Lupus Nefritli Çocuklarda İntravenöz Siklofosfamid Tedavisinin Etkinliğinin Değerlendirilmesi

Yıl 2017, Cilt: 17 Sayı: 2, 77 - 83, 01.04.2017

Işık Odaman Al Sevinç Emre Ilmay Bilge Alev Yılmaz Bağdagül Yavaş Aksu

https://doi.org/10.5222/j.child.2017.077

Öz

Amaç: Sistemik lupus eritematozus seyrinde renal tutulum önemli morbidite ve mortalite nedenidir. Lupus nefriti tedavisinde siklofosfamid yaygın olarak kullanılmaktadır. Bu çalışmadaki amacımız, çocuklardaki lupus nefritinde intravenöz siklofosfamid tedavisinin etkinliğini değerlendirmektir.Gereç ve Yöntem: İstanbul Tıp Fakültesi Çocuk Nefrolojisi Bilim Dalı tarafından 1991-2011 yılları arasında intravenöz siklofosfamid tedavisi alan 28 lupus nefritli hasta retrospektif olarak değerlendirildi. Tüm hastalarda öykü, başvuru sırasındaki bulgu ve belirtiler, laboratuvar tetkikleri, renal biyopsi sonuçları, tedavi ve prognoza ait veriler kaydedildi.Bulgular: Başvuru sırasında, 27 hastada %96.5 proteinüri, 4 hastada %14.3 makroskopik hematüri, 15 hastada %53.5 hipertansiyon, 11 hastada %39.2 ise böbrek yetersizliği saptandı. En sık saptanan ekstrarenal klinik bulgular artrit/artralji %67.9 , konstitüsyonel bulgular %64.3 ve cilt bulguları %60.7 idi. Hastalarımızda histopatolojik bulgu olarak en sık Class 4 %53.5 , daha sonra sırasıyla Class 2 %21.6 , Class 3 %10.7 ve Class 5 %3.5 lupus nefriti saptandı. Çalışma grubunda toplam 62.7±49 aylık 6-204 ay izlem boyunca 21 hastada %75 renal remisyon sağlandı. On dokuz hasta %67.8 hem renal hem de ekstrarenal bulgular açısından remisyonda idi. Son dönem böbrek yetersizliği gelişme oranı %14.2 ve mortalite oranı %3.5 olarak belirlendi. Lupus nefriti vakalarında SDBY ve ölüm başlangıçtaki serum kreatinin yüksekliği ile istatistiksel olarak ilişkili bulundu p: 0.047 . Çalışma grubundaki hastaların %39.2’sinde intravenöz siklofosfamide bağlı yan etki görülürken, en sık görülen yan etki nötropeni %21.4 idi.Sonuç: Bu çalışmamızda, pediyatrik lupus nefriti vakalarında intravenöz siklofosfamid tedavisinin minimal yan etki ile renal ve ekstrarenal remisyon sağlanmasında etkin ve güvenilir olduğu gösterilmiştir. Başlangıçtaki serum kreatinin yüksekliği kötü prognostik faktör olarak bulunmuştur

Anahtar Kelimeler

Sistemik lupus eritematozus, çocuk, siklofosfamid, lupus nefriti

Evaluation the Effectiveness of Intravenous Cyclophosphamide Treatment in Children with Lupus Nephritis

Öz

Objective: Renal involvement in systemic lupus erythematosus is an important cause of morbidity and mortality. Cyclophosphamide is widely used in the treatment of lupus nephritis. The aim of this study is to evaluate the effectiveness of intravenous cyclophosphamide treatment in children with lupus nephritis.Material and Method: In this study, 28 patients with lupus nephritis treated by intravenous pulse cyclophosphamide between the years 1999, and 2011 in Istanbul Faculty of Medicine, Department of Pediatric Nephrology were investigated retrospectively. Clinical history, presenting symptoms and findings, laboratory analysis, results of renal biopsy, treatment methods and prognosis were evaluated.Results: Proteinuria was determined in 27 96.5% , macroscopic hematuria in 4 14.3% , hypertension in 15 53.5% , and renal failure in 11 patients 39.2% as initial presentations. The most frequent extrarenal clinical findings were arthritis/arthralgia 67.9% , constitutional 64.3% and skin findings 60.7% . The most frequent histopathological finding of lupus nephritis patients in our study group was Class 4 lupus nephritis 53.5% , followed by Class 2 21,6% , Class 3 10,7% and Class 5 3.5% nephritis respectively. Renal remission was obtained in 21 75% patients throughout 62.7±49 months of follow up period in study group. Nineteen patients 67.8% were in remission in terms of both renal and extrarenal findings. Morbidity ratio ESRF was 14.2%, and mortality rate was 3.5% in our study group. ESRF and death in the study group were statistically related to increased serum creatinine levels during the initial presentation p: 0.047 . Side effects of intravenous cyclophosphamide were detected in 39.2% of the patients, while most frequent side effect was neutropenia 21.4% . Conclusion: In this study, intravenous cyclophosphamide treatment was determined as effective and reliable with minimum side effects in order to obtain renal and extrarenal remission in patients with pediatric lupus nephritis. The presence of high serum creatinine during the initial presentation was found as a poor prognostic factor

Anahtar Kelimeler

Systemic lupus erythematosus, child, cyclophosphamide, lupus nephritis

Kaynakça

• Bilge I. Sistemik lupus eritamatozus. In: Olcay Neyzi, Türkan Ertuğrul (eds): Pediatri. Nobel Tıp Kitabevleri, İstanbul. 2010:1257-61.
• Hochberg mC. Updating the American College of Rheumatology revised criteria for the sınıfification of systemic lupus erythematosus. Arthritis and Rheumatism 1997:40:1725.
• https://doi.org/10.1002/art.1780400928
• The primary nephrotic syndrome in children. Identification of patients with minimal change nephro- tic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981;98(4):561-4.
• https://doi.org/10.1016/S0022-3476(81)80760-3
• Niaudet P, Salomon r. Systemic lupus erythematosus. In: Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, Springer 2009:1127-53.
• https://doi.org/10.1007/978-3-540-76341-3_47
• Schwartz mm, Lan SP, Bernstein J, Hill gS, Holley k, Lewis EJ. Irreproducibility of the activity and chro- nicity indices limits their utility in the management of lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis 1993;21:374-7.
• https://doi.org/10.1016/S0272-6386(12)80263-0
• Boumpas DT, austin Ha 3rd, vaughn Em, klippel JH, Steinberg aD, Yarboro CH, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992;340:741-5.
• https://doi.org/10.1016/0140-6736(92)92292-N
• şirin a, Emre S, Nayır a, Bilge I. Nefroloji. In: Devecioğlu Ö, Öneş Ü, Ünüvar E (eds): Pediatride Rutinler, İstanbul. 2005:485-545.
• Schwartz gJ, Haycock gB, Edelmann Cm Jr, Spitzer a. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259-63.
• mok CC. Update on the therapies of severe lupus neph- ritis. Current Rheumatology Reviews 2006;2:186-90.
• https://doi.org/10.2174/157339706776876026
• Baştuğ F, Poyrazoğlu H, gündüz z, Tülpar S, Düşünsel r. Juvenil lupus eritematozus: Fourteen years of experience. Turk J Rheumatol 2011;26(4):308- 15.
• https://doi.org/10.5606/tjr.2011.049
• Caeiro F, michielson Fm, Bernstein r, Hughes gr, ansell Bm. Systemic lupus erythematosus in childho- od. Ann Rheum Dis 1981;40:325-31.
• https://doi.org/10.1136/ard.40.4.325
• Bakr a. Epidemiology treatment and outcome of childhood systemic lupus erythematosus in Egypt. Pediatr Nephrol 2005;20:1081-6.
• https://doi.org/10.1007/s00467-005-1900-2
• Emre S, Bilge I, Sirin a, kılıcaslan I, Nayır a, Oktem F, et al. Lupus nephritis in children: Prognostic significance of clinicopathological findings nephron. 2001;87:118-26.
• gourley mF, austin Ha 3rd, Scott D, Yarboro CH, vaughan Em, muir J, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med 1996;125(7):5495-57.
• https://doi.org/10.7326/0003-4819-125-7-199610010-00003
• Ioannidis JP, Boki ka, katsorida mE, Drosos aa, Skopouli FN, Boletis JN, et al. Remission, relapse, and re-remission of proliferative lupus nephritis treated with cyclophosphamide. Kidney International 2000;57: 258-64.
• https://doi.org/10.1046/j.1523-1755.2000.00832.x
• Liang TJ. Gastrointestinal vasculitis and pneumatosis intestinalis due to systemic lupus erythematosus: Successful treatment with pulse intravenous cyclop- hosphamide. Am J Med 1988;85:555-8.
• https://doi.org/10.1016/S0002-9343(88)80096-2
• rosenbaum JT, Simpson J, Neuwelt Cm. Successful treatment of optic neuropathy in association with syste- mic lupus erythematosus using intravenous cyclop- hosphamide. Br J Ophthalmol 1997;81:130-2.
• https://doi.org/10.1136/bjo.81.2.130
• Schnabel a, reuter m, gross WL. Intravenous pulse cyclophosphamide in the treatment of interstitial lung disease due to collagen vascular diseases. Arthritis Rheum 1998;41:1215-20.
• https://doi.org/10.1002/1529-0131(199807)41: 73.0.CO;2-Y
• Croca S, rodrigues T, Isenberg Da. Assessment of a lupus nephritis cohort over a 30-year period. Rheumatology 2011;50:1424-30.
• https://doi.org/10.1093/rheumatology/ker101
• Steinberg aD, Steinberg SC. Long-term preservation of renal functionin patients with lupus nephritis recei- ving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991;34(8):945-50.
• https://doi.org/10.1002/art.1780340803
• Baqi N, moazami S, Singh a, ahmad H, Balachandra S, Tejani a. Lupus nephritis in children: a longitudinal study of prognostic factors and therapy. J Am Soc Nephrol 1996;7(6):924-9.
• Lee HS, Choi Y. Clinical outcomes of childhood lupus nephritis: a single centre’s experience. Pediatr Nephrol 2007;22:222-31.
• https://doi.org/10.1007/s00467-006-0286-0
• al Salloum a. Cyclophosphamide therapy for lupus nephritis poor renal survival in Arab children. Pediatr Nephrol 2003;18:357-61.
• reinaldo m, Perira LJC, Santos ESC, Heonir r. Clinical effects of intermittent, intravenous cyclop- hosphamide in severe systemic lupus erythematosus. Nephron 1996;74(2):313-7.
• https://doi.org/10.1159/000189327
• Das u, kv Dakshina murty, Prasad N, Prayag a. Pulse cyclophospamide in severe lupus nephritis: Southern Indian Experience Saudi J Kidney Transpl. 2010;21(2):372-8.
• Yokoyama H, Wada T, Hara a, Yamahana J, Nakaya I, kobayashi m, et al. The outcome and a new ISN/ RPS 2003 sınıfification of lupus nephritis in Japanese. Kidney Int 2004;66(6):2382-8.
• https://doi.org/10.1111/j.1523-1755.2004.66027.x
• ayodele OE, Okpechi Ig, Swanepoel Cr. Predictors of poor renal outcome in patients with biopsy-proven lupus nephritis. Nephrology (Carlton) 2010;15(4):482-90.
• https://doi.org/10.1111/j.1440-1797.2010.01290.x
• rush PJ, Baumal r, Shore a, Balfe JW, Schreiber m. Correlation of renal histology with outcome in children with lupus nephritis. Kidney Int 1986;24:1066–71.
• https://doi.org/10.1038/ki.1986.108
• Dhir v, aggarwal a, Lawrence a, agarwal v, misra r. Long term outcome of Lupus Nephritis in Asian Indians. Arthritis Care&Research 2012;64(5):713-20.
• https://doi.org/10.1002/acr.21597
• austin Ha, Boumpas DT, vaughan Em, Balow JE. High-risk features of lupus nephritis: importance of race and clinical and histological factors in 166 pati- ents. Nephrol Dial Transplant 1995;10:1620-8.
• gruppo Italiano Per Lo Studio Della Nefrite Lupica (gISNEL). Lupus nephritis: prognostic factors and probability of maintaining life-supporting renal functi- on 10 years after the diagnosis. Am J Kidney Dis 1992;19:473-9.
• https://doi.org/10.1016/S0272-6386(12)80957-7
• rygg m, Pistorio a, ravelli a, maghnie m, Dilorgi N, Bader-meunier B, et al. Paediatric Rheumatology International Trials Organisation (PRINTO) A longitudinal PRINTO study on growth and puberty in juvenile systemic lupus erythematosus. Ann Rheum Dis 2012;71: 511-7.
• https://doi.org/10.1136/annrheumdis-2011-200106
• appel gB, Cohen DJ, Pirani CL, meltzer JI, Estes D. Long-term follow-up of patients with lupus nephri- tis. A study based on the sınıfification of the World Health Organization. Am J Med 1987;83(5):877-85.
• https://doi.org/10.1016/0002-9343(87)90645-0
• Esdaile Jm, abrahamowicz m, mackenzie T, Hayslett J, kashgarian m. The time-dependence of long-term prediction in lupus nephritis. Arthritis Rheum 1994;37:359-68.
• https://doi.org/10.1002/art.1780370309
• Naiker IP, Chrystal v, randeree Ig, Seedat Yk. The significance of arterial hypertension at the onset of clini- cal lupus nephritis. Postgrad Med J 1997;73: 230-3.
• https://doi.org/10.1136/pgmj.73.858.230
• Esdaile Jm, Levington C, Federgreen W, Hayslett JP, kashgarian m. The clinical and renal biopsy pre- dictors of long-term outcome in lupus nephritis. Q J Med 1989;72:779-833.
• al Salloum a. Cyclophosphamide therapy for lupus nephritis poor renal survival in Arab children. Pediatr Nephrol 2003;18:357-61.
• mok CC, Ying kY, Nq WL, Lee kW, To CH, Lau CS, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis Treated with cyclophosphamide. The American Journal of Medicine 2006;119:25-33.
• https://doi.org/10.1016/j.amjmed.2005.08.045
• Yang LY, Chen WP, Lin CY. Lupus nephritis in children-a review of 167 patients. Pediatrics 1994;94: 335-40.
• Font J, Cervera r, Espinosa g, Pallares L, ramos- Casals m, Jimenez S, et al. Systemic lupus erythema- tosus (SLE) in childhood: analysis of clinical and immunological findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum Dis 1998;57:456-9.
• https://doi.org/10.1136/ard.57.8.456
• mosca m, Bencivelli W, Neri r, Pasquariello a, Batini v, Puccini r, et al. Renal flares in 91 SLE pati- ents with diffuse proliferative glomerulonephritis. Kidney Int 2002;61:1502-9.
• https://doi.org/10.1046/j.1523-1755.2002.00280.x
• moroni g, Pasquali S, Quaglini S, Banfi g, Casanova S, maccario m, et al. Clinical and prognostic value of serial renal biopsies in lupus nephritis. Am J Kidney Dis 1999;34:530-9.
• https://doi.org/10.1016/S0272-6386(99)70082-X
• al Salloum a. Cyclophosphamide therapy for lupus nephritis poor renal survival in Arab children. Pediatr Nephrol 2003;18:357-61.
• Dooley ma, Hogan S, Jennette C, Falk r. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney Int 1997;51:1188-95.
• https://doi.org/10.1038/ki.1997.162
• Huang JL, Lin CJ, Hung IJ, Luo SF. The morbidity and mortality associated with childhood onset systemic lupus erythematosus. Changgeng Yi Xue Za Zhi 1994; 17:113-20.
• Singh S, Devidayal, kumar L, Joshi k. Mortality patterns in childhood lupus: 10 years’ experience in a developing country. Clin Rheumatol 2002;21:462-5.
• https://doi.org/10.1007/s100670200116
• Lewis EJ, Hunsicker Lg, Lan SP, rohde rD, Lachin Jm. A Controlled trial of plasmapheresis the- rapy in severe lupus nephritis. The New England Journal of Medicine 1992;326(21):1373-9.
• https://doi.org/10.1056/NEJM199205213262101
• Dau PC, Callahan J, Parker r, golbus J. Immunologic effects of plasmapheresis synchronized with pulse cyclophosphamide in systemic lupus erythe- matosus. J Rheumatol 1991;18:227-76.
• Yamaji k, kim YJ, Tsuda H, Takasaki Y. Long-term Clinical outcomes of synchronized therapy with plas- mapheresis and intravenous cyclophosphamide pulse therapy in the treatment of steroid-resistant lupus neph- ritis. Therapeutic Apheresis and Dialysis 2008;12(4): 298-305.
• https://doi.org/10.1111/j.1744-9987.2008.00591.x
• Danieli mg, Palmieri C, Salvi a, refe mC, Strusi aS, Danieli g. Synchronized therapy and high-dose cyclophosphamide in proliferative lupus nephritis. J Clin Apher 2002;17:72-7.
• https://doi.org/10.1002/jca.10020