NOTE:

*GFR expressed in mL/min/1.73 m².

SCREENING FOR CKD

Screening for CKD is cost-effective in high-risk populations such as African Americans, Native Americans, Hispanics, and in patients with diabetes mellitus and hypertension. This is because therapeutic strategies such as angiotensin blockade and tighter blood pressure control are proven to be effective at earlier stages. Thus, early detection of CKD could potentially prevent ESRD in a significant proportion of high-risk patients. African Americans and Native Americans develop kidney failure at a fourfold higher rate than white Americans (953 and 652 cases per million in African Americans and Native Americans, respectively, compared to 237 per million among Caucasians). Patients with diabetes mellitus and hypertension and those with urine dipstick positive for protein have a higher risk of developing CKD. The NKF KDOQI guidelines for CKD recommend that all individuals should be assessed as part of routine health examinations to determine whether they are at increased risk for developing CKD. Individuals at high risk for kidney disease, particularly those with diabetes, hypertension, or a family history for these conditions and/or for kidney disease, should undergo formal testing. Such testing can be performed easily with a urinalysis, a first morning or a random “spot” urine sample for albumin or protein and creatinine assessment, and a serum creatinine level. The American Diabetes Association (ADA) recommends that for all type 2 diabetics at the time of diagnosis and all type 1 diabetics 5 years after initial diagnosis, an evaluation for microalbuminuria should be performed. If the dipstick is positive for either red or white blood cells, a microscopic analysis of the urinary sediment should be done.

NKF KDOQI GUIDELINES FOR CKD SCREENING IN PATIENTS WITH HYPERTENSION

• Serum creatinine measurement for GFR estimation

• Protein-to-creatinine ratio in a first morning or random “spot” urine specimen

• Either dipstick testing or urine sediment examination for red blood cells or white blood cells

In patients with hypertension found to have CKD

• Imaging of the kidneys, commonly by ultrasound

• Measurement of serum electrolytes (Na⁺, K⁺, Cl^–, HCO₃^–)

MEASUREMENT OF KIDNEY FUNCTION

USE OF SERUM CREATININE

Measurement of serum creatinine is currently the most widely utilized measure for the assessment of kidney function. However, the use of serum creatinine has several limitations (table 63.2). Because creatinine production is dependent on muscle mass, it needs to be interpreted cautiously among individuals with low muscle mass, among females, and in elderly patients. In patients with low muscle mass, the serum creatinine underestimates the degree of kidney function impairment, whereas among individuals with large muscle mass (such as body builders), the serum creatinine overestimates actual GFR. Another source of inaccuracy is the effect of noncreatinine chromogens when the alkaline picrate assay (Jaffe reaction) for creatinine is utilized. These factors include acetoacetate, cephalosporins, and high concentrations of furosemide. Modern versions of the Jaffe assay have reduced these effects by adjusting temperature, assay constituents, and various calibration settings.

    Given these limitations with serum creatinine as a measure of actual GFR, the NKF KDOQI and the National Kidney Disease Education Program (NKDEP) have recommended the use of actual or, when this is unavailable, a prediction equation for estimating GFR. Since in most situations direct measurement of GFR is not feasible, a prediction equation to estimate GFR is the most practical and accurate method to assess kidney function. The modification of diet in renal disease (MDRD) and Cockcroft-Gault equations are now the most popular prediction equations to assess GFR in adults.

    The MDRD (MDRD 3) equation is as follows:

    175 × [SCr]^–1.154 × [Age]^–0.203 × [0.742 if patient is female] × [1.21 if patient is black].

PREDICTION EQUATIONS FOR GFR

Cockroft-Gault Equation

This prediction equation is commonly used in clinical practice. Its major limitations are these: (1) It has limited generalizability. This is because it was originally formulated to calculate the creatinine clearance in patients without kidney disease (Canadian males). It has not been widely validated in different populations and under different clinical situations. (2) The Cockroft-Gault (CG) equation tends to overestimate GFR, especially among patients with chronic kidney disease. This is because it utilizes serum creatinine to estimate creatinine clearance. The limitations of measuring creatinine clearance apply to the CG equation. Among patients with moderate to severe kidney disease, creatinine secretion as a proportion of total creatinine excretion increases, resulting in an overestimation of the creatinine clearance. (3) Like the MDRD equation, the CG equation is inaccurate among individuals with normal or near-normal kidney function. (4) The CG equation uses weight, which frequently results in inaccuracies at extremes of weight and/or when there is a measurement error in the assessment of weight. Despite these limitations CG remains popular, especially among pharmacists who utilize it for drug-dosing adjustments in patients with reduced kidney function.

Modification of Diet in Renal Disease

The MDRD Study GFR prediction equation was developed in 1999. This equation has been validated in American black and white racial groups. It has also been validated in diabetics, predialysis patients, renal transplant recipients, and Asians. The MDRD formula yields an eGFR normalized to 1.73 m² body surface area. Adjusting for body surface area is necessary when comparing a patient’s eGFR with normal values or when determining the stage of CKD. However, an uncorrected eGFR may be preferred for clinical use in some situations, such as drug dosing.

    The advantages of the MDRD equation over the CG equation are shown in box 63.2. However, there are several clinical situations in which caution should be applied in using the MDRD equation (box 63.3).

    More recently, a new equation called the CKD-Epi equation has been proposed. This equation has less bias at high eGFRs and can be used to report eGFRs >60 mL/min/1.73 m². However, it has not yet been applied widely by clinical laboratories.

Box 63.2 ADVANTAGES OF THE MDRD OVER CG EQUATION

Box 63.3 WHEN THE MDRD EQUATION SHOULD BE USED CAUTIOUSLY

CLEARANCE BY RADIOLOGIC CONTRAST AGENTS AND RADIOACTIVE ISOTOPES

GFR can be calculated by the measurement of urinary or plasma clearances of isotopes or via images produced from a gamma camera. There are four different agents that are used in clinical practice: ¹²⁵I-iothalamate, ⁵¹Cr-ethylenediaminetetraacetic acid, ^99mTc-diethylenetriaminepentaacetic acid, and iohexol. These agents have been shown to correlate well with inulin clearance. They also have high precision in the setting of moderate to severe renal dysfunction. Inulin clearance is the gold standard for measurement of actual GFR because it is freely filtered and neither secreted nor reabsorbed by the kidney. However, it is not widely used in clinical practice largely for logistical reasons.

CREATININE CLEARANCE MEASUREMENT BY 24-HOUR URINE COLLECTION

Difficulties with 24-hour urine creatinine measurements include variations in urine collection (i.e., incorrect collections) and variations in the tubular secretion of creatinine. Studies have shown that in trained patients there can be up to a 14% variation in urine creatinine (Cr) quantity secondary to incorrect collection, and in untrained patients this can be as high as 70%. With regard to variations in tubular secretion, in patients with moderate to severe renal dysfunction, >50% of the urinary Cr can result from tubular secretion, thus leading to overestimation of the creatinine clearance by this method. In order to compensate for overestimation of GFR from tubular secretion of Cr in the 24-hour urine collection, the collection can be performed after oral administration of cimetidine, an organic cation that is a known competitive inhibitor of creatinine secretion. Alternatively, the use of the mean of urea and creatinine clearance measurements calculated from 24-hour urine collections has been suggested. Creatinine clearance overestimates GFR because creatinine is both filtered by the glomerulus and to a lesser degree, secreted by the proximal tubule. On the other hand, urea underestimates GFR because it is both filtered and reabsorbed. The mean value of the creatinine and urea clearance more closely approximates the actual GFR in the setting of GFR measurements <15 mL/min/1.73 m².

CYSTATIN C

Cystatin C is a nonglycosylated basic protease inhibitor produced by nucleated cells at a constant rate, is freely filtered by glomeruli, and is completely metabolized after tubular reabsorption. Unlike creatinine, serum cystatin C level is not dependent on muscle mass and is not differentially expressed based on gender. GFR as estimated from the plasma cystatin C concentration has been found to correlate well with iothalamate GFR measurements in Pima Indians with diabetes mellitus (DM) and normal or supranormal GFR. Cystatin has greater sensitivity than Cr for small changes in GFR. Recent studies suggest that cystatin C may be a better indicator of predicting risk for cardiovascular disease than either serum creatinine or a GFR prediction equation.

MANAGEMENT OF CKD PROGRESSION

CKD is characterized by reduced kidney function and impaired ability to adequately excrete waste products and maintain the constancy of the body’s homeostatic functions. Mild CKD is asymptomatic; moderate CKD is frequently characterized by hypertension, anemia, and abnormalities in mineral metabolism, and advanced CKD by uremia. CKD may become relentlessly progressive as the damage to functioning nephrons leads to a maladaptive response among the remaining nephrons. The progressive decline in kidney function in individuals with CKD is variable and depends both on the cause of the underlying insult and patient-specific factors. There is consensus that renal disease progression rates are heterogeneous both between different etiologies and within the same etiology. Thus, patients with polycystic kidney disease (PKD) may progress more slowly than patients with diabetic nephropathy; however, among patients with diabetic nephropathy there are patients who progress fast and others who progress hardly at all. Evidence also points to the importance of several factors in modulating kidney progression. These include albuminuria, the presence of systemic hypertension, age, gender, genetic factors, and smoking. However, regardless of the initial insult, the end result from a pathology standpoint is a scarred end-stage kidney (Figure 63.1).

    End-stage renal disease is the term used to denote CKD requiring renal replacement therapy (dialysis or transplantation). The incidence of ESRD in the United States is approximately 268 cases per million population per year. However, ESRD is overrepresented by about 4-fold among African Americans compared with white Americans. The major causes of ESRD in the United States are diabetes mellitus (44%), hypertension (30%), glomerular disease (15%), polycystic kidney disease, and obstructive uropathy. Elsewhere in the world, where the incidence of diabetes mellitus has not reached epidemic proportions—for example in Europe and parts of the developing world—chronic glomerulonephritis (20%) and chronic reflux nephropathy (25%) are the commonest causes of ESRD.

    CKD is usually asymptomatic when there is mild impairment in kidney function, whereas when GFR is markedly reduced, the patient is usually markedly symptomatic and may be severely disabled. In the early stages of CKD (stages 1 and 2 using the NKF KDOQI CKD stages), patients may present simply with an elevated serum creatinine and blood urea nitrogen (BUN) level but no symptoms. These individuals are usually unaware that they have any abnormalities in their kidney function, and they usually fail to register on the “radar screen” of their internists. However, even at this early stage insidious effects on target organs may become manifest. For example, patients may have mild to moderate hypertension, mild anemia, left ventricular hypertrophy, and subtle changes in bone structure from renal osteodystrophy. As kidney function gradually declines—with glomerular filtration rates reaching 15 mL/min, early features of uremia become evident. These include worsening or more difficult to control hypertension, extracellular volume expansion (manifest as edema and dyspnea), hyperkalemia and acidosis, anemia, and abnormalities in cognitive, psychological, and physical functions. Uremia reflects the accumulation of metabolic toxins, some characterized and others unknown, that influence the functioning of a variety of organ systems. The clinical presentation is often quite heterogeneous (Figure 63.2) and is thought to reflect a variable balance between biochemical and endocrine deficiencies and excesses (Figure 63.3). In this late stage the need for renal replacement therapy is imminent, and dialysis and/or transplantation becomes inevitable in order to sustain life (box 63.4).

Box 63.4 INDICATIONS FOR INITIATION OF RENAL REPLACEMENT THERAPY

    The indications for initiating renal replacement therapy include severe refractory abnormalities in biochemistry (severe hyperkalemia and acidosis), severe pulmonary edema, bleeding, metabolic encephalopathy, and the presence of pericarditis. Subtler but no less important indications include malnutrition and marked tiredness and lethargy.

    Life expectancy for a 49-year-old patient with ESRD is, on average, approximately 7 years, lower than that for colon cancer and prostate cancer and one-quarter that of the general population. This reduction in life expectancy is largely attributable to cardiovascular complications. Nearly 50% of all deaths in patients with ESRD are due to cardiovascular causes. The risk is 17 times that of the general population. Remarkably, this gap is largest in young patients with end-stage renal disease. The risk factors for cardiovascular disease in individuals with chronic renal failure include the magnitude of the calcium-phosphorus product with its risk of coronary calcification, the presence of dyslipidemia, hypertension, hyperhomocysteinemia, and the presence of left ventricular hypertrophy (LVH). The clinical manifestations of cardiovascular disease in ESRD patients include LVH, left ventricular dilatation, diastolic dysfunction, macro- and microvascular disease, and abnormalities in autonomic function—increased sympathetic discharge and increased circulating catecholamine levels. Vascular disease may involve calcification of coronary vessels and valve disease. Indeed, calcification of the mitral valve annulus and the aortic valve cusps is common among ESRD patients.

KDOQI ACTION PLAN BY STAGE OF CKD

The NKF KDOQI group has released an action plan for management of patients with CKD as determined by stage of CKD. In stage 1 CKD these guidelines suggest the diagnosis and treatment of CKD, treatment of comorbid conditions, prevention of progression of renal disease, and CVD risk reduction. In stage 2 the issue of primary concern is that of estimating and managing renal disease progression. The focus in stage 3 disease is that of evaluating and treating complications, whereas stage 4 CKD, the immediate predialysis stage, consists of preparation for renal replacement therapy. The management of stage 5 CKD is that of initiation and maintenance of renal replacement therapy. Thus, in addition to the task of diagnosing and treating the specific etiology of renal disease, the broad themes that govern early versus late renal disease management are those of prevention of progression in the early stages of CKD, management of complications beginning in the early stages and continuing throughout the follow-up of patients, and preparation for renal replacement in the later predialysis phase (figures 63.4 and 63.5).

    Declining kidney function is associated with altered clearance of many drugs (e.g., aminoglycosides), as well as increased toxicity (e.g., iodinated contrast agents and phosphate-based enemas). In addition, gadolinium exposure in patients with moderate-to-severe CKD may be associated with an increased risk of nephrogenic systemic fibrosis. Lastly, some drugs are contraindicated in patients with moderate-to-severe CKD (e.g., metformin, because of the risk of lactic acidosis).

    There are three important elements to the management of progression in CKD patients.

The Use of Angiotensin Blockers to Protect the Kidney

Both landmark studies in animals by Brenner and colleagues as well as studies in humans support an independent role for angiotensin blockade in renoprotection. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) can be used. The dose of ACE inhibitor or ARB should be titrated to maximal levels using reduction of proteinuria as the yardstick for efficacy. In addition, sodium restriction and diuretics in conjunction with ACE inhibitor/ARB therapy increase their antiproteinuric effects and should be used in an adjunctive fashion. (ACE inhibitors and ARBs are contraindicated in patients who are pregnant and in patients with a history of angioedema.) The use of dual blockade with both an ACE inhibitor and an ARB is not recommended because of a higher rate of adverse events.

Control of Blood Pressure

The MDRD study demonstrated that patients targeted to MAP of 92 and 107 mm Hg had rates of decline of GFR of –3.56 and –4.10 mL/min/year, respectively, and that there was greater effect with increasing levels of albuminuria. This study, taken in conjunction with several other studies that have been published subsequently, all point to beneficial effects of controlling blood pressure on kidney disease. On the other hand the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study has demonstrated that among diabetic patients, being assigned to the more aggressive control of blood pressure (<120 versus <140 mm Hg systolic pressure) is associated with a higher rate of adverse events (hypotension and bradycardia). Among a subset of patients with impaired kidney function who were enrolled in ACCORD, aggressive blood pressure control was associated with higher number of renal complications (doubling of serum creatinine or end-stage renal disease). Therefore, the 2013 American Diabetes Association now recommends a blood pressure goal of <140/80 mmHg. On the other hand, the 2013 JNC8 guidelines recommend a target BP in CKD patients of <140/90 mmHg. The 2012 KDIGO clinical practice guidelines for the management of blood pressure in CKD patients are shown in box 63.5.

Box 63.5 2003 NKF-KDOQI CLINICAL PRACTICE GUIDELINES FOR ANTIHYPERTENSIVE THERAPY RECOMMENDATIONS

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