《国际循环》：心衰患者发生利尿剂抵抗的机制是什么？怎样处理利尿剂抵抗？

    <International Circulation>: What are the mechanisms for diuretic resistance in patients with heart failure and what are the strategies to overcome diuretic resistance?

    Yancy博士：利尿剂抵抗（即对利尿剂治疗反应差）越来越多见，处理起来相当棘手。我们需要关注慢性心衰和急性心衰这两大方面。就慢性心衰来讲，我们发现随着利尿剂应用时间的延长，有些患者对同等剂量的利尿剂反应差。从表面上看，利尿剂抵抗是肾脏局部异常所致，可能是非甾体类抗炎药物（NSAIDs）诱发肾损伤的表现，也可能是神经体液持续激活所致肾脏疾病全面进展的标志。我认为是后者。
 现在我们逐渐认识到，无论对心肌还是肾小球，神经体液激活均会产生不良影响，除了导致左室重构以外，也会引起肾小球/肾脏重构。当慢性肾衰患者出现利尿剂抵抗时，我们不应认为这仅仅是肾功能障碍的表现。实际上，这标志着整个心脏/肾脏神经体液异常的进展。
 急性心衰患者如果出现利尿剂抵抗，那么问题更为严重。因为对于失代偿性心衰患者，如果对常规剂量的利尿剂治疗无反应的话，我们就将面临着一系列问题，因为我们必须要纠正心衰。此时可以选择“团注”大剂量利尿剂、持续输注利尿剂或给予肾脏替代治疗。这方面的最新证据来自DOSE试验。该试验显示预先持续输注利尿剂并不优于“团注”利尿剂。不过，对于失代偿性心衰患者，“团注”大剂量利尿剂更好。
 综上所述，利尿剂抵抗是需要我们特别关注的问题。它提示心衰患者由于神经体液激活所导致心肾综合征的全面进展。而急性心衰患者出现利尿剂抵抗则是一种严重的特殊情况，因为加大利尿剂剂量时患者病情仍会加重。对此，目前的最佳治疗手段可能是大剂量利尿剂团注，而不是持续输注。至于肾脏替代治疗是否应当作为心衰的常规治疗，目前还未达成共识，现有证据显然还不足以支持此种做法。但是，在其他治疗都不奏效的情况下，也可以应用肾脏替代治疗。
 最后，除了利尿剂抵抗，还有心肾综合征。心肾综合征可能提示过早死亡。因此，我们应当认识到这一系列的级联反应相当重要。即使是轻微的肾功能下降，例如血清肌酐升高0.3 mg/dl，也会导致转归不良。因此，在未来，我们应当更加重视利尿剂用量、心肌灌注和肾功能指标之间的联系，而以往我们忽视了这一问题。
 我们很欣喜地看到目前已经开发出来一些更为特异的肾功能指标。在过去，我们只有尿素氮和肌酐。但是，现在还可以测定半胱氨酸蛋白酶抑制物C。中性粒细胞明胶酶相关载脂蛋白-2（NGAL）是反映肾功能的一个新指标。因此，上述指标有助于我们在患者进展至严重肾功能障碍之前更加准确地发现肾功能障碍的早期征象。

    Dr. Yancy: That is a very provocative question and increasingly we need to address the absence of a robust response to the administration of diuretics. The two broad areas that need focus are chronic care and acute care. In chronic care， we recognize that over time there are patients who are less responsive to the same diuretic dose. Ostensibly that is because of something that has happened in the kidney space. It is either an injury phenomenon to the kidney concomitant to medicines like NSAIDs or it is a surrogate of the general progression of disease as an ongoing neurohormonal activation. I think it is the latter. We are beginning to understand that at the glomerular and myosite level the same negative influences are operative that are not only causing ventricular remodeling but also glomerular/renal remodeling. In the chronic space， when we see diuretic resistance， we should not just think that it is just evidence of kidney dysfunction because it is evidence of progression of the entire cardiorenal neurohormonal maladaptation process. Acutely it is a much more critical problem because for the decompensated patient who receives what should be a conventional dose of diuretics and does not respond， we are beset with a number of problems， i.e. the diuretic resistance issue， because we have to decongest that patient. We can either take the approach of very high dose bolus diuretics， continuous infusion diuretics， or renal replacement strategies. The most recent data comes from the DOSE trial， which demonstrated the a priori administration of continuous infusion diuretic therapy versus bolus diuretic therapy was not proven to be superior to bolus diuretic therapy. What was proven to be superior was high dose bolus diuretic therapy in those patients with decompensation. Therefore， diuretic resistance is a very real concern and is indicative of the overall progression of cardiorenal disease due to ongoing neurohormonal maladaptation. Acutely it represents a unique and serious problem because those patients do less well when they are exposed to more diuretics， but today the right approach is probably high dose bolus therapy and not continuous infusion. Whether or not renal replacement strategies are part of the everyday practice of heart failure therapy still remains open to debate. It is clearly not yet indicated but appropriate if all other measures have failed. Finally， what goes beyond diuretic resistance is cardiorenal syndrome， which is probably a harbinger of premature death so we must respect that this cascade is very important. Even mild (03:44) on renal function changes in serum creatinine of 0.3 mg/dl are associated with poorer outcomes. Thus， we have not in the past， but we should in the future have much more respect for this interface of myocardial perfusion， diuretic dosing， and markers of renal function. We are delighted to see that more specific makers of renal function are coming forward. Previously we just looked at BUN and creatinine， but now we can look at cystatin c and there is a new marker called NGAL. Therefore， we now have the opportunity to have more precision in identifying early evidence of renal dysfunction before it becomes manifest as a clinical burden.

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