groups., Conclusion: It seems that pathologic assessment remains the most accurate way to diagnose VAN nephrotoxicity. Changes in urinary enzymes could be not detected in minor tubular injuries; however, LDH appears to be the most sensitive factor. In multiple-dose studies, activity of AAP and GGT seems not to be a reliable index of nephrotoxicity.

One of the major adverse effects of vancomycin (VAN) is nephrotoxicity, which the mechanism is not fully understood. However, there is some evidence that oxidative injury could be involved in its pathogenesis. In this study, we examined two antioxidants 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (tempol) a superoxide dismutase mimetic and 2,3-dihydroxybenzoic acid (DHB) an iron chelator in VAN-induced nephrotoxicity in rats. DHB at doses of 50 and 100 mg/kg and tempol at doses of 7.5, 15 and 30 mg/kg were administered subcutaneously to rats 30 min prior to intraperitoneal injection of 200 mg/kg VAN. Drug administrations were done every 12 h for 7 days. In animals which received only VAN, the activity of urinary gamma-glutamyl-transferase (GGT) decreased and the activity of lactate dehydrogenase (LDH) in urine increased significantly compared to controls. Serum urea and creatinine (Cr) concentrations and the weight of animals' kidneys increased and body weights were decreased significantly in this group compared to controls. DHB at both doses normalized the GGT activity, but only at the higher dose restore the LDH activity. Both doses of DHB ameliorated the rise in serum urea and Cr concentrations and improved the changes in kidney and body weights significantly. Tempol did not show any beneficial effects at all. There were marked pathologic changes in tubules of kidneys of VAN treated animals. The tissue injury was prevented by both doses of DHB and there was almost no sign of tubular injury in 100 mg/kg treated group. Tempol in any doses could not prevent the tissue injury and there were significant differences in tissue injury in all tempol treated rats with controls. It seems that VAN-induced nephrotoxicity is at least partly due to free radical formation. Hydroxyl radicals might play a major role in VAN-induced nephrotoxicity, since an iron chelator (DHB) could reverse the adverse effects. However, production of other radicals such as superoxide is also probable.

Diagnosis of diabetic nephropathy in the early stages is very important since there are no clinical signs or symptoms. Urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion has been recommended as a tubular dysfunction marker that elevates before other markers, such as microalbuminuria and a decrease in creatinine clearance. In this study, we compared excretion of urinary enzymes with other markers that are used routinely in diabetic nephropathy assessment. Urinary NAG, lactate dehydrogenase (LDH), alkaline phosphatase (AP) activities, urea, creatinine, and albumin, with levels of serum glucose and creatinine and whole blood glycosylated hemoglobin (HbA1c) were measured in 32 diabetes mellitus patients and 25 healthy subjects (controls). Notably, urinary NAG, AP, LDH excretion, and microalbuminuria in the diabetic patients group were significantly increased compared to those in the control groups (P<0.001, P<0.05, P<0.01, and P<0.01, respectively). Meanwhile, our results showed that the urinary NAG excretion had the highest sensitivity and specificity (100% and 87.5%, respectively) compared to other markers. We showed that measuring urinary NAG excretion could be useful for the assessment of renal failure in diabetes mellitus patients and confirmed the use of NAG as a routine screening test.

A study was conducted to determine whether the ethanol extract of the roots of Brassica rapa (EBR) ameliorates cisplatin-induced nephrotoxicity in terms of oxidative stress, as characterized by lipid peroxidation, reactive oxygen species (ROS) production, and glutathione (GSH) depletion in LLC-PK1 cells. Pretreatment of cells with EBR prevented cisplatin-induced decreases in cell viability and cellular GSH content. The effect of EBR was then investigated in rats given EBR for 14 d before cisplatin administration. A single dose of cisplatin (7 mg/kg, i.p.) caused kidney damage manifested by an elevation in blood urea nitrogen (BUN), serum creatinine, and urine lactate dehydrogenase (LDH) levels. Also, renal tissue from cisplatin-treated rats showed a significant increase in malondialdehyde (MDA) production, and in the activities of aldehyde oxidase (AO) and xanthine oxidase (XO). Moreover, a significant decrease in the activities of antioxidant enzymes, such as, glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) was observed in cisplatin-treated rats versus saline-treated normal group. In contrast, rats given EBR showed lower blood levels of BUN and creatinine, and of urinary LDH. Moreover, EBR prevented the rise of MDA production and the induction of AO and XO activities. This extract also recovered the reduced activities of GPx, SOD and CAT. Taken together, our data indicate that the ethanol extract of the roots of Brassica rapa (EBR) has a protective effect against cisplatin-induced nephrotoxicity because it attenuates oxidative stress.

Introduction: The present study was conducted to determine whether the urinary levels of excreted enzymes, gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), aspartate (AST) and alanine aminotransferases (ALT), can efficiently indicate, within 24 h, an acute nephrotoxicity due to an overdose of paracetamol (PAR)., Methods: A baseline urine was collected from the experimental group. Thereafter, blood collected from the orbital sinus (1.0 ml) and paracetamol (650 mg/kg of body weight) was administered by gavage. After the drug administration, animals were returned to the metabolic cages and then urine was collected in the next 22 h. Blood and urine collection was performed at time 0+24 h (T(24)), as well as at times 48 and 72 h (T(48) and T(72)). After the last urine and blood collection, the rats were killed and the kidneys removed and prepared for histological examination. Plasma creatinine and urinary levels of creatinine (to determinate glomerular filtration rate-GFR), GGT, ALP, LDH, ALT and AST were measured. Kidney tissues were stained with hematoxylin and eosin stain for histological assessment., Results: Urinary levels of GGT, ALP and LDH enzymes were significantly higher (P<0.05) at T(24) when compared to the levels at T(0) and returned to basal levels at T(48) and T(72). The number of urinary epithelial cells at T(24) was significantly higher when compared to the control time (T(0)) (P<0.001). The GFR was significantly reduced 24, 48 and 72 h after the drug administration., Conclusion: The number of urinary epithelial cells and urinary enzymes levels are a simple and low cost procedure that is available and can help in the detection of renal acute lesions.

A number of animal models have been developed to investigate calcium oxalate (CaOx) nephrolithiasis. Ethylene glycol (EG)-induced hyperoxaluria in rats is most common, but is criticized because EG and some of its metabolites are nephrotoxic and EG causes metabolic acidosis. Both oxalate (Ox) and CaOx crystals are also injurious to renal epithelial cells. Thus, it is difficult to distinguish the effects of EG and its metabolites from those induced by Ox and CaOx crystals. This study was performed to investigate hydroxy-L-proline (HLP), a common ingredient of many diets, as a hyperoxaluria-inducing agent. In rats, HLP has been shown to induce CaOx nephrolithiasis in only hypercalciuric conditions. Five percent HLP mixed with chow was given to male Sprague-Dawley rats for 63 days, resulting in hyperoxaluria, CaOx crystalluria, and nephrolithiasis. Crystal deposits were surrounded by ED-1-positive inflammatory cells. Cell injury and death was followed by regeneration, as suggested by an increase in proliferating cell nuclear antigen-positive cells. Both osteopontin (OPN) and CD44 were upregulated. Staining for CD44 and OPN was intense in cells lining the tubules that contained crystals. Along with a rise in urinary Ox and lactate dehydrogenase, there were significant increases in 8-isoprostane and hydrogen peroxide excretion, indicating that the oxidative stress induced cell injury. Thus, HLP-induced hyperoxaluria alone can induce CaOx nephrolithiasis in rats.

Purpose of Review: The presence of urine in the pleural space (urinothorax) is a rarely recognized cause of pleural effusion. To date, only 58 cases have been reported. In this article the features of urinothorax are analyzed, and clinical and biochemical characteristics are reviewed in order to propose a classification, founded on pathogenic criteria, that will be useful in achieving the diagnosis., Recent Findings: Recently reported cases of urinothorax provide a more detailed description of the biochemical characteristics that allow a better understanding of this entity., Summary: Urinothorax can be divided into two categories: (1) obstructive urinothorax, due to bilateral obstructive uropathy; and (2) traumatic urinothorax, due to unilateral traumatic injury of the urinary system, mostly iatrogenic. In patients with urinothorax, the pleural effusion usually has the biochemical characteristics of a transudate, with a pH lower than 7.30 and a pleural fluid/serum creatinine ratio higher than 1. These characteristics are not always present, however, and individually are shared by a significant number of pleural effusions of different etiology.

Background: In experimental settings, uranium is toxic to kidneys, but effects on humans are unclear. Ingestion of water from drilled wells is a source of high uranium exposure in some populations., Methods: Uranium exposure was measured in 95 men and 98 women aged 18 to 81 years who had used drinking water from drilled wells for an average of 16 years. Urinary N-acetyl-gamma-d-glucosaminidase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, and glutathione-S-transferase; serum cystatin C; and urinary and serum calcium, phosphate, glucose, and creatinine were measured to evaluate possible toxic effects of uranium on kidney cells and renal function. In addition, supine blood pressure was measured. Associations between uranium exposure and the outcome variables were modeled by using linear regression with adjustment for age, sex, body mass index, smoking, and analgesic use., Results: Median uranium concentration in drinking water was 25 microg/L (interquartile range, 5 to 148 microg/L; maximum, 1,500 microg/L). Indicators of cytotoxicity and kidney function did not show evidence of renal damage. No statistically significant associations with uranium in urine, water, hair, or toenails was found for 10 kidney toxicity indicators. Uranium exposure was associated with greater diastolic and systolic blood pressures, and cumulative uranium intake was associated with increased glucose excretion in urine., Conclusion: Continuous uranium intake from drinking water, even at relatively high exposures, was not found to have cytotoxic effects on kidneys in humans.

Cyclosporin, an immunosuppressive drug, is known to affect macrophage and to exert a nephrotoxic effect. Aminopeptidases play important roles for renal and macrophage functions. In this work, we attempt to test the hypothesis that the aminopeptidases participate within macrophage and renal effects induced by cyclosporin. Macrophage and renal aminopeptidase activities of cyclosporin-treated and control mice were evaluated, as well as renal caspase 3 activity, hematocrit, urinary protein and plasma osmolality, creatinine and uric acid concentrations. Cyclosporin treatment increased caspase 3 activity, hematocrit and osmolality, while urinary protein, creatinine and uric acid were unaltered. Soluble and particulate aminopeptidases in resident and elicited macrophages were unaffected by cyclosporin. The treatment with cyclosporin increased neutral, basic, cystyl, prolyl imino and pyroglutamyl soluble aminopeptidase activities in the renal cortex. Acid and basic soluble aminopeptidase activities increased in the renal medulla. Increased levels of particulate form in the cortex were detected for acid and pyroglutamyl aminopeptidase activities. Cyclosporin increased cortical soluble while decreased medullar particulate prolyl dipeptidyl aminopeptidase IV activity. With the exception of prolyl dipeptidyl aminopeptidase IV, particulate aminopeptidase activities returned to levels similar to controls after fifteen days of cyclosporin withdrawal, and soluble aminopeptidase activities did not regress. Our data indicate that the adopted regimen of cyclosporin treatment produced mild renal impairment with consistent changes on the levels of renal but not macrophage aminopeptidase activities. The obtained profiles of macrophage and renal aminopeptidase activities should be considered into the elaboration of new potential strategies for preventing nephrotoxicity during the treatment with cyclosporin.

Aim: To determine whether urinary macromolecules (UMM), which are the high molecular weight substances in urine, can provide protection against the oxalate-associated injury to the renal tubular cells., Methods: UMM were extracted from 24-h urine of 12 healthy adult male volunteers and 13 recurrent-stone-former male patients. Urine parameters in relation to urolithiasis were measured, including the level of glycosaminoglycans (GAG) in the UMM. Madin-Darby canine kidney (MDCK) cells were used to evaluate the protective activity of UMM from oxalate-induced cytotoxicity by LDH release measurement and methyl-thiazolyl tertrazolium (MTT) assay., Results: Considering urinary parameters, citrate was significantly higher in urine from normal subjects than stone-former subjects; the other parameters show no differences between the groups. Total UMM and the level of GAG in the UMM were also significantly higher in the normal subject group. Compared with normal subject and stone-former subject UMM, after cells were treated with the UMM and then exposed to oxalate solution, LDH release was significantly higher in stone-former group. In the MTT assay, we found that more viable cells were observed after treatment with UMM compared to control in both groups. Moreover, UMM from the normal subjects showed higher protective activity against oxalate-related cytotoxicity than UMM from the stone-former subjects., Conclusion: UMM protected renal epithelial cells from oxalate-related injury. This protective activity was found to be higher in normal subject UMM than stone-former UMM. Among other factors, a higher concentration of GAG and citrate in normal subject UMM might affect some parts in this finding.

Assays of blood serum and urine samples from patients with cancer of the urinary bladder established enhanced levels of lactate dehydrogenase (LDH). The findings were significant as far as malignancies were concerned. Male patients with transitional cell carcinoma revealed significant increase in DH blood serum while, in moderately- and low-differentiated tumor cases, it was higher in urine. In female patients, increased levels were registered in urine and in low-differentiated tumor only. Prognostic value of LDH levels in males was relatively higher.

Aim: This study has been carried out to see whether renal function is acutely altered in patients undergoing sevoflurane anaesthesia. For this purpose, the urinary levels of markers of renal tubular function, namely leucine amino peptidase (LAP), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and beta-2 microglobulin (beta-2M), and urinary albumin as a predictor of renal glomerular function were measured before and after sevoflurane anaesthesia., Methods: This study was comprised of 20 patients (11 males and nine females) aged 18-55, who underwent various elective surgical procedures under general anaesthesia. Urine samples of all patients were collected before and 1, 2 and 8 h after the anaesthesia. The levels of LAP, GGT, beta-2M, and albumin were then expressed as factored by urinary creatinine. In all patients, the anaesthesia was maintained with sevoflurane (2% end-tidal) at a high flow-rate (6 L/min)., Results: Urinary beta-2M and LAP levels after anaesthesia were unchanged (P > 0.05). While urinary GGT and ALP levels were found elevated in the first hour, LDH levels were higher in the second hour (P < 0.05). They returned to normal levels in the later periods after the anaesthesia. Urinary albumin excretion (UAE) was significantly elevated in the second hour after the anaesthesia (P < 0.001). Although UAE was decreased in the eighth hour after the anaesthesia, it still remained higher than the pre-anaesthesia level (P < 0.001)., Conclusions: These results suggest that a 2% end-tidal concentration of sevoflurane at a high flow-rate (6 L/min) acutely alters renal glomerular function but does not have a significant acute effect on biochemical markers of renal tubular damage.

Background: In clinical practice, the assessment and follow-up of early renal dysfunction is important in diabetic nephropathy. Therefore, this study was designed to determine whether the serum cystatin C (Cys C) and activities of some tubular enzymes could be used as screening markers for renal dysfunction in diabetic patients., Methods: Serum Cys C levels and urinary activities of N-acetyl-b-D-glucosaminidase (NAG), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) and whole blood glycolyse hemoglobin (HbA1C) were measured in 56 diabetic patients and 20 healthy subjects (controls). The results were compared with serum creatinine (Cr) and creatinine clearance (CCr), which were measured and estimated with the Cockcroft-Gault formula (CCG) and 24-hr urine microalbuminuria (MAU). We examined the influence of albuminuria, HbA1C and CCr levels of patients on the levels of the analyzed parameters. Sensitivity and specificity for the diagnosis of renal impairment were calculated by a receiver operating characteristics (ROC) curve for serum Cys C, Cr and urinary enzymes., Results: In normoalbuminurics, only serum Cys C levels and urinary NAG activities were found elevated as compared to controls. In addition to the elevation of serum Cys C levels and urinary activities of NAG, urinary ALP and LDH activities were also found elevated in microalbuminurics. Serum Cys C levels and urinary NAG, ALP, LDH activities started to increase above the normal range when CCr declined and while serum Cr was in the normal range in patients with 50

To explore the relationship between the experimental parameters including the neopterin (Npt), LDH and beta(2)-MG concentrations in serum or urine and the therapeutic effect on non-Hodgkin's lymphoma (NHL). Npt, LDH and beta(2)-MG levels in serum and urine collected from 27 patients with NHL before and after chemotherapy were measured by ELISA, biochemistry analyzer and RIA. The relationship between the concentrations of the Npt, LDH, beta(2)-MG in serum or urine and the therapeutic effect of follow-up of NHL cases were analysed. The results indicated that the levels of serum and urine Npt and serum LDH, beta(2)-MG concentrations of pre- and post-chemotherapy in CR and PR patients were lower than that in NC and PD patients (P < 0.05). In conclusion, Npt levels of serum and urine and serum LDH, beta(2)-MG before chemotherapy can be used as prediction parameters of the therapeutic effect on NHL and the assay for Npt from the urine is more convenient than that from the serum.

The model nephrotoxin gentamicin was administered to male Wistar-derived rats daily, for 7 days, at 60 mg kg-1 day-1, subcutaneously, twice daily. Conventional clinical chemistry urinalysis showed a significant increase in N-acetyl-beta-D-glucosaminidase (NAG) activity from day 3. At necropsy on day 9, clear histological damage to the kidney was noted with all animals showing a generally severe nephropathy primarily focused on the proximal convoluted tubules. The urinary excretion pattern of endogenous metabolites over the time course of the study was studied using a combination of 1H-NMR spectroscopy and HPLC-TOF-MS/MS using electrospray ionization (ESI). Changes in the pattern of endogenous metabolites as a result of daily administration of gentamicin were readily detected by both techniques with significant perturbations of the urinary profile observed from day 7 onwards. The findings by 1H-NMR included raised glucose and reduced trimethylamine N-oxide (TMAO). Changes in metabonomic profiles were observed by HPLC-MS in both positive and negative ESI. The MS data showed reduced xanthurenic acid and kynurenic acid, whilst neutral loss experiments also revealed a changed pattern of sulphate conjugation on gentamicin administration.

Objective: To investigate nephroprotective effects of a mixture of 8 L-amino acids on renal ischemia-reperfusion injury and its effects on renal endothelin-1 (ET-1)., Methods: The mixture of 8 L-amino acids includes glycine, alanine, threonine, serine, valine, leucine, isoleucine and proline. Acute ischemic renal injury was induced by clamping renal pedicle for 45 minutes in rats. Sixty male Sprague-Dawley rats were randomly divided into 3 groups: a sham-operated group (Group A, n=8), a control group (Group B, n=26) and an amino acid-treated group (Group C, n=26). Amino acids were infused at a rate of 1 ml x 100g(-1) x h(-1) I hour before ischemia and during 3 hours of the whole reperfusion. The serum creatinine values, BUN levels, creatinine clearance, urine sodium and potassium excretion, urine lactate dehydrogenase (LDH), the rate of urine flow and histological examination were measured. Renal ET-1 levels were assayed with radioimmunological assay (RIA) RESULTS: The creatinine clearance was 471.0 microl/min+/-121.5 microl/min in Group C and 227.0 microl/min+/-27.0 microl/min in Group B 3 hours after reperfusion, P<0.01). The urine flow rate was 63.6 microl/min+/-15.2 microl/min in Group C and 24.3 microl/min+/-7.7 microl/minin Group B, P<0.01) 1.5 hours after reperfusion. The serum creatinine was 85.0 microl/min+/-7.7 micromol/L and BUN concentration 11.4 mmol/L+/-3.9 mmol/L in Group C and 112.7 micromol/L+/-19.5 micromol/L and 20.7 mmol/L+/-6.6 mmol/L respectively in Group B after 24 hours of reperfusion (P<0.05). The mean histological score by standards of Paller in kidneys was 108.7+/-15.7 in Group C, and 168.8+/-14.8in Group B (P<0.01). The renal ET-1 levels 15 minute and 3 hours after reperfusion were 7.2 pg/mg+/-0.8 pg/mg and 9.6 pg/ml+/-1.0 pg/ml in Group C, and 10.1 pg/ml+/-2.8 pg/ml and 13.0 pg/ml+/-2.7pg/ml in Group B (P<0.01)., Conclusions: The mixture of 8 L-amino acids can provide remarkable protection against renal ischemia-reperfusion injury in rats. This may associate with attenuation of renal ET-1 disorder.

Rapid, intravenous (i.v.) administration of high doses of bisphosphonates has been associated with acute renal toxicity. This controlled, preclinical study over 25 weeks investigated the potential for subclinical renal damage to accumulate to clinically relevant levels when minimally nephrotoxic doses of ibandronate (1 mg/kg) or zoledronate (1 or 3 mg/kg) were given intermittently, with a between-dose interval of 3 weeks, or as a single dose by i.v. injection. In rats, a single dose and intermittent dosing of ibandronate resulted in a similar incidence (one of six and two of six rats, respectively) and severity score (1.0 for both) of proximal tubular degeneration and single cell necrosis. No accumulation of histopathological renal damage occurred. However, intermittent dosing of zoledronate induced a higher incidence (six of six rats) and severity score (3.0) of renal damage compared with single dosing (four of six rats and 1.3, respectively). Accumulation of renal damage was also observed for a lower intermittent dose of zoledronate (1 mg/kg) that had not exhibited histopathological renal damage when given as a single 1 mg/kg dose. Biochemical parameters confirmed these histopathological findings. In summary, the results from this study indicate that administering ibandronate intermittently provides sufficient time for regeneration of potential subclinical renal damage.

The value of the tumour markers vanillylmandelic acid (VMA) and homovanillic acid (HVA) in urine (u) and serum (s), neurone-specific enolase (NSE), and lactate dehydrogenase (LDH) in the early prediction of relapse/progression in neuroblastoma is not known. We analysed the data of neuroblastoma patients who had successfully completed first-line treatment and had laboratory results available from their initial diagnosis and from relapse/progression (n=196). Patients' overall survival from relapse or progression was 21.5+/-4.2% (mean+/-standard deviation). At diagnosis, we found abnormal results in 75% for VMA and/or HVA (s), 92% for VMA and/or HVA (u), 90% for NSE, and 81% for LDH. We found a lower incidence of abnormal results at relapse or progression with 40% for VMA and/or HVA (s), 54% for HVA and/or VMA (u), 61% for NSE, and 48% for LDH. Sensitivity of all markers was higher for metastatic compared with local recurrence. NSE was the best, being able to detect 42% of the localised relapses, 77% of the combined local/metastatic relapses, and 69% of the metastatic recurrences. Relapse or progression in neuroblastoma cannot be detected reliably by monitoring tumour markers alone. Therefore, follow-up of neuroblastoma patients must include clinical assessment and imaging studies.

Background: Cellular damage and inflammation after ischemia contribute to sustained acute renal failure (ARF)., Methods: To quantify cellular damage and inflammation in postischemic ARF and identify markers of renal functional outcome, urine specimens from 40 renal allograft recipients, including 30 cadaveric (9 "sustained ARF" and 21 "recovery" subjects) and 10 living donor allografts ("LD"), were analyzed for actin, gamma-glutamyl transpeptidase (GGTP), lactate dehydrogenase (LDH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8) during the first posttransplant week., Results: On day 0, urinary actin, GGTP, IL-6, and IL-8 were elevated in recipients destined to have sustained ARF compared with those destined to recover. Median values per gram of urine creatinine in the sustained ARF, recovery, and LD groups were 263.9, 0.0, and 0.0 microg for actin; 5000.0, 892.9, and 5555.6 U for GGTP; 193.1, 27.2, and 10.5 ng for IL-6; and 382.0, 17.8, and 18.5 ng for IL-8, respectively. In contrast, urinary LDH and TNF-alpha increased in recipients with recovering function compared with those who had sustained ARF. The corresponding median values were 36.7 and 16.3 U (recovery versus sustained ARF) for LDH, and 18.4 and 7.6 ng (LD versus sustained ARF) for TNF-alpha. Computational analyses using the Receiver Operating Characteristic Curve found that elevated urinary actin, IL-6, and IL-8 on day 0 were strong predictors of sustained ARF, where the calculated areas under the curve were 0.75, 0.91, and 0.82, respectively., Conclusion: Increased urinary actin, IL-6, and IL-8 may be useful markers for the prediction of sustained ARF after ischemia.

Background: Early detection of acute tubular necrosis (ATN) could permit implementation of salvage therapies and improve patient outcomes in acute renal failure (ARF). The utility of single and combined measurements of urinary tubular enzymes in predicting ARF in critically ill patients has not been evaluated using the receiver-operating characteristic (ROC) plot method., Methods: In this prospective pilot study, 26 consecutive critically ill adult patients admitted to the intensive-care unit were studied. Urine samples were collected twice daily for up to 7 days. ARF was defined as an increase in plasma creatinine of > or = 50% and > or = 0.15 mmol/l. ROC plot analysis was applied to the tubular marker data to derive optimum cut-offs for ARF., Results: Four of the 26 study subjects (15.4%) developed ARF. Indexed to urinary creatinine concentration, gamma glutamyl transpeptidase (gamma GT), alkaline phosphatase (AP), N-acetyl-glucosaminidase (NAG), and alpha- and pi-glutathione S-transferase (alpha- and pi-GST) but not lactate dehydrogenase (LDH) were higher in the ARF group on admission (P<0.05). gamma GT, and alpha- and pi-GST remained elevated at 24 h. The onset of ARF based on changes in plasma creatinine varied from 12 h to 4 days (median 36 h). ROC plot analysis showed that gamma GT, pi-GST, alpha-GST, AP and NAG had excellent discriminating power for ARF (AUC 0.950, 0.929, 0.893, 0.863 and 0.845, respectively). The discriminating strength of creatinine clearance, while lower, was still significant (AUC 0.796). Positive and negative predictive values for ARF on admission were 67/100% for gamma GT, 67/90% for AP, 60/95% for alpha-GST, and 67/100% for pi-GST indices. Positive and negative predictive values for ARF for creatinine clearance < or = 23 ml/min were 50 and 91%, respectively. Creatinine clearances tended to be lower in ARF than in non-ARF patients on admission (P=0.06) and were significantly lower (P=0.008) after 12 h. Plasma urea and fractional sodium excretion were unhelpful., Conclusions: Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for gamma GT and AP suggests that estimation of these enzymes in random urine samples may be particularly useful for identifying patients at high risk of ARF.

Aim: The purpose of this study was to assess the acute nephrotoxicity of formaldehyde, as it is believed to be the toxic component of formocresol., Methods: A sample of 24 Sprague-Dawley rats was used in the study and divided into 3 groups of 8 rats each. The following procedures were performed: group A) formaldehyde equivalent dose to 20 pulpotomies, injected into the main vein of each rat's tail; group B) formaldehyde equivalent dose to 100 pulpotomies injected; group C) control group with a saline solution injected. Blood analyses were performed after 24 and 48 hours to assess urea and creatinine levels. Urine samples were taken after 24 hours to analyse for LDH protein levels. Rats were sacrificed after 48 hours and histology samples of renal tissue were studied for any pathological defects., Results: Evaluation of histological samples of kidney tissue did not show any inflammation or other tissue lesions. No significant differences were found, using an ANOVA test procedure, among the variables of LDH protein or creatinine levels after 24 and 48 hours. Significant differences were found between the levels of urea and creatinine after 48 hours between the control group and the other test groups., Conclusion: The use of formaldehyde at the usual clinical doses or with an amount equivalent to 100 pulpotomies did not produce renal tissue damage and the blood and urine factors analysed did not show significant changes after 48 hours in the experimental model used.

Background: Ischemic acute renal failure (iARF) is associated with increased nitric oxide (NO) production during the reperfusion period, as endothelial nitric oxide synthase (eNOS) is maximally activated, and renal tubular inducible NOS (iNOS) is stimulated. Increased NO production leads to augmented tubular injury, probably through the formation of peroxynitrite. l-Arginine (l-Arg), the only precursor for NO, is transported into cells by cationic amino acid transporters, CAT-1 and CAT-2. We hypothesized that the increased NO production observed in iARF may result from increased l-Arg uptake, which would be reflected in the augmented expression of l-Arg transporter(s)., Methods: Ischemic acute renal failure was induced in rats by right nephrectomy + left renal artery clamping for 60 minutes. l-Arg uptake was examined in freshly harvested glomeruli and tubuli from control, sham operated, and animals subjected to 15, 30, and 60 minutes, and 24 hours of reperfusion, following 60 minutes of ischemia. Using RT-PCR, renal tissues were examined further for the expression of iNOS, CAT-1, CAT-2, arginase I and arginase II., Results: Tubular expression of iNOS mRNA was initiated by ischemia, continued to increase after 60 minutes of reperfusion, and decreased after 24 hours. l-Arg transport into glomeruli was similar in all experimental groups. l-Arg uptake into tubuli was markedly augmented following the 60-minute reperfusion, while it moderately increased after 24 hours of reperfusion. This was accompanied by a parallel, preferential increase in tubular CAT-2 mRNA expression at 60 minutes of reperfusion. CAT-1 mRNA expression was unchanged, as detected by RT-PCR. In addition, the expression of arginase II and arginase I mRNA was attenuated by 30 minutes and one hour of reperfusion, and returned to baseline values after 24 hours of reperfusion., Conclusions: Ischemic ARF is associated with augmented tubular CAT-2 mRNA expression, which leads to enhanced l-Arg transport and increased NO production. This may contribute to the renal injury exhibited in iARF.

We report the results of a dose-intense chemotherapy regimen designed to rapidly induce remissions in patients with advanced multiple myeloma (MM). Patients received VAD for 3-6 cycles depending on response kinetics. This was followed by three sequential cycles of cyclophosphamide (CTX) at 3 g/m2 every 15 days with G-CSF support. 71% of these patients had stage IIIa, 23% had renal failure. The median age was 58, median beta-2 microglobulin 4.6 and median albumin was 3.5, indicating poor prognosis. Of 35 patients, 66% achieved a complete response (CR) (SWOG). Six patients (18%) had a partial response. Fifty percent of the patients with renal failure recovered their kidney function. High-dose CTX contributed to tumor-mass reduction particularly in patients presenting with high-tumor burden. Tumor-mass reduction following three pulses of dexamethasone (4 days each) is significantly higher than with one pulse (p < 0.005). While high beta-2 microglobulin and LDH levels (p < 0.05) were associated with poor outcome, patients who responded faster to chemotherapy had a longer survival (p = 0.005). We conclude that this regimen is safe and effective. A rapid response may be useful in selecting patients who may benefit from further high dose chemotherapy and stem cell support.

Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion. The right kidney was removed before reperfusion. The postischemic glomerular filtration rate (GFR) showed that renal function was less impaired and recovered more quickly in rats receiving glycine. For example, at day 7, GFR in controls (0.31 +/- 0.03 ml x min(-1) x 100 g(-1)) was about one-half that of glycine-treated rats (0.61 +/- 0.06 ml x min(-1) x 100 g(-1), P < 0.05). Furthermore, tubular injury and cast formation observed in controls was minimized by glycine (pathology score, 3.2 +/- 0.4 vs. 1.0 +/- 0.4, P < 0.05). Urinary lactate dehydrogenase (LDH) concentration was elevated by ischemia-reperfusion in the control group (260 +/- 22 U/l), but values were significantly lower by about fourfold (60 +/- 30 U/l) in glycine-fed rats. Similarly, free radical production in urine was significantly lower in glycine-treated animals. Importantly, on postischemic day 1, binding of pimonidazole, an in vivo hypoxia marker, was increased in the outer medulla in controls; however, this phenomenon was prevented by glycine. Two weeks later, mild leukocyte infiltration and interstitial fibrosis were still observed in controls, but not in kidneys from glycine-treated rats. In conclusion, these results indicate that administration of glycine indeed reduces mild ischemia-reperfusion injury in the kidney in vivo, in part by decreasing initial damage and preventing chronic hypoxia.

Evidence has accumulated for a role of toxic oxygen radicals in the pathogenesis of ischemia-reperfusion injury in the kidney. The aim of this study was to evaluate the hypothesis that reducing postischemic renal injury is possible by delivery of the gene for the antioxidant enzyme superoxide dismutase (SOD). Female Sprague-Dawley rats received intravenous injections of recombinant adenovirus (1 x 10(9) pfu) containing the transgenes for Escherichia coli beta-galactosidase (Ad-LacZ, as control) or human Cu/Zn-SOD (Ad-SOD). Three days later, renal ischemia was produced by cross-clamping the left renal vessels for 60 min. The right kidney was removed before reperfusion and processed for the transgene. Renal SOD protein and activity in rats given Ad-SOD was 2.5-fold higher than from the animals receiving Ad-LACZ: Urinary lactate dehydrogenase concentrations were elevated by ischemia-reperfusion in the Ad-LacZ group (1403 +/- 112 U/L), yet values were 50% lower in Ad-SOD-treated rats. Free radical production was elevated by ischemia-reperfusion but was significantly lower in SOD-treated animals. Importantly, on postischemic day 1, glomerular filtration rates were reduced to 0.21 ml/min per 100 g in the Ad-LacZ group, whereas values remained significantly higher (0.39) in the Ad-SOD group. Two weeks after ischemia-reperfusion, inflammation, interstitial fibrosis, tubular atrophy and tissue levels of tumor necrosis factor alpha and interleukin-1 were significantly higher in the Ad-LacZ-treated than in Ad-SOD-treated rats. In conclusion, these results indicate that SOD expression can be increased by delivery of the sod gene to the kidney by intravenous injection and that sod gene transduction minimized ischemia-reperfusion-induced acute renal failure.

In this study, the ultrastructural observations in rat kidneys were studied 2, 24 and 48 h after intravenous injection of 1, 3 and 9 g iodine per kg body of ioxaglate and iohexol. The effect of the contrast media was mainly on the proximal convoluted tubule cells, the presence of vacuoles containing granular and membranous structures was a striking feature. In the distal convoluted tubular cells, pycnotic nuclei and cytoplasmic bulges toward the lumen were observed. In some glomeruli, membranous structures in cytoplasm of podocytes and thickening of glomerular basal membrane were seen. Values of biochemical analysis were slightly higher especially at high doses in experimental groups when compared to the control. The results suggest that iohexol causes more degeneration than ioxaglate. Not only proximal convoluted tubule cells but also the other parts of the nephron were affected by contrast media.

A bolus dose of cadmium metallothionein (CdMT) produces renal proximal tubular dysfunction because it accumulates in the tubular epithelial cells and undergoes rapid degradation, releasing Cd. Morphologically, mitochondria appear to be the target organelle. The present study examined changes in renal cortical mitochondrial function following CdMT administration and investigated whether some of these effects could be ascribed to Cd2+ accumulation in the mitochondria. Sprague-Dawley rats were injected ip with 0.3 mg Cd as CdMT/kg and the animals were sacrificed after 6, 8, or 12 h. Two- to threefold increases in urinary protein excretion and LDH activity were evident at 8 h, with marked elevations (11- and 29-fold) thereafter. Renal cortical mitochondria were swollen and rounded at 12 h. The mitochondrial Cd level was 399 pmol/mg protein at 6 h and did not change significantly during the next 6 h; however, mitochondrial respiratory function declined with time. At 12 h, state 3 oxygen consumption, respiratory control ratio (RCR), and ADP:O (P/O) ratio were 48, 49, and 76% of control values, respectively, indicating inhibition of electron transfer and oxidative phosphorylation. The direct effect of Cd on mitochondrial function was examined by incubating mitochondria from untreated rats with 0.1-2 microM CdCl2. Rapid uptake of Cd resulted in concentration-dependent effects on respiration. After 1 min of incubation with 2 microM Cd, the mitochondria contained 262 microgCd/mg protein and state 3 respiration and RCR values were 75 and 33% of control levels, respectively. Thus, renal proximal tubular cell damage following a bolus dose of CdMT involves perturbations in mitochondrial respiration, brought on by the accumulation of Cd.

Progressive renal dysfunction in 5/6 nephrectomized (NX) rats can be physiologically divided into three stages, coinciding with morphological stages, after definition of physiological parameters for identification of stage. Now, for the establishment of a toxicity screening approach using 5/6 NX rats, our concept, "Differential toxicity synchronized with renal dysfunction process could be identified using 5/6 NX rats" was examined by dosing gentamicin. Firstly, electrophoretic fractional changes of urinary proteins during gentamicin treatment were clarified with determination of amino acid sequences and the three differential features were proven, revealing the unpredictable depression of urinary albumin with progression of the stages in NX rats. Secondly, marked elevation of urinary lactate dehydrogenase (LDH) and glucose (GLU) was evident, indicating the intensified hypoxic conditions and glycolysis in tubular cells synchronized with increased tubular damage. Thirdly, these transit metabolic changes were proven as intensive cause for the advancement of renal dysfunction by the reduction of FRelectrolytes and water at the end of each dosing period. These results indicate that toxicity studies of newly developed drugs using 5/6 NX rats have potentiality prior to clinical dosing to the patients.