Chronic kidney disease is an increasing health and economical problem in our world.

Obesity
and diabetes mellitus, the two most common cause of CKD, are becoming epidemic in our
societies. (Monika Göőz, 2012)
Penyakit ginjal kronis merupakan masalah kesehatan yang terus meningkat di seluruh dunia dan
menimbulkan masalah perekonomian. Obesitas dan diabetes mellitus merupakan dua penyebab
utama terjadinya PGK dan sudah mewabah di masyarakat.

Kidney disease is an increasing, yet under recognized, contributor to the global burden of disease.
Chronic kidney disease (CKD) was ranked 18th in the global causes of death in a report
published in 2012, having risen from 27th in 1990.(Lozano, 2012) During this period, the docu-
mented number of deaths from CKD has risen by 82%,(Jha, 2013) and this dramatic rise is
among the highest observed for all known reported diseases, following only HIV and AIDS, and
diabetes. (Jha, 2013)
Meningkatnya penyakit ginjal menjadi kontributor dalam beban penyakit secara global. Penyakit
ginjal kronis menduduki peringkat ke-18 sebagai penyakit yang banyak menyebabkan mortalitas
di dunia pada tahun 2012, dimana sebelumnya pada tahun 1990 PGK berada di peringkat ke-
27.(Lozano, 2012)

Lozano R, Naghavi M, Foreman K, et al. Global and regionalmortality from 235 causes of death
for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease
Study 2010. Lancet 2013; 380: 2095–128.

Prevalensi gagal ginjal kronis berdasarkan pernah didiagnosis dokter di Daerah Istimewa
Yogyakarta sebesar 0,3 persen ( Kementerian Kesehatan RI, Pokok Pokok Hasil Riskesdas
Provinsi Daerah Istimewa Yogyakarta 2013 Lembaga Penerbitan Badan Litbangkes,)

Chronic kidney disease (CKD) affects approximately 26 million adults in the United Sates and
millions of others are at risk. CKD is associated with significant morbidity and mortality, and
these patients face many other medical problems related to CKD. One of the major medical
issues facing this population is anemia, which often develops early in the course of CKD and
contributes to poor quality of life. It has been shown to be strongly predictive of adverse effects,
including complications and death from cardiovascular causes. (Lankhorst, 2010)
PGK dialami setidaknya 26 juta orang dewasa di US dan jutaan orang lainnya berisiko
mengalami PGK. PGK diasosiasikan dengan morbiditas dan mortalitas yang signifikan, pasien
dihadapkan dengan berbagai permasalahan kesehatan yang berkaitan dengan PGK, salah satunya
adalah anemia. Anemia mulai berkembang pada awal perjalanan penyakit dan menjadi penyebab
rendahnya kualitas hidup pada pasien PGK.

Because the kidneys secrete 90% of the endogenous hormone erythropoietin, an endogenous
hormone necessary for erythropoiesis, declining kidney function can lead to erythropoietin
deficiency and anemia. The prevalence of anemia at specific stages of CKD is difficult to
ascertain because of limited available data and use of various definitions.1 Estimates of anemia
(hemoglobin of less than 12 g/dL) prevalence in patients with a GFR greater than 80 mL/min per
1.73 m2 are between 1% and 30%.104 The true prevalence rate estimation is unclear as other
factors, such as ethnicity, age, and gender, can also contribute to anemia. The prevalence of a
hemoglobin less than 13 g/dL increases considerably in stages 3 to 5 CKD.1 Anemia can lead to
symptoms of fatigue, weakness, and shortness of breath. However, mild anemia, especially when
present for a prolonged time period, can be asymptomatic. The NKF K/DOQI guidelines
recommend evaluating hemoglobin levels in all patients with CKD, noting the increase in anemia
prevalence beginning with stage 3.105 The treatment of anemia can improve or resolve
symptoms and may help to stabilize kidney function.106 Chapter 47 discusses the management
of anemia in CKD. (Dipiro, 7th ed)

ANEMIA OF CHRONIC KIDNEY DISEASE

The primary cause of anemia in CKD patients is a decrease in production of the hormone
erythropoietin by the progenitor cells of the kidney, where 90% of production typically occurs.
Plasma concentrations of erythropoietin increase exponentially in individuals with normal kidney
function as hemoglobin/hematocrit decline (i.e., in response to decreased oxygenation). In
contrast, there is no correlation between the degree of anemia and erythropoietin concentrations
in anemic ESRD patients. The result is a normochromic, normocytic anemia, unless the
individual has concomitant iron deficiency, which can result in a microcytic anemia, or a folate
or B12 deficiency, which can result in a macrocytic anemia. Additional factors contributing to
the development of anemia of CKD are the decreased red cell life span in the presence of uremia
(from the normal of 120 days to approximately 60 days in ESRD), iron deficiency, blood loss
from regular laboratory testing, and blood loss with hemodialysis for patients requiring this
modality of renal replacement therapy. Iron deficiency is the primary cause of resistance to
therapy with erythropoieticstimulating agents (ESAs; i.e., epoetin alfa or darbepoetin alfa).
(Dipiro, 7th ed)

The anemia of CKD is characterized by normochromic normocytic red blood cells. Although
several factors (eg, decreased red cell production or survival, blood loss) may contribute to the
development of anemia in patients with CKD, the primary cause is believed to be a deficienct in
erythropoietin production by the failing kidneys (Abu-Alfa, 2003).
Anemia pada PGK ditandai dengan sel darah merah normokromik normositik. Beberapa
faktor seperti berkurangnya produksi sel darah merah, rendahnya kelangsungan hidup sel darah
merah, dan hilangnya darah berkontribusi dalam perkembangan anemia pada pasien PGK.
Namun, defisiensi produksi eritropoietin diyakini sebagai penyebab utama anemia pada PGK
(Abu-Alfa, 2003).
MLA Abu-Alfa, Ali K. "CKD series: Evaluation and treatment of anemia in chronic
kidney disease." Hospital Physician 39.7 (2003): 31-38.

See: Anemia in renal disease

WHO, 2008, Worldwide prevalence of anaemia 1993–2005 : WHO global database on anaemia,
WHO Press, Switzerland.
Anemia is defined by the World Health Organization as a Hb concentration less than 13.0 g/dL
in adult males and nonmenstruating females and less than 12.0 g/dL in menstruating females.3
(WHO,2009, Database of anemia. Worldwide prevalence of anaemia 1993–2005.
<www.who.int/vmnis>) Anemia is a common problem in patients with CKD, and its incidence
increases as glomerular filtration rate declines. Population studies such as the National Health
and Nutrition Examination Survey (NHANES) by the National Institutes of Health and the
Prevalence of Anemia in Early Renal Insufficiency (PAERI) study suggest that the incidence of
anemia is less than 10% in CKD stages 1 and 2, 20–40% in CKD stage 3, 50–60% in CKD stage
4 and more than 70% in CKD stage 5.4,5
Anemia menurut WHO adalah apabila kadar Hb kurang dari 13.0 g/dL pada pria dewasa (usia
≥15.00 tahun) dan kurang dari 12.0 g/dL pada wanita dewasa (usia ≥15.00 tahun) yang tidak
dalam keadaan hamil. Anemia merupakan komplikasi yang sering terjadi pada pasien PGK, dan
insidensinya meningkat seiring dengan menurunnya Glomerular Filtration Rate (GFR).
Berdasarkan penelitian dari National Institutes yaitu National Health and Nutrition Examination
Survey (NHANES), dijelaskan bahwa insidensi anemia pada pasien PGK stadium 1 dan 2 adalah
kurang dari 10%, pada stadium 3 sebesar 20-40%, pada stadium 4 sebesar 50-60%, dan pada
stadium 5 lebih dari 70% (Lankhorst, 2010)

Menurut KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease, anemia
pada PGK dapat diterapi dengan preparat Fe, ESA dan adjuvan lainnya (selain Fe), dan transfusi
sel darah merah.

Locatelli, F., Aljama, P., Bárány, P., et al, 2004, Revised European best practice guidelines for
the management of anaemia in patients with chronic renal failure, Nephrology Dialysis
Transplantation 19, Suppl 2, ii16–ii31.

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:

Terapi dengan ESA

ESA harus diberikan pada seluruh pasien PGK dengan kadar hemoglobin yang konsisten

di bawah 11 g/dl (dalam dua kali pengukuran dengan rentang waktu dua minggu tiap kali

pengukuran). Seluruh pasien yang mendapat terapi ESA harus diberikan suplemen besi untuk

mempertahankan target hemoglobin yang diinginkan. Pasien yang menjalani hemodialisis

biasanya membutuhkan suplemen besi dalam jumlah yang lebih besar dibandingkan pasien yang

tidak menjalani hemodialisis. Selain besi, terdapat terapi dengan vitamin dan adjuvan lainnya

yang dapat membantu mengoptimalkan respon terhadap terapi menggunakan ESA. Pilihan

terakhir sebagai terapi anemia adalah transfusi, bila memungkinkan transfusi darah sebaiknya

dihindari terutama untuk pasien dengan penyakit ginjal kronis yang akan menjalani transplantasi

ginjal. Transfusi hanya diberikan pada pasien dengan anemia yang memburuk secara akut akibat

kehilangan darah (hemoragi atau pembedahan) atau hemolisis, anemia simtomatik dan/atau yang

memiliki faktor risiko (diabetes, gagal jantung, penyakit arteri koroner, arteriopati, usia lanjut),

dan pasien yang resisten atau hiporesponsif terhadap terapi ESA (KDIGO, 2012; Locatelli, 2004)

Terapi dengan suplemen besi

Terapi dengan vitamin dan adjuvan selain besi

Terapi dengan transfusi

Ershler et al, 2005 (Economic Burden of Patients with Anemia in Selected Diseases)
Among the six diseases, CKD anemic patients incurred the greatest average annual direct
costs and the greatest unadjusted cost difference between nonanemic and anemic patients.
In the CKD and IBD populations, nonanemic patients incurred higher average annual
costs than the anemic patients.
As expected, anemic patients incurred higher costs than nonanemic patients. The highest
differences in cost between anemic and nonanemic patients were observed among patients with
CHF, CKD, and cancer; their annual cost differences ranged from $18,418 to $29,511 per patient.
Moreover, data are now becoming clearer that treatment of anemia can improve quality
of life [21]. For clinical and economic reasons, those responsible for the care of populations
should be concerned about patients with anemia. What remains unanswered is whether
identification and management of anemia can reduce the economic burden in these patients.
Further research is needed to answer this important policy question.

Direct health-care costs and indirect costs due to

loss of productivity and STD were the dependent
variables used in the regression models (as described
later in this paper). Direct costs (from the health
plan perspective) included payments for inpatient
hospital, ER, outpatient hospital, physician office
visits, and pharmacy.
After adjusting for differences in demographics, a
portion of condition severity, and comorbidity,
patients with anemia had high costs and anemic
patients had substantially higher costs than nonanemic
patients.
Although patients with anemia were observed to have higher costs than nonanemic patients with the same
condition, it could be questioned whether these costs can be truly attributed to the anemia or rather from the
underlying condition severity. Patients with anemia are likely to be sicker than their nonanemic counterparts; with
this in mind, various adjustment factors were included in the analysis. Attention was focused on defining disease
severity as an important adjuster: severity was based on ICD-9 diagnostic codes, selected CPT codes, certain
medications as indicators of sicker patients, durable medical equipment codes, and evidence of hospitalization. In
addition to disease severity, the adjustment included two measures of comorbidity: the CCI and a measure of the
number of anemia-associated conditions present for each patient. Results showed that the severity adjustment
significantly lowered the differences between the anemic and nonanemic populations for each disease; the adjusted
differences in cost between the anemic and nonanemic patients ranged from onehalf to two-thirds of the unadjusted
differences in cost.
- patients with diagnostic designations of anemia are costly and should be of concern.
- but what is known is that patients with anemia consume a significant amount of health-care resources.

Nissenson, Economic Burden of Anemia in an Insured

Population
that disease severity would therefore be
the primary driver for any observed cost differences, our multivariate
analysis was designed to adjust for the presence of key
conditions and the severity of those conditions as well as for
other factors that could influence costs (i.e., patient age, gender,
and coverage type).

Sikand, Cost Analytic Model to Determine the Least Costly

Inpatient
Erythropoiesis Stimulating Therapy Regimen
The number
of potential treatments received was calculated using
average length of stay for each disease state.

Total biaya terapi pada pasien anemia PGK dipengaruhi oleh beberapa faktor, seperti

lama rawat inap, stadium penyakit, komorbid dan komplikasi, usia, kelas perawatan, serta cara

bayar. Stadium penyakit, dalam hal ini keparahan penyakit merupakan salah satu faktor utama

yang mempengaruhi perbedaan total biaya terapi, di samping itu juga terdapat faktor lain seperti

usia, jenis kelamin, dan coverage (cara bayar). Selain keparahan penyakit, faktor komorbiditas

juga mempengaruhi pengukuran biaya pada pasien anemia. Hal ini dibuktikan dengan lebih
besarnya biaya pada pasien anemia dibandingkan dengan pasien tanpa anemia, perbedaan biaya

keduanya cukup signifikan (Nissenson et al., 2005; Ershler, 2005).

Data on costs during the transition from CKD to ESRD show very high expenditures in the
month of dialysis initiation, reaching nearly $15,000. Most of this amount, not surprisingly, is
related to hospitalization.
In 2010, overall per person per year (PPPY) costs for patients with CKD reached $22,323 for
Medicare patients age 65 and older, and $13,395 for patients age 50-64 in the Market Scan
database. Compared to costs for patients with CKD stage 1-2, costs for those with stage 4-5 were
50 percent greater in the Medicare population and 81 percent higher among MarketScan patients.
(USRDS Annual Data Report 2012)

Chronic kidney disease (CKD) is becoming a major public health issue worldwide and an
important contributor to the overall non-communicable disease burden. It is associated with
major serious consequences including increased risk of mortality, end-stage renal disease,
accelerated cardiovascular disease (CVD), mineral and bone disease, adverse metabolic and
nutritional consequences, infections, reduced cognitive function and increased risk of acute
kidney injury. The global economic impact of CKD is tremendous (Jha, 2012).
PGK telah menjadi isu kesehatan yang menyebar luas di seluruh penjuru dunia terutama
dalam hal beban penyakit. Beberapa konsekuensi serius yang diakibatkan oleh PGK yaitu
meningkatnya risiko mortalitas, end-stage renal disease (ESRD), penyakit kardiovaskular,
penyakit tulang dan mineral, efek merugikan terkait nutrisi dan metabolisme, infeksi, fungsi
kognitif yang menurun dan meningkatnya risiko Acute Kidney Injury (AKI). Akibatnya, dampak
ekonomi PGK secera global sangatlah besar. (Jha, 2012)
The major consequences of CKD include loss of kidney function leading to end-stage renal
disease (ESRD), accelerated cardiovascular disease (CVD) and death. Other important
complications include anemia, bone disease, infections, reduced cognitive function and increased
risk of acute kidney injury (AKI) (Jha, 2012).

Nissenson et al, 2005 Economic Burden of Anemia in Insured Population

Vol. 11, No. 7 September 2005 JMCP Journal of Managed Care Pharmacy
Anemia prevalence is higher among individuals with certain chronic conditions, including
chronic kidney disease (CKD), human immunodeficiency virus (HIV), rheumatoid arthritis (RA),
inflammatory bowel disease (IBD), congestive heart failure (CHF), and cancer.2,5 In previous
studies, anemia with chronic disease has been identified in 36% of patients with CKD6 and 27%
of patients with RA. (Nissenson, 2005)

The average annualized total cost per anemic patient was more than twice the average for
nonanemic patients. Both outpatient and inpatient costs were more than twice as high for anemic
patients as for nonanemic patients.
Prevalensi anemia ditemukan lebih tinggi pada orang yang menderita penyakit kronis
tertentu, seperti PGK. Rata-rata biaya total per pasien per tahunnya bisa dua kali lebih besar
dibandingkan rata-rata biaya total pada pasien yang tidak mengalami anemia. Baik rawat jalan
maupun rawat inap, total biaya untuk keduanya pada pasien ddengan anemia melebihi dua kali
biaya pada pasien tanpa anemia. (Nissenson et al, 2005)

Among anemic patients, average total annualized costs were $14,535 per patient. Inpatient care
accounted for nearly one third ($4,775, 33%) of the average total costs.
Rata-rata biaya total per tahun pada pasien anemia adalah sebesar $14,535 per pasien. Dimana
perawatan pasien rawat inap tercatat menghabiskan hampir sepertiga (33%) dari rata-rata biaya
total terapi anemia, yaitu sebesar $4,775. (Nissenson et al, 2005)

What is Medicare?
Medicare is the federal health insurance program for people who are 65 or older, certain younger
people with disabilities, and people with End-Stage Renal Disease (permanent kidney failure
requiring dialysis or a transplant, sometimes called ESRD).

The different parts of Medicare help cover specific services:

Medicare Part A (Hospital Insurance)

Part A covers inpatient hospital stays, care in a skilled nursing facility, hospice care, and some home
health care.

Medicare Part B (Medical Insurance)

Part B covers certain doctors' services, outpatient care, medical supplies, and preventive services.
Medicare Part C (Medicare Advantage Plans)
A Medicare Advantage Plan is a type of Medicare health plan offered by a private company that
contracts with Medicare to provide you with all your Part A and Part B benefits. Medicare Advantage
Plans include Health Maintenance Organizations, Preferred Provider Organizations, Private Fee-for-
Service Plans, Special Needs Plans, and Medicare Medical Savings Account Plans. If you're
enrolled in a Medicare Advantage Plan, Medicare services are covered through the plan and aren't
paid for under Original Medicare. Most Medicare Advantage Plans offer prescription drug coverage.

Medicare Part D (prescription drug coverage)

Part D adds prescription drug coverage to Original Medicare, some Medicare Cost Plans, some
Medicare Private-Fee-for-Service Plans, and Medicare Medical Savings Account Plans. These plans
are offered by insurance companies and other private companies approved by Medicare. Medicare
Advantage Plans may also offer prescription drug coverage that follows the same rules as Medicare
Prescription Drug Plans.

A wide variety of comorbid conditions which develop during the course of CKD leads to higher
mortality and higher cost of care (St. Peter et al, 2004)

As health care expenditure continues to escalate, health care providers are seeking
strategies to constrain cost, while maintaining better standards of patient care. The first
necessary step to control the growth of the health care cost is to understand the underlying cause
of its increase. Increasing comorbidity during chronic kidney disease (CKD) patients may be
responsible for rapid escalation of cost after the initiation of dialysis. The societal burden of the
CKD is increasing and its prevalence in the United States adult population has been estimated to
be approximately 20 million (St. Peter et al, 2004).
Meningkatnya komorbiditas pada pasien PGK diikuti dengan peningkatan biaya yang
sangat cepat. Tanggungan masyarakat terhadap PGK semakin meningkat begitu juga dengan
prevalensinya di Amerika, diperkirakan 20 juta orang dewasa mengidap PGK (St. Peter et al,
2004).

St. Peter, W.L., Khan, S.S., Ebben, J.P., et al, 2004, Chronic kidney disease: The distribution of
health care dollars, Kidney International, 66, 313–321.