Kidney Albumin Reabsorption

• Albumin is filtered by the glomerulus, with a sieving coefficient of 0.00062.
• About 3.3 g of albumin is filtered daily in human kidneys.
• The proximal convoluted tubule reabsorbs 71% of filtered albumin.
• The loop of Henle and distal tubule reabsorb 23% of filtered albumin.
• The collecting duct reabsorbs 3% of filtered albumin.
• These indicate that kidneys play an important role in protein metabolism.
• Dysfunction of albumin reabsorption in proximal tubules may explain microalbuminuria in early-stage diabetes.
• Massive nonselective proteinuria results from disorders of the glomerular filtration barrier.
• These disorders include podocyte detachment, glomerular basement membrane rupture, and slit diaphragm dysfunction.
• These disorders are observed in focal segmental glomerulosclerosis, membranous nephropathy, and other glomerulonephritis.
• Selective albuminuria with foot process effacement and tight junction-like slit alteration occurs in minimal-change nephrotic syndrome patients.
• Albumin uptake is enhanced in the podocyte cell body, possibly mediated by albumin receptors.
• It needs to be investigated if enhanced podocyte albumin transport elucidates the mechanism of selective albuminuria in minimal-change disease
• Kidneys maintain homeostasis of body fluids, regulating water, electrolytes, and acid-base balance.
• Kidneys excrete uremic toxins and produce hormones like renin and erythropoietin, and activate of vitamin D3.
• The role of protein metabolism by the kidney has received little attention.
• Primitive urine contains many proteins smaller than albumin, and renal proximal tubules actively reabsorb them.
• Reabsorbed proteins are degraded to amino acids in lysosomes and returned to the blood.
• Glomerular albumin filtration is restricted by size and charge barriers of the basement membrane and slit diaphragm.
• The question of why slit diaphragms do not clog if all filtered albumin molecules pass through them has been raised.
• Glomerular albumin filtration could occur by diffusion across the GBM.
• It's unclear how albumin molecules diffuse across effaced podocyte foot processes in minimal-change nephrotic syndrome.
• Discussed are the ultrastructural morphological changes of the glomerular filtration barrier in various glomerular diseases.
• A new mechanism of glomerular albumin filtration is proposed for minimal-change nephrotic syndrome.

Albumin Filtration Under Normal Conditions

• Albumin contains three spherical domains with a molecular weight of 69 kDa and a net charge of -15.
• It is a flexible, ellipsoid-shaped molecule, measuring 3.8 nm in diameter and 15 nm long.
• The slit pore size was originally reported to be approximately 40 by 140 Å in cross section and 70 Å in length.
• Glomerular slit-pores are 35 Å (3.5 nm) in diameter with some variation in size by recent electron tomography study.
• The effective Stock-Einstein radius of albumin is 35 Å (70 Å in diameter).
• Some albumin molecules pass through the slit pores due to their flexibility and ellipsoid shape.
• Early micropuncture studies showed albumin concentration values form 3 to 728 µg/mL in primitive urine in Bowman's capsule in normal rats.
• The fractional micropuncture method avoides serum albumin contamination.
• This yields of a value of 22.9 µg/mL in Bowman's capsule, and an albumin-sieving coefficient of 0.00062.
• Isotope-labeled albumin clearance studies measured both urinary excretion and tubular uptake.
• Clearance studies showed consistent values with fractional micropuncture data.
• Albumin clearance studies involve blocking proximal tubular reabsorption with L-lysine, treatment with low temperatures, or studies of congenital abnormalities of tubular reabsorption.
• The fractional excretion of albumin in Fanconi syndrome patients is 0.00008, possibly equivalent to the glomerular-sieving coefficient in the normal kidney.
• Nephron segments downstream reabsorb about 26% of glomerular filtrated albumin even if proximal tubular albumin reabsorption is impaired in Fanconi syndrome
• Glomerular albumin-sieving coefficient may be greater than 0.00011 in humans.
• A study using tritium-labeled albumin reported a sieving coefficient of 0.074
• Another study with Alexa-labeled albumin and confocal microscopy gave 0.0341 sieving coefficient.
• Technical limitations included sensitivity of measurements, interference by out-of-focus fluorescence, and incomplete removal of unbound labeling molecules.
• Solving the problem of out-of-focus fluorescence contamination was achieved utilizing internal photodetectors.
• Internal photodetectors performing two-photon microscopy studies calculated the glomerular sieving coefficient.
• Alexa fluor labeled-rat serum albumin calculated the sieving coefficient at 0.002.
• Rhodamine labeled 70-kD dextran calculated it at 0.001.
• The glomerular-sieving coefficient responds to oscillational changes in GFR, temperature, or laparotomy.
• It varies from 0.0001 to 0.0006 under normal conditions.

Role of the Kidney in Protein Metabolism

• Renal tubules reabsorb about 3g of albumin per day in humans
• The albumin reabsorption capacity measured in the isolated rabbit proximal tubule was 99.9 × 10-3 ng/min/mm.
• Nephron segments downstream of the proximal convoluted tubules reabsorb about 26% of filtered albumin.
• The total amount of albumin reabsorption in the kidney equals 2.6 g per day.
• Albumin molecules are taken up into lysosomes in the proximal tubule within 6-15 minutes and then degraded to amino acids after 30-120 minutes.
• The kidney should be regarded as an organ that plays an important role in protein metabolism.
• The high sieving coefficient values suggest about 200g of albumin per day are filtered and reabsorbed in the proximal tubule.
• Abundant amounts of albumin are not detected in the normal kidney by immunostaining.
• It is unlikely that the proximal tubule transports huge amounts of intact albumin under physiological conditions.
• The kidneys albumin filtration and metabolism are not larger than the liver's daily production (~20 g).
• Kidneys albumin filtration and metabolism is not larger than the total plasma albumin (~125 g).
• Tubular dysfunction of protein metabolism cannot be compensated for by hemodialysis.
• Dysfunction causes deposits of low-molecular weight proteins in organs, causing amyloidosis in hemodialysis patients.
• The kidneys protein metabolism role must be accounted for

Microalbuminuria In Diabetic Nephropathy

• Microalbuminuria is an early marker of diabetic nephropathy and is believed to occur due to increased glomerular permeability and glomerular hyperfiltration.
• Proximal tubular albumin reabsorption decreases without increased glomerular albumin filtration in stages of streptozotocin-induced diabetic nephropathy.
• Tubular dysfunction is a possible the mechanism of microalbuminuria in early-stage diabetes.
• Megalin, the receptor for albumin endocytosis, decreases in diabetic rats, supporting this mechanism.
• Albumin clearance after the blockade of proximal reabsorption with lysine also supports this, utilizing isotope labeled-bovine serum albumin.
• Renin-angiotensin system (RAS) inhibitors restore megalin expression, ameliorate tubular dysfunction, and reduce albuminuria in diabetic rats.
• Albumin is reabsorbed by receptor-mediated endocytosis into endosomes, where ligand-receptor dissociation must occur to recycle the albumin-binding receptors to the plasma membrane.

Glomerular Albumin Filtration Through Slit Pores In Nephrotic Syndrome

• The glomerular filtration barrier includes the fenestrated endothelium covered and a negatively charged glycocalyx.
• Also includes glomerular basement membrane.
• The membrane contains laminin and type IV collagen .
• Heparan sulfate generates a charge barrier.
• Considered a fine filter is the slit diaphragm between foot processes.