Spontaneous decline in exercise-induced proteinuria during a 100-mile triathlon

To study the effect of prolonged exercise on glomerular permeability and proteinuria, we collected serial urine samples from six athletes during a 100-mile triathlon. Urine collected just before, at the midpoint of, and immediately after the race was analyzed for creatinine by an automated chemistry analyzer, pack method, and for microalbumin by radioimmunoassay. By midrace, the urinary albumin-creatinine ratio increased from the prerace mean +/- SEM of 3.5 +/- 0.5 to 38.3 +/- 11.7 mg/g. The ratio then declined to 12.5 +/- 2.7 mg/g by the end of the race (P less than .04). Similarly, the urinary albumin level increased significantly from 5.9 +/- 0.7 to 80.5 +/- 26.8 micrograms/mL by midrace, followed by a decline to 39.2 +/- 12.9 micrograms/mL. The initial increase in albuminuria was expected and reflects the increase in exercise-induced cardiac output and glomerular permeability. The subsequent decline in albuminuria and albumin-creatinine ratio, despite continued exercise, was unexpected and indicates a decrease in glomerular permeability. Further study is warranted to determine the mechanism of this apparently protective renal response to prolonged exercise.     

Renal glomerular and tubular impairment during strenuous exercise in young women

Creatinine, total protein, albumin and beta2-microglobulin were measured in the urine of fifteen healthy women before and after strenuous short-term exercise. The heavy intermittent load produced an increased urinary excretion of total protein, albumin and beta2-microglobulin, while creatinine was unaffected. The renal clearance of albumin and beta2-microglobulin showed very high values after stopping the exercise. However, 45 min after the end of exercise, total protein returned to initial values while albumin and beta2-microglobulin remained high. The urinary ratio between beta2-microglobulin and albumin is higher in urine collected after exercise than in normal proteinuria. This implies that post-exercise proteinuria is of glomerular and tubular origin.     

Glomerular filtration and tubular reabsorption of albumin in preproteinuric and proteinuric diabetic rats.

Microalbuminuria (26-250 mg/d) is considered to be an indicator of incipient diabetic nephropathy in humans in insulin-dependent diabetes (IDD). However, before microalbuminuria is observed, glomerular alterations, such as glycosylation of the glomerular basement membrane and glomerular hyperfiltration, in IDD may result in increased filtration of albumin before any observed increase in albumin excretion. Glomerular and tubular albumin kinetics were examined in streptozotocin (65 mg/kg body wt, i.v.) diabetic, Munich-Wistar rats at 7-10 (untreated) and 50-70 d (poorly controlled with small doses of insulin) after the onset of diabetes and compared with nondiabetic controls. Additional rats in each condition received acute lysine treatment to prevent tubular protein reabsorption. Urinary albumin excretion and nonvascular albumin distribution volumes were measured in the renal cortex and compared with morphometric measurements of interstitial space and the proximal tubule to assess intracellular uptake of albumin in the proximal tubule. Urinary albumin excretion under anesthesia was not different in 7-10-d IDD versus controls (19 +/- 3 vs. 20 +/- 3 micrograms/min) but increased in the 50-70-d IDD (118 +/- 13 micrograms/min, P < 0.05). Lysine treatment resulted in increased albumin excretion compared with respective nontreatment in 7-10-d IDD (67 +/- 10 micrograms/min, P < 0.05) but not in controls (30 +/- 6 micrograms/min) or in 50-70-d IDD (126 +/- 11 micrograms/min). Glomerular filtration rate was increased both in 7-10-d IDD (2.7 +/- 0.1 ml/min, P < 0.05) and in 50-70-d IDD (2.6 +/- 0.1 ml/min, P < 0.05) compared with control (2.2 +/- 0.1 ml/min). Calculated urinary space albumin concentrations increased early in IDD with 2.5 +/- 0.4 mg% in 7-10-d IDD and 4.9 +/- 0.6 mg% in 50-70-d IDD compared with control (1.4 +/- 0.3 mg%). The increase in filtration of albumin is in excess of that attributable to hyperfiltration before increased albumin excretion early in diabetes. In 50-70-d IDD, absolute tubular reabsorption of albumin is decreased, correlating to the decrease in brush border height of the proximal tubule.     

The effect of exercise on urinary excretion of different size proteins in patients with insulin-dependent diabetes mellitus

To examine whether exercise-induced proteinuria in diabetes is dependent upon the size of the excreted protein, we measured urinary excretion of beta 2-microglobulin, kappa light chains, albumin and IgG before and after 20 min of moderate ergometer exercise in 34 patients with insulin dependent diabetes mellitus (IDDM) and in eight healthy control subjects. Seventeen patients with newly diagnosed IDDM and 17 patients (seven of which had elevated albumin excretion rate) with longstanding IDDM were studied. Exercise did not significantly influence protein excretion in control and newly diagnosed IDDM subjects. In contrast, exercise enhanced excretion of beta 2-microglobulin (p less than 0.05-0.01), kappa light chains (p less than 0.001), albumin (p less than 0.005-0.001) and IgG (p less than 0.01-0.001) in patients with long-standing IDDM independently of whether the patient had proteinuria in the resting state or not. In conclusion, proteinuria induced by moderate exercise is not observed in the early stages of IDDM, and is independent of the size of the excreted protein. Therefore, moderate exercise does not appear to influence the size selectivity of the glomerular capillary wall in patients with longstanding IDDM.     

Decreased (Ca2++Mg2+)-Stimulated ATPase Activity in Erythrocyte Membranes from Polycythemia Vera Patients

Urinary albumin and β₂,-microglobulin excretion rates were measured by radioimmunological methods in 60 children and adolescents at rest and during physical exercise. The geometric mean of the albumin excretion rate was 4.4 (μg/min)/m² at rest and rose to 7.9 (μg/min)/m² during exercise (P<0.001), while the geometric mean of β₂-microglobulin was 31.9 (ng/min)/m² at rest and 26.2 (ng/min)/m² during exercise. These results indicate that exercise-induced proteinuria is of a glomerular leaking type. The albumin excretion rate was not dependent on the age or sex of the subjects. The exercise-induced albuminuria correlated weakly but significantly with the maximal blood pressure (r = 0.27; P<0.05) and with the physical fitness of the subjects (r = 0.28; P<0.05).     

Increased urinary excretion of digoxin-like immunoreactive substance by insulin-dependent diabetic patients: a linkage with hypertension?

Excretion of digoxin-like immunoreactivity (DLIS) was measured by RIA in timed overnight urine collections from 91 normotensive nondiabetic subjects and 104 normotensive insulin-dependent diabetic (IDDM) patients. The mean +/- SD DLIS excretion rate for the diabetic patients significantly exceeded that for the controls (73 +/- 41 vs 63 +/- 36 pg/min, P = 0.024). In both groups, the mean DLIS excretion rates for men were significantly higher (P = 0.0014, P = 0.006) than for women. In the controls, the DLIS excretion rate significantly correlated with the urinary excretion rate of creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05), and with the subjects' body weight (P less than 0.01), body mass index (P less than 0.05), and systolic blood pressure (P less than 0.05). In the diabetics, the DLIS excretion rate was significantly correlated with body weight (P less than 0.05) and with urinary excretion rates for albumin (P less than 0.01), creatinine (P less than 0.01), Na+ (P less than 0.05), and K+(P less than 0.05). Our data indicate that: (a) increased amounts of a cardiac glycoside-like substance (or a group of substances) are excreted in the urine of IDDM patients; (b) the urinary excretion of DLIS seems to depend on glomerular filtration rate and physiocochemical properties of glomerular membrane, as well as on subjects' body mass; and (c) because cardiac glycoside-like substances may increase peripheral vascular resistance, increased urinary excretion of DLIS by IDDM patients may indicate a tendency to develop hypertension.     

Tubular secretion of Tamm-Horsfall protein in type 1 (insulin-dependent) diabetes mellitus using a simplified enzyme linked immunoassay.

The relationship between glomerular and tubular dysfunction and metabolic control in type 1 diabetes was studied. To that end the urinary excretion rates of albumin and Tamm-Horsfall protein as well as HbA1c levels were measured in 58 patients with different degrees of diabetic nephropathy and in 76 apparently healthy subjects matched for sex and age. The urinary Tamm-Horsfall protein levels were measured by a simplified enzyme linked immunoassay. The intra- and interassay variations were 8.9% and 13.6%, respectively. The intraindividual variation was 41% and the sensitivity of the assay was 4 micrograms/l. The Tamm-Horsfall protein excretion rate was 42.1 x/2.0 micrograms/min (geometric mean x/tolerance factor) in the diabetic patients compared to 34 x/1.9 micrograms/min in the control subjects (NS). The diabetic patients had higher albumin excretion rate (38.5 x/7.3 micrograms/min) than the control subjects (4.7 x/2.3 micrograms/min; P less than 0.001). By using multivariate analysis of variance, HbA1c level was found to be the only independent variable associated with Tamm-Horsfall protein excretion rate in diabetic patients (r = -0.28; P = 0.04), while no relationship was found between Tamm-Horsfall protein excretion rate and age, age at onset and duration of diabetes, gender, serum creatinine, diuresis, urinary albumin excretion rate, systolic and diastolic blood pressure levels and antihypertensive treatment. The urinary albumin excretion rate was associated with diastolic blood pressure (r = 0.34; P = 0.02) but not with HbA1c levels when testing the above variables by multivariate analysis of variance. In conclusion, these results may indicate a lack of relationship between glomerular and tubular dysfunction. The former was influenced only by diastolic blood pressure levels and the latter only by the degree of metabolic control. However, the correlations were weak and do not provide any insight into what is actually responsible for glomerular and tubular dysfunction.     

Effects of acute, heavy-resistance exercise on urinary peptide hormone excretion in humans.

To examine physical exercise-related changes in urinary excretion of protein/peptide hormones and to correlate modifications with the general increase in post-exercise proteinuria, urine C-peptide, insulin and insulin-like growth factor-I (IGF-I) and their plasma concentrations were measured. Plasma and urinary C-peptide, insulin and IGF-I before (Bex) and at the end (Eex) of physical exercise (a 2.5-hour competition, 102 km) were analysed in 20 young cyclists. At Eex compared with Bex, concentration of urinary C-peptide decreased slightly but significantly (21.3 +/- 2.7 vs. 13.5 +/- 1.7 nmol/l), but urinary insulin and urinary IGF-I concentrations significantly increased at Eex (92.5 +/- 4.2 vs. 131.4 +/- 15.7 pmol/l and 10.0 +/- 2.1 vs. 33.6 +/- 3.8 pmol/l, respectively). Plasma insulin and plasma C-peptide significantly decreased, whereas plasma IGF-I was unchanged. Urinary concentrations of total proteins and creatinine significantly increased. Both Eex urinary C-peptide/urinary protein and urinary C-peptide/urinary creatinine ratios were significantly reduced. The correlation between C-peptide and insulin in plasma was confirmed at Bex as well as Eex, but in urine only at Bex. An increased renal tubular reabsorption of C-peptide at the end of exercise might be suggested, but the expected values considering creatinine excretion were almost three times less. The Eex urinary insulin concentration was higher than expected, considering the circulation levels, but lower when compared with the expected concentration considering creatinine excretion. Physical exercise proteinuria, related to an increased protein filtration and a saturation of the mechanisms responsible for the reabsorption, does not appear similar for all peptide hormones.     

Acute and long-term effect of antihypertensive treatment on exercise-induced albuminuria in incipient diabetic nephropathy

The aim of the study was to clarify whether antihypertensive treatment could affect the systolic blood pressure (SBP) and urinary albumin excretion (UAE) in diabetics during exercise (450 kpm/min, followed by 600 kpm/min, 20 min each). Young male insulin-dependent diabetics with normal UAE (n = 9) and diabetics with incipient nephropathy (n = 7) were examined in an acute study. Five patients with incipient diabetic nephropathy participated in a long-term study. Incipient diabetic nephropathy is defined as persistently elevated UAE (greater than 15 micrograms/min), but no clinical proteinuria. In the acute study, using placebo/metoprolol 10 mg i.v. in patients with normal UAE, the maximal SBP at 600 kpm/min was reduced by 17 mmHg +/- 10 (SD) (2p less than 1.0%) and the maximal SBP at 600 kpm/min in the patients with incipient nephropathy was reduced by 15 mmHg +/- 11 (SD) (2p less than 1.0%). However, no difference was observed in UAE, in patients with normal UAE or those with incipient nephropathy. Five of the patients with incipient nephropathy were followed with repeated exercise tests before and during 2.6 years of antihypertensive treatment, using metoprolol 200 mg/24 h and subsequently also hydroflumethiazid 25 mg/24 h. The maximal SBP at 600 kpm/min at the end of the study compared to the pretreatment level was reduced by 38 mmHg +/- 12 (SD) (2p less than 1.0%), and furthermore the exercise-induced elevated UAE was reduced by 61% +/- 29 (SD) (2p = 2.0%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal handling of Zn-alpha2-glycoprotein as compared with that of albumin and the retinol-binding protein.

An unusual electrophoretic pattern of the urine from a patient with malignant lymphoma was observed. One of the major proteins, identified Zn-alpha2-glycoprotein (Zn-alpha2), was isolated from the urine and partly characterized. The Stokes radius was found to be 3.24 nm and the molecular weight, determined by sodium dodecyl sulfate polyacrylamide electrophoresis, 42,000. The plasma level in healthy individuals was 39 +/- 7 (SD) mg/liter. In 12 of 25 healthy individuals, Zn-alpha2 was measurable in the urine and was found to be 1.0 +/- 1.1 mg/liter. In 23 patients with chronic glomerulonephritis (CGN), in 9 with proximal tubular dysfunction (PTD), in 23 with various renal diseases (VRD), and in 10 with malignant lymphoma, the plasma level and the urinary excretion were compared with those of albumin (mol wt 67,000) and of the retinol-binding protein (RBP, mol wt 21,000). A close correlation was found between the urine-to-plasma (U/P) ratios of Zn-alpha2 and albumin in the patients with CGN, whereas in the PTD patients the U/P ratios of Zn-alpha2 and RBP were correlated. No significant renal arteriovenous difference in Zn-alpha2 could be demonstrated. The Zn-alpha2 excretion was increased also in two patients with malignant lymphoma and proteinuria of a tubular pattern. The plasma Zn-alpha2 varied inversely with the glomerular filtration rate in the patients with renal disease, but was normal in those with malignant lymphoma. The results are consistent with the assumption of a sieving coefficient of Zn-alpha2, substantially exceeding that of albumin, but notably lower than that of smaller low-molecular-weight proteins. An increased excretion of Zn-alpha2 may be due to increased glomerular permeability as well as to defective proximal tubular reabsorption.     

Atrial natriuretic peptide increases albuminuria in type I diabetic patients: evidence for blockade of tubular protein reabsorption

BACKGROUND: It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type I diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved. PATIENTS AND METHODS: We have studied the effects of ANP in nine microalbuminuric IDDM patients. After obtaining baseline parameters, ANP was infused over a 1-h period (bolus 0.05 microgram kg-1, infusion rate 0.01 microgram kg-1 min-1). Renal haemodynamics, sodium and water clearance and tubular protein handling were studied. RESULTS: The glomerular filtration rate (GFR) increased from 116.4 +/- 8.9 to 128.3 +/- 8.8 mL min-1 1.73 m-2, whereas the effective renal plasma flow (ERPF) decreased from 534.3 +/- 44.3 to 484.9 +/- 33.3 mL min-1 1.73 m-2 (P < 0.05). As a result, the filtration fraction was significantly higher during infusion of ANP. ANP attenuated proximal tubular sodium reabsorption. Urinary albumin excretion rose from 87.57 +/- 21.03 to 291.40 +/- 67.86 micrograms min-1 (P < 0.01). Changes in the urinary excretion of beta 2-microglobulin and free kappa light chains were more marked, the excretion of beta 2-microglobulin increasing from 0.28 +/- 0.21 to 51.87 +/- 10.51 micrograms min-1 (P < 0.01), and of free kappa-light chains from 4.73 +/- 1.74 to 46.14 +/- 6.19 micrograms min-1 (P < 0.01). CONCLUSIONS: The observed rise in albuminuria during infusion of ANP does not simply reflect a change in glomerular pressure, but might at least partly result from an attenuation of tubular protein reabsorption.     

Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of β2-microglobulin, albumin, and total protein

A low molecular weight beta(2)-globulin (beta(2)-microglobulin), albumin, and total protein were measured in concentrated 24-hr urine specimens from 20 healthy subjects and 30 patients with clinical proteinuria of glomerular or tubular type. Classification of proteinuria was made on the basis of clinical diagnosis and size distribution of urinary proteins after gel chromatography. The molecular radii (Stokes' radii) of beta(2)-microglobulin and albumin, estimated by gel chromatography, were 15 A and 35 A.The average 24-hr urinary excretion in healthy subjects was 0.12 mg for beta(2)-microglobulin, 10 mg for albumin, and 80 mg for total protein. The patients with renal glomerular disorders had normal or only somewhat increased excretion of beta(2)-microglobulin, despite considerably increased excretion of albumin and total protein. Most of the patients with tubular dysfunction excreted large amounts of beta(2)-microglobulin, although they excreted normal or only slightly increased amounts of albumin and only moderately increased quantities of total protein. Consequently, the ratio or urinary albumin/urinary beta(2)-microglobulin was high in glomerular proteinuria (1100: 14,200), intermediate in normal proteinuria (33: 163), and low in tubular proteinuria (1.0: 13.3). Determinations of urinary clearances of beta(2)-microglobulin and albumin in four healthy subjects and 11 patients indicated that increased excretions of the two proteins were associated with increased clearances. The results suggest that quantitative determinations of urinary beta(2)-microglobulin and urinary albumin may be useful for detecting disorders of the renal handling of plasma proteins. The findings also seem to suggest a selective tubular reabsorption of the two proteins.Estimates on sera revealed a close correlation between serum levels of beta(2)-microglobulin and creatinine and also a greatly raised serum concentration of beta(2)-microglobulin after bilateral nephrectomy.     

The gelatin-derived plasma substitute Gelofusine causes low-molecular-weight proteinuria by decreasing tubular protein reabsorption

PURPOSE: Proteinuria is frequently encountered in patients in the intensive care unit, most likely as a result of renal tubular cell injury. It has been reported that gelatin-derived plasma substitutes contribute to an increase in renal protein excretion. The aim of this study was to investigate the magnitude and the mechanism of the proteinuric effect of Gelofusine, a modified gelatin. MATERIALS AND METHODS: In six healthy male subjects, renal hemodynamics and urinary protein excretion were measured before and after infusion of 330 mL of Gelofusine. RESULTS: Gelofusine had a minor effect on blood pressure, glomerular filtration rate, effective renal plasma flow, and on urinary excretion of immunoglobulin, and albumin. In contrast, there was a major increase in the urinary excretion of the low-molecular-weight proteins beta2-microglobulin (from 0.06 +/- 0.04 to 43.52 +/- 11.75 microg/min; P <.01) and alpha1-microglobulin (from 11 +/- 8 to 72 +/- 24 microg/min; P <.01). The urinary excretion of N-acetyl-beta-D-glucosaminidase (beta-NAG) remained unchanged, suggesting that there was no significant renal tubular cell injury. CONCLUSIONS: When analyzing proteinuria in patients in the intensive care unit it should be considered that Gelofusine increases the urinary excretion of proteins, in particular those of low molecular weight. This effect is most likely due to competitive inhibition of tubular protein reabsorption.     

Low concentrations of intravenous polygelines promote low-molecular weight proteinuria

BACKGROUND: Previously we observed that atrial natriuretic peptide (ANP)-induced albuminuria was accompanied by an increase in urinary excretion of the low-molecular weight protein (LMW protein) beta2-microglobulin (beta2-m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel (Hoechst, Behring-Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel or Gelofusine (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel on proteinuria. In addition, we have reassessed the effects of ANP. MATERIALS AND METHODS: We measured urinary beta2-microglobulin (beta2-m) and albumin excretion in healthy volunteers after infusion of a high-dose pure Haemaccel (0.04 mL kg(-1) min(-1) for 60 min), a low-dose Haemaccel (0.01 mL kg(-1) min(-1) for 60 min followed by infusion of 0.02 mL kg(-1) min(-1) for 60 min) and a low-dose Gelofusine (dose comparable to the low-dose Haemaccel). In addition we performed similar studies using ANP dissolved in saline and Haemaccel. RESULTS: Infusion of Haemaccel caused a dose-dependent increase in urinary excretion of beta2-m. There were no differences between Haemaccel and Gelofusine. After infusion of ANP dissolved in Haemaccel urinary beta2-m excretion increased from 0.05 +/- 0.03 microg min(-1) to 27 +/- 10 microg min(-1) and urinary albumin excretion increased from 4.5 +/- 1.1 microg min(-1) to 9.7 +/- 6.3 microg min(-1) (P<0.05). During ANP + saline infusion, urinary beta2-m excretion did not change, whereas the urinary albumin excretion increased from 5.3 +/- 1.5 microg min(-1) to 7.9 +/- 2.4 microg min(-1) (P<0.05). CONCLUSIONS: Our study demonstrates that even low doses of the polygelines Haemaccel and Gelofusine profoundly attenuate the tubular reabsorption of the low-molecular weight protein beta2-m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.     

Urine protein excretion in acute pancreatitis

The mechanism of the increased renal clearance of amylase and the amylase to creatinine clearance ratio (CAM/CCR) in acute pancreatitis remains controversial with both renal tubular dysfunction and altered glomerular permeability being invoked as explanations. To differentiate between these mechanisms, we investigated the quantity and character of protein excretion in 10 patients with pancreatitis. For a short period of time, seven of 10 patients had mild proteinuria with a mean protein excretion rate of 230 +/- 154 mg/24 hr. Proteinuria decreased in 9/9 survivors to 17 +/- 18 mg/24 hr. Albumin excretion rate initially was minimally increased in 10/10 patients with a mean of 61 +/- 40 mg/24 hr, decreasing during recovery in 8/9 survivors to 10.9 +/- 10.4 mg/24 hr (P less than 0.01). Electrophoresis of urine obtained during the acute phase consistently showed a low molecular weight proteinuria pattern that cleared with recovery. Twenty-one of 22 urinary samples with an elevated CAM/CCR had a low molecular weight protein pattern. All the above findings can be explained by alterations in renal tubular reabsorption of proteins without changes in glomerular permeability. In 2/4 patients a low molecular weight protein was present in urine specimens from the acute phase that was not present in highly concentrated urine specimens from the recovery period. This raises the possibility that an abnormal low molecular weight protein enters the serum in acute pancreatitis, which, after glomerular filtration, produces the renal tubular malfunction found in acute pancreatitis.     

Factors affecting the urinary excretion of albumin in insulin-dependent diabetes

To determine the specificity of the urine excretion of albumin as a measure of glomerular permeability in early insulin-dependent diabetic nephropathy, the effect of variable glomerular filtration and urine flow rates on albumin, beta 2-microglobulin excretion, and the fractional renal clearance of neutral dextran (Stokes Einstein Radius 24-46 A) was examined. Five insulin-dependent diabetic subjects with normal glomerular permeability (albumin excretion less than 30 micrograms/min) and one with elevated albumin excretion (195 micrograms/min) were studied pre and post strict glucose control with constant subcutaneous insulin infusion for 7 days. The albumin excretion in the 5 subjects never exceeded 30 micrograms/min during wide variations in glomerular filtration and urine flow rates. A positive correlation between beta 2-microglobulin excretion and urine flow (r = 0.81), and glomerular filtration (r = 0.77) rates was observed. In contrast, albumin excretion showed no correlation, indicating different factors affect the excretion rate of albumin and beta 2-microglobulin. Therefore, elevated albumin excretion (greater than 30 micrograms/min) in insulin-dependent diabetes is due to increased glomerular permeability and not changes in glomerular filtration and urine flow rates, and the albumin/ beta 2-microglobulin ratio may not be a valid indicator of changing glomerular permeability. The fractional neutral dextran clearances remained unchanged with variation in glomerular filtration and urine flow rates. The sieving curve was identical in all subjects for neutral dextran 40 A, the size of albumin, suggesting that reduced glomerular charge selectivity may contribute to increased albuminuria in progressive diabetic glomerulosclerosis.     

Determinants of intra-individual variation in kidney function in normoalbuminuric insulin-dependent diabetic patients: importance of atrial natriuretic peptide and glycaemic control.

1. In order to investigate the modulation of kidney function in insulin-dependent diabetes mellitus, intraindividual variation in glomerular filtration rate, renal plasma flow, urinary albumin excretion rate and mean arterial blood pressure was assessed in 22 normoalbuminuric patients [age 31 +/- 8 years, duration of diabetes 9 +/- 5 years, mean arterial blood pressure 90 +/- 5 mmHg (means +/- SD), urinary albumin excretion rate 5.4 x/divided by 1.6 micrograms/min]. The variation in these parameters was calculated from the results of two clearance studies (continuous infusion of [125I]-iothalamate and 131I-hippuran as markers for glomerular filtration rate and renal plasma flow, respectively) and was subsequently analysed in relation to individual variation in plasma concentrations of atrial natriuretic peptide, arginine vasopressin, angiotensin II and aldosterone and measures of glycaemic control. 2. Simple correlation analysis showed a significant association between intra-individual variation in glomerular filtration rate and atrial natriuretic peptide (sigma = 0.66, P = 0.003). Besides variation in atrial natriuretic peptide, multiple regression analysis identified variation in glycated haemoglobin (P = 0.026) and arginine vasopressin (P = 0.057) as variables having independent association with variation in glomerular filtration rate [R2 with the three variables included (adjusted for degrees of freedom) = 0.50, analysis of variance: P = 0.002]. 3. With respect to variation in renal plasma flow, differences in fasting blood glucose concentration and mean arterial blood pressure were suggested as determinants (R2 = 0.36, analysis of variance: P = 0.009). 4. Variation in urinary albumin excretion rate (after log transformation) was statistically associated with variation in glycated haemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary albumin excretion in normal and diabetic subjects

Using an albumin radio-immuno-assay, urinary albumin concentration and excretion rate have been measured in diabetics and control subjects overnight, after several hours ordinary activity and during two successive one hour periods of recumbency. The urine albumin concentration was relatively constant throughout each of the four collection periods. Variations in albumin excretion rate were directly related to changes in urine flow. In assessing changes in urinary albumin, concentration and urine flow should be reported as well as the calculated albumin excretion rate.In the diabetics, selected for absence of clinical proteinuria, the mean concentration of albumin did not differ significantly from that of the controls. The overnight albumin excretion rate was higher in the diabetics, but this was due to the greater volume of urine.     

Amelioration of glomerular injury in doxorubicin hydrochloride nephrosis by dimethylthiourea.

The hydroxyl radical scavengers dimethylthiourea (DMTU), sodium benzoate, and dimethylsulfoxide (DMSO) were administered to rats before doxorubicin hydrochloride (ADR) (5 mg/kg, IV) to probe the role of free radicals in mediating proteinuria in doxorubicin hydrochloride nephrosis (AN). Because ADR stimulates free radical production, the role of renal glutathione was also evaluated; glutathione metabolism is involved in tissue detoxification processes. DMTU administration to rats with AN caused a significant (p less than 0.01) reduction in their proteinuria after 7 days (52.84 +/- 13.21 mg/24 hours) when they were compared with ADR controls (155.81 +/- 20.16 mg/24 hours). In similar fashion, their urine albumin excretion was also significantly reduced when compared with that of ADR controls (11.13 +/- 2.75 mg/24 hours vs 32.08 +/- 4.14 mg/24 hours; p less than 0.01). DMTU-treated rats also had significantly (p less than 0.001) reduced urinary protein and albumin excretion at 14 days when compared with rats that received ADR alone. The urinary excretion of lysozyme and N-acetyl-glucosaminidase, markers of renal tubular injury, were significantly increased after 7 or 14 days in rats with AN, despite DMTU treatment. Creatinine clearance was significantly reduced (p less than 0.05) in rats receiving ADR alone (0.223 +/- 0.011 ml/min/100 gm) when compared with that in normal controls (0.331 +/- 0.027 ml/min/100 gm) or DMTU-treated rats (0.289 +/- 0.035 ml/min/100 gm). Unlike DMTU, neither sodium benzoate nor DMSO reduced proteinuria in rats with AN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative assessment of urinary protein and enzyme excretion--a diagnostic programme for the detection of renal involvement in type I diabetes mellitus.

In an effort to establish a reliable programme for the clinical monitoring of renal involvement in patients with type-I diabetes mellitus, we quantified the urinary excretion of immunoglobulin G (IgG), transferrin (Tf), albumin (Alb), alpha 1-microglobulin (alpha 1MG), N-acetyl-beta-D-glucosaminidase (NAG), and total protein in 130 dipstick negative children and young adults with type-I diabetes. Eighty-five sex- and age-matched healthy persons served as a control group for the definition of the upper reference limits (95th centiles; micrograms min-1 1.73 m2): transferrin 1.4; albumin 16.6; total protein 27.1; NAG: 2.0 mU min-1 1.73 m2. Sex-related differences were detected for IgG (men: 3.8; women: 1.7) and alpha 1 MG (men: 6.0; women: 4.0 micrograms min-1 1.73 m2). The urinary excretion of IgG, Tf, alpha 1MG, NAG, and total protein was significantly higher in subjects with diabetes when compared to healthy controls (p < 0.01). Furthermore, 20 patients (15%) showed an elevated excretion of tubular markers (alpha 1MG and NAG), and 3 patients (2%) of at least two glomerular markers (Alb and/or Tf and/or IgG). Additionally, 18 individuals (14%) presented a mixed excretion pattern of both tubular and glomerular markers. These data suggest that the quantitation of both glomerular and tubular proteinuria provides a sensitive and cost-effective instrument for the non-invasive screening for renal involvement in patients with diabetes mellitus.