PUPU 2010-6-3 11:40
Sirolimus可停止自體顯性遺傳多囊性腎臟疾病患者之囊的生長
作者：Pauline Anderson
出處：WebMD醫學新聞
May 13, 2010 — 一項線上登載於美國腎臟學會期刊(Journal of the American Society of Nephrology)的新先驅隨機跨世代試驗發現，將免疫抑制藥物sirolimus加入傳統治療中，可停止自體顯性遺傳之多囊性腎臟疾病(autosomal dominant polycystic kidney disease，ADPKD)患者的腎囊生長與增加實質器官體積。
「Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease Renal Efficacy and Safety (SIRENA)」這個單一中心的研究顯示，ADPKD病患單用傳統治療，囊之體積會顯著增加且腎臟實質組織沒有可察覺的改變。
第一作者、義大利Bergamo Mario Negri藥理研究中心、罕見疾病臨床研究中心Norberto Perico醫師等人寫道，在這篇驗證觀念的研究中，我們提供了明確證據指出，ADPKD病患在6個月的sirolimus治療之後，停止了腎囊生長，且看來健康的腎臟實質組織體積似乎也增加了，副作用還可接受。
ADPKD是一種遺傳性系統性異常，主要是腎臟方面，它是最常見的遺傳性腎臟病，發生率約為400-1000分之一，是腎衰竭的主因。
之前的研究顯示，有一個路徑控制細胞生長和分裂，所謂的rapamycin 哺乳動物目標物，研究者相信sirolimus阻斷這個路徑，這個藥物也被用於腎臟移植接受者，作為維持免疫抑制治療的一部分，也當做抗腫瘤製劑，也用於預防冠狀動脈狹窄的塗藥支架。
目前研究的具體目標是評估ADPKD病患使用sirolimus治療在相對短期內的風險/利益資料。
該研究最初包括了21名成人ADPKD病患，腎功能正常或略為不佳(腎絲球過濾速率至少40 mL/分鐘/1.73 m2)，這些病患被隨機分成兩組，一組接受6個月的sirolimus (商品名Rapamune；Wyeth藥廠)治療加上傳統治療，然後只有傳統治療；另一組則是療程順序相反。在6個月時，每個病患交叉到另一個治療組，sirolimus每日劑量平均為3.6 ± 0.7 mg，整個治療期間劑量範圍為1-6 mg。
研究開始之後，有6個病患因各種原因退出試驗。在完成試驗的15個病患中，7人被隨機指派到接受sirolimus後傳統治療組，8人被指派接受傳統治療後使用sirolimus組。
該研究發現，平均而言，比較治療前後的測量數據時(P = .047)，sirolimus組的整體腎臟體積(使用螺旋式電腦斷層測量) (46 ± 81 mL)增加程度比單用傳統治療組(70 ± 72 mL；P = .002)少，兩組之間的整體腎臟體積差異並不顯著。
Sirolimus治療期間的囊體積並無可察覺的變化，但是只有傳統治療時則顯著增加(4 mL ± 52 [P = .808] vs 55 ± 75 mL [P = .013])。比較囊體積的相對變化時，sirolimus組的囊體積增加顯著小於傳統治療組。
作者們解釋，使用sirolimus治療顯著減少腎囊成長的這個研究發現，驗證了「未控制之rapamycin 哺乳動物目標物活化在ADPKD的病理上有所影響」的假設。
有一個意外的發現是，使用sirolimus治療時的實質組織體積顯著增加，而傳統治療者的則是不變(平均26.0 vs-2.7 mL；P < .009)。
作者們寫道，我們假設，進行sirolimus治療時，因為週遭囊的緩解效果，使得實質組織可以擴展，實際上，成長的囊對於殘餘實質組織之壓迫、腎臟微血管因為組織低灌注而延長，和次發性病變與縮小，都被視為影響正常組織結構之逐漸破壞的因素。
該研究發現，使用sirolimus治療或傳統治療的收縮壓和舒張壓都未顯著改變，不過，總膽固醇值從184.5顯著增加到220.5 mg/dL (P < .01)，有9個病患在以sirolimus治療時，超過正常範圍的上限。
作者們表示，不過，未接受對於脂質有不良影響相關藥物如類固醇或calcineurin抑制劑的病患中，高膽固醇血症是輕微的，且可以藉由飲食諮商輕易地控制，因此，這個副作用似乎不是sirolimus治療的主要缺點。
Sirolimus組的尿液白蛋白和蛋白質分泌略為增加但不顯著(P < .001)，單用傳統方式治療者則無可察覺的改變。整個研究期間，腎絲球過濾速率依舊相對穩定。
治療劑量調整到血中目標波谷值5-10 ng/mL之後，並無嚴重的副作用，sirolimus組中，最常見的副作用，影響達10人的是發生口腔潰瘍，但是這可以用局部治療緩解。
研究限制包括，研究期間相對較短，樣本數太少而無法檢測各種sirolimus劑量，此外，統計強度不足以評估sirolimus治療對於左心室肥大的影響。
作者們表示，研究發現提供了進行適當強度之試驗的基礎，分析更長期的sirolimus治療是否可改善ADPKD病患的臨床結果，不過，這些長期結果的試驗應有仔細的病患監測，以確保sirolimus治療的耐受性。
丹佛科羅拉多大學腎臟病與高血壓小組的Robert W. Schrier醫師在編輯評論中表示，該研究有一些需注意之處，他指出，退出率達28%，統計分析不是採用治療意向，完成研究的15人中有10人發生口腔潰瘍。
他也指出，治療組與肝臟酵素與及脂質顯著增加、血比容減少、尿液白蛋白/蛋白質分泌增加有關。他寫道，這對進行ADPKD終身治療會有一些麻煩，因此，對ADPKD病患進行更大型與追蹤期間更長的rapamycin哺乳動物目標物研究相當重要。
不過，Schrier醫師寫道，這篇研究與登載於同一期期刊、其他探討多囊性肝臟和腎臟疾病患者使用somatostatin類似物的研究，為減少多囊性肝臟和腎臟帶來希望，希望可藉此改善ADPKD病患的發病率和死亡率。
研究作者們皆宣告沒有相關財務關係，Schrier 醫師是Otsuka Pharmaceuticals藥廠的顧問。
J Am Soc Nephrol. 線上發表於2010年5月13日，編輯評論線上發表於2010年4月29日。
Sirolimus Halts Cyst Growth in Patients With Autosomal Dominant Polycystic Kidney Disease
By Pauline Anderson
Medscape Medical News
May 13, 2010 — Adding the immunosuppressive drug sirolimus to conventional therapy halts the growth of kidney cysts and increases parenchymal volume in patients with autosomal dominant polycystic kidney disease (ADPKD), a new pilot randomized crossover trial, published online today in the Journal of the American Society of Nephrology, has found.
The single-center study — Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease Renal Efficacy and Safety (SIRENA) — also showed that conventional therapy alone in patients with ADPKD resulted in significant increase in cyst volume with no appreciable changes in kidney parenchyma.
"In this proof-of-concept study, we provided clear-cut evidence that in patients with ADPKD, 6 months of sirolimus therapy halted the growth of renal cysts and increased the volume of seemingly healthy kidney parenchyma with acceptable adverse effects," write lead author Norberto Perico, MD, from the Clinical Research Center for Rare Diseases, Mario Negri Institute for Pharmacological Research, Bergamo, Italy, and colleagues.
ADPKD is an inherited systemic disorder with major renal manifestation. It is the most common genetic kidney disease, occurring in 1 of between 400 and 1000 people, and a major cause of kidney failure.
Previous studies have shown that signals within a pathway — known as the mammalian target of rapamycin — control cell growth and division. Researchers believe that sirolimus blocks this pathway. This drug also has been used in kidney transplant recipients as part of maintenance immunosuppressive therapy, as an antitumor agent, and in drug-eluting stents to prevent coronary artery stenosis.
The broad aim of the current study was to assess the risk/benefit profile of a relatively short period of sirolimus therapy in patients with ADPKD.
The study initially included 21 adult patients with ADPKD and normal or slightly impaired kidney function (glomerular filtration rate, at least 40 mL/minute/1.73 m2). The patients were randomly assigned to 2 sequences of 6 months of treatment with sirolimus (Rapamune; Wyeth) added to conventional therapy, followed by conventional therapy alone, or vice versa. At 6 months, each patient crossed over to the other treatment group. The sirolimus daily dosage averaged 3.6 ± 0.7 mg and ranged from 1 to 6 mg throughout the treatment period.
After the start of the study, 6 patients were prematurely withdrawn for various reasons. Among the 15 patients who completed the trial, 7 were randomly assigned to receive sirolimus followed by conventional therapy, and 8 were assigned to receive conventional therapy followed by sirolimus.
The study found that on average, total kidney volume (measured by spiral computerized tomography) tended to increase less with the addition of sirolimus (46 ± 81 mL), when comparing pretreatment measurements with posttreatment measurements (P = .047), than conventional therapy alone (70 ± 72 mL; P = .002). The total kidney volume differences between the group receiving sirolimus and the group receiving only conventional therapy was not significant.
The cyst volume did not change appreciably during sirolimus treatment but increased significantly during conventional therapy alone (4 mL ± 52 [P = .808] vs 55 ± 75 mL [P = .013]). When relative cyst volume changes were compared, the increase in cyst volume with sirolimus was significantly less than with conventional therapy.
The finding that sirolimus therapy reduced kidney cyst growth corroborates the hypothesis that uncontrolled mammalian target of rapamycin activation may play a pathogenic role in ADPKD, explain the authors.
An unexpected finding was that parenchyma volume increased significantly during sirolimus therapy and was stable with conventional therapy (mean, 26.0 vs ?2.7 mL; P < .009).
"We hypothesize that while on sirolimus therapy, the parenchyma was allowed to expand upon relief of the mass effect of surrounding cysts," write the authors. "Indeed, the compression of growing cysts on residual parenchymal tissue and the stretching of kidney microvessels with secondary tissue hypoperfusion have been suggested to play a role in the progressive disruption of the normal tissue architecture, with secondary atrophy and shrinking."
The study found that systolic and diastolic blood pressure did not significantly change during sirolimus or conventional therapy. Total cholesterol levels, however, increased significantly from 184.5 to 220.5 mg/dL (P < .01) and exceeded the upper limit of the normal range in 9 patients during sirolimus therapy.
However, said the authors, in patients who do not receive concomitant medications that may also adversely affect the lipid profile, such as steroids or calcineurin inhibitors, hypercholesterolemia is mild and can be easily managed with dietary counseling. "Thus, this adverse effect does not seem to be a major drawback of sirolimus therapy."
Urinary albumin and protein excretion increased marginally but significantly (P < .001) during sirolimus therapy but did not appreciably change during conventional therapy alone. The glomerular filtration rate remained relatively stable throughout the study.
There were no serious adverse events after the treatment dose was titrated to target trough blood levels between 5 and 10 ng/mL. The most frequent adverse event, which affected 10 patients during sirolimus therapy, was the development of aphthous stomatitis, but this was relieved with topical therapy.
Among the limitations of the study was that it was relatively short in duration and that its sample size was too small to allow for testing of various sirolimus doses. In addition, the statistical power was not sufficient to evaluate the effects of sirolimus therapy on left ventricular mass.
The study findings provide the rationale for adequately powered trials aimed to assess whether and to what extent long-term sirolimus therapy may improve clinical outcomes of patients with ADPKD, said the authors. "These long term efficacy trials, however, should require careful patient monitoring for ensuring tolerability of sirolimus therapy."
In an accompanying editorial, Robert W. Schrier, MD, from the Division of Renal Diseases and Hypertension, University of Colorado, Denver, said the study had a number of caveats. He pointed out that the dropout rate was 28%, the statistical analysis was not by intention to treat, and that 10 of the 15 study subjects who completed the study developed aphthous stomatitis.
He also noted that the treatment was associated with significant increases in liver enzymes and lipids, a decrease in hematocrit, and an increase in urinary albumin/protein excretion. "This is potentially bothersome regarding possible lifelong therapy for ADPKD," he writes. "Thus results of larger and longer follow-up studies of [mammalian target of rapamycin] inhibitors in patients with ADPKD will be very important."
However, Dr. Schrier writes, this study, along with another study investigating a somatostatin analogue in patients with polycystic liver and kidney disease that appeared in the same issue of the journal, "give hope that increases in polycystic liver and kidney volume can be attenuated and thereby improve morbidity and mortality in patients with ADPKD."
The authors of the study have disclosed no relevant financial relationships. Dr. Schrier is a consultant for Otsuka Pharmaceuticals.
J Am Soc Nephrol. Published online May 13, 2010. The accompanying editorial was published online April 29, 2010.