Chapter 045. Azotemia and Urinary Abnormalities (Part 2) Assessment of Glomerular Filtration Rate Monitoring the GFR is important in both the hospital and outpatient settings, and several different methodologies are available (discussed below). In most acute clinical circumstances a measured GFR is not available, and the serum creatinine level is used to estimate the GFR in order to supply appropriate doses of renally excreted drugs and to follow short-term changes in GFR. Serum creatinine is the most widely used marker for GFR, and the GFR is related directly to the urine creatinine excretion and inversely to the serum creatinine (U Cr /P Cr ). The creatinine clearance is calculated from these measurements for a defined time period (usually 24 h) and is expressed in mL/min. Based upon this relationship and some important caveats (discussed below), the GFR will fall in roughly inverse proportion to the rise in P Cr . Failure to account for GFR reductions in drug dosing can lead to significant morbidity and mortality from drug toxicities (e.g., digoxin, aminoglycosides). In the outpatient setting, the serum creatinine is often used as a surrogate for GFR (although much less accurate; see below). In patients with chronic progressive renal disease there is an approximately linear relationship between 1/P Cr and time. The slope of this line will remain constant for an individual patient, and when values are obtained that do not fall on this line, an investigation for a superimposed acute process (e.g., volume depletion, drug reaction) should be initiated. It should be emphasized that the signs and symptoms of uremia will develop at significantly different levels of serum creatinine depending upon the patient (size, age, and sex), the underlying renal disease, existence of concurrent diseases, and true GFR. In general, patients do not develop symptomatic uremia until renal insufficiency is usually quite severe (GFR < 15 mL/min). A reduced GFR leads to retention of nitrogenous waste products (azotemia) such as urea and creatinine. Azotemia may result from reduced renal perfusion, intrinsic renal disease, or postrenal processes (ureteral obstruction; see below and Fig. 45-1). Precise determination of GFR is problematic as both commonly measured indices (urea and creatinine) have characteristics that affect their accuracy as markers of clearance. Urea clearance may significantly underestimate GFR because of tubule urea reabsorption. Creatinine is derived from muscle metabolism of creatine, and its generation varies little from day to day. Creatinine is useful for estimating GFR because it is a small, freely filtered solute. However, serum creatinine levels can increase acutely from dietary ingestion of cooked meat, and creatinine can be secreted into the proximal tubule through an organic cation pathway, leading to overestimation of the GFR. There are many clinical settings where a creatinine clearance is not available, and decisions concerning drug dosing must be made based on the serum creatinine. Two formulas are widely used to estimate GFR: (1) Cockcroft-Gault, which accounts for age and muscle mass (this value should be multiplied by 0.85 for women, since a lower fraction of the body weight is composed of muscle): and (2) MDRD (modification of diet in renal disease): Approach to the patient with azotemia. WBC, white blood cell; RBC, red blood cell; GBM, glomerular basement membrane Although more cumbersome than Cockcroft-Gault, the MDRD equation is felt to be more accurate, and numerous websites are available for making the calculation (www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). The gradual loss of muscle from chronic illness, chronic use of glucocorticoids, or malnutrition can mask significant changes in GFR with small or imperceptible changes in serum creatinine concentration. More accurate determinations of GFR are available using inulin clearance or radionuclide-labeled markers such as 125 I-iothalamate or EDTA. These methods are highly accurate due to precise quantitation and the absence of any renal reabsorption/secretion and should be used to follow GFR in patients in whom creatinine is not likely to be a reliable indicator (patients with decreased muscle mass secondary to age, malnutrition, concurrent illnesses). (See also Table 274-2.) Cystatin C is a member of the cystatin superfamily of cysteine protease inhibitors and is produced at a relatively constant rate from all nucleated cells. Cystatin C production is not affected by diet or nutritional status and may provide a more sensitive indicator of GFR than the plasma creatinine concentration. However, it remains to be validated in many clinical settings. . Chapter 045. Azotemia and Urinary Abnormalities (Part 2) Assessment of Glomerular Filtration Rate Monitoring the GFR is important in both the hospital and outpatient settings, and. products (azotemia) such as urea and creatinine. Azotemia may result from reduced renal perfusion, intrinsic renal disease, or postrenal processes (ureteral obstruction; see below and Fig fraction of the body weight is composed of muscle): and (2) MDRD (modification of diet in renal disease): Approach to the patient with azotemia. WBC, white blood cell; RBC, red blood cell;