Isoform 3 (NHE-3) appears to be the main transporter responsible for luminal H + (and NH 4 +) secretion 7, but so far has not been linked to a form of clinical RTA. In the proximal tubule most of the H + secretion is coupled to Na + absorption via the Na +-H + exchanger (which also transports NH 4 + to secrete it from the proximal tubular cells) of which several isoforms have been cloned 5, 6. The actual mechanisms of cellular H + secretion described so far are illustrated in Figure 3. As an example, hyperkalaemia (especially when due to a lack of aldosterone, see Box 1) can reduce acid excretion by inhibiting NH 4 + production 4. Its journey to urine can be disrupted at each step and thereby impair net acid excretion, even when cellular H + secretion is normal. Ammonium reaches the urine by a complex route that involves proximal tubular secretion, subsequent reabsorption along the thick ascending limb of the loop of Henle and lastly diffusion trapping within the collecting duct lumen and so to the final urine. In addition to secreting H +, the proximal tubular cells can generate new bicarbonate from the metabolism of glutamine, which also produces ammonium (NH 4 +), the key urinary buffer (see Box 2). CA=carbonic anhydrase PC=principal cell α-IC=intercalated cell p.d.=potential difference To illustrate this, we must first describe how the kidney maintains long-term acid-base balance.Ĭurrent cellular models of tubule acidification (proximal versus distal). Advances in renal physiology, and most recently in molecular genetics as applied to renal tubular cell physiology, have now made it possible to describe RTA in more functional terms and even to predict likely causes. This terminology gives no hint as to the process of renal acid excretion and therefore to the potentially defective underlying cellular mechanism 2. The current classification of RTA can be confusing, especially the older terminology of ‘types’, which was originally chronological ( Box 1). In uraemic acidosis H + excretion per functioning nephron is increased the underlying cellular mechanisms of H + secretion are preserved and responding normally to a systemic acid-load that cannot be excreted because of too few nephrons 1. Defined in this way, it could also include the low acid excretion of renal failure, but RTA is distinguished from uraemic acidosis by a normal or only slightly reduced glomerular filtration rate (GFR) and a hyperchloraemic normal (rather than increased) anion gap metabolic acidosis-the only other important cause of which is loss of alkali (bicarbonate) from diarrhoea.
RTA signifies an inability of the kidney to excrete adequately an acid (H +) load and so contribute to maintaining normal acid-base balance.
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