High Fat Intake: A Dietary Consideration for Uric Acid Nephrolithiasis?

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The prevalence of uric acid nephrolithiasis and its proportion of all kidney stones, now at 14%, is increasing.¹ Attention has understandably focused on modifiable factors to treat, and ideally prevent, this increasingly prevalent condition. The increase in uric acid nephrolithiasis prevalence has occurred with increased prevalence of metabolic syndrome-related conditions; its greater risk in persons with these conditions might indicate shared contributing factors.² Because diet contributes importantly to these metabolic syndrome-related conditions, including obesity and type 2 diabetes mellitus,² investigators have sought to identify dietary aspects common to metabolic syndrome-related conditions and uric acid nephrolithiasis that might constitute targets for its management and/or ideally, its prevention.

Three contributors to uric acid nephrolithiasis include the level of urine uric acid excretion, the volume of urine in which it is contained, and composition of the excreted urine. The principal sources of uric acid production are de novo synthesis, tissue catabolism, and dietary purine load, with approximately 50% from the first 2 sources and approximately 50% from the latter.² Foods high in purines, such as organ meats should be limited to lower the uric acid load for excretion. In addition, patients should maintain hydration with dilute urine to reduce the risk for uric acid precipitation. Nevertheless, urine composition is the most important determinant of uric acid precipitation, namely the concentration of “free” (i.e., unbound to buffers) protons (H⁺) in solution, expressed as pH,^1,2 the latter being the negative log of [H⁺] expressed in moles/l.

Kidneys excrete > 95% of metabolic (as opposed to the “respiratory” acid of dissolved CO₂ gas) acid produced from endogenous H⁺ production and from metabolism of certain foods that yields H⁺.³ Most modern diets are net acid producing and persons eating them excrete approximately 0.7 to 1.0 mmoles/kg bw of metabolic acid daily.^3,4 Kidneys of a 70 kg person excreting 0.7 mmoles/kg bw/d of acid would excrete 49 mmoles/d of acid. Because the lower limit of urine pH in human kidneys is approximately 4 (that is, 10⁻⁴ moles/l or 0.1 mmoles of acid/l of urine), excreting that daily acid load as “free” H⁺ would require 49 mmoles/0.1 mmoles/l = 490 liters of urine! This reminds us that nearly all acid excreted in urine is bound to buffers.³ The more urine buffer, the less urine “free” acid, and the higher the urine pH.

The major urine buffer is typically ammonium (NH₄⁺), formed from binding H⁺ to ammonia (NH₃) produced by the kidney proximal tubule.³ Kidney energy production, including to produce proximal tubule NH₃, comes predominantly from amino acid metabolism under most conditions.⁵ Production of NH₃ or NH₄⁺, or ammoniagenesis, occurs mostly in kidney proximal tubules through deamination (i.e., removal of an amine [NH₂^-]) from glutamine to form glutamate followed by deamination from glutamate to form α-ketoglutarate. The second most abundant urine buffer is a group of substances, mostly phosphate, collectively called titratable acidity. Urine NH₄⁺ is the component that typically increases most in response to dietary acid challenges, with only modest increases in titratable acidity.³

As discussed, the maximum concentration of “free” H⁺ in human urine, that is, the lowest pH, is approximately 4. The upper pH limit in humans not given alkali loading is approximately 7 to 8. This indicates that the common urine pH range for humans under standard conditions is 4 to 7. Whether a substance such as uric acid will release a H⁺ bound to become “free” (or “ionized”) in solution, depends on the following: (i) how tightly uric acid binds H⁺, and (ii) the amount of “free” H⁺ (or pH) that is already in the urine. The more tightly uric acid binds H⁺, or the more free H⁺ that is already in the urine, the more likely the H⁺ will remain bound to the parent uric acid molecule. When H⁺ remains bound to the parent uric acid molecule (i.e., UAH), it is not “ionized” (i.e., UA⁻); “un-ionized” UAH can precipitate from solution and eventually form a stone.

The parameter assessing how tightly a substance such as uric acid binds its H⁺ is its pKa. The higher the pKa, the more tightly the parent substance binds H⁺ and the less likely it will release H⁺ into solution. Because the uric acid system (UAH/UA^-) is “ionized” (UA⁻) when unbound to H⁺, the treatment and prevention goal is to facilitate urine composition that promotes its “ionized” or soluble form. Uric acid pKa is 5.35 at 37 ^oC. This means that at ambient urine pH < 5.35, most UAH/UA⁻ is in its H⁺-bound form (UAH), that is, its nonionized salt that can precipitate. In contrast, at ambient urine pH is > 5.35, certainly > 6.0, most UAH/UA⁻ is unbound to H⁺ (UA⁻), that is, its “ionized” phase, and remains in solution. Relatedly, the NH₃/NH₄⁺ system has pKa 9.3, meaning that it strongly binds H⁺ under standard urine pH ranges. The bound phase (NH₄⁺) is ionized, remains in solution, and can be produced in amounts to bind the H⁺ secreted by kidney tubules that come from the acid-production of most modern diets. Together, this discussion shows that the urine composition that limits uric acid nephrolithiasis is higher pH (> 6) that is facilitated by higher amounts of buffer, mainly NH₄⁺.

In this issue of Kidney International Reports, Zomorodian et al.⁶ address effects of fat intake, an understudied dietary factor in humans that contributes to the metabolic syndrome, on urine parameters that mediate uric acid precipitation. Canine studies showed that acute fat infusion lowered urine NH₄⁺ excretion, with decreased urine pH, by shifting kidney energy production from amino acid metabolism to fatty acid utilization, thereby reducing ammoniagenesis with reduced urine NH₄⁺ excretion.⁷ Other studies showed decreased NH₄⁺ transport activity in kidney tubules with steatosis in chronically obese and diabetic rats, potentially limiting urine NH₄⁺ excretion for H⁺ buffering.⁸ In contrast, acute fat loading in normal rats, presumably without steatosis, only transiently lowered urine pH due to reduced urine NH₄⁺ excretion, an effect the investigators attributed to a substrate switch from amino acid to fat metabolism.⁸ Zomorodian et al.⁶ explored if substrate switch from baseline amino acid metabolism to fat reduces ammoniagenesis in humans and thereby leads to urine parameters that contribute to uric acid nephrolithiasis.

The investigators studied 7 patients who were uric acid stone formers (UASF) and 8 normal controls (Ctrl) who had been equilibrated on a fixed metabolic diet for 4 days while remaining outpatients at home. On day 4, they were admitted to a Clinical Translational Research Center, fasted overnight, and orally given heavy cream hourly for 8 hours without other foods. Arterialized blood and urine were collected over the subsequent 10 hours.

Baseline body mass index (BMI) for both groups was elevated (34–35 kg/m²) reflecting a common demographic in patients with uric acid nephrolithiasis.¹ Most baseline blood studies were comparable; however, UASF compared with Ctrl had creatinine reflective of lower estimated glomerular filtration rate (76 vs. 99 ml/min per 1.73 m², P < 0.01) and lower serum bicarbonate (22 vs. 25 mmol/l, P < 0.01). Fasting levels of free fatty acids ketone bodies, β-hydroxybutyrate, and acetoacetate were not different between groups. Most baseline fasting urine parameters were comparable, except that UASF versus Ctrl had lower pH (5.3 vs. 6.6, respectively, P < 0.001), higher titratable acidity (2.1 vs. 1.2 mEq/h, respectively, P < 0.01), and lower ratio of urine NH₄⁺ to urine net acid excretion (NAE) (0.6 vs. 0.7 mEq/mEq, respectively, P < 0.002). Urine citrate excretion in UASF versus Ctrl was numerically, but not significantly, lower in (0.2 vs. 0.4 mEq/h, respectively, P = 0.07).

During the 10-hour protocol, both groups exhibited significant and similar increases in serum free fatty acids. Urine pH in Ctrl progressively decreased from 6.6 to 5.6 over 10 hours (P < 0.001) but remained unchanged in UASF. Baseline urine NAE was higher in UASF than in Ctrl, did not change with fat loading in UASF, but increased in Ctrl. Although urine NH₄⁺ excretion was not different at baseline, by the end of the protocol it was higher in Ctrl than UASF (P < 0.02). The fraction of NAE as NH₄⁺ decreased significantly in both groups during the fat load; in Ctrl, because of greater NAE increase than NH₄⁺.

The investigators report 3 main effects of fat loading on urine parameters that promote uric acid precipitation as follows: (i) Urine pH: baseline was lower in UASF than Ctrl, remained lower in UASF, but declined progressively in Ctrl; (ii) Urine NAE: baseline was higher in UASF than Ctrl despite matched diets, and increased in Ctrl but not in UASF; (iii) NH₄⁺/NAE ratio: baseline was lower in UASF than in Ctrl, and decreased in both groups.

The data show that baseline urine composition of UASF compared with Ctrl was conducive to uric acid precipitation; lower urine pH and lower NH₄⁺/NAE ratio (proportionately less NH₄⁺ buffer). The latter supports compromised NH₄⁺ production because patients with this level of remaining estimated glomerular filtration rate (76 ml/min per 1.73 m²) can typically maintain urine NH₄⁺ comparable to those with normal estimated glomerular filtration rate.⁹ Instead, despite having greater baseline urine NAE, NH₄⁺/NAE ratio in UASF was less than in Ctrl; the expectation would be for NH₄⁺ to comprise a greater proportion of NAE when NAE was increased above baseline.³ Fat loading decreased urine pH in Ctrl but it remained unchanged in UASF. Similarly, unlike the decrease in urine NH₄⁺ with fat loading in Ctrl in animal studies,⁸ this parameter was unchanged with fat loading in UASF. These data are consistent with a fixed and functional lesion not present in the BMI-matched Ctrl, pointed out by the investigators, apparently matching the chronic effects of steatosis described in animal studies.⁸ Why BMI-matched Ctrl participants, presumably eating similar fat-containing diets, responded as described to acute fat loading, appeared not to have this lesion, warrants further study.

A factor in addition to lower urine buffer content that favors uric acid precipitation is higher urine acid content. Interestingly, UASF had higher baseline NAE despite being equilibrated on similar diets. Reflective of apparent compromised ammoniagenesis, UASF relied on a greater contribution of titratable acidity to buffer excreted acid than Ctrl, a physiologically atypical response to mediate a needed increasing in urine NAE.³ In addition, UASF appear to have greater steady state body acid accumulation, supported by lower serum bicarbonate concentration, lower urine bicarbonate excretion, and lower (but not significantly) citrate excretion. Steady-state acid accumulation has been reported in patients with chronic kidney disease and with levels of estimated glomerular filtration rate comparable to those of UASF.S1 Assuming that dietary acid intake was the same between the 2 groups, UASF might have had greater endogenous acid production as suggested by the authors.

These studies show that high dietary fat intake can promote urine composition supportive of uric acid precipitation, at least temporarily, in persons with increased BMI but without a history of uric acid stones. The studies also show that persons with a comparable BMI but with a history of such stones have a fixed defect in NH₄⁺ production and increased urine NAE, both which chronically promote urine composition conducive to uric acid precipitation. Whether their defect reflects kidney tubule steatosis as seen in animal studies or another defect not evident in similarly obese persons without a history of uric acid stones requires further study. In any case, the data support yet another adverse effect of a dietary component that helps contribute to a spectrum of the metabolic syndrome, that is, increased fat intake.

Disclosure

DEW receives consulting fees from Renibus Therapeutics, South Lake, Texas, USA.

Supplementary Material

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