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The nephrotoxic effects of different platinum compounds based combination chemotherapies were compared. Chemotherapy consisted of either cisplatin fractionated over 5 days (5 x 20 mg/m2) or given as a single-day infusion (1 x 50 mg/m2) plus ifosfamide (4 g/m2) or high-dose chemotherapy was applied including carboplatin (3 x 500 mg/m2) and ifosfamide (3 x 4 g/m2) fractionated over three consecutive days. Conventional parameters such as serum creatinine and glomerular filtration rate (GFR), as well as urinary protein excretion of N-acetyl-beta-D-glucosaminidase (NAG)) and alpha 1-micro-globulin were assessed in 52 patients. Fractionation over 5 days without adding other nephrotoxic agents, i.e. ifosfamide, prevented decreases in GFR following cisplatin, whereas the combination of conventional dose cisplatin and ifosfamide, given as a single-day infusion, and high-dose carboplatin/ifosfamide yielded a pronounced fall of GFR. All groups showed increases in the urinary excretion levels of serum derived proteins and NAG, but with significant differences; about 2 to 3-fold for 5-days cisplatin, 3 to 5-fold for single-day cisplatin/ifosfamide, and 20 to 35-fold for high-dose chemotherapy. Thus, conventional approaches can reduce but not prevent the nephrotoxicity of cisplatin-based chemotherapy. In particular, high-dose chemotherapy regimens including carboplatin and ifosfamide are associated with comparable or even higher nephrotoxicity to single-day cisplatin/ifosfamide. In the light of the long-term consequences of persistent renal damage prevention of nephrotoxicity should be further improved.

Background: Children have been considered a risk group for lead (Pb) toxicity, mainly because of neurophysiological or neuro-cognitive deficits following Pb exposure. Blood Pb levels (b-Pb) of 100 microg/l currently have been defined as the lowest adverse effect level. The aim of this study was to compare, with the help of urinary markers, the kidney function of children with b-Pb just above this threshold with that of unexposed children, to assess from a nephrological point of view whether the current threshold is justified and whether children really are a particularly vulnerable risk group in terms of Pb-induced kidney damage., Methods: In a cross-sectional study, 112 children, either from unexposed areas (controls, n=50) or Pb-contaminated areas (n=62), the latter partly with a known history of elevated b-Pb, were examined. Twenty nine urinary or serum markers mostly related to the function or integrity of specific nephron segments were determined (e.g. filtered plasma proteins, tubular enzymes, tubular antigens, eicosanoids)., Results: b-Pb were 39+/-13 microg/l in controls and 133+/-62 microg/l in exposed children. The main findings were increased excretion rates of prostaglandins and thromboxane B2, epidermal growth factor, beta2-microglobulin and Clara cell protein in the exposed children. A relationship between b-Pb and the prevalence of values above the upper reference limits was observed., Conclusions: With the help of urinary markers, nephron segment-specific effects of chronic low-level Pb exposure could be detected in children. The pattern of effects on glomerular, proximal and distal tubular and interstitial markers was similar to that previously observed in adults. The changes, however, occur at lower b-Pb levels than in adults. The current threshold appears to be justified also from a nephrological point of view, and children can indeed be considered a special risk group.

Background: Vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF) is a selective mitogen for endothelial cells; it increases microvascular permeability and has been shown to relax isolated canine coronary arteries by an endothelium-dependent mechanism. In many tissues VEGF/VPF is expressed after an appropriate stimulus, mostly hypoxia. In the kidney VEGF/VPF is constitutively expressed in glomerular podocytes and epithelia of collecting duct. Glomerular and peritubular capillary endothelia also constitutively express specific VEGF receptors. The in vivo function of renal VEGF/VPF is unknown., Method: In the present study the effects of human recombinant VEGF165 on renal haemodynamics and glomerular permselectivity was investigated in the isolated perfused kidney of the rat., Results: In kidneys preconstricted by noradrenaline (NA 1.5 x 10(-7) mol/l) VEGF/VPF (155 pmol/l) caused an almost complete return of renal perfusion flow rate to pre-NA values (before NA 113 +/- 4%, after NA 100%, 15 min with VEGF/VPF 111 +/- 4%). Shortly after VEGF/VPF administration VEGF/VPF-induced relaxation commenced, and became significant after 2 min (15 min with VEGF/VPF vs without VEGF/VPF 111 +/- 4% vs 103 +/- 2%; P<0.05). In the presence of the NO-synthase inhibitor N(W)-nitro-L-arginine (L-NNA; 5 x 10(-5) mol/l) VEGF/VPF caused only small, transient relaxations (before NNA 109 +/- 5%, after NNA 100%, 15 min with VEGF 95 +/- 2%). The cyclooxygenase inhibitor diclofenac failed to inhibit the relaxing activity of VEGF/VPF (before NA 119 +/- 4%, after NA + diclofenac 100%, 15 min with VEGF/VPF 123 +/- 5%). VEGF demonstrated no significant increase in renal protein excretion rate (after NA pretreatment (= 100%): 12.5 min with VEGF/VPF vs without VEGF/VPF: 119 +/- 10% vs 132 +/- 11%, n.s.) (after NNA pretreatment (= 100%) 12.5 min with VEGF/VPF vs without VEGF/VPF 94 +/- 5% vs 96 +/- 4%; n.s.) or clearance quotient of albumin. Glomerular filtration rate was not influenced by VEGF/VPF in kidneys pretreated with NA (before NA 105 +/- 5%, after NA 100%, 12.5 min with VEGF/VPF 94 +/- 2%) or with NNA (before NNA 107 +/- 6%, after NNA 100%, 12.5 min with VEGF/VPF 96 +/- 2%). Fractional glucose and fractional sodium excretion showed flow-dependent changes., Conclusion: VEGF/VPF can contribute to the relaxing capacity of the renal vasculature. This relaxation is partly mediated by the NO/endothelium-derived relaxing factor (EDRF) pathway. In the isolated perfused rat kidney the glomerular permeability for albumin is not affected by VEGF/VPF.

Groups of industrial workers exposed to heavy metals (cadmium, mercury, and lead) or solvents were studied together with corresponding control groups. The cohorts were collected from several European centers (countries). Eighty-one measurements were carried out on urine, blood, and serum samples and the results of these analyses together with questionnaire information on each individual were entered into a central database using the relational database package Rbase. After the completion of the database construction phase, the data were exported in a format suitable for analysis by the statistical package SAS. The potential value of each test as an indicator of nephrotoxicity was then assessed. Rigorous exclusion criteria were applied which resulted in the elimination of some tests and samples from the dataset. The measurable contributions of smoking, gender, metal exposure, and site were either singly or in combination assessed by biomarkers for nephrotoxicity. The parameters measured included three urinary enzymes, six specific proteins, total protein, two extracellular matrix markers, four prostaglandins and anti-GBM antibodies, and beta 2-microglobulin in serum. The most sensitive renal tests included the urinary enzymes N-acetyl-beta-D-glucosaminidase (NAG) and intestinal alkaline phosphatase (IAP), brush border antigens, and urinary low-molecular-weight proteins. Of the newer tests investigated the prostaglandins were the most promising. Different patterns of biomarker excretion were observed following exposure to lead, cadmium, or mercury. The dataset provides a unique repository of data which could provide the basis of an enlarging source of information on normal human reference ranges and on the effects of exposure to toxins and the use of biomarkers for monitoring nephrotoxicity.

Within the framework of an European Commission-funded project, groups of industrial workers exposed to heavy metals (cadmium, mercury and lead) or solvents were studied together with corresponding control groups. Eighty-one measurements were carried out on urine and serum samples and the scientific results together with individual questionnaire information were entered into a central database. Data obtained was assessed centrally and individually in subsidiary studies. The measurable contributions were assessed either singly or in combination, of smoking, gender, metal exposure and site, to nephrotoxicity. The potential value of each test as an indicator of nephrotoxicity was then assessed on the basis of sensitivity and specificity. A number of new tests including prostaglandins and for extracellular matrix components were investigated as well as established tests for renal damage and dysfunction. The data obtained from this comprehensive study emphasises the value of noninvasive biomarkers for the early detection of nephrotoxicity due to environmental toxins. The urinary profile varied with the type of environmental/occupational toxin. By careful selection of a small panel of markers they can be used to indicate the presence of renal damage, the principal region affected, and to monitor the progress of disease and damage. Biomarkers were also used to confirm and tentatively establish safe exposure levels to nephrotoxins.

The present study was designed to investigate whether microalbuminuria at the onset of diabetic nephropathy might be partially due to the glycation of serum albumin. It is postulated elsewhere (Ghiggeri et al., Proc. Eur. Dial. Transplant. Assoc. 21 (1984) 633-636) that the glycation of serum albumin and the subsequent cationization may induce microalbuminuria. To investigate whether a relationship exists between the amount of glycated albumin in its cationized form and the development, and progression of diabetic nephropathy, the urinary excretion of glycated albumin was studied in diabetic patients. The diabetic patients (type I and II diabetes) were divided into groups according to their albumin excretion rates: group I diabetics had a normal albumin excretion (n = 30, x = 4.2 mg/12 h); group II diabetes displayed microalbuminuria (n = 17, x = 38.6 mg/12 h); group III diabetics displayed macroalbuminuria (n = 21, x = 582.5 mg/12 h). The fraction of glycated albumin in serum (Glyco Gel Test Kit) was 0.032 in group I, 0.042 in group II, and 0.038 in group III, all these values were significantly higher than the value for the controls (0.014%; n = 17, 2 alpha = 0.001) as measured with the Glyco Gel Test Kit. The concentration of glycated albumin in the urine of the controls and group I was below the detection limit. Urine in group II contained only a glycated albumin fraction of 0.0002 of total albumin, and the fraction for group III was 0.0008. Isoelectric focussing (IEF) and chromato-focussing revealed native albumin with an isoelectric point of 4.7-4.9, and anionic glycated albumin with a pI of 3.0-4.2.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of the addition of N omega-nitro-L-arginine (L-NNA, 10 and 100 microM) to isolated rat kidneys perfused with a complex medium containing 21 amino acids has been studied. A cyclooxygenase inhibitor was added throughout to block prostaglandin synthesis. L-NNA caused significant reductions in renal perfusion flow rate (PFR, 9.8 +/- 1.4 vs. 15.9 +/- 1.1 ml.min-1.g kidney wt-1, P less than 0.0001), glomerular filtration rate (GFR, 566 +/- 57 vs. 705 +/- 47 microliters.min-1.g kidney wt-1, P less than 0.05) and an increase in the relative filtration fraction (%FF, 7.0 +/- 0.6 vs. 5.2 +/- 0.4%, P less than 0.05) compared to control kidneys. L-NNA perfused kidneys had a lower absolute sodium (72 +/- 9 vs. 88 +/- 4 mumol.min-1.g kidney wt-1, P less than 0.05) and glucose reabsorption (3.5 +/- 0.5 vs. 5.4 +/- 0.4 mumol.min-1.g kidney wt-1, P less than 0.05), corresponding mainly to a lower sodium and glucose filtration. However, the relative reabsorption of sodium and glucose in the presence of L-NNA was attenuated, too (82.8 +/- 2.0 vs. 87.0 +/- 3.3% P less than 0.05 and 91.3 +/- 1.1 vs. 94.1 +/- 0.5%, P less than 0.05). Potassium handling and protein excretion were not changed significantly; fractional protein excretion increased slightly with the addition of L-arginine (47 +/- 5 vs. 55 +/- 7 ng.microliters-1, P less than 0.05). The differences between control and L-NNA treated kidneys (with the exception of differences in FRGluc) could be fully (L-NNA, 10 microM) or partially (L-NNA 100 microns) reversed by adding L-arginine (1 mM) to the perfusion medium. The observed results could be obtained in two different rat strains (Sprague-Dawley and Wistar). Only L-NNA and L-arginine caused the observed changes, while D-NNA and D-arginine were without effect. It is concluded that NO/EDRF is basally released from the isolated perfused rat kidney, and is of importance not only in the regulation of renal hemodynamics but also in the regulation of renal tubular function.

The effect of L-Arg depletion on glomerular hemodynamics and tubular function of isolated rat kidneys perfused with a medium containing 21 amino acids has been studied. A cyclooxygenase inhibitor was added throughout for blockade of prostaglandin synthesis. Arg depletion caused significant (approximately 30%) reductions in renal perfusion flow rate (PFR, 13.9 +/- 1.2 vs. 19.8 +/- 0.6 ml.min-1.g (kidney wt-1), glomerular filtration rate (GFR, 598 +/- 79 vs. 924 +/- 42 microliters.min-1.g kidney wt-1), and urine flow rate (139 +/- 38 vs. 192 +/- 13 microliters.min-1.g kidney wt-1) compared with control kidneys, which were perfused with a physiological concentration of Arg (200 microM). Filtration fraction (FF) increased with Arg depletion (5.1 +/- 0.4 vs. 4.4 +/- 0.4%). Arg-depleted kidneys had a lower absolute sodium (TNa, 75.7 +/- 8.8 vs. 107.9 +/- 6.0 mumol.min-1.g kidney wt-1) and glucose reabsorption (T glucose, 3.7 +/- 0.6 vs. 5.6 +/- 0.5 mumol.min-1.g kidney wt-1), corresponding to a lower sodium and glucose filtration. Potassium handling and reabsorption of free water were not changed. Oxygen consumption (QO2) was lower in Arg-depleted kidneys (4.6 +/- 0.3 vs. 5.5 +/- 0.5 mumol.min-1.g kidney wt-1). The effects of Arg depletion were completely reversed by the addition of Arg (1 mM) at 120 min and partly reversed by the addition of citrulline (1 mM). Ornithine depletion or addition had no effect on PFR, GFR, FF, TNa, T glucose, and QO2. N omega-methyl-L-arginine, a specific inhibitor of nitric oxide endothelium-derived relaxing factor, produced the same effect as Arg depletion.(ABSTRACT TRUNCATED AT 250 WORDS)

The anticancer drug adriamycin (ADR) induces severe nonselective glomerular proteinuria in rats. The proliferation of the glomerular mesangium in chronic ADR nephrosis suggests a disturbed metabolism of extracellular matrix proteins. In the present study the structural protein fibronectin was analyzed by immunological methods in urine and plasma in two rat strains after a single injection of 5 mg of ADR/kg b.wt. After ADR administration the excretion of 220 kd-plasma fibronectin, identified by its electrophoretic mobility and Western blotting, increased. This was confirmed by quantitative measurement (ELISA) of total urinary fibronectin (ADR-treated Munich Wistar Frömter rats: 85.4 +/- 49.5 ng/hr, N = 31; controls: 1.7 +/- 0.7 ng/hr, N = 26; day 7 after ADR injection). Control urines contained distinct fragments of fibronectin with a molecular weight range of 40 to 60 kd. It is suggested that these fragments did not originate from plasma inasmuch as only little correspondence between the fibronectin patterns of urine and plasma was found, and also because in ADR-treated rats the excretion of the fibronectin fragments decreased from day 4 of ADR administration. The data suggest that the urinary fibronectin fragments are released from cellular fibronectin during the normal catabolism of the glomerular extracellular matrices, and that ADR interferes in the metabolism of matrix components. Only as a consequence of an enhanced glomerular permeability is plasma fibronectin excreted in ADR-treated rats.

The separation of sex dependent urinary proteins of the rat (SDP) by micro-disc electrophoresis results in at least eight well defined protein bands with differing molecular weights. The hepatic origin of a sex dependent urinary protein, named alpha 2u-globulin, has been demonstrated before by other authors applying immunological methods. In the present study, it could been shown that SDP circulate in the plasma at a concentration of 23.8 mg/l. The origin of those protein bands which appear typically upon electrophoresis was still under dispute because they could not been demonstrated in proximal tubular fluid. The present study confirms the extrarenal source of SDP and suggests identity with alpha 2u-globulin. The attempt to track down SDP from plasma to excreted urine demonstrated that, in contrast to proximal fluid, samples from nephron parts distal to the loop of Henle contain large amounts of SDP. An isolated kidney model was used to determine the sieving coefficient and tubular reabsorption of SDP, obtained from male rat urine. We have found a correlation between the sieving coefficient and the molecular weight of SDP. The sieving coefficient ranged from 0.375 to 0.834. The tubular reabsorption which has been determined with an isolated kidney perfused with albumin and erythrocytes also showed variation with regard to molecular weight and was 61.7%, on average.

For uraemic diabetics the loss of insulin by dialysis with highly permeable membranes has clinical relevance. We investigated renal handling (in isolated perfused rat kidneys) of insulin and c-peptide and their dialytic clearances and sieving coefficients using cuprophan and polyacrylonitrile membranes. Rat kidney catabolic clearances were five times (insulin) and 12 times (c-peptide) greater than urinary clearances and twice inulin clearance. Cuprophan membrane was found to be virtually impermeable for both hormones. Polyacrylonitrile sieving coefficients were 0.3 (insulin) and 0.4 (c-peptide). Both hormones are filtered as well as tubularly and peritubularly catabolised in the kidney. Insulin removal during dialysis and haemofiltration with polyacrylonitrile membranes has to be considered in treating uraemic diabetics.

A variety of sex-dependent urinary proteins of low molecular weight, absent in females and in castrated males, can be identified in male rats by disc electrophoresis. In the urine of male rats of age 5.5 months, albumin comprises only 1-2% of the total protein. Albumin excretion increases greatly with age and associated kidney disease. Total protein excretion, however, stays the same or even decreases slightly as the rat ages, due to a loss of low molecular weight, sex-dependent, proteins. These are virtually absent in senescent rats (38 months of age), although total protein excretion rises tenfold in these animals due to high molecular weight plasma proteins passing into the urine; the glomerular filtration rate decreases to 70% of the value measured at 5.5 months of age.

The anatomy and ultrastructure of the lizard kidney (Sceloporus cyanogenys) have been studied by light and electron microscopy. The number of glomeruli was counted in serial sections and estimated to be 2,000 (in the two kidneys). Beginning with the glomerulus and Bowman's capsule the nephron segments are sequentially: (a) proximal tubule; (b) intermediate ciliated segment consisting of a proximal and distal part; (c) distal tubule, which can be divided into two segments, followed by (d) connecting tubule and (e) initial collecting duct. The initial collecting ducts from several nephrons open into the collecting duct. Tubular epithelium in this lizard has similarities to that of other reptiles. The lateral borders do not overlap like in mammals, but interdigitate by fingerlike projections. The length of the nephron segments was measured in disected tubules and the diameter was measured on light and electron micrographs. From these measurements estimates of inner tubular surface area were made. Together with data from physiological studies (Stolte et al., '76; Schmidt-Nielsen, '76) the estimated surface area was used to calculate transport rates per unit area across the epithelium. Comparisons of structure and transport rates per unit area across the epithelium. Comparisons of structure and transport rates were made between S. cyanogenys and other reptiles and mammals.

Renal handling of uremic middle molecules (MW 300-2000 daltons) was investigated (1) in the diseased kidney in nine patients suffering from chronic renal failure in the pre-dialysis phase, and (2) in the isolated perfused rat kidney using hemofiltrate and albumin (5 gm/100 ml) containing perfusate. Middle molecules clearances are compared to the simultaneously measured inulin and creatinine clearances. Four middle molecule fractions (peak 7a, 7b, 7c, and 7d) were quantitated after high-speed gel filtration and gradient elution chromatography and found to be freely filtered (= middle molecules clearances not differing from inulin and creatinine clearances) in uremia in man. In the "intact" (isolated perfused) rat kidney, elimination also takes place by glomerular filtration (peak 7a, 7c at high perfusate levels). Peaks 7b and 7d are slightly reabsorbed (15% and 25%, respectively, of filtered load), whereas 7c1 is secreted up to 220% of inulin clearance at low perfusate levels. No renal catabolism and high urinary excretion of middle molecules clearly indicate different renal handling of this species in comparison to other peptides or peptide hormones of the same molecular weight range.

cis-Diamminedichloroplatinum (DDP) and ifosfamide (IPP) are effective cytostatic agents with a considerable nephrotoxicity. Because of the known synergism of both drugs in animals the combination has been studied in man with disseminated testicular cancer. Nature and extent of nephrotoxicity of DDP in combination with vinblastine, bleomycin and with or without IPP was investigated. The renal involvement was studied during volume expansion and mannitol diuresis. In addition to total kidney function (creatinine clearance and renal electrolyte handling), tubular function has been determined by quantitative assessment of urinary albumin, beta 2-microglobulin, maltase and leucine aminopeptidase excretion. The urinary protein pattern was also analyzed by microgradient electrophoresis to determine low and high molecular weight proteins. The total protein excretion was raised in the groups of patients with DDP and IPP to a 5-fold of the normal (976 +/- 96 mg/24 h) versus a 4-fold increase (756 +/- 102 mg/24 h) without IPP. This was mainly due to renal tubular involvement. For example, IPP raised the tubular toxicity induced by DDP considerably with a 200-fold increase of the beta 2-microglobulin excretion versus only a 10-fold increase without IPP (p less than 0.02). All lesions were reversible and caused no lasting impairment of kidney function. It is concluded that combination regimens including DDP and IPP can be used without a major risk of acute or chronic renal insufficiency. However, urinary protein excretion should be monitored to make certain that the tubular function improves between or after the treatment courses.

The concentration of nine endogenous free L-alpha-amino acids (ALA, LEU, ILE, PHE, TYR, LYS, GLU, PRO, GLY) and of taurine were determined simultaneously along the nephron of the rat kidney using free-flow micropuncture techniques without altering plasma amino acid concentration or kidney function. The amount of each amino acid was determined after dansylation (14C-labelled dansyl-chloride) in the micropuncture sample followed by thinlayer chromatography. The main site of reabsorption is the proximal tubule. After 15-20% of the proximal tubule length the bulk of reabsorption has taken place (18.9 plus or minus 3.4% S.E. of the filtered load remaining). Net reabsorption continues to a small but significant extent along the distal nephron (disal tubule and collecting duct). Reabsorption of taurine is less rapid (% remaining of filtered load at the early proximal tubule 37.0 plus or minus 4.6%). The transtubular concentration ratio of all amino acids except taurine follows a homogeneous course. Under the experimental conditions of this study no distction with respect to different systems of reabsorption "neutral", "basic", "acidic", "imino-glycine") could be made.

In order to decide whether foot process abnormalities in nephrotic states are the cause or the consequence of proteinuria, the polycation protamine has been applied to isolated perfused rat kidneys and functional parameters and morphology have been compared. With 110 micrograms/ml protamine the albumin clearance ratio increased from 2.0 +/- 0.7 x 10(-3) in controls to 14.8 +/- 6.9 x 10(-3) 10-20 min after application and even to 98.0 +/- 30.8 x 10(-3) after 50-80 min. Micropuncture samples collected from early proximal tubules with pressure control were used to calculate the sieving coefficient which correlated with albumin clearance ratios (controls: 1.8 +/- 1.0 x 10(-3); after 10-20 min: 11.8 +/- 6.4 x 10(-3); after 50-80 min: 52.0 +/- 8.5 x 10(-3). Glomerular filtration rate decreased in the early beginning from 1.1 +/- 0.2 ml x min-1 x g-1 kidney to 0.7 +/- 0.2 ml x min-1 x g-1 kidney, but remained constant throughout the whole experiment. Despite the markedly increased albuminuria there were no changes in glomerular foot process morphology with the protamine dose used.

1. In the atlantic hagfish (Myxine glutinosa) binding sites for atrial natriuretic peptide (ANP) were visualized by autoradiography in contractile structures of the renal system (glomeruli, neck segment, and archinephric duct) and in the aorta. 2. Since the location of binding sites is comparable to that in higher vertebrates including man, these results suggest that ANP may act as a hormone already in cylcostomata.

Little is known of the normal renal handling of potential uremic toxins in the middle molecular weight (MMW) range (300-2,000 daltons). In this study the isolated rat kidney has been used as a model to investigate renal clearance and possible renal metabolic effects on uremic MMW species. Isolated rat kidneys were perfused with hemofiltrate from chronic renal failure patients containing 5% bovine albumin. Middle molecules (MM) were isolated from perfusates and urines by high-speed gel filtration (peak 7) and further separated by gradient elution chromatography to give 7-8 definable uremic MMW species (7a, b, c, etc.). Species 7b, d, e and f were tubularly reabsorbed by 15, 25, 23 and 34%, respectively, as indicated by simultaneous inulin clearances. 7a was freely filtered with negligible reabsorption. 1 MM (7c1) was found to be secreted by up to 220% at low perfusate concentrations, secretion being masked at high perfusate levels. No MMs were catabolized by the kidney, although one species (7c2) appeared to be synthesized. The results suggest that uremic MMs have differing biological or physicochemical activities as indicated by the selectivity of renal handling.

The fine structure of the kidney (glomerulus and archinephric duct) of the hagfish. Myxine glutinosa (L.) was studied in thin sections and by freeze-fracture technique. The glomerular filtration barrier is similar to that of mammalian kidneys. However, endothelial fenestrations are relatively scanty and the basement membranes of endothelial cells and podocytes always appear separated by a layer of collagen fibrils and microfibrils often surrounding numerous and extended mesangial cells. Between podocytes and their processes maculae occludentes and peculiar junctions of another type occur. The zonulae occludentes between epithelial cells of the archinephric duct are composed of five or more strands, occasionally of only one or two.

The kidneys of winter flounders transferred to hypotonic medium were investigated for glomerular and tubular handling of fluid and electrolytes and for the urinary excretion of proteins. Media were sea water (925 mosm X kg-1) and brackish water (70 mosm X kg-1). In sea water, the urine was hypertonic to the plasma in 7 fish of this study. Urine flow rate was correlated with the GFR. After adaptation to brackish water a delay of 1 to 3 days was observed until the kidneys switched from fluid retention to the excretion of large amounts of dilute urine. GFR and urine flow rate were increased from 0.61 +/- 0.08 to 1.58 +/- 0.29 ml X h-1 X kg-1 and from 0.14 +/- 0.02 to 0.68 +/- 0.08 ml X h-1 X kg-1, respectively (mean +/- SEM). With increased filtered load the tubular reabsorption of fluid decreased from 74 +/- 2.4% to 45 +/- 11.2%. The excretion rates of sodium and potassium were increased due to decreased fractional sodium and potassium reabsorption. The urinary excretion of divalent cations, however, was reduced because the net tubular reabsorption of calcium was increased and the net secretion of magnesium was diminished. Both the urinary total protein concentration and the protein pattern showed no significant change, but the rate of protein excretion was increased from 0.21 +/- 0.04 to 0.60 +/- 0.05 mg X h-1 X kg-1. The comparison of protein patterns obtained from urine and serum samples revealed that high molecular weight (HMW) proteins prevail in the serum whereas low molecular weight (LMW) proteins dominate in the urine. The diminished quantity of the HMW-protein fraction in the urine thus may reflect size selectivity of the glomerular filtration barrier for serum proteins also in the winter flounder.