C h ro n i c K i d n e y D i s e a s e

a b,
Cornelia Charles, MD , Allison H. Ferris, MD *

KEYWORDS
 CKD  Chronic kidney disease  Chronic renal failure  Primary care  Albuminuria
 Slowing progression  Renal disease

KEY POINTS
 Chronic kidney disease is a common disease with increasing prevalence and is tied
closely with diabetes and hypertension.
 The progression of chronic kidney disease can be slowed with several interventions
including controlling blood pressure and diabetes.
 Both chronic kidney disease and the presence of albuminuria are risk factors for cardio-
vascular disease.
 Attention must be given to mitigating cardiovascular risk, avoiding drugs or interventions
that can worsen renal function, and referring patients to a nephrologist when necessary.
 Primary care physicians play a key role in diagnosing and managing chronic kidney dis-
ease to slow its progression and prevent complications.

DEFINITION, EPIDEMIOLOGY, AND PREVALENCE

Kidney Disease: Improving Global Outcomes (KDIGO) in their 2012 Clinical Practice
Guidelines for Evaluation and Management of Chronic Kidney Disease created a uni-
versal definition of chronic kidney disease that is widely applied to patient populations
throughout the world.1 Chronic kidney disease is defined as abnormalities of kidney
structure or function, present for greater than 3 months with specific implications
for health. This is defined as a GFR less than 60 mL/min/1.73 m2 or one or more
markers of kidney dysfunction including albuminuria. Box 1 lists markers of kidney
damage.
Chronic kidney disease is further classified into stages based on the estimated
glomerular filtration rate (eGFR), as shown in Table 1.
According to the United States Renal Data System, it is estimated that 14.8% of the
United States’ general population was affected by chronic kidney disease in 2013 to
2016, with the most prevalent stage being chronic kidney disease stage 3.2 The overall
prevalence of chronic kidney disease in the United States has been stable for the last
2 decades, but when looking at stages, there has been a small increase in stage 3 from

a
Department of Veterans Affairs Medical Center - West Palm Beach, 7305 North Military Trail,
West Palm Beach, FL 33410; b Charles E. Schmidt College of Medicine, Florida Atlantic Uni-
versity, 800 Meadows Rd, Boca Raton, FL 33486
* Corresponding author.
E-mail address: ferrisa@health.fau.edu

Prim Care Clin Office Pract 47 (2020) 585–595

https://doi.org/10.1016/j.pop.2020.08.001 primarycare.theclinics.com
0095-4543/20/ª 2020 Elsevier Inc. All rights reserved.
586 Charles & Ferris

Box 1
Criteria for chronic kidney disease (either of the following present for 3 months)
Markers of Albuminuria (albumin excretion rate 30 mg/24 h;
kidney damage (1) albumin-to-creatinine ratio 30 mg/g [3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities owing
to tubular disorders
Abnormalities detected by histology
Structural abnormalities detected by
imaging History of kidney transplantation
Decreased GFR GFR <60 mL/min/1.73 m2 (GFR categories G3a–G5)

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO
2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
Kidney Int Suppl. 2013;3:1–150; with permission. Copyright 2013.

2001 to 2016.2 During that same time period, the prevalence of chronic kidney disease
among patients with diabetes was around 36%, whereas it is 31% in individuals with
hypertension.2 Age has the highest correlation with low eGFR (eGFR <60 mL/min/
1.73 m2), and chronic kidney disease has the highest prevalence in individuals over
the age of 60 years.2,3 Compared with men, women have a slightly higher prevalence
of both a GFR of less than 60 mL/min/1.73 m2 (7.9% vs 6.4% per the above study) and
albuminuria (10.9% vs 8.8%).4
The most common causes of chronic kidney disease in the United States are dia-
betes mellitus and hypertension, accounting for more than one-half of the cases. A
higher body mass index (30 kg/m2), cardiovascular disease, family history of kidney
disease, black race, personal factors such as smoking or heavy alcohol use, medica-
tions, and other systemic diseases have also shown an association. Chronic kidney
disease is an independent risk factor for cardiovascular disease, cognitive dysfunc-
tion, hospitalization, and all-cause mortality,5 so its importance to primary care physi-
cians cannot be understated.
Despite its prevalence, however, universal screening for chronic kidney disease in
adults is not recommended; in fact, the US Preventative Services Task Force and

Table 1
GFR categories for chronic kidney disease

GFR
(mL/
GFR min/
Category 1.73 m2) Terms
G1 90 Normal or high
G2 60–89 Mildly decreased
G3a 45–59 Mildly to moderately decreased
G3b 30–44 Moderately to severely decreased
G4 15–29 Severely decreased
G5 <15 Kidney Failure

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012
clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney
Int Suppl. 2013;3:1–150; with permission. Copyright 2013.
 Chronic Kidney Disease 587

the American College of Physicians advises against screening asymptomatic individ-

uals.6,7 The American Society of Nephrology, however, recommends that those indi-
viduals at increased risk for chronic kidney disease should be screened, including
those with diabetes, hypertension, or age above 55.8

PATHOGENESIS AND PATHOPHYSIOLOGY

Chronic kidney disease occurs as a consequence of 2 mechanisms: an initial trigger

and a perpetuating mechanism.9,10 The initiating stimulus can be a baseline kidney
issue (it is abnormal from development or it is injured along the way), an inflammatory
or immune-mediated cause, or a toxic insult. This kidney damage is then perpetuated
by the process of hyperfiltration and hypertrophy of remaining nephrons. Several path-
ways can cause this: hormones (such as the renin–aldosterone system), cytokines,
and growth factors. This process causes an increase in arterial filling pressure to
the nephrons, thereby causing changes to the glomerular architecture and structure
as well as changes to podocytes; this damages the filtration system. Ultimately, these
continued insults lead to sclerosis of nephrons and a further decrease in renal function.
Specific etiologies of chronic kidney disease are outlined elsewhere in this article, but
a few entities and their mechanisms of action are discussed here with additional infor-
mation of various specific diseases elsewhere in this issue.
Diabetes mellitus leads to chronic kidney disease by 3 main mechanisms.11 First,
hyperglycemia by itself causes increases in growth factor, angiotensin II, endothelin,
and advanced glycation end products, all of which contribute to the hyperfiltration ef-
fect. Second, with hyperfiltration, the capillary pressure increases, which ultimately
leads to changes in the glomerulus, including the classic thickened basement mem-
brane, expanded mesangium, increase in extracellular matrix, and eventual fibrosis.
As the kidney develops these changes, albuminuria develops, which is an additional
risk factor for cardiovascular disease.1
Hypertensive changes to the kidney occur by a slightly different mechanism.12
There is loss of the usual autoregulation of the afferent arteriole leading to hyperfiltra-
tion and, in response, the afferent arteriole undergoes vascular changes. As hyperfil-
tration persists, there is further damage and further worsening of hypertension, both at
the systemic level and the glomerular level, perpetuating the cycle of insult and injury.
Eventually glomerulosclerosis occurs and, finally, atrophy and/or necrosis.
Glomerulonephritides use another mechanism to initially injure the kidney and lead
to chronic kidney disease.13 It often starts with immune complexes depositing into the
basement membrane, triggering the release of chemokines that draw in various neu-
trophils, T cells, and macrophages. These immune cells trigger a cascade of additional
chemokines and cytokines that further perpetuate the inflammation and damage.
Furthermore, there can be proteases, complements, and oxidants that directly dam-
age the glomerular structure. Ultimately, interstitial nephritis develops, leading to
loss of filtrating and concentrating abilities, causing proteinuria, which triggers more
inflammatory mediators and activation of the renin–angiotensin system. This process
then produces hypertensive and ischemic changes, and the damaged tubules trigger
additional growth factors that eventually culminates in fibrosis and scarring.
Polycystic kidney disease is an example of a developmental kidney abnormality that
leads to chronic kidney disease.14 The development of cysts disrupts the architecture
of the kidney and, as they grow, the cysts compress surrounding healthy tissue lead-
ing to obstruction and eventual death of healthy nephron units, triggering the ongoing
decline of renal function. Additionally, this process releases cytokines, chemokines,
and growth factors, which triggers inflammation and eventual fibrosis.
588 Charles & Ferris

DIAGNOSIS

Chronic kidney disease is classified by cause, GFR category, and albuminuria cate-
gory, also known as the CGA classification. Cause for chronic kidney disease is
assigned based on presence or absence of systemic disease and the location within
the kidney of observed or presumed pathologic–anatomic findings. Estimated risk of
concurrent complications and future outcomes can be predicted by using GFR cate-
gories and level of albuminuria (Fig. 1).
Early stages of chronic kidney disease are typically asymptomatic, and symptoms
do not manifest until stage G4 and G5 or when GFR falls below 30 mL/min/1.73 m2.
Metabolic abnormalities and electrolyte disturbances lead to complications, including
anemia and secondary hyperparathyroidism.4 Once chronic kidney disease has pro-
gressed to end-stage renal disease, several nonspecific symptoms can occur such
as fatigue, nausea, loss of appetite, confusion, difficulty concentrating, irritability,
insomnia, and pruritis. A careful history and physical examination can help to reveal
the cause of the chronic kidney disease. Oftentimes, however, chronic kidney disease
is incidentally found from serum chemistry panels that include a serum creatinine. The
GFR should be estimated because this parameter provides a more accurate measure
of renal function. This calculation can be accomplished by using creatinine-based
equations that adjust for factors that affect serum creatinine and creatinine clearance
including age, sex, race and muscle. Most widely used is the Chronic Kidney Disease
Epidemiology Collaboration equation:15

GFR 5 141  min (Scr/8,1)a  max(Scr/8,1) 1.209

 0.993AGE  (1.018 if female) 
(1.159 if black)

[Scr – serum creatinine, 8 – 0.7 for females and 0.9 for males, a – 0.329 for females
and 0.411 for males, min – the minimum of Scr/8 or 1, max – maximum of Scr/8 or 1]

Fig. 1. Prognosis of chronic kidney disease by GFR and albuminuria categories. (Adapted
from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012
clinical practice guideline for the evaluation and management of chronic kidney disease.
Kidney Int Suppl. 2013;3:1–150; with permission. Copyright 2013.)
 Chronic Kidney Disease 589

The Modification of Diet in Renal Disease equation similarly can be used in esti-
mating GFR, but this equation is less accurate for a GFR of greater than 60 mL/min/
1.73 m2. Additionally, certain conditions that affect the GFR, such as extremes of mus-
cle mass or diet, may require the measurement of cystatin C, and the GFR can be
confirmed using the Chronic Kidney Disease Epidemiology creatinine–cystatin equa-
tion.16 In assessing for albuminuria, the primary care physician should order a random
urine albumin–creatinine ratio.
Further laboratory testing should include serum electrolytes (sodium, potassium,
chloride, and bicarbonate), urinalysis (for specific gravity, pH, red blood cells, and
leukocyte counts), and complete blood count.17,18 Because chronic kidney disease
is an independent risk factor for cardiovascular disease, a lipid panel should also be
obtained. A renal ultrasound examination should be ordered in all patients with chronic
kidney disease to look for hydronephrosis, cysts, or stones and to assess the size,
symmetry, and echogenicity of the kidneys.17 If suggested by the history, antinuclear
antibodies can be obtained to evaluate for lupus, serologic testing for hepatitis B and
C as well as human immunodeficiency virus, serum antineutrophil cytoplasmic anti-
bodies to evaluate for vasculitis, and serum and urine protein immunoelectrophoresis
for multiple myeloma.17 If the prior evaluation is not indicative of the etiology of the
chronic kidney disease, a kidney biopsy should be considered to determine etiologies
that are less common, including unexplained tubulointerstitial disease, glomerulone-
phritis, or membranous nephropathies (Table 2).

MANAGEMENT

The management of chronic kidney disease revolves around slowing the progression
of the disease and minimizing additional insults to the kidney. The primary care physi-
cian has an important role in this process given that they are likely the first person to
recognize the decline in GFR and best know the patient’s comorbidities and contrib-
uting factors for worsening chronic kidney disease. Predictors of progression are
listed in Table 3.19
Although some of the predictors are modifiable, others such as age and sex are
obviously not. The “other” category includes predictors that may be partially modified,
but not fully, because the damage has already been done. In any event, the primary
care physician should work with the patient to control those factors that are able to
be modified. Resources such as the 2012 KDIGO guidelines are a great source of in-
formation for primary care physicians to help guide the care of these patients. Ulti-
mately, there are 4 interventions that are shown to delay progression of chronic

Table 2
Suggested initial studies for patients with suspected chronic kidney disease

If Etiology
Still Not
All Patients If Suggested by History Clear
Basic metabolic panel Antinuclear antibodies Renal biopsy
Urinalysis Hepatitis B and hepatitis C serology –
Complete blood counts Human immunodeficiency virus –
Lipid profile Antineutrophil cytoplasmic antibodies –
Renal ultrasound examination SPEP, UPEP –

Abbreviations: SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

590 Charles & Ferris

Table 3
Predictors of progression in chronic kidney disease

Modifiable Nonmodifiable Other

Hypertension Age Cause of chronic kidney disease
Hyperglycemia Sex GFR level
Dyslipidemia Race/ethnicity Amount of albuminuria
Smoking – Presence of cardiovascular disease
Obesity – –
Use of nephrotoxic agents – –

kidney disease: controlling hypertension, using renin–angiotensin–aldosterone system

blockers, managing diabetes and hyperglycemia, and correcting metabolic
acidosis.20

Managing Comorbidities
Hypertension is one of the most important comorbidities to control in patients who
have chronic kidney disease, regardless of whether it was hypertension that initially
lead to the chronic kidney disease or not. Both the JNC8 and the KDIGO guidelines
(1B recommendation) recommend keeping blood pressure less than 140/90 mm Hg
in patients who have chronic kidney disease.19,21 If a patient already has albuminuria,
there is some evidence (2D recommendation) to support keeping the blood pressure
at less than 130/80 mm Hg to help slow the progression of chronic kidney disease,
with an additional suggestion to use an angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker if the albuminuria is greater than 300 mg/24 h.19
Because it is well-known that hyperglycemia ultimately damages the kidney and
diabetes is a leading cause of chronic kidney disease in the United States, it is critical
to control blood sugars. KDIGO gives a 1A recommendation to keep the hemoglobin
A1c around 7%, with the permission to be more liberal if the patient has a limited life
expectancy.19 Patients with chronic kidney disease are at risk of hypoglycemia owing
to decreased metabolism of the medications used to treat diabetes, so any patient
who has already had issues with hypoglycemia can also be allowed to have a higher
A1c if needed.
Given the high rate of cardiovascular disease in patients with chronic kidney dis-
ease, special attention must be given to screening for and treating this entity. KDIGO
gives a 2B recommendation to putting patients with chronic kidney disease on low-
dose aspirin unless there is an increased bleeding risk.19 Most patients with chronic
kidney disease should also be considered for statin therapy given their increased
risk of cardiovascular disease.19,20
Lifestyle recommendations cannot be overlooked in patients with chronic kidney
disease. The KDIGO guidelines give a 1C recommendation to limiting sodium to
less than 2000 mg/d. Additionally, they give level 2 evidence to limiting protein intake
to less than 0.8 g/kg/d in both diabetic and nondiabetic patients with G4 to G5 chronic
kidney disease. Primary care physicians should strongly consider referring patients to
nutritionists familiar with chronic kidney disease (1B recommendation) because they
can often assist patients in making good food and beverage choices, taking into
consideration protein, calories, micronutrients, and electrolytes. Furthermore, patients
should be encouraged to do 150 min/wk of aerobic exercise, keep their body mass
 Chronic Kidney Disease 591

index between 20 and 25, and not smoke tobacco products (all 1D
recommendations).19
Managing Sequelae of Chronic Kidney Disease
Anemia
Anemia is a common complication of chronic kidney disease. Given that 80% of the
body’s erythropoietin comes from the kidney’s peritubular interstitial cells, it is no sur-
prise that erythropoietin production decreases as the GFR decreases.22 As the GFR
decreases to less than 60, annual measurement of hemoglobin is suggested.9 As
the hemoglobin decreases to less than 10 g/dL, erythropoietin treatment is given, usu-
ally subcutaneously (because this route allows lower doses to be used than if given
intravenously) with a goal hematocrit of 33% to 35% within 2 to 4 months.22 Special
attention should be paid to iron stores as well, often providing supplemental iron if
the ferritin is less than 100 or the transferrin saturation is less than 20%.
Calcium, phosphorus, parathyroid hormone, and bones
The complex interplay of calcium, phosphorus, and parathyroid hormone on bone
health necessitates monitoring in patients with chronic kidney disease. KDIGO gives
a 1C recommendation to measuring and monitoring calcium, phosphorus, parathyroid
hormone, and alkaline phosphatase when the GFR decreases to less than 45.19 Pri-
mary care physicians should aim to maintain phosphorus levels in the normal range
(2C recommendation) by suggesting a decreased dietary intake of phosphorus and
using phosphate binders with meals to limit their absorption. Physicians should also
aim to manage the secondary hyperparathyroidism by using agents such as calcitriol,
paricalcitol, or cinacalcet,23 but generally this would be done by a nephrologist,
because secondary hyperparathyroidism as a consequence of chronic kidney disease
is an indication for referral to nephrology.19,20 Although patients with chronic kidney
disease are at risk of bone disease, it is not recommended (2B evidence) to routinely
test the bone mineral density in these patients.19
Metabolic acidosis
Serum bicarbonate levels are an important factor to monitor in patients with chronic
kidney disease. KDIGO recommends (2B) to keep the serum bicarbonate in the normal
range, supplementing when the level is <22 mmol/L. Oral supplement options include
sodium bicarb 650 mg 3 times per day or sodium citrate 30 mL/d.20
Protecting the Kidney from Nephrotoxins
The kidney is a major system for drug metabolism and excretion; therefore, it is impor-
tant to consider the effect of any medication or agent on the kidneys when it is pre-
scribed. Some drugs require dose adjustment, whereas others should be avoided
entirely. Sometimes it is not feasible to avoid a drug that is potentially nephrotoxic;
therefore, it is important to closely monitor renal function during and after treatment
with such an agent. Some over-the-counter medications and supplements have un-
known effects on the kidney and in chronic kidney disease; therefore, herbal supple-
ments should not be used, and any over-the-counter medications should be
discussed with a physician or pharmacist before using (1B recommendation).19
Contrast agents present a special dilemma for primary care physicians, especially
when patients may need radiologic studies to diagnose other medical conditions.
Like with many situations in medicine, the risks and benefits must be considered
before ordering any diagnostic test that requires the use of contrast agents. In regards
to iodinated radio contrast agents, KDIGO recommends avoiding high-osmolar agents
(1B recommendation), use the lowest dose (no grade), hold any other potentially
592 Charles & Ferris

nephrotoxic drugs periprocedurally (1C recommendation), allow adequate hydration

before, during, and after the procedure (1A recommendation), and measure the
GFR 2 to 3 days after the test (1C recommendation).19 Gadolinium-based contrast
should be avoided in patients with a GFR less than 15 (1B recommendation), and it
is suggested to use a special formulation of gadolinium in patients whose GFR is
less than 30 (2B recommendation).19

Vaccines
The immune system in patients with chronic kidney disease is impaired, raising their
risk of infection. For this reason, KDIGO recommends vaccinating against influenza

Table 4
Summary of recommendations for managing patients with chronic kidney disease

Grade of rec/
Level of
Recommendation Who Evidence
BP <140/90 mm Hg All 1B
BP <130/80 mm Hg Chronic kidney disease 2D
with albuminuria
ACE-I/ARB treatment Albuminuria >300 mg/24 h 1B
A1c w7% (can be more liberal All patients with DM 1A
if short life expectancy or
high risk of hypoglycemia)
Dietary sodium <2000 mg/d All 1C
Dietary protein <0.8 g/kg/d G4-5 2C if patient
with DM,
2B if patient
without DM
Referral to nutritionist All 1B
Exercise >150 min/wk All 1D
Goal body mass index 20–25 All 1D
No smoking All 1D
Check Hgb annually; All No grade
anemia if <13 (male),
<12 (female)
Keep serum bicarbonate normal All 2B
Check calcium, phosphorus, GFR of <45 1C
parathyroid hormone,
and alkaline phosphatase
Daily low-dose aspirin All who are at risk of 2B
chronic kidney disease
(and not at high risk
of bleeding)
Vaccines
Influenza 1B
Pneumococcal 1B
Hepatitis B All 1B
(if likely to need RRT)

Abbreviations: A1c, glycosylated hemoglobin; ACE-I, angiotensin-converting enzyme inhibitor;

ARB, angiotensin receptor blocker; BP, blood pressure; DM, diabetes mellitus; Hgb, hemoglobin;
RRT, renal replacement therapy.
 Chronic Kidney Disease 593

Box 2
When to refer to a nephrologist

GFR less than 30 mL/min/1.73 m2

Greater than 25% decrease in GFR
Progression of chronic kidney disease (sustained decline of GFR >5 mL/min/1.73 m2 per year)
Significant albuminuria
Unexplained hematuria that is persistent
Complications of chronic kidney disease: secondary hyperparathyroidism, worsening anion gap
acidosis, non–iron deficiency anemia
chronic kidney disease with hypertension requiring 4 medications
Persistent hyperkalemia or hypokalemia
Nephrolithiasis that is recurrent or extensive
Hereditary etiology of chronic kidney disease
Unknown etiology of chronic kidney disease

Data from Inker LA, Astor BC, Fox CH, et al. KDOQI US commentary on the 2012 KDIGO clinical
practice guideline for the evaluation and management of CKD. Am J Kidney Dis.
2014;63(5):713–35.

(1B recommendation) and pneumococcal (1B recommendation) disease. Additionally,

for patients who have advanced chronic kidney disease and are expected to progress
to needing renal replacement therapy, it is suggested to vaccinate against hepatitis B
(1B recommendation) (Table 4).19

NEPHROLOGY CONSULTATION AND REFERRAL

Although primary care physicians can mitigate further damage to kidneys and decline
in renal function, there are specific instances in which referral to a nephrologist is rec-
ommended.1,19 Given the chance of requiring renal replacement therapy in the near
future, any patient with a GFR of less than 30 mL/min/1.73 m2 should be managed
by a nephrologist. Having that relationship early allows for proper discussions and
planning for future needs in regards to possible dialysis or transplant consideration.
Additionally, any patient with a 25% or greater decrease in the GFR or progressive
worsening of the GFR of more than 5 mL/min/1.73 m2 per year should also be referred
to nephrology for further evaluation and management. Significant albuminuria (albu-
min/creatinine ratio of >300 mg/g or albumin excretion rate of 300 mg/24 h) is also
an indication to consult a nephrologist, unless the etiology is known to be diabetes
and the primary care physician is appropriately managing both the diabetes and the
albuminuria. Box 2 lists reasons to consider a nephrology referral in patients with
chronic kidney disease.

SUMMARY

Chronic kidney disease is an entity that all primary care physicians need to be comfort-
able diagnosing and managing. Although diabetes and hypertension are the most
common etiologies of chronic kidney disease, understanding the pathophysiology
and comorbid conditions associated with chronic kidney disease will help the primary
care physician to better assess and manage these patients. Attention must be given to
594 Charles & Ferris

mitigating cardiovascular risk, avoiding drugs or interventions that can worsen renal
function, and referring patients to a nephrologist when necessary.

DISCLOSURE

The authors have nothing to disclose.

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