SITI SYAZANA SAAD 08-6-52

DRUGS ADJUSTMENT IN RENAL IMPAIRMENT ACCORDING TO ESTIMATION OF GLOMERULER FILTRATION RATE

Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturerrecommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 1040% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.

The Cockcroft-Gault (CG)

The glomerulus produces a selective ultrafiltrate of the blood. The rate of ultrafiltration is called the glomerular filtration rate which is about 120 ml/min or 170 litres per day. This is written 120 ml/min/1.73m2, to emphasise the fact that the rate is closely related to the body surface area. The glomerular filtration rate increases from birth - in the neonate it is about one millilitre per minute. In children the GFR may be estimated from the plasma creatinine as follows: GFR = height (in cm) x 40 / plasma creatinine In adults, there are various methods that may be used to estimate GFR: Cockcroft-Gault equation is often used as a method of estimating GFR (although it was developed as a method of predicting creatinine clearance) from knowledge of serum creatinine, age and weight: creatinine clearance = (((140 - age in years) x (wt in kg)) x 1.23) / (serum creatinine in micromol/l) For women multiply the result of calculation by 0.85.The calculation is unreliable if the patient has unstable renal function, is very obese, or is oedematous.

SITI SYAZANA SAAD 08-6-52 An alternative is the 4-variable Modification of Diet in Renal Disease (MDRD) equation (1): GFR (mL/min/1.73m2) = 186 x {[serum creatinine (mol/L)/88.4] ^-1.154} x age (years) ^-0.203 x 0.742 if female and x 1.21 if African-Caribbean Notes: GFR estimates between 60 and 89 mL/min/1.73 m2 do not indicate chronic kidney disease unless there is other laboratory/clinical evidence of disease there is no need to collect 24 h urine samples to measure creatinine clearance in primary care in cases where there are extremes of muscle mass - for example, in bodybuilders, amputees or people with muscle wasting disorders - interpret the eGFR with caution reduced muscle mass will lead to overestimation and increased muscle mass to underestimation of the GFR advise people not to eat any meat in the 12 hours before having a blood test for GFR estimation. Avoid delaying the despatch of blood samples to ensure that they are received and processed by the laboratory within 12 hours of venepuncture

MDRD Study Equation

Because mild and moderate kidney injury is poorly inferred from serum creatinine alone, NKDEP strongly encourages clinical laboratories to routinely estimate glomerular filtration rate (GFR) and report the value when serum creatinine is measured for patients 18 and older, when appropriate and feasible. An estimated GFR (eGFR) calculated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) Study equation is a simple and effective way in which laboratories can help health care providers detect CKD among those with risk factorsdiabetes, hypertension, cardiovascular disease, or family history of kidney disease. Providers also may use eGFR to monitor patients already diagnosed with CKD. The following is the IDMS-traceable MDRD Study equation (for creatinine methods calibrated to an IDMS reference method) GFR (mL/min/1.73 m2) = 175 (Scr)-1.154 (Age)-0.203 (0.742 if female) (1.212 if African American) The equation does not require weight or height variables because the results are reported normalized to 1.73 m2 body surface area, which is an accepted average adult surface area.

Rationale for Use

There are several reasons for using the MDRD Study equation to estimate GFR, including: The normal serum creatinine reference interval does not necessarily reflect a normal GFR for a patient. Because the MDRD Study equation employs age, gender, and race, providers may observe that CKD is present despite a serum creatinine concentration that appears to fall within or just above the normal reference interval. The MDRD Study equation is the most thoroughly validated equation. The equation has been validated extensively in Caucasian and African American populations between the ages of 18 and

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70* with impaired kidney function (eGFR < 60 mL/min/1.73 m2) and has shown good performance for patients with all common causes of kidney disease1. The MDRD Study equation is currently superior to other methods of approximating GFR. Direct comparison of the MDRD to other equations such as Cockcroft-Gault and to creatinine clearance measured from 24-hour urine collections has demonstrated this superiority. Note that creatinine clearance should be considered when the patient's basal creatinine production is very abnormal. This may be the case with patients of extreme body size or muscle mass (e.g., obese, severely malnourished, amputees, paraplegics, or other muscle-wasting diseases), or with unusual dietary intake (e.g., vegetarian, creatine supplements). Measurement of kidney function (eGFR or creatinine clearance) is essential once albuminuria is discovered.

When Not to Use the MDRD Equation

The MDRD Study equation is not for all patients. Although an excellent tool for assessing kidney function, eGFR derived from the MDRD Study equation may not be suitable for all populations. MDRD-based estimates of GFR, like all creatinine-based estimates of kidney function (e.g., CockcroftGault, reciprocal of serum creatinine), are only useful when renal function is stable; serum creatinine values obtained while kidney function is changing will not provide accurate estimates of kidney function. Additionally, the equation is not recommended for use with:
Nonadults. This includes all individuals under the age of 18. The Schwartz equation should be used to estimate GFR for infants, toddlers, children, and teens under age 18. Individuals with unstable creatinine concentrations. This includes pregnant women; patients with serious co-morbid conditions; and hospitalized patients, particularly those with acute renal failure. The MDRD Study equation should be used only for patients with stable creatinine concentrations. Persons with extremes in muscle mass and diet. This includes, but is not limited to, individuals who are amputees, paraplegics, bodybuilders, or obese; patients who have a muscle-wasting disease or a neuromuscular disorder; and those suffering from malnutrition, eating a vegetarian or low-meat diet, or taking creatine dietary supplements.

Application of the equation to these patient groups may lead to errors in GFR estimation4. GFR estimating equations have poorer agreement with measured GFR for ill hospitalized patients5 and for people with near normal kidney function1 than for the patients in the MDRD Study.
*The equation has not been validated in patients older than 70, but an MDRD-derived eGFR may still be a useful tool for providers caring for patients older than 70.

As noted above, providers should exercise judgment regarding clinical status when presented with an MDRD Study-derived eGFR for a patient with an unstable creatinine level or other condition for which the equation is not suitable. Providers may not understand that estimating equations like the

SITI SYAZANA SAAD 08-6-52 MDRD are derived from large populations of patients and provide the best estimate of mean GFR for a group of people of a certain age, race, gender, and serum creatinine value. Thus, the reported eGFR is the best estimate of a patient's GFR; it is not the patient's actual GFR. Reduce Rounding Errors NKDEP recommends using serum creatinine values in mg/dL to two decimal places (e.g., 0.95 mg/dL) OR values in mol/L to the nearest whole number (e.g., 84 mol/L) when calculating eGFR using the MDRD Study equation. This practice will reduce rounding errors that may contribute to imprecision in the eGFR value.

The CKD-EPI Equation The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
CKD-EPI equation is a new equation, published in 2009, to estimate glomerular filtration rate (GFR) from serum creatinine, age, sex, and race for adults age 18 years 1. The National Kidney Disease Education Program has not made a recommendation on general implementation of this equation. The equation is still being validated and, while offering some improvement for eGFR between 60 and 120 mL/min/1.73 m2, it is not clear that implementing CKD-EPI in place of the Modification of Diet in Renal Disease (MDRD) equation would alter clinical detection or management of patients with CKD. However, a laboratory that reports eGFR numeric values > 60 mL/min/1.73 m 2 should consider using the CKD-EPI equation. Although the CKD-EPI equation is, on average, more accurate for values > 60 mL/min/1.73 m2 than is the MDRD Study equation, the influence of imprecision of creatinine assays on the uncertainty of an eGFR value is greater at higher eGFR values and should be considered when determining the highest eGFR value to report. The equation is based on the same four variables as the MDRD Study equation but uses a 2-slope "spline" to model the relationship between GFR and serum creatinine, age, sex, and race. The equation is given in the following table for creatinine in mg/dL (see Appendix for creatinine in mol/L). The equation can be expressed in a single equation (see table legend) or as a series of equations for different race, sex, and creatinine conditions (see table rows).

SITI SYAZANA SAAD 08-6-52 Table 1: CKD EPI Equation for Estimating GFR Expressed for Specified Race, Sex and Serum Creatinine in mg/dL (From Ann Intern Med 2009;150:604-612, used with permission)

CKD-EPI equation expressed as a single equation:

GFR = 141 min (Scr /, 1) max(Scr /, 1)-1.209 0.993Age 1.018 [if female] 1.159 [if black] where: Scr is serum creatinine in mg/dL, is 0.7 for females and 0.9 for males, is -0.329 for females and -0.411 for males, min indicates the minimum of Scr / or 1, and max indicates the maximum of Scr / or 1.

Limitations of the CKD-EPI Equation

Limitations using creatinine as a filtration marker: both the MDRD study and CKD-EPI equations are based on serum creatinine. Despite modest reduction in bias with the CKD-EPI equation, estimates remain imprecise, with some people showing large differences between the measured and estimated GFR. Like all other creatinine-based estimation equations, they suffer from physiologic limitations of creatinine as a filtration marker3, 6. The terms for age, sex, and race in both equations only capture some of the non-GFR determinants of creatinine concentration in blood plasma, and the coefficients represent average effects observed in the population used to develop the equations. All estimates of GFR based on serum creatinine will be less accurate for patients at the extremes of muscle mass (including frail elderly, critically ill, or cancer patients), those with unusual diets, and those with conditions associated with reduced secretion or extra-renal elimination of creatinine. Confirmatory tests with exogenous measured GFR or measured creatinine clearance should be performed for people in whom estimates based on serum/plasma/blood creatinine alone may be inaccurate. Populations not well represented in the development or validation cohorts: Elderly people and blacks with higher levels of GFR, racial and ethnic minorities other than blacks.

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The influence of creatinine measurement imprecision at low creatinine concentrations (high eGFR) has not been carefully studied but has likely contributed to the variability at higher eGFR values.

Prescribing in renal impairment

Drugs that are renally excreted may need to have their doses reduced in patients with renal insufficiency or end-stage renal disease: For prescribing purposes renal impairment is usually divided into three grades: Mild: GFR 20-50 ml/minute; serum creatinine approximately 150-300 mol/l. Moderate: GFR 10-20 ml/minute; serum creatinine approximately 300-700 mol/L. Severe: GFR less than 10 ml/minute; serum creatinine >700 mol/L.

Patients with a GFR above 50 ml/min do not usually require any dosage adjustment. Nephrotoxic drugs should, if possible, be avoided in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when the renal reserve is already reduced. The situation may change if a patient begins dialysis, since some drugs will be removed by the dialysis. Dialysis may lead to the loss of therapeutic effect for some drugs. Drugs to which particular attention must be given include many antibiotics, histamine H2-receptor antagonists, digoxin, anticonvulsants and non-steroidal anti-inflammatory drugs (NSAIDs). For many drugs with only minor or no dose-related side-effects very precise modification of the dose regimen is unnecessary and a simple scheme for dose reduction is sufficient. For more toxic drugs with a small safety margin, dose regimens based on GFR should be used. The total daily maintenance dose of a drug can be reduced either by reducing the size of the individual doses or by increasing the interval between doses. For some drugs, if the size of the maintenance dose is reduced it will be important to give a loading dose if an immediate effect is required. The loading dose should usually be the same size as the initial dose for a patient with normal renal function.

REFERENCES: http://www.slideserve.com/dorcas/estimated-gfr-based-on-creatinine-and-cystatin-c http://nkdep.nih.gov/lab-evaluation/gfr/estimating.shtml