CHRONIC KIDNEY DISEASE
Karl Skorecki
Tel: 8543250, email: skorecki@tx.technion.ac.il
Note: slides without a green star (
) in the upper left hand corner, are for your
reference only and are not part of the actual syllabus
Harrison’s 16th edition
Chapter 261
Chronic Renal Failure
pp 1653-1663
What is Meant by Renal Failure?
‫אי ספיקת (כשל) כלייתי‬
DEFINITIONS:
• END STAGE RENAL DISEASE: A “state” of irreversible loss of
endogenous kidney function which renders a patient forever dependent
upon renal replacement therapy by dialysis or transplantation. Most
commonly, this state is a consequence of Chronic Renal Failure [CRF],
but occasionally it is a consequence of Acute Renal Failure [ARF].
• CHRONIC RENAL FAILURE: A pathophysiologic process with
multiple etiologies, resulting in an irreversible decline in nephron
function, irrespective of underlying etiology.
• UREMIA / AZOTEMIA: A clinical/biochemical syndrome or
symptom/sign complex reflecting dysfunction of all organ systems
resulting from loss of kidney function.
Functions of Kidney
Glomerular filtration (non-volatile nitrogenous products of
protein catabolism)
Fluid and electrolyte balance through regulated
reabsorption and secretion (water, sodium, chloride,
potassium, magnesium, calcium, phosphate)
Acid-base balance (bicarbonate reclamation and net acid
secretion)
Hormones: erythropoeitin, active form of Vit-D, other
Confuse medical students
Other (glucose, amino acids, uric acid, insulin degradation
etc.)
INCIDENCE OF CRF
ESRD
Uremia
symptoms
CRF
CLASSIFICATION OF CRF - NKF
STAGE
DESCRIPTION
GFR(ml/mt)
0
WITH RISK FACTORS
>90
I
>90
II
KIDNEY DAMAGE (WITH
NORMAL OR  GFR)
MILD
III
MODERATE
30-59
IV
SEVERE
15-29
V
KIDNEY FAILURE
<15
60-89
GFR
(mL/min/1.73 m2)
Detection,
Evaluation, and
Management
US Prevalence in
2000⁎
CKD Stage
Description
1
Kidney damage
with normal or ↑
GFR
>90
Diagnosis and
treatment, treatment
of comorbid
conditions, slowing
progression, CVD
risk reduction
5,600(2.8)
2
Kidney damage
with mild ↓ GFR
60-89
Estimation of
progression
5,700(2.8)
3
Moderate ↓ GFR
30-59
Evaluating and
treating
complications
7,400(3.7)
4
Severe ↓ GFR
15-29
Referral to
nephrologist and
consideration for
kidney replacement
therapy
300(0.1)
5
Kidney failure
<15
Kidney
replacement
therapy (if uremia
present)
300†(0.2)
90%
Chronic
Renal
Failure
10%
End Stage
Renal Disease
Acute
Renal
Failure
Acute Renal Failure
Death
]frequent[
Renal
Recovery
(common)
CKD
(rare)
ACUTE RENAL FAILURE
PRE -
POST -
* Hypovolemia
- absolute
- relative
* Cardiorenal
* Hepatorenal
* Bladder
- above
- below
INTRA -
VASCULAR
GLOMERULAR
TUBULAR
INTERSTITIAL
Acute Renal Failure  End Stage Renal
Disease
• Bilateral cortical necrosis
- Vascular catastrophe
- Very severe ATN
- ATN in pregnancy
• Rapidly Progressing Glomerulonephritis [RPGN]
• Thrombotic microangiopathy
- Thrombotic Thrombocytopenic Purpura [TTP]
- Hemolytic Uremic Syndrome [HUS]
- Disseminated Intravascular Coagulation [DIC]
- Eclampsia
Etiology of CKD
.1Glomerular
- Primary (no systemic disease identified)
*
examples :IgA Nephropathy, Membranous GN, Focal
Sclerosis
- secondary[ systemic disease identified]
* examples: Metabolic: Diabetes
infectious - Poststreptococcal
Infiltrative - Amyloidosis
Drugs and Toxins - Gold
Immune - SLE
Genetic - Alport
Etiology of CKD – (cont’d)
Tubulo-interstitial
obstruction
reflux[ also glomerualr]
immune[ [sarcoid etc.
analgesic
pyelonephritis
myeloma [ also acute]
uric acid
idiopathic
rejection
Hereditary[ PKD ]
.3Vascualr
HBP
.2
vasculitis – Wegener’s
ischemic – Renal Artery Stenosis
Top 4 Etiologies of Chronic Renal failure
•
•
•
•
DM
HBP
Glomerular Diseases
Polycystic Kidney Disease
Prevalence Counts by Major Etiology for U.S. Medicare – Treated
End Stage Renal Disease for 1999
Prevalence,
n=340,261
Count
Percent
Diabetes
116,082
33.7
Hypertension
78,586
22.8
Glomerulonephritis
54,802
15.9
Cystic disease
14,993
4.4
ESRD Incidence Rates* by Primary Diagnosis,
Rate/Million Pop./Year 1988-97
150
100
Diabetes
Hypertension
50
Other
Glomerulonephritis
0
1988
89
90
91
*Adjusted for age, sex, and race
**Preliminary
92
Year
93
94
95
96
1997 *
II -8
USRDS 1999
*
Incident rates for diabetic ESRD,
all patients
adjusted for age, gender, ethnicity & race
140
*
100
80
60
40
20
0
19
80
19
81
19
82
19
83
19
84
19
85
19
86
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
per million population
120
* preliminary
Summary of clinical presentations that may suggest given major categories of causes of CRF
Clinical presentation
Cause of CRD
Diabetic kidney disease
History of diabetes, proteinuria, retinopathy
Hypertension
Elevated blood pressure, normal urinalysis, family
history.
Non-diabetic glomerular disease
Nephritic or nephrotic presentations
Cystic kidney disease
Urinary tract symptoms, abnormal urinary sediment,
radiologic imaging abnormalities
Tubulo-interstitial disease
History of urinary tract infections and reflux, chronic
medication and drug exposure, abnormalities in urinary
tract imaging, tubular syndromes including urine
concentrating defect, abnormal urinalysis
Comparison of Glomerular and
Interstitial Renal Diseases
Glomerular
Proteinuria
>2g/d
Sodium
Retention
Acidosis
Increased Anion Gap
Radiology of Kidneys Small, smooth,
normal calyces
Interstitial
<2g/d
Wasting
Normal Anion Gap
Small, irregular,
blunted calyces
Pathophysiology
 of: loss of nephrons, even after
underlying etiology no longer active
of: Uremia
Pathophysiology of Nephron Loss
 Normally each nephron does not work at its maximal capacity, and not all
nephrons are engaged (renal reserve).
 When a critical number of nephrons are lost (% varies in different populations),
then remaining nephrons undergo a process of hypertrophy and hyperfiltration, in
an effort to maintain normal overall filtration. This is mediated in part by the
angiotensin axis, which increases intrglomerular pressure. This is “altruisitic” in
the short run – but “maladaptive” in the long term.
 At the same time, TGF-b is stimulated (by AII), and results in scarring of
nephrons. As glomerulus hypertrophies, podocytes which are post-mitotic and
undergo apoptosis, stretch, weaken and “blow out” resulting in adhesions to
Bowman’s capsule.
This leads to a “final common pathway” for inexorable attrition of nephron
function, irrespective of initiating or underlying disease process. The “secret” of
preventing chronic renal failure rests with inhibition of the mechanisms involved
in this “final common pathway”.
Pathophysiology of Uremia
UREMIA IS A STATE OF
SYSTEMIC POISONING
DUE TO CUMULATIVE EFFECTS OF FAILURE OF
MANY FUNCTIONS OF KIDNEY
Glomerular filtration (non-volatile nitrogenous products of
protein catabolism)
Fluid and electrolyte balance through regulated reabsorption
and secretion (water, sodium, chloride, potassium, magnesium,
calcium, phosphate)
Acid-base balance (bicarbonate reclamation and net acid
secretion)
Hormones: erythropoeitin, active form of Vit-D, other
Other (glucose, amino acids, uric acid, insulin degradation etc.)
UREMIA PATHOPHYSIOLOGY
Na+ BALANCE
H2O BALANCE
K+ BALANCE
H+ BALANCE
Ca,Mg,,P,Vit D
METABOLISM
LOSS OF NEPHRONS
CATABOLSIM OF
PEPTIDES
EXC.OF NITROGENOUS
WASTES
ERYTHROPOIETIN
EXC. OF DRUGS
DR.V.KANNAN
UREMIA
What makes patients sick?
- “uremic” toxins
- these are substances normally excreted by the kidney,
but retained in kidney failure
- > 5000 potential toxins have been identified
- retained urea and creatinine are measured as markers
of renal failure, but are not toxic themselves
CLASSIFICATION OF CRF - NKF
STAGE
DESCRIPTION
GFR(ml/mt)
0
WITH RISK FACTORS
>90
I
>90
II
KIDNEY DAMAGE (WITH
NORMAL OR  GFR)
MILD
III
MODERATE
30-59
IV
SEVERE
15-29
V
KIDNEY FAILURE
<15
60-89
Estimation of GFR using creatinine
Creatinine
generated in muscle
excreted in urine
Chronic Renal Failure - Diagnosis (cont’d)
• Serum creatinine is also proportional to body muscle
mass:
– eg. Young well-muscled man with a serum creatinine of 2.2
mg/dl
• if his “normal” serum creatinine is 1.1, then he now has a doubling of
serum creatinine, or a halving of creatinine clearance
– eg. Elderly wasted woman with a serum creatinine of 2.2
– if her “normal” serum creatinine is 0.5 then she now has
fourfold increase in creatinine, or CrCl reduced to 1/4
Estimation of GFR using Creatinine (urine collection)
P[creat]
Afferent
Efferent
GFR - in what volume
did this same amount of
creatinine “used” to be
in, when it was at the
same concentration as in
plasma.
Low
concentration in
high volume
High concentration
in low volume
U[creat]
50 % loss of GFR
before
CCT
120 ml/min
P[creat]
1 mg/100 ml
U[creat]*V 1.8 gm/day
after steady state
?
?
?
Relationship of Nephron Loss to GFR
protein load
renal
reserve
120 ml/min
basal
NEPHRONS
0
2 X 106
Estimation of GFR using Creatinine (urine collection)
P[creat]
secretion
Afferent
Efferent
GFR - in what volume
did this same amount of
creatinine “used” to be
in, when it was at the
same concentration as in
plasma.
Low
concentration in
high volume
High concentration
in low volume
U[creat]
20
20
40
60
80
CCT ml/min
100
120
140
160
40
60
GFR
ml/min
contribution of tubule
secretion
120
140
160
contribution of tubule
secretion
“RENAL RESERVE”
PLASMA
CREATININE
mg/dl
(linear increase)
0
NEPHRON
LOSS
(%)
100
20
40
60
ml/min
120
140
160
Estimation of GFR using creatinine
Creatinine
generated in muscle
excreted in urine
Rise in Creatinine also in:
secretion inhibited
muscle production 
rhabdomyolysis
Ingestion of cooked meat
‫‪UREA - BUN‬‬
‫יצירה‪:‬‬
‫הפרשה‪:‬‬
‫עולה‪:‬‬
‫אבל גם‪:‬‬
‫חלבון באוכל‬
‫חלבון קטבולי‬
‫דם במערכת עיכול‬
‫‪GFR‬‬
‫ספיגה‬
‫‪Pre-Renal Azotemia‬‬
‫אי‪-‬ספיקת כליות‬
‫דימום במערכת עיכול‬
‫מצב קטבולי‬
‫תרופות‪ :‬סטרואידים‪ ,‬טטרציקלין‬
Estimate of GFR based on Plasma values and Patient Characteristics
MDRD Equation:
Estimated GFR (ml/min/1.73m2) =
1.86 x (PCR)-1.154 x (age)-0.203 x (0.742 if female) x (1.21 if African American)
Cockroft-Gault Equation:
Estimated creatinine clearance =
(140-8) x weight in kg
72 x PCR x (0.85 if female)
Clinical examples
•
Consider the following two patients with
identical serum creatinines of 1.2 mg/ dL.
– Patient 1 - a 60 year old 50 kg woman
– Patient 2 - a 30 year old 90 kg man
•
The first patient has a GFR of 39 ml/min/1.73 m2,
which is markedly abnormal, while the second
has a GFR of 115 ml/min/1.73 m2, well within
the normal range.
• MOST CRF PATIENTS ARE
ASYMPTOMATIC AND ARE
DETECTED DURING SCREENING
EITHER ROUTINE OR FOR
UNRELATED ILLNESS
Investigation and Diagnosis
Patient presents de novo with  creatinine and BUN.
Most Important Question:
Acute appreciation of Chronic Renal Failure versus Acute
Renal Failure.
Best ways to discriminate these:
• Creatinine Hx.
• Kidney size
Imaging Studies
• renal ultrasound
o one or two
o size
o obstruction
other:
• radionuclide scan +/- angiography
- only if strong suspicion of renovascular etiology
(asymmetry on US, bruit on auscultation, HBP)
• retrograde
- only if strong suspicion of obstruction
• VCUG
- reflux
• CT – NO CONTRAST!
- stone
• IVP
- Almost never in investigation of renal failure - WHY?
Significance of Kidney Size
1. Bilateral small kidneys - chronic disease
2. Bilateral normal or large kidneys:
i. Polycystic Kidney Disease
ii. Amyloidosis
iii. Diabetes Mellitus
3. One small, other large - consider:
RENAL ATRTERY STENOSIS
FACTORS SUGGESTING
CHRONICITY







DURATION OF SYMPTOMS FOR MONTHS
ABSENCE OF ACUTE ILLNESS IN FACE OF
VERY HIGH UREA AND CREATININE
BLAND URINE SEDIMENT
SMALL KIDNEYS ON IMAGING
BONE DISEASE
NEUROLOGICAL COMPLICATIONS
SKIN / NAIL / EYE CHANGES
Role of Kidney Biopsy in
Chronic Renal Failure ?
Chronic Renal Failure - Diagnosis (cont’d)
• Clues to distinguish acute vs. chronic renal failure previous creatinines:
– eg. Mr GP is a 68 year old man who went to a new family
doctor, feeling tired
– serum creatinine was 9.0, assumed to be chronic
– referred to start chronic dialysis
– call to previous family doctor: serum creatinine 6 months
before was 0.8
acute or chronic ?
Stages of CKD
Loss of Renal Reserve (Stages 0-1)
GFR normal but attenuated response to protein challenge
Moderate Renal Insufficiency (stages 1-3)
- GFR 30-90 ml/min
- BUN, Creat 
- dimished renal concentrating ability
- mild anemia
- abnormal divalent ion balance and metabolic bone disease
Severe Renal Insufficiency (Stage IV)
- GFR 15-30 ml/min
- BUN, Creat 
- acidosis, electrolytes
- anemia
End Stage (Stage V)
- GFR < 10-15 ml/min
- need for renal replacement
Uremic Syndrome
•
•
•
•
•
•
Azotemia / Uremia
Salt + Water
Potassium
Calcium & Phosphate
Acid Base
Magnesium
Azotemia / Uremia
• Accumulation of nitrogenous toxins
• In the steady state excretion = generation but
at the expense of elevated levels
• The “uremic toxins” have not been identified
but surrogate markers are:
Urea [BUN]
Creatinine
Top Five
•
•
•
•
•
anorexia and nausea
itching
weakness and lethargy
asterixis [DDx: cirrhosis, respiratory acidosis]
hiccoughs
 note: conspicuous absence of symptoms related to
urinary tract per se.
SYMPTOMS / SIGNS
SYSTEM
SYMPTOMS
GENERAL
FATIGUE,
SKIN
ITCHING / BRUISING
PALLOR,
DRYNESS
FROST, EXCORIATIONS
ANOREXIA / NAUSEA
GI BLEED
GIT
WELL BEING
SIGNS
WASTED,SALLOW COMPLEXION
PIGMENTATION
VOMITING / HICCUPS
CVS
EDEMA, CHEST PAIN
HT / CARDIOMEGALY
DYSPNEA
RUB / CRACKLES
MUSCULO
BONE PAIN
DEFORMITIES / MYOPATHY
SKELETAL
GROWTH FAILURE
NS
NUMBNESS / CRAMPS
NEUROPATHY / ASTERIXIS
INSOMNIA / IMPOTENCE
MYOCLONUS / ACIDOSIS
Signs and Symptoms of Uremia
[GFR < 30 ml/min]
1. General symptoms: fatigue, weakness and lassitude
2. Nervous system:
- CNS - confusion, coma, asterixis, seizures, decreased
intellectual ability.
- PNS - restless leg syndrome, sensory/motor neuropathy,
nocturnal muscle cramping
3. Respiratory system:
- pleuritis
- lung calcification
- hiccoughing
Signs and Symptoms of Uremia
[GFR < 30 ml/min] (cont.)
4. Cardiovascular system:
- Hypertension - may be “volume dependent” secondary
to salt and water retention or “renin dependent” due to
activation of rennin/angiotensin system.
- Congestive heart failure - salt and water retention,
anemia, hypertension, atherosclerosis
- Pericarditis - may be complicated by tamponade (1255% of cases) and, later stages, by constrictive
pericarditis.
- Vascular calcification - may lead to gangrene.
- Atherosclerosis - accelerated due to high VLDL and
low HDL and accounts for 50% of deaths in uremic
patients.
Signs and Symptoms of Uremia
[GFR < 30 ml/min] (cont.)
5. Gastrointestinal system:
- Oral, esophagus - stomatitis, esophagitis
- Gastroduodenal - UGI hemorrhage
- Colon - constipation, ulceration, pseudomembranous colitis
- Miscellaneous - nausea, vomiting, singultus
6. Dermatological
- Pruritus - 86% of patients: due to xerosis, Ca X P product,
PTH, uremic polyneuropathy, number of mast cells.
- Skin pigmentation – urochromes deposited in skin, increase
in melanin, porphyria cutanea tarda, hemosiderosis.
- Purpura
Signs and Symptoms of Uremia
[GFR < 30 ml/min] (cont.)
7. Hematological
- Anemia - decreased production of erythropoetin;
decrease red cell survival, 50-70 days instead of the
normal 120 days; dietary deficiency of iron, folate.
- Bleeding - qualitative platelet function defect; increased
capillary permeability; abnormal bleeding time: normal
PT, PTT and platelet count.
- WBC - decreased phagocytic function; abnormal
cellular immunity – Staph, gram negative sepsis.
Signs and Symptoms of Uremia
[GFR < 30 ml/min] (cont.)
8. Endocrine and metabolic systems
- Carbohydrate metabolism - abnormal GTT; due to decreased release of
insulin, increased sensitivity to insulin, increase glucagon release; increase
half-life of insulin   insulin requirements in uremia; glycogen depletion
due to starvation, gluconeogenesis.
- Lipid metabolism - hyperlipidemia; triglycerides  VLDL, HDL
cholesterol.
- Protein metabolism - negative nitrogen balance; loss of muscle mass;
increased protein requirement.
- Uric acid - hyperuricemia usual but clinical gout rare.
- Reproductive function
Males - testosterone  LH; sperm count, libido, impotence.
Females - estrogen, progesterone, no cycling (no LH surge),
amenorrhea, cystic ovaries, dysfunctional uterine bleeding.
- Thyroid - T3, normal free T4, TSH
- Prolactin - secretion, degradation  impotence, amenorrhea.
Uremic Syndrome
•
•
•
•
•
•
Azotemia / Uremia
Salt + Water
Potassium
Calcium & Phosphate
Acid Base
Magnesium
Salt and Water Excretion (normal)
Reabsorb:
Water 180 L/d
Salt 25,000 mmol/d
[180 X 140]
178 L/d Water
24,900 mmol/d Salt
2 L/d 1%
100 mmol< 1%
Salt and Water Excretion in CRF
Reabsorb:
10% GFR
Water 18 L/d
Salt 2,500 mmol/d
16 L/d Water
2,400 mmol/d Salt
2 L/d 10%
100 mmol< 4%
Uremic Syndrome
•
•
•
•
•
•
Azotemia / Uremia
Salt + Water
Potassium
Calcium & Phosphate
Acid Base
Magnesium
Excitable cell
K+ 150 meq/L
Ki
Ko
40
1
K+ 4 meq/L
Resting
membrane
potential
- [K+]e
Action
Potential
threshold
potential
Ca2+
Ca2+
Hyperkalemia
- 90
resting
membrane
potential
Hypokalemia
Why do we care?
Distrubance in [K+]eInternal
balance
External
balan ce
[K+]p
8
ICF
ECF
6
4
# insulin
# pH
# SNS
2
Total body K+ approx.
4,500 mmol
K+ Excretion
K+ filtered
4 X 180 = 720 meq/d
200 meq
K+
secrete
daily
load
500 meq
K+
Approx. 50-100 meq/d
Na+
Cl-
Na+
K+
K+ 3 - 4
K+ 
K+ Excretion
- sodium delivery
URINE
· - urine flow
· - ALDO
CELL
BLOOD
Potassium
In order to prevent potassium intoxication, there is an increase
in potassium secretion by the surviving nephrons, balancing
the decrease in filtration and thus maintaining potassium
balance. There is also increased excretion via the
gastrointestinal tract.
Hyperkalemia may occur in the following situations: protein
catabolism, hemolysis, bleeding, blood transfusion, steroid
therapy, and in metabolic acidosis (exchange of hydrogen ion
for intracellular potassium).
Potassium
BEWARE: Beta-blockers, ACE inhibitors,
potassium sparing diuretics [amiloride, triamterene,
spironolactone], nonsteroidal anti-inflammatory
agents (NSAIA).
Ultimately hyperkalemia is common with advanced
renal failure, and indicates the need for renal
replacement therapy.
Uremic Syndrome
•
•
•
•
•
•
Azotemia / Uremia
Salt + Water
Potassium
Calcium & Phosphate
Acid Base
Magnesium
Calcium – Phosphate - Bone
Bottom-line
tendency to
Hypo-Ca2+
Hyper-PO42Increased PTH
Decreased Vitamin D
bone
disease
osteomalacia
adynamic bone
:osteodystrophy
Metabolic Bone Disease
Mechanisms
! Primary problem is decrease in filtration of PO42-.
 phosphate retention
 Pi X Ca2+ lowers Ca2+ [also soft tissue calcification]
hydroxylation of Vitamin D in kidney [renal mass;
inhibition by high Pi]

osteomalacia
Together: Ca2+ + PO42- + Vit. D  PTH
PTH tries to restore phosphate excretion by kidney
Price is PTH toxicity
= osteodystrophy
neuropathy
myopathy
Chronic Renal Failure - PTH
– PTH is postulated to be one of the “uremic toxins”
– besides bone problems, excess levels of PTH
associated with
• anemia
• pruritis
• myocardial fibrosis
Uremic Syndrome
•
•
•
•
•
•
Azotemia / Uremia
Salt + Water
Potassium
Calcium & Phosphate
Acid Base
Magnesium
Acid Base Balance (normal)
Reclaimed
NaHCO3 5000 mmol
Normal
NaHCO3
5000 mmol
Diet: Net Acid
HX + 70 NaHCO3
70NaX + H2O + CO2
70 NEW HCO3Generated
HPO42-  H2PO4NH3  NH4+
Acid Base Balance in CRF
CRF
Filters ONLY
500 mmol
Reclaimed
NaHCO3 500 mmol
CANNOT
Excrete
CANNOT filter NaX
ACCUMULATE
NH3  NH4+
+
H
= 25 x PCO2
HCO3
Magnesium
Slightly elevated serum levels are commonly found
in chronic renal failure due to inability of the kidney
to excrete oral magnesium load. These levels do not
usually give rise to symptoms, unless the intake of
magnesium is increased by using laxatives and
antacids that contain this ion.
Chronic Renal Failure - Diagnosis (cont’d)
• Typical laboratory profile of a patient presenting with
chronic renal failure for the first time:
Na+ 137 mmol/L
Ca++ 8.4 mg/dl
K+ 5.2 mmol/L
P
7.8 mg/dl
Cl 100 mmol/L
PTH 550
HCO3 18 mmol/L
Creatinine 7.4umol/L
Hemoglobin 9.1 g/L, WBC 5.6, platelets 285,000
Chronic Renal Failure
One sort of typical story: SV
26 year old woman presents with weight loss, amenorrhea,
calf cramps at night, fatigue
O/E pale, bp 160/100, hypertensive changes on funduscopic
exam
Urinalysis: small blood, protein, granular casts
Ultrasound: small, contracted kidneys bilaterally
Serum creatinine 9mg/dl
Chronic Renal Failure
One sort of typical story: SV (cont’d)
• kidneys get small over a long period of time
• etiology of renal failure: who knows?
• Why we don’t rush to kidney biopsy in this instance:
– technically difficult to biopsy small kidneys
– “window of opportunity” for treatment has passed
– likely to see “endstage” fibrotic kidney tissue only
Chronic Renal Failure
Another sort of typical story: RL
36 year old man found to have hypertension, microscopic
hematuria and proteinuria by FD
Renal biopsy: IgA nephritis with +++ interstitial fibrosis
and many sclerosed glomeruli
1997: creatinine 1.8
1999: creatinine 4.0
2001: creatinine 9.8
Chronic Renal Failure - Diagnosis
• may be suspected on basis of clinical presentation
• more often, diagnosed by blood tests
– elevated serum creatinine
– elevated serum urea
• may be discovered incidentally during workup for
anemia, amenorrhea or anorexia
Management
Learning to Think with Your Kidneys
1. prevent cardiovascular morbidity and mortality
2. slow the process
3. reversible components
4. “conservative” measures to substitute kidney
function
5. prepare for end-stage
INCIDENCE OF CRF
ESRD
Uremia
symptoms
CRF
Chronic Renal Failure
• Cardiovascular Abnormalities
– Hypertension
– accelerated atherosclerosis
– “uremic” cardiomyopathy:
•
•
•
•
left ventricular hypertrophy
intermyocardiocytic fibrosis
myocardial and coronary artery calcification
rarely, pericardial fibrosis or inflammation
CARDIOVASCULAR RISK
FACTORS IN CKD
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•
•
•
•
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SUSTAINED & REFRACTORY HTN
CHRONIC ANEMIA
DYSLIPIDEMIA
S.PHOSPHATE &VASCULAR CALCIFICATION
INCREASED OXIDANT STRESS
HYPERHOMOCYSTINEMIA
• Cardiovascular Abnormalities - Results
– accelerated coronary artery and peripheral arterial
disease
– left ventricular systolic and diastolic dysfunction
– premature death from cardiovascular disease
The increased mortality from cardiovascular
disease in renal failure cannot be explained
just by “conventional” risk factors such as
hypertension, lipid abnormalities, etc.
4/5 CRD patients don’t make it to dialysis
because of CVS death
CVS disease is the leading cause of mortality in
dialysis patients
Management Guidelines for BP
Control in CRF
* Target BP in CRF
130/80-85 mm Hg
* with proteinuria (>1gm/d)
125/75mm Hg(MAP 92 mm Hg)
* Recommended medications
- diuretics to achieve normovolemia
- in diabetic nephropathy or CRF with
proteinuria – ACE inhibitor or AGII
receptor antagonists alone or in
combination with long acting.
In other causes of CRF, calcium
entry blocker and beta blockers.
considered as alternatives.
RECOMMENDATIONS FOR CVS RISK REDUCTION
AGGRESSIVE BP CONTROL (<130/80)
MAXIMISE ACEI/ARB THERAPY
DIURETICS AND SALT RESTRICTION NEEDED IN MOST
ASSESS ANEMIA. USE EPOITEN WHEN HB<10-11G%
KEEP PHOSPHATE CONTROL(<5.5mg%). DIET ADVICE AND
PHOSPHATE BINDERS
ASSESS LIPID PROFILE AND USE DIET THERAPY, STATINS,
FISH OIL SUPPLEMENTS TO KEEP LDL-C < 130mg%
DAILY ANTIOXIDANT VITAMINS VIT-E (MIXTURE OF
NATURAL ISOMERS) 400-800 IU,VIT-C 500mg, NATURAL CAROTENE - UPTO 10,000IU
SCREEN FOR HOMOCYSTENEMIA. IF ELEVATED ADVICE
FOLIC ACID-15mg, B6-100mg, & B12-1000mg/DAY
Management
Learning to Think with Your Kidneys
1. prevent cardiovascular morbidity and mortality
2. slow the process
3. reversible components
4. “conservative” measures to substitute kidney
function
5. prepare for end-stage
Slow the Process
SPECIFIC:
GFR
Underlying etiology e.g. Rx Lupus
NON - SPECIFIC:
Reduce hyperfiltration injury
-ACE inhbitors (definite; watch K)
-Protein restrction
time
Management
Learning to Think with Your Kidneys
1. prevent cardiovascular morbidity and mortality
2. slow the process
3. reversible components
4. “conservative” measures to substitute kidney
function
5. prepare for end-stage
Reversible Components
 volume depletion
 accelerated hypertension
 infection
 obstruction (e.g. papillary)
 drugs (e.g. NSAID’s, ACEI,
contrast agents,OTC’s, herbals)
 flare of underlying disease
GFR
time
Management
Learning to Think with Your Kidneys
1. prevent cardiovascular morbidity and mortality
2. slow the process
3. reversible components
4. “conservative” measures to substitute kidney
function
5. prepare for end-stage
Conservative Measures to Replace Kidney
Function
•
•
•
•
•
•
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•
protein
sodium
potassium
water
acid / base
bones: PO4- intake, bind, Ca2+, Vit D, acidosis
anemia
drugs [e.g. Digoxin, Tetracyclines…]
PROTEIN RESTRICTION
INITIATE WHEN SERUM CREATININE IS >2.0
mg/dL in Men and >1.5 mg/dL in Women
RESTRICT PROTEIN < 0.8G/Kg/DAY
ENCOURAGE PROTEIN OF HIGH BIOLOGICAL
VALUE
MONITOR NUTRITIONAL PARAMETERS
(ALBUMIN)
PROTEIN ENERGY MALNUTRITION IS AN
INDICATION TO BEGIN RENAL REPLACEMENT
Management Guidelines – Dietary Protein Restriction in CRD
CRD stage
Protein, g/kg per d
Phosphorus, g/kg per d
Stage 1 and 2
Protein restriction not usually
recommended
No restriction
Stage 3
0.6 g/kg per d including 0.35
g/kg per d of HBV
10
Stage 4 and 5
0.6 g/kg per d including 0.35 g/kg per
d of HBV
or
0.3 g/kg per d supplemented with EAA
or KA
10
9
GFR < 60ml/min
(nephrotic syndrome)
0.8 g/kg per d (plus 1g protein/g
proteinuria) or 0.3 g/kg per d
supplemented with EAA or KA (plus 1g
protein/g proteinuria)
12
9
NOTE: GFR, glomerular filtration rate; HBV, high biologic value protein; EAA, essential amino acid
supplement; KA, ketoanalogue supplement
PRINCIPLES OF DIVALENT ION
MANAGEMENT IN CKD
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CORRECTION OF HYPOCALCEMIA
CORRECTION OF ACIDOSIS
CORRECTION OF HYPERPHOPHATAEMIA
MONITORING PTH LEVELS AND CONTROL
OF RENAL OSTEODYSTROPHY
RECOMMENDATIONS FOR
DIVALENT IONS MANAGEMENT
HYPOCALCEMIA - MONITOR, ORAL CaCO3+/- CALCITRIOL
ACIDOSIS - 1-4G OF NaHCO3 IF NOT CONTRAINDICATED BY
HTN CONTROL AND FLUID BALANCE
HYPERPHOSPHATAEMIA - MONITOR TARGET(<5.5mg%)
DIET ADVICE, TO AVOID MILK & MILK PRODUCTS,
PHOSPHATE BINDERS, BEST SEVALAMER - COSTLY,
OTHERS CALCIUM CONTAINING - MONITOR S. CALCIUM,
AVOID ALUMINIUM CONTAINING IN LONG TERM TRT.
PTH LEVELS
GFR
PTH
>50ml
UPPER NORMAL
20-50ml/mt
1.0-1.5 TIMES
<20ml/mt
1.5-2.0 TIMES
DIALYSIS
2.0-3.0 TIMES
CORRECT HYPOCALCEMIA & HYPERPHOSPHATEMIA
CALCITRIOL THERAPY
Stepped-care parallels impairment of GFR
• Degree of CKD
GFR
Action
• Mild
Moderate
Severe
60-90 ml/min/1.73 m 2
30- 59 ml/min/1.73 m 2
15- 29 ml/min/1.73 m 2
Steps 1,2
Steps 1,2,3
Steps 1,2,3,4
• Step 1 - slow the progression of chronic kidney disease to end stage renal disease
(ESRD)
• Step 2 - identify and treat co-morbid conditions (cardiovascular)
Step 3 - identify and prevent complications of CKD (anemia, divalent ions,
malnutrition)
• Step 4 - prepare the patient mentally and physically for renal replacement therapy
Management
Learning to Think with Your Kidneys
1. prevent cardiovascular morbidity and mortality
2. slow the process
3. reversible components
4. “conservative” measures to substitute kidney
function
5. prepare for end-stage
Renal Replacement Therapy Modalities
• Hemodialysis
• Peritoneal Dialysis
• Transplantation
Renal Replacement Therapy
[Dialysis and Transplantation]
It is generally better to initiate chronic dialysis before the patient
is severely ill from uremia. It is better to start a few weeks too
early, than a few days too late.
Indications for dialysis include:
a. Asymptomatic, but serum creatinine > 12 mg/dl; Creatinine
clearance , 3-5 ml/min; Diabetic and serum creatinine > 8 mg/dl.
b. Uremic complication: pericarditis; neuropathy;
encephalopathy; anorexia, nausea, vomiting.
c. Volume retention with unresaponsiveness to diuretic therapy.
d. Hyperkalemia not managed with diet.
e. Metabolic acidosis - not manageable with NaHCO3.
• PREPARE VASCULAR ACCESS MONTHS IN ADVANCE
• WARN PATIENT
Chronic Renal Failure
Goals of Dialysis
1. Solute/toxin removal (blood purification)
2. Removal of salt and water (ultrafiltration)
Peritoneal Dialysis
Chronic Renal Failure
Peritoneal Dialysis
• catheter is inserted surgically or laparoscopically into
peritoneal cavity
• dialysis fluid high in glucose concentration is instilled
through catheter and allowed to dwell in the cavity
• uremic toxins diffuse from ECF into the peritoneal fluid
• ultrafiltration by osmosis (glucose in fluid)
Chronic Renal Failure
Peritoneal Dialysis
• patient can manually exchange dialysis fluids during the
day, and leave an exchange in peritoneal cavity overnight
• cycler dialysis: fluid exchanges overnight while patient
sleeps, and leaves an exchange in peritoneal cavity
during the daytime
Chronic Renal Failure
Peritoneal Dialysis - Complications
• infection of the peritoneal dialysis fluid (peritonitis)
• glucose diffusion from dialysis fluid into body: caloric
load, hyperglycemia in some, hyperinsulinemia, elevated
triglycerides
• increased intra-abdominal pressure
Chronic Renal Failure
Hemodialysis
• blood is removed from the body and travels to the
hemodialysis machine where it is run across a
semipermeable membrane with a physiologic solution on
the other side of the membrane
• uremic toxins cross into dialysate by diffusion and
convection
• ultrafiltration by a hydraulic pressure (Δ P ) placed
across the dialysis membrane
Hemodialysis
Chronic Renal Failure
Hemodialysis (cont’d)
• usually done as an intermittent procedure, eg for 4 hours
3 X a week
• requires a vascular access to allow for repeated needle
insertion and high blood flow rates
– construction of an arteriovenous fistula in the forearm, or
– insertion of a prosthetic vascular graft in the arm, or
– indwelling catheter into a major vein
Chronic Renal Failure
Hemodialysis - Complications
• majority are related to the vascular access
– infection
– thrombosis
– inadequate blood flows
• disequilibrium syndromes related to rapid solute and
water fluxes over a short period of time
Chronic Renal Failure
With either type of dialysis, correction of uremia is only
partial
• typical creatinines still are about 5-10
• very low level of creatinine may reflect muscle wasting
and not effective dialysis
Patient suitable for both modalities
(slight preference for HD)
• dependent lifestyle
• Severe lung disease
• dementia
• Problems with personal hygeine
• Intra-abdominal adhesions
• diabetic gastroparesis
Slight preference for PD
• Unstable CAD
• residual renal function
• Need to felxible time schedule
• Contagious disease
Clear preference for PD
• Vasuclar access failure
• infant
• Strong personal preference for autonomy
• Geogrpahic distance from HD center
• Complications on HD
• Artifical heart valves
Clear preference for HD
• Complicated IBD
• Ischemic bowel disease
• Active diverticulitis
• Cognitive impairment
• Psychotic state
• Homeless state
• Complications with PD
Continued Medical Therapy on Dialysis
• ANTIHYPERTENSIVES [approx. 50%]
• PO4- restriction and binding, Ca2+ supplementation, Vit D
• Erythropoetin [EPO]
Management Guidelines - Correction of
Anemia in CRF
EPO
S.C. - 80-120 units/kg/week [divided into x 2-3/week]
I.V. - 120-180 units/kg/week [divided into x 3/week]
Target Hct/Hb - 33-36% / 11-12 gr/dl
- Optimal rate of correction – increase Hct by 4-6% over 4-week period
[achieve goal values within 2-3 months]
IRON
- Monitor iron stores by percent transferrin saturation [TSAT] and serum
ferritin.
- If patient is iron deficient [TSAT < 20%, ferritin < 100 ng/ml] administer
iron 50-100 mg IV twice per week for 5 weeks [or for 10 successive dialysis
sessions]. If iron indices are still low, repeat the same course.
- If iron indices are normal, yet Hct/Hb are still inadequate, administer IV
iron as outlined above. Monitor Hct/Hb, TSAT and ferritin.
- Withhold iron therapy when TSAT > 50% and/or ferritin > 800ng/ml
Table 261-7
Management Guidelines Correction of Anemia of CRD
Epoetin alfa
Starting Dosage:
50-150 units/kg/week IV or SC (once, twice or three
times per week)
Target Hb:
11-12 g/dL
Optimal Rate of Correction:
Increase Hb by 1-2 g/dL over 4-week period
Darbepoetin alfa
Starting Dosage:
0.45 mcg/kg administered as a single IV or SC
injection once weekly
0.75 mcg/kg administered as a single IV or SC injection once every
2 weeks
Target Hb:
12 g/dL
Optimal Rate of Correction:
Increase Hb by 1-2 g/dL over 4-week period
IRON
Monitor iron stores by percent transferring saturation (TSAT) and serum ferritin.
1.If patient is iron deficient (TSAT <20%; serum ferritin <100 mcg/L) administer iron 50-100 mg IV twice per
week for 5 weeks. If iron indices are still low, repeat the same course.
2.If iron indices are normal yet Hb is still inadequate, administer IV iron as outlined above. Monitor Hb, TSAT
and serum ferritin.
3.Withhold iron therapy when TSAT >50% and/or serum ferritin >800 ng/mL (>800 g/L).
If correction of anemia is inadequate, consider causes for refractoriness as outlined in text.
Complications of Dialysis
GENERAL
• atherosclerotic vascular disease
- CAD
- Cerebrovascular
- PVD
• infection
UREMIC
• pericarditis
• neuropathy
• encephalopathy
• osteodystrophy
Complications of Dialysis Modality Specific
PD
• Peritonitis
• Hyperglycemia
• Albumin loss
HD
• Access infection and thrombosis
• Bleeding
• Episodic hypotension
Outcome of Dialysis Therapy
• Highly dependent on co-morbid conditions
• Overall annual mortality is approximately 10%
per annum
• 25% not alive after first year
• 70% not alive after 5 years
Effect of Dialysis on Uremia
I – improves
with dialysis
P- persists
despite dialysis
Fluid and electrolyte
disturbances
Neuromuscular
disturbances
Dermatologic
disturbances
Volume expansion and
contraction (I)
Hypernatremia and Hyponatremia
(I)
Hyperkalemia and Hypokalemia
(I)
Metabolic acidosis (I)
Hyperphosphatemia (I)
Hypoclacemia (I)
Fatigue (I)
Sleep disorders (P)
Headache (I or P)
Impaired mentation (I)
Lethargy (I)
Asterixis (I)
Muscular irritability (I)
Peripheral neuropathy (I or P)
Restless legs syndrome (I or P)
Paralysis (I or P)
Myoclonus (I)
Seizures (I or P)
Coma (I)
Muscle cramps (D)
Dialysis disequilibrium
syndrome (D)
Myopathy (P or D)
Pallor (I)
Hyperpigmentation (I, P or D)
Pruritus (P)
Ecchymoses (I)
Uremic frost (I)
Endocrine-metabolic
disturbances
Secondary hyperparathyroidism
(I or P)
Adynamic osteomalacia (D)
Vitamin D – deficient
osteomalacia (I)
Carbohydrate intolerance (I)
Hyperuricemia (I or P)
Hypertriglyceridemia (I or P)
Increased Lp(a) level (P)
Decreased high-density
lipoprotein level (P)
Protein-energy malnutrition (I or
P)
Impaired growth and
development (P)
Infertility and sexual dysfunction
(P)
Amenorrhea (P)
Hypothermia (I)
Dialysis-induced β2-microgobulin
Associated amyloidosis (P)
Cardiovascular and
pulmonary
disturbances
Arterial hypertension (I or P)
Congestive heart failure or
pulmonary edema (I)
Percarditis (I)
Cardiomyopathy (I or P)
Uremic lung (I)
Accelerated atherosclerosis (P
or D)
Hypotension and arrythmias
(D)
Vascular calcification (P or D)
Gastrointestinal
disturbances
Anorexia (I)
Nausea and vomiting (I)
Uremic fetor (I)
Gastroenteritis (I)
Peptic ulcer (I or P)
Gastrointestinal bleeding (I, P or D)
Hepatitis (D)
Idiopathic ascites (D)
Peritonitis (D)
Hematologic and
immunologic disturbances
Anemia (I)
Lymphocytopenia (P)
Bleeding diathesis (I or D)
Increased susceptibility to infection
(I or P)
Splenomegaly and hypersplenism
(P)
Leukopenia (D)
Hypocomplementemia (D)
Chronic Renal Failure
• Renal Transplantation
– a successful kidney transplant is the only way to fully, or
almost fully, correct uremia
• Types of Renal Transplantation
– cadaveric (4 to 5 years waiting time)
– living related
– living unrelated
Transplantation
• living related
* parents, siblings
• living non-related
* [spouse or altruisitic in ISRAEL]
• cadaveric
• quality of life vastly improved
• actual survival improved
Chronic Renal Failure
• Renal Transplantation - Immunosuppression
–
–
–
–
prednisone
cyclosporin, FK 506
mycophenolate mofetil (MMF)
azathioprine
Chronic Renal Failure
• Renal Transplantation - Complications
– short term:
• sepsis
• rejection
• exposure to large amount of immunosuppressive
agents
Chronic Renal Failure
• Renal Transplantation - Complications
– long term:
• accelerated atherosclerosis and early death from
cardiovascular disease
• chronic rejection
• recurrence of original renal disease in the allograft
• malignancy, sepsis
Chronic Renal Failure
• Renal Transplantation - Survival
– cadaveric kidney
• 1 yr graft survival 85%
• 5 yr graft survival 75%
– living donor kidney
• HLA identical: 1 yr 90-95% graft survival
• in non-HLA identical: living related same as living
unrelated !
– Common cause of long-term “graft loss” now is
patient death with a functioning transplant !
HD
PD
Tx