BAB I PENDAHULUAN
5.6 Hubungan Sitokin MIF Terhadap Proteinuria
Peranan proteinuria menetap dengan kerusakan struktur (tubulo
interstisial) dan gangguan fungsi ginjal merupakan dasar studi
eksperimental dan studi klinis tentang kerusakan ginjal (Zandi-Nejad et al.,
2004). Pasien proteinuria nefrotik menetap lebih sering mengalami PGK
stadium lanjut daripada pasien dengan derajat rendah atau tidak ada
proteinuria (Abate, Zoja dan Remuzzi, 2006).
Tubulus dan interstisial renal memiliki peranan penting terhadap
terjadinya kerusakan struktur dan gangguan fungsi ginjal pada proteinuria
menetap. Albumin bekerja sebagai pembawa (carrier) terhadap mediator
inflamasi yang diperankan oleh angiotensin II dan selanjutnya
ke tubulointerstisial. Hal ini mengaktifkan sel tubulus proksimal melalui
signal intrasel terhadap aktivasi transkripsi gen sitokin serta fibrosis (Wolf,
2000; Takase et al., 2003; Eddy, 2004).
Pada keadaan normal membran basalis tubulus berfungsi sebagai
barier antara tubulus dan kapiler, tetapi bila proteinuria persisten terjadi
kerusakan barier. Hal ini berperan dalam sintesis protein matriks (Zeisberg
et al., 2002) hingga terjadi kerusakan berat tubulointerstisial (Eddy, 2004).
Makrofag merupakan sel multifungsi yang berkemampuan mensekresi
sitokin/protein matriks, dan berdampak terhadap kerusakan
tubulointerstisial (Abate et al, 1998; Donadelli et al., 2000). Penarikan sel
ini dari sirkulasi pada tahap awal kerusakan akut sebenarnya merupakan
langkah yang penting dalam penyembuhan kerusakan semua organ
termasuk ginjal. Namun, jika sel ini persisten/menetap setelah kerusakan
akut menyembuh, respon fibrogenik akan terus berlanjut hingga terjadi
kerusakan berat sel-sel ginjal (Abate, Zoja dan Remuzzi, 2006)
Sitokin MIF dihasilkan oleh makrofag, tetapi bekerja menghambat
migrasi makrofag dari tempat awal kerusakan akut sehingga makrofag
persisten di lokasi tersebut (Subowo, 2009). Akibatnya, terjadi aktivasi
reseptor MIF dan berperan dalam kerusakan renal (Lan, 2008). Ekspresi
MIF pada sel tubulus proksimal (secara in vivo) meningkat signifikan bila
dipajan dengan urin penderita proteinuria masif (Huang et.al., 2008). Hal
ini menunjukkan peranan overload proteinuria terhadap aktivasi mediator
Glukokortikoid seharusnya mampu menghambat aksi sitokin ini,
tetapi MIF diinduksi glukokortikoid bekerja antagonis. Konsentrasi
glukokortikoid yang besar di sirkulasi menimbulkan komplikasi respon
endotel vaskular (Iuchi et al., 2003), yang kemudian menimbulkan
hiperfiltrasi/hipertensi glomerular sehingga timbul proteinuria persisten.
Pada keadaan stres akut, peran fungsional MIF memunyai dua efek
yang berbeda, yaitu penting dalam pertahanan tubuh, pada sisi lain
ketidakseimbangan MIF menyebabkan disfungsi organ (Stoppe,
Bernhagen dan Rex, 2013). Namun, di dalam kronisitas penyakit, efek
peningkatan MIF serum tidak selalu menguntungkan. Kontribusi studi ini
dalam aplikasi selanjutnya adalah apabila peningkatan kadar MIF serum
diperbaiki bersama dengan pengelolaan tekanan darah, akan membantu
menurunkan proteinuria dan memperlambat progresivitas PGK.
Studi ini memang hanya studi sekat lintang dan hal ini merupakan
keterbatasan studi ini. Namun, pada era sekarang ini sudah tidak
zamannya lagi “menangisi” keterbatasan, tetapi bagaimana membuat
keterbatasan itu berguna bagi orang banyak (Walach et al., 2006). Oleh
karena itu, data dalam studi ini juga berperan dalam peningkatan kualitas
hidup penderita SNRS dan pencegahan menuju PGK tahap akhir.
5.7 Kelebihan dan Kelemahan Studi
Studi ini memiliki beberapa kelebihan dan kelemahan. Studi ini
memberikan informasi tambahan tentang hubungan antara polimorfisme
studi pertama, setelah melakukan studi literatur yang intensif, yang
mengukur kadar MIF serum dan angiotensin II plasma pada penderita SN.
Kadar MIF serum dan angiotensin II plasma dari subjek manusia lebih
menggambarkan keadaan klinis penderita dibandingkan dengan hasil
percobaan binatang. Akhirnya, pada analisis multivariat studi ini, nyata
bahwa angiotensin II memengaruhi regulasi MIF merupakan mekanisme
yang berkontribusi terhadap perkembangan/pemeliharaan hipertensi.
Temuan dari studi ini diharapkan membantu klinisi untuk melakukan
penatalaksanaan yang optimal pada anak SNRS.
Beberapa kelemahan yang terjadi pada studi ini antara lain:
pertama, populasi studi secara klinis amat bervariasi (misalnya, umur dan
lama sakit) dan kemungkinan heterogenitas secara histopatologis besar
sehingga memengaruhi hasil studi ini. Kedua, studi ini merupakan studi
potong lintang sehingga tidak semua relevan data diperoleh, misalnya,
hubungan sebab akibat peninggian MIF serum dan angiotensin II pada
SNRS dengan alel G dan alel C. Hal ini dikarenakan adanya temporal
ambiguity dalam studi. Studi genetika tentunya sudah dimulai sejak masa
prenatal, sedangkan penilaian kadar MIF dan angiotensin II diperiksa
sesaat. Namun, keadaan ini menurut kami tidak memengaruhi hasil yang
substansial dari studi karena adanya analisis multivariat. Analisis
multivariat menggunakan banyak asumsi sehingga penilaiannya
bergantung pada teori yang mendasari. Studi lebih lanjut tetap dibutuhkan
untuk menjelaskan peranan antibodi MIF dan/atau penghambat enzim MIF
BAB VI
SIMPULAN DAN SARAN 6.1 Simpulan
1. Frekuensi alel C pada kelompok SNRS lebih tinggi dibandingkan
kelompok SNSS dan anak sehat.
2. Kadar MIF serum lebih tinggi pada SNRS dibandingkan SNSS dan
anak sehat.
3. Grup SNRS menunjukkan kadar angiotensin II plasma lebih tinggi
dibandingkan SNSS dan anak sehat.
4. Ada kekuatan korelasi positif sangat lemah antara kadar angiotensin
II plasma dan MIF serum.
5. Model regresi menjawab sebahagian variabel, yaitu alel C -173 gen
MIF secara bersama sama dengan hipertensi berkontribusi terhadap
SNRS. Walaupun angiotensin II plasma dan MIF serum secara
bersama-sama belum menjawab model yang ada, kepentingan
kedua variabel terhadap variabel hipertensi menunjukkan peran
keduanya dalam analisis model terbaik, untuk keberadaan resisten
steroid.
6.2 Saran
1. Karena pemeriksaan genetika MIF masih mahal, pemeriksaan
polimorfisme dibuat atas indikasi, misalnya pasien SNRS dengan
ditambah alel C berkisar 91,7%. Hal ini berarti beda peran gen dan
nongen terhadap risiko SNRS pada individu dengan hipertensi
berkisar 18% lagi. Walaupun demikian, validasi nilai ini dalam
praktik sehari hari, masih memerlukan penelitian lanjutan.
2. Mengingat bahwa angiotensin II memengaruhi regulasi MIF
merupakan mekanisme yang berkontribusi terhadap
perkembangan/pemeliharaan hipertensi, maka perlu dikembangkan
antibodi anti-MIF atau inhibitor aktivitas enzim katalis MIF sebagai
terapi sparring steroid bersama dengan pengelolaan hipertensi untuk
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