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Purpose: Inpatient glycemic management typically involves use of point-of-care (POC) glucose measurements to inform insulin dosing decisions. This study evaluated a hybrid monitoring protocol using real-time continuous glucose monitoring (rtCGM) supplemented with POC testing at a community hospital., Methods: Adult inpatients receiving POC glucose testing were monitored using rtCGM in a telemetry unit. The hybrid monitoring protocol required a once-daily POC test but otherwise primarily relied on rtCGM values for insulin dosing decisions. Outcomes assessment included surveillance error grid (SEG) and Clarke Error Grid (CEG) analysis results, the mean absolute relative difference (MARD) for available rtCGM-POC value pairs before and after study protocol application, the number of POC tests avoided, and the number of hypoglycemic events involving a blood glucose value of <70 mg/dL identified by rtCGM and POC values., Results: Data were collected from 30 inpatients (the mean age was 69.4 years, 77% were female, 80% had type 2 diabetes, and 37% were at-home insulin users). With the protocol applied, a total of 202 rtCGM-POC pairs produced a MARD of 12.5%. SEG analysis showed 2 pairs in the "moderate" risk category, with all other pairs in the "none" or "slight" risk categories. CEG analysis showed 99% of paired values to be in the clinically acceptable range. Six hypoglycemic events in 5 patients were resolved without incident. Three hundred three POC tests were avoided, a 60% reduction for the study duration., Conclusion: Use of a hybrid monitoring protocol of rtCGM and POC testing in a community hospital demonstrated sustained rtCGM accuracy and was found to reduce the frequency of POC testing to manage inpatient glycemia., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The World Health Organization calls for stronger cross-cultural emphasis in medical training. Bioethics education can build such competencies as it involves the conscious exploration and application of values and principles. The International Pediatric Emergency Medicine Elective (IPEME), a novel global health elective, brings together 12 medical students from Canada and the Middle East for a 4-week, living and studying experience. It is based at a Canadian children's hospital and, since its creation in 2004, ethics has informally been part of its curriculum. Our study sought to determine the content and format of an ideal bioethics curriculum for a culturally diverse group of medical students., Methods: We conducted semi-structured interviews with students and focus groups with faculty to examine the cultural context and ethical issues of the elective. Three areas were explored: 1) Needs Analysis - students' current understanding of bioethics, prior bioethics education and desire for a formal ethics curriculum, 2) Teaching formats - students' and faculty's preferred teaching formats, and 3) Curriculum Content - students' and faculty's preferred subjects for a curriculum., Results: While only some students had received formal ethics training prior to this program, all understood that it was a necessary and desirable subject for formal training. Interactive teaching formats were the most preferred and truth-telling was considered the most important subject., Conclusions: This study helps inform good practices for ethics education. Although undertaken with a specific cohort of students engaging in a health-for-peace elective, it may be applicable to many medical education settings since diversity of student bodies is increasing world-wide.

The UK Food Standards Agency (FSA) convened an international group of scientific experts to review three Agency-funded projects commissioned to provide evidence for the relative contributions of two sources, dietary vitamin D intake and skin exposure to UVB rays from sunlight, to vitamin D status. This review and other emerging evidence are intended to inform any future risk assessment undertaken by the Scientific Advisory Committee on Nutrition. Evidence was presented from randomised controlled trials to quantify the amount of vitamin D required to maintain a serum 25-hydroxy vitamin D (25OHD) concentration >25 nmol/l, a threshold that is regarded internationally as defining the risk of rickets and osteomalacia. Longitudinal evidence was also provided on summer sunlight exposure required to maintain 25OHD levels above this threshold in people living in the British Isles (latitude 51 degrees-57 degrees N). Data obtained from multi-level modelling of these longitudinal datasets showed that UVB exposure (i.e. season) was the major contributor to changes in 25OHD levels; this was a consistent finding in two Caucasian groups in the north and south of the UK, but was less apparent in the one group of British women of South Asian origin living in the south of the UK. The FSA-funded research suggested that the typical daily intake of vitamin D from food contributed less than UVB exposure to average year-round 25OHD levels in both Caucasian and Asian women. The low vitamin D status of Asian women has been acknowledged for some time, but the limited seasonal variation in Asian women is a novel finding. The Workshop also considered the dilemma of balancing the risks of vitamin D deficiency (from lack of skin exposure to sunlight in summer) and skin cancer (from excessive exposure to sunlight with concomitant sunburn and erythema). Cancer Research UK advises that individuals should stay below their personal sunburn threshold to minimise their skin cancer risk. The evidence suggests that vitamin D can be produced in summer at the latitude of the UK, with minimal risk of erythema and cell damage, by exposing the skin to sunlight for a short period at midday, when the intensity of UVB is at its daily peak. The implications of the new data were discussed in the context of dietary reference values for vitamin D for the general population aged 4-64 years. Future research suggestions included further analysis of the three FSA-funded studies as well as new research.

The determinants of glomerular capillary wall (GCW) permeability to proteins have been subject of controversial discussion. To study this question we have developed a modified isolated perfused rat kidney model in which tubular transport processes are completely blocked by perfusion fixation with glutaraldehyde. This model allows to directly titrate the charge density of the GCW using albumin solutions buffered over a wide pH-range, a manipulation that cannot be performed in the intact kidney. Analyzing the results of these experiments helped to determine a fixed charge density of the GCW of 43 mEq/L. In the present work, we used the isolated perfused fixed rat kidney model to study the influence of this fixed charge on the transglomerular passage of proteins. To do this, the fixed kidney was perfused with albumin solutions containing different isoforms of horseradish peroxidase. The lowest sieving coefficient was obtained with the acidic isoform (0.035+/-0.008, n = 7), while the isoforms at pI 6.85 and 8.45 showed higher sieving coefficients (0.059+/-0.008, n = 7 and 0.090+/-0.008, n = 4, respectively). The highest sieving coefficient (0.59+/-0.031, n = 6) was observed in perfusion experiments of the fixed kidney with cationic HRP (pI > or = 9.30). However, when comparing the sieving coefficients, the highly cationic isoform was excluded because it has a lower molecular weight than the other isoforms. The sieving coefficients of the other isoforms were significantly different (p < 0.05. ANOVA, Scheffé test). In conclusion, the presence of a discrete (even if lower than previously thought) "fixed" charge on the GCW of 43 mEq/L restricts the transglomerular passage of isoforms of horseradish peroxidase by a factor 2-3. These results imply that the influence of charge selectivity has been overstated in the literature.

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.

This study evaluates the degree of kidney damage during cisplatin/ifosfamide-based combination chemotherapy and its possible prevention by amifostine. Thirty-one patients with solid tumors stratified according to pretreatment were randomized to receive cisplatin/ifosfamide-based chemotherapy with or without amifostine (1000 mg absolute) given as a short infusion prior to cisplatin. Chemotherapy consisted of cisplatin (50 mg/m2), ifosfamide (4 g/m2) and either etoposide (500 mg/m2) (VIP regimen) or paclitaxel (175 mg/m2) (TIP regimen) repeated at 3 weekly intervals. For all patients the glomerular filtration rate (GFR) measured by creatinine clearance, serum creatinine, electrolytes and differential urinary protein excretion were determined prior to, during and after each treatment cycle. A total of 62 cycles of chemotherapy were evaluable. In the amifostine arm the GFR was almost completely maintained after application of two cycles of chemotherapy (121 to 108 ml/min), whereas in the control group a 30% reduction of the GFR (105 to 80 ml/min) was observed. In both groups marked increases of glomerular and tubular marker profiles peaking at day 3 after chemotherapy were found with a nearly complete reversibility of these changes prior to the next chemotherapy cycle. Patients receiving amifostine had a lower degree of hypomagnesemia, as well as a lower urinary excretion of N-acetyl-glucosaminidase and albumin, indicating less tubular damage compared to the control patients. Treatment with 1000 mg amifostine resulted in an almost complete preservation of GFR. This corresponded to a slightly reduced excretion of tubular marker proteins and a lower incidence of hypomagnesemia during chemotherapy in amifostine patients compared to controls. This dose of amifostine may be sufficient for nephroprotection in patients without pre-existing risk factors for renal damage who undergo a restricted number of chemotherapy cycles.

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.

Previous investigations performed in human diabetics demonstrate an increase in their urinary fibronectin excretion which was already present in subjects without microalbuminuria and which was elevated prior to functional restrictions. The present study was performed to examine whether in an experimental model these data obtained in men can be confirmed using an animal experimental model, and to further study pathomechanisms of diabetic nephropathy in rats. Fibronectin levels in serum and urine, and renal functional properties such as creatinine clearance, urinary albumin and protein excretion were studied in rats rendered diabetic with streptozotocin and compared with values of control and insulin treated animals for 5 months. Diabetic animals demonstrated the same creatinine clearance, but slightly decreased albumin and total protein excretion rates compared to controls and insulin "treated", euglycaemic animals. Diabetic rats showed a significantly increased excretion following day 42 compared to controls and insulin "treated" group. Concerning serum fibronectin, there was no significant difference between control, diabetic and insulin "treated" animals. The urinary fragment pattern of fibronectin was analyzed qualitatively by immunoblotting pattern and consisted of two main bands (M(r) 66,000 and 45,000). These bands were not altered in controls, insulin "treated" and diabetic rats, independent of the stage of renal involvement in diabetes. Present data provide evidence that fibronectin excretion is elevated in diabetic animals prior to functional restrictions, confirming results obtained in human diabetics. Therefore, determination of urinary fibronectin can serve as a more sensitive indicator for renal involvement in diabetes mellitus than microalbuminuria or changes in glomerular filtration rate. Urinary excretion may therefore serve as an early marker for the renal involvement in diabetes before the onset of clinical symptoms.

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.

Chemotherapy (Ctx) and/or radiotherapy (Rtx) are effective in the treatment of Hodgkin's disease (HD) but potentially involve late toxicities, including nephrotoxic side effects. Therefore a follow-up study has been performed to screen patients for late signs of an impaired tubular or glomerular function and to correlate data of renal function with type of therapy and cumulative doses of cytotoxic agents applied. 81 patients in complete remission for at least 2 years and a median follow-up of 96 (39-304) months, and 53 controls were examined. Clinical routine parameters such as creatinine and electrolytes were determined. A differentiation of proteinuria into the albumin, high molecular weight (HMW) and low molecular weight (LMW) fractions made it possible to assess glomerular and tubular function based on the LMW/HMW ratio. The structural protein fibronectin served as an additional, sensitive marker of glomerular integrity. Routine parameters of kidney function did not show any signs of late nephrotoxicity. However, patients treated for HD had a higher ratio of LMW/HMW in comparison to the group of healthy volunteers (p < 0.01), indicating subclinical tubular renal damage. When the cutoff for tubular damage was defined as LMW/HMW > 1.5, 50% of the patients treated with combined modality, and 42 and 37% of the patients with Ctx or Rtx alone had subclinical tubular alterations, respectively. A tendency towards a higher prevalence of subclinical tubular changes was observed in patients with higher cumulative doses of methotrexate or ifosfamide and in patients with combined Ctx and Rtx with radiation fields involving the renal area. Changes in glomerular function were not observed. It is concluded that treatment of HD is not associated with clinically apparent long-term impairment of renal function but can lead to subclinical alterations. Further clinical implications of these subclinical tubular alterations cannot be assessed at present. A differentiation of proteinuria does not have to be performed routinely but might be useful in the follow-up of selected patients with an increased risk.

Basement membrane thickening and mesangial expansion characterize the renal involvement in diabetes mellitus and precede any symptoms of renal dysfunction, e.g., albuminuria and changes in glomerular filtration rate. Since the morphological changes can only be diagnosed by biopsy, this study was designed to investigate whether the urinary excretion of renal extracellular matrix proteins might reflect the morphological alterations. To specify the extent of renal involvement in diabetes, the patients, type I as well as type II diabetics, were classified according to their urinary albumin excretion: normal albumin excretion below 30 micrograms/min, microalbuminuria from 30 to 300 micrograms/min, and overt albuminuria above 200 micrograms/min. Laminin, collagen IV, and fibronectin, all intrinsic components of the renal extracellular matrix, were determined in serum and urine by radioimmunoassay or enzyme-linked-immunosorbent-assay, respectively. The results are given as median values (mean). Additionally, the urinary fragment pattern of fibronectin was analysed qualitatively by immunoblotting. Laminin concentrations in serum and in urine did not change in diabetics. Collagen IV decreased in serum of patients with increased albumin excretion (controls: mean = 255 micrograms/l, normoalbuminuric patients: mean = 56 micrograms/l, microalbuminuric patients: mean = 52 micrograms/l, and patients with overt albuminuria: mean = 70 micrograms/l; alpha < 0.01) and increased in urine (controls, normoalbuminuric and microalbuminuric patients: not detectable, patients with overt albuminuria: mean = 5 ng/12 h; apha < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic proteinuria were studied in rats, using lysosomal cathepsin B and L as marker enzymes for tubular protein degradation. The activity of cathepsin B and L has been determined in microdissected segments S1, S2 and S3 of the proximal tubule by an ultramicroassay. Z-Phenylalanyl-arginine-7-amido-4-methylcoumarin served as a substrate. In normoproteinuric Sprague-Dawley rats, induction of acute unselective glomerular proteinuria with Adriamycin (5 mg/kg body weight) revealed a moderate activity increase of cathepsin B and L in the S2 segment, reaching 12.6 +/- 5.6 versus 8.6 +/- 4.2 pmol.mm-1.min-1 in controls. In contrast, Munich Wistar Frömter (MWF) rats, that are characterized by a genetically determined, chronically elevated glomerular protein excretion, showed a very high activity of cathepsin selectively in S2 of 25.0 +/- 12.1 pmol.mm-1.min-1. Acute proteinuria induced by Adriamycin in chronic proteinuric MWF rats could increase cathepsin activity in the S3 segment only, showing 12.0 +/- 8.3 versus 6.8 +/- 4.0 pmol.mm-1.min-1 in MWF control rats. In conclusion, chronically increased protein filtration changes the functional reserve capacity of the proximal tubule. While acutely induced glomerular proteinuria in normoproteinuric rats stimulates lysosomal proteolytic activity mainly in S2 segment, chronic proteinuric MWF rats may display already a maximally stimulated cathepsin activity in this segment probably due to long-term increased tubular protein load. In case of acute elevation of chronic proteinuria, the consecutive S3 segment shows increased lysosomal function for protein conservation.

This study was designed to validate an alternative in vitro system with isolated glomeruli of the Atlantic hagfish Myxine glutinosa as a model to study alterations in glomerular protein metabolisms in pharmaco-toxicology of anticancer drugs. A morphometric characterization of the glomeruli of Myxine glutinosa reveals a calculated glomerular volume of 180 nl/glomerulus. The glomerular extracellular volume, measured as inulin space, is 38.5 nl/glomerulus. Total glomerular protein content of Myxine glutinosa amounts to 3.56 micrograms/glomerulus and total DNA content to 0.44 microgram/glomerulus. Metabolic properties, estimated as glomerular protein synthesis, are comparable with mammalian glomeruli. The glomeruli of Myxine glutinosa are viable in a tissue culture for up to 12 hr. The incorporation rate of radiolabeled amino acids into glomerular, acid-precipitable proteins is almost identical to that of rats (e.g. Myxine glutinosa 1091 +/- 98 DPM/micrograms DNA vs. rat 1340 +/- 84 DPM/micrograms DNA after 4 hr incubation). To evaluate how nephrotoxic substances affect glomerular metabolism in this model, the anticancer drug Adriamycin (ADR) was used to experimentally induce a glomerular lesion. ADR caused an increase in glomerular protein synthesis in isolated glomeruli of Myxine glutinosa, which is in accordance with data found in rats. Cisplatin, in contrast, known to mainly interfere with tubular integrity, had no effect on glomerular protein synthesis, confirming the specificity of the model. The isolated glomeruli of Myxine glutinosa are suggested as a valid alternative multicellular in vitro system for studying alterations in glomerular metabolism under pharmaco-toxicological conditions and for the evaluation of specific target-cell toxicity of selected nephrotoxins.

Using an in vitro microperfusion technique, the filtration characteristics of single isolated glomeruli of the Atlantic hagfish (Myxine glutinosa) were investigated. The suitability of the method as a model to study glomerular function was evaluated. Experiments with a protein-free perfusate led to a filtration coefficient Kf (0.189 +/- 0.181 nl x s-1 x mm Hg-1) that was in the same order of magnitude as determined in vitro for other vertebrates. Morphometric analysis on serial thin sections (1 microns) revealed a glomerular capillary surface (A) of 1.84 +/- 0.72 mm2. A linear relationship between glomerular diameter and A allowed the calculation of the hydraulic conductivity Lp (0.618 +/- 0.384 microliter x s-1 x mmHg-1 x cm-2). The data indicate that the isolated perfused glomerulus of M. glutinosa has filtration characteristics similar to higher vertebrates. The glomeruli of M. glutinosa, which in contrast to glomeruli of other animals are easy to dissect, are a suitable model for the study of glomerular filtration and permeability characteristics of vertebrates. An example of a possible application of the model is a study into the effects of adrenaline on glomerular filtration characteristics. Adrenaline led to increases in ultrafiltration pressure (PUF), single nephron glomerular filtration rate (SNGFR) and filtration fraction (FF); Kf remained unaffected.

Background: Fibronectin (FN) is a major component of the glomerular extracellular matrix and it is also abundant in plasma. In physiologic conditions, FN fragments are excreted into urine. Increased urinary FN excretion has been observed in renal diseases raising the question whether urinary FN could reflect changes in the renal extracellular matrix. This study examines whether urinary FN is filtered from plasma or derived from the kidney and it attempts to specify the potential renal source of urinary FN., Experimental Design: (a) To investigate whether urinary FN is filtered from plasma, labeled, biotinylated FN (b-FN) was injected into rats and urine samples were specifically analyzed for b-FN by an immunoblot procedure. (b) To specify the renal source of urinary FN and to evaluate possible alterations of this protein during passage into final urine, tubular fluid was collected from distinct localizations of the nephron by micropuncture techniques. The samples were analyzed for endogenous FN by a highly sensitive immunoblot system, and the pattern was compared with that normally found in final urine., Results: (a) Urine samples collected over a period of 5 days after injection of b-FN contained no labeled FN. Control experiments in rats with highly elevated glomerular permeability confirmed that the plasma levels of injected b-FN were sufficiently high since b-FN was detected in urine in this condition. (b) The FN fragment pattern, with two protein bands at 75 and 45 kilodaltons, that is normally found in final urine, was already present in samples taken from the early proximal tubule and the distal tubule., Conclusions: The fibronectin fragments normally found in urine originate from the kidney and are not derived from plasma. Since these fragments are already observed in early proximal tubular fluid, the glomerulus is the probable source of urinary FN. The FN fragment pattern of early proximal tubular fluid is not substantially altered during passage into final urine, thus reflecting glomerular FN release in urine. It is suggested that examination of urinary FN excretion could be helpful in the assessment of altered glomerular extracellular matrix in pathologic conditions.

Fibronectin (FN) turnover and turnover changes induced by the anticancer drug Adriamycin (ADR) were measured in human mesangial cells (HMC) in vitro. HMC cultures synthesize cellular FN (2.2 +/- 0.3% of total protein synthesis; n = 12) which is secreted and incorporated into a fibrillar extracellular matrix (ECM). A 24 hr incubation of HMC with ADR (0.5-5 micrograms/ml) resulted in an accumulation of FN in the culture medium, with a maximum increase following 5 micrograms/ml (7.3 +/- 2.3 pg/cell vs. controls: 4.4 +/- 1.9 pg/cell; n = 10). Correspondingly, radioactively labeled immunoprecipitable FN was increased in a dosage-dependent manner in the culture medium up to 50% vs. controls. The incorporation of radioactively labeled FN into ECM was significantly increased following 2 micrograms ADR/ml. In accordance, immunofluorescence staining revealed an expansion of pericellular FN fibers in cultures exposed to 2 micrograms ADR/ml. Concomitant with the accumulation of extracellular FN, radioactively labeled FN in the cells was reduced by 22%. Qualitative characterization of FN patterns revealed a diminished number of degradation products in the culture medium of ADR-treated HMC. These data suggest that ADR interferes with the turnover of FN secreted by HMC in vitro in such a way that FN accumulates extracellularly. This in turn leads to a reduced FN synthesis. These findings are compatible with a loss of urinary FN degradation products accompanying the onset of proteinuria in ADR-treated rats.

The barrier function of glomerular capillaries in vivo, which prevents the leakage of plasma proteins and cellular elements, depends on the basic morphological and electro-chemical fine structure of the glomerular capillary wall, and on a functional barrier maintained by components obtained from blood, which effect the definitive barrier against the leakage of plasma proteins and cellular elements. The functional component of the barrier may explain the variability and some of the phenomena known as functional proteinuria. A certain size and number of morphological "defects" are thought to represent the normal condition, but under pathological conditions they may increase in size and number, resulting in a shift to an increasing permeability for higher molecular mass proteins; also an increase of the size and number of larger defects may enable more red cells to pass the barrier compared with the normal condition. These defects are different from the minimal glomerular lesions which are due to charge defects in the glomerular capillary membrane, primarily the lamina rara interna and the lamina rara externa of the basement membrane.

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 glomerular permeability of the isolated perfused kidney is manifold higher than in vivo, although structural changes at the glomerular filtration barrier are not described. It has been proposed that in vivo high molecular weight plasma proteins are concentrated at the glomerular endothelium forming an additional filtration barrier ('concentration polarization'). To test this hypothesis, isolated rat kidneys were perfused with substrate-enriched Krebs-Henseleit solutions containing albumin (50 g/l) or albumin/globulin (40/10 g/l), or with plasma. The pO2 was 675 mm Hg. Furthermore, experiments were carried out with the addition of erythrocytes with and without a reduced O2 supply (pO2 35 mm Hg). Independent of the composition of the perfusate a continuously increasing glomerular permeability was observed immediately after perfusion was started. After about 10 min, a steady state value for the glomerular permeability was reached. The addition of globulin to the perfusate or perfusion with plasma did not prevent the initial increase of the permeability. However, after addition of 5% erythrocytes to the perfusate the increase of permeability was much less pronounced. Neither the reduction of the O2 supply nor the addition of erythrocytes to a higher concentration than 5% had any further effect on the glomerular permeability. These data show that concentration polarization of high molecular weight proteins does not take place at the endothelium of the glomerulus. Independent of their ability to carry O2 erythrocytes play an important role in the glomerular filtration process.

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 anticancer drug adriamycin (ADR) is selectively toxic to glomerular cells when administered intravenously (5 mg/kg b.w.) to female MWF/Ztm rats. Recent data have shown that the proteinuria associated with the lesion does not occur in cortical glomeruli, suggesting the selective injury of juxtamedullary glomeruli. In the present study, the effect of ADR on glomerular metabolism was studied with special reference to possible differences between cortical and juxtamedullary glomeruli. On day 7 after ADR treatment, cortical and juxtamedullary glomeruli were separately isolated by the sieving method and 14C glucose oxidation to 14CO2 and the incorporation of 3H proline into macromolecules were measured in vitro and used to study target selective injury in ADR-treated rats compared to control rats. The investigations revealed differences in the response of cortical and juxtamedullary glomeruli to ADR. ADR treatment increased proline incorporation over a 4-hour incubation period in both glomerular populations compared to controls, but the effect was significantly (p less than 0.05) more pronounced in juxtamedullary glomeruli (juxtamedullary: 187 +/- 8% of control; cortical: 167 +/- 4% of control). Glucose oxidation was enhanced after 4 h only in juxtamedullary glomeruli (juxtamedullary: 132 +/- 3% of control; cortical: 82 +/- 10% of control). These data show that glomerular damage caused by ADR is associated with a stimulating effect on glomerular metabolism which is more marked in juxtamedullary than in cortical glomeruli, thus indicating a heterogenous response of different glomerular populations and supporting the concept that the selective damage of juxtamedullary glomeruli accounts for the proteinuria.

A new colorimetric test for kinetic determination of beta-N-acetylglucosaminidase activity in urine is evaluated according to the diagnostic usefulness in patients after kidney transplantation and in workers exposed to cadmium. The new test is suited to monitor renal parenchymal alterations.

The glomerular epithelial cells of the Atlantic hagfish (Myxine glutinosa) lack a slit diaphragm which is replaced by filaments. The epithelial cells show numerous occluding junctions (maculae and fasciae occludentes), septate desmosome-like junctions and desmosomes. The present findings are compared with available data on developing and mature glomerular epithelial cells of mammals.

In latent hereditary diabetes mellitus increased protein excretion has been found in male diabetic mice compared to controls. This proteinuria is partly due to an increased excretion of higher molecular weight proteins, which could be identified as deriving from plasma. The suggested glomerular proteinuria has been verified by an increase in the renal excretion of high molecular weight PVP. No changes in GFR occurred in this early stage of diabetic glomerulopathy. No changes in morphology could be detected, suggesting some changes in the biochemical membrane structure that cause the findings of increased permeability of the diabetic basement membrane for plasma proteins.

This report describes 3 cases of yellow nail syndrom. The examination either did not reveal lymphedemas or only transitory edemas were found. But both typical changes of nails and chronic inflammation of the respiratory tract were found. Remarkably enough, two of our patients showed a decrease in serum immunoglobulin M (IgM). Both patients had a most serious disorder of the respiratory tract. In the form of a table this report contains a survey of the literature published hitherto about the combinations of symptoms of yellow nail syndrom occurring most frequently.