Staging and Management of Chronic Kidney DiseaseLesley A. Inker | Andrew S. Levey

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Chronic kidney disease (CKD) is a growing worldwide pub-lic health problem, characterized by increasing prevalence, high cost, and poor outcomes. The poor outcomes of CKD are not restricted to progression of kidney disease leading to chronic kidney failure, but also include increased risk for acute kidney injury (AKI), cardiovascular disease (CVD), and mortality, as well as a wide variety of other complications.

In 2002, the Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation (NKF) spon-sored guidelines for the definition, classification, evalua-tion, and risk stratification of CKD. The purpose of these guidelines was to create uniform terminology to improve communications among all involved in the care and man-agement of CKD, including patients, physicians, research-ers, and policymakers. The guidelines were adopted with minor modification by Kidney Disease: Improving Global Outcomes (KDIGO) in 2005. In response to controversy and accumulation of new data, KDIGO sponsored a Contro-versies Conference in 2009, which recommended maintain-ing the definition of CKD but modifying the classification, ultimately leading to new guidelines in 2012. The goals of this chapter are to describe the conceptual model for the progression of CKD, the revised KDIGO guidelines for the definition and stages of CKD, and the associated preva-lence and clinical action plan, with emphasis on the role of nephrologists in the care of these patients.

DEFINITION AND STAGING OF CHRONIC KIDNEY DISEASE

COURSE OF CHRONIC KIDNEY DISEASE

Figure 53.1 shows a conceptual model for the course of CKD, and Table 53.1 outlines the outcomes. This model describes the natural history of CKD, beginning with ante-cedent conditions associated with increased risk for develop-ing kidney disease, followed by the stages of CKD (kidney damage, decreased glomerular filtration rate [GFR], and kidney failure), and associated complications.

Risk factors for development of CKD include exposure to factors that cause kidney disease, such as hypertension, diabe-tes, autoimmune diseases, and kidney stones, and characteris-tics that increase susceptibility to kidney disease, such as older age, minority racial and ethnic status, and reduced nephron mass. The mechanisms underlying increased susceptibility have not been completely described or proven. For example, minority race or ethnicity may imply an underlying genetic tendency, or it may be a marker for lack of access to health

care. Susceptibility factors may explain why a family history of kidney disease, regardless of the cause, places an individual at increased risk for development of kidney disease.

The horizontal arrows in Figure 53.1 indicate transitions among kidney outcomes. The arrows pointing from left to right emphasize the progressive nature of CKD. How-ever, the rate of progression is variable, and not all CKD progresses; thus, not all patients with CKD develop kidney failure. Interventions in earlier stages may slow or prevent the progression to later stages. Early stages of kidney dis-ease may be reversible, and individuals with kidney failure can revert to earlier stages through kidney transplantation, shown as dashed arrowheads pointing from right to left. Studies suggest that CKD is a risk factor for development of AKI, and that episodes of AKI may increase the risk for pro-gression of CKD. The earlier stages and the risk factors for progression to higher stages can be identified, permitting improvement in outcome by prevention, earlier detection, and initiation of therapies that can slow progression and prevent the development of kidney failure.

The diagonal arrows emphasize complications of CKD other than kidney outcomes. Metabolic and endocrine complications of decreased GFR, including anemia, bone and mineral disorders, malnutrition, and neuropathy, have long been recognized as consequences of kidney failure, but these abnormalities may appear with lesser reduction in GFR. Similarly, nephrotic syndrome occurs in patients with marked albuminuria, but hyperlipidemia and hypercoagula-bility may be observed with lesser increases in albuminuria. It is well accepted that both decreased GFR and albumin-uria are associated with an independent risk of CVD and all-cause mortality. More recently, recognized complications are threats to patient safety from systemic toxicity from drugs and procedures, as well as an increased risk of infections and impaired cognitive and physical function. Strategies for prevention, early detection, and treatment of CKD complica-tions may prolong survival and improve quality of life even if there is no effect on kidney disease progression.

DEFINITION OF CHRONIC KIDNEY DISEASE

Chronic kidney disease is defined as either kidney damage or GFR of less than 60 mL/min/1.73 m2 of body surface area lasting for longer than 3 months (90 days). CKD can be diagnosed without knowledge of its cause (Table 53.2).

Kidney damage can be within the parenchyma, large blood vessels, or collecting systems, and it is usually inferred from markers rather than direct examination of kidney tissue. As discussed later, the markers of kidney damage often provide

459 CHAPTER 53 — STAGING AND MANAGEMENT OF CHRONIC KIDNEY DISEASE

Complications

DeathKidneyfailure

↓ GFRDamageIncreasedriskNormal

Screeningfor CKD

risk factors

CKD riskreduction;Screeningfor CKD

Diagnosisand treatment;Treat comorbid

conditions;Slow progression

Estimateprogression;

Treatcomplications;

Prepare forreplacement

Replacementby dialysis

and transplant

Figure 53.1 Conceptual model for chronic kidney disease. The continuum of development, progression, and complications of chronic kidney disease (CKD) and strategies to improve outcomes. Dark green circles, Stages of CKD; light green circles, potential antecedents of CKD; lavender circles, consequences of CKD; thick arrows between circles, development, progression, and remission of CKD. Complications refers to all complica-tions of CKD, including complications of decreased glomerular filtration rate and cardiovascular disease. Complications may also arise from adverse effects of interventions to prevent or treat the disease. Horizontal arrows pointing from left to right emphasize the progressive nature of CKD. Dashed arrowheads pointing from right to left signify that remission is less frequent than progression. (Reproduced with modifications from the National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39[2 Suppl 1]:S1-266; 2002, and Levey AS, Stevens LA, Coresh J: Conceptual model of CKD: applications and implications, Am J Kidney Dis 53:S4-S16, 2009.)

a clue to the likely site of damage within the kidney and, in association with other clinical findings, the cause of kidney disease. Because most kidney diseases in North America are caused by diabetes or hypertension, persistent albuminuria is the principal marker. Other markers of damage include

Table 53.1 Outcomes of Chronic Kidney Disease and Relationship to Kidney Disease Characteristics

Outcomes of CKD

Kidney Disease Characteristics

GFR Albuminuria Cause

Kidney Outcomes

CKD progression (GFR decline and worsening albuminuria)

+ +++ +++

AKI +++ + +Chronic kidney failure +++ + +++

Complications (Current and Future)

CVD and mortality +++ +++ ++Systemic drug toxicity +++ + +Metabolic/endocrine

(anemia, bone and mineral disorders, malnutrition, and neuropathy)

+++ + +

Infections, cognitive impairment, frailty

++ ++ ++

AKI, Acute kidney injury; CKD, chronic kidney disease; CVD, cardiovascular disease; GFR, glomerular filtration rate.

Number of + indicates the strength of the risk relationship between the kidney disease characteristic and the outcome.

abnormalities in urine sediment (e.g., tubular cells or casts), abnormal findings on imaging studies (e.g., hydronephro-sis, asymmetry in kidney size, polycystic kidney disease, small echogenic kidneys), and abnormalities in blood and urine chemistry measurements (those related to altered tubular function, such as renal tubular acidosis). A history of kid-ney transplantation is also defined as a marker of kidney damage, and patients with a functioning transplant are con-sidered to have CKD, irrespective of the presence of other markers of kidney damage or the level of GFR.

Decreased GFR, specifically GFR less than 60 mL/min/1.73 m2, lasting more than 3 months is defined as CKD, irrespective of age. The level of GFR is usually accepted as the best overall index of kidney function in health and disease. GFR less than 60 mL/min/1.73 m2 represents the loss of half or more of the adult level of nor-mal kidney function, and it is associated with an increased prevalence of systemic complications. The normal level of GFR varies according to age, gender, and body size.

Table 53.2 Definition of Chronic Kidney Disease

Criteria for CKD*

Markers of Kidney Damage

• Albuminuria greater than 30 mg/day• Urine sediment abnormalities• Electrolyte and other abnormalities

caused by tubular disorders• Pathologic abnormalities• Imaging abnormalities• History of kidney transplantation

Decreased GFR • GFR less than 60 mL/min/1.73 m2

CKD, Chronic kidney disease; GFR, glomerular filtration rate.*Either of the listed items for more than 3 mo.

460 SECTION 10 — CHRONIC KIDNEY DISEASE AND ITS THERAPY

Table 53.3 Classification of Cause of Chronic Kidney Disease Based on Presence or Absence of Systemic Disease and Location of Pathologic-Anatomic Findings

Examples of Systemic Diseases Affecting the Kidney Examples of Primary Kidney Diseases

Glomerular Diseases Diabetes, autoimmune diseases, systemic infections, drugs, neoplasia (including amyloidosis)

Diffuse, focal, or crescentric proliferative glomerulo-nephritis; focal and segmental glomerulosclerosis; idiopathic membranous nephropathy; minimal change disease

Tubulointerstitial Diseases Systemic infections, autoimmune diseases, sarcoidosis, drugs, urate, environmental toxins (lead, aristolochic acid), neoplasia (myeloma)

Urinary tract infections, stones, obstruction

Vascular Diseases Decreased perfusion (heart failure, liver dis-ease, renal artery disease), atherosclerosis, hypertension, ischemia, cholesterol emboli, vasculitis, thrombotic microangiopathy, systemic sclerosis

ANCA-associated vasculitis; fibromuscular dysplasia

Cystic and Congenital Diseases

Polycystic kidney disease, Alport syndrome, Fabry disease, oxalosis

Renal dysplasia, medullary cystic disease

Diseases Affecting the Transplanted Kidney

Recurrence of native kidney disease (diabetes, oxalosis, Fabry disease)

Chronic rejection; calcineurin inhibitor toxicity; BK virus nephropathy; recurrence of native kidney disease (glomerular disease)

ANCA, Antineutrophil cytoplasm antibody.Note: Genetic diseases are not considered separately, because some diseases in each category are now recognized as having genetic

determinants.

Normal GFR is approximately 120 to 130 mL/min/1.73 m2 in a young adult, and declines with age by approximately 1 mL/min/1.73 m2 per year after the third decade. More than 25% of individuals aged 70 years and older have GFR of less than 60 mL/min/1.73 m2; whether this results from normal aging or the high prevalence of systemic vascular diseases that cause kidney disease remains controversial. Whatever its cause, GFR less than 60 mL/min/1.73 m2 in the elderly is an independent predictor of adverse outcomes such as death and CVD. As in younger patients, adjustment of drug doses is required in elderly patients with this level of GFR.

Kidney failure is defined either as a GFR less than 15 mL/min/1.73 m2 or a need to start kidney replacement therapy (dialysis or transplantation). A number of terms refer to severe decrease in kidney function, which is not syn-onymous with kidney failure. Uremia is defined as elevated concentrations within the blood of urea, creatinine, and other nitrogenous end products of amino acid and protein metabolism that are normally excreted in the urine. The ure-mic syndrome, the terminal clinical manifestation of kidney failure, is the group of symptoms, physical signs, and abnor-mal findings on diagnostic studies that result from the fail-ure of the kidneys to maintain adequate function. End-stage renal disease (ESRD) generally refers to kidney failure treated by dialysis or transplantation, regardless of the level of kid-ney function, and is used administratively in the United States and elsewhere. The availability of dialysis and trans-plantation for treatment of kidney failure varies around the world. ESRD might not include patients with kidney failure who are not treated with dialysis or transplantation.

STAGES OF CHRONIC KIDNEY DISEASE

The NKF-KDOQI classification system for stages of CKD was based on the severity of the disease defined only by

tclKdoaldfadrorhr

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FaaHf3aThalrtri

he level of GFR. The KDIGO classification is based on the ause of the disease and level of albuminuria as well as the evel of GFR. The more detailed classification adopted by DIGO relates more closely to prognosis. The cause of isease is generally classified according to the presence f absence of systemic diseases (secondary or primary) nd the presumed location of the pathologic-anatomic esions (glomerular, tubulointerstitial, vascular, cystic, or isease in the kidney transplant) (Table 53.3). Categories

or GFR and albuminuria levels are shown in Tables 53.4 nd 53.5. Figure 53.2A shows the two-dimensional grid eveloped for the 2009 KDIGO Controversies Conference elating the risk of kidney outcomes and mortality to level f GFR and albuminuria. The green, yellow, orange, and ed shaded categories represent patients at low, moderate, igh, and very high risk of kidney outcomes and mortality, espectively.

REVALENCE

igure 53.2B shows the prevalence estimates derived from single measurement of serum creatinine to estimate GFR nd albumin-to-creatinine ratio (ACR) during National ealth and Nutrition Examination Surveys (NHANES)

rom 1988 to 2006. The prevalence of ACR greater than 0 mg/g or GFR less than 60 mL/min/1.73 m2 (gray shaded rea) is approximately 13.8% of the U.S. adult population. he proportion of participants in the groups at moderate, igh, and very high risk (as categorized in Fig. 53.2A) is bout 73%, 18%, and 9%, respectively, representing a preva-ence in the general population of about 10%, 2%, and 1%, espectively. This prevalence is more than 50 times greater han the prevalence of treated ESRD of approximately 0.2% eported by the United States Renal Data System during this nterval. Because kidney disease usually begins late in life

461 CHAPTER 53 — STAGING AND MANAGEMENT OF CHRONIC KIDNEY DISEASE

Table 53.4 Categories of Chronic Kidney Disease by the Level of Glomerular Filtration Rate and Corresponding Clinical Action Plan

Category GFR Levels (mL/min/1.73 m2) Terms Clinical Action Plan

G1* Greater than 90 Normal or high Diagnose and treat the causeTreat comorbid conditionsEvaluate for CKD risk factorsStart measures to slow CKD progressionStart measures to reduce CVD risk

G2* 60 to 89 Mildly decreased† Estimate progressionG3a 45 to 59 Mildly to moderately decreased Adjust medication dosages as indicated

Evaluate and treat complicationsG3b 30 to 44 Moderately to severely decreasedG4 15 to 29 Severely decreased Prepare for kidney replacement therapy

(transplantation and/or dialysis) if appropriate

G5 Less than 15 Kidney failure (add D if treated by dialysis)

Start kidney replacement therapy (if uremia present)

CKD, Chronic kidney disease; CVD, cardiovascular disease; GFR, Glomerular filtration rate.*GFR stages G1 or G2 without markers of kidney damage do not fulfil the criteria for CKD.†Relative to young adult levelNote: GFR in mL/min/1.73 m2 may be converted to mL/s/1.73 m2 by multiplying by 0.01667.

Table 53.5 Categories of Chronic Kidney Disease by the Level of Albuminuria and Corresponding Clinical Action Plan

Category AER (mg/day)

Approximately Equivalent ACR

Terms Clinical Action Plan(mg/mmol) (mg/g)

A1 Less than 30 Less than 3 Less than 30 Normal to mildly increased

Diagnose and treat the causeTreat comorbid conditionsEvaluate for CKD risk factorsStart measures to slow CKD progressionStart measures to reduce CVD risk

A2 30 to 299 3 to 30 30 to 299 Moderately increased*

Treatment with renin-angiotensin system blockers and lower blood pressure goal if hypertensive

A3 Greater than 300 ≥30 Greater than 300 Severely increased Treat nephrotic syndrome (if present)

ACR, Albumin-to-creatinine ratio; AER, albumin excretion rate; CKD, chronic kidney disease; CVD, cardiovascular disease.*Relative to young adult level.

and progresses slowly, most people in the earlier stages of CKD die before reaching kidney failure. In these patients, the burden of CKD is reflected in the complications of ear-lier stages, including increased mortality and morbidity, reduced quality of life, and high cost.

DIAGNOSIS, EVALUATION, AND MANAGEMENT

Chronic kidney disease care is directed by the cause, as well as by the level of GFR and albuminuria (see Tables 53.3, 53.4, and 53.5). Four key points must be emphasized. First, the action plan for each GFR and albuminuria stage includes recom-mended care for the cause of disease, as well as addressing factors associated with progression to more advanced stages. Second, the action plan is cumulative, in that recommended care at each stage of disease includes care for earlier stages.

Third, care for patients with CKD requires multiple inter-ventions, and the coordinated, multidisciplinary effort of primary-care physicians, allied healthcare workers, and other specialists in addition to nephrologists. Fourth, the management of each stage of disease must take into consideration kidney outcomes and complications. The stage-specific clinical action plan is a guide, but not a replacement, for the physician’s assessment of the needs of each specific patient. Figure 53.3 provides a 5-step over-view of the diagnosis and evaluation of CKD. More details regarding evaluation and management are discussed in other chapters.

DIAGNOSIS

As part of routine checkups, all patients should be evaluated to determine whether they are at increased risk for develop-ing CKD. Those deemed at high risk should at minimum

Albuminuria stages,description and range (mg/g)

A1 A3

Optimal andhigh-normal

Very high andnephrotic

<10 10–29

A2

High

30–299 300–1999 ≥2000

>105

90–104

75–89

60–74

45–59

30–44

15–29

<15

High andoptimal

Mild

Mild-moderate

Moderate-severe

Severe

KidneyfailureA

G1

G2

G3a

G3b

G4

G5

GFRstages,

descriptionand range

(mL/min per1.73 m2)

Albuminuria stages,description and range (mg/g)

A1 A3

Optimal Veryhigh

<10 10–29

A2

HighHigh-normal

30–299 >300

72.2% 18.8% 7.8% 1.3%

31.4%

100.0%

0.0% 0.0% 0.0% 0.1% 0.1%

0.1% 0.1% 0.1% 0.1% 0.4%

0.6% 0.4% 0.4% 0.2% 1.5%

2.5% 1.1% 0.8% 0.2% 4.7%

8.2% 2.7% 1.3% 0.1% 12.2%

17.3% 4.1% 1.6% 0.2% 23.0%

20.0% 4.7% 1.7% 0.3%

23.6% 5.7% 1.9% 0.1%

26.7%

All

>105

90–104

75–89

60–74

45–59

30–44

15–29

<15

Optimal

Mild

Mild-moderate

Moderate-severe

Severe

Kidneyfailure

G1

G2

G3a

G3b

G4

G5

GFRstages,

descriptionand range(mL/min/1.73 m2)

AllB

Figure 53.2 A, Composite ranking for relative risks by glomerular filtration rate and albuminuria (Kidney Disease: Improving Global Out-comes, 2009). Colors reflect the ranking of relative risk by glomerular filtration rate (GFR) and albuminuria. Green, No chronic kidney disease (CKD); yellow, moderate risk; orange, high risk; red, very high risk. The ranks were assigned for five outcomes (all-cause mortality, cardiovascular disease mortality, end-stage renal disease, acute kidney injury, and CKD progression) from a metaanalysis of general population cohorts, and they were averaged across all five outcomes for the 28 GFR and albuminuria categories (GFR greater than 15 mL/min/1.73 m2 and albuminuria less than 2000 mg/g). The categories with mean rank numbers 1 to 8 are green, mean rank numbers 9 to 14 are yellow, mean rank numbers 15 to 21 are orange, and mean rank numbers 22 to 28 are red. Color for twelve additional cells with diagonal hash marks is extrapolated based on results of the metaanalysis of CKD cohorts. The highest level of albuminuria is termed nephrotic to correspond with nephrotic-range albuminuria, and it is expressed here as greater than 2000 mg/g. Albuminuria is expressed as albumin-to-creatinine ratio (ACR). Column and row labels are combined to be consistent with the number of estimated GFR (eGFR) and albuminuria stages agreed on at the conference. (Reproduced from Levey AS et al: The definition, classifica-tion and prognosis of chronic kidney disease: a KDIGO Controversies Conference report, Kidney Int 80:17-28, 2011.) B, Prevalence of chronic kidney disease in the United States by glomerular filtration rate and albuminuria. Grey shading represents chronic kidney disease (CKD) defined by glo-merular filtration rate (GFR) or albuminuria (13.8%). Cells show the proportion of adult population in the United States. Data from the National Health and Nutrition Examination Survey (NHANES) 1988-06 (N = 18 026). GFR is estimated with the CKD-EPI (epidemiology) equation and standardized serum creatinine. Albuminuria is established by one measurement of albumin-to-creatinine ratio (ACR); thus proportions for GFR greater than 60 mL/min per 1.73 m² exceed those reported based on persistence of albuminuria. Values in cells might not total to values in margins because of rounding. Category of very high albuminuria includes nephrotic range. (Reproduced from Levey AS, Coresh J: Chronic kidney disease, Lancet 379:165-180, 2012.)

463 CHAPTER 53 — STAGING AND MANAGEMENT OF CHRONIC KIDNEY DISEASE

Albuminuria stages,description and range (mg/g)

A1 A3

Optimal andhigh-normal

Very high andnephrotic

<10 10–29

A2

High

30–299 300–1999 ≥2000

>105

90–104

75–89

60–74

45–59

30–44

15–29

<15

High andoptimal

Mild

Mild-moderate

Moderate-severe

Severe

Kidneyfailure

G1

G2

G3a

G3b

G4

G5

GFRstages,

descriptionand range(mL/min/1.73 m2)

CFigure 53.2, cont’d C, Management of chronic kidney disease by glomerular filtration rate and albuminuria stages. Management for all patients includes identifying the clinical diagnosis, slowing the progression of chronic kidney disease (CKD), and reducing the risk for cardiovas-cular disease. Therapies focusing on complications of decreased glomerular filtration rate (GFR) are shown as horizontal lines; therapies focused on complications of albuminuria are shown as vertical lines (see Tables 53.4 and 53.5). Width of lines corresponds to intensity of management.

have a measurement of serum creatinine concentration to estimate GFR and an assessment of albuminuria. The rec-ommended method for assessing albuminuria is measure-ment of the ACR in an untimed (“spot”) urine sample. Current guidelines suggest testing in patients with hyper-tension, diabetes, CVD, cancer, human immunodeficiency virus (HIV) infection, and before imaging procedures with iodine-based or gadolinium-based contrast. Clinical practice also includes measurement of serum creatinine with GFR estimation as part of the basic metabolic panel for patients with acute illness or before planned invasive procedures. At present, there are few data regarding the optimal frequency of testing for CKD in high-risk individuals, although annual testing is recommended in patients with hypertension, dia-betes, and HIV. Until evidence is available, it is reasonable to suggest that others at increased risk be tested at least every 3 years.

EVALUATION

The goals of evaluation are to identify the duration and cause of kidney disease, to assess severity based on the levels of GFR and albuminuria, and to determine the risk for progression of kidney disease and of complications. In patients in whom CKD has been diagnosed, evaluation starts with a thorough history and physical examination to detect any signs and symptoms that may be clues to the etiology of kidney disease and, in particular, any revers-ible or treatable causes (e.g., uncontrolled hypertension, use of nonsteroidal antiinflammatory drugs). Medications should be reviewed to identify those that can cause kidney

toxicity and others that must be adjusted based on GFR. The physical examination should include particular atten-tion to details such as blood pressure, fundoscopy, and vas-cular examination. Laboratory tests should be performed to detect other markers of damage or functional distur-bances (e.g., urine specific gravity, urine pH, urine sedi-ment examination, serum electrolytes). Imaging studies should be performed if indicated based on clinical clues. Ultrasonography can be performed to detect anatomic abnormalities and to exclude obstruction of the urinary tract. Further testing may be indicated if there is concern about anatomic abnormalities. It has been recommended that individuals with GFR less than 60 mL/min/1.73 m2 should have measurements of hemoglobin as well as serum calcium, phosphate, albumin, and parathyroid hormone, but these measures are often not abnormal until GFR is less than 45 mL/min/1.73 m2. Laboratory evaluation should also include a search for traditional CVD risk factors, such as a lipid profile, and possibly tests for nontraditional risk factors such as insulin resistance and inflammation. Addi-tional studies may be necessary to evaluate symptoms of CVD more fully or to detect asymptomatic CVD in patients with multiple risk factors.

As discussed earlier, many elderly individuals meet the criteria for a diagnosis of CKD because of estimated GFR less than 60 mL/min/1.73 m2. In the absence of risk fac-tors for CKD, albuminuria, or other markers of kidney dam-age, patients with isolated decreased GFR may be at low risk for progression to kidney failure, but are at increased risk for CKD complications and for CVD. In such patients, cli-nicians may elect to defer some parts of the evaluation for

464 SECTION 10 — CHRONIC KIDNEY DISEASE AND ITS THERA

CKD; however, a search for reversible causes of decreased GFR, adjustment of medication dosages for decreased GFR, appropriate attention to CVD risk-factor management, and subsequent monitoring of estimated GFR are appropriate measures.

EVALUATION OF DURATIONKidney diseases and disorders may be acute or chronic depending on their duration. The distinction between acute and chronic is arbitrary, but is useful in clinical practice. KDIGO defines chronicity as duration longer than 3 months (90 days), and the term acute kidney diseases and disorders (AKD) could be used to describe kidney dis-ease with duration less than 3 months, including AKI. The duration of kidney disease may be documented or inferred based on the clinical context. For example, a patient with decreased kidney function or kidney damage in the midst of an acute illness, without previous documentation of kidney disease, may be inferred to have AKD. A patient with similar findings in the absence of an acute illness may be inferred to have CKD. In both cases, repeat ascertainment of kidney function and kidney damage is recommended for accurate diagnosis. The timing of the evaluation depends on clinical judgment, with earlier evaluation for patients suspected of having AKD and later evaluation for patients suspected of having CKD.

1. Recognition of increased risk for CKD• Increased susceptibility to CKD• Exposure to diseases or conditions that cause CKD

2. Testing for CKD• Measure serum creatinine to estimate GFR• Measure urinary albumin or protein• Search for other markers of kidney damage specific to the risk (urine sediment or imaging abnormalities, renal tubular syndrome)• Confirmatory tests (if indicated)

3. Detection of CKD• GFR <60 mL/min/1.73 m2 (measured or estimated)• Kidney damage (albuminuria, urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, pathologic abnormalities, imaging abnormalities, or history of kidney transplantation)• Duration ≥3 months (documented or inferred)

4. Evaluation of clinical diagnosis for implementation of specific therapy• Diabetic kidney disease (type 1 or type 2)• Nondiabetic kidney disease (glomerular diseases other than diabetic kidney disease, vascular diseases, tubulointerstitial diseases, cystic diseases)• Kidney disease in kidney transplant recipients

5. Evaluation of GFR and albuminuria categories for implementation of nonspecific therapy

Figure 53.3 Detection and evaluation of chronic kidney disease. CKD, Chronic kidney disease; GFR, glomerular filtration rate.

PY

EVALUATION OF CAUSEIdentification of the cause of kidney disease enables treat-ments directed at the etiology, such as infection, drug toxic-ity, autoimmune disease, or obstruction of the urinary tract. In addition, the cause of kidney disease has implications for the rate of progression and the risk of complications. In clinical practice, CKD is most often detected as decreased estimated GFR during evaluation and management of other medical conditions. Thus, cause of disease is generally estab-lished by recognition of the clinical setting and the presence or absence of markers of kidney damage. A simplified clas-sification emphasizes diseases in native kidneys (diabetic or nondiabetic in origin) and diseases in transplanted kidneys. Diabetic nephropathy is the largest single cause of kidney failure in the United States, accounting for approximately one third of new cases. Its earliest manifestation is albu-minuria with normal or elevated GFR. Nondiabetic kidney disease includes glomerular, vascular, tubulointerstitial, and cystic kidney disorders. Clinical judgment should determine whether additional methods are necessary to characterize kidney disease, including imaging studies, other urine or serum markers, or biopsy of the kidney. For many patients with CKD (especially older patients with hypertension or diabetes and no evidence of the other disorders mentioned earlier), the cause will be unknown and presumed to be a result of vascular disease. In these cases, management will be based primarily on levels of GFR and albuminuria.

EVALUATION OF GLOMERULAR FILTRATION RATECurrent guidelines focus on estimated GFR rather than serum creatinine alone for a variety of reasons. Serum cre-atinine is affected by factors other than GFR. Consequently, there is a wide range of “normal” serum creatinine, and in many patients GFR must decline by approximately 50% before serum creatinine rises above this threshold. This is particularly important in the elderly, in whom the serum creatinine does not reflect the age-related decline in GFR because of a concomitant decline in muscle mass and creati-nine production. For these reasons, it is difficult to use the serum creatinine alone to estimate the level of GFR, espe-cially to detect earlier stages of CKD. GFR estimating equa-tions are discussed in Chapter 3.

EVALUATION OF ALBUMINURIAThe KDIGO guidelines focus on albuminuria rather than proteinuria for several reasons. Albumin is the principal com-ponent of urinary protein in most kidney diseases; recent rec-ommendations for measurement of urine proteins emphasize quantification of albuminuria rather than total protein; and, as noted before, recent epidemiologic data demonstrate a strong graded relationship of the quantity of urine albumin with both kidney and CVD risk. The ratio of concentrations of albumin-to-creatinine in a spot urine specimen has now replaced 24-hour excretion rates as the preferred method for initial evaluation of albuminuria. Use of such a ratio cor-rects for variations in urinary protein concentration because of urinary concentration, and is far more convenient than timed urine collections. A “positive” result for a spot urine ACR is greater than 30 mg/g, although this does not take into account variation in creatinine excretion by age, gender, and race. If a more accurate assessment is required, confir-mation may be sought by measurement of albumin excretion

465 CHAPTER 53 — STAGING AND MANAGEMENT OF CHRONIC KIDNEY DISEASE

Table 53.6 Albuminuria and Proteinuria Measures

Measure Categories

Normal to Mildly Increased Moderately Increased Severely Increased

AER (mg/24 hr) Less than 30 30 to 300 Greater than 300PER (mg/24 hr) Less than 150 150 to 500 Greater than 500ACR(mg/mmol) Less than 3 3 to 30 Greater than 30(mg/g) Less than 30 30 to 300 Greater than 300PCR(mg/mmol) Less than 15 15 to 50 Greater than 50(mg/g) Less than 150 150 to 500 Greater than 500Protein reagent strip Negative to trace Negative to positive Positive or greater

ACR, Albumin-to-creatinine ratio; AER, albumin excretion rate; PCR, protein-to-creatinine ratio; PER, protein excretion rate.Urine ACR may be divided into more than three categories. The normal urinary ACR in young adults is less than 10 mg/g; ACR 10 to 29 mg/g

is high normal. Urine ACR greater than 2000 mg/g is accompanied by signs and symptoms of nephrotic syndrome (low serum albumin, edema, and high serum cholesterol).

Relationships between excretion rates and concentration ratios with urine creatinine are inexact. Excretion of urinary creatinine indicates muscle mass and varies with age, gender, race, diet, and nutritional status, and generally exceeds 1.0 g/day in healthy adults; therefore, the numeric value for urinary ACR (mg/g) is usually less than the rate of urinary albumin excretion (mg/day). Rates of 30 to 300 mg/day and greater than 300 mg/day correspond to microalbuminuria and macroalbuminuria, respectively.

Relationships between urinary albumin and total protein are inexact. Normal urine contains small amounts of albumin, low-molecular-weight serum proteins, and proteins that are from renal tubules and the lower urinary tract. In most kidney diseases, albumin is the main urine pro-tein, comprising about 60% to 90% of total urinary protein when total protein is very high. Values corresponding to normal, high-normal, high, very high, and nephrotic-range total protein are approximately less than 50, 50 to 150, 150 to 500, greater than 500, and greater than 3500 mg/g, respectively.

Threshold values for standard international (mg/mol) and conventional units (mg/g) are not exact. Conversion factor for ACR: 1.0 mg/g = 0.113 mg/mmol.

rate in a timed urine collection. Table 53.6 provides a rough guide to measures of urine albumin and total protein in spot and timed urine collections that correspond to the KDIGO albuminuria stages. Further discussion of albuminuria and proteinuria is provided in Chapter 5.

MANAGEMENT

The essential features of management according to GFR and albuminuria stages are shown in Tables 53.4 and 53.5, and Figures 53.1 and 53.2C: treating specific causes of kidney disease; treating other reversible conditions causing kidney damage or decreased GFR; slowing progression of kidney disease by use of ACE inhibitors and ARBs and a lower blood-pressure goal in patients with higher levels of albuminuria; assuring medication safety by avoiding drugs that are toxic to the kidney and adjusting doses of drugs that are excreted by the kidney in patients with decreased GFR; treating meta-bolic and endocrine complications of decreased GFR; treat-ing the nephrotic syndrome; treating CVD and its risk factors; and preparing for kidney replacement therapy in patients with severely decreased GFR.

Patient education is central to the management strategy. CKD is often asymptomatic, and patients may not under-stand the importance of multidrug regimens and laboratory testing without explicit education. Complete management requires behavioral change by the patient, which may include lifestyle alterations, self-monitoring of blood pres-sure, and adherence to medication regimens and medical follow-up. Patient education is also important with respect to avoiding medications that are toxic to the kidneys. Patients must be aware that any drug or herbal remedy may

be directly nephrotoxic or may require a dosage adjustment for the level of kidney function.

HEALTHCARE STRUCTURE FOR TREATMENT OF CHRONIC KIDNEY DISEASE

NEPHROLOGY REFERRAL

Chronic kidney disease can be a life-threatening condition. Nephrologists have multiple roles in the diagnosis and care of patients at all stages of CKD, including determining the cause of CKD, recommending specific therapy, suggesting treatments to slow progression in patients who have not responded to conventional therapies, identifying and treat-ing kidney disease–related complications, and preparing for dialysis.

Recommendations for referral to a kidney disease spe-cialist are not universal, as specific practice patterns are dependent on healthcare systems and available resources in a geographic region. The strongest evidence regarding the importance of referral to a nephrologist is for management of GFR stages 4 and 5 (GFR less than 30 mL/min/1.73 m2). Late referral to a nephrologist (i.e., less than 3 months before the start of dialysis therapy) has been associated with higher mortality after the initiation of dialysis. It is there-fore recommended by many organizations, regardless of the healthcare system or geographic region, that all patients with GFR stage 4 be referred to a nephrologist. During GFR stage 4, it is important to prepare the patient for the pos-sible onset of kidney failure (GFR stage 5). Preparation involves estimating the risk of progression to kidney failure,

466 SECTION 10 — CHRONIC KIDNEY DISEASE AND ITS THERAPY

Table 53.7 Recommendations for Referral to Specialists for Consultation and Comanagement of Chronic Kidney Disease

GFR less than 30 mL/min/1.73 m2 Kidney disease specialistACR greater than 300 mg/g Kidney disease specialistHematuria not from urologic conditions Kidney disease specialistInability to identify a presumed cause of CKD Kidney disease specialistIncreased risk for progression of kidney disease Kidney disease specialistGFR decline greater than 30% within 4 mo without explanation Kidney disease specialistDifficult to manage complications of CKD such as anemia requiring erythropoietin stimulating

therapy, or abnormalities of bone and mineral metabolism requiring phosphorus binders or vitamin D preparations

Kidney disease specialist

Hyperkalemia (serum potassium concentration greater than 5.5 mEq/L) Kidney disease specialistResistant hypertension (BP greater than 130/80 mm Hg despite adherence to a three-drug

antihypertensive regimen that includes a diuretic)Kidney disease or hypertension

specialistDifficult-to-manage drug complications Kidney disease or hypertension

specialistAcute presentations of CVD CVD specialistComplex or severe chronic CVD conditions CVD specialistAge less than 18 yr Pediatric kidney disease specialist

Adapted from National Kidney Foundation: KDOQI clinical practice guidelines for hypertension and antihypertensive agents in chronic kidney disease. Reproduced from Am J Kidney Dis, 43: S1-S268, 2004.

ACR, Albumin-to-creatinine ratio; BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; GFR, glomerular filtration rate.

holding discussions regarding kidney replacement therapy (dialysis and transplantation), and instituting conserva-tive therapy for those who are not willing or are unable to undergo kidney replacement therapy. In patients who elect replacement therapy, timely creation of vascular access for hemodialysis, home dialysis training, and donor evaluation for preemptive transplantation should occur during GFR stage 4. For patients with CKD in GFR stages 1 to 3 (GFR greater than 30 mL/min/1.73 m2), only a subset is likely to require referral to a specialist. Table 53.7 lists clinical criteria for referral to specialists.

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