To compare renal handling of uric acid in patients with primary gout with that of a control group.
To compare renal handling of uric acid in patients with primary gout with that of a control group.
A case–control study of 100 patients with primary gout and 72 healthy controls was undertaken. Creatinine clearance, uric acid clearance, 24-hour uric acid urinary excretion, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, urinary uric acid to creatinine ratio, and glomerular uric acid filtered load were calculated using 24-hour urine samples. After treatment with allopurinol to achieve similar glomerular filtered load of uric acid, patients were again compared with controls.
Patients with gout showed lower uric acid clearance, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to creatinine ratio than controls at baseline, when patients showed hyperuricemia. Although the glomerular uric acid filtered load was much higher in patients with gout than controls, 24-hour uric acid excretion was not statistically different. After treatment with allopurinol, and achieving similar uric acid filtered loads, patients still showed lower figures than controls. When patients with 24-hour urinary uric acids levels >700 mg/day were compared with controls, they had lower uric acid clearance and fractional excretion of uric acid than controls, both at baseline and after achieving similar filtered loads with allopurinol therapy.
Renal underexcretion is the main mechanism for the development of primary hyperuricemia in gout, but even patients showing apparent high 24-hour uric acid output show lower uric acid clearance than controls, indicating that relative, low-grade underexcretion of uric acid is at work.
Renal underexcretion of uric acid is considered to be the most frequent mechanism for the development of hyperuricemia and gout (1). This is especially true in patients with secondary hyperuricemia in whom reduction of renal function and concomitant diuretic drugs are the main mechanisms involved in the reduction of renal clearance of uric acid. However, a selective defect of the tubular secretion of purines, including uric acid, xanthine, and hypoxanthine, has been reported in patients with primary gout (2). Also, tubular transport of phosphate has been reported to be impaired in patients with gout (3). These findings suggest that tubular dysfunction is at work in most patients with primary gout.
The most common method used in clinical practice to classify patients as having renal underexcretion of uric acid is measuring urinary uric acid output during a 24-hour period (24hUur). Patients with urinary uric acid output >700 mg/day while on a normal, unrestricted diet are considered to have primary gout due to overproduction of uric acid (4). But, do they really have a normal renal handling of uric acid?
In this study we compare renal handling of uric acid in patients with primary gout with that of a control group.
Patients with primary gout were compared in a case–control study with healthy controls. Patients with gout were consecutively included in the study when they did not show renal function impairment and were not taking medications known to change renal handling of uric acid (such as diuretics, aspirin, cyclosporine, pyrazinamide, etc.) or taking urate-lowering therapy in the previous 2 weeks. Patients with arterial hypertension were not included because hypertension has been related to reduced renal handling of uric acid (5). Also, patients with myeloproliferative diseases were not included. Controls were selected from age-matched subjects who were referred to the nephrology division for evaluation of hypertension, but who were confirmed not to have real hypertension or renal disease.
All patients and controls underwent renal function tests while on an unrestricted diet (avoiding excessive purine intake and with absolute avoidance of alcohol) and using 24-hour urine collection. These tests included clearance of creatinine (Ccr), clearance of uric acid (Cur), fractional excretion of uric acid (FEur), glomerular load of uric acid (FLur), 24hUur, excretion of uric acid per volume of glomerular filtration (EurGF), urinary uric acid (Uur) to urinary creatinine (Ucr) ratio, and tubular reabsorption of phosphate (TRP). Clearance of creatinine was calculated from the formula Ccr = Uv × Ucr/Scr, expressed in ml/min (where Uv is urine volume/time, Ucr is urinary creatinine, and Scr is serum creatinine). Clearance of uric acid was calculated from the formula Cur = Uv Uur/Sur, expressed in ml/min (where Uur is urinary uric acid and Sur is serum uric acid). Fractional excretion of uric acid was calculated as FEur = (Uur × Scr)/(Sur × Ucr) × 100, expressed as percentage. Excretion of uric acid per volume of glomerular filtration was calculated as follows: EurGF = (Uur × Scr)/Ucr, expressed in mg/dl of glomerular filtration. Urinary uric acid to creatinine ratio was calculated as Uur/Ucr, expressed as absolute value. Glomerular load of uric acid was calculated as FLur = Ccr × Sur. Tubular reabsorption of phosphate was calculated from the formula TRP = (1- [(Up × Scr)/(Sp × Ucr)]) × 100 (where Up is urinary phosphate and Sp is serum phosphate). Ccr, Cur, 24hUur, and FLur were normalized for a body surface area of 1.73 m2. Normal 24-h urinary urate was considered to be >700 mg/day/1.73m2.
The same calculations were made after patients were treated with allopurinol to achieve normal serum uric acid levels and similar glomerular loads.
Statistical analysis was made with a statistical software package (EPIinfo 6.04; Centers for Disease Control and Prevention, Atlanta). Differences between groups were estimated with the analysis of variance test. Comparisons of data at baseline and after allopurinol therapy were made with a paired t-test. Data are expressed as means ± standard deviations.
One hundred patients with gout and 72 controls were studied. Seventy-eight of 100 patients had a diagnosis of gout based on observation (by FP-R) of monosodium urate crystals in samples from synovial fluid or tophi. They all were male and showed Ccr > 80 ml/minute/1.73 m2. Neither age or Ccr differed significantly between groups (Table 1).
|Controls n = 72||Gout patients, all n = 100||Treated patients, before treatment n = 58||Treated patients, after treatment n = 58|
|Age, years||50.0 ± 12.6||51.4 ± 10.4||50.4 ± 10.7||50.4 ± 10.7|
|Ccr, ml/minute/1.73 m2||111 ± 18||109 ± 18||107 ± 19||105 ± 22|
|Sur, mg/dl||5.01 ± 0.85||8.92 ± 1.22†||8.84 ± 1.19†||5.49 ± 0.75‡|
|24hUur, mg/day/1.73 m2||594 ± 143||628 ± 154||673 ± 144†||424 ± 118†‡|
|Cur, ml/minute/1.73 m2||8.31 ± 1.85||4.96 ± 1.30†||5.35 ± 1.25†||5.36 ± 1.28†|
|FEur, %||7.57 ± 1.85||4.59 ± 1.19†||4.98 ± 1.19†||5.52 ± 1.41†|
|FLur, mg/minute/1.73 m2||5.58 ± 1.22||9.73 ± 2.02†||7.75 ± 0.43†||5.78 ± 1.52‡|
|EurGF, mg/dl/1.73 m2||0.38 ± 0.10||0.40 ± 0.09||0.43 ± 0.09||0.28 ± 0.08†‡|
|Uur/Ucr||0.37 ± 0.10||0.39 ± 0.10||0.41 ± 0.08||0.27 ± 0.18†‡|
Uric acid renal handling parameters in controls were the following. Mean 24hUur was 594 ± 143 mg/day/1.73 m2, median 605 mg/day/1.73 m2; 95% confidence interval (95% CI) 556–630 mg/day/1.73 m2. Mean Cur was 8.31 ± 1.85 ml/minute/1.73 m2, median 8.45 ml/minute/1.73 m2; 95% CI 7.87–8.74 ml/minute/1.73 m2. Mean FEur was 7.57 ± 1.85%, median 7.33%; 95% CI 7.13–8.01%. Mean EurGF was 0.37 ± 0.10 mg/dl, median 0.38 mg/dl; 95% CI 0.34–0.40 mg/dl. Mean Uur/Ucr ratio was 0.37 ± 0.10, median 0.37; 95% CI 0.34–0.37.
Data related to Sur, Ccr, and renal uric acid handling parameters in patients and controls are included in Table 1. FLur was higher in patients than in controls (9.73 ± 2.02 mg/minute versus 5.58 ± 1.22 mg/minute; P < 0.001) but 24hUur was not statistically different (628 ± 154 mg/day/1.73 m2 versus 594 ± 143 mg/day/1.73 m2; P = 0.137). Cur and FEur were also lower in patients with gout than in controls (4.95 ± 1.30 ml/minute/1.73 m2 versus 8.31 ± 1.85 ml/minute/1.73m2; P < 0.001; and 4.59 ± 1.19% versus 7.57 ± 1.85%; P < 0.001, respectively). TRP was also lower in patients with gout than in controls (82 ± 8% versus 87 ± 7%; P = 0.013). EurGF and Uur to Ucr ratio were not different in patients and controls (0.40 ± 0.09 mg/dl versus 0.38 ± 0.10 mg/dl; P = 0.070; and 0.39 ± 0.10 versus 0.37 ± 0.10; P = 0.276, respectively).
Fifty-eight patients were treated with allopurinol. After achieving normal serum uric acid levels and similar glomerular loads (treated patient, 5.78 ± 1.52 mg/minute versus control, 5.58 ± 1.22 mg/minute; P = 0.392), patients still showed lower Cur and FEur, but also lower EurGF and Uur/Ucr than controls (Table 1). Cur and FEur did not change after allopurinol therapy, contrary to 24hUur, EurGF, and Uur/Ucr.
Twenty-five patients who were treated with allopurinol and showed a 24hUur >700 mg/day before urate-lowering therapy, that is, those who were supposed to show normal renal handling of uric acid, were compared with controls (Table 2). Gouty patients before allopurinol treatment showed age and Ccr similar to controls, but lower Cur rates (6.39 ± 0.69 ml/minute/1.73 m2 versus 8.31 ± 1.85 ml/minute/1.73 m2; P < 0.001) and FEur (5.77 ± 1.03% versus 7.57 ± 1.85%; P < 0.001). Conversely, EurGF and Uur/Ucr ratio were higher in patients with 24hUur greater than 700 mg/day than in controls (0.50 ± 0.06 mg/dl versus 0.38 ± 0.10 mg/dl; P < 0.001; and 0.48 ± 0.07 versus 0.37 ± 0.10; P < 0.001). Twenty-five of the 35 patients with 24hUur >700 mg/day were treated with allopurinol, achieving similar FLur rates to controls (6.03 ± 1.36 mg/minute versus 5.58 ± 1.22 mg/minute, respectively; P = 0.071). Patients showed lower Cur and FEur, but also lower EurGF and Uur/Ucr than controls (Table 2). Cur and FEur figures were unchanged after allopurinol therapy, contrary to 24hUur, EurGF, and Uur/Ucr.
|Controls||Gout and hyperuricemia (G&H) n = 25||Gout with allopurinol (G&A) n = 25||P (C versus G&H)||P (C versus G&A)|
|Ccr (ml/minute/1.73 m2)||111 ± 18||113 ± 20||111 ± 22||0.572||0.907|
|Sur (mg/dl)||5.01 ± 0.85||8.87 ± 1.06||5.52 ± 0.50†||<0.001||0.006|
|FLur (mg/minute/1.73 m2)||5.58 ± 1.22||8.03 ± 1.80||6.03 ± 1.36†||<0.001||0.071|
|Cur (ml/minute/1.73 m2)||8.31 ± 1.85||6.39 ± 0.96||6.37 ± 1.03||<0.001||<0.001|
|FEur (%)||7.57 ± 1.85||5.77 ± 1.03||5.92 ± 1.37||<0.001||<0.001|
|EurGF (mg/dl/1.73 m2)||0.38 ± 0.10||0.50 ± 0.06||0.32 ± 0.08†||<0.001||0.009|
|Uur/Ucr||0.37 ± 0.10||0.48 ± 0.07||0.32 ± 0.07†||<0.001||<0.001|
The mechanism most commonly involved in either primary or secondary hyperuricemia is an impairment of renal excretion of uric acid, due to a reduction of glomerular filtration (with the associated reduction of the glomerular filtration of uric acid), increased tubular resorption, or decreased tubular secretion of uric acid (2). The primary capacity of renal excretion of uric acid is probably of genetic origin, as has been demonstrated in studies of the clearance of uric acid comparing data between monozygotic and dizygotic twins (6). Comparing patients with gout and controls with normal renal function, in whom a reduction of glomerular filtration is not at work, a tubular defect of the excretion of uric acid has been observed in patients with gout (7). This defect was not dependant on the glomerular uric acid filtered load. The reduction of tubular secretion of uric acid persisted despite the reduction of serum uric acid levels to <3 mg/dl after allopurinol therapy in patients, and tubular secretion remained unchanged in controls. This defect of tubular secretion is not selective for uric acid, but also is seen for other purines, such as xanthine and hypoxanthine (2). More recently, these results have been confirmed by others, the defect in tubular secretion of uric acid appearing especially in patients with gout and hypertension (8). Also, a decreased renal phosphate threshold has been reported in patients with gout compared with controls (3). All these data support the renal tubule as the target for the defect of renal excretion in gouty patients. Renal underexcretion of uric acid is also observed in most patients with psoriasis and hyperuricemia (9), despite the fact that this condition usually is reported as related to overproduction of uric acid.
Data about normal limits of the parameters of renal handling of uric acid are not frequently reported in the literature. Khaeny et al (10) studied renal handling of uric acid in patients with autosomal dominant polycystic kidney disease (ADPCD) and ADPCD relatives. Renal handling of uric acid was related to the extent of renal function impairment. When 106 patients and 112 relatives with normal renal function were considered, no differences in renal handling of uric acid were observed: Cur was 8.4 ± 0.3 ml/minute/1.73 m2 and 8.1 ± 0.3 ml/minute/1.73 m2 and FEur was 8.2 ± 0.3% and 7.7 ± 0.3%, very similar to the values obtained in our controls. In the series of Tykarsky (8), controls and patients with essential hypertension, normal Sur, and younger than 60 years showed Cur 10.40 ± 2.32 ml/minute and 10.03 ± 3.00 ml/min and FEur of 9.1 ± 1.7% and 8.4 ± 2.4%, respectively. Their figures seem to be somewhat higher than ours, but their data were not corrected for body surface. Other series with 72 and 26 controls with normal renal function (3, 11) disclosed Cur of 7.8 ± 3.6 ml/minute/1.73 m2 and 6.4 ± 1.3 ml/minute/1.73 m2, respectively, and FEur of 7.87% and 6.4 ± 1.5% (FEur has been calculated from data of Cur and Ccr reported in this series). In the later series, the figures for Cur and FEur are somewhat lower than those observed in our controls. However, only 26 controls were studied and their age was paired to gouty patients, the mean being 61 years; older than our patients and controls.
In the present series, we have used all the methods that have been reported to be useful to evaluate renal handling of uric acid, such as 24hUur, Cur, FEur, EurGF, and Uur/Ucr ratio (2–4, 7, 8, 12–15). All these parameters have been observed to be lower in patients with gout than in controls, supporting that the predominant mechanism for hyperuricemia is renal underexcretion of uric acid. Interestingly, Cur and FEur did not change after allopurinol therapy, differing from previous reports. This fact indicates that some parameters of renal handling of uric acid do not change with different FLur. In the study of Garcia Puig et al (7), tubular secretion of uric acid was impaired at any filtered load of uric acid. An apparent reduction of Cur was observed; however, it must be considered that their data are not paired. Furthermore, the baseline number of gouty patients (56) was twice the number of the patients in whom final renal handling of uric acid was reported (30), so some bias may have been inferred.
When patients with urinary uric acid output >700 mg/day were considered, lower Cur and FEur were also observed in gouty patients than in controls. The observation of higher figures of EurGF and Uur/Ucr at baseline in patients than in controls may be interpreted at first sight as signs of overproduction of uric acid in patients with gout (12). Nevertheless, it should be remembered first that neither of these 2 parameters take into account serum uric acid levels, thus omitting the effect of the FLur, and second, that these parameters are influenced by the uric acid FLur (13). Because patients had an almost 2-fold filtered load compared with controls at baseline, you might expect that if they were real overproducers of uric acid with normal renal handling of uric acid, the excretion of uric acid in these patients would be much higher than that observed. In fact, reducing serum uric acid levels with allopurinol and achieving similar filtered loads of uric acid, both EurGF and Uur/Ucr showed a decrease and were lower in patients than in controls.
The reduction of clearance of creatinine has been shown to increase EurGF (13) and it may falsely indicate that some patients with low renal function are actually overproducers of uric acid (14). Data from series studying EurGF (12, 15) show that patients with serum creatinine up to 1.5 mg/dl were included, and probably showed reduction of renal function. In the present series, renal function was not evaluated with plasmatic creatinine levels, but with clearance of creatinine. To be included in the study, all patients and controls had normal renal function, so bias due to renal function impairment was avoided.
In conclusion, renal underexcretion of uric acid is present in most patients with gout, including patients with apparent overexcretion of uric acid.
The authors acknowledge the contribution of Dr. Peter Simkin's work to the knowledge of renal handling of uric acid, and especially to the applicability of midmorning spot urine samples in clinical practice.