Increase In Fractional Clearance Research Articles

Are filtered plasma proteins processed in the same way by the kidney?

In order to understand the mechanism of albuminuria we have explored how other plasma proteins are processed by the kidney as compared to inert molecules like Ficolls. When fractional clearances are plotted versus protein radius there is a remarkable parallelism between protein (molecular weight range 30–150kDa) clearance in healthy controls, in Dent’s disease, in nephrotic states and the clearance of Ficolls. Although there are significant differences in the levels of fractional clearances in these states. Dent’s disease results in a 2-fold increase in the fractional clearance of proteins as compared to healthy controls whereas in nephrotic states there is a further 3-fold increase in fractional clearance. Previous thinking that albumin uptake was controlled primarily by the megalin/cubilin receptor does not explain the albumin urinary excretion data and is therefore an incorrect concept. Protein clearance in nephrotic states approach the fractional clearance of inert Ficolls for a given radius. It therefore appears that there are two pathways processing these proteins. A low capacity pathway associated with megalin/cubilin that degrades filtered protein (that is inhibited in Dent’s disease) and a high capacity pathway that retrieves the filtered protein and returns it to the blood supply (without retrieval nephrotic protein excretion will occur and this will account for hypoproteinemia). On the other hand low molecular weight proteins (<20kDa) are processed entirely differently by the kidney. They are not retrieved but are comprehensively degraded in the kidney with the degradation products predominantly returned to the blood supply.

Novel Role of Enteral Monosaccharides in Intestinal Lipoprotein Production in Healthy Humans

Overproduction of triglyceride-rich lipoproteins (TRLs) by liver and intestine contributes to hypertriglyceridemia and may increase cardiovascular risk. Dietary carbohydrates, especially fructose, have been shown to amplify postprandial lipemia but little is known about its effect on intestinal TRL particle production. Here, we examined intestinal and hepatic TRL particle production in response to enteral glucose or fructose in the presence of enteral lipid. In 2 randomized studies, 4 to 6 weeks apart, 7 healthy male subjects received intraduodenal infusion of Intralipid plus saline or glucose. TRL-apolipoprotein (apo) B48 and apoB100 kinetics were assessed under pancreatic clamp conditions. In a separate study of another 7 subjects under similar conditions, glucose was replaced by fructose. When coinfused with Intralipid into the duodenum, glucose markedly stimulated TRL-apoB48 production (P<0.01), with a concomitant moderate increase in fractional clearance (P<0.05), resulting in net elevation of TRL-apoB48 concentration. TRL-apoB100 concentration, fractional clearance, and production were not significantly affected by glucose. When glucose was replaced by fructose, both TRL-apoB100 and apoB48 production (P<0.05), but not fractional clearance, were enhanced compared with Intralipid alone. These results reveal a novel role of monosaccharides in acutely enhancing intestinal lipoprotein particle production, thereby aggravating hyperlipidemia.

Acute Effects of High-Dose Furosemide on Residual Renal Function in CAPD Patients

♦ Background High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. ♦ Methods Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140–1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). ♦ Results The median increase in urine volume was 400 mL (range 270 – 910 mL, p &lt; 0.02) and the increase in sodium excretion was 54 mmol (range 25 –118 mmol, p &lt; 0.02). No change in GFR was found between P1 (2.4 mL/minute, range 0.6 – 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 – 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality ( p &lt; 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 – 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 – 7.8 mg/24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 – 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion ( r=0.93, p &lt; 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3%–11.3%/mg). ♦ Conclusion High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.

Glomerular Permselectivity Factors Are Not Responsible for the Increase in Fractional Clearance of Albumin in Rat Glomerulonephritis

The increased fractional clearance of albumin in nephrotic states has long been attributed to glomerular permselectivity dysfunction. Using radiolabeled rat serum albumin, transferrin, IgG, and polydisperse Ficoll, this study investigated the changes in their in vivo fractional clearance in puromycin aminonucleoside nephrosis and anti-glomerular basement membrane glomerulonephritis. In control rats the lack of charge selectivity was confirmed by the demonstration that carboxymethyl Ficoll (valence approximately -39) had the same fractional clearance as uncharged Ficoll. Both diseases exhibited similar effects on fractional clearance measurements suggesting an underlying common mechanism. In disease, there was good agreement between the fractional clearance of proteins determined by radioactivity as compared to those determined by radioimmunoassay. A small increase in the fractional clearance for IgG was evident in disease as compared to controls, which mirrored the change in the equivalent size Ficoll, suggesting that the increase is because of the development of a small proportion of large pores in the glomerular capillary wall. There was no increase, however, in the fractional clearance of Ficoll of equivalent size to albumin in either disease, yet the fractional clearance of the albumin increased by 12 to 14 times as determined by radioactivity and 4500 to 6600 times as determined by radioimmunoassay. This study demonstrates that glomerulonephritis is not a disease associated with changes in glomerular permeability to albumin but is because of alterations in albumin processing by cells distal to the glomerular basement membrane. It is also apparent that approaches to glomerular pathology and proteinuria as risk factors in renal disease must be reassessed.

Puromycin aminonucleoside nephrosis results in a marked increase in fractional clearance of albumin.

Puromycin aminonucleoside nephrosis (PAN) results in a marked increase in the fractional clearance of albumin. The increase in the fractional clearance of [(3)H]albumin to approximately 0.045, as measured both in vivo and in the isolated perfused rat kidney (IPK) with PAN, occurs without an accompanying equivalent increase in glomerular capillary wall size selectivity as previously measured with dextrans. This is very similar to the marked increase in albuminuria seen with kidneys treated with inhibitors of endocytosis by the tubular epithelium, particularly lysine (T. M. Osicka, L. M. Pratt, and W. D. Comper. Nephrology 2: 199-212, 1996). The similarity is further established that, like in the presence of lysine, [(3)H]albumin excreted in urine from rats with PAN is essentially intact whereas, in both in vivo and IPK control experiments, excreted [(3)H]albumin is heavily degraded. The same observations have also been made for (3)H-labeled anionic horseradish peroxidase. These observations suggest that the significant albuminuria that occurs in PAN is primarily post-glomerular basement membrane in origin.

Charge selectivity of proteinuria in diabetic glomerulopathy.

Differential macromolecule clearances were used to elucidate the mechanism of proteinuria in patients with diabetic glomerulopathy. Uncharged dextrans of graded size, combined with albumin and IgG separated into narrow fractions of varying charge by preparative electrofocusing, were used to probe the filtration barrier. Analysis of the fractional clearance profile of dextrans in the 30- to 60-A interval revealed a small fraction of filtrate volume (0.0023-0.0097) permeating large nonrestrictive glomerular pores and correlating strongly with the fractional clearances of albumin (r = .88, P less than .001) or IgG (r = .91, P less than .001). The fractional clearance of the most anionic species of albumin [isoelectric point (pI) 4.0-4.5] significantly exceeded that of less anionic species (pI 4.5-5.5) at all levels of proteinuria. A corresponding increase in fractional clearance of anionic (pI 4.5-5.0) over neutral (pI 7.0-7.5) IgG species was observed in patients with subnephrotic-range proteinuria. We conclude that a loss of barrier size selectivity underlies proteinuria in diabetic glomerulopathy. In addition, either facilitated filtration of polyanions or preferential tubular reabsorption of polycations can be invoked to explain the final composition of urinary protein. Similar loss of size selectivity combined with enhanced fractional clearance of anionic IgG in a group of nondiabetic patients with nephrotic syndrome indicates that the foregoing abnormality of renal protein handling is not unique to diabetic glomerulopathy.

Primate kidney function in hemorrhagic shock as influenced by dibutyryl cyclic AMP

Standardized hemorrhagic shock was employed to study alterations in electrolyte and water handling in the owl monkey, either normally hydrated or moderately dehydrated. Increase in fractional clearance of osmolarity,sodium, and calcium occurred with retransfusion after the hypotensive phase. In the hydrated animals, free-water clearance became positive, and the urine-to-plasma osmolarity ratio [(U/P)osM] decreased below 1.0. In the dehydrated animals, free-water reabsorption (TCH2O) decreased but remained negative,while (U/P)osM remained above 1.0. Dibutyryl cyclic AMP (DBcAMP) was infused into the renal arterial supply in an attempt to correct a possible deficiency of cyclic AMP production. In the hydrated group, free-water clearance (CH2O) became more positive with infusion, and (U/P)osM decreased even further, with no effect on fractional sodium clearance. Effects were less or absent in the dehydrated group. Possible explanations for the observed effects of DBcAMP are considered. It was concluded that the loss of concentrating power seen in hemorrhagic shock occurs at a step beyond the production of cyclic AMP by adenylate cyclase.