Color Atlas of Physiology 2003 thieme

Glomerular Filtration and Clearance

The glomerular filtration rate (GFR) is the total volume of fluid filtered by the glomeruli per unit time. It is normally about 120 mL/min per 1.73 m2 of body surface area, equivalent to around 180 L/day. Accordingly, the volume of exchangeable extracellular fluid of the whole body (ca. 17 L) enters the renal tubules about 10 times a day. About 99% of the GFR returns to the extracellular compartment by tubular reabsorption. The mean fractional excretion of H2O is therefore about 1% of the GFR, and abso. - lute H2O excretion (= urine output/time = VU) is about 1 to 2 L per day. (The filtration of dissolved substances is described on p. 154).

The GFR makes up about 20% of renal plasma flow, RPF (!p. 150). The filtration fraction (FF) is defined as the ratio of GFR/RPF. The filtration fraction is increased by atriopeptin, a peptide hormone that increases efferent arteriolar resistance (Re) while lowering afferent arteriolar resistance (Ra). This raises the effective filtration pressure in the glomerular capillaries without significantly changing the overall resistance in the renal circulation.

The effective filtration pressure (Peff) is the driving “force” for filtration. Peff is the glomerular capillary pressure (Pcap !48 mmHg) minus the pressure in Bowman’s capsule (PBow

Peff at the arterial end of the capillaries equals 48–13–25 = 10 mmHg. Because of the high filtration fraction, the plasma protein concentration and, therefore, πcap values along the glomerular capillaries increase (!p. 378) and Peff decreases. (The mean effective filtration pressure, Peff, is therefore used in Eq. 7.7.) Thus, filtration ceases (near distal end of capillary) when πcap rises to about 35 mmHg, decreasing Peff to zero (filtration equilibrium).

GFR is the product of Peff (mean for all glomeruli), the glomerular filtration area A (de-

pendent on the number of intact glomeruli), and the water permeability k of the glomerular filter. The ultrafiltration coefficient Kf is used to

Indicators present in the plasma are used to measure GFR. They must have the following properties:

—They must be freely filterable

—Their filtered amount must not change due to resorption or secretion in the tubule

—They must not be metabolized in the kidney

—They must not alter renal function

Inulin, which must be infused intravenously, fulfills these requirements. Endogenous creatinine (normally present in blood) can also be used with certain limitations.

The amount of indicator filtered over time (!A) is calculated as the plasma concentration of the indicator (PIn, in g/L or mol/L) times the GFR in L/min. The same amount of indicator/time appears in the urine (conditions. 2 and 3; see above) and is calculated as VU (in L/min), times the indicator conc. in urine. (UIn, in g/L or mol/L, resp..), i.e. PIn ! GFR = VU ! UIn, or:

GFR ! VU ! UIn [L/min] (!A). [7.8]

PIn

The expression on the right of Eq. 7.8 represents clearance, regardless of which substance is being investigated. Therefore, the inulin or creatinine clearance represents the GFR. (Although the plasma concentration of creatinine, Pcr, rises as the GFR falls, Pcr alone is a quite unreliable measure of GFR.)

Clearance can also be regarded as the completely indicator-free (or cleared) plasma volume flowing through the kidney per unit time. Fractional excretion (FE) is the ratio of clearance of a given substance X to inulin clearance (CX/CIn) and defines which fraction of the filtered quantity of X was excreted (cf. p. 154). FE "1 if the substance is removed from the tubule by reabsorption (e.g. Na+, Cl–, amino acids, glucose, etc.; !B1), and FE #1 if the substance is subject to filtration plus tubular secretion (!B2). For PAH (!p. 150), tubular secretion is so effective that FEPAH !5 (500%).

The absolute rate of reabsorption or secretion of a freely filterable substance X (mol/ min) is calculated as the difference between the filtered amount/time. (GFR · PX) and the excreted amount/time (VU · UX), where a positive result means net reabsorption and a negative net secretion. (For inulin, the result would be zero.)

Uln (g/L) . V·U (mL/min) = Pln (g/L) . GFR (mL/min)

GFR = Uln . V.U (mL/min)

Pln

GFR ≈ ca. 120mL/min

per 1.73m2 body surface area

!

Reabsorption in different segments of the tubule. The concentration of a substance X (TFX) and inulin (TFin) in tubular fluid can be measured via micropuncture (!A). The values can be used to calculate the non-reabsorbed fraction (fractional delivery, FD) of a freely filtered substance X as follows:

FD = (TFX/PX)/(TFin/Pin),

where PX and Pin are the respective concentrations in plasma (more precisely: in plasma water).

Fractional reabsorption (FR) up to the sampling site can then be derived from 1 – FD (!D, columns 2 and 3, in %).

Reabsorption and secretion of various substances (see pp. 16–30, transport mechanisms). Apart from H2O, many inorganic ions (e.g., Na+, Cl–, K+, Ca2+, and Mg2+) and organic substances (e.g., HCO3–, D-glucose, L-amino acids, urate, lactate, vitamin C, peptides and proteins; !C, D, p. 158ff.) are also subject to tubular reabsorption (!B1–3). Endogenous products of metabolism (e.g., urate, glucuronides, hippurates, and sulfates) and foreign substances (e.g., penicillin, diuretics, and PAH; !p. 150) enter the tubular urine by way of transcellular secretion (!B4, C). Many substances, such as ammonia (NH3) and H+ are first produced by tubule cells before they enter the tubule by cellular secretion. NH3 enters the tubule lumen by passive transport (!B5), while H+ ions are secreted by active transport (!B6 and p. 174ff.).

Na+/K+ transport by Na+-K+-ATPase (!p. 26) in the basolateral membrane of the tubule and collecting duct serves as the “motor” for most of these transport processes. By primary active transport (fueled directly by ATP consumption), Na+-K+-ATPase pumps Na+ out of the cell into the blood while pumping K+ in the opposite direction (subscript “i” = intracellular and “o” = extracellular). This creates two driving “forces” essential for the transport of numerous substances (including Na+ and K+): first, a chemical Na+ gradient ([Na+]o ! [Na+]i) and (because [K+]i ! [K+]o), second, a membrane potential (inside the cell is negative relative to the outside) which represents an electrical gradient and can drive ion transport (!pp. 32ff. and 44).

Transcellular transport implies that two membranes must be crossed, usually by two different mechanisms. If a given substance (D- glucose, PAH, etc.) is actively transported across an epithelial barrier (i.e., against an electrochemical gradient; !see p. 26ff.), at least one of the two serial membrane transport steps must also be active.

Interaction of transporters. Active and passive transport processes are usually closely interrelated. The active absorption of a solute such as Na+ or D-glucose, for example, results in the development of an osmotic gradient (!p. 24), leading to the passive absorption of water. When water is absorbed, certain solutes are carried along with it (solvent drag; !p. 24), while other substrates within the tubule become more concentrated. The latter solutes (e.g., Cl– and urea) then return to the blood along their concentration gradients by passive reabsorption. Electrogenic ion transport and ion-coupled transport (!p. 28) can depolarize or hyperpolarize only the luminal or only the basolateral membrane of the tubule cells. This causes a transepithelial potential which serves as the driving “force” for paracellular ion transport in some cases.

Since non-ionized forms of weak electrolytes are more lipid-soluble than ionized forms, they are better able to penetrate the membrane (non-ionic diffusion; !B2). Thus, the pH of the urine has a greater influence on passive reabsorption by non-ionic diffusion. Molecular size also influences diffusion: the smaller a molecule, the larger its diffusion coefficient (!p. 20ff.).