无症状者筛查肾病是否合理？ACP与ASN立场相悖

根据美国内科医师协会(ACP)发布的最新指南，没有早期慢性肾病症状或危险因素的成年人不应当接受针对该病的筛查。

但ACP指南引起了美国肾病学会(ASN)的不满，后者强烈建议不论有无危险因素都应当考虑进行肾病筛查。

ACP主席Molly Cooke 博士在接受采访时表示：“没有证据表明，在无肾病危险因素的无症状者中检测基线肌酐水平或筛查肾功能不全可以改善患者结局。”

这是ACP首次发布有关成年人1~3期慢性肾病筛查、监测与治疗的临床实践指南。成年人中慢性肾病的主要危险因素包括糖尿病、高血压和心血管疾病。这部ACP指南发表于《内科学年鉴》10月22日在线版上([doi:10.7326/0003-4819-159-12-201312170-00726])。

ACP临床指南委员会利用Medline和Cochrane数据库系统评价了1985~2011年11月期间发表的所有相关数据。这部指南评估的结局包括全因死亡、心血管事件和疾病、肾脏与血管事件的复合终点、终末期肾病、生活质量、躯体功能，以及日常生活活动。研究者确定，没有足够证据用来评估早期慢性肾病筛查的获益和危害，因此建议临床医生不开展这样的筛查。

ACP尤其反对在有或无糖尿病以及目前正在服用血管紧张素转换酶(ACE)抑制剂或血管紧张素Ⅱ受体阻滞剂(ARB)的成年人中进行尿蛋白检测。

Cook博士表示，这一建议“提醒临床医生不要做不会改变患者管理的检查”。ACE抑制剂或ARB本身就是对微量白蛋白尿(轻度蛋白尿的一种类型)的治疗。“没有证据表明通过监测蛋白尿评估高血压药物治疗效果可带来更好的结局。”

ASN：不筛查？没门儿！

ACP的建议立即招致了ASN的驳斥。ASN执行理事Tod Ibrahim博士在声明中指出：“早期发现是防止患者进展到依靠透析存活的关键。ASN及其近15,000名成员——均为肾病领域的专家——对ACP不负责任的建议感到失望。”

ASN主席指出，早期慢性肾病筛查的获益与危害的证据不足，正是临床医生应当检查早期慢性肾病的原因所在。“关于慢性肾病的一个问题是，我们还没有掌握早期发现慢性肾病的有效机制。”他在接受采访时说：“我们已经掌握的是筛查蛋白尿，这是一种非常简单、便宜的检测，却能提供非常有价值的信息。”

至于对正在服用ACE抑制剂或ARB的成年人进行蛋白尿检测，Molitoris博士解释称可能有更微妙的获益。“对于正在服用降压药的患者，假如你告诉他/她不控制好血压就可能发生进展性肾病，将会进一步提高其依从性。并不是所有高血压患者都首先使用一线降压药的。”

ACP赞成采用ACE抑制剂或ARB治疗患有高血压或1~3期慢性肾病的患者，以及给予早期慢性肾病患者合适的他汀类药物治疗以遏制低密度脂蛋白水平升高。然而，ACP认为进行额外的筛查和治疗在很大程度上是多余的。

Cooke博士表示：“对于那些将噻嗪类利尿剂或β受体阻断剂作为初始降压选择的临床医生，这部指南应该会改变他们的实践做法。”

然而，由于许多“报告单”要求糖尿病患者每年接受1次尿微量白蛋白检测，很多医生对已经在服用ACE抑制剂或ARB的患者进行这项检测。“这部指南应当会使他们在遇到患者要求进行这项检测时答复称‘不符合适应证’。”

ACP发现，ACE抑制剂和ARB之间在结局方面没有显著差异，尽管ACE抑制剂和ARB联合治疗的确会明显增加不良反应风险(咳嗽、高钾血症和透析)。

与此同时，全国肾脏基金会(NKF)建议，所有患有糖尿病、高血压、心血管疾病，年龄超过60岁，或有肾脏衰竭家族史的患者，均应接受血液检查以估算肾小球滤过率(GFR)和蛋白尿检测。

“ACP指南对慢性肾病临床结局的看待方式与我们的指南非常不同。”NKF发言人Sean Roach提醒道，ACP把“1~3期慢性肾病一概而论，然而实际上它们有着明显不同的不良结局风险，而且ACP没有考虑到所有因忽视肾功能水平而引起的患者安全性问题”。

Roach指出：“我们承认尚无有关慢性肾病筛查的随机试验，但是我们的建议是以对糖尿病和降压药观察性试验和临床经验的大量分析为基础的。”

批评者质疑慢性肾病标准

不久前，美国预防服务工作组(USPSTF)的报告遭遇了与ACP指南相似的质疑。该报告声称目前没有足够证据支持推荐以一般人群为基础的筛查。报告指出，虽然早期筛查可能影响已被诊断为糖尿病或高血压等疾病的患者的结局，但没有证据显示对无危险因素者进行早期治疗有益。

ASN迅速做出了回应。Molitoris博士指出：“我们向USPSTF致信，要求他们重新考虑。结果他们改为‘高度建议’收集更多数据以分析筛查的成本效益。”

2002年，NKF发起的肾病：改善全球结局(KDIGO)发布了具有里程碑意义的慢性肾病指南。这部指南在2012年更新，仍维持2002年确立的慢性肾病标准，包括GFR＜60 ml/min•1.73 m²和白蛋白/肌酐比率(ACR)≥30 mg/g的诊断阈值。KDIGO还维持了五期慢性肾病分类系统。而目前该指南已将五期分类系统扩大，在3级GFR分类中新增了2个亚分类——G3a，GFR：45~59和G3b，GFR：30~44，并额外增加了3个蛋白尿分类(Ann. Intern. Med. 2013;158:825-30)。

这些CKD标准不仅引起了ACP的质疑，一些循证医学学者也有不同意见。今年在线发表在BMJ上的一项分析中，澳大利亚熏蒸时间研究中心的Roy Moynihan博士引用数据称，KDIGO判断早期慢性肾病的GFR值与年龄＞60岁的男性和年龄＞50岁的女性的正常范围有重叠。“新定义将如此多的症状风险低的人归为慢性肾病，势必会导致过度诊断。”(BMJ 2013;347:f4298)。

Moynihan博士指出，回溯至KDIGO发布慢性肾病标准的2002年之前，估计美国成年人慢性肾病患病率约为1.7%。2002年之后，使用KDIGO标准，成年人患病率上升至1/8(约14%)。

“争议之处在于，GFR下降到什么程度才算异常？”Molitoris博士指出：“如果你的GFR下降，并且出现了蛋白尿，那我们知道这就是不正常。”这也正是蛋白尿筛查的重要性之所在。欧洲的观点是，如果只是GFR降至某种程度，也有可能是衰老的正常表现，Molitoris博士认同这一观点。

“不同的全球观点”

Cooke博士表示，不清楚KDIGO为何扩展其慢性肾病标准。她猜测这可能是“不同的全球观点”现象。

“‘检测每个人的肌酐水平’是一个颇有些诱人的说法。但就像前列腺癌筛查那样：一旦你将检测的全部成本——不仅是费用——纳入计算，你就会明白了。”

但Molitoris博士反驳称，慢性肾病筛查更类似于检测心血管疾病。“不妨与血脂检测相比，想想看我们对多少患者进行了血脂筛查。更何况血脂检测是有创的抽血检查，而蛋白尿检测只需要采集尿液。尿液检查毫无危险，只需要采集尿液，将试纸插入尿液中，然后读数即可。如果结果为阳性，就采用更精密的化学检测进行随访。不仅如此，蛋白尿检测极少出现假阳性结果。”

ACP指南为临床医生提供了所谓的“高价值医疗建议”：略过早期慢性肾病筛查，原因是缺乏证据表明筛查可改善临床结局，“检测会增加成本(包括筛查检测、随访检测和假阳性结果带来的成本)，增加就医，并增加维持或得到健康保险的成本。”

Molitoris博士不同意这一看法，理由是所有分期的肾病都具有“进展性和沉默性的特点”。“在进行成本分析时，应当对比筛查成本和透析成本。1例患者透析1年的成本介于80,000~90,000美元，拿这笔钱可以做大量筛查。”

Cooke博士说，ACP呼吁在一个“中间地带”讨论对患者(而非医生)而言最有利的是什么。

美国内科医师协会资助者这部指南。指南作者们无相关利益冲突披露。

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By: WHITNEY MCKNIGHT, Internal Medicine News Digital Network

Adults who don’t show symptoms of, or have risk factors for, early chronic kidney disease should not be screened for it, according to new guidelines from the American College of Physicians.

But the ACP’s recommendation prompted the American Society of Nephrology to counter with its own strong recommendation in favor of kidney disease screening regardless of a patient’s risk factors.

"There is no evidence that obtaining a ‘baseline creatinine’ level, or screening for renal dysfunction in asymptomatic individuals with no risk factors for kidney disease, improves outcomes for patients," said ACP President Molly Cooke in an interview.

The clinical practice guidelines are the first issued by the ACP for the screening, monitoring, and treatment of stage 1-3 chronic kidney disease in adults. Major risk factors for CKD in adults include diabetes, hypertension, and cardiovascular disease.

The ACP published the guidelines online in Annals of Internal Medicine 2013 Oct. 22 [doi:10.7326/0003-4819-159-12-201312170-00726]).

The college’s Clinical Guidelines Committee used Medline and Cochrane databases to systematically review all relevant data published between 1985 and November 2011.

Outcomes assessed for the guidelines included all-cause mortality, cardiovascular events and disease, composite renal and vascular outcomes, end-stage renal disease, quality of life, physical function, and activities of daily living.

The investigators determined that there was not enough evidence to evaluate the benefits and harms of screening for early CKD, and so they recommended that clinicians not perform it.

The ACP specifically recommended against proteinuria testing in adults with or without diabetes and who are currently taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).

That recommendation was a “reminder to physicians not to do tests that will not change patient management,” Dr. Cooke said. ACE inhibitors or ARBs are already the treatment for microalbuminuria, a form of low-grade proteinuria.

“There is no evidence that monitoring proteinuria to assess the effects of pharmacological hypertension management produces better outcomes,” she added.

ASN: No screen? No way!

The ACP’s recommendations spurred an immediate rebuke from the American Society of Nephrology.

“Early detection is the key to preventing patients from progressing to relying on dialysis to stay alive,” Dr. Tod Ibrahim, the ASN’s executive director, said in a statement. “ASN and its nearly 15,000 members – all of whom are experts in kidney disease – are disappointed by ACP’s irresponsible recommendation.”

The lack of evidence on the benefits and harms of early CKD screening is precisely why physicians should test for early-stage CKD, according to ASN President Bruce Molitoris.

“One of the problems with CKD is we don’t have effective mechanisms to detect it early,” he said in an interview. “What we do have is screening for proteinuria, which is a very simple, extremely inexpensive test that can give great insight.”

As for proteinuria testing in adults taking ACE inhibitors or ARBs, there might be a more nuanced benefit, Dr. Molitoris explained.

“It’s a little bit more incentive to increase compliance in a patient who is taking a medication for hypertension if you tell them they’re getting progressive kidney disease if they don’t control their blood pressure,” he said. “Not all patients with hypertension are started out on those first-line drugs,” he added.

The ACP endorses treating patients who have hypertension or stage 1-3 CKD with ACE inhibitors or ARBs, as well as giving patients with early CKD appropriate statin therapy to manage elevated levels of low-density lipoprotein. However, the college calls additional screening and treatment largely superfluous.

“For doctors who have been using a thiazide diuretic or a beta-blocker as their initial antihypertensive of choice, this guideline should change their practice,” said Dr. Cooke.

However, because many practice “report cards” call for an annual urine microalbumin test in diabetic patients, many physicians perform the test on patients who are already on an ACE inhibitor or an ARB, she said.

“This guideline should prompt them to respond ‘test not indicated’ when it is requested,” Dr. Cooke said.

The ACP found no significant differences in outcomes between ACE inhibitors and ARBs, although it did note that the risk of adverse effects (cough, hyperkalemia, hypotension, and dialysis) significantly increased in combined ACE inhibitor and ARB therapy.

Meanwhile, the National Kidney Foundation recommends that anyone with diabetes, hypertension, cardiovascular disease, age over 60, or a family history of kidney failure have a blood test to estimate their glomerular filtration rate (GFR) and a urine test for proteinuria.

“The ACP guidelines looked at the clinical outcomes of CKD very differently than our guidelines did,” cautioned Sean Roach, spokesperson for the NKF, in an e-mail. The ACP put “CKD stages 1-3 together when they have markedly different risks of adverse outcomes, and [didn’t take] into account all of the patient safety issues that arise due to ignorance of a patient’s level of kidney function.

“We acknowledge that there have been no randomized trials of CKD screening,” Mr. Roach noted, “but our recommendations are based on extensive analysis of observational trials, clinical trials of diabetes and antihypertensive drugs, and clinical experience.”

Critics question CKD criteria

A recent U.S. Preventive Services Task Force (USPSTF) report took a position similar to the ACP’s, stating there is currently insufficient evidence to recommend general population-based screening.

That report noted that although early screening could affect outcomes for people already diagnosed with conditions such as diabetes or hypertension, no evidence existed to show the benefits of early treatment in people without these risk factors.

The ASN swiftly responded. "We sent [the USPSTF] a letter asking them to reconsider," said Dr. Molitoris. "That was within the last 6 months. They came back with a ‘high recommendation’ for collecting more data to analyze the cost effectiveness of screening."

In 2002, the NFK-sponsored Kidney Disease: Improving Global Outcomes (KDIGO) released landmark guidelines on CKD. In a 2012 guidelines update, KDIGO kept the criteria it established in 2002 for CKD, including diagnostic thresholds of a GFR less than 60 mL/min per 1.73 m2 and an albumin/creatinine ratio (ACR) of at least 30 mg/g. And it maintained its five-stage CKD classification system.

But it expanded the existing five-stage classification system to include two subcategories of grade 3 GFR categories – G3a, with a GFR of 45-59; and G3b, with a GFR of 30-44 – and three additional categories of albuminuria (Ann. Intern. Med. 2013;158:825-30).

Those CKD criteria raised eyebrows not just at the ACP, but also with some evidence-based medicine scholars. In an analysis published online earlier this year in BMJ, Dr. Roy Moynihan of the Centre for Research in Evidence-Based Practice, Robina, Australia, cited data that the GFR value used by KDIGO to determine early CKD falls within the normal range for men over age 60 and women over age 50.

By "labeling so many people at low risk of symptoms as having chronic kidney disease, the new definition axiomatically produces overdiagnosis," Dr. Moynihan and his colleagues cautioned (BMJ 2013;347:f4298).

Prior to the 2002 publication of the KDIGO criteria for CKD, according to Dr. Moynihan, the incidence rate for CKD in U.S. adults was estimated to be around 1.7%. After 2002, using the KDIGO criteria, it rose to 1 in 8 adults, or about 14% of the adult population.

"The controversial aspect around that is, at what point as your GFR decreases does it become abnormal?" cautioned Dr. Molitoris. "If you have a reduced GFR, and proteinuria, we know that’s abnormal.

That’s why the screening for proteinuria is so important. If you just have a reduced GFR to a certain extent, it may be a normal aging process. That’s the European perspective, and I think they have a point there."

‘Different worldview’

While the ACP guidelines for CKD refer to the KDIGO criteria as their counterpoint, Dr. Cooke said she did not know what motivated KDIGO to expand the criteria. She suggested it might be the "different worldview" phenomenon that often occurs between subspecialists and generalists.

"It’s tempting to say, ‘Let’s just test everybody’s creatinine,’ " Dr. Cooke noted. "But it’s just like with prostate cancer screening: Once you start to factor in all the costs – and not just the money – of testing on that broad of a scale, it doesn’t [add up]."

But Dr. Molitoris countered that CKD screening is more akin to testing for cardiovascular disease.

"One could make the comparison to checking for cholesterol, only that’s invasive – that’s drawing blood," he said. "This is just taking urine, and yet, how many people do we screen for cholesterol?

There is no risk in doing the proteinuria test. You collect the urine, put a stick into it, and read it. If it’s positive, then you will follow up with a more sophisticated chemical test." He also noted that false positives in proteinuria tests are rare.

The ACP guidelines offer physicians what it calls "high-value care advice": Skip early CKD screening, because in the absence of evidence that screening improves clinical outcomes, "testing will add costs, owing to both the screening test and additional follow-up tests (including those resulting from false-positive findings), increased medical visits, and costs of keeping or obtaining health insurance."

Dr. Molitoris disagreed, citing "the aggressive and silent nature" of kidney disease in all its stages.

"You have to think of the cost analysis as how many screenings you can do for the cost of one patient who goes on to need dialysis. That costs between $80,000 and $90,000 a year to maintain for every year [a patient is] on it," Dr. Molitoris explained. "You can do a lot of screening on that."

Dr. Cooke said the ACP was calling for a "middle ground" to bring the discussion back to what is best for the patient, not the practitioner.

"We are saying that unless the patient has a reason for you to be concerned, other than the fact that they are a human being, there is no reason to screen for CKD every year," she explained. "There is no evidence that diagnosing the average person on the street as stage 1 or 2 [CKD] does them any good if they don’t have any risk factors."

The American College of Physicians funded the guidelines. The guidelines’ authors had no relevant disclosures.