Altered filtration of macromolecules due to decreased electrical charge of the glomerular basement membrane might be the initial step in the development of albuminuria in patients with Type 1 (insulin-dependent) diabetes mellitus. We therefore investigated the selectivity index, i.e. renal clearance of non-glycated plasma albumin/clearance of glycated plasma albumin in 38 patients with Type 1 diabetes mellitus. The two albumin molecules differed slightly in charge, non-enzymatic glycated albumin being more anionic at physiological pH compared with unmodified plasma albumin. Glycated albumin in plasma and urine was determined by a specific, sensitive and highly reproducible chromatographic procedure. In diabetic patients with normal urinary albumin excretion, the selectivity index was increased three-fold compared with that of non-diabetic subjects (2 p less than 0.01). A significant correlation (r = 0.53, 2 p less than 0.01) between haemoglobin A1c and selectivity index was demonstrated in these patients, indicating a change in charge-dependent renal filtration could possibly be attributed to non-enzymatic glycation of components in the glomerular basement membrane and tubuli. Diabetic patients with increased albumin excretion rate had a significantly lower selectivity index compared with patients with normal albumin excretion (2 p less than 0.01). A significant negative correlation (r = 0.85, 2 p less than 0.001, exponential curve fit) was seen between urinary albumin excretion and selectivity index in the diabetic patients, indicating that the capability of differentiating between macromolecules of different charges is again lost with increasing urinary albumin excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND-The increased plasma disappearance of albumin has previously been described in decompensated congestive heart failure (CHF); this disappearance normalized after diuretic treatment. Cardiac transplantation (HTX) and current medical treatment affect microvascular structure and function. We investigated the plasma disappearance of albumin and the impact of microvascular thickness and electrostatic properties in patients with compensated CHF and after HTX. METHODS AND RESULTS-The fraction of intravascular albumin that passes to the extravascular space per unit time, as determined from the plasma disappearance of intravenously injected (131)I-labeled albumin, was increased to 7.8+/-1.7% in 16 patients with CHF compared with 18 controls (6.5+/-1.9%, P<0.05); these levels normalized after HTX (5.8+/-2.6%, P<0.01, n=17). The change in ratio between (131)I-albumin and simultaneously injected negatively charged glycosylated (125)I-albumin (selectivity index, >1/hour in controls) was lower in patients with HTX (0.993+/-0. 022/hour) than in controls (1.008+/-0.019/hour; P<0.05), which indicated a relatively increased plasma disappearance of negatively charged albumin in HTX patients. Capillary basement membrane thickness was evaluated semiquantitatively from skin biopsies and showed no difference in the 3 groups (control, CHF, and HTX patients). However, in all 3 study groups, subjects with thicker capillary basement membranes had lower albumin escape rates (6.1+/-1. 8%, n=32, versus 7.6+/-2.6% in subjects without thickening of capillary basement membranes, n=19; P<0.05). CONCLUSIONS-The plasma disappearance of albumin increased in patients with compensated CHF and it normalized after HTX. The present normalized capillary basement thicknesses in patients with CHF and the direct association between this parameter and plasma albumin disappearance indicate that previous compensatory microvascular basement membrane growth results in restricted permeability. Microvascular electrostatic properties did not relate to plasma albumin disappearance.

The transcapillary escape rate and relative plasma disappearance of glycated and non-glycated albumin were measured in 25 male Type 1 (insulin-dependent) diabetic patients using a double tracer technique. The patients were divided into three groups on the basis of their urinary albumin excretion: group 1, normal albumin excretion (less than 30 mg/24 h) (n = 8); group 2, microalbuminuria (30-300 mg/24 h) (n = 9); and group 3, clinical nephropathy (greater than 300 mg/24 h) (n = 8). Six male age-matched non-diabetic persons served as control subjects. The transcapillary escape rate of glycated albumin was similar in group 1 and control subjects (4.7 +/- 2.1 versus 5.1 +/- 1.7%), but significantly increased in group 2 (7.0 +/- 1.7%, p less than 0.05) and in group 3 (7.9 +/- 3.1%, p less than 0.05). The transcapillary escape rate of glycated albumin was slightly lower than that of non-glycated albumin in all groups, but significant only in normal control subjects. No difference in the catabolic rate of glycated and non-glycated albumin was found. We conclude that the in vivo effects of glycation on the clearance and transcapillary passage of albumin are small and not likely to play any significant role in the development of late diabetic microvascular complications.

The fractional plasma escape rates of glycated and non-glycated albumin have earlier been measured in groups of Type 1 (insulin-dependent) diabetic patients and control subjects. The escape of non-glycated albumin was similar in control subjects and normoalbuminuric patients, but elevated in patients with micro or macroalbuminuria. In all groups the escape rate of glycated albumin was lower than that of non-glycated albumin. Glycation increases the anionic charge of albumin. To assay for charge-dependent alterations of transport a selectivity index (non-glycated albumin/glycated albumin transport ratio) was determined from the disappearance data. The index was high in control subjects (1.021 +/- 0.0057 (SEM)). This reflects a mean difference between the two escape rates of 2.1% per hour (for comparison the mean of the fractional escape rate of non-glycated albumin of the normal control subjects was 4.7% per hour). The index was numerically even higher in normoalbuminuric patients (1.031 +/- 0.0047 (SEM)), but reached significantly lower levels in patients with microalbuminuria (1.013 +/- 0.0030 (SEM), p < 0.02). Patients with clinical nephropathy had very low levels indicating loss of selectivity (1.002 +/- 0.0068 (SEM), p < 0.001). This pattern accords well with measurements of renal clearance selectivity indices, suggesting a general, progressive deterioration of anionic perivascular barrier components in diabetic microangiopathy. The structural target for these changes is likely to be the glycosaminoglycans of the glomerular basal membrane and the interstitial matrix.

The simultaneous plasma disappearance curves of albumin and fibrinogen were recorded in eight normal subjects from 10 to 60 min following intravenous injection. Additional samples were taken at 3, 4, 5, 6 and 7 min. The initial distribution volume (IDV) of albumin calculated by semilogarithmic extrapolation to zero time was 5.56% (range 3.73-8.53) larger than that of fibrinogen, denoting an initial high-rate function of albumin efflux extending from zero to about 10 min after tracer injection. The following slower phase of the albumin curve from 10 to 60 min was found to be similar to the so-called transcapillary escape rate (TER) of single-tracer experiments. By introducing the value Cp(0) (i.e. the estimated curve height at t = 0, from the injected amount of albumin tracer divided by the IDVf), the entire initial part of the albumin curves was analysed. From this analysis the mean value of 0.0135 +/- 0.0038 min-1 was determined for initial slope, corresponding to a whole-body unidirectional albumin efflux [j(0)] of 0.0572 +/- 0.0160 ml 100 g-1 min-1. The result is about 16 times higher than normal estimates of total lymphatic albumin return, indicating a huge backflux of interstitial albumin at the whole-body capillary level. Both phases of efflux seem to reflect uptake in a variety of peripheral tissues, and the hypothesis that the second phase (TER) expresses the initial slope of albumin escape into non-liver tissues is not substantiated. Based on the difference in IDV of the tracers demonstrated, the uncritical use of albumin as a plasma volume marker is not justified.