Renal albumin filtration: alternative models to the standard physical barriers

Abstract

Human kidneys produce more than 4 million litres of virtually protein-free primary urine in a lifetime. In healthy individuals, the sieving process is accomplished by the glomerular filter without the smallest sign of clogging, even in old age. How nature accomplishes this extraordinary task is a mystery, but unravelling the functioning of the glomerular filter is important. The basic principles that govern glomerular filtration are probably also true for peripheral filtering by fenestrated capillaries. In addition, understanding the sieving process is a prerequisite to understanding the pathogenesis of proteinuria (that is, the leakage of plasma proteins into the urine). Proteinuria is the hallmark of glomerular disease and a major risk factor for systemic cardiovascular complications, a fact that emphasizes the relationship between the glomerular and peripheral filtering capillaries. In this Review, we briefly summarize the major models that have been proposed for the mechanisms of glomerular filtration and discuss their strengths and limitations. A special emphasis is placed on the 'electrokinetic model' that we have proposed, a model that could potentially resolve many of the seemingly strange characteristics of the glomerular filtration barrier.

Albumin Is Recycled from the Primary Urine by Tubular Transcytosis

“…21,22 In addition, we have used an expansion of this model, which also considers electrical effects. [23][24][25] This electrokinetic model proposes that an electrical field is generated across the glomerular filter by forced filtration of the small ions (e.g., sodium and chloride), which pass the filter at different speeds because of physical interactions with the charged filter surface ( Figure 1B). 25 Recently, this streaming potential has been experimentally verified by direct measurements.…”

Podocytes are key—although albumin never reaches the slit diaphragm

“…Nephrol. 9, 266-277; 2013) 1 and the others in the Nature Reviews Nephrology collection, which raises two important issues that must be addressed (Albuminuria is controlled primarily by proximal tubules. Nat.…”

“…3,4 Several lines of evidence support this position. 1,3 For example, micropuncture studies in the rat kidney have demonstrated very low albumin concentrations in the primary filtrate. In cooled or fixed isolated perfused kidney, cubilin/megalin knockout mice or human patients with Fanconi syndrome, only very little protein is excreted in the urine (<1 g albumin per day in humans).…”

“…Accordingly, the electrokinetic model predicts that any insult that impairs homogeneous filtration will interfere with the generation of a homogeneous electrical field and result in proteinuria. 1 Injury to podocytes usually leads to a uniform response: effacement of foot processes. As a consequence, larger parts of the glomerular filter surface will block filtration because they are covered by flattened podocytes.…”

“…Interestingly, the electrokinetic model also provides explanations for other riddles: for example, why the filter becomes more permeable when filtration pressure is decreased below the autoregulatory range (as in orthostatic proteinuria), and why the filter never 'clogs' . 1 Next, Comper states that out-of-focus fluorescence has no physical basis in twophoton microscopy and cannot explain high albumin GSC values. The two-photon microscope is a powerful new tool that can be used to measure the intensity of fluorescently labelled albumin in Bowman's space and glomerular blood plasma in vivo, thereby enabling direct measurement of albumin GSC in laboratory animals.…”