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

PATHOGENESIS OF CRF

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

4 -RENAL OSTEODYSTROPHY

Secondary : high

parathyroid hormone

levels.

Early stages (1-2-3)

hyperphosphatemia

Hypocalcaemia

Later stages( 4-5)

decreased synthesis of

1α-hydroxylase

4 -RENAL OSTEODYSTROPHY

by negative feedback.

To compensate low calcium

→ Increases parathyroid hormone

secretion

Secondary and tertiary

hyperparathyroidism

High bone turnover

4 -RENAL OSTEODYSTROPHY

osteoporosis Osteomalacia

High bone turnover

Calcium deposition in soft tissue.

high blood calcium levels

4 -RENAL OSTEODYSTROPHY

Uremia-induced

platelet dysfunctionUremic

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 dysfunctionUremic

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

AIM OF TREATMENT

1. PREVENTION OF FURTHER DETERIORATION

2. TREAT COMPLICATION

3. ESTABLISHMENT OF TREATMENT STRATEGY FOR

ESRD

AIM OF TREATMENT

1.PREVENTION OF FURTHER DETERIORATION

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 inhibitorSitagliptin GFR > 50 mL/min/1.73 m2 : 100 mg daily

GFR 30-50 mL/min/1.73 m2 : 50 mg dailyGFR 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

HYPERGLYCEMIA : DIABETIC KIDNEY DISEASE (DKD)

RAAS : HYPERTENSION 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

HYPERGLYCEMIA : DIABETIC KIDNEY DISEASE (DKD)

RAAS : HYPERTENSION 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

COMPLICATIONS OF CRF

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).

IRON DOSES REGIMENS

(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/dLover 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/dLover 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: ActiveVitamin 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)

1. PREVENTION OF FURTHER DETERIORATION

2. TREATMENT OF COMPLICATIONS

3. ESTABLISHMENT OF TREATMENT STRATEGY FOR

ESRD

AIM OF TREATMENT

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.Dialyzer2.Dialysate production unit3.Roller blood pump4.Heparin infusion pump5.Devices to monitor the conductivity,temperature,flow rate and pressure of dialysate

The frequency and duration of dialysis treatment are related to1. Body size2. residual renal function3.Protein intake4.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 of1.Biochemical abnormalities2.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 unnecessarySO used as PRIMARY therapy/as a TEMPORARY MEASURE

2.RENAL TRANSPLANTATION

Treatment of choice for patients with irreversible kidney failureHowever the use of transplantation is limited by organ availability

INDICATIONS:1. ESRD2. Glomerulonephritis3.Pyelonephritis4.Congenital abnormalities5.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

BMY