In vitro exposure of isolated rat kidney mitochondria to cyclosporin A, a new immunosuppressive agent with serious nephrotoxic side-effects, leads to alterations of both succinate-and glutamate plus malate-supported respiration in a dose-related manner. ADP-and 2,4-dinitrophenol-stimulated respiration, respiratory control indices, and ADP/O ratios are decreased. The mitochondrial alterations are discussed as possible pathogenetic reasons of cyclosporin A nephrotoxicity.
We measured the excretion rates of six urinary enzymes that either originate from the proximal renal tubule, like alanine aminopeptidase (EC 3.4.11.2), alkaline phosphatase (EC 3.1.3.1), gamma-glutamyltransferase (EC 2.3.2.2), and N-acetyl-beta-D-glucosaminidase (EC 3.2.1.30), or that are typical low-molecular-mass proteins, like lysozyme (EC 3.2.1.17) and pancreatic ribonuclease (EC 3.1.27.5). These rates were compared with those of total protein and albumin in urine of 36 insulin-dependent diabetic men and 30 healthy men. Seventeen of the diabetics had "clinical proteinuria," defined as excretion of more than 7.5 g of protein per mole of urinary creatinine (group B). Group A comprised the 19 diabetics without proteinuria. Except for gamma-glutamyltransferase, the excretions of enzymes and proteins were significantly higher in diabetics than in controls and were greater in group B than in group A. N-Acetyl-beta-D-glucosaminidase was the analyte most often increased in group A (89%), followed by albumin and alkaline phosphatase (each 32%). All patients in group B showed increased excretion of N-acetyl-beta-D-glucosaminidase. We conclude from the comparative data that this enzyme may be useful as an early predictor of diabetic nephropathy.
We developed a sandwich enzyme immunoassay for determining cystatin C in serum by using commercially available antibodies. We optimized each assay step (e.g., concentrations of coating rabbit anti-human cystatin C antibodies and horseradish peroxidase-conjugated antibodies) and studied the binding kinetics of antigen and antibodies. The within-assay CV was < 5%, the between-assay CV was 8.8%, the detection limit was 0.9 microgram/L, and the assay can be performed within 2 h. Cystatin C concentrations in sera from men were significantly higher than in women (mean and SD: 2.14 +/- 0.31 vs 1.78 +/- 0.26 mg/L). We studied the cystatin C concentrations in sera of 31 outpatients with suspected kidney damages to characterize the behavior of this low-M(r) protein as a possible indicator for estimating the glomerular filtration rate. The correlation with the values obtained by a standard isotopic method involving 99mTc-diethylenetriaminopentaacetic acid was rs = -0.89. The diagnostic sensitivity of cystatin C was 88.2% of that of the standard isotope clearance method and better than those of the conventional serum indicators of reduced kidney function, beta 2-microglobulin (64.7%) and creatinine (52.9%).
We tested the diagnostic sensitivity of various urinary analytes for detecting cadmium-induced nephropathy at an early stage. We investigated 73 healthy persons (control group 1) and individuals exposed to cadmium, either environmentally (n = 36, risk group 2) or occupationally (n = 62, exposed group 3). All data were related to limits of the central 95% reference intervals of the control group. The serum creatinine and ribonuclease values, indicators of the glomerular filtration rate, were not different in the three groups. In the exposed persons (group 3), proximal tubular indicators (low-M(r) proteins lysozyme, ribonuclease, retinol-binding protein, and alpha 1-microglobulin) were more often increased than the glomerular indices (higher-M(r) proteins transferrin, IgG, and albumin). Both the low-M(r) proteins and tubular enzymes were differently altered in their excretion rates. Alanine aminopeptidase, alkaline phosphatase, and N-acetyl-beta-D-glucosaminidase increased even in the risk group 2. alpha 1-Microglobulin was increased in the exposed persons whose cadmium excretion was < 5 mumol/mol creatinine. The combined determination of alpha 1-microglobulin and N-acetyl-beta-D-glucosaminidase exceeded the corresponding upper reference limits in 30% of group 2 and 39% of group 3. We recommend screening for these two analytes to detect cadmium-induced renal dysfunction at an early stage.
Fifteen various serum and urine parameters were evaluated as indicators of renal alterations induced by lead in 82 male workers of a battery plant chronically exposed to lead (median of blood lead concentration: 2.03 mumol/l). The control group comprised 44 non-exposed healthy volunteers (0.34 mumol/l). High-molecular-mass proteins (transferrin, immunoglobulin G (IgG), (albumin)) were determined in urine as markers of glomerular integrity; low-molecular-weight proteins and parenchymal enzymes (alpha 1-microglobulin, beta 2-microglobulin, retinol-binding protein, lysozyme, ribonuclease, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT)) as indicators of changes in the proximal tubule; Tamm-Horsfall glycoprotein and kallikrein as markers of the distal tubule. There was a positive correlation between tubular indicators and blood lead concentration as well as the erythrocyte protoporphyrin (EPP). About 30% of the lead-exposed workers showed an increased excretion of alpha 1-microglobulin, NAG, ribonuclease, and/or Tamm-Horsfall protein, whereas the glomerular indicators remained unchanged. The combined determination of NAG and alpha 1-microglobulin in urine could be helpful in the early detection of lead-induced changes in the nephron.
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