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Nephrolithiasis in renal tubular acidosis

Nephrolithiasis in renal tubular acidosis
Author:
Gary C Curhan, MD, ScD
Section Editor:
Richard H Sterns, MD
Deputy Editor:
John P Forman, MD, MSc
Literature review current through: Dec 2022. | This topic last updated: Jan 26, 2022.

INTRODUCTION — Hypercalciuria, hypocitraturia, alkaline urine pH, nephrolithiasis (often composed of calcium phosphate), nephrocalcinosis, and skeletal abnormalities are frequently associated with untreated distal (type 1) renal tubular acidosis (RTA) [1-4]. Stone disease is also seen with carbonic anhydrase inhibitors but typically not with proximal (type 2) RTA. Most of the studies on RTA and nephrolithiasis have been small, and there is variability in individual phenotype and the response to therapy [5]. The following should be read with these cautions in mind.

PATHOGENESIS

Distal (type 1) RTA — Several factors can contribute to the relationship between distal renal tubular acidosis (RTA) and stone formation or nephrocalcinosis. In some families, for example, hypercalciuria appears to be the primary abnormality, with calcium-induced interstitial and tubular damage possibly responsible for the RTA [2].

In most cases, however, RTA is the initial condition with subsequent acidemia promoting stone formation by increased calcium phosphate release from bone during bone buffering of retained acid, increased intestinal absorption of calcium, and direct reduction in the tubular reabsorption of these ions [1,6,7]. The degree of hypercalciuria is roughly proportional to the severity of the acidemia.

Two other factors also contribute importantly to stone formation in this disorder: the persistently high urine pH, which favors the precipitation of calcium phosphate (but not calcium oxalate, the solubility of which is relatively insensitive to pH in the physiologic range); and reduced citrate excretion [8], since acidemia enhances proximal citrate reabsorption [9]. Urinary citrate is normally a potent inhibitor of calcium stone formation (oxalate and phosphate), both by forming a soluble complex with calcium and by inhibiting stone growth by agglomeration of calcium crystals. (See "Kidney stones in adults: Epidemiology and risk factors".)

Kidney histopathology of stone formers with distal RTA reveals calcium phosphate deposits plugging inner medullary collecting and Bellini ducts [10]. Significant interstitial fibrosis is also observed, even in areas without plugging. Although further study is needed to verify these results, some of the radiographic calcifications in these patients may represent surgically approachable stones rather than nephrocalcinosis.

Proximal (type 2) RTA — By contrast, stone formation does not appear to occur more frequently in individuals with proximal RTA in which the primary defect is a reduction in bicarbonate reabsorptive capacity in the proximal tubule [3]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

At least three factors may protect against stone formation in this disorder:

Once the plasma bicarbonate concentration has fallen to the level of reabsorptive capacity (usually between 12 and 20 mEq/L), all of the filtered bicarbonate can be reabsorbed. At this time, bicarbonaturia ceases (unless exogenous bicarbonate is given) and the urine can be normally acidified. The acid urine pH increases the solubility of calcium phosphate, thereby preventing its precipitation.

Reabsorption of all of the filtered bicarbonate means that the daily acid load can be excreted as ammonium and titratable acids, as in normal individuals. Thus, in the steady state, untreated patients with proximal RTA are in acid-base balance, although at a lower plasma bicarbonate concentration and extracellular pH than normal. As a result, there is no continued increase in calcium phosphate release from bone due to buffering of unexcreted acid.

Proximal tubular dysfunction can lead to increased excretion of organic anions (including citrate). These solutes can form soluble complexes with calcium, thereby limiting the amount of free calcium available for precipitation with phosphate.

Carbonic anhydrase inhibitors — Carbonic anhydrase is important for both proximal and distal acidification. Carbonic anhydrase inhibitors, such as acetazolamide, are thought to act primarily in the proximal tubule, where they inhibit bicarbonate reabsorption, producing a picture similar to proximal RTA. However, unlike in proximal RTA (in which the risk of calcium stones is not elevated), the risk of calcium stones is raised with acetazolamide therapy [11,12] and with two other commonly used drugs that have carbonic anhydrase inhibitory activity, topiramate and zonisamide [13-18]. The stones have primarily been composed of calcium phosphate [12,17], but calcium oxalate stones can occur [11]. A marked reduction in urinary citrate excretion had been documented in these patients and is a known risk factor for stone formation [12,17]. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Low urine citrate'.)

Data are limited on the absolute risk of stone formation with carbonic anhydrase inhibitor therapy. In a study of 20 patients chronically treated with acetazolamide for neuromuscular disease, three (15 percent) developed renal calculi [11]. The reported prevalence was much lower in a series of 167 patients treated with zonisamide (3.7 percent) [14] and 1800 patients treated with topiramate (1.5 percent) [18], both of which appear to be a weaker carbonic anhydrase inhibitor than acetazolamide [19]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

TREATMENT — Patients with renal tubular acidosis (RTA) and nephrolithiasis should undergo a metabolic evaluation to design the optimal regimen to prevent growth of existing stones and new stone formation. A bone density examination should also be performed because of the frequent finding of skeletal abnormalities. (See "Kidney stones in adults: Evaluation of the patient with established stone disease".)

All of the above changes in distal RTA can be reversed by complete correction of the acidemia: less calcium phosphate release from bone, lower rates of urinary calcium and phosphate excretion, a rise in urinary citrate excretion (although not necessarily to the reference range), and prevention of new stone formation [1-3,20,21]. The decrease in stone formation can occur even in patients with the incomplete form of distal RTA who have a persistently alkaline urine pH and hypocitraturia, but a normal or near normal extracellular pH [20]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Incomplete distal RTA'.)

Potassium citrate (citrate is rapidly metabolized to bicarbonate) or potassium bicarbonate can be used to correct the acidemia in stone formers with distal RTA [20,22,23]. Potassium citrate is available in a tablet form, while potassium bicarbonate needs to be dissolved in water. The use of either potassium salt will directly treat hypokalemia.

On the other hand, the increase in sodium intake associated with sodium citrate or sodium bicarbonate administration can produce an undesirable increase in urinary calcium excretion since calcium reabsorption passively follows that of sodium in the proximal tubule and loop of Henle [22,23]. Thus, we recommend avoiding sodium alkali salts.

The potential efficacy of potassium alkali (citrate or bicarbonate) therapy can be illustrated by the following observations in studies in which stone formation rates were compared before and after therapy; randomized placebo-controlled trials have not been performed:

In a report of nine patients with incomplete distal RTA and nephrolithiasis, treatment with potassium citrate (60 to 80 mEq/day) for almost three years was associated with complete cessation of new stone formation compared to a mean of 39 stones per patient formed in the three years prior to potassium citrate therapy [20].

In a study of incomplete distal RTA and hypocitraturia associated with medullary sponge kidney, potassium citrate therapy was given to patients with stone risk factors (eg, hypercalciuria and hypocitraturia) at an initial dose of 20 mEq/day that was increased gradually until urinary citrate excretion exceeded 450 mg/day or the urine pH reached 7.5 [21]. There were 65 patients who were treated for one year and ten patients who did not accept or adhere to therapy. The stone event rate, defined as passage or surgical extraction or fragmentation of a stone was markedly reduced in the adherent patients (0.10 versus 0.58 stones per year per patient). The adherent patients had a substantial and significant reduction in urinary calcium excretion (378 to 178 mg/day) and a significant increase in citrate excretion (268 to 460 mg/day). Neither of these changes were seen in the nonadherent patients, while the urine volume and sodium excretion were similar in the two groups. (See "Kidney stones in adults: Prevention of recurrent kidney stones" and "Medullary sponge kidney", section on 'Kidney stones and nephrocalcinosis'.)

The inverse relationship between urinary citrate excretion and calcium-containing stone formation is continuous; thus, the higher the urine citrate concentration is, the lower the stone risk. However, the administration of potassium alkali has the potential to increase the risk of stones by raising the urine pH, thereby increasing the likelihood of calcium phosphate crystal formation. Thus, alkali therapy must be undertaken with caution. We monitor the urine pH and citrate excretion with the following goals:

In patients with complete distal RTA, the goal of potassium citrate therapy is to increase the plasma bicarbonate concentration to the low end of the reference range, which should prevent a substantial increase in urine pH. We typically discontinue citrate therapy if the urine pH rises above 7.0 without a substantial increase in urinary citrate excretion or a reduction in urinary calcium excretion. Among such patients, we balance the need to administer alkali to maintain the serum bicarbonate level with the risk associated with a higher urine pH. Thus, if the serum bicarbonate level is acceptable, then the alkali dose is reduced or even discontinued and we administer a thiazide diuretic with the goal of lowering the urine calcium level. A thiazide diuretic may also be added in patients with low bone density, given the evidence that thiazides can help maintain bone density. (See "Drugs that affect bone metabolism", section on 'Thiazide diuretics' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Calcium phosphate stones'.)

In patients with incomplete distal RTA, the goal is to increase urinary citrate concentration without exceeding a urine pH of 7.0. A thiazide diuretic can be added to reduce urinary calcium if stone formation persists, even if the urine calcium is in the traditional "normal" range [24]. A thiazide diuretic may also be added in patients with low bone density, but this does not seem to be a common finding in incomplete distal RTA [25]. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Incomplete distal RTA'.)

Among patients with stone disease due to the administration of a carbonic anhydrase inhibitor, discontinuation of the medication will prevent new stone formation. However, for patients who cannot stop their carbonic anhydrase-inhibiting medication (eg, topiramate), other approaches to stone prevention may still be successful [26].

SUMMARY AND RECOMMENDATIONS

Patients with distal (type 1) renal tubular acidosis (RTA) may be at increased risk for nephrolithiasis due to higher urinary calcium excretion, higher urine pH, and lower urinary citrate excretion. (See 'Distal (type 1) RTA' above.)

Stone disease is also seen with carbonic anhydrase inhibitors but typically not with proximal (type 2) RTA. (See 'Carbonic anhydrase inhibitors' above and 'Proximal (type 2) RTA' above.)

Patients with an RTA and nephrolithiasis should undergo a metabolic evaluation to design the optimal regimen to prevent growth of existing stones and new stone formation. A bone density exam should also be performed because of the frequent finding of skeletal abnormalities. (See 'Treatment' above.)

In stone-forming patients with distal RTA, correction of the systemic acidosis with oral alkali (usually potassium citrate or potassium bicarbonate) may substantially reduce the risk of new stone formation. The urine pH should be followed carefully to be sure that it does not rise excessively. Some patients may also require a thiazide diuretic to reduce urine calcium excretion. Close follow-up is required to manage this life-long metabolic abnormality. (See 'Treatment' above.)

Among patients with stone disease due to the administration of a carbonic anhydrase inhibitor, discontinuation of the medication will prevent new stone formation. For those patients who cannot stop their carbonic anhydrase-inhibiting medication (eg, topiramate), other approaches to stone prevention may still be successful. (See 'Treatment' above.)

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