Monte Minute‎ > ‎Monte Minute‎ > ‎

Renal Tubular Acidosis - 9/4/2012

posted Sep 4, 2012, 11:10 AM by Rohit Das   [ updated Dec 27, 2012, 6:58 AM by Purnema Madahar ]

Ahhh, that hiatus was pretty refreshing…but let’s get back to it. Today’s topic at resident report was renal tubular acidosis (RTA), a subject more daunting than figuring out how to comply with duty hour regulations. Nevertheless, I think it’s a topic worth reviewing and understanding. WARNING YOU - this is going to be on the longerrrrr side, so sit down, relax and let the information slowly percolate into your brain.

The kidney has three main ways of handling acid, and defects in these individual mechanisms are what lead to the different types of RTA, as below:

  • Proximal Tubule Reabsorption of Bicarbonate – 90% of Bicarbonate is reabsorbed in the proximal tubule, and 10-15% is reabsorbed in the thick ascending limb of the LoH. A defect in the former is what leads to Proximal (Type II) RTA
  •  Distal urinary acidification – Less than 1% of H+ is present in its free form, and most of is bound via titratable acids, mainly phosphate. To acidify urine, H+ needs to be secreted into the collecting tubule, and defects in this process lead to distal (type 1) RTA. Importantly, free H+ is the SOLE determinant of urine pH.
  • Buffering of H+ via Ammonia – Ammonium also buffers H+ in the collecting tubule, and is very important in renal acid-base handling. For complex and relatively unclear reasons, hyperkalemia leads to decreased urinary ammonium excretion and therefore retainment of H+. This defect on urinary ammonium excretion caused by hyperkalemia is referred to as Hyperkalemic (Type IV) RTA.

Ok, let’s go over these three specifically, trying to understand how to differentiate between them. RTA, in general, should be suspected in any patient with a normal anion gap (hyperchloremic) metabolic acidosis in the context of normal to moderate renal function (can’t be diagnosed in later-stage renal failure). One thing to realize is that proximal and distal RTAs are RARE, because the wide variety of diseases that cause them are also rare.

Proximal RTA, in adults, is most commonly due to excretion of monoclonal light chains, in the context of the MGUS – Multiple Myeloma spectrum. Tenofovir is a common ARV that also causes Type II RTA. Proximal RTA may or may not be associated with Fanconi syndrome and loss of other solutes, like phosphate and glucose. Table 2 of the attached article gives a good overview of the causes.

  • Since distal urinary acidification is IN TACT in Proximal RTA. Urine pH in the setting of acidosis is still acidic (5.5 or less), UNLESS a bicarbonate load is given (usually to help diagnosis) and the impaired proximal tubule reabsorption is overwhelmed. In that case, the urine pH will be alkaline (greater than 5.5).
  • If bicarbonate levels are above the threshold for reabsorption, potassium will be wasted along with bicarb (the negative charge has to go with a positive charge), leading to hypokalemia. But, if you’re below the threshold, potassium is not wasted.
  • Diagnosis is based on documenting an increasing urine pH with normalization of the serum bicarbonate level, and can be confirmed by documenting an increased fractional excretion of bicarbonate, (above 15-20%) once the proximal tubule’s capacity is exceeded. Because proximal RTA is self-limited and a new acid-base equilibrium is ultimately reached, bicarbonate levels are not terribly low, ranging from 14-20, depending on the degree of impairment.

Distal RTA…is complicated. I’ll try to summarize as best I can, but if I stop abruptly, it’s because my brain got fried.

  • There are three ways in which distal urinary acidification can be impaired, and each have their own etiologies; 1) Impaired H+ secretion; 2) backleak of secreted H+; and 3) inability to maintain a lumen-negative differential in the distal nephron that drives H+ secretion.
  • The first is caused by a variety of disorders, though in adults, this most commonly occurs in the context of autoimmune diseases – like SLE nephritis and Sjogren’s Syndrome. The second mechanism is usually due to amphoterrible. Finally, the third has various causes, including sickle cell disease, obstructive uropathy, and various drugs. Table 3 gives a nice overview.
  • As compared to proximal RTA, Bicarb levels are usually much lower, as no steady state is reached. Furthermore, urine pH is inappropriately high in the context of acidosis (greater than 5.5), due to impaired distal acidification of urine. Also, in order to maintain electroneutrality, K+ secretion is enhanced, leading to  HYPOkalemia.
  • HOWEVER – there are HYPERkalemic forms of distal RTA, which are due to the third mechanism I described above. When sodium reabsorption is impaired for various reasons, the lumen-negative potential for both H+ and K+ secretion is impaired, leading to both acidosis and HYPERkalemia. This is also referred to as “voltage-dependent” RTA…
  • Because H+ secretion is impaired in all forms of distal RTA, urinary ammonium (remember, it buffers H+) is also decreased. This is reflected in a POSITIVE urine anion gap (UAG). Just remember – the more POSITIVE the UAG, the LOWER the urinary ammonium. In non-RTA acidoses, urinary ammonium appropriately skyrockets, and the gap is NEGATIVE.

So, TAKE HOME POINTS

  • Proximal RTA – VARIABLE urine pH (low if below threshold, high if above) and hypo/normokalemia. A steady state is reached, and bicarbonate is around 14-20, and acidosis is mild-moderate.
  • Distal RTA – ALWAYS ALKALINE pH, and hypo or hyper-kalemia, depending on the etiology. No steady state is every reached, and patients will have low bicarbonate levels and be more acidotic than proximal RTA patients. The urine anion gap is POSITIVE (and usually NEGATIVE in non-RTA hyperchloremic acidoses).

Type IV, Hyperkalemic RTA, is in the context of hypoaldosteronism and consequent impairment of potassium secretion, leading to persistent hyperkalemia. As mentioned above, the hyperkalemia is thought to directly lead to a metabolic acidosis due to its effects on ammonia metabolism.

·  In adults, this is usually due to diabetic nephropathy with associated CKD. In this sense, type IV RTA is probably most important, as it is associated with a common disease.

·  As compared to “voltage-dependent” hyperkalmemic distal RTA, distal acidification is usually still intact (urine pH is still maintained at low levels), and the decrease in serum bicarbonate is mild (usually above 17). Also, aldoseterone levels are normal in patients with distal RTA.

· Diagnosis can be confirmed with measurement of renin/aldo levels, and treatment is via mineralcorticoids. Since fludrocortisone has hemodynamic adverse effects, management is often more directed to just hyperkalemia – chronic potassium binding resins, diuretics, etc.

Treatment of proximal/distal RTA is with supplemental alkali (higher doses for proximal more than distal)…but…why should we even treat these disorders?

  • Well, distal RTA, via multiple mechanisms, is particularly associated with calcium phosphate stone deposition, which leads to nephrolithiasis, and long term, nephrocalcinosis and chronic kidney disease. In one series from 1988, of 58 cases, 70% has issues related to the above.
  • As above, potassium regulation is another issue, which generally corrects with treatment. In that same series, 35% of patient with distal RTA had associated hypokalemia. However, it is important to realize that excessive bicarbonate supplementation will actually WORSEN hypokalemia (the +K goes with the –Bicarb wasted in the urine, remember?). So, potassium needs to be monitored with treatment, and often supplemented
  • Chronic metabolic acidoses have important metabolic complications, including nitrogen/protein wasting and increased Calcium/Phosphate mobilization from bone (for buffering of acid), leading to wasting syndromes and consequences of bone demineralization. 

Quite a bit of information here on a relatively rare topic, but, still something to be relatively familiar with. I’ve attached a good review article on this topic to help, and add to your library. Keep on reading!


Renal Tubular Acidosis: The Clinical Entity

Soriano, J Am Soc Neph 2002, Volume 13: 2160-2170


Metabolic and Endocrine Effects of Metabolic Acidosis in Humans

Wiederkehr et. al., Swiss Med Wkly 2011, Volume 131: 127-132



Comments