Definitions of CKD

Koda-Kimble&Young’s Applied Therapeutics, 10th Ed, Chapter 31: Chronic Kidney Disease
(Darius L. Mason and Magdalene M. Assimon, 2013)
Brian K. Alldredge, Robin L. Corelli, Michael E. Ernst, B. Joseph Guglielmo, Pamala A. Jacobson, Wayne A. Kradjan, Bradley
R. Williams
Chronic kidney disease is characterized by a progressive deterioration in kidney function with time
characterized by irreversible structural damage to existing nephrons. A staging system is used to classify kidney
disease according to the eGFR, which is estimated clinically using creatinine clearance (CrCl) (Table 31-2).
Specifically, CKD is defined as kidney damage with normal or a mildly decreased eGFR (stages 1 and 2) or an
eGFR less than 60 mL/minute/1.73 m2 for at least 3 months with or without evidence of kidney damage (stages 3 to
4). Kidney damage is indicated by pathologic abnormalities of the kidneys or markers of kidney injury, including
abnormalities in blood or urine tests and imaging studies. 1 The presence of protein in the urine (defined as
proteinuria, albuminuria, or microalbuminuria based on protein type and amount) is an early and sensitive marker
of kidney damage (Table 31-3).
Penyakit ginjal kronis dikarakterisasi dengan adanya penurunan fungsi ginjal secara progresif dalam jangka
waktu tertentu yang ditandai dengan kerusakan struktural pada nefron yang bersifat irreversibel. Secara spesifik,
PGK didefinisikan sebagai kerusakan ginjal dengan eGFR normal atau eGFR yang sedikit menurun (pada stadium 1
dan 2) atau eGFR kurang dari 60 mL /minute/1.73 m2 selama setidaknya 3 bulan dengan atau tanpa bukti kerusakan
ginjal (pada stadium 3 dan 4). Kerusakan ginjal ditandai dengan abnormalitas patologi dari ginjal atau dengan
adanya marker dari kerusakan ginjal, yaitu abnormalitas pada tes darah maupun urin dan pencitraan ginjal. Adanya
protein pada urin (proteinuria, albuminuria, maupun mikroabuminuria berdasarkan jenis dan banyaknya protein)
merupakan marker awal yang sensitif pada kerusakan ginjal (Alldredge, 2013).

KDIGO, 2013, CKD Guideline

Kidney disease is defined as an abnormality of kidney structure or function with implications for the health
of an individual, which can occur abruptly, and either resolve or become chronic. CKD is a general term for
heterogeneous disorders affecting kidney structure and function with variable clinical presentation, in part related to
cause, severity and the rate of progression. The concept of CKD evolved after the recognition of the contribution of
disordered kidney structure and function on the health of individuals across a wide range of severity. 1 The utility of
the concept is that recognition of CKD will have implications for the individual and their care. Kidney failure is
traditionally considered as the most serious outcome of CKD. Symptoms are usually due to complications of
decreased kidney function and when severe, they can be treated only by dialysis or transplantation. Earlier stages of
kidney disease are often asymptomatic, are detected during the evaluation of comorbid conditions, and may be
reversible. Rapidly progressive diseases may lead to kidney failure within months but most diseases evolve over
decades, and some patients do not progress during many years of follow-up.
Penyakit ginjal didefinisikan sebagai abnormalitas pada struktur atau fungsi ginjal yang berimplikasi pada
kesehatan individual, yang dapat terjadi secara tiba-tiba, dan dapat diatasi atau malah menjadi kronis. PGK
merupakan istilah umum untuk gangguan heterogen yang mempengaruhi struktur dan fungsi ginjal dengan berbagai
gambaran klinis, sebagian berkaitan dengan penyebab, tingkat keparahan, dan progresivitas.
Complications of CKD affect all organ systems. Kidney failure leads to the commonly recognized
symptoms of uremia. Less severe CKD has been recognized as an independent risk factor for cardiovascular disease
(CVD) and other common conditions affecting the elderly, such as infection and impairments in physical function
and cognition. In addition, CKD is associated with increased risk from adverse effects of drugs, intravascular
radiocontrast administration, surgery and other invasive procedures. Altogether, these complications are associated
with higher morbidity, mortality and cost. If CKD is detected early, the associated complications and the progression
to kidney failure can be delayed or even prevented through appropriate interventions.

K/DOQI, 2002
Chronic kidney disease is defined according to the presence or absence of kidney damage and level of kidney
function—irrespective of the type of kidney disease (diagnosis). Among individuals with chronic kidney disease, the
stages are defined based on the level of kidney function. Identifying the presence and stage of chronic kidney
disease in an individual is not a substitute for accurate assessment of the cause of kidney disease,

Chronic kidney disease has been defined according to the criteria listed in Table 11.
Menurut Kidney Disease Outcomes Quality Initiative (KDOQI) PGK didefinisikan sebagai kerusakan ginjal baik
secara struktural maupun fungsional yang terjadi selama lebih dari 3 bulan, dengan atau tanpa penurunan GFR
(K/DOQI,2002)

Etiology

Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.

Although the stages are defined functionally by the GFR, the classification system also accounts for
structural evidence of kidney damage. Normal kidney function in adults is approximately 120 mL/min/1.73 m2 of
GFR. Even though a GFR of >90 mL/min/1.73 m2 is considered normal kidney function, a patient can be diagnosed
with CKD if the patient has proteinuria, hematuria, or evidence of structural damage from a kidney biopsy. Stage 5
CKD was previously referred to as end-stage renal disease (ESRD) or end-stage kidney disease.

Walker, R., Edwards, C., 2012, Clinical Pharmacy and Therapeutics 5th ed, 247-252, Churchill Livingstone.,
Philadelphia.
The reduction in renal function observed in CKD results from damage to the infrastructure of the kidney in
discrete areas rather than throughout the kidney. The nephron is the functional unit of the kidney and while the mechanism
of damage depends on the underlying cause of renal disease, as nephrons become damaged and fail, remaining nephrons
compensate for loss of function by hyperfiltration secondary to raised intra-glomerular pressure. This causes ‘bystander’
damage with secondary nephron loss. This vicious cycle is illustrated in Fig. 18.5. The patient remains well until so many
nephrons are lost that the GFR can no longer be maintained despite activation of compensatory mechanisms. As a
consequence there is a progressive decline in kidney function.
Reduksi fungsi ginjal yang teramati pada CKD disebabkan oleh kerusakan infrastruktur ginjal pada bagian yang
berbeda-beda, bukan keseluruhan bagian ginjal. Mekanisme kerusakan ginjal bergantung pada penyebab utama penyakit
ginjal, terjadinya kerusakan dan kegagalan fungsi nefron menyebabkan nefron lainnya mengkompensasi fungsi yang
hilang tersebut dengan hiperfiltrasi sekunder untuk meningkatkan tekanan intra-glomerular.
CKD arises from a variety of causes (Table 18.2), although by the time a patient has established CKD it may not
be possible to identify the exact cause. However, attempting to establish the cause is useful in the identification and
elimination of reversible factors, to plan for likely outcomes and treatment needs, and for appropriate counselling when a
genetic basis is established. The causes of CKD listed in Table 18.2 are ordered according to prevalence. It is important to
note the prevalence of these factors is different in CKD and end stage renal disease. In end stage renal disease, diseases
such as adult polycystic kidney disease (APKD) are overrepresented and ischaemic/hypertensive nephropathy
underrepresented. The reasons for this are that individuals with APKD are likely to survive to reach end stage renal disease
while those with diabetes or ischaemic renal damage may succumb to cardiovascular disease before end stage renal
disease is reached.
PGK muncul disebabkan oleh berbagai sebab, walaupun diagnosis telah ditegakkan pada pasien namun sulit
untuk mengeidentifikasi penyebab pasti dari PGK. Padahal, penyebab pasti dari PGK sangat diperlukan untuk menentukan
terapi yang diperlukan dan outcome yang akan dicapai. Menurut UK Renal Registry 17th Annual Report, penyebab PGK
yaitu diabetes, glomerulonefritis, pyelonefritis, hipertensi, ginjal polikistik, penyakit renovaskuler, serta penyebab lain,
dan beberapa tidak diketahui penyebabnya (Walker, 2012; Renal Registry, 2014)

UK Renal Registry, 2014. The 17th Annual Report. Renal Association, Bristol.
Patofisiologi
Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.

Kidney damage can result from heterogeneous causes. For example, diabetic nephropathy
is characterized by glomerular mesangial expansion; in hypertensive nephrosclerosis, the
kidney’s arterioles have arteriolar hyalinosis; and renal cysts are present in polycystic kidney
disease. Therefore, the initial structural damage may depend on the primary disease affecting the
kidney. However, the majority of progressive nephropathies share a final common pathway to
irreversible renal parenchymal damage and ESRD (Fig. 46–1). The key elements of this pathway
are: (a) loss of nephron mass; (b) glomerular capillary hypertension; and (c) proteinuria.
The exposure to any of the initiation risk factors can result in loss of nephron mass. The
remaining nephrons hypertrophy to compensate for the loss of renal function and nephron mass.
Initially, this compensatory hypertrophy may be adaptive. Over time, the hyper trophy can lead
to the development of intraglomerular hypertension, possibly mediated by angiotensin II.
Angiotensin II is a potent vasoconstrictor of both the afferent and efferent arterioles, but
preferentially affects the efferent arterioles, leading to increased pressure within the glomerular
capillaries and consequent increased filtration fraction. The development of intraglomerular
hypertension usually correlates with the development of systemic arterial hypertension.
Proteinuria alone may promote progressive loss of nephrons as a
result of direct cellular damage.88,95 Filtered proteins such as albumin,
transferrin, complement factors, immunoglobulins, cytokines,
and angiotensin II are toxic to kidney tubular cells.
Kerusakan ginjal dapat diakibatkan oleh berbagai macam penyebab. Kerusakan awal
pada struktur tergantung pada penyakit utama yang mempengaruhi ginjal. Namun demikian,
sebagian besar nefropati progresif menghasilkan jalur yang umumnya mengarah pada kerusakan
parenkim ginjal dan end-stage renal disease (ESRD). Faktor-faktor penting dari jalur ini adalah
hilangnya massa nefron, hipertensi kapiler glomerulus, dan proteinuria (Dipiro, 2008).

Koda-Kimble&Young’s Applied Therapeutics, 10th Ed, Chapter 31: Chronic Kidney Disease
(Darius L. Mason and Magdalene M. Assimon, 2013)
Brian K. Alldredge, Robin L. Corelli, Michael E. Ernst, B. Joseph Guglielmo, Pamala A. Jacobson, Wayne A. Kradjan, Bradley
R. Williams
As the leading causes of ESRD in the United States, diabetes mellitus, hypertension, and glomerular diseases have
been the focus of research to identify their associated mechanisms of kidney damage.
a. Diabetes
In the case of diabetes mellitus, excess filtration of glucose and contact with glomerular and
tubular cells leads to increased cellular osmotic pressure and thickening of the capillary
basement membrane.
b. Hipertensi
Systemic hypertension is a potent stimulus for the development and progression of kidney
disease caused by the association with increased single-nephron eGFRs.13,15 Hypertension,
whether the primary cause of kidney disease or a coexisting disease in the presence of other
etiologies, can promote kidney damage through transmission of elevated systemic pressure to
glomeruli. The result is glomerular capillary hyperperfusion and hypertension leading to
progressive kidney damage as nephron destruction continues.
c. Proteinuria
Proteinuria, one of the initial diagnostic signs of kidney disease, can also contribute to the
progressive decline in renal function. A faster rate of progression has been associated with
higher protein excretion.18 Immunologic and hemodynamic mechanisms have been
identified to explain the glomerular injury. Increases in renal plasma flow are associated with
proteinuria and high protein intake.

Sebagai penyebab utama dari ESRD di Amerika Serikat, diabetes mellitus, hipertensi,
dan penyakit glomerulus telah menjadi fokus penelitian untuk diidentifikasi kaitannya dengan
mekanisme kerusakan ginjal.
d. Diabetes
Pada diabetes mellitus, filtrasi glukosa secara besar-besaran serta kontak dengan glomerulus
sel tubulus berakibat pada peningkatan tekanan osmotik sel dan penebalan membran dasar
kapiler.
e. Hipertensi
Hipertensi sistemik adalah stimulus yang poten bagi perkembangan penyakit ginjal yang
penyebabnya berkaitan dengan peningkatan eGFR. Hipertensi, baik sebagai penyebab utama
penyakit ginjal, maupun sebagai penyakit penyerta dapat menyebabkan kerusakan ginjal
berkembang hingga terjadi peningkatan tekanan sistemik glomerulus. Sehingga terjadi
hiperperfusi dan hipertensi kapiler glomerulus yang berakibat pada kerusakan ginjal secara
progresif dengan kerusakan nefron yang terus berlanjut.
f. Proteinuria
Proteinuria yang menjadi salah satu tanda dalam diagnosis PGK juga dapat berkontribusi
pada penurunan fungsi ginjal secara progresif. Semakin tinggi protein yang disekresikan
maka kecepatan progresi juga semakin tinggi. Peningkatan aliran plasma ginjal dikaitkan
dengan proteinuria dan tingginya asupan protein.
(Alldredge, 2013)

Lopez-Novoa, J.M., Martinez-Salgado, C., Rodriguez-Pena, A.B., and Hernandez, F.J.L.,

Common Pathophysiological Mecanisms of Chronic Kidney Disease : Therapeutic Perspectives,
Pharmacology and Theurapetics 128 (2010) 61-81.
 Presently, diabetes and hypertension are the two leading causes of CKD, although
infectious glomerulonephritis, renal vasculitis, ureteral obstruction, genetic alterations,
autoimmune diseases and others are also common causes of CKD.
Diabetes dan hipertensi merupakan 2 penyebab utama dari PGK, walaupun
glomerulonefritis menular, vaskulitis ginjal, obstruksi ureter, perubahan genetik, penyakit
autoimun, dan lain-lain juga merupakan penyebab PGK yang banyak terjadi (Novo et a,l, 2010).

Hypertensive nephropathy
Accordingly, nephropathy can also be viewed as a primary
renal lesion that progresses in parallel to and initiates the rise in blood
pressure.
Diabetic nephropathy
It is important to consider that hyperglycemia
is a primary initiator of diabetic nephropathy. In the absence of
elevated glycemia, nephropathy does not develop.
Renal mass reduction
the number of nephrons decreases during
the progression of CKD. The remaining nephrons increase their filtration rate in
order to maintain the excretory need of the organism. Renal
dysfunction appears when the remaining nephrons cannot cope
with the sustained extra load. However, over time the adaptive
mechanisms contribute to the deterioration of the remnant nephrons. Initially, the RMR-induced increment of glomerular volume
reflects the compensatory response of the remnant renal mass. RMR
develops different degrees of systemic and glomerular hypertension
and proteinuria, initially focal in nature but developing to global
glomerulosclerosis accompanied by a gradual reduction of GFR and
progressive tubulointerstitial damage. This culminates in renal failure
and death
Obstructive nephropathy
Obstruction of the urinary pathway (chiefly resulting from
blockade of one or, exceptionally, both ureters) causes progressive
deterioration of renal structures leading to chronic dysfunction.
Ureteral obstruction gives rise to the hydronephrotic syndrome,
characterized by kidney enlargement due to urine collection in the
renal pelvis or calyces

Kerusakan ginjal dapat diakibatkan oleh berbagai macam penyebab. Kerusakan awal pada
struktur tergantung pada penyakit utama yang mempengaruhi ginjal. Namun demikian, sebagian
besar nefropati progresif menghasilkan jalur yang umumnya mengarah pada kerusakan parenkim
ginjal dan end-stage renal disease (ESRD). Faktor-faktor penting dari jalur ini adalah hilangnya
massa nefron, hipertensi kapiler glomerulus, dan proteinuria (Dipiro, 2008).

Faktor Risiko
Koda-Kimble&Young’s Applied Therapeutics, 10th Ed, Chapter 31: Chronic Kidney Disease
(Darius L. Mason and Magdalene M. Assimon, 2013)
Brian K. Alldredge, Robin L. Corelli, Michael E. Ernst, B. Joseph Guglielmo, Pamala A. Jacobson, Wayne A. Kradjan, Bradley
R. Williams
A variety of risk factors associated with development, initiation, and progression of CKD have been
identified. Initiation factors are medical conditions that directly cause kidney damage. Risk factors for the
progression of CKD exacerbate kidney damage and are related to an accelerated decline in kidney function with
time. The majority of susceptibility factors are not modifiable, but may identify peoplewho are at high risk for
developing CKD. In contrast, pharmacotherapy and lifestyle interventions have been shown to modify CKD-related
initiation and progression factors (see Prevention and Diabetic Nephropathy section). A summary of risk factors
associated with CKD can be found in Table 31-4.
 Berbagai macam faktor risiko yang telah teridentifikasi pada PGK berhubungan dengan perkembangan,
inisiasi, dan progresi penyakit.
a. Susceptibility factors merupakan faktor yang meningkatkan kerentanan akan risiko terjadinya PGK, diantaranya
yaitu usia lanjut, berkurangnya massa ginjal, berat badan lahir rendah, ras/etnis minoritas, riwayat keluarga,
edukasi dan pendapatan yang rendah, inflamasi sistemik, serta dislipidemia.
b. Initiation factors merupakan kondisi medis yang secara langsung menyebabkan kerusakan ginjal, seperti
diabetes mellitus, hipertensi, glomerulonefritis, induksi oleh obat atau toksisitas obat, merokok, dan obesitas.
c. Progression factors merupakan faktor yang menyebabkan perburukan kerusakan ginjal dan mempercepat
penurunan fungsi ginjal, yaitu glikemia, hipertensi, proteinuria, merokok, dan obesitas.
(Alldredge, 2013; K/DOQI, 2002)

K/DOQI, 2002

Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.

Pharmacoeconomic considerations
Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.
The financial and societal costs of the care of individuals with CKD are high, especially the care of those
with ESRD—this population of beneficiaries comprises only 0.5% of the total Medicare population, yet accounts for
5% of all Medicare expenditures.179 Annualized expenditures per beneficiary ranged from $36,000 for those 24
years of age and younger to $51,000 for those 75 years of age and older.179 These costs for the care of advanced
CKD are estimated to increase dramatically over the next decade, reaching an estimated $28 billion dollars by the
year 2010 for Medicare alone.180 There have been a few evaluations of the potential pharmacoeconomic impact of
screening for microalbuminuria and the subsequent initiation of various pharmacotherapeutic regimens in type 1
diabetic patients.181,182 According to one study, the historical standard approach to proteinuria reduction was
considered to be treatment with hydrochlorothiazide at the time of hypertension diagnosis, while the newer
treatment approach assumed three different screening and treatment strategies with ACEIs. The results from this
evaluation suggested that with early screening and treatment of persistent microalbuminuria with ACEIs, it is
possible to realize a cost-effectiveness of $7,900 to $16,500 per year of life saved. This amount is similar to the cost-
effectiveness associated with treating hypertension in the general population. A similar costeffectiveness analysis
using different strategies but the same basic model was also performed182 and projected that treating all patients
with an ACEI 5 years after the diagnosis of diabetes was as cost effective as annual screening for microalbuminuria
beginning 5 years after diagnosis, with the initiation of an ACEI when and if persistent microalbuminuria was
detected.

Manifestasi Klinis
Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.

CKD is often asymptomatic, and should be suspected in individuals with conditions such as diabetes,
hypertension, genitourinary abnormalities, and autoimmune diseases. In addition, individuals of older age and those
with a family history of kidney disease should be considered for CKD screening. Recommended screening studies
include serum creatinine and GFR measurement, urinalysis, and/or imaging studies of the kidneys. Abnormal
elevations of serum creatinine, reflecting decreases in GFR, or presence of urinary or imaging study abnormalities
are indications for a full evaluation of CKD.1 _ The rate of GFR loss can vary in CKD because of differences in the
underlying disease process and extent of kidney damage, treatment responsiveness, and compliance with therapies.
The NKF K/DOQI developed a classification system that divides CKD into five stages, with each increasing number
indicating a more advanced stage of the disease, as defined by GFR1 (see Table 46–1). These stages are based on
kidney function and evidence of kidney damage. Therefore, one can have CKD with a normal GFR (>90 mL/min
per 1.73 m2) if there is evidence of structural damage to the kidneys (e.g., presence of proteinuria). The GFR rather
than serum creatinine was used to define kidney function in this official classification system because the serum
creatinine is an inadequate measure of kidney function (see Chap. 44). The NKF K/DOQI defines kidney damage as
the presence of clinical proteinuria. Table 46–3 summarizes the methods available to detect and interpret proteinuria
and albuminuria. In addition, Chap. 44 provides a detailed discussion of the relative merits of the various methods
currently available for the detection of urinary protein.
PGK sering kali bersifat asimtomatic atau tanpa gejala, dan patut dicurigai pada individu yang menderita
diabetes, hipertensi, abnormalitas genitourinari, dan penyakit autoimun. Terlebih lagi pada individu yang berusia
lanjut dan memiliki riwayat keluarga terhadap penyakit ginjal harus dipertimbangkan untuk mengevaluasi PGK.
Evaluasi yang direkomendasikan termasuk pengukuran serum kreatinin dan GFR
 Secara umum, perkembangan PGK di awal tersembunyi dan sering kali tanpa gejala yang terlihat.
Diagnosis PGK membutuhkan pengukuran serum kreatinin, estimasi GFR, dan urinalisis terutama protein dan/atau
ekskresi albumin. PGK stadium 3,4, dan 5 membutuhkan pemeriksaan lebih lanjut untuk mengidentifikasi
komplikasi anemia, penyakit kardiovaskular, penyakit metabolik tulang, malnutrisi, serta gangguan cairan dan
elektrolit (Dipiro, 2008).
Gejala pada umumnya tidak tampak pada PGK stadium 1 dan 2, dan kemungkinan kecil muncul pada
stadium 3 dan 4. Gejala umum yang berkaitan dengan stadium 1 hingga adalah edema, intoleransi dingin, kesulitan
bernafas, palpitasi, kram dan nyeri otot, depresi, ansietas, kelelahan, serta disfungsi seksual (Dipiro, 2008)
Tanda-tanda PGK diantaranya:
a. Gangguan kardiovaskular dan pulmonari, seperti edema, hipertensi yang memburuk, aritmia, dislipidemia
b. Gangguan GI, yaitu GERD (Gastroesophageal reflux disease) dan kehilangan berat badan
c. Gangguan endokrin, yaitu hiperparatiroidisme sekunder, penurunan aktivasi vitamin D, deposisi β 2-
mikroglobulin, dan gout
d. Gangguan hematologik, seperti anemia, defisiensi besi, dan pendarahan
e. Gangguan cairan/elektrolit, yatu hipernatremia, hiponatremia, hiperkalemia, dan asidosis metabolik
f. Gangguan sistem saraf pusat, yaitu kebingungan, kejang, dan koma
g. Gangguan tulang, yaitu osteomalasia, nyeri, dan osteosklerosis
(Dipiro, 2008; Walker, 2012)
Klasifikasi GGK
Carroll, L.E., 2006, The Stages of Chronic Kidney Disease and the Estimated Glomerular Filtration Rate, The
Journal of Lancaster General Hospital,vol 1-2.
Based on estimated GFR, the NKF guidelines categorize CKD into 5 stages, which are reflective of kidney
function regardless of the underlying pathological cause of dysfunction. (Table 1)
Berdasarkan nilai GFR, National Kidney Foundation mengklasifikasikan PGK ke dalam 5 stadium yang
menggambarkan fungsi ginjal.
Komplikasi
K/DOQI,2002

Thomas, Robert, Kanso, Abbas, Sedor, John R., 2008, Chronic Kidney Disease and Its
Complications,
Thomas R, Kanso A, Sedor JR. Chronic kidney disease and its complications. Prim Care.
2008;35:329-44, vii.
Komplikasi yang terjadi pada PGK kebanyakan dapat dicegah atau ditunda melalui deteksi dan
terapi lebih awal. Komplikasi yang sering ditemukan pada pasien PGK yaitu:
a. Anemia
Anemia normokromik normosistik biasanya menyertai progresivitas dari PGK.
Anemia terdiagnosa pada berbagai stadium PGK, namun terdapat korelasi antara
prevalensi anemia dengan keparahan PGK. Sebanyak 25% pasien PGK stadium 1, 50 %
pasien PGK stadium 2, 3, dan 4, serta 75% pasien PGK yang menjalani dialisis
mengalami anemia. Penurunan sintesis eritropoetin merupakan penyebab terjadinya
anemia pada PGK yang spesifik dan yang paling penting .
b. Gangguan mineral dan tulang
Gangguan yang terjadi adalah meliputi abnormalitas pada tulang dan metabolisme
mineral dan/atau kalsifikasi ekstraskeletal sekunder pada patofisiologi PGK.
c. Risiko kardiovaskular
Hipertensi merupakan faktor yang berkontribusi pada risiko kardiovaskular yang
berkaitan dengan PGK. Tekanan darah yang tinggi mulai berkembang pada awal
terjadinya PGK. Tingginya tekanan darah pada pasien PGK akan mempercepat
penurunan fungsi ginjal dan terjadinya penyakit kardiovaskular.
d. Dislipidemia
Profil lipid pada pasien PGK sangatlah beragam dan menggambarkan fungsi
ginjal serta derajat proteinuria. Secara umum, prevalensi hiperlipidemia meningkat
seiring dengan menurunnya fungsi ginjal. Parahnya kerusakan ginjal akan sebanding
dengan derajat hipertrigliseridemia dan peningkatan kolesterol LDL.
e. Malnutrisi
 Selama berkembangnya PGK, kebutuhan nutrisi pada pasien berubah sehingga
mempengaruhi metabolisme protein, air, garam, kalium, dan fosfor. Perubahan ini
menyebabkan produksi energi menjadi tidak efektif meskipun asupan protein dan
karbohidrat telah terpenuhi.
f. Neuropati
Manifestasi neuropati pada penyakit ginjal adalah berupa ensefalopati,
polineuropati perifer, disfungsi saraf otonom, gangguan tidur, dan yang jarang terjadi
yaitu mononeuropati perifer. Terjadinya neuropati berhubungan dengan fungsi ginjal,
bukan dengan jenis penyakit ginjal.
(Thomas et al, 2008; K/DOQI, 2002)

Komorbid
K/DOQI,2002

Komorbid didefinisikan sebagai kondisi yang dialami pasien selain dari penyakit utama
(dalam hal ini yaitu PGK). Komplikasi dari PGK bukan termasuk kondisi komorbid. Terdapat 3
tipe kondisi komorbid pada PGK yang diklasifikasikan oleh K/DOQI:
a. Penyakit yang menyebabkan PGK
Contoh : diabetes, tekanan darah tinggi, obstruksi saluran kemih
b. Penyakit yang tidak berhubungan dengan PGK
Contoh : penyakit paru obstruktif kronis (PPOK), gastroesophageal reflux disease
(GERD), penyakit sendi degeneratif, alzheimer, malignansi
c. Penyakit kardiovaskular
Contoh : atherosklerosis, hipertrofi ventrikel kiri, gagal jantung
(K/DOQI, 2002)

Diagnosis
Walker, R., Edwards, C., 2012, Clinical Pharmacy and Therapeutics 5th ed, 247-252, Churchill Livingstone.,
Philadelphia.

Although the diagnosis of CKD may be suspected because of signs and symptoms of
renal disease, more often it is discovered incidentally. There are patients with CKD for whom no
cause can be identified, often because they have two small kidneys which are not safe to biopsy.
This appearance results from damage at some unspecified time in the past.
Functional assessment of the kidney may be performed by testing serum and urine. The
serum creatinine level is a more reliable indicator of renal function than the serum urea level
though both are normally measured. Hyperkalaemia, acidosis with a correspondingly low serum
bicarbonate level, hypocalcaemia and hyperphosphataemia are frequently present and can help to
differentiate a new presentation of CKD from AKI. Urine should be examined visually and
microscopically and urinalysis performed for assessment of urinary sediment and a spot urine
assessment of the ACR. The patient may report change in urine colour, which might result from
blood staining by whole cells or haemoglobin, drugs or metabolic breakdown products. Urine
may also appear milky after connection with lymphatics, cloudy following infection, contain
solid material such as stones, crystals, casts, or froth excessively in proteinuria.
Dipstick tests enable simple, rapid estimation of a wide range of urinary parameters
including pH, specific gravity, leucocytes, nitrites, glucose, blood and protein. Positive results
should, however, be quantified by more specific methods. Structural assessments of the kidney
may be performed using a number of imaging procedures, including:
• ultrasonography
• intravenous urography (IVU)
• plain abdominal radiography
• computed tomography (CT), magnetic resonance imaging
(MRI) and magnetic resonance angiography (MRA).

K/DOQI,2002
 Estimasi GFR
 Assessment of poteinuria
 Markers of Chronic Kidney Disease Other Than Proteinuria

1. Pemeriksaan fungsional menggunakan serum darah dan urin

 Serum
a) Kreatinin
b) Urea
c) Kalium
d) Bikarbonat
e) Phospat
f) Kalsium
 Urinalisis
a) Pemeriksaan visual, seperti perubahan warna urin dan adanya endapan.
b) Pemeriksaan mikroskopis, dilakukan kultur dari sampel urin.
c) Tes dipstik, untuk mengetahui pH, adanya leukosit, nitrit, hematuria, dan
proteinuria
d) Estimasi GFR menggunakan klirens inulin

2. Pemeriksaan struktural
Melalui pencitraan
 Ultrasoonography (USG)
 Intravenous Urography (IVU)
 Plain abdominal radiography
 Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Magnetic
Resonance Angiography (MRA).
 Biopsi ginjal

Terapi
Turner JM, Bauer C, Abramowitz MK, Melamed ML, Hostetter TH (2012) Treatment of chronic kidney
disease. Kidney Int 81: 351–362 doi: 10.1038/ki.2011.38022166846 [PubMed]
Treatment of chronic kidney disease (CKD) aims to slow progression to end-stage renal
disease (ESRD) and to prepare for ESRD. Because the symptoms of chronically progressive
renal failure develop slowly, therapy of CKD is usually directed at an asymptomatic condition
detected only by laboratory testing (Turner, 2012).
 Pengobatan PGK bertujuan untuk memperlambat progres penyakit menuju penyakit
ginjal stadium akhir. Karena gejala dari gagal ginjal kronis yang progresif berkembang secara
lambat, terapi pada PGK biasanya mengarah pada kondisi asimtomatis yang hanya terdeteksi
dengan uji laboratorium (Turner, 2012).

Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.
The goal of therapy is to delay the progression of CKD, thereby minimizing the
development or severity of associated complications including cardiovascular disease.
Nonpharmacologic and pharmacologic interventions are available to slow the rate of CKD
progression and they may also decrease the incidence and prevalence of ESRD.
a. PGK dengan diabetes
1) Hiperlipidemia
Hiperlipidemia dapat diatasi secara nonfarmakologi dengan membatasi asupan
kolesterol, menurunkan berat badan dan berolahraga. Sedangkan untuk terapi
farmakologi dapat digunakan lipid-lowering agents.
2) Membatasi diet protein
Asupan protein pada penderita diabetes perlu dibatasi hingga 0,6 g/kg/hari.
3) Mengatasi proteinuria
Diperlukan evaluasi atau pengamatan ekskresi albumin dalam urin sekali dalam
setahun. Apabila terdapat mikroalbuminuria (30‒300 mg/hari) atau albuminuria
(>300 mg/hari) maka perlu inisiasi pemberian ACEI (atau ARB), titrasi dosis hingga
dicapai efek maksimal dan terus monitor kadar serum kalium, kreatinin, dan ekskresi
albumin dalam urin.
4) Mengatasi hipertensi
Pada pasien diabetes, tekanan darah perlu diturunkan hingga ≤130/80 mmHg melalui
modifikasi gaya hidup seperti yang disebutkan dalam JNC VII, the seventh report of
the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure.
5) Kontrol metabolit rendah
Diperlukan kontrol glikemia secara intensif, dengan target gula darah dalam keadaan
puasa 70‒120 mg/dL dengan cara pemberian injeksi insulin multiple dose harian atau
dengan pompa insulin yang diberi melalui infus subkutan. Untuk meminimalisir
hipoglikemia maka perlu monitor gula darah hingga 4 kali sehari.
b. PGK nondiabetes
1) Manajemen nutrisi (diet protein)
(a) Pada individu dengan serum kreatinin <1,2 mg/dL dan GFR >55 mL/menit, maka
asupan protein yang dikonsumsi dilanjutkan sebagaimana biasanya.
(b) Pada individu dengan serum kreatinin 1,2‒2,5 mg/dL dan GFR 25‒55 mL/menit,
apabila GFR/serum kreatinin stabil, maka asupan protein yang dikonsumsi
dilanjutkan sebagaimana biasanya. Sedangkan apabila terjadi peningkatan serum
kreatinin dan/atau penurunan GFR maka asupan protein perlu dibatasi menjadi
0,8 g/kg/hari.
(c) Pada individu dengan serum kreatinin >2,5 mg/dL dan GFR 13‒24 mL/menit,
maka asupan protein perlu dibatasi menjadi 0,6 g/kg/hari.
2) Kontrol tekanan darah
 Target tekanan darah pada individu yang tidak menderita diabetes adalah <130/80
mmHg. Target tekanan darah dapat dicapai melalui modifikasi gaya hidup seperti
yang disebutkan dalam JNC VII, the seventh report of the Joint National Committee
on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.,
maupun terapi farmakologi seperti β‒blocker, klonidin, minoxidil, maupun α‒blocker.
Apabila terjadi retensi cairan (klirens kreatinin <30 mL/menit) maka diberi loop
diuretic atau kombinasi loop diuretic dengan thiazid atau metolazon.

ANEMIA

Definisi
Thomas R, Kanso A, Sedor JR. Chronic kidney disease and its complications. Prim Care.
2008;35:329-44, vii.
Anemia is defined as a reduction in one or more of the major red blood cell measurements;
hemoglobin concentration, hematocrit, or red blood cell count. The World Health Organization
defines anemia as a hemoglobin level less than 13 g/dL in men and post-menopausal women,
and less than 12 g/dL in pre-menopausal women6. The NKF defines anemia as a hemoglobin
of less than 13.5 g/dL in men and less than 12.0 g/dL in women 7.
Anemia didefinisikan sebagai penurunan dari satu atau lebih pengukuran utama sel darah merah, yaitu
kadar hemoglobin, hematokrit, atau jumlah sel darah merah (Thomas et al, 2008).

Koda-Kimble&Young’s Applied Therapeutics, 10th Ed, Chapter 31: Chronic Kidney Disease
(Darius L. Mason and Magdalene M. Assimon, 2013)
Brian K. Alldredge, Robin L. Corelli, Michael E. Ernst, B. Joseph Guglielmo, Pamala A. Jacobson, Wayne A. Kradjan, Bradley
R. Williams
Anemia is a reduction in red blood cell (RBC) mass. It often is described as a decrease in the number of
RBCs per microliter (μL) or as a decrease in the hemoglobin (Hgb) concentration in blood to a level below the
normal physiologic requirement for adequate tissue oxygenation. The term anemia is not a diagnosis, but rather an
objective sign of a disease.
Anemia adalah penurunan massa dari sel darah merah. Anemia dikarakterisasikan dengan penurunan
jumalah sel darah merah per mikroliter (μL) atau penurunan kadar hemoglobin dalam darah hingga dibawah
kebutuhan normal fisiologis untuk memenuhi oksigenasi jaringan. Anemia bukan merupakan suatu diagnosis, tapi
merupakan tanda dari suatu penyakit.

Anemia adalah penurunan massa dari sel darah merah, sehingga anemia didefinisikan
sebagai penurunan dari satu atau lebih pengukuran utama sel darah merah, yaitu kadar
hemoglobin, hematokrit, maupun jumlah sel darah merah. Anemia dikarakterisasikan dengan
penurunan jumlah sel darah merah per mikroliter (μL) atau penurunan kadar hemoglobin dalam
darah hingga dibawah kebutuhan normal fisiologis untuk memenuhi oksigenasi jaringan.
Anemia bukan merupakan suatu diagnosis, tapi merupakan tanda dari suatu penyakit. Anemia
pada PGK menurut KDIGO adalah apabila kadar Hb <13.0 g/dl pada pria dan <12.0 g/dl pada
wanita baik orang deawasa maupun anak-anak >15 tahun. Sedangkan untuk anak-anak penderita
PGK, apabila kadar Hb <11.0 g/dl pada anak usia 0.5–5 tahun, <11.5 g/dl pada anak usia 5–12
tahun, dan <12.0 g/dl pada anak usia 12–15 tahun (Alldredge, 2013; Thomas et al, 2008; KDIGO,
2012)

a. Diagnose anemia in adults and children >15 years with CKD when the Hb concentration
is <13.0 g/dl (<130 g/l) in males and <12.0 g/dl (<120 g/l) in females. (Not Graded)
 b. Diagnose anemia in children with CKD if Hb concentration is <11.0 g/dl (<110 g/l) in
children 0.5–5 years,<11.5 g/dl (115 g/l) in children 5–12 years, and <12.0 g/dl (120 g/l)
in children 12–15 years. (Not Graded)

Diagnosis
AJKD, 2006
Although erythropoietin deficiency is common among patients with anemia and CKD, other potential
causes and potentially contributing disorders should be identified or excluded. The recommended laboratory
evaluation provides information regarding the degree and cause of anemia, activity of the erythroid and
nonerythroid marrow, and assessment of iron stores and iron availability for erythropoiesis.
In the opinion of the Work Group, initial assessment of anemia should include the following tests:
 A complete blood count (CBC) including—in addition to the Hb concentration—red blood cell indices
(mean corpuscular hemoglobin [MCH], mean corpuscular volume [MCV], mean corpuscular
hemoglobin concentration [MCHC]), white blood cell count, and differential and platelet count.
 Absolute reticulocyte count
 Serum ferritin to assess iron stores.
 Serum TSAT or content of Hb in reticulocytes (CHr) to assess adequacy of iron for erythropoiesis.

Diagnosis Anemia pada PGK dilakukan melalui beberapa prosedur berikut:

a. Complete Blood Count (CBC)
Meliputi konsentrasi Hb, indeks sel darah merah (mean corpuscular hemoglobin [MCH],
mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration
[MCHC]), white blood cell count, serta differential and platelet count.Pemeriksaan ini
dilakukan untuk mengetahui keparhan anemia dan kecukupan fungsi sumsum tulang.
b. Jumlah retikulosit absolut
Digunakan untuk menentukan efektifitas proliferasi eritropoietin.
c. Serum ferritin
Digunakan untuk mengevaluasi penyimpanan besi dalam tubuh. Kadar serum ferritin ≤30
ng/ml (≤30 mg/l) mengindikasikan defisiensi besi yang berat dan dapat diprediksi tidak
adanya cadangan besi pada sumsum tulang.
d. Serum TSAT (saturasi transferrin)
Digunakan untuk mengukur ketersediaan besi untuk eritropoiesis. TSAT adalah
parameter yang sangat banyak digunakan untuk mengevaluasi kecukupan suplai besi
untuk eritropoiesis. TSAT juga dipengaruhi oleh status gizi dan inflamasi.
e. Serum vitamin B12 and folate levels
Defisiensi asam folat dan vitamin B12 jarang terjadi namun merupakan penyebab penting
pada anemia yang dapat diobati, terutama yang berkaitan dengan sel darah merah
makrositosis. Evaluasi asam folat dan vitamin B12 umumnya dipertimbangkan sebagai
komponen standar dalam evaluasi anemia, khususnya apabila terdapat makrositosis.

(AJKD, 2006)

KDIGO, 2012
Diagnosis of anemia
c. Diagnose anemia in adults and children >15 years with CKD when the Hb concentration
is <13.0 g/dl (<130 g/l) in males and <12.0 g/dl (<120 g/l) in females. (Not Graded)
 d. Diagnose anemia in children with CKD if Hb concentration is <11.0 g/dl (<110 g/l) in
children 0.5–5 years,<11.5 g/dl (115 g/l) in children 5–12 years, and <12.0 g/dl (120 g/l)
in children 12–15 years. (Not Graded)

Investigation of anemia
In patients with CKD and anemia (regardless of age and CKD stage), include the
following tests in initial evaluation of the anemia (Not Graded):
 Complete blood count (CBC), which should include Hb concentration, red cell indices, white
blood cell count and differential, and platelet count
 Absolute reticulocyte count
 Serum ferritin level
 Serum transferrin saturation (TSAT)
 Serum vitamin B12 and folate levels

Mikhail, A., Shrivastava, R., Richardson, D., 2012, Clinical Practice Guidelines Anaemia of
CKD, UK Renal Association, 5th Edition. Tersedia online www.renal.org/guidelines.

TSAT is the most widely used test to assess the adequacy of iron supply for
erythropoiesis but is limited by high day to day variations. TSAT is also influenced by nutritional
status and inflammation.
TSAT adalah parameter yang sangat banyak digunakan untuk mengevaluasi kecukupan
suplai besi untuk eritropoiesis. TSAT juga dipengaruhi oleh status gizi dan inflamasi.

Folate and vitamin B12 deficiency are uncommon but important causes of treatable
anemia, typically associated with macrocytic red blood cell (RBC) indices. Assessment of folate
and vitamin B12 levels are generally considered standard components of anemia evaluation,
especially in the presence of macrocytosis.
Defisiensi asam folat dan vitamin B12 jarang terjadi namun merupakan penyebab penting
pada anemia yang dapat diobati, terutama yang berkaitan dengan sel darah merah makrositosis.
Evaluasi asam folat dan vitamin B12 umumnya dipertimbangkan sebagai komponen standar
dalam evaluasi anemia, khususnya apabila terdapat makrositosis.

Etiologi

Nurko, S., 2006, Anemia in chronic kidney disease: Causes, diagnosis, treatment, CLEVELAND
CLINIC JOURNAL OF MEDICINE, Volume 73(3):289-97
Factors likely contributing to anemia in chronic kidney disease include blood loss, shortened red
cell life span, vitamin deficiencies, the “uremic milieu,” erythropoietin (EPO) deficiency, iron deficiency,
and inflammation. Unfortunately, we know little about the relative contributions of the different factors
and conditions in the early stages of chronic kidney disease.
Faktor yang kemungkinan besar berkontribusi dalam anemia pada PGK di antaranya yaitu
kehilangan darah, umur sel darah merah semakin pendek, defisiensi vitamin, uremic milieu, defisiensi
EPO, defisiensi besi, dan inflamasi (Nurko, 2006).
NIDDK http://www.niddk.nih.gov/health-information/health-topics/kidney-disease/anemia-in-kidney-
disease-and-dialysis/Pages/facts.aspx
NIH Publication No. 14–4619 May 2014
When kidneys are diseased or damaged, they do not make enough EPO. As a result, the bone
marrow makes fewer red blood cells, causing anemia. When blood has fewer red blood cells, it deprives
the body of the oxygen it needs. Other common causes of anemia in people with kidney disease include
blood loss from hemodialysis and low levels of the following nutrients found in food: iron, vitamin B12,
folic acid. These nutrients are necessary for red blood cells to make hemoglobin, the main oxygen-
carrying protein in the red blood cells.
Kerusakan pada ginjal menyebabkan ginjal tidak dapat memenuhi kecukupan produksi EPO.
Akibatnya, sumsum tulang akan memproduksi sel darah merah dalam jumlah kecil pula yang
menyebabkan terjadinya anemia. Ketika di dalam darah hanya terdapat sejumlah kecil sel darah merah,
maka kebutuhan oksigen tubuh tidak tercukupi. Penyebab lain yang banyak terjadi adalah kehilangan
darah akibat hemodialisis dan rendahnya kadar nutrien seperti besi, vitamin B12, dan asam folat. Nutrien-
nutrien ini sangat dibutuhkan oleh sel darah merah untuk membentuk hemoglobin sebagai protein utama
yang membawa oksigen di dalam sel darah merah (NIH, 2014).

Klasifikasi
Walker, R., Edwards, C., 2012, Clinical Pharmacy and Therapeutics 5th ed, 247-252, Churchill Livingstone.,
Philadelphia.

Di dalam Clinical Pharmacy and Therapeutics 5th Edition anemia diklasifikasikan

berdasarkan ukuran dan warna dari sel darah merah:
a. Hipokromik mikrositik
Yaitu pada anemia defisiensi besi, sideroblastik, dan anemia penyakit kronis.
b. Normokromik makrositik
Yaitu pada defisiensi folat, dan defisiensi vitamin B12.
c. Polikromatofilik makrositik
 Contohnya yang terjadi pada hemolisis.
(Walker, 2012)

Patofisiologi
Lankhorst, C.E., Wish, J.B., 2010, Anemia in Renal Disease: Diagnosis and Management, Blood
Reviews., 24, 39–47.
The cause of anemia in patients with CKD is multifactorial. The most well-known cause
is inadequate erythropoietin (EPO) production, which is often compounded by iron deficiency.
As renal failure progresses, the contribution of EPO deficiency to anemia increases. The role of
decreased renal EPO synthesis in CKD associated anemia is supported by the severe anemia seen
in anephric patients.6 However, the mechanisms impairing renal EPO production are not well
understood. The production capacity of EPO remains significant even in end stage renal disease
(ESRD) as these patients have been shown to respond with increased EPO synthesis in the
setting of an additional hypoxic stimulus.7 This suggests that the decrease in EPO production in
CKD is, in part, a physiologic response to achieve a chronically reduced Hb concentration.
Red blood cells also have a decreased life span in patients with CKD. While the normal
life span of an RBC is about 120 days, it has been demonstrated that this is shortened to only 60–
90 days in CKD patients. In patients without CKD, the bone marrow has significant capacity to
increase red blood cell production and to correct for the shortened life span, but this response is
blunted in patients with CKD by the relative EPO deficiency.

Anemia pada pasien PGK disebabkan oleh banyak faktor (multifaktor). Penyebab yang
paling sering terjadi adalah tidak tercukupinya produksi EPO, dan seringkali diperparah dengan
defisiensi besi. Selama gagal ginjal terus berkembang, kontribusi dari defisiensi EPO terhadap
anemia terus meningkat. Penurunan produksi EPO pada PGK merupakan respon fisiologis untuk
mencapai kadar Hb yang berkurang secara kronis.
Umur sel darah merah pada pasien PGK mengalami penurunan. Sel darah merah normal
memiliki umur 120 hari, sedangkan pada pasien PGK hanya berumur 60–90 hari. Pada pasien
yang tidak menderita PGK, sumsum tulang memiliki kapasitas yang signifikan untuk
meningkatkan produksi sel darah merah dan untuk memperbaiki umur hidup yang memendek.
Namun, pada pasien PGK fungsi ini tidak berjalan.

Manifestasi klinis
Lankhorst, C.E., Wish, J.B., 2010, Anemia in Renal Disease: Diagnosis and Management, Blood
Reviews., 24, 39–47.

The history should include any prior diagnosis of anemia and the presence of symptoms related to anemia, such as fatigue, exercise
intolerance, dyspnea, and changes in mentation.

Anemia has a profound impact on patients with CKD. The most common symptoms are fatigue (both with activity and at rest), loss
of libido, dizziness, shortness of breath, and decreased sense of well being. These symptoms generally occur when the Hb is less
than 10 g/dL and become more severe as Hb levels decrease further. Other more dangerous adverse outcomes include
cardiovascular disease with left ventricular hypertrophy (LVH) and congestive heart failure. These may occur when the patient is
otherwise asymptomatic and contribute to the excess cardiovascular morbidity and mortality rate observed among patients with
CKD. In patients who already have coronary artery disease, decreased myocardial oxygen delivery may lead to worsening
anginal symptoms. Decreased peripheral oxygen delivery due to anemia also leads to peripheral vasodilation, increased
sympathetic nervous system activity, increased heart rate and stroke volume and, ultimately, LVH
Walker, R., Edwards, C., 2012, Clinical Pharmacy and Therapeutics 5th ed, 247-252, Churchill Livingstone.,
Philadelphia.
Dipiro, J.T., Talbert, R.L., Yee, G.C., Matzke, G.R., Wells, B.G., Posey, L.M., 2008, Pharmacotherapy: A
Pathophysiologic Approach Seventh Edition, TheMcGraw-Hill Companies, Inc., USA.

Gejala yang terjadi pada anemia yaitu menurunnya toleransi terhadap latihan fisik, mudah
lelah, pusing, iritabilitas, kelemahan, palpitasi, vertigo, sesak napas, nyeri dada, serta gejala
neurologis pada defisiensi vitamin B12. Sedangkan tanda-tandanya adalah takikardi, pucat
(terutama pada konjungtiva), ketajaman mental menurun, meningkatnya intensitas murmur katup
jantung, hilangnya kepekaan terhadap getaran dan abnormalitas cara berjalan pada defisiensi
vitamin B12 (Dipiro, 2008).

Terapi
Nurko, S., 2006, Anemia in chronic kidney disease: Causes, diagnosis, treatment, CLEVELAND
CLINIC JOURNAL OF MEDICINE, Volume 73(3):289-97

Epoietin alfa and darbepoetin alfa

In the United States, the two agents available for treating anemia in chronic kidney disease are
recombinant epoietin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In my opinion, both are
effective and safe. Patients on dialysis can receive them intravenously; those not on dialysis can receive
them subcutaneously. According to the manufacturers, these products differ in pharmacodynamic and
pharmacokinetic properties, affinity for the EPO receptor,39 and half-life.38,40 These different
characteristics could be used to apply different dosing regimens.
Iron supplementation
 Patients should receive iron supplementation while on ESA therapy, because pharmacologically
induced erythropoiesis is limited by the iron supply,17 as shown by lower ESA requirements after iron
supplementation. In addition, as patients make more red blood cells they use up more iron, which can lead
to iron deficiency. Serum ferritin and percent transferrin saturation have been shown to drop after 1 week
of ESA therapy in both healthy people and iron-replete patients with chronic kidney disease on dialysis.41
Because patients with kidney disease have altered iron metabolism, their serum ferritin levels and percent
transferrin saturation should be maintained at levels higher than in the normal population.16
Recommended maintenance levels for serum ferritin are at least 200 ng/mL; for percent transferrin
saturation at least 20%.2 Most patients with chronic kidney disease need parenteral iron supplementation
to achieve the recommended iron levels.2 Possible explanations for the failure of oral iron
supplementation include a diminished ability of the oral mucosa to absorb iron and poor patient
compliance (due to difficult dosing, side effects, and cost).

NIDDK http://www.niddk.nih.gov/health-information/health-topics/kidney-disease/anemia-in-kidney-
disease-and-dialysis/Pages/facts.aspx
NIH Publication No. 14–4619 May 2014
Depending on the cause, a health care provider treats anemia with one or more of the following
treatments:

Iron
The first step in treating anemia is raising low iron levels. Iron pills may help improve iron and
hemoglobin levels. However, for patients on hemodialysis, many studies show pills do not work as well
2
as iron given intravenously.

Erythropoietin
If blood tests indicate kidney disease as the most likely cause of anemia, treatment can include injections
of a genetically engineered form of EPO. A health care provider, often a nurse, injects the patient with
EPO subcutaneously, or under the skin, as needed. Some patients learn how to inject the EPO themselves.
Patients on hemodialysis may receive EPO intravenously during hemodialysis.
Studies have shown the use of EPO increases the chance of cardiovascular events, such as heart attack
and stroke, in people with CKD. The health care provider will carefully review the medical history of
the patient and determine if EPO is the best treatment for the patient’s anemia. Experts recommend
using the lowest dose of EPO that will reduce the need for red blood cell transfusions. Additionally,
health care providers should consider the use of EPO only when a patient’s hemoglobin level is below
10 g/dL. Health care providers should not use EPO to maintain a patient’s hemoglobin level above
2
11.5 g/dL. Patients who receive EPO should have regular blood tests to monitor their hemoglobin so
2
the health care provider can adjust the EPO dose when the level is too high or too low. Health care
providers should discuss the benefits and risks of EPO with their patients.
Many people with kidney disease need iron supplements and EPO to raise their red blood cell count to a
level that will reduce the need for red blood cell transfusions. In some people, iron supplements and EPO
will improve the symptoms of anemia.

Red Blood Cell Transfusions

If a patient’s hemoglobin falls too low, a health care provider may prescribe a red blood cell transfusion.
Transfusing red blood cells into the patient’s vein raises the percentage of the patient’s blood that
consists of red blood cells, increasing the amount of oxygen available to the body.

Vitamin B12 and Folic Acid Supplements

A health care provider may suggest vitamin B12 and folic acid supplements for some people with CKD
and anemia. Using vitamin supplements can treat low levels of vitamin B12 or folic acid and help treat
anemia. To help ensure coordinated and safe care, people should discuss their use of complementary
and alternative medical practices, including their use of dietary supplements, with their health care
provider.

KDIGO, 2012

ESA
The development of rHuEPO was aimed at replacing
the insufficient endogenous erythropoietin (EPO) production
related to CKD progression. The immediate
benefit of rHuEPO in CKD patients with severe
anemia and anemia-related signs and symptoms was clear. In
addition, the reduction in the need for regular blood
transfusions was another major benefit, resulting in
less frequent transmission of blood-borne viral diseases,
such as hepatitis B and C, less allosensitization, predisposing
to prolonged wait times or failure to receive a kidney
transplant, transplant rejection, and less transfusional
hemosiderosis.

After diagnosing anemia in a patient with CKD all correctable

causes should be treated before considering ESA therapy. There are several reasons why correctable causes other
than erythropoietin deficiency should be actively sought. As
in any disease state, pathological conditions which can be
cured should be corrected first. As examples, ESA treatment
is unlikely to be fully effective in raising Hb concentrations
until either severe systemic bacterial infections or severe
secondary hyperparathyroidism are appropriately treated

RCT

1. When rapid correction of anemia is required to stabilize the patient’s condition (e.g., acute hemorrhage, unstable
myocardial ischemia)
2. When rapid pre-operative Hb correction is required
3. When symptoms and signs related to anemia are present in patients in whom ESA therapy is ineffective (e.g., bone
marrow failure, hemoglobinopathies, ESA resistance)
4. When symptoms and signs related to anemia are present in patients in whom the risks of ESA therapy may outweigh the
benefits

Vitamin B12 dan asam folat

The goals of treatment for vitamin B12 deficiency include reversal of
hematologic manifestations, replacement of body stores, and prevention
or resolution of neurologic manifestations.
Therapy for folic acid deficiency consists of administration of exogenous
folic acid to induce hematologic remission, replace body
stores, and resolve signs and symptoms.
Tujuan dari terapi defisiensi Vitamin B12 adalah untuk memperbaiki gejala hematologi,
mengganti cadangan vitamin B12 dalam tubuh, dan mencegah atau mengatasi gejala neurologis.
Pada terapi defisiensi asam folat juga tidak jauh berbeda, tujuannya adalah untuk menginduksi
remisi hematologi, mengganti cadangan asam folat dalam tubuh,serta memperbaiki gejala dan
tanda (Dipiro, 2008).
Terapi anemia diberikan berdasarkan penyebabnya:

a. Besi
Langkah pertama dalam mengoreksi anemia adalah menaikkan kadar besi yang rendah.
Perbaikan defisiensi besi dengan suplemen besi oral maupun intravena dapat menurunkan
keparahan anemia pada pasien PGK. Defisiensi besi yang tidak teratasi merupakan penyebab
penting pada hiporesponsif terhadap terapi ESA (Erythropoietin Stimulating Agents).
Pemberian suplemen besi tepat apabila cadangan besi pada sumsung tulang habis (NIH, 2014;
KDIGO, 2012).
b. Eritropoietin
Setelah anemia terdiagnosis pada pasien PGK, seluruh penyebab anemia yang dapat
dikoreksi harus diobati terlebih dahulu. Seperti pada penyakit tertentu, kondisi patologis yang
dapat disembuhkan harus ditangani terlebih dahulu. Sebagai contoh, terapi ESA tidak akan
efektif meningkatkan kadar Hb sebelum infeksi bakteri sistemik atau hiperparatiroidisme
sekunder yang berat belum tertangani. Penggunaan ESA pada terapi anemia menimbulkan
banyak manfaat, salah satu manfaat yang cukup besar adalah berkurangnya kebutuhan
transfusi darah sehingga dapat mengurangi risiko terkena penyakit yang ditularkan melalui
darah (KDIGO, 2012).
c. Transfusi darah
Terdapat beberapa indikasi digunakannya transfusi darah pada koreksi anemia, yaitu:
1) Apabila koreksi anemia secara cepat dibutuhkan untuk menstabilkan kondisi pasien
(contohnya pada hemoragi akut, iskemia miokard yang tidak stabil),
2) Apabila dibutuhkan koreksi Hb praoperasi secara cepat,
3) Apabila terdapat gejala dan tanda anemia pada pasien dengan terapi ESA yang tidak
efektif (contohnya pada kegagalan sumsum tulang, hemoglobinopati, dan resistensi
terhadap ESA)
4) Apabila terdapat gejala dan tanda anemia pada pasien yang mendapat terapi ESA dimana
risikonya melebihi manfaat.
(KDIGO, 2012)
d. Suplemen vitamin B12 dan asam folat
Tujuan dari terapi defisiensi Vitamin B12 adalah untuk memperbaiki gejala hematologi,
mengganti cadangan vitamin B12 dalam tubuh, dan mencegah atau mengatasi gejala
neurologis. Pada terapi defisiensi asam folat juga tidak jauh berbeda, tujuannya adalah untuk
menginduksi remisi hematologi, mengganti cadangan asam folat dalam tubuh,serta
memperbaiki gejala dan tanda (Dipiro, 2008).
Guideline III.1: Treatment of anaemia with erythropoiesis-stimulating agents
I. Erythropoiesis-stimulating agents (ESAs) should be given to all patients with chronic kidney
disease (CKD) with haemoglobin (Hb) levels consistently (i.e. measured twice at least 2 weeks
apart) below 11 g/dl [haematocrit (Hct) <33%], where all other causes of anaemia have been
excluded (see Guideline I.2). This applies equally to:
II. The recommended route of administration is dependent on the patient group being treated and
the type of ESA used.
III. The frequency of administration of ESA is influenced by several factors including dose, route,
treatment phase, type of ESA used and patient group being treated.
IV. The starting dose of ESA to correct renal anaemia may depend on several factors such as the
degree and underlying cause of the anaemia.
V. ESA dose should be titrated in response to Hb level.
VI. Blood pressure should be monitored closely in all patients with CKD, particularly during
initiation of ESA therapy until the target Hb is reached. Target blood pressure should be the
same as for CKD patients who are not receiving ESA therapy. One or more of the following
strategies may be needed to control an increase in blood pressure related to ESA therapy:
VII. The function of the vascular access should be monitored in all HD patients to prevent
thrombosis. However, treatment with ESAs does not necessitate increased surveillance of the
vascular access. Some evidence indicates that the risk of thrombosis in patients bearing
polytetrafluoroethylene (PTFE) grafts is increased when Hb levels are normalized. (Evidence
level B )
VIII. The dialysis schedule should not be altered during ESA therapy as the incidence of
potential adverse events such as seizures and headache, loss of dialyser clearance and
hyperkalaemia does not significantly increase. There is also no increased need for heparin
anticoagulation during HD in patients receiving ESA therapy. (Evidence level B)

Guideline III.2: Treatment of anaemia with iron

I. All chronic kidney disease (CKD) patients with renal anaemia undergoing treatment with an
erythropoiesis-stimulating agent (ESA) should be given supplementary iron to maintain (or reach)
the targets set in Guideline II.1, regardless of dialysis status. Patients undergoing haemodialysis
(HD) usually have greater iron requirements than those not undergoing HD. (Evidence level B)
II. i.v. administration is the optimum route for the delivery of iron to patients with CKD, as oral
iron is poorly absorbed in uraemic individuals. (Evidence level A)
III. No definitive recommendation can be made regarding the optimum frequency for the
administration of iron therapy. (Evidence level C)
IV. The optimal i.v. iron dose is 25–150 mg/week for the first 6 months of ESA therapy.
(Evidence level B )
V. Iron status should be assessed regularly in CKD patients.
VI. When selecting a source of supplementary iron, the tolerability profile of different sources of
iron must be considered.

Guideline III.4: Treatment of anaemia with vitamins and adjuvant therapies other than iron
Definition
Adjuvant therapies are defined here as forms of therapy which may help to optimize a patient’s
response to treatment with erythropoiesis-stimulating agents (ESAs).
I.With the exceptions of iron and pharmacological doses of certain vitamins, the benefits of
adjuvant therapies are not well established and are not widely recommended in routine clinical
practice. However, some forms of adjuvant therapy may benefit individual patients. (Evidence
level B )
II. In patients with CKD, routine, low-level vitamin supplementation does not increase
haemoglobin (Hb) levels. However, therapeutic doses of specific vitamins may improve control
of anaemia, when combined with ESA therapy.
III. A subpopulation of CKD patients (those on maintenance HD) may benefit from carnitine
supplementation, but this form of adjuvant therapy is not recommended for general or routine
use. (Evidence level B)
IV. Androgen therapy may be used to stimulate erythropoiesis in some patients.
V. Reduced glutathione and other antioxidant treatments may reduce resistance to erythropoetic
protein therapy through the reduction of oxidative stress. (Evidence level B )

Guideline III.6: Treatment of anaemia by transfusion

I. Red blood cell transfusions should be avoided, if at all possible, in patients with chronic
kidney disease (CKD), especially those awaiting kidney transplantation. (Evidence level B)
II. Transfusions should not be given unless patients have one or more of the following:
- symptomatic anaemia (fatigue, angina, dyspnoea) and/or associated risk factors (diabetes,
heart failure, coronary artery disease, arteriopathy, old age)
- acute worsening of anaemia due to blood loss (haemorrhage or surgery) or haemolysis
- severe resistance to, or hyporesponsiveness to, ESA therapy, e.g. due to the presence of a
haematological disease or severe inflammatory systemic disease. (Evidence level C)