Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis.

BACKGROUND: The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. METHODS: In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. RESULTS: Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. CONCLUSION: Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.     

Glomerular size and charge selectivity in insulin-dependent diabetes mellitus

The pathogenesis of clinical nephropathy in Type 1 (insulin-dependent) diabetes was investigated by measuring renal fractional clearances of albumin, total IgG, IgG4 and beta 2-microglobulin, four plasma proteins which differ in size and charge. Seventy patients and eleven control subjects were studied. In diabetic patients with normal urinary albumin excretion (less than 30 mg/24 hr), fractional IgG clearance was two to three times higher than in control subjects, whereas fractional clearance of the anionic plasma proteins IgG4 and albumin was similar to that of control subjects. These alterations indicate an increase in anionic pore charge within the glomerular basement membrane concomitant with an increase in either pore size or impairment of tubular reabsorption. Diabetic patients, whose urinary albumin excretion has started to rise (30 to 100 mg/24 hr), had unchanged fractional IgG compared to patients with normal albumin excretion, while fractional IgG4 and albumin clearances were increased three- to fourfold; indicating unchanged glomerular pore size, but a decrease in anionic pore charge. In patients demonstrating urinary albumin excretion of greater than 100 mg/24 hr fractional IgG clearance increased to the same extent as fractional albumin clearance, indicating an increase in large pore area. Fractional beta 2-microglobulin clearances were similar to that of control subjects in the different patient groups indicating unchanged tubular reabsorption of proteins. Thus, the increase in large pore area seen in patients with clinical nephropathy is preceded by loss of anionic charge in the glomerular basement membrane. It is likely that this loss of anionic charge is due to loss of heparan sulphate-proteoglycan.     

Urine excretion of protein HC in proteinuric glomerular diseases correlates to urine IgG but not to albuminuria.

BACKGROUND: Proteinuric glomerular diseases often are associated with tubulointerstitial injury, which imposes on the progression of renal failure. Tubular damage is partly referable to toxic effects on the tubular epithelial cells induced by filtered plasma proteins. Patients with nonselective proteinuria, that is, increased urine excretion of high-molecular-weight plasma proteins such as IgG in comparison to albumin, often have poor renal outcome. The present observational study examined correlations between the degree of tubular damage, measured by urine concentration of protein HC, and the levels of urine IgG and albuminuria. METHODS: Measurements of urine concentrations of IgG, albumin, and protein HC were performed in 56 proteinuric patients (33 males and 23 females) with nondiabetic glomerular diseases at the time of the diagnostic renal biopsy and at a mean of 49 follow-up months. RESULTS: A highly significant correlation between the urine IgG excretion and the urine protein HC concentration was found both at the start and at the end of the observational time (r = 0.74 and 0.65, respectively, P < 0.001). Furthermore, alterations in the urinary excretion of the two proteins in single patients correlated significantly to each other (r = 0.84, P < 0.001). The correlation between the degree of albuminuria and the protein HC excretion was significant at the time of kidney biopsy, but ceased to exist during the follow-up time. Stepwise linear regression analysis showed that in comparison with the creatinine clearance and albuminuria, only the changes in urinary IgG excretion were related to the corresponding changes in urinary protein HC excretion (r = 0.84 and r2 = 0.7, P < 0.001). CONCLUSION: The findings of the study suggest that the urinary protein HC concentration correlates to the degree of IgG-uria but not to the degree of albuminuria during the course of proteinuric glomerular disease. Whether this correlation is to be explained by an intrinsic toxic effect on tubular cells executed by IgG or perhaps by some other high molecular weight proteins, needs to be investigated further. However, the results contribute to the understanding of the poor renal survival in patients with glomerular diseases and nonselective proteinuria.     

Urinary albumin excretion in patients with non-insulin-dependent diabetes mellitus in an early microalbuminuric stage.

We investigated the urinary albumin excretion and renal hemodynamics of normotensive nonobese patients with impaired glucose tolerance (IGT) and non-insulin-dependent diabetes mellitus (NIDDM) in an early microalbuminuric stage (defined by albuminuria less than 30 mg/day). In comparison with normal subjects, a significant increase in urinary albumin excretion was observed already in the IGT stage [U-albumin/U-creatinine: NL (20 subjects), 5.3 +/- 1.7 mg/g Cr; IGT (23 subjects), 11.9 +/- 6.7 mg/g Cr; DM (20 subjects), 12.8 +/- 5.7 mg/g Cr]. A 3-week diet therapy combined with physical exercise prescribed for 53 normotensive non-obese mild NIDDM patients resulted in improvement in glucose tolerance, concomitant with lowered systemic blood pressure and a decrease in urinary albumin excretion (SBP: 128.4 +/- 13.0 to 106.4 +/- 10.2 mm Hg, p less than 0.01; DBP: 78.2 +/- 10.8 to 66.0 +/- 8.0 mm Hg, p less than 0.01; U-albumin: 19.4 +/- 10.3 to 10.1 +/- 9.1 mg/day, p less than 0.01). However, glomerular filtration rate, renal plasma flow, filtration fraction and urinary beta 2-microglobulin excretion remained unchanged. From these results, we hypothesized that focal glomerular hyperperfusion increases urinary albumin excretion in patients with early NIDDM.     

Urinary excretion of alpha1-microglobulin and albumin in acute myocardial infarction. Correlation with plasma concentrations of troponin I and C-reactive protein

OBJECTIVES: Microalbuminuria associated with myocardial infarction (MI) is normally ascribed to glomerular factors, but could just as well involve pathophysiological processes located in other parts of the nephron, e.g. proximal tubules where plasma albumin normally filtered through the glomerulus is almost completely reabsorbed. The aims of this study were to establish whether impaired tubular reabsorption of filtered albumin contributes to microalbuminuria during MI, and whether the urinary excretion of protein relates to plasma levels of C-reactive protein (CRP) and troponin I. MATERIAL AND METHODS: We monitored plasma CRP and troponin I as well as the urinary excretion of albumin and alpha1-microglobulin, a low-molecular-weight plasma protein and marker of tubular proteinuria, in 18 patients with MI. RESULTS AND CONCLUSIONS: The urinary excretion of alpha1-microglobulin and albumin was significantly elevated in nine patients, and the urinary excretion of the two proteins correlated significantly. A decrease in tubular reabsorption of albumin may thus be at least one of the causative factors underlying microalbuminuria during MI. The plasma levels of CRP and troponin I were also significantly higher in this group of nine patients, and correlated with urinary protein excretion, suggesting an interrelationship between inflammatory response and tubular dysfunction. Extrarenal inflammatory processes seem to affect renal tubular function, thereby contributing to microalbuminuria during MI.     

Study on urinary splitting enzymes and proteins. III. Effect of non-ionic contrast medium on renal function

Renal toxicity of non-ionic contrast medium (iohexol) for drip infused pyelography (DIP) was studied in a randomized trial of nine patients with normal renal function. Urine samples were collected before and immediately after DIP, and analyzed for albumin, an index of glomerular permeability; gamma-glutamyl transpeptidase (gamma-GTP), a brush-border enzyme; N-acetyl-beta-glucosaminidase (NAG), a lysosomal enzyme; alpha 1 microglobulin (alpha 1MG) and beta 2 microglobulin (beta 2MG), an index to tubular proteinuria; and creatinine. The urinary excretion of enzymes and proteins was compared with urinary creatinine. Urinary excretion of gamma-GTP and NAG increased significantly (P less than 0.001, 0.02) after DIP. Urinary alpha 1 MG and beta 2-MG did not change significantly. The change of urinary albumin was mild. Our data suggest that non-ionic, low osmolal radiocontrast medium ioheol shows a lower renal tubular toxicity, and the brush-border enzyme gamma-GTP and lysosomal enzyme NAG are considered as a good index for renal tubular damage.     

Effects of protein meals on the urinary excretion of various plasma proteins in healthy subjects

To examine whether hemodynamic changes in response to acute protein loadings with different protein sources cause increases in urinary excretion of plasma proteins in healthy subjects, urinary excretions of various plasma proteins with various molecular radii and isoelectric points, namely albumin (Alb), IgG, IgG4, ceruloplasmin (CRL), and alpha2-macroglobulin (A2), were measured in healthy subjects after ingestion of a beef meal or of a tuna fish meal. Significant increases in urinary excretions of the negatively charged IgG4 and CRL and of the neutrally charged IgG were found in parallel with enhanced creatinine clearances after each protein ingestion. These renal responses returned to basal levels 9 h after the test. This finding suggests that in healthy subjects, the increase in glomerular filtration rate after acute protein loading caused selective enhancement of urinary excretions of plasma proteins with a molecular radius of approximately 55 A (the radius of IgG, IgG4, and CRL), irrespective of the charge barrier of the glomerulus. The increases in these three plasma proteins may be induced by leakage via the shunt pathway in the glomerulus, as proposed earlier (see text). In contrast, increases in urinary excretions of A2 and Alb were not found. The former finding may be explained by the possibility that A2 would not pass through this pathway, since the molecular radius of A2 (88 A) is larger than that of IgG, although the latter finding may be partially explained by preferential renal tubular reabsorption of Alb.     

Renal function in children with β-thalassemia major and thalassemia intermedia

In beta-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies demonstrating proteinuria, aminoaciduria, low urine osmolality, and excess secretion of the tubular damage markers, such as urinary N-acetyl-D-glucosaminidase (U(NAG)) and beta2 microglobulin, in patients with thalassemia. The object of this study was to analyze renal tubular and glomerular function in pediatric patients with beta-thalassemia and to correlate the renal findings to iron overload. Thirty-seven patients with beta-thalassemia major and 11 with thalassemia intermedia were studied. Twelve children without iron metabolism disorders or renal diseases served as a control group. No difference in blood urea nitrogen (BUN), serum creatinine, creatinine clearance, electrolytes, fractional excretion of sodium and potassium, and tubular phosphorus reabsorption was found. Serum uric acid was equal in the two groups, but its urine excretion was significantly higher in the thalassemic group. U(NAG) and U(NAG) to creatinine ratio (U(NAG/CR)) were elevated in all patients with thalassemia compared with the control group (p < 0.001) and were directly correlated to the amount of transfused iron but not to actual ferritin level. We found that renal tubular function is impaired in children with beta- thalassemia major and intermedia. It is not known whether these functional abnormalities would have any long-term effects on the patients. Further studies are needed, and means of preventing these disturbances should be sought.     

Effect of induced hypotension on damage to renal tubular cells

Urinary excretion of renal tubular cell enzymes, N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GTP) was evaluated to elucidate the renal cell damage before, during and after the induced hypotension with trimetaphan (TMP), nitroglycerin (TNG) and prostaglandin E1 (PGE1) under halothane-nitrous oxide-oxygen anesthesia in patients undergoing neurosurgery. Significant increases in excretion of NAG and gamma-GTP were observed in TNG group. Urinary excretion of these two enzymes in TMP group tended to increase, but its increases were not statistically significant. In PGE1 treated group, there was no tendency for urinary NAG excretion, while gamma-GTP excretion tended to decrease compared with that observed before the induced hypotension. Among these three drugs, TNG exerted the most significant effect on urinary excretion of both enzymes and TMP ranked next. Effect of PGE1 on urinary enzyme excretion was weakest. According to the general opinions, degree in stray of renal tubular cell enzyme into urine is thought to parallel with the injury of renal tubular cells. Therefore, the finding obtained in this study suggests that the induced hypotension with PGE1 has a less harmful effect on renal tubular cells.     

The mechanisms of exercise-induced proteinuria--relationship between urinary excretion of proteins and lactate after exhaustive exercise

Exercise-induced proteinuria is of the mixed glomerular-tubular type and has been thought to be due to increased glomerular permeability to macromolecular proteins in response to activation of the renin-angiotensin system and catecholamines and a reduction in renal hemodynamics. The excretion of the tubular type of proteins, however, can't be explained by the above mechanism. Two groups, consisting of subjects with the highest (H-alb, n = 20) and the lowest (L-alb, n = 20) excretion of albumin 30 min after exhaustive exercise were selected from a total of 69 normal male participants. No differences in VO2max, maxHR, changes in plasma angiotensin II, catecholamines, urine volume, or Ccr following exercise were observed between the two groups. The increase in blood lactate concentration immediately after exercise, increases in urinary excretion of lactate, pyruvate, alpha 1 M, beta 2 M, albumin and decrease in Cl- excretion 30 min after exercise in the H-alb group were significantly greater than in the L-alb group. The greater the urinary excretion of lactate and pyruvate, the greater the excretion of albumin, alpha 1M and beta 2M, and the less the urinary excretion of Cl-. The coefficient of correlation between the urinary excretion of lactate and beta 2M was 0.757, and between urinary excretion of albumin and beta 2M, 0.756 (p less than 0.001). These results suggest that exercise-induced organic acids and/or decrease in renal circulatory pH caused by organic acids may alter renal glomerular permeability and inhibit renal tubular reabsorption of low molecular weight proteins (alpha 1M, beta 2M). The permeability of the glomerular basement membrane (GBM) to macromolecular proteins may be altered by a reduction in the charge barrier of the GBM, which may be caused by the over-production of organic acids and a lower pH.     

Acute physiological changes in canine kidneys following exposure to extracorporeal shock waves

Nine anesthetized dogs were studied for four to five hours after administration of extracorporeal shock waves to one kidney, the contralateral organ serving as control. Urinary excretion of electrolytes, N-acetyl-beta-glucosaminidase (NAG) and kallikrein, clearances of creatinine, inulin and para-amino-hippuric acid (PAH), serum aldosterone level and plasma renin activity (PRA) were determined. On the exposed side there was a significant increase in urinary flow and urinary NAG excretion, and a significant fall in urinary osmolality. Effective renal plasma flow (ERPF) was reduced and glomerular filtration rate (GFR) unchanged, thus filtration fraction (FF) was increased. Extraction of PAH was significantly reduced compared with the control kidney. On the control side there was a significant increase in urinary flow and excretion of electrolytes, and a significant fall in urinary osmolality. GFR was increased and ERPF unchanged. FF therefore increased also on this side. The mean rise of PRA in the exposed kidney was higher than in the control kidney, the difference being not significant (p = 0.09). Our results may indicate a triggering of the renin-angiotensin system, and an effect on proximal tubular function following exposure of extracorporeal shock waves.     

Low molecular weight protein excretion in glomerular disease: a comparative analysis

We studied 23 children with steroid-sensitive nephrotic syndrome (SSNS), 21 children with steroid-resistant types of nephrotic syndrome and 32 children with other types of nephritis. Our controls were 43 apparently healthy children. We measured the urinary excretion of N-acetyl-β-D-glucosaminidase (NAG) and the low molecular weight (LMW) proteins β₂-microglobulin (B2M), retinol-binding protein (RBP), α₁-microglobulin (A1M) and urine protein 1 (UP1). Results for B2M were considered only for a urine pH greater than 6.0. Comparisons were made with urine albumin excretion, glomerular filtration rate (GFR) and tubular abnormalities in selected renal biopsy samples. We found that abnormalities of LMW protein excretion occurred in between 50% (B2M) and 88% (UP1) of all subjects. In children with SSNS, A1M (r = 0.73), UP1 (r = 0.65) and NAG (r = 0.54) excretion were significantly correlated with albumin excretion, but not RBP or B2M excretion. Increased fractional excretion of A1M, B2M and UP1 and increased plasma A1M were demonstrated in 9 children with SSNS, suggesting competition for tubular reabsorption with albumin, most marked for UP1. In the steroid-resistant nephrotic and nephritic syndromes, correlation with albumin was found for all proteins. In these subjects, RBP (r = 0.37), B2M (r = 0.42) and A1M (r = 0.28) were inversely correlated with GFR, but not UP1, NAG or albumin. We found that RBP excretion was significantly greater in the presence of severe tubular abnormalities in 11 children with recent renal biopsies, but not A1M, UP1 or NAG. We conclude that LMW proteinuria is common in children with glomerular disease, and does not necessarily imply a poor prognosis. Factors other than histologically proven tubular abnormality may account for elevated LMW protein excretion. RBP is the LMW protein most closely associated with structural abnormality and least affected by increasing albuminuria. Received January 31, 1996; received in revised form and accepted October 22, 1996     

Pathophysiology of proteinuria

Proteinuria is consequence of two mechanisms: the abnormal transglomerular passage of proteins due to increased permeability of glomerular capillary wall and their subsequent impaired reabsorption by the epithelial cells of the proximal tubuli. In the various glomerular diseases, the severity of disruption of the structural integrity of the glomerular capillary wall correlates with the area of the glomerular barrier being permeated by "large" pores, permitting the passage in the tubular lumen of high-molecular-weight (HMW) proteins, to which the barrier is normally impermeable. The increased load of such proteins in the tubular lumen leads to the saturation of the reabsorptive mechanism by the tubular cells, and, in the most severe or chronic conditions, to their toxic damage, that favors the increased urinary excretion of all proteins, including low-molecular-weight (LMW) proteins, which are completely reabsorbed in physiologic conditions. Recent clinical studies showed that in patients with glomerular diseases the urinary excretion of some HMW proteins [immunoglobulins G and M (IgG and IgM)] and of some LMW proteins, alpha1-microglobulin, beta2-microglobulin, correlates with the severity of the histologic lesions, and may predict, better than the quantity of proteinuria, the natural course, the outcome, and the response to treatment. It is suggested that some patients have already, at the time of clinical presentation, a structural damage of the glomerular capillary wall (injury of podocytes) and of the tubulointerstitium, the severity and scarce reversibility of which are reliably indicated by an elevated urinary excretion of HMW and LMW proteins.     

Complement activation products in the urine from proteinuric patients

The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding, i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.     

Study of lead exposure from automobile exhaust as a risk for nephrotoxicity among traffic policemen

BACKGROUND: Traffic policemen are the most exposed population to lead (Pb) from automobile exhaust. There has been increasing concern about the possible harmful effects of Pb from automobile exhaust on health of traffic policemen. However, no such study was concerned with the impact of Pb exposure on renal function among them. Therefore, we aimed to study the effect of Pb exposure from automobile exhaust on renal integrity among traffic policemen. METHODS: Markers of tubular damage [urinary excretion of beta(2)-microglobulin (beta(2)M), N-acetyl-beta-D-glucosaminidase (NAG), alkaline phosphatase (ALP) and gamma-glutamyl transferase (gamma-GT)], a marker of glomerular injury (albuminuria), and markers of glomerular filtration [serum creatinine, serum beta(2)M and blood urea nitrogen (BUN)] were determined in 43 traffic policemen (Pb-exposed group) and 52 matched healthy persons (control group). Pb levels in blood, urine, hair and nails were determined in the two groups as exposure indices of Pb. RESULTS: The results obtained show that the Pb-exposed group had higher Pb levels in blood, urine, hair and nails than the controls. Among the Pb-exposed group, Pb levels in blood, hair and nails showed significant and positive correlations with the duration of exposure to Pb which is measured as the duration of employment. Among the studied markers of kidney damage, urinary excretion of NAG and albumin were significantly higher in the Pb-exposed group than in the controls. Urinary excretion of NAG was positively correlated with duration of exposure, blood Pb and nail Pb. Urinary albumin was positively correlated with duration of exposure, blood Pb and hair Pb. The other markers of kidney damage were neither elevated nor correlated with exposure indices of Pb. CONCLUSION: Traffic policemen are liable to Pb toxicity, and the determination of Pb in blood, hair and nails are good markers of such toxicity. In these exposure conditions, kidney damage is possible. Such damage is both tubular and glomerular in nature and can be documented by determination of the urinary excretion of NAG and albumin.     

Urinary Excretion of Thromboxane and Markers for Renal Injury in Patients Undergoing Cardiopulmonary Bypass

Abstract: Urinary excretion of selected markers for renal injury, as well as urinary excretion rates of the thromboxane metabolite, 11–keto–thromboxane B₂ (llk–TXB₂), was studied in 36 male patients undergoing coronary bypass surgery using cardiopulmonary bypass (CPB). In all patients, excretion of both tubular (AT–acetyl–(β–D–glucosaminidase [βNAG]; α₁–microglobulin [α, –MG]) and glomerular markers (albumin [Alb]; transferrin [Trf]; immunoglobulin G [IgG]) sharply increased on Day 1 after CPB, and they remained elevated throughout the observation period of 5 days. Urinary excretion rates of 11k–TXB₂ markedly increased on Day 1 after surgery, and they rapidly decreased thereafter. In 12 of the 36 patients, a temporary increase of serum creatinine levels (>1. 30 mg/dl) was noted following surgery. A positive correla tion was found between serum creatinine levels and excretion of the tubular enzyme βNAG (r = 0. 36; p < 0. 05), but not between creatinine levels and α₁–MG or the glomerular markers. Furthermore, no correlation between urinary excretion of llk–TXB₂ and any of the urinary markers for renal injury could be detected. Our data do not strengthen the hypothesis that acute renal injury observed during CPB is related to exaggerated thromboxane biosynthesis in these patients. Monitoring of urinary markers for incipient renal damage, particularly excretion of βNAG, might be of additional diagnostic value for detection of otherwise subclinical renal injury in patients undergoing CPB.     

The renal uptake of proteins: a nonselective process in conscious rats

The selectivity of the renal reabsorption of proteins has been investigated by competition experiments in conscious rats. The animals were intravenously injected with increasing doses of proteins over a wide range of net charge and size, including lysozyme, cytochrome C, metallothionein, beta 2-microglobulin, retinol-binding protein, albumin and IgG. The urinary excretion of exogenous proteins injected concomitantly (human beta 2-microglobulin, retinol-binding protein, albumin and/or egg white lysozyme depending on the experiment) and of rat beta 2-microglobulin, albumin and IgG was determined with specific immunoassays. The results show that low molecular weight cationic proteins and low or high molecular weight anionic proteins can increase each other's urinary excretion. Several observations strongly suggest that these effects result from a competitive inhibition of renal uptake. The phenomenon is dose-related in most cases and, as evidenced by cytochrome C injection, transient, reproducible and saturable. In addition, the injected proteins induce a tubular type proteinuria irrespective of their net charge and size. In the case of cationic proteins, this finding excludes the possibility of an enhanced glomerular permeability due to a partial neutralization of the glomerular polyanion which, as demonstrated with protamine sulfate, entails a glomerular type proteinuria. These quantitative data on the mutual inhibition of renal uptake of a wide spectrum of specific proteins lead us to challenge the concept of charge- and size-selective tubular reabsorption of proteins, and to postulate that proteins filtered through the glomeruli are taken up by common tubular endocytotic sites irrespectively of their physicochemical features. As demonstrated by the ability of beta 2-microglobulin and IgG to inhibit the uptake of lysozyme, the affinity of a protein for reabsorption sites is not simply related to its size and net positive charge. Evidence is also presented that proteins, when administered intravenously at high doses, induce a lysosomal enzymuria most likely reflecting a stimulated exocytosis.     

Factors causing variation in urinary N-nitrosamine levels in enterocystoplasties

OBJECTIVE: To evaluate changes in protein leakage in the glomerular filtration barrier, and in the ability of the tubule to reabsorb proteins during and after acute urinary retention (AUR). PATIENTS AND METHODS: Glomerular and tubular function was investigated in 24 men during AUR (mean age 68 years, mean retention time 31 h and mean retention volume 1140 mL) who were then followed for 6 months by measuring the urinary excretion of glomerular and tubular proteins, and the glomerular filtration rate (GFR). Retention was relieved by inserting a suprapubic catheter and the cause of retention treated one month later. No patient had a previous renal disease or diabetes. RESULTS: During AUR, and after 1 and 6 months, albuminuria was detected in 100%, 92% and 54% of patients, and increased excretion of alpha1-microglobulin in 52%, 36% and 58%, of IgG in 79%, 58% and 40%, and of IgG4 in 67%, 42% and 20%, respectively. The mean GFR was normal during retention and during the follow-up. CONCLUSION: AUR causes disturbances in both the glomerular filtration and tubular reabsorption of proteins. Albuminuria and increased excretion of IgG, IgG4 and alpha1-microglobulin occurred in most patients during AUR. After relieving retention, the albuminuria and elevated alpha1-microglobulin excretion persisted, indicating slight glomerular dysfunction and a permanent defect in the proximal tubule to reabsorb proteins. This could be caused partly by previous chronic obstruction. AUR should be relieved immediately and the basic cause treated effectively to prevent further deterioration of renal function.     

Urinary protein excretion and renal function in young people with diabetes mellitus.

To detect early renal involvement in young diabetic patients (IDDM), urinary protein excretion and renal function were examined in 110 patients aged 5.9-25.0 years. Clearances of inulin and PAH were determined as well as albumin (Alb), IgG, N-acetyl-beta-D-glucosaminidase (NAG) and creatinine (Cr) excretion rates (UV). The patients were grouped according to IDDM duration (2- less than 5, 5-10 and greater than 10 years) and albumin excretion rate (non-albuminuria less than 20, microalbuminuria 20-200, and albuminuria greater than 200 micrograms/min per 1.73 m2). Four patients had overt albuminuria, 17 microalbuminuria (equally distributed among the duration groups). Grouped according to albumin excretion rate, the mean GFR was increased in those without albuminuria but 'normalized' in patients with microalbuminuria/albuminuria. Grouped according to albumin excretion rate and the duration of the disease, the non-albuminuric patients with IDDM for greater than 10 years had a lower GFR than those with a shorter duration of IDDM. The patients with microalbuminuria/albuminuria and IDDM for less than 5 years had a reduced GFR. Patients with increased NAG excretion rate had lower Na excretion rate, lower fractional Na excretion and greater creatinine excretion than those with normal NAG excretion. Albumin excretion correlated with IgG excretion, but also with NAG excretion. Our results suggest that early albuminuria in IDDM is of both glomerular and tubular origin. The hyperfiltration declines with increasing albumin excretion but also with the duration of the disease.     

Influence of albumin infusion on the urinary excretion of beta2-microglobulin in patients with proteinuria

Most filtered proteins are reabsorbed by the renal proximal tubule by a mechanism that involves binding to the brush border membrane and endocytosis. Under normal conditions the low-molecular-weight protein beta2-microglobulin (beta2M), which is used to detect tubular injury, is reabsorbed almost completely. However, in proteinuric patients an increased urinary excretion of beta2M may not simply reflect tubular damage but might also result from a decreased tubular reabsorption due to competitive mechanisms. To examine the magnitude of such an effect we have studied the renal effects of albumin infusion (40 g in 2 h of a 20% solution) in 10 patients with a glomerular disease and proteinuria >3.5 g/24 h. Before, during and after albumin infusion the GFR (inulin clearance), RPF (PAH clearance), blood pressure and the urinary excretion of albumin, IgG, transferrin and beta2M were measured. Albumin infusion resulted in a slight decrease of the GFR (72 +/- 11 ml/min before and 67 +/- 10 ml/min after infusion), an increase of the RPF (379 +/- 66 ml/min before and 445 +/- 83 ml/min after), a decrease of the filtration fraction (0.20 before and 0.17 after), and hemodilution. After infusion the urinary excretion of albumin increased from 4.5 +/- 0.7 to 8.4 +/- 1.6 mg/min (p < 0.05). The urinary excretion of IgG and transferrin increased, probably reflecting a change in glomerular size-selectivity. In contrast, the urinary excretion of beta2M did not change significantly (baseline 12 +/- 5 microg/min, end 13 +/- 6 microg/min, percentage change 16.8 +/- 11%). To correct for changes in tubular load we calculated the fractional reabsorption of beta2M. The initial rise in albuminuria during infusion did not affect fractional tubular reabsorption (Delta%: 0. 72 +/- 0.52%, median 0.005%). In the period after infusion a slight decrease was noted (median -0.33%, p < 0.01). A decrease in the fractional reabsorption was particularly observed in patients with pre-existing tubular damage. In conclusion: infusion of albumin in proteinuric patients has no clinically relevant effect on the tubular reabsorption of beta2M. Therefore, beta2M is useful as a parameter to detect tubular injury and alterations in tubular handling of proteins in patients with proteinuria and glomerular diseases.