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。
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.
