Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease

A total of 612 patients were screened at the ADPKD clinic in Seoul National University Hospital. ADPKD was diagnosed according to the unified criteria proposed by Pei et al. [14]. We selected 365 patients aged > 18 years with an estimated GFR (eGFR) of > 15 mL/min/1.73 m² at the initial evaluation and who were followed up for > 1 year. Patients with certain conditions that can independently influence renal function such as diabetes [15], pregnancy, or malignancy were excluded from the analysis. The data were collected retrospectively from each patient between August 1999 and March 2012. The patients underwent a standardized evaluation including detailed family history, renal function, and computed tomography (CT) scan, which was obtained using a multidetector CT scanner (Somatom Sensation 16, Siemens; LightSpeed Ultra 8, GE; Brilliance CT 64, Philips; Somatom Definition, Siemens). The following clinical data and information were collected every 3–6 months: baseline epidemiologic profiles (age, sex, and body weight), medical history including diabetes, hypertension, and gout, medication history including antihypertensive medications and hypouricemic agents, blood pressure, and laboratory results (serum creatinine (sCr), sUA, hemoglobin, serum albumin levels, and urine dipstick). The CT scan was performed every 2 years and total kidney volume (TKV) was calculated using the modified ellipsoid method [16]. This study was approved by the Institutional Review Board of Seoul National University Hospital (H-1002-028-309). Informed consent was obtained from the subjects in accordance with the Declaration of Helsinki.

The sCr was measured at 3- or 6-month interval using the Jaffe method by Hitachi 7600 and Toshiba-200FR, which was calculated to Isotope Dilution Mass Spectrometry (IDMS)-traceable sCr. The Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) formula was used to calculate eGFR. Delta eGFR (ΔeGFR/year) was calculated using the equation (recent eGFR − eGFR at initial visit)/follow-up duration (years). The CKD stage was classified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines [17]. ESRD was defined by an eGFR of <15 mL/min/1.73 m² or initiation of renal replacement therapy. Albuminuria was defined as a stick albumin level of >1+ by urine dipstick test. Urine albumin was quantified by the immunoturbidimetric assay using Toshiba-120FR. Hypertension was defined by a systolic blood pressure of >140 mmHg, diastolic blood pressure of >90 mmHg, or current use of antihypertensive medication.

The sUA level was determined using the uricase method (Hitachi 7600 and Toshiba-200FR). Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in males and ≥ 6.0 mg/dL in females or when patients have received hypouricemic treatment. Hypouricemic medications were prescribed in patients with gout, a history of uric acid stones, or persistent elevation of sUA level of > 8.0 mg/dL that was not controlled by dietary modification in 2 successive visits.

The clinical characteristics of 365 patients on initial evaluation are summarized in Table 1. They were divided into normouricemic (Group A, n = 278) and hyperuricemic (Group B, n = 87) groups. In Group B, 12 patients (3.3%) underwent hypouricemic treatment. The prevalence of hyperuricemia increased according to CKD stage as follows: 6.3% (6/95) in stage 1, 15.2% (28/184) in stage 2, 52.4% (33/63) in stage 3, and 87.0% (20/23) in stage 4.

When compared with those in Group A, the patients in Group B were slightly older (47.1 ± 13.2 vs. 42.4 ± 11.3 years, p = 0.003), had higher prevalence of hypertension (81.6% vs. 66.9%, p = 0.004), showed male predominance (70.1% vs. 43.5%, p < 0.001), and had shorter follow-up duration (64.7 ± 42.1 vs. 76.2 ± 43.5 months, p = 0.031). Group B had higher sCr levels (1.67 ± 0.69 vs. 1.01 ± 0.23 mg/dL, p < 0.001) and lower eGFR (54.5 ± 26.3 vs. 81.6 ± 19.3 mL/min/1.73 m², p < 0.001) compared to Group A.

Associations between sUA and sCr levels, eGFR, TKV, and albumin to creatinine ratio (ACR) were analysed (Figure 1). The sUA level was positively correlated with sCr level (R ² = 0.370, p < 0.001), ACR (R ² = 0.011, p = 0.111) and TKV (R ² = 0.045, p < 0.001) but negatively correlated with eGFR (R ² = 0.202, p < 0.001). Simple linear regression analysis in 353 patients without hypouricemic treatments at the initial evaluation revealed that age, albuminuria, TKV, and sUA level were correlated with reduced initial eGFR. After adjustment for age, male sex, blood pressure, albuminuria, and TKV, sUA levels still remained a significant factor (β = −5.117, p < 0.001; Table 2).

Among 365 patients, 42 patients (11.5%; 20 in Group A and 22 in Group B) progressed to ESRD during the follow-up (mean duration, 73.5 ± 43.4 months). When evaluating the deterioration of eGFR, we examined 296 patients not taking hypouricemic medication (255 patients from Group A and 41 patients from Group B) to exclude the influence of hypouricemic agents (Table 3). The mean sUA level was 4.69 ± 1.08 mg/dL in normouricemic Group A and 7.61 ± 0.95 mg/dL in Group B (p < 0.001), indicating a difference of 2.9 mg/dL. Progression to ESRD occurred in 14 (34.1%) out of 41 patients in Group B and 14 (5.4%) out of 255 patients in Group A (p < 0.001). Group B showed a faster annual decline in eGFR (ΔeGFR/year) than Group A in absolute (−1.87 ± 3.30 vs. −0.29 ± 4.22 mL/min/1.73 m² per year, p = 0.026) and relative values (−6.23% ± 9.84% vs. −0.72% ± 6.03% per year, p = 0.001).

Linear regression analysis was performed to determine the factors influencing ΔeGFR/year. In univariate analysis, age, hypertension, initial eGFR, and sUA level were significantly associated with ΔeGFR/year. However, after adjusting for age, sex, blood pressure, and initial eGFR, neither sUA level nor hyperuricemia was significantly associated with ΔeGFR/year (Table 4). In the same manner, multivariate Cox regression analysis showed that hyperuricemia was not an independent risk factor for ESRD (Table 5).

Although we were not able to show the independent association of sUA level with renal progression in ADPKD patients who were not taking hypouricemic agents, we did exploratory analysis in a subgroup of our cohort to investigate the effect of hypouricemic treatment on eGFR. Among 57 patients newly starting hypouricemic treatment during follow-up period, 53 patients had follow-up period more than 1 year of pre- and post-treatment. Serum UA and eGFR were measured every 3 months. The slopes of the annual change in eGFR before and after hypouricemic treatment were analyzed in 53 patients receiving either allopurinol (n = 12) or benzbromarone (n = 41) more than a year.

Among them, 13 patients were included in CKD stage 1 or 2, 19 in CKD stage 3a, 11 in CKD stage 3b, and 10 in CKD stage 4 before treatment initiation. Mean sUA was 8.70 ± 0.78 mg/dL and mean eGFR was 47.9 ± 20.3 mL/min/1.73 m² at the time of hypouricemic treatment initiation. The change in sUA and eGFR before and after 1 year of treatment initiation was analyzed (Table 6). After the hypouricemic treatment, the annual decline of renal function (ΔGFR/year) slowed from −5.3 ± 8.2 to 0.2 ± 6.2 mL/min/1.73 m² per year (Wilcoxon signed-rank test, p = 0.001). Further analysis showed that correction of hyperuricemia may attenuate renal function decline in early CKD stages (1 ~ 3a) whereas it may not attenuate renal function decline in advanced CKD stages (3b ~ 4). Serial changes in sUA and eGFR are presented in Figure 2 and Additional file 1: Table S1. There was no difference between allopurinol and benzbromarone group (data not shown). However, significant changes in systolic blood pressure were also observed after hypouricemic treatment (Additional file 1: Table S2). Because lowering blood pressure itself and change of anti-hypertensive medication (32.1% during the observation period), especially of renin-angiotensin system blockers may affect eGFR, the effect of blood pressure on eGFR was examined by using generalized estimating equation, showing that no significant effect over 2-year observation period (data not shown). In summary, blood pressure changes did not significantly influence eGFR changes after hypouricemic treatment.