慢性肾病进展新定义：eGFR2年下降30%

拉斯维加斯——最近一项里程碑式研究为临床医生提供了对于慢性肾病临床显著进展的新定义，这一新定义既可用作临床试验的主要终点，亦可用于日常临床实践。

约翰霍普金斯大学George W. Comstock 公共卫生研究与预防中心主任Josef Coresh博士在由美国肾脏基金会（NKF）举办的会议上指出，这项由全球慢性肾病预后联合会开展的研究表明，如果2年内估计肾小球滤过率（eGFR）下降30%，则预示着接下来2~3年内发生终末期肾病（ESRD）的风险增加4~5倍。

Josef Coresh博士

eGFR在2年内降低30%所对应的ESRD风险增加幅度，在很大程度上独立于患者的基线慢性肾病分期。也就是说，基线时eGFR＜60 ml/min·1.73 m²的患者如果eGFR降低30%，则与2年内eGFR无变化的患者相比，校正后ESRD风险增加4.4倍；基线时eGFR≥60 ml/min·1.73 m²的患者，如果eGFR降低30%，则ESRD风险增加5倍。

Coresh博士报告了对28个队列、150万名受试者的个体水平meta分析结果。在大约50万名基线eGFR＜60 ml/min·1.73 m²的受试者中，在从2年基线期结束时开始的平均2.4年随访期内共发生7,523例ESRD事件。基线eGFR≥60ml/min·1.73 m²的受试者，在随访期内发生了1,009例ESRD事件。

这项研究是NKF与食品药品管理局（FDA）协作的产物。FDA官员已承认，临床试验采用的慢性肾病进展终点——血清肌酐浓度比基线水平翻倍——阻碍了治疗的进步，原因是这一替代终点是一种晚期事件，因而要求研究纳入更大量样本和进行更长期随访。因此，FDA期盼出现支持更佳替代终点的证据。

这项最新meta分析证实，2年内血清肌酐浓度翻倍确实是慢性肾病进展的有效终点，在基线eGFR＜60 ml/min·1.73 m²的受试者中与ESRD风险增加31倍相关，在基线eGFR≥60 ml/min·1.73 m²的受试者中与ESRD风险增加57倍相关。但是，2年内血清肌酐浓度翻倍是一种较罕见的情况，在基线eGFR较低和较高的受试者中的发生率分别仅为＜1%和0.1%。而2年内eGFR降低30%的发生率约为eGFR翻倍的10倍。

Coresh博士指出：“eGFR翻倍这一终点仅能覆盖随访期间10%的ESRD人群归因风险，而eGFR降低30%在基线eGFR较低组和较高组中分别可以覆盖44%和28%的ESRD。”

在这项meta分析所包含的28项研究中，Coresh博士观察到了结果的高度一致性。“这种高度一致性使我们更有信心认为，如果2年内eGFR降低30%，就可以高度怀疑ESRD风险将增加约4倍。”

Coresh博士强调，这项meta分析显示，绝对风险不仅取决于2年内的eGFR变化，基线eGFR水平和随访时间也是关键因素。

“例如，一些基线eGFR为50 ml/min·1.73 m²但2年内保持稳定的患者，10年后ESRD风险仅为5%；如果2年内eGFR降低30%，则10年风险骤升至21%。对于基线eGFR为35ml/min·1.73 m²的患者，如果eGFR在2年内无变化，则10年ESRD风险为18%；如果2年内eGFR降低30%，则10年风险骤升至64%。因此，我们在头2年内就可以较准确地预测远期结局。”

上述结果基本独立于患者年龄、是否合并糖尿病和蛋白尿等因素。

这项meta分析获得了NKF和国立糖尿病、消化病与肾病研究所（NIDDKD）的支持，在接下来的1年内将发布6篇相关论文。第一篇已于6月3日在《美国医学会杂志》上发表（JAMA 2014 [doi:10.1001/jama.2014.6634]）。为了包含与eGFR变化相对应的全因死亡风险数据，这篇论文的发表时间晚于Coresh博士在拉斯维加斯的报告时间。Coresh博士指出，这类数据非常重要，因为多数慢性肾病患者在尚未发展为ESRD之时即死于心血管和其他原因。在这项meta分析中，2年内eGFR降低30%与全因死亡风险增加80%相关。

Coresh博士报告称无相关利益冲突。

爱思唯尔版权所有 未经授权请勿转载

By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

LAS VEGAS – A landmark study has provided physicians with an improved definition of clinically significant progression of chronic kidney disease for use as a major endpoint in clinical trials as well as in daily medical practice.

Specifically, it’s now clear from the study conducted by the global CKD Prognosis Consortium that a 30% decline in estimated glomerular filtration rate (eGFR) over the course of 2 years portends a 5- to 6-fold increased risk of developing end-stage renal disease (ESRD) during the next 2-3 years, Dr. Josef Coresh reported at a meeting sponsored by the National Kidney Foundation.

The magnitude of increased risk of ESRD in patients with a 30% 2-year decline in eGFR was similar regardless of their baseline stage of CKD. That is, patients with a low baseline eGFR of less than 60 mL/min per 1.73 m² had an adjusted 5.4-fold increased risk if they had a 30% drop in eGFR, compared with those whose eGFR remained unchanged over a 2-year period, while those with a 30% eGFR drop starting from a higher baseline of 60 mL/min per 1.73 m² or more had a 6-fold increased risk, said Dr. Coresh, professor of epidemiology and director of the George W. Comstock Center for Public Health Research and Prevention at Johns Hopkins University, Baltimore.

He presented an individual-level meta-analysis of 1.5 million participants in 28 cohorts. Among roughly half a million patients in the 19 cohorts with an initial eGFR below 60 mL/min per 1.73 m², there were 7,523 ESRD events during a mean 2.4 years of follow-up beginning at the close of the 2-year baseline period. An additional 1,009 ESRD events occurred during the follow-up period in participants with an initial eGFR of 60 mL/min per 1.73 m² or more.

This study grew out of a collaboration between the National Kidney Foundation and the Food and Drug Administration. Officials at the regulatory agency now accept that the established endpoint used to document CKD progression in clinical trials – that is, a doubling of serum creatinine concentration from baseline – has held back therapeutic progress in the field. That’s because this FDA-mandated surrogate endpoint is a late event and thus requires studies with large sample sizes and long follow-up times. The agency is eager for evidence in support of a better surrogate endpoint, explained Dr. Coresh, who is also director of the cardiovascular epidemiology training program at Johns Hopkins.

The new meta-analysis confirmed that a doubling of serum creatinine concentration over the course of 2 years is indeed a valid endpoint for CKD progression. It was associated with a 32-fold increased risk of developing ESRD in patients who started with an eGFRbelow 60 mL/min per 1.73 m² and a 57-fold increased risk in patients with a higher starting eGFR. However, a doubling of serum creatinine in a 2-year time frame was also a rare outcome, occurring in less than 1% of patients with a low initial eGFR and in 0.1% of those with a higher initial value. In contrast, a 30% drop in eGFR over a 2-year period was 10 times more common.

"A doubling of serum creatinine captures only 10% of the excess or population-attributable risk of ESRD during follow-up, whereas a 30% decline in eGFR captures 44% of the population with ESRD in the baseline low-eGFR group and 28% in those with a baseline eGFR of 60 mL/min per 1.73 m² or greater," Dr. Coresh said.

An impressive level of consistency in the results was seen across the 28 studies included in the meta-analysis, which featured adjustment for confounders.

"I think this level of remarkable consistency makes it safer to think that in many settings, if you have a 30% decline in eGFR over 2 years, you will have a substantially increased risk of ESRD of approximately 5-fold," according to the physician.

He stressed that the meta-analysis demonstrated that it’s not just the change in eGFR over the course of 2 years that’s important in determining risk, but that the starting eGFR level and duration of follow-up are also key in determining absolute risk.

"For example, someone who starts at 50 mL/min per 1.73 m² and is stable for 2 years has a subsequent risk of ESRD 10 years later of only 5%. If, on the other hand, that patient had a 30% decline in eGFR during 2 years, the 10-year risk becomes 21%. And if you start out at an eGFR of 35 mL/min per 1.73 m², your 10-year risk of ESRD goes from 18% if your eGFR is unchanged for 2 years to 64% if your eGFR falls by 30%. So within the first 2 years, you have the ability to detect things that will happen a long time from now, with pretty good power," Dr. Coresh said.

The findings held true regardless of patient age, the presence or absence of diabetes, and albuminuria.

This meta-analysis, which was supported by the National Kidney Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases, will result in six publications during the next year. The first was published online on June 3 (JAMA 2014 [doi:10.1001/jama.2014.6634]). The JAMA report goes beyond Dr. Coresh’s time-limited Las Vegas presentation in that it also includes data on all-cause mortality risk according to change in eGFR. He noted this is important because the majority of patients with CKD die of cardiovascular and other causes without ever reaching ESRD. In the meta-analysis, a 30% decline in eGFR over the course of 2 years was associated with an 80% increased risk in all-cause mortality.

Dr. Coresh reported having no relevant financial conflicts.