Kidney Albumin Reabsorption

• Albumin filters through 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 the glomerular filtered albumin, indicating the kidney's role in protein metabolism.
• Dysfunction of albumin reabsorption in proximal tubules from reduced megalin expression may cause microalbuminuria in early-stage diabetes.
• Massive nonselective proteinuria is caused by glomerular filtration barrier disorders like podocyte detachment and slit diaphragm dysfunction.
• Focal segmental glomerulosclerosis, membranous nephropathy, and glomerulonephritis are disorders that can cause massive nonselective proteinuria
• Selective albuminuria with foot process effacement and tight junction-like slit alteration occurs in minimal-change nephrotic syndrome.
• Albumin uptake gets enhanced in the podocyte cell body, possibly mediated by albumin receptors in the low-dose puromycin model.
• Enhanced podocyte albumin transport needs investigation to understand selective albuminuria in minimal-change disease.

Kidney Function:

• Kidneys maintain body fluid homeostasis by regulating water, electrolyte, and acid-base balance.
• Kidneys excrete uremic toxins, produce hormones like renin and erythropoietin, and activate vitamin D3.
• The role of protein metabolism by the kidney has received little attention.
• Primitive urine filtered by the glomerulus contains proteins smaller than albumin.
• Renal proximal tubules actively reabsorb these proteins, which are degraded to amino acids in lysosomes and returned to the blood.

Glomerular Albumin Filtration

• Glomerular albumin filtration is restricted by size and charge barriers of the glomerular basement membrane and slit diaphragm pores.
• Smithies questioned the slit diaphragms, asking why they do not “clog” with albumin

Glomerular Albumin Filtration in Normal Conditions:

• Albumin has three spherical domains, with a molecular weight of 69 kDa and a net charge of -15.
• Albumin is ellipsoid-shaped, 3.8 nm in diameter and 15 nm long.
• The slit pore size is about 35 Å (3.5 nm) in diameter, but true size is likely larger.
• Albumin molecules pass through slit pores due to flexibility and shape, despite the effective Stock-Einstein radius of albumin being 35 Å

Micropuncture Studies

• Early micropuncture studies showed wide-ranging albumin concentration values like 3 to 728 µg/mL in primitive urine in Bowman's capsule in normal rats
• Large variation was interpreted to be serum albumin contamination.
• Fractional micropuncture minimizes contamination by measuring the fourth fraction of tubular fluid.
• Fractional micropuncture yields a value of 22.9 µg/mL in Bowman's capsule, and albumin-sieving coefficient of 0.00062.
• Isotope-labeled albumin clearance studies showed similar values to fractional micropuncture data when measuring urinary excretion and tubular uptake. Clearance studies after blocking proximal tubular reabsorption display slightly smaller values.

Abnormalities and Filtration

• Fractional excretion of albumin in Fanconi syndrome patients is 0.00008, and is equivalent to the glomeruli-sieving coefficient
• Segments downstream of the proximal convoluted tubules can reabsorb around 26% of filtrated albumin
• Aberrant high sieving coefficient values suggest the likelihood of 200 g of filtered albumin reabsorbed in the proximal tubule

Kidney's Role in Protein Metabolism:

• Renal tubules reabsorb approximately 3 g of albumin per day in humans
• An isolated rabbit proximal tubule reabsorbs 99.9 × 10-3 ng/min/mm

Mechanism of Microalbuminuria in Diabetic Nephropathy:

• Microalbuminuria is an early marker of diabetic nephropathy.
• It is believed to a result of increased glomerular permeability and hyperfiltration.
• A micropuncture study showed proximal tubular albumin is reduced without an increase in the filtration.
• Megalin decreases result in tubular dysfunction, since it serves as a receptor for albumin endocytosis in the proximal tubules.
• RAS inhibitors can restore megalin expression, improve reabsorption and reduce albuminuria, since albumin is reabsorbed with receptor-mediated endocytosis into endosomes

Glomerular Filtration Barrier

Makes up three layers

• The fenestrated endothelium covered by a negatively charged glycocalyx
• The glomerular basement membrane where size barrier exists combined with type IV collagen and a charge barrier generated by heparan sulfate
• The slit diaphragm

Tracer Studies

• Tracer studies call into question whether the GBM or slit diaphragm is more critical
• Ferritin accumulates in the GBM, while horseradish peroxidase is also on the GBM, but under the slit diaphragm
• Slit diaphragm restriction and GBM importance are both key

Potential Selective Albuminuria Mechanisms

• Lack or presence of podocyte detachment
• Lower nephrin expression

Research Regarding Kidneys

• By utilizing human biopsies and electron images, lesion can be identified as responsible for proteinuria in glomerular diseases
• GBM shows a prone adhesion which induces segmental sclerosis
• Podocyte can undergo mechanisms such as stretching from hemodynamics and immunology

How Albumin is Transported and Excreted

• Albumin is filtered through the endothelial fenestrae, basement and lastly impaired slit diaphragm
• Albumin is filtered through capillary when podocytes are lost, enabling enlarged slit pores and nonselective
• Albumin becomes receptor transported which can explain the selective in a normal manner, potentially preventing issues with the nephrotic.