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Table 28-3

Staging of Chronic Kidney Disease Based on eGFR Category

1

GFR Categories (mL/minute/1.73 m2) Description Range

G1 Normal or high ≥90

G2 Mildly decreased 60–89

G3a Mildly to moderately decreased 45–59

G3b Moderately to severely decreased 30–44

G4 Severely decreased 15–29

G5 Kidney failure <15

CKD, chronic kidney disease; GFR, glomerular filtration rate.

Table 28-4

Albuminuria Categories: Description and Range

1

A1 A2 A3

Description Normal to mildly increased Moderately Increased Severely Increased

Albumin-to-creatinine ratio

(mg/g)

<30 30–300 >300

Albumin excretion rate

(mg/24 h)

<30 30–300 >300

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Table 28-5

Examples of CKD Staging

1

Cause GFR Category Albuminuria Category Criterion for CKD

Diabetic kidney disease G5 A3 Decreased GFR,

albuminuria

Idiopathic focalsclerosis G2 A3 Albuminuria

Kidney transplant recipient G2 A1 History of kidney

transplantation

Polycystic kidney disease G2 A1 Imaging abnormality

Vesicoureteral reflex G1 A1 Imaging abnormality

Distal renal tubular

acidosis

G1 A1 Electrolyte abnormalities

Hypertensive kidney

disease

G4 A2 Decreased GFR and

albuminuria

CKD presumed due to

diabetes and hypertension

G4 A1 Decreased GFR

CKD presumed due to

diabetes and hypertension

G2 A3 Albuminuria

CKD presumed due to

diabetes and hypertension

G3a A1 Decreased GFR

CKD cause unknown G3a A1 Decreased GFR

Patients above the thick horizontal line are likely to be encountered in nephrology practice. Patients below the thick

horizontal line are likely to be encountered in primary care practice and in nephrology practice.

CGA, cause, GFR category and albuminuria category; CKD, chronic kidney disease; GFR, glomerular filtration

rate.

A substantial decline in kidney function also leads to azotemia, the accumulation of

nitrogenous wastes such as urea in the plasma, and an increased risk for developing

complications of CKD. Uremic signs and symptoms from accumulation of

nitrogenous wastes and other toxins manifest clinically as an elevated blood urea

nitrogen (BUN) and lead to a myriad of complications affecting most major organ

systems. Laboratory biochemical abnormalities include azotemia,

hyperphosphatemia, hypocalcemia, hyperkalemia, metabolic acidosis, and worsening

anemia. Clinical signs of CKD and its associated complications, including

hypertension, uremic symptoms (e.g., nausea, anorexia), and bleeding, are observed

as the disease advances to categories 3 through 5. Interventions to slow the

progression of kidney disease are critical. Patients who reach an eGFR of less than

30 mL/minute/1.73 m2

(category 4), in general, will ultimately progress to ESRD.

Epidemiology of Chronic Kidney Disease

INCIDENCE AND PREVALENCE

The United States Renal Data System (USRDS) is a national data system which

collects, analyzes, and distributes information about all categories of CKD in the

United States. Data describing CKD incidence and prevalence are made available

annually by the USRDS and the USRDS provides data from approximately 2 years

prior.

3 The 2014 USRDS report estimated CKD to affect 14% of the US population

in 2012. Category 3 CKD reported the greatest increase in prevalence from 4.5% to

6.0%. The NKF’s Kidney Early Evaluation Program (KEEP) screens high-risk

individuals across the United States with high blood pressure (BP), diabetes, or a

family history of kidney failure. Based on the high-risk participants from the KEEP

screenings from 2000 to 2011, 24% of the participants had CKD.

4

Based on the 2014 USRDS data from 2012, there were 114,813 new cases of

ESRD; 102,277 of those cases started hemodialysis. This ESRD number includes

peritoneal, hemodialysis, and transplant recipients. The rate of ESRD has declined

each year since 2009. The 2012 adjusted incidence rate of 353/million/year was the

lowest incidence rate since 1997. There were 449,342 patients receiving dialysis

therapy (408,711 on hemodialysis and 40,631 on peritoneal dialysis) as of December

31, 2012. This was an increase in prevalence of 3.8% and 57.4% larger than in

2000. Prevalence was lowest in the New England and Northwest regions whereas it

was highest in the Midwest regions. African Americans and Native Americans had a

3.3 and 1.85 times greater incidence rate of kidney failure, respectively, compared

with white individuals. Hispanic patients had the highest ESRD incidence rate

compared to the non-Hispanic population.

3

In 2012, the majority of the increase in prevalence of ESRD occurred in patients

aged 45 and over.

1 The age groups with the highest incidence of ESRD were those

aged 65 to 74 years with 6,302 ESRD cases per million of the population. Those

greater than age 75 had the greatest increase in cases at 50% since 2000. The African

American population had the highest prevalence per million of the population that

was 2-fold higher than Native Americans, 2.5-fold higher than Asians, and 4-fold

higher than whites.

3

CKD is a health priority identified as a disease prevention target for the Healthy

People 2020 (HP2020) national health initiative; one of the specific CKD-related

objectives is to reduce the number of cases of ESRD.

5 The HP2020 target rate of

ESRD cases is 13.7% of the population. Currently, the adjusted prevalence from

1999 to 2004 is 15.2% of the population.

5 Additional objectives such as increasing

awareness, improving cardiovascular care, and reduction of mortality in CKD

patients can be found at the HealthyPeople.gov website.

ETIOLOGY

In CKD, the progressive loss or damage to functioning nephrons as a function of time

is the result of a primary disorder or disease of the kidney, a secondary complication

of certain systemic diseases (e.g., diabetes mellitus or hypertension), or an acute

injury to the kidney that results in irreversible kidney damage. In 2012, the leading

causes of ESRD in newly diagnosed American patients were diabetes mellitus

(44%), hypertension (28%), and chronic glomerulonephritis (GN; 7%).

3 The

remaining cases of ESRD can be attributed to a variety of other pathologies;

examples include polycystic kidney disease, congenital malformations of the kidneys,

nephrolithiasis, interstitial nephritis, renal artery stenosis, renal carcinoma, and

human immunodeficiency virus–associated nephropathy.

RISK FACTORS

A variety of risk factors associated with development, initiation, and progression of

CKD have been identified. Initiation factors are medical conditions that directly

cause kidney damage. Risk factors for the progression of CKD exacerbate kidney

damage and are related to an accelerated decline in kidney function with time. The

majority of susceptibility factors are not modifiable, but may identify people who are

at high risk for developing CKD. In contrast, pharmacotherapy and lifestyle

interventions have been shown to modify CKD-related initiation and progression

factors (see Prevention and Diabetic Nephropathy section). A summary of risk

factors associated with CKD can be found in Table 28-6.

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Table 28-6

Risk Factors for Chronic Kidney Disease

Susceptibility Initiation Progression

Advanced age

Reduced kidney mass

Low birth weight

Racial/ethnic minority

Family history

Low income or education

Systemic inflammation

Dyslipidemia

Diabetes mellitus

Hypertension

Glomerulonephritis

Drug induced or toxicity

Smoking

Obesity

Glycemia

Hypertension

Proteinuria

Smoking

Obesity

KDOQI. KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and

stratification. Am J Kidney Dis. 2002;39(2, Suppl 1):S73.

MORBIDITY AND MORTALITY

Rates of hospitalizations and mortality are much greater in those with kidney disease

compared with the non-CKD population. Not surprisingly, mortality rates increase

with progressing stages of CKD, patient health complexity, and age. The mortality

rate of non-dialysis patients with CKD was 36% higher compared with those without

CKD, and the adjusted rates of all-cause mortality were 6 to 8 times higher for

dialysis patients compared with the general population.

3

Advances in dialysis and transplantation have improved patient care, and as a

result, mortality rates continue to decline. From 2003 to 2012, the mortality rate fell

by 25%, whereas from 1993 to 2002, there was only a 9% reduction in mortality.

3

Cardiovascular-related events, particularly cardiac arrest and myocardial infarction,

remain the leading causes of hospitalizations and death in both the non–dialysis CKD

and ESRD populations. This is not surprising given the high prevalence of coexisting

cardiac disorders in patients with kidney disease and the elevated risk for mortality

associated with these conditions. However, since 1999, the overall rate of

cardiovascular mortality in the ESRD population has continued to decline. After

CVD, infection (predominantly septicemia) is a substantial contributor to overall

morbidity and mortality in patients with ESRD.

3

The mortality rates during the first year of hemodialysis are the highest. However,

reductions in the first year of hemodialysis have decreased by 19%, 30%, and 56%

for all-cause, cardiovascular, and infection death as compared to 2001, respectively.

Although improvements in mortality are acknowledged, only 54% and 65% of

hemodialysis and peritoneal dialysis patients survive beyond 3 years after ESRD

onset.

3

Medication Use

Data regarding medication use in the kidney disease population reveal non–dialysis

CKD patients are prescribed an average of 6 to 8 medications and HD patients are

prescribed approximately 12 medications (10 home medications and 2 in-center

medications).

5,6 These patterns of medication use are reflective of the higher

prevalence of complications and comorbidities in the latter stages of CKD, which

require additional drug therapies. The extent of medication use and the complexity of

prescribed drug regimens contribute to nonadherence and medication-related

problems (MRPs) in the ESRD population.

7

To manage MRPs, some dialysis units use a clinical pharmacist as part of the

multidisciplinary health care team to provide pharmaceutical care to ESRD patients.

Services provided by a clinical pharmacist have been shown to be cost-effective and

associated with maintenance of health-related quality of life.

8,9 Additionally, a

randomized study of 104 ESRD patients investigated the impact of pharmaceutical

care (individualized drug therapy reviews conducted by a clinical pharmacist) to

standard care (brief drug therapy reviews conducted by a nurse) on drug use, drug

costs, hospitalization rates, and MRPs. After a 2-year follow-up, patients who

received pharmaceutical care were taking fewer medications and had fewer allcause hospitalizations compared with those receiving standard care.

10

Economics

The cost of treating both non–dialysis CKD patients and ESRD patients is

substantial. In 2012, the overall per person per year cost of medical treatment for

Medicare non–dialysis CKD patients was more than $20,162 and the cost of medical

care for those with stages 4 to 5 CKD was 1.4 times higher than those with CKD

stages 1 to 2.

3 Furthermore, the majority of the costs of medical care provided to

those with ESRD are paid by the federal government. In 2012, the cost for ESRD

was $28.6 billion dollars, corresponding to 5.6% of the Medicare budget.

3 This

amount reflects a consistent increase from prior years. The increase is most likely

associated with the higher prevalence of ESRD, changes in the standard of care,

reimbursement structure, and types of patients being treated (e.g., diabetic patients

versus nondiabetic patients).

The continually growing costs of ESRD care require careful attention, given the

implementation of the Centers for Medicare and Medicaid Services’ bundled

payment system that changed how Medicare pays for dialysis services. Under the

bundled system, Medicare provides a single payment to ESRD facilities to cover all

dialysis-related services for each dialysis treatment.

10

In the prior reimbursement

system, Medicare paid a composite rate to dialysis units to cover the costs of an

individual’s dialysis treatment, certain routine medications (e.g., heparin), laboratory

tests, and supplies. In addition to the composite rate, Medicare was billed separately

for other related dialysis services and billable items (e.g., erythropoietin [EPO]-

stimulating agents).

8 The bundled payment system is likely to reduce the government

reimbursement for dialysis services, but may increase barriers to care for some

ESRD patients.

10

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Pathophysiology

Progression of kidney disease to ESRD generally occurs over the course of months to

years and is assessed by the rate of GFR decline. Each kidney contains

approximately 1 million nephrons (the functional units of the kidney), and every

nephron maintains its own single-nephron GFR. In the face of nephron loss, the

remaining functional nephrons maintain renal function by increasing their singlenephron GFR via compensatory glomerular hemodynamic changes.

9 With time, this

compensatory increase in single-nephron GFRs eventually leads to hypertrophy and

an irreversible loss of nephron function from sustained increases in glomerular

pressure. Furthermore, glomerulosclerosis (glomerular arteriolar damage) develops

from prolonged elevation of glomerular capillary pressure and increased glomerular

plasma flow, resulting in a continuous cycle of nephron destruction. Regardless of the

cause, a predictable and continuous decrease in kidney function occurs in patients

when the eGFR drops below a critical value, approximately one-half of normal.

11

Usually, the rate of decline in kidney function remains fairly constant for an

individual, but can vary substantially among patients and disease states. A rapid rate

of decline in kidney function has been associated with black race, proteinuria, male

sex, older age, and smoking.

12–14 Rapid progression of kidney disease is defined as

persistent decline in GFR >5 mL/minute/1.73 m2

/year.

1 Although early changes in

kidney function can be detected through routine laboratory monitoring (e.g., serum

creatinine [SCr]), most patients do not develop signs and symptoms of uremia until

they have reached the more severe stages of the disease (i.e., CKD categories 4, 5,

and/or ESRD).

As the leading causes of ESRD in the United States, diabetes mellitus,

hypertension, and glomerular diseases have been the focus of research to identify

their associated mechanisms of kidney damage. In the case of diabetes mellitus,

excess filtration of glucose, excessive glucose contact with the glomerular and

tubular cells leads to increased cellular osmotic pressure and thickening of the

capillary basement membrane and other anatomic changes. Systemic hypertension is

a potent stimulus for the development and progression of kidney disease caused by

the association with increased single-nephron GFRs.

9,14 Hypertension, whether the

primary cause of kidney disease or a coexisting disease in the presence of other

etiologies, can promote kidney damage through transmission of elevated systemic

pressure to glomeruli. The result is glomerular capillary hyperperfusion and

hypertension leading to progressive kidney damage as nephron destruction continues.

Glomerular ischemia induced by damage to the preglomerular arteries and arterioles

also occurs. People with coexistent diabetes mellitus and hypertension increase the

risk of developing ESRD by fivefold to sixfold compared with those with

hypertension alone.

11 Most glomerular diseases are mediated by immune

mechanisms. The deposition and formation of immune complexes in the glomerulus

cause injury, resulting in increased glomerular permeability to macromolecules (e.g.,

proteins).

15

Proteinuria, one of the initial diagnostic signs of kidney disease, also contributes

to the progressive decline in kidney function. A faster rate of progression is

associated with higher protein excretion.