Chronic Kidney Disease

Nephrology

With Amy Sussman, M.D.

Learning Objectives
• Define chronic kidney disease (CKD)

• How to assess kidney function

• Glomerular filtration rate (GFR)

measurement

• Proteinuria

• Common causes of CKD

• Progression and consequences of CKD

• Risk factors for progression of disease

and interventions to slow the disease
process

• How to care for the CKD patient

A 29-year-old Woman and a 52-year-old Man Test case

A 29-year-old woman is noted to have microscopic hematuria Chronic kidney disease

and 2+ positive-dipstick proteinuria (no proteinuria on dipstick
is normal) on screening labs for a life insurance policy. It was
confirmed on a repeat urinalysis 3 months later. Her serum
creatinine is normal.

A 52-year-old man with a history of hypertension is noted to

have a serum creatinine of 1.7 mg/dL (normal 0.5 1.2 mg/dL). Chronic kidney disease
His urinalysis is unremarkable. In review of his past records, his
serum creatinine was elevated to 1.7 mg/dL 6 months prior.

Which one of these patients has chronic kidney

disease?
They both have chronic kidney disease!
Chronic Kidney Disease

Pathological abnormalities

Clinical markers of kidney damage:

• Proteinuria

• > 150 mg of proteinuria per day

Decreased kidney function
• > 30 mg of albuminuria per day for with a decreased
glomerular filtration rate (GFR)
• Glomerular hematuria

• Dysmorphic RBCs or RBC casts

Chronic Kidney Disease

Clinical markers of kidney damage:

Renal cortex
• Imaging
• Polycystic kidneys

• Hydronephrosis

• Small kidneys with thinned

cortices

Dilated renal
pelvis

Morning2k, Ultrasonographic
Chronic Kidney Disease

Clinical markers of kidney damage:

• Imaging
• Polycystic kidneys Renal cortex

• Hydronephrosis

• Small kidneys with thinned

cortices

Kristoffer Lindskov Hansen et al., https://commons.wikimedia.org/wiki/File:Ultrasonography_of_chronic_renal_disease_caused

_by_glomerulonephritis.jpg, CC BY 4.0, no changes
Chronic Kidney Disease

Clinical markers of kidney damage: Decreased kidney function:

• Imaging • GFR < 60 mL/min/1.73 m2 for

• Polycystic kidneys
• Normal GFR ~90 120 mL/min/1.73 m2
• Hydronephrosis
• Document at least 2 measurements
• Small kidneys with thinned separated by at least 2 weeks
cortices
Assessment of Kidney Function

How do we assess kidney function?

GFR Measurement

Serum creatinine

• Derived from metabolism of creatine in

CH3
skeletal muscle and dietary meat intake

• Released into circulation at constant rate

stable plasma concentration

• Freely filtered across glomerulus and

neither reabsorbed nor metabolized

• Inversely proportional to GFR

• Can only be used with stable kidney Creatinine

function

Ben Mills, PD
Limitations to Using Serum Creatinine as a Measurement

It is not accurate in patients with Certain medications can inhibit secretion

little muscle mass. of creatinine into the tubular fluid.

• Liver disease, malnourished • Increase in serum creatinine despite not

patients, congenital dwarfism having changes in GFR (e.g.,
trimethoprim)

Monitoring serum creatinine level

does not detect early changes in GFR.
Serum Creatinine Level Does Not Reflect Early Changes in GFR

Initial small rise in serum creatinine reflects

marked change in GFR. Marked rise in serum
creatinine with advanced disease reflects
only small absolute reduction in GFR.
Relationship Between Serum Creatinine and GFR

Serum creatinine, 8
mg/dL

4 5 mL/min loss 40 mL/min loss

6
5 mg/dL
4 4 mg/dL

1.1 mg/dL 0.7 mg/dL

2
1.1

0 GFR mL/min
20 40 60 80 100 120 140
Creatinine Clearance

Clearance is the rate at which a substance

is removed or cleared from the body by the
kidneys.
Creatinine Clearance

UV/P

Urinary concentration Volume of urine per Plasma concentration

of a substance set time (i.e. 24 h) of a substance

Creatinine is filtered and not reabsorbed by the tubule

→ can measure the clearance of creatinine to obtain the measurement of GFR
Limitations of Creatinine Clearance

Creatinine is also secreted into tubule.

→ Urinary creatinine concentration will be higher than what is actually filtered.

→ Creatinine clearance will exceed the true GFR by ~10 20%.

Inaccurate collection

→ Patients will over- or undercollect urine.

Creatinine clearance is no longer recommended for routinely assessing GFR.

Modifications of Diet and Renal Disease Equation (MDRD)

Estimated GFR (eGFR) Using MDRD equation

Estimates GFR by incorporating known demographic and clinical variables as observed
surrogates for unmeasured factors other than GFR that affect serum creatinine:

Age Gender

Ethnicity Creatinine
Modifications of Diet and Renal Disease Equation (MDRD)

Estimated GFR (eGFR) Using MDRD equation

Estimates GFR by incorporating known demographic and clinical variables
-1.154 -0.203 as observed
eGFR = 186 x serum creatinine x age
surrogates for unmeasured factors other than GFR that affect serum creatinine:
x [1.212 if African American] x [0.742 if female]

• Used to not only estimate GFR but to follow changes in GFR

• Becomes less accurate when GFR > 60 mL/min/1.73 m2

CKD-EPI Formula

Estimated GFR (eGFR) Using Chronic Kidney Disease Epidemiology

Collaboration Equation (CKD-EPI)
• Developed to create a formula more accurate than MDRD
when actual GFR > 60 mL/min/1.73 m2

• Also estimates GFR based on:

Age Gender

Ethnicity Creatinine
CKD-EPI Formula

Estimated GFR (eGFR) Using Chronic Kidney Disease Epidemiology

Collaboration Equation (CKD-EPI)
• Developed to create a formula more accurate than MDRD
when actual GFR > 60 mL/min/1.73 m2

• Better accuracy than MDRD when GFR > 60 mL/min/1.73 m2

• Know which method your institution uses!

An 82-year-old Woman and a 26-year-old Grandson Test case

An 82-year-old woman weighing 48 kg (106 lb) has a creatinine

of 1.2 mg/dL.

Her 26-year-old grandson who competes in

bodybuilding competitions weighs 90 kg (198 lb) and has a
creatinine of 1.2 mg/dL.

Do they have the same renal function?

An 82-year-old Woman and a 26-year-old Grandson Test case

An 82-year-old woman weighing 48 kg (106 lb) has a creatinine She has much less muscle
of 1.2 mg/dL. mass than her grandson

Her 26-year-old grandson who competes in

bodybuilding competitions weighs 90 kg (198 lb) and has a
creatinine of 1.2 mg/dL.

Do they have the same renal function?

No this underscores the importance of using

estimated GFR equations that are based on
demographic variables
Serum Creatinine vs. Estimated GFR
eGFR
Age Gender Race SCr (mg/dL)
(mL/min/1.73 m2)

20 M AA 1.3 91

20 M C 1.3 75

20 F C 1.3 56

50 F C 1.3 46

50 F AA 1.3 56

70 F C 1.3 43
Why Is Measurement of GFR Important?

1 Important to evaluate patients with kidney disorders

2 Critical to appropriately dose medications cleared by the kidney

3 Avoidance of nephrotoxic medications (i.e. iodinated contrast)

4 Staging of chronic kidney disease in efforts to target a population at risk

Proteinuria

Proteinuria is defined by abnormal quantities

of protein in the urine.
Proteinuria

Clinical marker of kidney damage

Normal quantity of Normal quantity of albumin

protein in urine (primary protein) in urine

< 150 mg over 24 h < 30 mg over 24 h

Proteinuria Methods to Measure Protein in the Urine

Protein-to-creatinine ratio and

Urine dipstick 24 h urine measurement
albumin-to-creatinine ratio

• Colorimetric test • Provides total protein • Spot urinary measurement

that does not excreted in the urine of protein (or albumin) and
quantify exact over a 24 h period creatinine
amount of protein
• Need to measure urinary • Estimates 24 h urinary
creatinine to ensure protein or albumin value
accurate collection
• Difficult to do regularly
when following patients
with proteinuria
Proteinuria
Protein-to-creatinine and albumin-to-creatinine ratios
estimate 24-hour urinary protein excretion.
Most people will generate 1 2 grams of urinary creatinine.

Men Women
20 25 mg/kg urinary creatinine daily 15 20 mg/kg urinary creatinine daily

80-kg (176-lb) man: 60-kg (132-lb) woman:

20 x 80 = 1600 mg of urinary creatinine 15 x 60 = 900 mg of urinary creatinine

Ratio of random spot urinary protein or albumin measurement

General estimate:
Random spot urinary creatinine
Stages of Chronic Kidney Disease

Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

Kidney damage
Kidney damage Moderate Severe
with normal Kidney failure
with mild ↓ GFR ↓ GFR ↓ GFR
or ↑ GFR

89 60 59 30 29 15 < 15 or dialysis
GFR (mL/min/1.73 m2)

End-stage renal disease (ESRD)

End-stage kidney disease (ESKD)
Causes of Chronic Kidney Disease
Subdivided into part of nephron that is affected

Tubulointerstitial Vascular Glomerular Postrenal

F.l.t.r.: Libertas Academica, Figure 1A, https://www.flickr.com/photos/libertasacademica/7137093023, cropped and scaled, CC BY 2.0, flickr; ©
by Lecturio
Tubulointerstitial Disease Polycystic Kidney Disease
Autosomal dominant presents in adulthood

• Associated with PKD 1 and PKD 2 mutations

• Most common cause of genetic kidney disease

• Most patients will progress to the need of renal

replacement therapy (dialysis or transplant)

Autosomal recessive presents in childhood

• Infantile polycystic kidney disease

• Cystic dilatations of the collecting duct and

congenital hepatic fibrosis
CDC/ Dr. Edwin P. Ewing, Jr., PD
Tubulointerstitial Disease Autoimmune Disease

• syndrome

• Sarcoidosis

• Inflammatory infiltrates in the

tubulointerstitium

• Often associated with tubular

dysfunction

© 2014 Vishwanath et al.; licensee BioMed Central Ltd., Figure 2, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031912/figure/F2/, CC BY

2.0, no changes
Tubulointerstitial Disease Autoimmune Disease

• syndrome

• Sarcoidosis Non-caseating granuloma

• Inflammatory infiltrates in the

tubulointerstitium Giant cell

• Often associated with tubular

dysfunction

© 2014 Bagnasco et al, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203836/figure/pone-0110778-g001/, CC BY 4.0, no changes

Tubulointerstitial Disease Autoimmune Disease

• syndrome

• Sarcoidosis

• Inflammatory infiltrates in the

tubulointerstitium

• Often associated with tubular

dysfunction

© 2014 Bagnasco et al, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203836/figure/pone-0110778-g001/, CC BY 4.0, no changes

Tubulointerstitial Disease Reflux Nephropathy

Vesicoureteral reflux Upper

urinary tract
• Passage of urine from the bladder into
the upper urinary tract

• Typically due to inadequate closure of

the ureterovesical junction

• Presents in childhood

© by Lecturio
Tubulointerstitial Disease Reflux Nephropathy

Vesicoureteral reflux Upper

urinary tract
• Passage of urine from the bladder into
the upper urinary tract

• Typically due to inadequate closure of Ureterovesical

the ureterovesical junction junction
• Presents in childhood

© by Lecturio
Tubulointerstitial Disease Reflux Nephropathy

Vesicoureteral reflux Upper

urinary tract
• Passage of urine from the bladder into
the upper urinary tract

• Typically due to inadequate closure of Ureterovesical

the ureterovesical junction junction
• Presents in childhood

© by Lecturio
Causes of Chronic Kidney Disease
Subdivided into part of nephron that is affected

Tubulointerstitial Vascular Glomerular Post-renal

F.l.t.r.: Libertas Academica, Figure 1A, https://www.flickr.com/photos/libertasacademica/7137093023, cropped and scaled, CC BY 2.0, flickr; ©
by Lecturio
Vascular Disease

Hypertensive vasculopathy Normal

• Associated with chronic hypertension

→ hypertensive nephrosclerosis

• Intimal thickening and luminal narrowing of

large and small renal arteries and glomerular
arterioles

Renovascular disease

• Due to either bilateral or unilateral renal

artery stenosis Hypertension

© by Lecturio
Vascular Disease

Hypertensive vasculopathy

• Associated with chronic hypertension

→ hypertensive nephrosclerosis

• Intimal thickening and luminal narrowing of

large and small renal arteries and glomerular
arterioles

Renovascular disease

• Due to either bilateral or unilateral renal

artery stenosis

ography
_in_a_patient_with_fibromuscular_dysplasia_(2).jpg, CC BY 2.0, no changes
Vascular Disease Renal Atheroembolic Disease

Plaque

• Cholesterol emboli caused by coronary

artery, aortic, or renal artery manipulation

• Also a cause of acute kidney injury

• Many do not recover function, which

leads to chronic kidney disease

© by Lecturio
Causes of Chronic Kidney Disease
Subdivided into part of nephron that is affected

Tubulointerstitial Vascular Glomerular Postrenal

F.l.t.r.: Libertas Academica, Figure 1A, https://www.flickr.com/photos/libertasacademica/7137093023, cropped and scaled, CC BY 2.0, flickr; ©
by Lecturio
Glomerular Disease

Diabetic nodules

Diabetic nephropathy

• Most common cause of CKD/ESRD

in the United States

Primary glomerular disease

• Nephritic and nephrotic diseases

© by Erika R. Bracamonte, MD; Jolanta Kowalewska, MD, PhD

Causes of Chronic Kidney Disease
Subdivided into part of nephron that is affected

Tubulointerstitial Vascular Glomerular Postrenal

F.l.t.r.: Libertas Academica, Figure 1A, https://www.flickr.com/photos/libertasacademica/7137093023, cropped and scaled, CC BY 2.0, flickr; ©
by Lecturio
Postrenal or Obstructive Uropathy

Prolonged obstruction without intervention

→ parenchymal loss
Renal
• Loss of nephron mass due to pelvis
compression from reflux of urine

• Benign prostatic hyperplasia

• Urethral stricture

• Chronic obstructive calculi

(nephrolithiasis or kidney stones)

• Pelvic masses (extrarenal

compression on ureters) Urethra
© by Lecturio
Postrenal or Obstructive Uropathy

Prolonged obstruction without intervention

→ parenchymal loss

• Loss of nephron mass due to

compression from reflux of urine

• Benign prostatic hyperplasia

• Urethral stricture

• Chronic obstructive calculi

(nephrolithiasis or kidney stones)

• Pelvic masses (extrarenal

compression on ureters)

National Cancer Institute, PD

Postrenal or Obstructive Uropathy

Prolonged obstruction without intervention

→ parenchymal loss

• Loss of nephron mass due to

compression from reflux of urine

• Benign prostatic hyperplasia

• Urethral stricture

• Chronic obstructive calculi

(nephrolithiasis or kidney stones)

• Pelvic masses (extrarenal

compression on ureters)

Akkoc A et al, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871399/figure/f4/, CC BY 4.0, cropped

Postrenal or Obstructive Uropathy

Prolonged obstruction without intervention

→ parenchymal loss

• Loss of nephron mass due to

compression from reflux of urine

• Benign prostatic hyperplasia

• Urethral stricture

• Chronic obstructive calculi

(nephrolithiasis or kidney stones)

• Pelvic masses (extrarenal

compression on ureters)

©2013 Vallone et al; licensee BioMed Central Ltd., Figure 1, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711724/figure/F1/, CC BY 2.0,
edited
63-year-old Woman with Elevated Serum Creatinine Test case

A 63-year-old woman is referred to you for evaluation of an

elevated serum creatinine of 1.6 mg/dL (eGFR 34 mL/min/1.73
m2 by CKD-Epi equation) noted on at least 3 occasions.

She has no history of diabetes mellitus, no history of chronic

NSAID use, no history of stones, and no hypertension.

A renal ultrasound shows an increase in echogenicity and slight

thinning of the renal cortices.

She discloses that she had an illness 1 year ago for which she
was hospitalized, at which time she was treated for septic
shock in the ICU. She notes nearly needing dialysis at that
time.
63-year-old Woman with Elevated Serum Creatinine Test case

A 63-year-old woman is referred to you for evaluation of an No predisposing

elevated serum creatinine of 1.6 mg/dL (eGFR 34 mL/min/1.73 conditions
m2 by CKD-Epi equation) noted on at least 3 occasions.

She has no history of diabetes mellitus, no history of chronic

NSAID use, no history of stones, and no hypertension.

A renal ultrasound shows an increase in echogenicity and slight Medical renal disease
thinning of the renal cortices.

She discloses that she had an illness 1 year ago for which she
was hospitalized, at which time she was treated for septic Unresolved tubular
shock in the ICU. She notes nearly needing dialysis at that injury
time.
63-year-old Woman with Elevated Serum Creatinine Test case

What is the most likely cause of her CKD?

Unresolved acute kidney injury

Acute Kidney Injury

• Chronic sequelae from initial

or repeated episodes of AKI

• Increasingly recognized as a
cause of CKD

Haymanj, PD
Pathophysiology of Chronic Kidney Disease

Regardless of the underlying disease or

inciting event, the final common pathway to
progressive CKD is a shared mechanism.
Pathophysiology of Chronic Kidney Disease
↓ Number of
nephrons Activation of
vasoactive
mediators,
cytokines, RAAS,
Initiating factor growth factors

Accelerated Diabetes, hypertension, Structural and

sclerosis toxin exposure, immune functional changes
of remaining complex deposition, of surviving
nephrons autoimmune disease, etc. nephrons

Hyperfiltration
↑ Intraglomerular
capillary pressure
49-year-old Man with Increased Serum Creatinine Test case

You are asked to see a 49-year-old man who is noted to have a

serum creatinine of 1.9 mg/dL (normal 0.5 1.0 mg/dL).

Four years ago his serum creatinine was 1.1 mg/dL. He has a
history of type 2 diabetes mellitus, hypertension, and
dyslipidemia.

Labs: Creatinine is 1.9 mg/dL (normal 0.5 1.0 mg/dL) with eGFR
40 mL/min/1.73 m2 by CKD-Epi. Urinalysis shows 2+ dipstick-
positive proteinuria. Proteinuria estimated at 1.2 g/g of
creatinine by spot ratio. Hemoglobin A1c (measures blood
glucose activity over a 3-month period) high at 9.4% (normal <
5.7%).

kidney disease?
49-year-old Man with Increased Serum Creatinine Test case

You are asked to see a 49-year-old man who is noted to have a

serum creatinine of 1.9 mg/dL (normal 0.5 1.0 mg/dL). CKD

Four years ago his serum creatinine was 1.1 mg/dL. He has a
history of type 2 diabetes mellitus, hypertension, and
dyslipidemia.

Labs: Creatinine is 1.9 mg/dL (normal 0.5 1.0 mg/dL) with eGFR Kidney damage
40 mL/min/1.73 m2 by CKD-Epi. Urinalysis shows 2+ dipstick-
positive proteinuria. Proteinuria estimated at 1.2 g/g of Uncontrolled diabetes
creatinine by spot ratio. Hemoglobin A1c (measures blood mellitus
glucose activity over a 3-month period) high at 9.4% (normal <
5.7%).

kidney disease?
49-year-old Man with Increased Serum Creatinine Test case

You are asked to see a 49-year-old man who is noted to have a

serum creatinine of 1.9 mg/dL (normal 0.5 1.0 mg/dL). CKD

Four years ago his serum creatinine was 1.1 mg/dL. He has a
history of type 2 diabetes mellitus, hypertension, and
dyslipidemia.

Labs: Creatinine is 1.9 mg/dL (normal 0.5 1.0 mg/dL) with eGFR Kidney damage
40 mL/min/1.73 m2 by CKD-Epi. Urinalysis shows 2+ dipstick-
positive proteinuria. Proteinuria estimated at 1.2 g/g of Uncontrolled diabetes
creatinine by spot ratio. Hemoglobin A1c (measures blood mellitus
glucose activity over a 3-month period) high at 9.4% (normal <
5.7%).

kidney disease?
Diabetic kidney disease
Common Diseases that Predispose to Chronic Kidney Disease

Diabetes mellitus a group of metabolic diseases

that manifests as hyperglycemia

• Pancreatic beta cells do not produce enough

insulin → type I diabetes

• Insulin resistance cells do not respond to insulin

→ type II diabetes

• 20 30% of patients with diabetes will develop

diabetic kidney disease/nephropathy

• Accounts for ~55% of new dialysis patients

Common Diseases that Predispose to Chronic Kidney Disease

Diabetic nodules
Diabetes mellitus disease manifestations

• Glomerulopathy

• Mesangial expansion

• Thickening of glomerular basement

membrane

• Glomerulosclerosis

© by Erika R. Bracamonte, MD; Jolanta Kowalewska, MD, PhD

Diabetes Mellitus Clinical Manifestations
Hyperfiltration and glomerular capillary Microalbuminuria (moderately increased
hypertension albuminuria)

• Earliest clinical manifestation of disease • Urinary albumin of 30 300 mg

• Predicts high risk for future overt
nephropathy (> 1 g proteinuria per day)

• Critical for effective therapy to target:

• Glomerular capillary hypertension
→ ACE inhibitors and angiotensin
receptor blockers

• Glycemic control
• Weight control
Diabetes Mellitus Clinical Characteristics
Overt proteinuria (severely increased Progressive disease with little or no
albuminuria) albuminuria

• Urinary albumin > 300 mg per day • Subset of diabetic patients that have
progressive CKD but decline in GFR is
• Progressive decline in GFR and ESRD NOT related to albuminuria
→ absence of effective therapy
• Presumed due to intrarenal vascular
disease

• Rate in decline of GFR is SLOWER

compared to albuminuric patients
Diabetes Mellitus Disease Course

Diabetes
onset

Increased or
normal GFR Micro- Overt Decreased
ESRD
normo- albuminuria nephropathy GFR
albuminuria

Time
Pathogenesis of Diabetic Nephropathy

Multifactorial:

Hyperglycemia
Impaired
Glomerular and advanced Elevated
podocyte-specific
hyperfiltration glycation end prorenin levels
insulin signaling
products
57-year-old Man with Increased Serum Creatinine Test case

You are asked to see a 57-year-old African American man who

is noted to have a serum creatinine of 2.1 mg/dL (normal
0.5 1.2 mg/dL).

Seven years ago his serum creatinine was 1.4 mg/dL. He has a
history of hypertension diagnosed 17 years ago and,
dyslipidemia, and he uses tobacco.

Retinal exam: Cotton wool spots due to retinal ischemia

Labs: Serum creatinine is 2.1 mg/dL (normal 0.5 1.2 mg/dL),

eGFR 34 mL/min/1.73 m2 by CKD-Epi. Urinalysis shows
1+ dipstick-positive proteinuria. Proteinuria is estimated at 680
mg/g creatinine by spot ratio.

chronic kidney disease?

57-year-old Man with Increased Serum Creatinine Test case

You are asked to see a 57-year-old African American man who

is noted to have a serum creatinine of 2.1 mg/dL (normal Chronic kidney disease
0.5 1.2 mg/dL).

Seven years ago his serum creatinine was 1.4 mg/dL. He has a
history of hypertension diagnosed 17 years ago and,
dyslipidemia, and he uses tobacco.
End-organ damage from
Retinal exam: Cotton wool spots due to retinal ischemia hypertension

Labs: Serum creatinine is 2.1 mg/dL (normal 0.5 1.2 mg/dL), Chronic kidney disease
eGFR 34 mL/min/1.73 m2 by CKD-Epi. Urinalysis shows
1+ dipstick-positive proteinuria. Proteinuria is estimated at 680
mg/g creatinine by spot ratio.

chronic kidney disease?

57-year-old Man with Increased Serum Creatinine Test case

disease?

Hypertension hypertensive vasculopathy

Hypertension
Chronic elevations in blood pressure

Tubulointerstitial disease Vascular Glomerular

F.l.t.r.: Libertas Academica, Figure 1A, https://www.flickr.com/photos/libertasacademica/7137093023, cropped and scaled, CC BY 2.0, flickr; ©
by Lecturio
Hypertension

African Americans have a much higher

risk of progressive CKD and ESRD despite
adequate blood pressure control.
Hypertension Association with Genetic Polymorphisms

Minor component of
HDL cholesterol
• When intracellular has the ability
to kill trypanosomes (cause of
HDL African sleeping sickness)

• Allelic variants probably confer a

selective biological advantage
Apolipoprotein L1 → resistance against
gene (APOL1) Trypanasoma brucei rhodesiense

• When inherited in a recessive

fashion → hypertensive CKD and
Chromosome 22 high progression to ESRD
Hypertension Clinical Manifestations

• Long history of hypertension

• Retinopathy

• Vascular changes in the retina

due to high arterial pressures

• Left ventricular hypertrophy

• Proteinuria

• < 1 g per day

Frank Wood, Hypertensive retinopathy, https://commons.wikimedia.org/wiki/File:Hypertensiveretinopathy.jpg, CC BY 3.0, cropped

61-year-old Man with Stage IIIb CKD Test case

You are seeing a 61-year-old man who has stage IIIb CKD due
to diabetic nephropathy and hypertension.

Labs: Serum creatinine is 2.1 mg/dL (normal 0.5 1.0 mg/dL) with
eGFR 31 mL/min/1.73 m2 (normal 90 120 mL/min/1.73 m2).
Proteinuria is estimated at 490 mg/g creatinine by spot ratio
(normal < 150 mg/g creatinine).

He is on an ACE inhibitor, but blood pressure is not controlled

(140s/80s mm Hg).

What is the most likely outcome for this man?

61-year-old Man with Stage IIIb CKD Test case

He will progress to stage V CKD and need dialysis/renal replacement therapy within the
next 3 years.

His creatinine will stay the same over the next 3 years.

He will die from a cardiovascular event (i.e. acute coronary syndrome etc.) within the
next 3 years.
61-year-old Man with Stage IIIb CKD Test case

He will progress to stage V CKD and need dialysis/renal replacement therapy within the
next 3 years.

His creatinine will stay the same over the next 3 years.

He will die from a cardiovascular event (i.e. acute coronary syndrome etc.) within the
next 3 years.
Consequences of CKD Cardiovascular Disease

The majority of patients with CKD will die from

cardiovascular disease rather than progress
to end-stage renal disease (ESRD).
Consequences of CKD Cardiovascular Disease

CKD and cardiovascular disease share many risk factors.

There is an independent risk for developing cardiovascular
disease in CKD patients.

Increased risk of cardiovascular disease is associated with both:

• Decreased GFR

• Increase in proteinuria
Consequences of CKD Cardiovascular Disease

N = 27,998 followed over 5 years

ESRD Cardiovascular death

Cases (%)

89 60 eGFR 59 30 eGFR 29 15 eGFR

Source: Keith DS Arch Int Med 2004 164:659-663
Consequences of CKD Hypertension

Hypertension presents in 80 85%

of patients with CKD.
Consequences of CKD Hypertension

Multifactorial:

Na+ retention Secondary

Enhanced activity hyperparathyroidism
of the sympathetic Rise in intracellular
nervous system calcium
→ vasoconstriction
Increased activity of
the renin-angiotensin-
Impaired nitric oxide synthesis and endothelium-mediated
aldosterone system
vasodilatation
Consequences of CKD Mineral and Bone Disease

↓ Urinary phosphorus
↓ GFR
excretion
↑ Phosphorus excretion to
maintain normal serum
phosphorus concentration

Inhibits 1-α- ↑ FGF-23

hydroxylase (phosphatonin)

↓ Intestinal calcium Secondary hyper-

↓ Calcitriol ↑ PTH
absorption parathyroidism
Consequences of CKD Mineral and Bone Disease
• Vascular calcification

• Renal osteodystrophy

• Osteomalacia: defective mineralization

• High turnover bone disease:

osteitis fibrosa peritrabecular fibrosis

• Mixed uremic bone disease:

features of both osteitis fibrosa and osteomalacia

• Adynamic bone disease:

iatrogenic → oversuppression of parathyroid hormone
(PTH) typically with active vitamin D analogues
→ decreased bone formation and turnover

• Trochanteric fractures
National Human Genome Research Institute, PD
Consequences of CKD Mineral and Bone Disease
• Vascular calcification

• Renal osteodystrophy

• Osteomalacia: defective mineralization

• High turnover bone disease:

osteitis fibrosa peritrabecular fibrosis

• Mixed uremic bone disease:

features of both osteitis fibrosa and osteomalacia

• Adynamic bone disease:

iatrogenic → oversuppression of parathyroid hormone
(PTH) typically with active vitamin D analogues
→ decreased bone formation and turnover

• Trochanteric fractures
© Faten Frikha et al., Figure 1, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343686/figure/F0001/, CC BY 2.0, no changes
Consequences of CKD Mineral and Bone Disease
• Vascular calcification

• Renal osteodystrophy

• Osteomalacia: defective mineralization

• High turnover bone disease:

osteitis fibrosa peritrabecular fibrosis

• Mixed uremic bone disease:

features of both osteitis fibrosa and osteomalacia

• Adynamic bone disease:

iatrogenic → oversuppression of parathyroid hormone
(PTH) typically with active vitamin D analogues
→ decreased bone formation and turnover

• Trochanteric fractures
Scott Ngyuen, CC0
Consequences of CKD Mineral and Bone Disease
• Vascular calcification

• Renal osteodystrophy

• Osteomalacia: defective mineralization

• High turnover bone disease:

osteitis fibrosa peritrabecular fibrosis

• Mixed uremic bone disease:

features of both osteitis fibrosa and osteomalacia

• Adynamic bone disease:

iatrogenic → oversuppression of parathyroid hormone
(PTH) typically with active vitamin D analogues
→ decreased bone formation and turnover

• Trochanteric fractures
Consequences of CKD Anemia

Anemia is defined by:

Hemoglobin (Hgb) < 13 g/dL Hgb < 12 g/dL

Men and postmenopausal women Premenopausal women

Consequences of CKD Anemia

Erythropoietin Produces

Kidney Bone marrow Red blood cells

~90% of patients with GFR < 30 mL/min/1.73 m2 have anemia.

due to decreased erythropoietin (Epo) production.

© by Lecturio
Risk Factors for CKD Progression to ESRD

• Proteinuria > 1 g per day

• Hypertension

• Type of underlying disease (DM, polycystic kidney

disease)

• African American race

• Male gender

• Obesity (increases glomerular capillary pressure)

Risk Factors for CKD Progression to ESRD

• Dyslipidemia (high lipid levels → faster rate of

progression of CKD)

• Smoking

• Hyperphosphatemia

• Metabolic acidosis

• Bicarbonate supplementation appears to slow

progression of CKD

• Reduction in tubulointerstitial inflammation?

Risk Factors for CKD Progression to ESRD

• High-protein diet increases glomerular capillary

pressure

• Hyperuricemia data emerging → lowering uric

acid levels may slow rate of GFR loss
Interventions that Slow Progression of CKD

Although progressive nephron loss cannot

be avoided there are interventions that can
slow the rate or progression.
56-year-old Man with Increased Serum Creatinine Test case

You are seeing a 56-year-old man who has stage 3a CKD due
to diabetic nephropathy.

Physical exam is remarkable for BP 148/90 mm Hg.

Labs: Serum creatinine is 1.4 mg/dL (normal 0.5 1.0 mg/dL) with
eGFR 50 mL/min/1.73 m2 (normal 90 120 mL/min/1.73 m2). He
has overt proteinuria estimated at 402 mg/g creatinine (spot
albumin-to-creatinine urinary ratio, normal < 30 mg/g
creatinine).
HgbA1c is 6.5% on insulin (Lantus and Novolog).

What is the next logical step in the management of this

56-year-old Man with Increased Serum Creatinine Test case

You are seeing a 56-year-old man who has stage 3a CKD due Risk factors for
to diabetic nephropathy. progression

Physical exam is remarkable for BP 148/90 mm Hg.

Labs: Serum creatinine is 1.4 mg/dL (normal 0.5 1.0 mg/dL) with
eGFR 50 mL/min/1.73 m2 (normal 90 120 mL/min/1.73 m2). He
has overt proteinuria estimated at 402 mg/g creatinine (spot
albumin-to-creatinine urinary ratio, normal < 30 mg/g
creatinine).
Controlled HgbA1c
HgbA1c is 6.5% on insulin (Lantus and Novolog).

What is the next logical step in the management of this

56-year-old Man with Increased Serum Creatinine Test case

What is the next logical step in the management of this

Add an oral hypoglycemic like glipizide in efforts to reduce his HbgA1c to < 6%.
He is already on insulin therapy, his HgbA1c is well controlled, there is no data that reducing HgbA1c < 7%
improves outcomes.

Add a calcium channel blocker like amlodipine to effectively control his BP and suppress
his albuminuria.
Although dihydropyridine calcium channel blockers are very effective at treating HTN, they do not suppress
albuminuria.

Add an ACE inhibitor to control BP and suppress his albuminuria.

Using an ACE inhibitor or ARB can control BP and suppress albuminuria by antagonizing RAAS.
56-year-old Man with Increased Serum Creatinine Test case

What is the next logical step in the management of this

Add an oral hypoglycemic like glipizide in efforts to reduce his HbgA1c to < 6%.
He is already on insulin therapy and his HgbA1c is well controlled. There is no data that reducing HgbA1c < 7%
improves outcomes.

Add a calcium channel blocker like amlodipine to effectively control his BP and suppress
his albuminuria.
Although dihydropyridine calcium channel blockers are very effective at treating HTN, they do not suppress
albuminuria.

Add an ACE inhibitor to control BP and suppress his albuminuria.

Using an ACE inhibitor or ARB can control BP and suppress albuminuria by antagonizing RAAS.
Interventions that Slow Progression of CKD

Blood pressure control

Goal: 125 130/< 80 mm Hg Goal: 120 125/< 80 mm Hg

Standard, routine clinician Using home blood pressure

office measurements measurement or continuous
ambulatory blood pressure monitoring

Lower goals (125/75 mm Hg) have been proposed for overt proteinuria
(> 1 g/day) < 125/75 mm HG but no convincing data support this target.
Interventions that Slow Progression of CKD

Renin-angiotensin-aldosterone antagonism

• ACE inhibitors and ARBs slow progression of CKD in proteinuric

diseases (albuminuria > 30 mg/day, proteinuria > 150 mg/day)

• Effects are independent

• Decreases glomerular capillary pressure

→ reduces hyperfiltration and mitigates tubulointerstitial
fibrosis
Interventions that Slow Progression of CKD

Sodium-glucose cotransporter 2 inhibitors

Slow progression of CKD with proteinuriaEffects are independent

• Not limited to patients with diabetes

• Block reabsorption of glucose

• Reduce intraglomerular pressure and hyperfiltration

Interventions that Slow Progression of CKD

Control of phosphorus levels Treat metabolic acidosis

• Dietary discretion • Sodium bicarbonate supplementation

• Phosphorus binders (taken with meals
→ bind to phosphorus and get Stop smoking
eliminated through stool)

Use of HMG-CoA reductase inhibitors Correct anemia

(statins)
• Erythrocyte stimulating agents (ESA)
• May be associated with slowing of GFR Epoetin alfa
but are important to reduce
cardiovascular risk • Begin when Hgb < 10 g/dL goal to
maintain Hgb 10 11.5 g/dL
Interventions that Slow Progression of CKD

Low-protein diet Treat underlying disease

• Benefit seen more in proteinuric • Strict glycemic control in diabetes

diseases (> 1 g/day) mellitus (Hemoglobin A1c < 7%)

• • Immunosuppression therapy for

primary glomerular diseases
• Goal 0.6 0.8 g/kg/day

• Should be followed by nutritionist to

avoid malnutrition
Care of the Chronic Kidney Disease Patient
Early referral to a Cardiovascular risk factor Preparation for renal
nephrologist modification replacement therapy

• Refer patients early in • HMG-CoA reductase • Initiated when GFR

the course of their inhibitors (statins) drops to ~6 15
disease for hyperlipidemia mL/min/1.73 m2
• GFR < 45 60 • Exercise, weight loss, • RRT should be initiated
mL/min/1.73 m2 tobacco cessation regardless of GFR if
• Albuminuria > 300 symptoms of uremia
mg/day • Nausea, vomiting,
• Early referral may be anorexia, dysgeusia,
associated with lower pruritus, altered sleep
health care costs and habits, impaired
decreased morbidity cognition, pericardial
and mortality effusion
Renal Replacement Therapy

Types of renal replacement therapy

In-center Home
hemodialysis hemodialysis

Peritoneal dialysis Kidney transplant

Renal Replacement Therapy

• Patients need to be educated about options for

RRT early!

• Preemptive transplant offers the best survival

advantage, but it is not always possible.

• Permanent vascular access should be placed at

least 8 12 weeks prior to the need for RRT if
choosing hemodialysis!