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Reliable and noninvasive biomarkers for the early diagnosis of non-small-cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver-operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early-stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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.

The potential renal tolerance of cefuroxime was investigated in 80 female albino Wistar rats and compared with that of cephacetrile. The drugs were administered i.m. in different dosages (1000, 2000, 3000 and 5000 mg/kg/day; dosage interval: 12 h) over a period of five days. The excretion of tubular cells and urinary malic dehydrogenase was assessed before, during and after administration of the antibiotics. In addition, the concentration of serum urea was analysed and the renal histology was examined. The following toxic threshold doses were estimated: cefuroxime 5000 mg/kg/day, cephacetrile 3000 mg/kg/day. In comparison with other cephalosporines cefuroxime belongs to those antibiotics with which a high degree of renal tolerance is demonstrated.

We studied the effect of D-glucaro-1,5-lactam on aminoglycoside-induced nephrotoxicity in rats. Parameters of nephrotoxicity were urinary excretion of tubule cells and malate dehydrogenase. When given in appropriate doses, either i. m. or via an oral tube, D-glucaro-1,5-lactam significantly reduced the excretion of cells and enzymes during the administration of gentamicin, tobramycin, dibekacin, netilmicin and ribostamycin. It did not impair the therapeutic efficacy of ribostamycin in the experimental treatment of acute pyelonephritis in rats. The protective effect of D-glucaro-1,5-lactam could be ascribed to its inhibition of beta-glucuronidase, an enzyme which is located in renal lysosomes and which is activated by aminoglycosides.

Renal tolerance tests in Wistar rats (n = 40) over 12 days showed that the tubulotoxic threshold dose of the cephalosporin antibiotic (6R,7R)-7-(2-[3,5-dichloro-4-oxo-1(4H)-pyridyl]-acetamido)-3-([(5-methyl-1,3,4-thiadiazol-2-yl)-thio]methyl)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid acid (cefazedone, Refosporen) is 2000 mg/kg/day when the cell excretion rates in the urine are used as the parameter of toxicity. It is concluded that cefazedone and cefazolin are similar in respect of their nephrotoxicity.

To evaluate the reliability of urinary enzymes as markers of renal tubular damage in obstructive jaundice, research was carried out on 26 Sprague-Dawley rats submitted to bile duct ligation and on 16 sham-operated rats. The fractional clearances of lysozyme (CfrLYS) and of malto-dehydrogenase (CfrMDH)-indices of tubular function-and the fractional excretions of gamma-glutamyltransferase (UfrGGT) and of alpha-glucosidase (UfrAGL)-indices of tubular anatomic damage - were measured 5, 10, 20 and 30 days after operation. Creatinine clearance, urinary sodium excretion, urinary potassium excretion, proteinuria, plasma bilirubin and bile acids were also measured. Kidneys were taken for histology. All rats submitted to common bile duct ligation had high levels of bilirubin and bile acids; proximal tubules were damaged and the extent of the lesions increased with time. However, creatinine clearance, urinary sodium excretion, proteinuria, CfrMDH and UfrAGL gave no indication of renal lesions, whereas CfrLYS and UfrGGT were significantly higher 20 and 30 days after bile duct ligation, respectively. These findings show that CfrLYS and UfrGGT could be useful tests for renal tubular lesions in jaundice.

Eight-week-old Wistar female rats were treated intramuscularly with 300, 1,000 and 3,000 mg/kg/day of cefotiam for five days. The nephrotoxicity of cefotiam was determined on the basis of the number of tubular epithelial cells excreted, the malate dehydrogenase activity in the urine and the histological examination of the kidneys. Cephalothin (3,000 mg/kg/day) was used as a reference compound. There were slight increases in the number of tubular epithelial cells excreted and in the malate dehydrogenase activity in the urine of some animals receiving 3,000 mg/kg/day of cefotiam or cephalothin. All of these changes disappeared within a few days after the dosing period. The histological examination of the kidneys at the end of both the dosing (5 days) and the recovery (7 days) periods revealed no pathological changes indicating nephrotoxicity. It was concluded that the nephrotoxicity of cefotiam was comparable to that of cephalothin; the urinary changes in animals receiving the highest dose were considered to be an early sign of nephrotoxicity. The maximum non-toxic dose of cefotiam was 1,000 mg/kg/day under the present experimental conditions.

Urinary MDH, LDH, gamma-GT, LAP and muramidase levels were studied in 11 healthy persons with a wide age range and in 51 male Winstar rats weighing 300 to 400 g. Normal ranges of these urinary enzymes were determined and compared with the results of other authors.

The goal of our study was: 1. To determine the urinary enzyme pattern from urine, taken by ureteral catheterization from the side of the renal disorder, and to compare it with the pattern from the healthy side of the same patient. 2. To compare the enzyme patterns of normal and tumor tissues with the corresponding urinary enzyme patterns.

The possible nephrotoxity of cephalothin and the antibiotic combinations cephalotin-gentamicin and cephalothin-tobramycin was investigated in standardized animal experiments. Toxicity parameters were blood-urea concentration, the urinary enzymes GOT, LDH, MDH and the cell excretion rate, supplemented by histological investigations of the kidneys. Compared with other cephalosporine derivates, the antibiotic cephalothin in a toxic threshold-dose of 3000 mg/kg/day proved to be realtively well tolerated by the kidneys. On comparison with the respective monotherapy, the renal tolerance for cephalothin-aminoglycoside combinations was reduced. The clinical value of these findings is discussed.

The urinary excretions of lysozyme (LYS), malate-dehydrogenase (MAD), gamma-glutamyltransferase (GGT) and alpha-glucosidase (AGL) were measured in a group of normal subjects in basic conditions, during forced diuresis, at different hours of the day and with urinary collection periods of different lengths. The results have been expressed in the principal ways used in clinical practice. The best way to express the excretions of GGT and AGL was with the fractional excretions. For LYS and MAD, the fractional clearances appeared to be theoretically valuable. They were not significantly influenced by sex or by the different urinary collections. Forced diuresis caused a significant scattering of enzymuria.

In a survey the present state of the activity determination of urinary enzymes after kidney transplantation as a diagnostic tool in the control of patients with transplanted kidney is described. A great number of enzymes has up to now been established in these patients. The most extensive data are present for the enzymes alanine-aminopeptidase, N-acetyl-beta-D-glucosaminidase and lysozyme. After the transplantation of the kidney typical excretion patterns of the enzymes in the urine are observed in immediate function, retarded onset of the function, without function and acute rejection of the graft. Particularly the behaviour of the urinary enzyme excretion during acute rejection reactions can be diagnostically used. Hereby, the diagnostic reliability of determinations of the activity of urinary enzymes is, however, differently assessed by various authors. In future works in close cooperation between clinic and laboratory the diagnostic validity of the determinations shall unambiguously be characterized and the determinations of the enzyme activity in the urine should be summarized together with other parameters to an optimum combination of parameters for the follow-up investigation of patients who underwent kidney transplantation.

Urinary enzymes were studied in 15 patients subjected to kidney transplantation. The investigation was initiated immediately after operation and was continued for a period of between 2 and 8 weeks. There was a significant increase in urinary MDH activity in 94.2% of cases, of LDH activity in 95,65% and of gamma-GT activity in 95,17% of the cases. This detected increase in urinary enzyme activities preceded the clinical diagnosis of rejection by activities preceded the clinical diagnosis of rejection by at least 24 hours. Determination of these enzymes provides a reliable tool for the early detection of rejection crises.

Since combinations of fosfomycin and vancomycin or tobramycin and vancomycin could be of advantage in the therapy of staphylococcal infections, we studied renal tolerance of both combinations. The experimental animal was the rat and the parameters of nephrotoxicity were cyturia and enzymuria. The experiments showed that fosfomycin at dosages of 50 and 250 mg/kg protected against nephrotoxicity caused by vancomycin (dose: 50 mg/kg), whereas the administration of both tobramycin (dose: 2.5 mg/kg) and vancomycin (dose: 50 mg/kg) resulted in an increase of cyturia and enzymuria. However, repeated dosing of vancomycin (single dose: 50 mg/kg) led to renal accumulation when combined with fosfomycin (single dose: 250 mg/kg); renal vancomycin concentrations were lower. This study suggests similarities in the renal handling of vancomycin and aminoglycosides and demonstrates the possibility of reducing drug-associated nephrotoxicity.

To assess the renal tubular damage in liver cirrhosis the fractional clearances of beta-2-microglobulin (B2m-fr.cl) and malate-dehydrogenase (MDH-fr.cl) were measured respectively in sixty-four and in forty-six out of seventy-nine patients with liver cirrhosis of different aetiology; furthermore the fractional excretions of gammaglutamyl-transpeptidase (fr-GGT) and of alpha-glucosidase (fr-AGL) were determined in fifty-three and in forty of them respectively. In all patients glomerular filtration rate (GFR) and renal plasma flow (RPF) were also measured. Twenty-five subjects were studied as a control group for the enzyme excretions, sixteen for B2m-fr.cl. B2m-fr.cl and MDH-fr.cl--indexes of tubular functions--on the average were normal and only slightly increased respectively in cirrhotics compared to controls. Nevertheless fr-GGT and fr-AGL--indexes of cytolysis of tubular cells--on the average were massively increased in cirrhosis compared to controls, particularly in those with reduced RPF and/or GFR. No clear relationship between the indexes of tubular damage studied and the indexes of liver function was found. Our results show that (1) A renal tubular anatomical damage was found by means of an increase in the release of enzyme from tubular cells in patients with liver cirrhosis, particularly in those with a significant reduction of RPF and/or GFR; even so renal reabsorption of low molecular weight proteins is generally maintained. (2) The tubular damage does not seem to be related to the degree of liver impairment.

The excretion patterns of several urinary enzymes were investigated in the following four experimental groups of Wistar rats and compared with the normal range of each urinary enzyme studied. One group received vitamin A in high dosage; a second group was given vitamin A before and after bilateral clamping of the renal artery for 30 minutes; in the third group the renal arteries were clamped for 30 or 60 minutes; the last group of experimental animals received first low (2mg/kg, 4mg/kg) and subsequently high doses (100 mg/kg) of gentamicin. Vitamin A administration produced no increase in urinary enzyme activity, even in the group of rats with ischaemically-damaged kidneys, where ischaemia (clampin of the arteries) was responsible per se for an increase in enzyme excretion. With low doses of gentamicin the urinary enzymes remained within normal limits, but increased immediately to significantly pathological values after the first dose 100 mg/kg gentamicin.