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CKD PHARMACOTHERAPY

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ak daud

on 3 January 2014

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Transcript of CKD PHARMACOTHERAPY

Chronic Kidney Disease
Pathophysiology
Clinical presentation
& assessnent

Introduction
Etiology
clinical presentation :
=> CKD development
and progression is insidious.
=> Stage 1 or 2
CKD usually asymptomatic ..
=> stages 3 to 5 =>
anemia, secondary hyperparathyroidism, CVD, malnutrition, and fluid and electrolyte abnormalities that are more common as kidney function deteriorates.

=> Uremic symptoms
(fatigue, weakness, shortness of breath, mental confusion, nausea, vomiting, bleeding, and anorexia) are generally absent in stages 1 and 2, minimal during stages 3 and 4, and common in patients with stage 5 CKD who may also experience itching, cold intolerance, weight gain, and peripheral neuropathies.
=> Signs and symptoms of uremia
are foundational to the decision to implement kidney replacement therapy.

albuminia/ protienuria
1. Marker of kidney damage, progression factor, and CV risk factor

Definitions
2. Assessment of proteinuria
a. Spot urine: Untimed sample is adequate for adults and children (screening test)
i. First-morning urine specimen preferred
ii. Urine dipstick
iii. Confirm positive dipstick tests (+1 or greater) with quantitative tests (albumin/creatinine ratio or protein/creatinine ratio),
iv. Proteinuria is confirmed by two or more quantitative tests (1-2 weeks apart),
v. Monitor proteinuria with quantitative tests.
b. Factors that can interfere with testing for albuminuria/proteinuria
i. Fluid balance: dehydration (+); fluid overload (-)
ii. Hematuria (+)
iii. Exercise (+)
iv. Urine proteins other than albumin (-)
v. Drugs that increase urine pH > 6 (+)

kidney function assessment
PERITONEAL DIALYSIS
Management
Management/Slowing Progression of CKD:
Nonpharmacologic:

Reduction of protein intake (in pnts with GFR < 25 ml/min/1.73 m2)…avoid malnutrition
Smoking cessation (suggested protective effect against proteinuria & reduced GFR)
Pharmacologic
Intensive Blood Glucose Control (in pnts with DM): HbA1c < 7%
Intensive insulin therapy (target: preprandial blood glucose = 70-120 g/dl & postprandial blood glucose < 180 g/dl
Aggressive BP management
JNC VII goal is
< 130/80 mm Hg for CKD stages 1-4
<140/90 before hemodialysis & <130/80 after hemodialysis for stage 5 CKD
<125/75 mm Hg for pnts with proteinuria
ACE-I & ARBs are preferred. Even in normotensive pnts (esp. pnts with proteinuria > 3 g/d)
Calcium channel blockers are second line to ACE-I/ARBs. Data emerging for combined therapy
Hyperlipidemia & anemia
Hyperlipidemia treatment:
1o goal: decrease the risk of progressive atherosclerotic cardiovascular disease
2o goal: reduce proteinuria & the decline in kidney function
Target: LDL-C < 100 mg/dl
Statins (HMG-CoA reductase inhibitors) & fibric acid derivatives

Anemia treatment:
To reduce the cardiovascular effects associated with it & to slow the progression of CKD

DIABETIC NEPHROPATHY
The most common cause of renal failure (50% of ESKD in US)
1. Pathogenesis (risk factors)
a. Hypertension (systemic and intraglomerular)
b. Glycosylation of glomerular proteins
c. Genetic links
d. Obesity
e. Hyperlipidemia
2. Diagnosis
a. Long history of diabetes
b. Proteinuria
c. Retinopathy (suggests microvascular disease)
d. High blood pressure
e. Progressive decline in GFR
3. Monitoring
a. Type I—Begin annual monitoring for microalbuminuria 5 years after diagnosis
b. Type II—Begin annual monitoring immediately (do not know how long they
have had diabetes mellitus).
Metabolites
Creatinine
1.38 H mmol/L = Increase

Blood Urea Nitrogen
82.11 H mmol/L = Increase
Albumin
Albumin
30.0 g/L = Decrease
Bleeding Factors
Prothrombin Time
13.1 seconds = Prolong
indication for dialysis
Should plan for dialysis when pnt is in stage 4 (GFR < 30 ml/min/1.73 m2)
If hemodialysis (HD) was chosen then a permanent arteriovenous access is surgically created when:
* CrCl or GFR < 25 ml/min *Scr > 4 mg/dl *Or 1 year before dialysis initiation
Hemodialysis
complications
2/2
=> Cramps:
The cause is often related to excessive ultrafiltration, which causes hypoperfusion of the muscles
Tx: decreasing the ultrafiltration rate and accurately determining the dry weight. Vitamin E (400 IU/d). Quinine (324 mg/d; 2nd-line)
=> Thrombosis:
Tx: saline flushes, balloon angioplasty, local administration of thrombolytic agents (Alteplase 2 mg/port & Reteplase 0.5 unit/port)

=> Infection: S. aureus & S. Epidermidis mainly
=> Nausea & vomiting
=> Headache
=> Chest & back pain
=> Pruritis
=> Fever & chills
complications
1/2
Intradialytic complications:
=> Hypotension (most common):
Primarily related to fluid removal
More common in elderly patients
Tx: administration of normal saline (100–200 mL), hypertonic saline (23.4%, 10–20 mL), or mannitol (12.5 g) to restore intravascular volume. Midodrine: 2.5-10 mg predialysis in HD pnts
Prevented via accurate determination of the “dry weight” and maintaining a constant ultrafiltration rate.
factors that may affect HD
Thanks too much
references:

=> dipiro hand book
Peritoneal dialysis
Complications:
Peritonitis:
Due to chemical irritation or infection
S. epidermidis: most common cause


Other bacteria: S. aureus, Streptococcus, E. coli, & P. aeruginosa
Patients who are elderly and/or diabetic have a higher infection rate.
A major cause of failure of peritoneal dialysis
Tx: broad-spectrum antibiotic. Empiric tx: cefazolin + ceftazidime, cefepime or an aminoglycoside. In case of allergy to cephalosporins the empiric tx is vancomycin + aminoglycoside.
complications of CKD
2. Initiation Factors
Chronic kidney insufficiency, progressive kidney disease, nephropathy

i. Kidney damage for > 3 months, as defined by structural or functional abnormality of the kidney, with or without decreased GFR, manifested by either pathologic abnormalities or markers of kidney damage, including abnormalities in the composition of blood or urine or abnormalities in imaging tests
ii. GFR < 60 mL/minute/1.73 m2 for 3 months, with or without kidney damage


Progressive decline in kidney function (a decrease in the number of functioning nephrons) occurring over a period of several months to years

Gradual replacement of normal kidney structure with parenchymal fibrosis

Usually irreversible

Definition

Kidney failure or dialysis

Kidney damage + severe decrease in GFR

Kidney damage + moderate decrease in GFR

Kidney damage + mild decrease in GFR

Kidney damage + normal GFR

Classification & Stages

kidney failure
less waste removed
more waste in blood
nitrogenous buildup in blood
Acute kidney
injury
chronic kidney disease
Risk factors categories:

Susceptibility factors: increase CKD risk but not direct causative factors

Initiation factors: directly cause CKD

Progression factors: result in faster decline in kidney function & worsening of CKD

Etiology

Not modifiable by pharmacologic therapy or lifestyle modifications
Used to develop screening programs for CKD

Advanced age
Reduced kidney mass
Low-birth weight
Racial/ethnic minority
Family hx of kidney disease
Dyslipidemia: drug-modifiable
Low income or education
Systemic inflammation


1. Susceptibility Factors

Modifiable by pharmacologic therapy

Diabetes mellitus (37%; esp. DM2)
12x higher risk to develop ESKD
Hypertension (24%)
Glomerulonephritis (14%)
Autoimmune disease
Polycystic kidney disease
Drug toxicity
Urinary tract abnormalities


Modifiable by pharmacologic therapy or lifestyle changes
to slow the progression :
Hyperglycemia/diabetes: poor blood glucose control
Hypertension
Proteinuria
Tobacco smoking
Hyperlipidemia
Obesity
3. Progression Factors

abrupt
reversible
develops slowly
progressive
irrepairable
1. Serum creatinine
Avoid use as the sole estimate of kidney function
Dependent on age, sex, weight, & muscle mass

2. Measurement of GFR
Inulin, iothalamate, and others not routinely used

3. Measurement of CrCl via a urine collection
Reserve for vegetarians, patients with low muscle mass, amputation, dietary assessment, & documentation of need to start dialysis
Urine collection will give a better estimate in patients with very low muscle mass. In most cases, equations will overestimate kidney function because creatinine levels will be low in patients with very low muscle mass

4. Calculated using Cockroft & Gault (mL/minute CrCl) - overestimates GFR
[(140 - age) x ideal body weight]/[ SCr x 72] x (0.85 if female)



Hypertension Management
Algorithm in CKD pnts

Nondiabetic Nephropathy
Management
Hemodialysis 2. Peritoneal dialysis 3. Kidney transplantation
Renal Replacement Therapy
Primary criteria for dialysis initiation:
presence of persistent anorexia, nausea, and vomiting, especially if accompanied by weight loss & fatigue
Declining serum albumin concentrations
Uncontrolled hypertension or CHF
Neurologic deficits
Pruritus
Acidosis (not responsive to bicarbonate)
Electrolyte abnormality (hyperkalemia; hyperphosphatemia)
Intoxication (boric acid; ethylene glycol; lithium; methanol; phenobarbital; salicylate; theophylline)
Fluid overload (symptomatic [pulmonary edema])
Uremia (pericarditis and weight loss)
Risks and benefits of dialysis should be evaluated when eGFR or CrCl is <15 mL/min/1.73 m2
=> Involves the exposure of blood to a semipermeable membrane (dialyzer) against which a physiologic solution (dialysate) is flowing.
=> Three primary processes for removal of substances from blood:
1- Diffusion
2- Ultrafiltration
3- Convection
=> Two primary goals of dialysis:
* Achieve a desired dry weight (the target
postdialysis weight at which the patient is
normotensive and free of edema)
* Achieve the adequate removal of endogenous
waste products such as urea (used to quantify
the adequacy of dialysis)


Factors that affect efficiency of hemodialysis.

1- Type of dialyzer used (changes in membrane
surface area and pore size).

2- Length of therapy.

3- Dialysis flow rate.

4- Blood flow rate.

5- Development of polarized protein layer on the filter surface.
Dialysis
The semipermeable membrane is the peritoneal membrane, and a sterile dialysate is instilled into the peritoneal cavity

Types:
1- Continuous ambulatory peritoneal dialysis (CAPD): the most common. The patient exchanges 1 to 3 L of dialysate every 4 to 6 hours throughout the day with a longer dwell time overnight.
2- Automated peritoneal dialysis (APD)
3- Continuous cycling PD (CCPD)
4- Nightly intermittent PD (NIPD)
5- Nocturnal tidal PD (NTPD)

PD COMPLICATIONS
COMPLICATIONS
Of CKD
Impaired Na & H2O homeostasis
Normal conditions: FENa = 1-3% & urine osmolality = 50-1200 mOsm/L
In CKD: FENa = 10-20%
Manifested as: edema (≥ stage 4) & nocturia (≥ stage 3)

Management:
Nonpharmacologic: gradual reduction of dietary Na
Pharmacologic: loop diuretics

Impaired Potassium homeostasis
Hyperkalemia due to decreased tubular secretion
Affects 50% of pnts with stage 5 CKD
Management:
Nonpharmacological:
Avoid abrupt increases in potassium intake
Potassium intake restriction (50-80 mEq/d)
Pharmacological:
Reversal of cardiac abnormalities associated with hyperkalemia (1 g IV of calcium gluconate or chloride)
Shifting of extracellular potassium to inside the cells:
Regular insulin (5-10 units IV) + dextrose (5-50% IV)
Nebulized albuterol (10-20 mg)
NaHCO3 if metabolic acidosis exists (pH < 7.2)
Increase potassium excretion:
Sodium polystyrene sulfonate: increases GI exc. Not good for acute hyperkalemia
Loop diuretics. But not in stage 5 CKD
metabolic acidosis
When GFR < 20-30 ml/min/1.73 m2 (80% of pnts)
Consequences:
↑ protein catabolism
↓ albumin synthesis
Resulting in muscle wasting & alteration of bone metabolism
Worsening of cardiac disease
Impaired glucose tolerance
Altered growth hormone & thyroid function
Inflammation



Uremic bleeding
Pathophysiology:
Uremia affects many mechanisms which contribute to bleeding:
Altered platelet function & aggregation due to decreased production of thromboxane
Altered platelet-vessel wall interactions due to decreased activity of von Willebrand’s factor. This is exacerbated with anemia

Risk of bleeding increases in hemodialysis due to administration of anticoagulant agents to prevent or treat clotting during hemodialysis or in vascular access sites


4. Secondary Hyperparathyroidism (sHPT) & Bone & Mineral Metabolism Disorders (BMMD; Renal Osteodystrophy)
Pathophysiology:
Due to decreased phosphorus excretion & decreased vitamin D activation which results in decreased calcium absorption

The most important driving force behind the process is hyperphosphatemia!

As a result the parathyroid gland is activated

sHPT is witnessed when GFR < 40 ml/min/1.73 m2

The most dramatic effect of sHPT is alterations in bone turnover & BMMD


Anemia
Hgb < 13.5 g/dl in males & < 12 g/dl in females
Progenitor kidney cells produce 90% of erythropoietin hormone (EPO)
Etiology:
Decreased EPO production (normocytic normochromic)
Uremia
Iron deficiency
Blood loss (due to regular laboratory testing & hemodialysis)
Hemodialysis
Decreased lifespan of RBCs (from 120 d to 60 d in stage 5)
CKD induced anemia is associated with increased cardiac output & left ventricular hypertrophy……thus, increasing cardiovascular risk & mortality
Risk correlates proportionally with degree of kidney dysfunction (in terms of decline in GFR): prevalence in stage 4 = 50% & 75% in stage 5

Pathophysiology:

Impaired acid/base homeostasis due to reduction in hydrogenions excretion occurs due to impaired generation of ammonia

Resulting in positive hydrogen balance leading to metabolic acidosis

Characterized by serum HCO3 = 15-20 mEq/L & ↑anion gap ≥ 17 mEq/L (due to accumulation of organic anions)




Treatment
Mainly pharmacologic in CKD stages ≥ 3

Target: achieve normal HCO3 level = 24 mEq/L
Base deficit Eqn.: [0.5 L/kg x (body weight)] x [(normal CO2) – (measured CO2)]
Treated slowly to avoid metabolic alkalosis
1. Sodium bicarbonate tablets 325→ →650 mg (7.7 mEq). SEs:
Sodium retention & volume overload resulting in exacerbation of HTN & CHF: avoided by administering the total base deficit over several days
Low tolerability due to CO2 production in the GI
2. Sodium citrate/citric acid-containing solutions (Shohl’s slon. & Bicitra)……..1 mEq/L of HCO3
3. Sodium/potassium citrate containing solutions (Polycitra)………2 mEq/L of HCO3


Treatment:
Reduced incidence with dialysis in ESKD pnts due to decrease in uremia which improves platelet function & reduces bleeding time
Anemia therapy & improved nutritional status also reduced uremic bleeding

Pharmacologic therapy:
Cryoprecipitate:
Decreases bleeding within 1 hr in 50% of pnts
Limited use because of cost & risk of infection


2. Desmopressin (DDAVP):
Induces the release of von Willebrand factor resulting in subsequent increase in factor VIII survival
Decreases bleeding time within 1 hr & the effect is sustained for 4-8 hrs
IV, SC, or intranasal

Estrogen
Slow onset
More sustained effect compared to previous
IV, oral, transdermal patches

Nonpharmacologic therapy:
Sufficient dietary iron
RBC transfusion if severe anemia or erythropoiesis-stimulating agents (ESAs) are C/I
Pharmacologic therapy:
ESA: 1st-line; Epoetin alfa & Darbepoetin alfa (longer t1/2)
SC is preferred over IV
IV when hemodialysis or pnts having an established IV access
Dose depends on:
Pnt’s Hgb level
Target Hgb
Rate of Hgb increase
Clinical circumstances


Inadequate Response to ESA
Causes:
Iron deficiency: most common cause of ESA resistance
Others:
Infection/inflammation
Chronic blood loss
Aluminum toxicity
Hemoglobinopathies
Folate or vitamin B]2 deficiency
Multiple myeloma
Malnutrition
Hemolysis
Vitamin C deficiency


Iron-replacement
Iron-replacement
If TSAT < 20% & serum ferritin < 100 ng/ml
Targets:
Ferritin: hemodialysis target = 200-500 ng/ml
peritoneal dialysis/CKD target = 100-500 ng/ml
Transferrin: >20%

Oral iron: 1st-line in non-hemodialysis CKD pnts

However, in combination with ESA, IV iron is administered (due to increased requirements & reduced oral abs.)
Iron dextran, sodium ferric gluconate, iron sucrose



Most adults require ≥ 1 g of elemental iron to replete iron stores

Iron stores usually replete for several weeks

For adult patients who undergo dialysis, an empiric 1000-mg dose is usually given, and equations are rarely used

Oral iron products usually do not provide sufficient iron for patients with CKD who are receiving erythropoietic therapy and should not be given to patients who are receiving parenteral iron therapy

RBC transfusion: only used in certain conditions like
For acute management of symptomatic anemia due to acute blood loss
Prior to surgical procedures that have a high risk of bleeding

D. Androgens: but no more used because of hepatotoxicity


Diagnosis: asymptomatic, Hg should be routinely measured in CKD pnts of all stages

Treatment:
Goal: maintain Hgb levels = 11-12 g/dl
Pnts should be evaluated for anemia when GFR < 60 ml/min or Scr > 2 mg/dl
Rule out other causes
Correct other possible etiologies (e.g. iron def., vit.B12 def., or folate def.)
Anemia workup:
Hgb/Hct
MCV
Reticulocyte count
Iron studies to avoid resistance to ESAs: TSat & ferritin
Stool guaiac: to detect fecal occult blood

Affects 25-85% of CKD pnts with advanced stages
Exact etiology is not known: Vit.A, histamine, sHPT,
accumulation of aluminum & magnesium, & others …..?!

Treatment:
Nonpharmacologic:
Proper nutritional intake , esp. phosphorus & protein
UV-B therapy
2. Pharmacologic:
1st-line therapy: antihistamines (e.g. hydroxyzine & diphenhydramine)
Cholestyramine
Oral activated charcoal
Oral ondansetron
Topical capsaicin
Pruritis
Pathogenesis
a. Nephron loss: decreased production of 1,25 dihydroxyvitamin D3 and phosphate retention
b. Increased phosphorous concentrations:
i. Inhibition of activation of vitamin D, reducing absorption of calcium in the gut
ii. Decrease levels of ionized (free calcium)
iii. Direct stimulation of PTH secretion
c. Elevated PTH levels:
i. Decreased reabsorption of phosphorus and increased reabsorption of calcium in proximal tube. This adaptive mechanism is lost as GFR falls below 30 mL/min.
ii. Important: Calcium is not well absorbed through the gut at this point, and calcium levels are maintained by increased bone resorption via elevated PTH
d. Unabated calcium loss from the bone results in renal osteodystrophy



Prevalence
Major cause of morbidity and mortality in patients undergoing dialysis
Is aggressively treated with dietary phosphate restriction, phosphate binders, and vitamin D analogs
Signs and symptoms
Insidious onset: Patients may complain of fatigue and musculoskeletal and gastrointestinal pain; calcification may be visible on radiography; bone pain and fractures can occur if progression is left untreated.
Laboratory abnormalities:
i. Phosphorus
ii. Corrected calcium
iii. Intact parathyroid hormone




Management/treatment:
Nonpharmacologic therapy:
Dietary phosphorus restriction (e.g. 800-1000 mg/d in stage 3 CKD pnts)
Hemodialysis or peritoneal dialysis (remove 2-3 g/week)
Restriction of aluminum: aluminum containing antacids or products are C/I in pnts with stage 4 or 5 because of risk of aluminum toxicity or uptake by bone
Parathyroidectomy: last resort considered in:
sHPT refractory to medical therapy
Persistently high PTH levels > 800 ng/L

Pharmacologic therapy:
Phosphate-binding agents: bind dietary phosphorus forming a nonabsorbable complex that is excreted in feces
Taken with meals
Products:
Aluminum-containing phosphate binders (aluminum hydroxide, aluminum carbonate, sucralfate)
Effectively lowers phosphorus concentrations
Reserved for acute treatment of severe hyperphosphatemia or used at low doses in combination with either calcium-containing binding agents or sevelamer in cases of hyperphosphatemia that is not responding to therapy with a single agent
Avoid. Not used as frequently because of aluminum toxicity (adynamic bone disease, encephalopathy, and erythropoietin resistance)
Calcium-containing phosphate binders (calcium carbonate, calcium acetate)
Widely used binder. Considered initial binder of choice. Relatively inexpensive
Also, treat hypocalcemia, which sometimes occurs in patients with CKD
Calcium carbonate can also decrease metabolic acidosis
Use may be limited by development of hypercalcemia
Total elemental calcium per day = 2000 mg/day (1500-mg binder; 500-mg diet)
Not recommended for dialysis patients who have persistent elevations in serum calcium >10.2 mg/dL (>2.55 mmol/L) or PTH values <150 pg/mL (150 ng/L).


Vitamin D therapy:
Calcitriol, doxercalciferol, & paricalcitol
Act directly on parathyroid gland & decrease PTH secretion
Calcitriol is the pharmacologically active form of 1,2 hydroxy vitamin D3; FDA label approved for the management of hypocalcemia and the prevention & treatment of sHPT
Oral & parenteral formulations
Does not require hepatic or renal activation
Low-dose daily oral therapy reduces hypocalcemia but does not reduce PTH levels significantly
High incidence of hypercalcemia limiting PTH suppression
Dose adjustment at 4-week intervals



Paricalcitol: vitamin D analog; FDA label approved for the treatment and prevention of sHPT
Parenteral & oral formulation
Does not require hepatic or renal activation
Less incidence of hypercalcemia (decreased mobilization of calcium from the bone & decreased absorption of calcium from the gut)
Dose adjustment as frequent as every 2 weeks

Doxercalciferol: vitamin D analog; FDA label approved for the treatment and prevention of sHPT
Parenteral & oral formulation
Pro-drug, requires hepatic activation; may have more physiologic levels
Less incidence of hypercalcemia (decreased mobilization of calcium from the bone & decreased absorption of calcium from the gut)
Dose adjustments at 4- to 8-week intervals
Calcimimetics (e.g. cinacalcet): approved for tx of sHPT in ESRD pnts & for tx of hypercalcemia in pnts with parathyroid carcinoma
It increases the sensitivity of receptors on the parathyroid gland to serum calcium
Used when vit.D cannot be used
Should not be used if serum Ca < 8.4 mg/dl
Initial dose is 30 mg, irrespective of patient PTH level
Monitor serum calcium every 1-2 weeks (risk of hypocalcemia -5%)
Can be used in pnts irrespective of phosphate binder (important) or vitamin D analog use
Caution in patients with seizure disorder (hypocalcemia may exacerbate)
Adverse effects are nausea (30%) & diarrhea (20%).
CYP2D6 metabolism: dose reductions for drugs with narrow therapeutic indexes may be required (flecainide, tricyclic antidepressants, thioridazine).
Ketoconazole increases cinacalcet concentrations up to twofold


Done by: Abdikarim Abdi

supervised by :
prof. Bahar Tuncan
1. Impaired sodium & water homeostasis
Normal conditions: FENa = 1-3% & urine osmolality = 50-1200 mOsm/L
In CKD: FENa = 10-20%
Manifested as: edema (≥ stage 4) & nocturia (≥ stage 3)

Management:
Nonpharmacologic: gradual reduction of dietary Na
Pharmacologic: loop diuretics
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