Chronic Renal Failure

CHRONIC RENAL
FAILURE
YOUAN BI BENIET MARIUS. PHARM
D, MASTER OF CLINICAL PHARMACY.
UNIVERSITY OF NAIROBI

OUTLINES
DEFINITION
ETIOLOGY and PATHOGENESIS
PATHOPHYSIOLOGY and CLINICAL MANIFESTATIONS
DIAGNOSIS
TREATMENT

DEFINITION
Progressive and irreversible loss of renal
function over time; based on a gradual decline in
the GFR and creatinine clearance ,frequently
leading to end stage renal disease (ESRD).

CRF=CRI=CRD= CKD
 Multiple terms have been applied to chronic renal failure
 the National Kidney Foundation’s Kidney Disease
Outcomes Quality Initiative (NKF KDOQI) has replaced
all of these terms with CKD
 It encompasses the continuum of kidney dysfunction
from mild kidney damage to kidney failure, and includes
end-stage renal disease (ESRD).

END STAGE RENAL DISEASE
A clinical state or condition in which there has been
an irreversible loss of renal function, and these
patients usually need to accept renal replacement
therapy in order to avoid life-threatening uremia.

UREMIA
Uremia is the clinical and laboratory syndrome,
reflecting dysfunction of all organ systems as a
result of untreated or undertreated acute or chronic
renal failure.

ESTABLISHED CHRONIC KIDNEY
DISEASE
1
Decline of kidney
function for 3
months or more
2
Evidence of kidney
damage or GFR
<60 mL/min/1.73 m2

5 DIFFERENT STAGES
Each patient is classified into one of the 5 following
stages of CRF because management and prognosis
varies according to the progression of damage.

Stage 1: Kidney damage with normal or
increased GFR
(>90 mL/min/1.73 m2)
Stage 2: Mild reduction in
GFR (60-89 mL/min/1.73 m2)
Stage 3: Moderate
reduction in GFR (30-59
mL/min/1.73 m2)
Stage 4: Severe
reduction in GFR
(15-29 mL/min/1.73 m2)
Stage 5: Kidney
failure (GFR <15

ETIOLOGY: COMMON CAUSES OF CRF
Diabetes mellitus
hypertension
glomerulonephritis
polycystic kidney

1-ALTERATIONS IN FLUIDS AND
2- METABOLIC ACIDOSIS
3- ANEMIA
4 -RENAL OSTEODYSTROPHY
5-COMPLICATIONS OF UREMIA
ELECTROLYTES

1-Alterations in Fluids and
Electrolytes
→Sodium & Water retention
→ Fluid movement into the extravascular space
→ pitting edema in the lower extremity
Swelling
1. Generalized edema
→Fluid accumulation
→ Pulmonary edema and loss of air space
→ Ventilation-perfusion mismatch.
Shortness of breath
2.Pulmonary crackles

Kidney damage : Inability to
secrete potassium
Malaise, palpitations,
arrhythmias
5. Hyperkalemia
in the urine
1-Water and Electrolytes disorders

4.Impaired H+ secretion from the body.
Protein-energy malnutrition due to
metabolic acidosis
Loss of lean body mass
4. Weight lost
2- METABOLIC ACIDOSIS

3.Loss of Erythropoietin
Fatigue, reduced exercise
capacity, and pallor
3. Anemia
release
3- ANEMIA

Firstly: kidney fail to
excrete phosphate.
Hyperphosphatemia
Secondary : high
parathyroid hormone
levels.

Early stages (1-2-3)
hyperphosphatemia
Hypocalcaemia
Later stages( 4-5)
decreased synthesis of
1α-hydroxylase
by negative feedback.

To compensate low calcium
→Increases parathyroid hormone
secretion
Secondary and tertiary
hyperparathyroidism
High bone turnover

osteoporosis Osteomalacia
High bone turnover
Calcium
deposition in
soft tissue.
high blood calcium levels

Uremia-induced
platelet dysfunction
Uremic
pericarditis
Urea and other toxins
accumulate in the blood and
cause life threatening issues
Uremic
encephalopathy
5-COMPLICATIONS OF UREMIA

COMPLICATIONS OF UREMIA
Uremia-induced
platelet dysfunction
Uremic
pericarditis
Uremic
encephalopathy
Increased tendency
to bleed and
ecchymosis
Ecchymosis, GI
bleeding
Chest pain,
malaise
Headaches,
confusion,
coma
Pericardial
friction rub

CHRONIC KIDNEY CLINICAL MANIFESTATIONS
COMPLICATIONS OF UREMIA
And

1. PREVENTION OF FURTHER DETERIORATION
2. TREAT COMPLICATION
3. ESTABLISHMENT OF TREATMENT STRATEGY FOR
ESRD
AIM OF TREATMENT

1.PREVENTION OF FURTHER DETERIORATION

 GLOMERULAR PERMEABILITY : PROTEINURIA
IN CHRONIC KIDNEY DISEASE
 HYPERGLYCEMIA : DIABETIC KIDNEY DISEASE (DKD)
 RAAS : HYPERTENSION IN CHRONIC KIDNEY DISEASE
1.PREVENTION OF FURTHER
DETERIORATION

DIABETIC KIDNEY DISEASE (DKD)
*Albumin-to-Creatinine Ratio (UACR)
Early Identification of Diabetic Nephropathy
UACR >30 mg albumin/g Cr (on ≥2 occasions 3–6 mo apart)
GFR <60 mL/min/1.73 m2 separated by 3 mo
Therapeutic Targets
Blood Pressure control : BP 120–130/75–80 mmHg
Glycemic control : Hb A1c <7.0%
Cholesterol control : LDL-C <70–100 mg/dL
Proteinuria control : UACR* <30 mg/g

4- Incretin mimetic or GLP-1 agonist
Exenatide (Byetta) in GFR 30 mL/min/1.73 m2
Liraglutide(Victoza) in GFR 60 mL/min/1.73 m2
1.GLYCEMIC CONTROL
• For all patients
• Some drugs are C.I. or require dose adjustments
2. BLOOD PRESSURE & PROTEINURIA CONTROL
:ACE inhibitor and ARB
•ACEI or ARB for type I and type II diabetes with UACR
30-300 mg/g(micro albuminuria)
•ACEI (captopril) preferred for type I diabetes with
UACR>300 (macro albuminuria).
•ARB (losartan or irbesartan) preferred for type II
diabetes with UACR > 300 (macro albuminuria).

3.For a SBP goal < 130
• Add diuretic first
• Then add CCB or Beta blockers
• Avoid DHPCCB without ACEI or ARB
4.For patients UACR> 500-1000
•Consider a low SPB goal
•Consider measure to reduce proteinuria
• - Increase dose of ACEI or ARB
•- Use ACEI and ARB in combination
•- Add others agent that lowers proteinuria ARA
(spironolactone,epleronone) because of ‘’aldosterone escape”
phenomenon. GFR >30 ml/min/1.73m2

4- Incretin mimetic or GLP-1 agonist
Exenatide (Byetta) in GFR 30 mL/min/1.73 m2
Liraglutide(Victoza) in GFR 60 mL/min/1.73 m2
5.Monitor serum potassium
•ACE and ARB also ARA may cause k
•Avoid others mdct that causes k (NSAID,COX2
inhibitors, K sparing diuretics Diuretics)
•Treat hyperkalemia with diuretics .caution
6. CHOLESTEROL CONTROL
•Patients with diabetes mellitus are at high risk for
cardiovascular disease
•Evidence of relationship between albuminuria and the
rate of LDL production
•Use LDL cholesterol-lowering medicines, such as statins
or a statin/ezetimibe combination

7. Monitor GFR
•If GFR decline is > 30% from
baseline within 4 weeks,
evaluate the cause.
•Continue ACEI and ARB if
GFR decline is < 30% over 4
mouths
FINALY

Drugs dosage in DKD
• ACEi : Captopril recommended dose for long-
term use is 25 mg orally 3 times a day
• ARB : Losartan Initial dose:50 mg orally once d.
Maintenance dose: 25 to 100 mg orally in 1 to 2
divided doses.
• ARA : Spironolactone :25 to 200 mg/day
orally in 1 or 2 divided doses.
•Statins : Gemfibrozil : 300 mg twice daily for
GFR <50 mL/min/1.73 m2

GLUCOSE LOWERING DRUGS CONTRE
INDICATED IN CKD
1- Biguanide :
Metformin if SCr 1.5 mg/dL in men, 1.4 mg/dL in women”
or GFR 30 mL/min/1.73 m2
2- sulfonylureas
Tolazamide ,Tolbutamide, Acetohexamide and Glyburide.
Chlorpropamide if GFR 50 mL/min/1.73 m2.
3- Alpha-glucosidase inhibitors
Acarbose if GFR 30 mL/min/1.73 m2
Miglitol if GFR 25 mL/min/1.73 m2

GLUCOSE LOWERING DOSE ADJUSTMENT
2. Second-generation sulfonylureas
Glimepiride : Start conservatively at 1 mg daily
1. First-generation sulfonylureas
Chlorpropamide : reduce dose 50% if GFR 50-80
mL/min/1.73 m2
3. DPP-4 inhibitor
Sitagliptin GFR > 50 mL/min/1.73 m2 : 100 mg daily
GFR 30-50 mL/min/1.73 m2 : 50 mg daily
GFR 30 mL/min/1.73 m2: 25 mg daily
Saxagliptin GFR > 50 mL/min/1.73 m2: 5 mg daily
GFR < 50 mL/min/1.73 m2: 2.5 mg daily

 GLOMERULAR PERMEABILITY : PROTEINURIA
IN CHRONIC KIDNEY DISEASE
PREVENTION OF FURTHER
DETERIORATION

HYPERTENSION IN CHRONIC
RENALE FAILURE
More patients develop hypertension from CRF than develop
CRF from hypertension ( hypertensive nephrosclerosis ).
Therapeutic Targets
120–130/75–80 mmHg
CVD risk increases at SBP ≤120 mmHg

1.First-line Agents
•GFR >20 mL/min/1.73 m2 give ACEI or ARB
2. Second-line Agents
•GFR ≥40 mL/min/1.73 m2 : Add thiazide if anti-
RAAS agent is first-line • Thiazide diuretics are
generally ineffective if the GFR <40 mL/min/1.73
•GFR <40 mL/min/1.73 m2 Add loop agent,
furosemide (twice daily dosing) or metolazone, if
anti-RAAS agent started as first line

3. Third-line Agents
• HR >84 bpm NDHPCCB( dihydropyridine calcium channel
blockers) (diltiazem, verapamil),BB or α/β blocker (labetalol )
• HR ≤84 bpm CCB ( amlodipine, diltiazem)
• Avoid DHPCCBs in proteinuric CRF(Amlodipine ,Nicardipine)
4. Initial BP: if SBP ≥150 mmHg
• Initiate a 2-drug regimen, ACEI/thiazide ,ARB/thiazide or
ACEI/CCB, in a patient taking no antihypertensive .
5. Caution .
• Sodium intake Should be low than 100 mEq/d
• Sympathomimetic (pseudephedrine, “diet” pills, cocaine) drugs and
NSAIDs must be avoid .

Drugs dosage in HKD
• Anti RAAS: same dosage with DKD
• Thiazide : Hydrochlorothiazide : ID:12.5 mg orally once a day.
M dose: 12.5 to 50 mg orally as a single or 2 divided doses
• Thiazide -like: Metolazone : 5 to 20 mg once daily.
• Loop D : Furosemide Oral: ID: 20 to 80 mg per dose.
M D: Increase in increments of 20 to 40 mg/dose every 6 to 8 hours to
desired effect. with a maximum daily dose of 600 mg.
• NDHPCCB: Diltiazem ID: 30 to 60 mg orally 3 to 4 times a day
Maintenance dose: 180 to 360 mg orally/day in divided doses.
• DHPCCB: Amlodipine Initial dose: 5 mg orally once a day
Maintenance dose: 5 to 10 mg orally once a day

 GLOMERULAR PERMEABILITY : PROTEINURIA IN
CHRONIC KIDNEY DISEASE
PREVENTION OF FURTHER
DETERIORATION

PROTEINURIA IN CRF
Therapeutic Targets
UPC <200 mg/g (protein as mg/dL; creatinine as g/dL)
UACR <30 mg/g
TREATMENT
2 different types : Diabetes proteinuria and non diabetes
proteinuria

First-line Agents for Proteinuria Reduction
•Non-diabetic proteinuria ACEI
•Diabetes, type 1 ACEI
•Diabetes, type 2 ARB or ACEI
Second-line Agents for Proteinuria
Reduction
•Diabetes, types 1 or 2 Anti-RAAS + Non-DHPCCB if
HR >60 bpm
Third-line Agents for Proteinuria Reduction
Diabetes, type I et II : ACEI + ARB or ARB + ACEI

1. PREVENTION OF FURTHER DETERIORATION
2. TREATMENT OF COMPLICATIONS
3. ESTABLISHMENT OF TREATMENT STRATEGY FOR
ESRD
AIM OF TREATMENT

TREATMENT OF CRF COMPLICATIONS

Metabolic Acidosis
• NaHCO3 0.5–1.0 mEq/kg daily
• Target HCO3 22–26 mEq/L

Iron Replacement (%TSAT, SF)
•1. 50-100 mg IV twice per week for 5 weeks;
if iron 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 ferritin.
•3. Withhold iron therapy when TSat >50%
and/or ferritin >800 ng/mL(>800 ug/L).

(ESAs) Therapy : Epoetin alfa only if Hb <10 g/dl
•Starting dosage 50-150 units/kg per week IV or SC
(once, twice, or three times per w
•Target hemoglobin(Hb): 11-12 g/dL
•Optimal rate of correction: Increase Hb by 1-2 g/dL
over 4-week
(ESAs) Therapy Darbepoetin alfa only if Hb< 10 g/dl
•Starting dosage: 0.45 ug/kg administered as a
single IV or SC injection once weekly or 0.75
ug/kg ad as a single IV or SC inj once every 2W
•Target Hb: ≤12 g/dL
•Optimal rate of correction : Increase Hb by 1-2 g/dL
over 4-week period

IMPORTANT FACTORS FOR TREATMENT
 2 Goals -HPTH suppression
- hyperphosphatemia suppression
 Corrected Ca = Serum Ca + [ 0.8 × (4.0 − Albumin)]
 Corrected Ca × P = Ca × P product (CPP)
 iPTH .

Therapeutic PTH suppression:
Vitamin D
•Sterols Ergocalciferol (D2)
•25(OH)D is <15 ng/mL: 50,000 IU q1 wk ×
4, thenq1 mo × 4, unless corrected Ca >9.5
g/dL and/orP >4.6 mg/dL
•25(OH)D is 15–30 ng/mL: 50,000 IU q1 mo
× 6, same condition.
•Cholecalciferol (D3)
•25(OH)D is <30 ng/mL: 1,750 IU once daily

Therapeutic PTH suppression: Active
Vitamin D sterols
•Calcitriol 0.25–0.50 mcg once daily in CKD
Stages 3 and 4
•Doxercalciferol
•iPTH is <600 pg/mL: 1.0–1.5 mcg once daily
•iPTH is 600–1200 pg/mL: 1.0–3.0 mcg once
daily

Phosphorus Binders
•Calcium acetate 1.0–1.5 g elemental Ca daily
for P >4.6 mg/dL and Ca 8.8–10.2 mg/dL
•Sevelamer HCl 800–2400 mg 3 times daily for
P >4.6 mg/dL and ifCa >10.2 mg/dL (Ca-
based P-binder contraindicated)

TREATMENT STRATEGY FOR ESRD
Renal Replacement Therapy (RRT)
required when the kidneys are functioning at less
than 10–15%. RRT is accomplished in one of the
following ways:
•1- Dialysis
• Hemodialysis
• Peritoneal dialysis
•2- Kidney transplant

1 - DIALYSIS (DIA-THROUGH ,
LYSIS –LOOSENING)
*When the access should be
created???
Serum creatinine> 4.0g/dL
GFR falls to <20 mL/min
*Close monitoring of nutritional status is
important

Chronic indications for dialysis:
1.Symptomatic renal failure
2.Difficulty in medically controlling fluid
overload, serum potassium, and/or serum
phosphorus when the GFR is very low
INDICATIONS:

Dialysis
(a)Haemodialysis
(b)Peritoneal dialysis
(a)Haemodialysis is the removal of
nitrogenous and toxic products of
metabolism from the blood by means of a
haemodialyzer system
NOT provides the same degree of health as renal function provides because
there is no resorptive capability in the dialysis membrane.
Exchange occurs between the
patient’s plasma and dialysate across a
semi permeable membrane that allows
uremic toxins to diffuse out of the
plasma while retaining the formed
components and protein composition
of blood

COMPONENTS of dialysis unit
1.Dialyzer
2.Dialysate production unit
3.Roller blood pump
4.Heparin infusion pump
5.Devices to monitor the
conductivity,temperature,flow rate and
pressure of dialysate

The frequency and duration of dialysis treatment are related to
1. Body size
2. residual renal function
3.Protein intake
4.Tolerance to fluid removal
#The typical patient undergoes
haemodialysis 3 times/week with each
treatment lasting approximately 3-4 hours
on standard dialysis units and slightly less
time on high efficiency/high flux dialysis
units
NEWER FORMS :Nocturnal and daily
dialysis with improved control of
1.Biochemical abnormalities
2.Blood pressure and volume status

Types of vascular access foe
maintenance haemodialysis
**Classic construction is side to side
anastomosis b/w the radial artery and
cephalic vein at the forearm
1.Primary arteriovenous(AV)
fistula/shunt/external cannula system:
Preferred for long term treatment.
2. Synthetic AV graft: Fistulae are
created by means of autografts,PTFE
grafts ,Dacron etc.
A fistula is an enlarged vein (usually in
your arm), created by connecting an
artery directly to a vein.
4.Cuffed tunneled catheters:
indwelling central venous catheters used

(B) Peritoneal dialysis(accounts for10%
of dialysis t/t)
1. access is achieved via a catheter
through the abdominal wall into
the peritoneum
2. 1-2 liters of dialysate is placed in
the peritoneal cavity and is
allowed to remain for varying
intervals of time
3. Substances diffuse across the
semipermeable peritoneal
membrane to dialysate

Hookup Infusion Diffusion
(fresh)
Diffusion
(waste)
Drainage

Various Regimens for peritoneal dialysis:
1.Chronic ambulatory patients..:2 L of
dialysis fluid instilled in the peritoneal
cavity, allowed to remain for 30 mins and
drained out
2.Continuous cyclic peritoneal dialysis,
in which 2-3 L of dialysate is exchanged
every hour over a 6-8 hour period
overnight,7days /week
as it allows (a)great deal of personal freedom
(b)No risk of air embolism and blood leaks
(c) Hepariniztion unnecessary
SO used as PRIMARY therapy/as a TEMPORARY MEASURE

2.RENAL TRANSPLANTATION
Treatment of choice for patients with
irreversible kidney failure
However the use of transplantation
is limited by organ availability
INDICATIONS:1. ESRD
2. Glomerulonephritis
3.Pyelonephritis
4.Congenital abnormalities
5.Nephrotic syndrome

DEFINITION OF DDS
The dialysis disequilibrium syndrome is defined as
a clinical syndrome of neurologic deterioration that
is seen in patients who undergo hemodialysis.
It is more likely to occur in patients during or
immediately after their first treatment, but can
occur in any patient who receives hemodialysis.

PATHOPHYSIOLOGY
the principle factor leading to the disequilibrium
syndrome is the development of an osmotic gradient
due to the rate of removal of urea causing water to
move into the brain

CLINICAL MANIFESTATION
The symptoms involve the neurologic system and are
similar to symptoms that occur with increased
intracranial pressure or acute hyponatremia, such as
 restlessness,
 headache,
 mental confusion
 coma

DIFFERENTIAL DIAGNOSIS FOR
SIGNS AND SYMPTOMS OF DD
 1. Subdural hematoma
 2. Uremia
 3.Non ketotic hyperosmolar
coma
 4. Acute cerebrovascular event
 5. Dialysis dementia
 6. Excessive ultrafiltration
and seizure
 7. Hypoglycemia
 8. Malignant hypertension
 9. Hyponatremia

PREVENTION OF THE DIALYSIS
DISEQUILIBRIUM SYNDROME
Goal is to prevent the development of an osmotic
gradient causing water to move into the brain.

FIRST METHOD : HEMOFILTRATION
perform hemofiltration on the patient instead of
dialysis . convective removal of solute from the
patient in place of diffusive removal. Thus, the
osmolalities of the body fluid compartments will not
change as rapidly as they do during standard
hemodialysis

SECOND METHOD :USING STANDARD
HEMODIALYSIS
The approach that is widely recommended is to slowly
lower the blood urea concentration.
A goal of reducing the urea concentration by 40 %
over 2 h for the first treatment is reasonable
This would be a urea reduction ratio
[URR0(pre-dialysis BUN − post-dialysis BUN)/
predialysis BUN] of 0.4

THIRD METHOD : ADD AN OSMOTIC
AGENT TO THE BLOOD STREAM
In addition to the slow removal of urea, another way
to prevent the syndrome is to add an osmotic
agent to the blood stream, as this will help prevent
the development of a blood–brain osmotic gradient
and consequently help prevent cerebral edema.

OSMOTIC AGENT
 Mannitol and glucose
 The easiest agent to add to the blood stream is
sodium
 Glycerol
 urea itself

TREATMENT OF THE DIALYSIS
DISEQUILIBRIUM SYNDROME
The treatment of disequilibrium after it has
developed is aimed at reducing the intracranial
pressure of the patient.
Standard maneuvers are to give mannitol or
hypertonic saline to raise the blood osmolality and
to hyperventilate the patient

Chronic Renal Failure

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