Chronic Kidney Disease:

Hesty Utami,M.Clin Pharm.,PhD.,Apt

 References
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group.
KDIGO 2012 Clinical Practice Guideline for the Evaluation and
Management of Chronic Kidney Disease. Kidney Int Suppl. 2013. 3:1-150.
2. National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative.
KDOQI Clinical Practice Guidelines for Chronic Kidney Disease:
Evaluation, Classification, and Stratification. Available
at http://www.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm.
2002; Accessed: February 28, 2018.
3. B.G. Wells, J.T. Dipiro, T.L. Schwinghammer, C.V. Dipiro.
Pharmacotherapy Handbook. 9th Edition. 2015. McGraw-Hill Education:
New York.
4. Pradeep Arora, MD. Chronic Kidney Disease Treatment & Management.
https://emedicine.medscape.com/article/238798-treatment
 Definition & Stages
According to National Kidney Foundation/Kidney dialysis
Outcome and Quality Initiative (NKF/KDOQI), chronic
Kidney disease (CKD) is defined as:
1. Kidney damage for ≥ 3 months, as defined by
structural or functional abnormalities of the kidney,
with or without decreased glomerular filtration rate
(GFR), manifest by either:
• Pathophysiological abnormalities
• Markers of kidney damage including abnormalities in the
composition of the blood or urine, or abnormalities in imaging
test
OR
2. GFR < 60 ml/min/1.73 m2 for ≥ 3 months, with or
without kidney damage.
 Etiology: Susceptibility Factors
• Susceptibility factors are the factors which have not been
proven to directly cause kidney damage.
• Although the factors may not be amenable to
pharmacologic or lifestyle interventions, they may be
useful for identifying high risk populations of CKD.
• The susceptibility factors to CKD may include: advanced
age, low income or education, low birth weight, family
history of CKD, reduced kidney mass, systemic
inflammation and dyslipidemia.
 Etiology: Initiation Factors
• Initiation factors are conditions that directly result in
kidney damage, and are modifiable by pharmacologic
therapy.
• The three most common causes are DM, hypertension
and glomerular disease.
• Other causes: autoimmune disease, polycystic kidney
disease, systemic infections, urinary tract infections,
urinary stones and drug toxicity.
 Etiology: DM as Initiation Factors
• Individuals with DM type 1 have a 40% lifetime risk of
developing CKD of any age, whilst DM type 2 have a
50% lifetime risk.
• A prospective study of 300,000 individuals estimated that
around 3% of individuals with DM will develop stage 5
CKD during their lifetime → diabetic patients have a 12-
fold greater relative risk of developing stage 5 CKD than
non-diabetic individuals.
 Etiology: Hypertension as Initiation Factor
• Hypertension increases the risk of CKD although the exact role as a
cause or consequence is often debated as the kidney has a role in
the development and modulation of high blood pressure.
• Hypertension generally develops concomitantly with progressive
kidney disease, for example hypertension is present in 40% of
individuals with GFR 90 mL/min; in 55% of those with GFR 60
mL/min and 75% of individuals with GFR 30 mL/min.
• Conversely, prospective studies have shown that elevated blood
pressure (BP) increases the risk for CKD development among
subjects without initial kidney diseases.
 Etiology: Progression Factor
• Progression factors are risk factors associated with
further kidney damage. These are generally evident of
the decline rate of kidney function in patients who
already have damaged kidneys.
• The most important predictors of progressive CKD are
the persistence of underlying initiation factors (e.g DM,
hypertension, glomerulonephritis, polycystic kidney
disease) and the progression factors of proteinuria,
hyperlipidemia, obesity and smoking.
 Pathophysiology
Kidney damage can result from heterogenous cause.
The majority of pathway of renal disease progression to
renal parenchymal damage involved 3 key elements:
1. Loss of nephron mass
2. Glomerular capillary hypertension
3. Proteinuria
 Clinical Presentation
 CKD is often asymptomatic and should be suspected in individuals
with conditions such as DM, hypertension, genitourinary
abnormalities and autoimmune disease. Elderly and those with
family history of CKD should be considered for screening.
 Recommended screening studies: serum creatinine and GFR
measurement, urinalysis and/or imaging studies of the kidneys.
Abnormal elevations of sCr → decreases in GFR or presence of
urinary or imaging abnormalities → indication for full evaluation of
CKD.
 CKD stages 3,4 and 5 require further workup for CKD complications
such as anemia, cardiovascular disease, metabolic bone disease,
malnutrition and disorders of fluid and electrolytes.
Symptoms are generally absent
in CKD stages 1-2, dan may be
minimal during stages 3-4.

General symptoms associated

with stages 1-4: edema, cold
intolerance, shortness of
breath, fatigue, depression,
muscle pain, palpitations and
sexual dysfunction
CKD: Management of
Complications
 Complications: Pathophysiology

• Progression of CKD to ESRD occurs over years to decades

• However, the complications of marked reductions in kidney function
are fairly uniform irrespective of the underlying etiology.
• Accumulation of several toxins particularly uremic toxins ultimately
results in altered organ and immune function and leads to a number
of secondary complications: fluid & electrolyte abnormalities,
anemia of CKD, metabolic acidosis, cardiovascular diseases,
secondary hyperparathyroidism and renal osteodystrophy.
 Pathophysiology: Fluid & Electrolyte (Na, K)
Abnormalities
In persons with normal kidney function, sodium intake is maintained
at 120-150 mEq/day → fractional excretion is 1-3%. Water balance
is also maintained with a normal range of urinary osmolality 500-800
mOsm/kg.
An osmotic diuresis occurs with an increase in fractional excretion of
Na to water losses and impairment in kidneys’ ability to
dilute/concentrate urine.
Nocturia is present relatively early in the course of CKD (stage 3)
secondary to the defect in urinary concentrating ability.
In patients with severe CKD (stage 4-5) → total renal Na excretion
decreases . Systemic hypertension (↑intravascular volume) and
volume overload with pulmonary edema can occur.
 Pathophysiology: Fluid & Electrolyte (Na, K)
Abnormalities
• The kidneys normally excrete 90-95% of the daily
potassium/K dietary load. Normally only 5-10% of
ingested K is excreted through the gut.
• Potassium homesotasis is also maintained by shifting
exrracellular K intracellularly immediately following
ingestion of K load.
• In patients with CKD, K balance is maintained by an
increase in distal tubular secretion in which aldosterone
plays an important role.
• Serum K is usually maintained in the normal range until
the GFR is < 20 ml/min/1.73 m2 → at which mild
hyperkalemia is likely to develop.
 Pathophysiology: Metabolic Acidosis
• Individuals with normal kidney function generate enough hydrogen
ion to reclaim all filtered bicarbonate and to secrete around 1
mEq/kg/day of hydrogen ions which are generated from the
metabolism of dietary protein → able to maintain body fluid pH
through buffering H+ by protein Hb, phosphate & bicarbonate.
• Renal ammoniagenesis and phosphate excretion → buffer the urine
and facilitate acid excretion.
• In severe CKD, all filtered bicarbonate is reclaimed but the ability of
kidney to synthesize ammonia is impaired.
• A clinically significant metabolic acidosis is commonly seen when
the GFR < 20 ml/min (stage 4)→ in these patients plasma
bicarbonate tends to stabilize at 15-20 mEq/L.
 Pathophysiology: Anemia of CKD
 Anemia: Hb < 13 g/dL (adult male ) or 12 g/dL (adult female)
 The primary cause of anemia in CKD patients is a decrease in
production of hormone Epo in the kidney.
 In normal individuals, Hb/hematocrite decline will lead to increased
production of Epo.
 Anemic ESRD → normocytic normochromic anemia. However, if the
CKD patients have concomitant iron deficiency → microcytic anemia
 Additional factors contributing to Anemia in CKD are the decreased
RBC lifespan in the presence of uremia (RBC lifespan 60 days in
ESRD), iron deficiency, blood loss due to hemodyalisis.
Pathophysiology: Hyperparathyroidism and Renal Osteodystrophy
 Pathophysiology: Cardiovascular Disease (CVD)
Patients with CKD are at increased risk of CVD independent of
etiology of the kidney disease.
In addition to traditional cardiac risk factors (hypertension,
hyperlipidemia, diabetes, tobacco use, physical inactivity), CKD
patients also have unique risk factors including
hyperhomocisteinemia, increased CRP and hemodynamic overload.
Complications e.g anemia and metabolic disorders (abnormalities of
Ca, P, PTH) contribute to CVD.
The primary types of CVD found in CKD patients may include
arterial vascular diseases (e.g atherosclerosis) and cardiomyopathy
lead to development of ischemic heart disease and its manifestation
including myocardial infarction.
CVD are the leading causes of death in ESRD patients.
 Clinical Presentation: Laboratory test and other
Diagnostic Procedures
• Decreased: creatinin clearance, bicarbonate (metabolic acidosis),
Hb/hematocrit (anemia), iron stores, Vit D, albumin (malnutrition),
glcose (decreased degradation of insulin with impaired kidney
function or poor oral intake), Calcium (eary stages), HDL cholesterol

• Increased: sCr, BUN, K, phosphorus, BP, glucose (uncontrolled

diabetes as the cause), LDL and triglycerides, T4 (hypothyroidism),
calcium (in ESRD)

• Other diagnostic tests: left ventricular hypertrophy, increased

homocysteine level, increased C-reactive protein.
 Treatment Focus:

1. Delaying or halting the CKD progression

2. Diagnosing and treating the CKD manifestations
3. Timely planning for long-term renal replacement therapy (RRT)
 Treatment Focus #1: Delaying/halting CKD
progression
• Treatment of the underlying condition if possible
• Aggressive blood pressure control
• Treatment of hyperlipidemia
• Aggressive glycemic control
• Avoidance of nephrotoxin (e.g., non-steroidal anti-inflammatory
drugs/NSAIDs, aminoglycosides, IV radiocontrast etc)
Treatment
Treatment of
of Hypertension
Hypertension in
in CKD
CKD without
without DM
DM
Treatment of Hypertension in CKD with DM
 Treatment of Hyperlipidemia
• The prevalence of hyperlipidemia increased as renal function
declines
• The use of statin is recommended in adults > 50 and older with
stage 1-5 CKD not on dialysis
 Treatment Focus #2: Diagnosing and treating the
CKD manifestations
• Anemia
• Electrolyte abnormalities (e.g., hyperkalemia)
• Metabolic and bone disorders (e.g., hyperphosphatemia,
hypoclacemia, hyperparathyroidism)
• Metabolic acidosis
• Volume overload
• Uremia
• Cardiovascular risk
 Management of Anemia
With erythropoietic-stimulating agent (ESA e.g., epoetin alfa,
dabepoietin alfa) → Target of Hb level 10-12 g/dL → normalization of
HB level associated with increased risk of adverse outcomes.
Before starting ESA → check iron stores → target iron saturation 30-
50% and ferritin 200-500 ng/mL.
Initiate ESA in CKD patients with Hb between 9-10 g/dL
Iron deficiency is the primary cause of resistance to treatment of
anemia iron → supplementation is required by most CKD patients.
Iron status should be reassessed every month during initial ESA and
every 3 months for those on a stable ESA regimen.
Hb should be monitored at least monthly or more frequently after
intitian of ESA and dose change until Hb is stable.
ESAs are well tolerated → hypertension is the most common
adverse event
 Management of Bone & Mineral Disorder (MBD)
• CKD-MBD are common and include abnormalities in parathyroid
hormone (PTH), calcium-phosphorus,, vitamin D, bone turnover,
soft tissue calcifications.
• Calcium-phosphorus balance is mediated through a complex
interplay of hormones and their effects on bones (e.g., PTH),
gastrointestinal tract, kidneys.
• As kidney disease progresses → renal activation of vit D is impaired
→ reduces gut absorption of calcium → hypocalcemia stimulates
secretion of PTH
• As renal function declines → serum calcium balance can be
maintained only at the expense of increased of bone resorption →
renal osteodystrophy
• Secondary hyperparathyroidism is associated with increased
morbidity and mortality in hemodialysis patients
 CKD-MBD: phosphate-binding agents/phosphate
binders
• Phosphate binders decrease phosphorus absorption from the gut
and are first line agents for controlling both serum phosphorus and
calcium level.
• Elemental calcium from calcium-containing binders should not
exceed 1500 mg/day and the total daily intake from all sources
should not exceed 2000 mg/day.
• Combination of calcium and non-calcium containing phosphate
binders (e.g., sevelamer HCl, lanthanum carbonate) may be
necessary to avoid hypercalcemia.
• Adverse effects of all phosphate binders are limited to GI effects
(constipation, diarrhoea,nausea, vomiting, abdominal pain)
• Aluminium (CNS toxicity and worsening of anemia) & magnesium
binders (hypermagnesemia, hyperkalemia) are not recommended
for regular use in CKD
 CKD-MBD: Vit D therapy
• Reasonable control of calcium and phosphorus must be achieved
before initiation and during continued vit D therapy
• Calcitriol (1,25-dihydroxyvitamin D3) directly suppresses PTH
synthesis and secretions and upregulates vitamin D receptors.
• The newer vit D analogues paricalcitol and doxercalciferol may be
associated with less hypercalcemia and hyperphosphatemia..
Vitamin D Agents
 Other CKD Manifestations

• Volume overload → treat with loop diuretics or ultrafiltration

• Uremia → dialysis
• Metabolic acidosis → bicarbonate supplementation (e.g., sodium
bicarbonate)
• Hypocalcemia: Treat with calcium supplements with or without
calcitriol
• Hyperkalemia: diuretic, potassium binder
 Cardiovascular risk
Guidelines issued in December 2013 by the Kidney Disease: Improving Global
Outcomes (KDIGO) workgroup recommend wider statin use among patients
with CKD. Specific recommendations include the following [77, 78] :
• Adults aged ≥50 years with GFR < 60 mL/min/1.73 m 2 who are not being
treated with long-term dialysis or kidney transplantation should be treated
with a statin or a statin plus ezetimibe
• Treatment with statins or statin/ezetimibe should not be initiated in adults
with dialysis-dependent CKD, but patients already being treated with a
statin at the time of dialysis should continue
• Adult kidney transplant patients should be treated with a statin because of
an increased risk for coronary events
• Adults aged 18-49 years with GFR < 60 mL/min/1.73 m 2 who are not being
treated with dialysis or kidney transplantation should be treated with statins
if they have coronary disease, diabetes, prior ischemic stroke, or an
estimated 10-year incidence of coronary death or nonfatal myocardial
infarction exceeding 10%
• Adults aged 50 years or older with CKD and GFR of 60 mL/min/1.73 m2 or
higher should be treated with a statin
Treatment Focus #3: Renal Replacement Therapy/ RRT
(Hemodialysis, Peritoneal Dialysis, Renal Transplant)
Indications for RRT:
• Severe metabolic acidosis
• Uremia
• Refractory Hyperkalemia
• Pericarditis
• Encephalopathy
• Uncontrollable volume overload
• Failure to thrive and malnutrition
• Peripheral neuropathy
• Uncontrollable gastrointestinal symptoms
• In asymptomatic adult patients → GFR 5-9 ml/min/1.73 m2
irrespective of the casue of CKD or the presence/absence of other
comorbidities.
Peritoneal Dialysis
Hemodialysis
 Non-Pharmacology Management
• Protein restriction (< 40 g/day)
• Phosphate restriction starting early in CKD
• Potassium restriction
• Sodium and water restriction as needed to avoid volume overload
• Smoking cessation