In the presence of a metabolic acid‐base disorder, the kidney is called upon to compensate appropriately, altering the net acid excretion in urine. Metabolic acidosis is normally associated with urine acidification. This process can be appreciated through two different explanatory models.

On the one hand, according to the widely adopted approach, pH regulation is achieved with proton (H⁺) removal through the urine, mainly in the form of ammonium cation ().1 Other buffers, such as phosphate, also contribute to H⁺ excretion although to a lesser degree. excretion results in the regeneration of bicarbonate (), which increases extracellular fluid pH. Specifically, the process of production by itself is considered to have no bearing in total acid‐base balance, in case the produced in the kidney is not excreted but, being absorbed in blood, is transferred to the liver where it participates in urea production. There, one is consumed along with one in the process of ureagenesis. Thus, it has been proposed that the net effect on extracellular fluid pH is because of being excreted rather than absorbed in blood and converted to urea in the liver; excretion of results in net gain.

Urine [] is indirectly assessed in clinical practice by measurement of the urine anion gap (U_AG).2 [U_AG] calculation formula reflects the difference between urine unmeasured cation (UCs) and unmeasured anion (UAs) concentrations. From the law of electrical neutrality, applying to aqueous solutions, it follows:

Quantitatively the main unmeasured cation in urine is. In this setting, increase of excretion, with more severe acidosis, leads to reduced/negative [U_AG] values.

In hyperchloraemic acidosis such a negative correlation between excretion and [U_AG] has long been demonstrated. In fact, [U_AG] is used as a differential marker for non‐anion gap metabolic acidosis, being largely negative in case of diarrhoea with normal kidney function and positive in case of distal renal tubular acidosis.2

[UAG] might offer a relatively accurate approximation of []. However, the association between [] in urine and [UAG] is disturbed in settings such as chronic renal failure, where the increased concentration of other unmeasured ions (sulphate and phosphate) creates discrepancies, making direct [] measurement in the urine seemingly necessary, in order to draw correct conclusions; nevertheless, these discrepancies may be overcome when urine sulphate and phosphate are accounted for in the [UAG] equation.2

The concept of changing the [H⁺] in a body fluid compartment by removing H⁺ from it contradicts Stewart's viewpoint.3 According to Stewart, what determines [H ⁺] in a body fluid is mainly [SID], that is the charge space created by the concentration difference of the strong anions and cations in it. The movement of H⁺/ in the aquatic environment of various compartments in the body cannot change their concentration; in fact, it does not really exist. Following Stewart's argument, when the [SID] in plasma/extracellular space ([SID]_ECV) decreases (metabolic acidosis), its gradual restoration to its original value (increase) is mediated by the kidney, that is by excretion of urine with [SID] ([SID]_u) <[SID]_ECV. Gattinoni et al4 proposed a comprehensive model for the restoration of [SID]_ECV, utilizing Stewart's physicochemical approach. They suggest that a change in the net electrical charge in extracellular space can be restored by a corresponding change in the net electrical charge in urine, taking into account the volume of body fluid where this change takes place and the rate of urinary excretion. Based on this model, in case of an acidosis disorder, considering that the [SID]_ECV is not affected by other modifiers (infusion of electrolyte solutions and metabolic disorders), each elementary part of plasma, which is filtered in the glomeruli and excreted by the kidneys as urine with lower [SID], will augment [SID]_ECV. Integration of these elementary changes over time will carry out the desired [SID]_ECV increase:

*Riemann‐Stieltjes integral; a and b represent the corresponding time points; V_(t) could be replaced by the urine production rate.

For a given urine production rate, the smaller the [SID]_u the greater the difference, that is the correction (increase) of [SID]_ECV. In fact, if [SID]_u becomes negative, the correction will be even greater, since the absolute value of [SID]_u will be added to that of [SID]_ECV. This translates into enhanced effectiveness of renal function to restore acidosis.

It is important to understand that, in solutions of strong ions with weak electrolytes, when the [SID] is positive (eg normal [SID] value in the extracellular space and plasma), and for a [SID] range from zero to [A_tot] (total concentration of weak, non‐volatile acids), changes of [H⁺] are very small, only a minuscule percentage of the [SID] change (provided that [A_tot] does not appreciably alter).3 However, in solutions with a negative [SID] value, positively charged weak ions are needed to maintain electrical neutrality, and the only ones available are H⁺. Therefore, the following equality holds: [H⁺] = −[SID]. Thus, adding strong acid to a solution with negative [SID] will increase [H⁺] as much as [SID] decreases.

[SID]_u is calculated by an equation identical to that of [U_AG]:

Urine acidity change is accomplished by an increase of urinary [Cl⁻], or of any strong anion concentration, that is not accompanied by a similar increase of urine [Na⁺], leading to a decrease of [SID]_u (Figure 1).

From Stewart's point of view, it makes no sense to refer to [SID]_u as indicative of the presence of some molecules that carry H⁺ in the urine, for example, . As stated, [SID]_u determines the extent of weak electrolyte and water dissociation in the excreted urine and therefore [H ⁺] there. For Stewart, does not function as a H⁺ transporter or, at least, it could function as such as any molecule of H₃O⁺ in urine would.3

Similarly, the commonly reported trade‐off between strong ions and H⁺ (in single‐digit integer proportions) across membranes separating body fluids and the resulting stoichiometric [H⁺] changes on them is questioned. As Stewart notices, the [SID] buffer value for human plasma equals Δ[SID]/Δ[H⁺] = −6.9 × 10⁵, meaning that [SID] should change by hundreds of thousands of Eq/L to produce a change of [H⁺] by 1 Eq/L.3 Only in solutions with negative [SID], a linear relationship between [SID] and [H⁺] changes can be observed.

is a weak cation (pKa = 9.24) that is formed from an add‐on base, that is NH₃. NH₃ that dissolves in water combines with H⁺ to form . The total concentration of NH₃ () in urine, affecting urine pH, may be of particular importance for the functionality of the strong ion channels that are pH sensitive.5

Apart from the one mentioned above, if we wanted to allocate a role in the in urine, unifying somehow the translational aspects that are presented, it would be that its presence there, spares the strong cations that, otherwise, would be excreted in urine, along with the strong acid anions (ie in urine prevents the loss of strong cations). This, consequently, would positively affect the [SID] in plasma and, generally, the extracellular space.

Nevertheless, the transfer of H⁺/ through membrane carriers and ion channels has been described in detail. An example is Na⁺/H⁺ exchanger 3 (NHE‐3), an antiporter that is thought to mediate H⁺ secretion across the apical membrane of epithelial cells in the proximal convoluted tubules.6 However, investigators have questioned the ability of individual H⁺ to participate in transport processes and biochemical reactions. For example, H⁺ generation and transport during lactate production, in glycolysis.7 A main reason the investigators invoke is the restricted mobility of H⁺ in aqueous solutions.

Indeed, studies indicate that H⁺ diffusion might be much more restricted than we previously thought. Their fleeting existence in water (their lifetime measured in picoseconds)8 as well as their tiny concentration in the aqueous solutions of the body (≈10⁻⁷M), which would make the conventional diffusion process extremely slow, raise reasonable doubts as to whether each individual H⁺ could, actually, participate in transmembranic transport. To account for the observed pH changes, the proponents of the physicochemical approach provide a simple argument: strong ion transport across membranes changes [SID] in the relevant fluid compartments. The [SID] change automatically alters [H⁺]/pH in the solution; this is misperceived as being created by the transfer of H⁺

In fact, a unique transport mechanism, known as the Grotthuss mechanism (also referred to as structural diffusion) has long been proposed in place of H⁺ movement.9 According to this mechanism, H⁺ transfer occurs in a stepwise manner in water or any chain of hydrogen‐bonded molecules. Interconversion of cationic complexes and charge re‐localization in the hydrogen bond network occur. Each hydrogen‐bonded molecule acts simultaneously as a charge donor and acceptor; that is, when an excess H⁺ is added to one end of the chain, the adjacent hydrogen bond in the chain releases another H⁺. The charge distribution in the network is highly polarizable and may be greatly distorted by changing the magnitude of electrostatic forces.10 Such a stimulus, for example, can be produced by the alteration of SID into a solution. In addition to the bulk water mass, a Grotthuss mechanism has also been proposed for the transfer of H⁺ through ion channels.9

These physicochemical observations seem to support the Stewart's notion. On the whole, Stewart's approach may provide a more solid explanatory footing, as it is based on fundamental physicochemical principles (electrical neutrality, conservation of mass and Guldberg‐Waage mass action law) claiming universal validity, and do not result from the individual interpretation of separate experimental data. Nevertheless, while both methods approach pathophysiologically the issue of metabolic acidosis from entirely different angles, there seems to be no clear benefit in clinical practice over one another when they are used correctly. All in all, whichever approach one chooses, the concomitant decrease of [SID]u/[UAG] values along with [SID]_ECV in the setting of metabolic acidosis demonstrates proper renal response, while greater [SID]u/[UAG] values in the same setting signify impaired urine acidification.

在存在代谢性酸碱失调的情况下，需要肾脏进行适当的补偿，从而改变尿液中的净酸排泄。代谢性酸中毒通常与尿液酸化有关。这个过程可以通过两种不同的解释模型来理解。

一方面，根据广泛采用的方法，pH 调节是通过尿液中的质子 (H ⁺ ) 去除来实现的，主要以铵阳离子 ( ) 的形式。1其他缓冲液，如磷酸盐，也有助于 H ⁺排泄，尽管程度较小。排泄导致碳酸氢盐再生，从而增加细胞外液的 pH 值。具体而言，生产过程本身被认为与总酸碱平衡无关，如果在肾脏中产生的物质不被排泄，而是被血液吸收，被转移到肝脏参与尿素的生产。在那里，一个与一个一起被消耗在尿素生成过程中。因此，有人提出对细胞外液 pH 值的净影响是因为被排泄而不是被血液吸收并在肝脏中转化为尿素。排泄结果的净收益。

在临床实践中，尿液 [ ] 通过测量尿液阴离子间隙 (U _AG ) 间接评估。2 [U _AG ] 计算公式反映了尿液未测阳离子（UCs）和未测阴离子（UAs）浓度之间的差异。根据电中性定律，适用于水溶液，如下：

定量分析，尿液中主要未测量的阳离子是. 在这种情况下，排泄增加，酸中毒更严重，导致 [U _AG ] 值降低/为负。

在高氯性酸中毒中，排泄与[U _AG ] 之间的这种负相关性早已得到证实。事实上，[U _AG ] 被用作非阴离子间隙代谢性酸中毒的鉴别标志物，在肾功能正常的腹泻情况下大部分为阴性，在远端肾小管酸中毒的情况下为阳性。2

[UAG] 可能提供 [ ] 的相对准确的近似值。然而，尿液中的 [ ] 和 [UAG] 之间的关联在慢性肾功能衰竭等环境中受到干扰，在这种情况下，其他未测量离子（硫酸盐和磷酸盐）的浓度增加会产生差异，因此在尿液中进行直接 [ ] 测量似乎是必要的，为了得出正确的结论；然而，当在 [UAG] 方程中考虑尿硫酸盐和磷酸盐时，这些差异可能会被克服。2

通过从体液隔室中去除 H ⁺来改变 [H ⁺ ] 的概念与 Stewart 的观点相矛盾。3根据斯图尔特的说法，决定体液中[H ^{+ ] 的主要是[SID]，即由其中强阴离子和阳离子的浓度差异产生的电荷空间。}体内各隔室水生环境中H ⁺ /的运动不能改变其浓度；事实上，它并不真正存在。根据 Stewart 的论证，当血浆/细胞外空间中的 [SID] ([SID] _ECV) 减少（代谢性酸中毒），其逐渐恢复到其原始值（增加）是由肾脏介导的，即通过尿液排泄 [SID] ([SID] _u ) <[SID] _ECV。Gattinoni 等人4利用 Stewart 的物理化学方法，提出了一个恢复 [SID] _{ECV的综合模型。}他们认为，考虑到发生这种变化的体液量和尿液排泄率，可以通过尿液中净电荷的相应变化来恢复细胞外空间净电荷的变化。基于此模型，在酸中毒的情况下，考虑到 [SID] _ECV不受其他调节剂（电解质溶液输注和代谢紊乱）的影响，血浆的每个基本部分，在肾小球中过滤并通过肾脏作为具有较低 [SID] 的尿液排出，将增加 [SID] _ECV。随着时间的推移，这些基本变化的整合将实现所需的 [SID] _ECV增加：

*Riemann-Stieltjes 积分；a和b代表对应的时间点；V _(t)可以用尿产生率代替。

对于给定的尿液产生率，[SID] _u越小差异越大，即 [SID] _ECV的校正（增加） 。事实上，如果[SID] _u变为负数，修正会更大，因为[SID] _u的绝对值将被添加到[SID] _ECV的绝对值上。这转化为增强肾功能恢复酸中毒的有效性。

重要的是要了解，在具有弱电解质的强离子溶液中，当 [SID] 为正时（例如，细胞外空间和血浆中的正常 [SID] 值），并且 [SID] 范围从零到 [A _tot ]（弱、非挥发性酸的总浓度），[H ⁺ ] 的变化非常小，仅占 [SID] 变化的很小百分比（前提是 [A _tot ] 没有明显变化）。3但是，在 [SID] 值为负的溶液中，需要带正电的弱离子来保持电中性，唯一可用的离子是 H ⁺。因此，以下等式成立： [H ⁺] = -[SID]。因此，在 [SID] 为负的溶液中加入强酸会使 [H ⁺ ] 的增加与 [SID] 的减少一样多。

[SID] _u的计算公式与 [U _AG ] 相同：

尿酸度变化是通过尿 [Cl ^- ] 或任何强阴离子浓度的增加来实现的，这不会伴随尿 [Na ⁺ ] 的类似增加，导致 [SID] _u降低（图 1） .

从 Stewart 的观点来看，将 [SID] _u称为尿液中某些携带 H ⁺的分子的存在是没有意义的，例如，。如前所述，[SID] _u决定了排泄的尿液中弱电解质和水分解的程度，因此决定了那里的 [H ⁺ ]。对于斯图尔特来说，它不能起到 H ⁺转运蛋白的作用，或者至少，它可以像尿液中的任何 H ₃ O ^{+分子那样发挥作用。}3

^{类似地，通常报道的强离子和 H +}之间的权衡（以个位数整数比例）跨越分离体液的膜以及由此产生的化学计量 [H ⁺ ] 变化受到质疑。正如 Stewart 所指出的，人血浆的 [SID] 缓冲值等于 Δ[SID]/Δ[H ⁺ ] = -6.9 × 10 ⁵，这意味着 [SID] 应该改变数十万 Eq/L 才能产生变化[H ⁺ ] 乘以 1 Eq/L。3只有在[SID]为负的解中，[SID]与[H ⁺ ]的变化呈线性关系。

是一种弱阳离子 (pKa = 9.24)，由附加碱基 NH ₃形成。溶于水的NH _3与H ⁺结合形成。_{影响尿液 pH 值的尿液中 NH 3} ( )的总浓度对于pH 敏感的强离子通道的功能可能特别重要。5

除了上面提到的之外，如果我们想在尿液中分配一个角色，以某种方式统一呈现的翻译方面，那就是它的存在，避免强阳离子，否则，会从尿液中排出，与强酸阴离子一起（即在尿液中防止强阳离子流失）。因此，这将对血浆中的 [SID] 产生积极影响，通常也会对细胞外空间产生积极影响。

尽管如此，已经详细描述了H ⁺ /通过膜载体和离子通道的转移。一个例子是 Na ⁺ /H ⁺交换器 3 (NHE-3)，一种反转运蛋白，被认为可介导 H ⁺分泌穿过近曲小管中上皮细胞的顶膜。6然而，研究人员质疑个体 H ⁺参与运输过程和生化反应的能力。例如，在乳酸生产过程中，在糖酵解中，H ^{+的产生和运输。}7研究人员提出的一个主要原因是 H ⁺在水溶液中的流动性受限。

事实上，研究表明 H ⁺扩散可能比我们以前认为的要受到更多限制。它们在水中的短暂存在（它们的寿命以皮秒为单位）8以及它们在身体水溶液中的微小浓度（≈10 ^-7 M），这将使传统的扩散过程非常缓慢，引发了合理的怀疑，即是否实际上，每个单独的 H ⁺都可以参与跨膜运输。为了解释观察到的 pH 变化，物理化学方法的支持者提供了一个简单的论点：跨膜的强离子传输改变了相关流体隔室中的 [SID]。[SID] 更改会自动更改 [H ⁺]/溶液中的pH值；这被误解为是由 H ^{+的转移造成的}

事实上，人们早就提出了一种独特的传输机制，称为 Grotthuss 机制（也称为结构扩散）来代替 H ⁺运动。9根据这一机制，H ⁺转移在水或任何氢键分子链中以逐步方式发生。阳离子络合物的相互转化和氢键网络中的电荷重新定位发生。每个氢键分子同时充当电荷供体和受体；即当链的一端加入过量的 H ⁺时，链中相邻的氢键会释放出另一个 H ⁺. 网络中的电荷分布是高度可极化的，并且可能通过改变静电力的大小而大大扭曲。10例如，这种刺激可以通过将 SID 变为溶液来产生。除了大体积水质量外，还提出了一种 Grotthuss 机制，用于通过离子通道转移 H ^{+ 。}9

这些物理化学观察似乎支持了斯图尔特的观点。总的来说，斯图尔特的方法可以提供一个更坚实的解释基础，因为它基于声称普遍有效的基本物理化学原理（电中性、质量守恒和 Guldberg-Waage 质量作用定律），而不是来自于个人对单独的实验数据。然而，虽然这两种方法在病理生理学上从完全不同的角度处理代谢性酸中毒问题，但如果正确使用它们，在临床实践中似乎没有明显的优势。总而言之，无论选择哪种方法，[SID]u/[UAG] 值随着 [SID] _ECV的降低 在代谢性酸中毒的情况下显示适当的肾脏反应，而在相同情况下较大的 [SID]u/[UAG] 值表示尿液酸化受损。