Renal Handling of Albumin—From Early Findings to Current Concepts

Albumin is the main protein of blood plasma, lymph, cerebrospinal and interstitial fluid. The protein participates in a variety of important biological functions, such as maintenance of proper colloidal osmotic pressure, transport of important metabolites and antioxidant action. Synthesis of albumin takes place mainly in the liver, and its catabolism occurs mostly in vascular endothelium of muscle, skin and liver, as well as in the kidney tubular epithelium. Long-lasting investigation in this area has delineated the principal route of its catabolism involving glomerular filtration, tubular endocytic uptake via the multiligand scavenger receptor tandem—megalin and cubilin-amnionless complex, as well as lysosomal degradation to amino acids. However, the research of the last few decades indicates that also additional mechanisms may operate in this process to some extent. Direct uptake of albumin in glomerular podocytes via receptor for crystallizable region of immunoglobulins (neonatal FC receptor) was demonstrated. Additionally, luminal recycling of short peptides into the bloodstream and/or back into tubular lumen or transcytosis of whole molecules was suggested. The article discusses the molecular aspects of these processes and presents the major findings and controversies arising in the light of the research concerning the last decade. Their better characterization is essential for further research into pathophysiology of proteinuric renal failure and development of effective therapeutic strategies.

Differential diagnosis and treatment of edema of lower extremities

The article gives a definition, classification and mechanisms for the development of edema (increased hydrostatic pressure, increased capillary permeability, decreased colloidal osmotic pressure). The main diseases accompanied by edematous syndrome are considered, diagnostic search algorithms are given. The clinic and treatment of edema of the lower extremities due to lymphatic and venous insufficiency are separately discussed. The data of a clinical study of the effectiveness of drugs based on diosmin and hesperidin in the treatment of chronic venous insufficiency are presented.

Non-hypertensive tetraPEGylated canine haemoglobin: correlation between PEGylation, O2 affinity and tissue oxygenation

TetraPEGylated canine Hb, [SP (succinimidophenyl)-PEG5K]4-canine-Hb, with PEGylation at its four reactive cysteine residues (α111 and β93) has been prepared and characterized. The hydrodynamic volume and the molecular radius of (SP-PEG5K)4-canine-Hb are intermediate to those of di- and hexaPEGylated human Hb as expected. However, the COP (colloidal osmotic pressure) of tetraPEGylated canine Hb is closer to that of hexaPEGylated human Hb than to that of diPEGylated human Hb. The O2 affinity of tetraPEGylated canine Hb is higher than that of canine Hb and comparable with that of hexaPEGylated Hb. The O2 affinity of tetraPEGylated canine Hb is not responsive to the presence of DPG (diphosphoglycerate) or chloride, but it retains almost full response to L-35, an allosteric effector that interacts at the αα-end of the central cavity. The tetraPEGylated canine Hb is vasoinactive in hamster in 10% top load infusion studies. It is also essentially non-hypertensive in an extreme exchange haemodilution protocol in hamster just as di- and hexaPEGylated human Hb. The O2 delivery by tetraPEGylated canine Hb is comparable with that of hexaPEGylated Hb but not as efficient as diPEGylated Hb. These results demonstrate that PEGylation-induced solution properties of PEG [poly(ethylene glycol)]–Hb conjugates are dictated by the level and chemistry of PEGylation and the interplay of these plays a critical role in tissue oxygenation. The studies imply the need to establish the right level (and/or pattern) of PEGylation and O2 affinity of Hb–PEG adducts in designing O2-carrying plasma volume expanders, and this remains the primary challenge in the design of PEGylated Hb as blood substitutes.

Serum colloidal osmotic pressure in the development of kwashiorkor and in recovery: its relationship to albumin and globulin concentrations and oedema

1. Serum colloidal osmotic pressure was measured in children ‘at risk’ to kwashiorkor, in others with frank signs of the disease and during recovery. Simultaneous estimations of serum albumin and globulin concentrations and assessments of the extent of oedema were also made.2. During the development of kwashiorkor, serum colloidal osmotic pressure did not decrease significantly until albumin concentration was 25.1–27.5 g/l. Above 30.0 g/l, colloidal osmotic pressure was maintained at normal levels during which time a significant reciprocal relationship existed between albumin and globulin concentrations. These findings provide support for suggestions that there may be an oncotic regulation of albumin synthesis.3. Low albumin concentrations were mainly responsible for the low colloidal osmotic pressures found in children with kwashiorkor and in agreement with previous findings the threshold for the formation of oncotic oedema was found to be about 2.35–2.65 kN/m2.4. Values for colloidal osmotic pressure calculated from serum albumin and gobulin concentrations using empirical formulas did not agree well with measured values and no constant correction factor suitable over the whole range of albumin concentrations found in rural Ugandan children could be devised. In many hypoalbuminaemic children only direct measurement of serum colloidal osmotic pressure will indicate the true extent of risk to an episode of oedema.

Localization and Characterization of Sodium Transport Along the Renal Tubule

The proximal tubular Na transport system was investigated using our stop flow analysis. During varying degrees of osmotic diuresis in dogs the ureter of one kidney was occluded for 2 1/2–8 minutes. Following occlusion serial urine samples were collected and analyzed for Na, creatinine, PAH or glucose. Using urinary creatinine concentrations as an index of water movement the mass of Na and water reabsorbed from the proximal segments during occlusion was calculated. In all experiments the calculations showed that the Na concentration in the proximal reabsorbate was of the same concentration which existed in plasma. Such behavior is inconsistent with a proximal Na pump which would otherwise reabsorb a supraplasma-level Na solution away from mannitol and Na in the tubule. The data suggest that Na and water transport out of the proximal tubules may be a passive process initiated by the colloidal osmotic pressure differences which exist between the intratubular urine and the peritubular capillary blood. A passive mechanism for Na and water reabsorption from the proximal segment resolves many difficulties faced by a Na pump.