Refining Diagnostic Approaches in Nephrolithiasis: Incomplete Distal Renal Tubular Acidosis

The pathophysiology of renal tubular acidosis (RTA) seems well worked out. Distal or type 1 renal tubular acidosis (dRTA) leads to positive proton balance, which results in decreased bone mineral density (BMD) and a urinary phenotype most consistent with calcium phosphate stone formation: hypocitraturia, hypercalciuria, and a high urine pH. Nephrocalcinosis and CKD are also seen. Proximal or type 2 RTA does not lead to positive proton balance, and therefore, in (nongrowing) adults, it does not lead to reduced BMD and is not associated with stones or nephrocalcinosis.

That dRTA and proximal RTA have a comprehensible pathophysiology is confirmed, because they result from well characterized genotypes that cause dysfunctional proteins critical to tubular acid-base physiology. For example, proximal RTA can occur as the result of mutations in the proximal tubule’s sodium bicarbonate cotransporter (NBC1, SLC4A4) (1). dRTA results from mutations in the V-ATPase (ATP6V0A4, ATP6V1B1) and Cl⁻/HCO₃⁻ exchanger (AE1, SLC4A1) responsible for urinary acidification (2). The type 3 designation was dropped when it was recognized that affected people have the combination of both proximal and distal lesions; deficiencies of carbonic anhydrase II impair apical proton secretion in both proximal and distal tubules and cause this phenotype (3). Type 4 RTA, associated with hyporeninemic hypoaldosteronism, is easily identified by the accompanying hyperkalemia. There is mystery about its etiology and why it is not associated with uric acid stone disease.

However, the most confounding category in RTA might be incomplete distal renal tubular acidosis (idRTA). The term is applied to the finding of impaired urinary acidification that does not lead to a reduction in serum bicarbonate concentration. If one considers the examples of proximal RTA and dRTA, idRTA has not compared, until recently, as a diagnosis that logically follows from well characterized mutations that cause the anticipated, disordered pathophysiology.

In this issue of the Clinical Journal of the American Society of Nephrology, Fuster and coworkers (4) seek a convenient and reproducible means of diagnosing idRTA. Wrong and Davies (5) described three patients who could not maximally acidify their urine after administration of ammonium chloride. This single-dose NH₄Cl test (an improvement over the previous multiday regimen) was somewhat unsatisfactory, because it was often associated with gastrointestinal intolerance. The development of an alternative test, simultaneous administration of furosemide and fludrocortisone (F&F), followed the work by Walsh et al. (6). The rationale was that the synthetic mineralocorticoid, fludrocortisone, would stimulate electrogenic sodium absorption in the collecting duct via its effects on the epithelial sodium channel (ENaC). Furosemide delivers sodium from the thick ascending limb to the collecting duct, stimulating the epithelial sodium channel–driven, luminal-negative potential difference. Mineralocorticoid also stimulates V-ATPase, which combined with the negative potential difference, maximally stimulates urinary acidification. In this article, the authors compare the diagnostic utility of the two tests as well as that of baseline characteristics (“nonprovocative parameters”), considering the NH₄Cl test the gold standard (4).

The development of kidney stones has usually been the indication for performing these tests of acidification, because otherwise, people with idRTA with normal serum bicarbonate would not seek medical attention. An exception is a recent study, which tested urinary acidification in people with low BMD, a potential characteristic of idRTA (7). The prevalence of idRTA in the general nonstone-forming healthy population without kidney stones, nephrocalcinosis, or low BMD is not known. This study replicates this selection strategy by simply including adults with at least one stone, regardless of composition.

idRTA is defined in this study, as is usual, by failure to acidify urinary pH to <5.3 in the presence of a serum bicarbonate concentration of >21 mEq/L. Applying that single criterion, 8% of people administered the NH₄Cl test and 20% of those given the F&F test had a nadir urinary pH ≥5.3. Stipulating that the former is the gold standard, sensitivity and specificity of the F&F test were 77% and 85%, respectively, resulting in a positive predictive value of 30% and a negative predictive value of 98%. On the basis of this calculation alone, if one thought that diagnosing idRTA is important, the performance of the test is not impressive. Consistent with this performance is the F&F test’s relative failure to cause the acidemia seen after NH₄Cl, in fact leading to a small increase in venous pH and bicarbonate. This lack of specificity for diagnosing idRTA is similar to the results of another study, in which both tests were administered (8).

The authors also explore the other characteristics of the patients with nadir urine pH >5.3 in response to one or both of the provocative tests. As expected and consistent with higher urine pH, those with idRTA after either test do not have stones composed of uric acid and were more likely to have calcium phosphate composition, although calcium oxalate was more common. Hypocitraturia and hypokalemia were more common with idRTA, but hypercalciuria was not.

An important question about the enrollees is raised by the finding that serum bicarbonate concentration was slightly higher, within the normal range, in those with idRTA at baseline than in those stone formers who lowered their urine pH more effectively. After NH₄Cl, serum bicarbonate fell less. Inability to control dietary intake could lead to important differences in acid-base balance in the participants, which could affect their responses to stimuli to urinary acidification.

Another surprising feature was that the NH₄Cl test led to a lower response in urinary ammonium excretion in the patients with idRTA compared with the other stone formers. The usual explanation for normal, not low, serum bicarbonate concentrations in this group has been that higher urine pH reduces titratable acidity, leading to a compensatory increase in ammoniagenesis and net acid excretion to achieve neutral proton balance (9). The contrary finding in this study highlights questions about exactly what populations with supposed idRTA compose this study and past studies. Reporting 24-hour urine ammonium excretion would have been desirable.

This paper’s most important conclusion is that “…urinary acidification capacity is not a dichotomous but a continuous trait in stone formers…which stands in contrast to…the currently held opinion that idRTA represents a distinct entity with respect to urinary acidification capacity” (4). In other words, perhaps no reason remains to consider making the diagnosis of idRTA. If we ask what distinguishes patients with idRTA from most calcium stone formers, much overlap and no clear separations are seen. Hypocitraturia, hypercalciuria, and reduced BMD have all been suggested to be characteristics of idRTA, but of course, they are all also variable characteristics of other calcium stone formers.

The question of BMD is worth mentioning. Low BMD in patients with idRTA is not expected if patients achieve acid balance by stimulation of ammoniagenesis. Similarly, hypercalciuria cannot be attributed to acidemia if serum bicarbonate is normal. In that case, bone would not need to buffer retained protons, and changes in nephronal calcium transport would not occur. Investigators showing lower BMD in idRTA suggest that periods of higher acid ingestion lead to positive proton balance or that failure to lower urine pH during fasting could be consequential for bone, but this has not been documented (10). In any case, lower BMD is more strongly associated with higher urine calcium than with failure to lower urine pH after an acid load (11); therefore, lower BMD cannot reliably define patients with idRTA. About one quarter of patients with low BMD and without kidney stones were found to have some defect in urinary acidification in response to a short NH₄Cl test, but without an unaffected control group, osteoporosis could not confidently be attributed to that defect (7).

If idRTA is not a distinct entity with respect to urinary acidification, can we justify performing NH₄Cl or F&F acidification tests, and should we worry about not doing these tests in calcium stone formers? At this point, the utility of these tests has really not been shown, and a reason for doing them has not been established. The administration of alkali is appropriate in the prevention of recurrent calcium stones (as well as for its effect on urine pH, which prevents uric acid and cystine stones) (12). Supplementation of potassium citrate is even effective in dRTA with higher urine pH and calcium phosphate stones. Alkali is effective prophylaxis for calcium stones regardless of whether hypocitraturia is present, and it is associated with an increase in BMD and a reduction in fractures.

Does idRTA eventually lead to full-blown RTA? There is minimal anecdotal evidence of this occurrence but no convincing longitudinal studies. The authors do not refer to their own report that some people with idRTA are heterozygous for ATP6V1B1 mutations that, when homozygous, cause dRTA (13,14). We do not know why they did not genotype this cohort, but cost is likely still an issue. The remaining indication for doing an NH₄Cl test might be to characterize the disordered pathophysiology of newly discovered mutations affecting acid-base balance, regardless of whether they are associated with kidney stones or not. Application of more widespread genetic screening for stone formers is approaching (15). Genotyping will soon be the new gold standard for diagnosing idRTA. In cohorts of patients with idRTA, examination of other candidate solute carriers and regulatory proteins would be a plausible strategy. Only when relevant mutations are identified does it seem likely that idRTA will be shown to either result from heterozygosity of genes that cause dRTA or constitute a distinct entity, perhaps worthy of the designation of type 5 RTA.

Disclosures

D.S.G. has been a consultant for Allena, Cymabay, Ironwood, Retrophin, and Revive; is an owner of Ravine Group; and has received funding from the National Institute of Diabetes and Digestive and Kidney Diseases and National Center for Advancing Translational Sciences.