GLOMERULAR FILTRATION RATE

GLOMERULAR FILTRATION RATERenal Blood Flow (RBF)Blood enters the kidney through the renal arteries and divides into progressively smaller arteries (interlobar, arcuate, and interlobular arteries) until it enters the glomerular capillary through the afferent arteriole. A portion of the plasma that enters the glomerulus is filtered across the glomerular membrane; this is called the filtration fraction. Renal Blood Flow (RBF)Under normal resting conditions, RBF is 20% of total cardiac output. Total blood flow is averaging 982 184 mL/min in women and 1209 256 mL/min in men. Renal plasma flow (RPF) is slightly less, averaging 592 mL/min in women and 659 mL/min in men, and varies with hematocrit (RPF = RBF [1Hct]). RBF to the outer cortex is 2 to 3 times greater than that to the inner cortex, which in turn is two to four times greater than that to the medulla.

Determinants of Glomerular FiltrationThrough the passive ultrafiltration of plasma across the glomerular membrane, the kidney is able to regulate total body salt and water content, electrolyte composition, and eliminate waste products of protein metabolism.

Determinants of Glomerular FiltrationThe glomerular filtration rate (GFR) is thus determined by both hydraulic and oncotic pressure differences between the glomerular capillary and the Bowman space, as well as by the permeability of the glomerular membrane:GFR = LpS (hydrostatic pressure oncotic pressure)Lp = glomerular permeabilityS = glomerular surface area

Determinants of Glomerular FiltrationThe rate at which filtration occurs within an individual nephron is termed the single nephron GFR (SN-GFR). A more relevant measurement is that of total GFR, which is the sum of all SN-GFR and is expressed in milliliters per minute. GFR is thus a reflection of overall renal function. Determinants of Glomerular FiltrationTransglomerular (hydraulic) pressure (TGP)Glomerular capillary is interposed between two arterioles (the afferent and efferent arterioles) and thus can regulate intraglomerular capillary pressure (IGP) independent of systemic pressures through changes in afferent and efferent arteriolar tone. Under normal circumstances, the pressure within the Bowman space is essentially zero, and only in conditions of urinary obstruction does the pressure increase to clinically significant levels. Determinants of Glomerular FiltrationRenal plasma flowIncreases in RPF lead to increases in GFR. Determinants of Glomerular FiltrationGlomerular permeabilityIncrease in permeability does not lead to an increase in GFR, because the glomerulus is already at maximal permeability for water and other relevant solutes. It may, however, lead to increased filtration of larger molecules not normally filtered, such as albumin. Reductions in permeability, or in glomerular surface area, can lead to reductions in GFR.

Determinants of Glomerular FiltrationOncotic pressureUnder normal circumstances, plasma proteins are not filtered across the glomerular membrane and so oncotic pressure within the Bowman space is essentially zero.

Regulation of GFRAutoregulationIncreases in mean arterial pressure (MAP), afferent arteriolar tone increases to minimize increases in IGP. Reductions in MAP, afferent arteriolar tone decreases to allow increased flow into the glomerulus to maintain IGP, thus maintaining GFR. Autoregulation of IGP is effective to a MAP of about 70 mm Hg, and below a MAP of 40 mm Hg, filtration ceases. It is likely mediated through myogenic stretch receptors in the afferent arteriole wall, possibly mediated by adenosine triphosphate (ATP.

Regulation of GFRTubuloglomerular feedback (TGF)If SN-GFR increases, delivery of sodium cations (Na+) and chloride anions (Cl) to the distal tubule also increases. This increased Cl delivery triggers a response by the macula densa, which ultimately leads to an increase in afferent arteriolar tone and subsequent decrease in RPF, thus returning SN-GFR (and tubular flow) back to baseline. It seems that angiotensin II plays a permissive role in TGF. Both adenosine and thromboxane can cause afferent arteriolar vasoconstriction and have been implicated in TGF. Nitric oxide is also believed to be important, particularly in minimizing TGF in the setting of increased NaCl intake.

Regulation of GFRBoth norepinephrine and angiotensin II play an important role in maintaining GFR through arteriolar vasoconstriction.Inhibition of PG synthesis can lead to severe vasoconstriction and acute reduction in GFR. Renal ClearanceThe best estimate of GFR can be obtained by measuring the rate of clearance of a given substance from the plasma. However, in order to be accurate, the substance to be measured must meet certain criteria. It must:Be able to achieve a stable plasma concentration,Be freely filtered across the glomerulus,Not be secreted, reabsorbed, synthesized, or otherwise metabolized by the renal tubules, andNot be impacted by any other means of removal from the plasma.

Renal ClearanceGFR = U[X] urine volume/P[X]This is called the clearance of a substance and reflects the amount of plasma that is completely cleared of the substance per unit time. Renal ClearanceThere are a number of substances that have been used clinically to estimate GFR :1. Inulin2. Radiolabelled compoundssuch as iothalamate or diethylenetriaminepentaacetic acid (DTPA).3. CreatininePlasma MarkersAn even simpler method to estimate GFR is with the use of plasma levels of substances that can be used as surrogate markers of GFR.Three such substances have been used:1. Plasma creatinine (PCr)2. Plasma urea3. Plasma cystatin C

Mathematical CorrectionThe two most widely used are the Cockcroft-Gault and modification of diet in renal disease (MDRD) formulas.Cockcroft-GaultOriginally developed from data collected from individuals with normal renal function; it is a simple formula to estimate CrCl (not GFR) that corrects for age, sex, and body mass. The formula is :

It has the advantage of being very simple, but is not as accurate as other methods when renal function is impaired.

MDRD FormulasA series of formulas derived from data collected in patients with severe renal impairment.They are more complex but more accurate than the Cockcroft-Gault. The simplest estimate of GFR is the four-variable equation :

Key PointsGFR reflects total renal function.GFR can be approximated by creatinine clearance.Formulas based on patients age, weight, and serum creatinine can best estimate GFR.