Monitoring of Glomerular Filtration Rate

Structure of the Glomerulus

In general, the GFR is determined by the rate of glomerular plasma flow (as it influences ultrafiltration pressure), systemic oncotic pressure, glomerular hydraulic pressure differences, and an ultrafiltration coefficient. The ultrafiltration coefficient is the product of glomerular capillary hydraulic permeability and total surface area available for filtration. The filtration rate across a capillary bed is therefore the product of surface area, pressure gradients, and permeability. In the glomerulus, the capillaries are configured in tufts, which increases their surface area. Hydrostatic pressures are normally maintained higher in glomerular capillaries than in other capillary beds by a delicate balance of preglomerular and postglomerular vascular tone in arterioles. The permeability of the glomerular capillary wall is equal for substances with molecular masses up to 5000 to 6000 daltons and decreases to almost zero at 60,000 to 70,000 daltons.^[40] Metabolic wastes and essential nutrients are filtered freely, and larger proteins, such as albumin and immunoglobulin G, are filtered in trace amounts or not at all. The glomerulopathic process in diabetes,^[41] for example, results from all of the factors that cause sustained increase in glomerular pressure and flow. Hyperglycemia induces a state of extracellular fluid volume expansion, structural hypertrophy of the kidney, and altered glucoregulatory and vasoregulatory hormone action. These hemodynamic consequences of hyperglycemia lead to renal vasodilation and increased plasma flow rate. The increase of plasma flow causes increased glomerular transcapillary flux of plasma proteins. The elevation in glomerular flow (i.e., pressure) also alters the permeability and selectivity of the glomerular basement membrane, resulting in increased protein filtration. The increased transglomerular flux of plasma proteins leads to their accumulation in the mesangium, which further propagates glomerulosclerosis.

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Inulin Clearance

GFR, the rate at which plasma water is filtered across the glomerulus, is an important index of renal function. Because the tubule reabsorbs most of the water filtered through the glomerulus, urine volume cannot be used to measure GFR. For measurement, a substance is required that is filtered through the glomerulus at the same rate as water and is excreted in the urine (i.e., neither reabsorbed nor secreted). The amount of such a substance filtered is then equal to the amount eliminated in the urine and can be determined from the product of the substance's concentration in plasma and the amount of plasma water filtered.

Inulin, an exogenous polysaccharide with a molecular mass of 5200 daltons, has been used to measure GFR because it is filtered freely in the glomerulus, not reabsorbed or secreted, and is excreted in the urine. Since its introduction into clinical practice in 1934, inulin clearance had been considered the standard for measurement of GFR.^[42] Its production is now limited, and it no longer remains a practical option in most clinical or experimental settings. To assess inulin clearance, the clinician administers a priming dose of inulin intravenously, followed by a continuous infusion calculated to maintain constant blood concentrations. After an equilibration period (usually 1 hour), clearance measurements are obtained. Urine is collected (typically with a Foley catheter), and venous blood samples are obtained at the midpoint of each clearance period. The longer the clearance period, the less likely is the introduction of error from incomplete voiding. The standard formula for calculation of clearance is as follows:

C_I = (U_I V)/P_I

U_I and P_I are the urine and plasma concentrations of inulin, C_I is the rate of insulin clearance, and V is the urine flow rate.

Creatinine Clearance

In clinical practice, the endogenous substance creatinine is used to measure clearance. Creatinine (molecular mass of 133 daltons) is a smaller substance than inulin and is produced from muscle metabolism. Creatinine is not an ideal substance for measuring clearance, because a small amount is secreted under normal conditions. Although creatinine clearance may exceed inulin clearance, the clearance of endogenous creatinine approximates that of inulin and has proved to be a reasonable measure of GFR.^[43] The creatinine-to-inulin clearance ratio is almost identical in normal infants, children, and adults. In subjects with moderate to severe renal insufficiency, however, the creatinine-to-inulin clearance ratio is increased.^[44] Increased secretion and clearance of creatinine in patients with renal insufficiency may therefore result in overestimates of true GFR.

Urea (molecular mass of 60 daltons) cannot be used to estimate GFR because, under normal conditions, it is filtered and reabsorbed. More importantly, urea clearance changes with the state of hydration; for example, under conditions of dehydration, urea clearance is significantly less than inulin clearance.