Kidney Albumin Reabsorption

• Albumin is filtered through the glomerulus with a sieving coefficient of 0.00062
• Approximately 3.3 g of albumin is filtered daily in human kidneys
• 71% of glomerular-filtered albumin is reabsorbed by the proximal convoluted tubule
• 23% of glomerular-filtered albumin is reabsorbed by the loop of Henle and distal tubule
• 3% of glomerular-filtered albumin is reabsorbed by the collecting duct
• Dysfunction of albumin reabsorption in the proximal tubules, from reduced megalin expression, may explain microalbuminuria in early-stage diabetes
• Massive nonselective proteinuria stems from disorders of the glomerular filtration barrier, including:
• Podocyte detachment
• Glomerular basement membrane rupture
• Slit diaphragm dysfunction in focal segmental glomerulosclerosis
• Membranous nephropathy
• Other forms of glomerulonephritis
• Selective albuminuria with foot process effacement and tight junction-like slit alteration is seen in patients with minimal-change nephrotic syndrome
• Albumin uptake is enhanced in the podocyte cell body, potentially via albumin receptors in the low-dose puromycin model
• Enhanced podocyte albumin transport needs investigation to clarify selective albuminuria mechanism in minimal-change disease

Introduction

• Kidneys maintain body fluid homeostasis via water, electrolyte, and acid-base balance regulation
• Kidneys excrete uremic toxins and produce hormones like renin and erythropoietin
• Kidneys activate vitamin D3
• Little attention has been given to the role of protein metabolism by the kidney
• Primitive urine contains many proteins smaller than albumin
• Renal proximal tubules actively reabsorb these proteins, degrading them to amino acids in lysosomes, returned to the blood
• Glomerular albumin filtration is thought to be limited by size and charge barriers, including slit diaphragm pores

Albumin Filtration by the Glomerulus under Normal Conditions

• Albumin comprises of three spherical domains
• Molecular weight of 69 kDa
• Net charge of negative 15
• Albumin is a flexible, ellipsoid-shaped molecule that is:
• 3.8 nm in diameter
• 15 nm long
• Slit pore size was originally thought have cross section of 40 by 140 Å and 70 Å in length
• A recent study revealed slit-pores are 35 Å (3.5 nm) in diameter with some size variation
• The size of the pores are likely larger in actuality since samples processed for electron microscopy, shrinks the pores slightly
• Albumin has an effective Stock-Einstein radius of 35 Å (70 Å in diameter)
• Flexibility and ellipsoid shape allows some albumin molecules to pass through
• Early micropuncture studies showed values from 3 to 728 µg/mL in primitive urine in Bowman's capsule in normal rats
• Variation in studies has been interpreted as contamination with albumin from the peritubular capillaries
• The fractional micropuncture method was developed to avoid serum albumin contamination
• It involves initially puncturing the renal tubules with an outer pipette
• It involves collecting tubular fluid in fractions with an inner pipette
• The albumin concentration is measured in the fourth fraction and is virtually free from contamination by serum albumin
• This yields a value of 22.9 µg/mL in Bowman's capsule and an coefficient of 0.00062

Table 1 Content

• Compared glomerular albumin-sieving coefficient (SC) values in many studies
• Authors, year, method, SC value, and species/animal model has been recorded for the studies

Contradictory Study Data

• Isotope-labeled albumin clearance studies measured urinary excretion and tubular uptake and showed consistent values with fractional micropuncture data
• Albumin clearance studies showed blocking proximal tubular reabsorption with L-lysine, low temperatures, or studies of congenital abnormalities of tubular reabsorption showed smaller values than micropuncture data
• The fractional excretion of albumin in patients with syndrome is 0.00008 and might approximate the coefficient in a normal kidney
• Downstream nephron segments of the proximal convoluted tubules can reabsorb around 26% of filtered albumin with Fanconi syndrome
• Glomerular filtration may be greater than 0.00011 in humans
• Results from another study showed that coefficients where larger at 0.074 [14], and another using Alexa-labeled albumin observed by confocal microscopy resulted in a sieving coefficient of 0.0341 [15]
• Technical limitations included measurement sensitivity, interference from out-of-focus fluorescence, and improper removal of unbound molecules also exist
• Coefficients also seem unrealistically high

Important Role of the Kidney in the Protein Metabolism

• Albumin concentration along the rat nephron had been measure in fractional micropuncture studies
• Renal tubules reabsorb about 3 g of albumin per day in humans
• The albumin reabsorption capacity measured in the isolated rabbit proximal tubule was 99.9 × ng/min/mm
• Human kidneys reabsorb 1.9g of albumin per day
• Nephron segments downstream of the proximal convoluted tubules reabsorb about 26% of filtered albumin
• The kidney reabsorbs a total of 2.6 g a day
• Albumin molecules are taken up into lysosomes in the proximal tubule within 15 minutes and degraded to amino acids after 120 minutes
• High sieving coefficient values reported by Russo et al. suggest that 200g of albumin per day are filtered in glomerulus and reabsorbed in tubular, which is unlikely
• Low-molecular-weight proteins are freely filtered with a sieving coefficient of 0.987, and 9.6 g are reabsorbed per day
• Dysfunction in chronic renal failure cannot be compensated for by hemodialysis

Mechanisms of Microalbuminuria in Diabetic Nephropathy

• Microalbuminuria is an early marker of diabetic nephropathy
• Fractional micropuncture studies show proximal tubular albumin reabsorption decreases, but without increased glomerular albumin filtration
• Megalin, the albumin endocytosis receptor in the proximal tubules, is lowered in studies with diabetic rats

Questions Pertaining to Glomerular Albumin Filtration

• Made up of three layers
• The fenestrated endothelium
• The basement membrane
• The slit diaphragm between foot processes
• All the layers act as a barrier against large molecules
• The slit diaphragm was identified by Yamada