What the does the pH of urine indicate?

What does the pH of urine indicate?

E.S.Prakash, Mercer University School of Medicine, Macon, GA, USA.

The pH of urine ranges from 4.5 – 8.0. This is simply an observed range of values. A given value may or may not be physiologically ‘appropriate’.

In the face of systemic acidosis, if urine pH is 4.5, it seems like it is a ‘good thing’ – physiologically appropriate.

Similarly, after a heavy meal, arterial plasma pH may increase slightly. The mechanism of this postprandial alkaline tide is that for every proton secreted by the parietal cell in the stomach, 1 bicarbonate ion is added to ECF. This may cause urine pH to hit 8, and it would be physiologically appropriate.

How can we assess if urine pH is physiologically appropriate or not?
See if urine pH is physiologically appropriate for the prevailing pH of arterial plasma. If plasma pH is 7.0 and urine pH is 6.0, it seems that the extent to which urine is acidified is suboptimal, given that the kidneys normally can acidify urine to a limiting pH of 4.5.  The cause of this may be any or a combination of the following: reduced renal plasma flow, reduced GFR, a defect in the ability of the proximal tubule or the collecting tubule and collecting ducts to secrete protons.

Also, equally, a seemingly appropriate urine pH in the context of metabolic acidosis is not necessarily a reliable index of total ‘net acid secretion’, as urine pH merely reflects the concentration of hydrogen ions in urine.

The function of the kidneys is to excrete the load of “fixed (nonvolatile) acid” – i.e., the proton load that the lungs cannot excrete without also losing bicarbonate. The daily load of fixed acid on a typical Western diet is about 1 mmol/kg body weight.  For a 70 kg healthy adult, it is about 70 mmol/day.  An equal amount of ‘net acid secretion’ is essential for acid-base balance.

Is this fixed acid load excreted by the kidneys primarily as free protons or in combination with buffers? What is the relative contribution of each?
For the purpose of understanding, although the lower limit of urine pH is 4.5, let us assume that urine can be acidified up to a pH of 4.4 (and that plasma pH is 7.4).

A pH of 7.4 corresponds to a [H+] of 40 nanomoles per liter.

A pH of 4.4 corresponds to a [H+] of 40 micromoles per liter.  [A pH of 4.4 corresponds to a 1000 fold increase in the concentration of protons compared to a pH of 7.4]

Let us say urine volume is 1 liter per day.

If urine pH were 4.4, the total amount of acid excreted as protons per day would be 40 micromoles per day, if there were no proton buffers in urine. In contrast, the daily load of fixed acid the kidneys excrete is of the order of 40-80 millimoles (1000-2000 times greater).  This underscores the importance of buffers in tubular fluid for net acid secretion (and elimination) in urine.

The contribution of renal tubular cells to acid-base balance can be classified this way:
1) Reclaiming all filtered bicarbonate (preserving buffer base)
2) “Net acid secretion” (i.e., secretion of protons coming off from hydration of CO2 or protons coming off from metabolic acids like ketoacids, lactic acid, and other fixed acids; and protons secreted in combination with NH3 as NH4+).

Renal plasma flow (RPF) is the input from which any substance including (‘fixed’ acid) is extracted and actively secreted into the tubular lumen.  Furthermore, phosphate, a major buffer in urine, is made available exclusively via glomerular filtration.  Thus, an extremely low GFR (< 10 ml/min/m2 body surface area), which is also associated with a low RPF, sustained for longer than a day or two is sufficient cause for metabolic acidosis, and it is more likely when the generation of acid load increases for any reason.   In acute severe ischemic renal failure (GFR < 15 ml/min/1.73  m2 body surface area, and it falls to such a low value rapidly over a few days), particularly when vasoconstriction is a prominent element of the pathogenesis, the decline in GFR and RPF limit the total amount of acid (as well as products of metabolism) excreted in urine.  (Renal plasma flow may be normal however in nephrotoxic ATN, and generalizations are difficult).

Likewise, in end-stage renal disease (stage 5 chronic kidney disease), a GFR (< 15 mL/min/1.73 m2 body surface area) which serves as a surrogate of functioning renal mass, is low that a reduction in GFR (and RPF) may constitute an adequate explanation for the prevailing metabolic acidosis.  Whether and additional effect at the level of generation of new bicarbonate (secretion of net acid) is present can be assessed clinically by assessing the delta AG/delta bicarbonate gap.

Are protons secreted primarily by filtration or secretion?
The concentration of protons in plasma is so low (normally 40 nanomoles/L at a pH of 7.4), and so the amount of protons filtered with a normal GFR is way below the acid load that needs to be excreted. In contrast, normal kidneys are able to concentrate protons up to approximately 1000 times relative to plasma (see above).

Buffers of protons in tubular fluid that allow acid excretion in urine:

Although HCO3 buffers protons secreted by the proximal tubule, this process essentially reclaims bicarbonate (into plasma), and does not normally contribute to excreting acid in urine.  (Reclamation of filtered bicarbonate does not contribute to net acid secretion.  It is simply conservation of plasma bicarbonate.)

Protons are lost in urine primarily in combination with two buffers – NH3 and HPO4; each of these buffers contributes to trapping approximately 50% of the total acid load excreted in urine. The relative (not absolute) contribution of NH4 to secretion of net acid in urine increases in CKD (via an adaptive increase in renal ammoniagenesis) when the availability of phosphate in tubular fluid is limited by a low GFR.  Hypophosphatemia due to any cause also limits the availability of phosphate in tubular fluid for buffering protons.

Quantification of total acid excretion in urine:
1 – Titratable acidity: We estimate the amount of alkali needed to titrate urine to the pH of plasma (from which it was derived). This provides an estimate of protons tied up with HPO4 as H2PO4.

2 – Urine anion gap, calculated as urine {[Na] + [K]} – {[Cl] + [HCO3]}, would reflect this: [Unmeasured anions] – [Unmeasured cations], in urine.  The major unmeasured cation in urine is NH4.  Thus, a negative urine anion gap would suggest normal excretion of NH4 in excess of unmeasured anions in urine. Urine anion gap has a narrow clinical application and is assessed only when renal tubular acidosis is suspected to be a cause of metabolic acidosis.

Are renal tubular acidosis and the acidosis of acute or chronic renal failure the same?
There are numerous causes of metabolic acidosis (example, diarrhea, diabetic ketoacidosis, starvation ketoacidosis etc).  When there is no obvious cause for metabolic acidosis in a patient with renal disease whose GFR and RPF are normal, one might suspect a defect in renal tubular epithelial cell secretion of protons or reclamation of bicarbonate as the cause of metabolic acidosis. This entity is called renal tubular acidosis. It should not be confused with acidosis that occurs in acute or chronic renal failure. Renal tubular acidosis is not diagnosed in a patient known to have acute or chronic renal failure because in renal failure, the low GFR and RPF are sufficient causes of acidosis. Rather, patients with renal tubular acidosis (example, associated with Fanconi syndrome) may in the long run develop chronic renal failure (now called advanced CKD).

If proximal RTA is suspected: An intravenous load of NaHCO3 that increases plasma [HCO3] to normal values [24 mM] is given; if this is followed by bicarbonaturia, then that indicates diminished renal threshold for bicarbonaturia.  Since bicarbonate is primarily reabsorbed in the proximal tubule, this would indicate a proximal RTA.

If distal RTA is suspected: If urine pH falls to below 5.3 following furosemide, that would indicate preservation of the ability of acid secretory mechanisms in the connecting tubule and the collecting ducts to acidify urine. If urine pH does not fall as expected with furosemide, then this suggests distal RTA.

How much bicarbonate (or new bicarbonate) do the kidneys generate?
If total acid excretion in urine is 70 millimoles per day, then 70 millimoles of ‘new’ bicarbonate is generated since for every proton lost in urine, one bicarbonate ion is added to ECF. The term ‘new’ in new bicarbonate might seem confusing, but the point is that if this load of protons were not excreted, there would be a corresponding drop in ECF bicarbonate concentration.

Total net acid secretion in urine is not assessed when the cause for a reduction in total acid secretion in urine is clinically apparent such as in severe acute renal failure or ESRD.  As noted above, and particularly in severe ischemic ATN, it may be that GFR and renal plasma flow is limited relative to the daily load of fixed acids, and organic and inorganic anions formed.  In ESRD, the total capacity of hyperfunctioning nephrons is overwhelmed  by normal acid loads such that persistent metabolic acidosis is typically observed in the absence of renal replacement therapy.  (The low e-GFR serves as a surrogate of total renal functional capacity.)


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