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

Background The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline. Methods This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed. Results Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test). Conclusions Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.

In the past, elevated serum uric acid was regarded as the cause of gout by deposition as monosodium urate crystal. Recently, the role of uric acid in cardiovascular disease (8)(9)(10)(11), metabolic syndrome (12,13), diabetes (14,15) and kidney disease have been getting attention.
Uric acid has been regarded as a marker rather than a risk factor for the  (17) showed that hyperuricemia is associated with increased risk of incident CKD.
Moreover, hyperuricemia has been reported to be associated with the development of end-stage renal disease (ESRD) (18,19).
The pathogenic role of hyperuricemia in the progression of CKD is still controversial (20). Hyperuricemia has been reported as a risk factor for renal progression in IgA nephropathy (21), whereas uric acid level was not associated with disease progression or kidney failure in general CKD population (22,23).
However, reduction of SUA by allopurinol has been reported to delay progression of CKD in people with both diabetic and nondiabetic CKD (11,24) Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease with the incidence of 1 per 500-1,000 persons in the general population (25). ADPKD is caused by two genes, PKD1 (chromosome 16p13.3) and PKD2 (chromosome 4q21) and characterized by multiple cysts in bilateral kidney, liver and pancreas (26). ADPKD is 4 th most common cause of renal failure after diabetes, hypertension and glomerulonephritis, accounting for 1.8% in end stage of renal disease in Korea (27). Several risk factors influencing kidney disease progression in ADPKD have been identified, such as PKD1 gene mutation, young age at onset of hypertension, presence of hypertension, large kidney size, male gender, proteinuria, and a younger age at diagnosis, etc (28). Recently, uric acid as a possible risk factor is getting attention.
Association between autosomal dominant polycystic kidney disease (ADPKD) and hyperuricemia was first described by Rivera et al (29). ADPKD is frequently associated with hyperuricemia and gout (30), although fractional excretion of uric acid was not different among CKD groups of different etiologies (31,32). Recent retrospective studies reported the association of high serum uric acid levels with early-onset hypertension, large kidney volume, and increased risk of ESRD (33) or progression of renal dysfunction (34).
In ADPKD, there is no data regarding serum uric acid levels and decline of eGFR  (20). ESRD was defined by an eGFR of <15 mL/min/1.73 m 2 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.
Uric acid measurement and hyperuricemia management Serum uric acid level was determined using the uricase method (Hitachi 7600 and Toshiba-200FR). Hyperuricemia was defined by a serum uric acid (sUA) level of ≥7.0 mg/dL or initiation of hypouricemic treatment. Hypouricemic medications were prescribed in patients with gout, a history of uric acid stones, or persistent elevation of uric acid level of >8.0 mg/dL that was not controlled by dietary modification in 2 successive visits.

Kidneys
One normal portion of kidney specimen and three polycystic kidney specimens were collected from patients who received radical nephrectomy after informed consent (Table 1)

Statistical analyses
Continuous variables were expressed as mean ± standard deviation. The Student t-test was used to compare the continuous variables between the groups. The linear regression analysis was used to find the association between sUA and clinical variables. Renal survival rate was calculated using the Kaplan-Meier method, and the log-rank test was used to compare renal survival between groups.
The Wilcoxon signed-rank test was used to evaluate the effect of medication. P < 0.05 was considered statistically significant. All the statistical analyses were performed using SPSS version 19.0 (SPSS Inc., Chicago, IL).

Results
Baseline clinical characteristics according to the presence of hyperuricemia The clinical characteristics of the 365 patients on initial evaluation are summarised in   Table 2). Associations between sUA and sCr levels, eGFR, TKV, and albumin to creatinine ratio (ACR) were analysed (Fig. 2). Serum uric acid 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 the 353 patients without hypouricemia treatments revealed that age, albuminuria, TKV, and sUA TKV, total kidney volume; ADPKD, autosomal dominant polycystic kidney disease 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 3). 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, either sUA level or hyperuricemia was no longer   (Table 5). A Kaplan-Meier survival curve also indicated that the patients in Group B progressed to ESRD faster than those in Group A (log rank test, p <0.001; Fig. 4), however, hyperuricemia was not a significant risk factor in ESRD in Cox regression analysis. (Table 6) Treatment of hyperuricemia prevented progression of renal dysfunction

Hyperuricemia influenced annual decline in eGFR
To investigate the effect of hypouricemic treatment on eGFR, the slope of the annual change in eGFR before and after hyperuricemic treatment were analysed in 53 patients receiving either allopurinol (n = 12) or benzbromarone (n = 41) and followed up for >1 year. Among these patients, 13 had CKD stage 1 or 2, 19 had stage 3a, 11 had stage 3b, and 10 had stage 4 before the hypouricemic treatment.
The mean sUA was 8.70 ± 0.78 mg/dL, and the mean eGFR was 47.9 ± 20.3 mL/min/1.73 m 2 at the time of hypouricemic treatment initiation. After the hypouricemic treatment, the overall ΔGFR/year was improved from -5.32 ± 8.15 to 0.21 ± 6.20 mL/min/1.73 m 2 (paired t -test, p = 0.001). In the subgroup analysis according to CKD stages, the hypouricemic agents were beneficial for patients in early CKD stages (1~3a) whereas renal function continued to decline in those in advanced CKD stages (3b~4) (Fig. 5, Table 7). There was no difference between allopurinol and benzbromarone group.

Discussion
In this retrospective cohort study, I demonstrated that serum uric acid level is associated with renal function in ADPKD. In addition, hyperuricemia contributed to the renal function decline, which may be reversed using hypouricemic treatment in early CKD stage. According to this immunohistochemical result, not only excretory transporters but also reabsorption transporters are overexpressed in compressed proximal tubules of ADPKD.
In this study, the prevalence of hyperuricemia increased as CKD stage progressed from 9.5% to 82.6%. I showed that sUA level is a factor associated with reduced eGFR, independent of age, sex, albuminuria, and TKV. This result is consistent with those from previous studies reporting that hyperuricemia is especially associated with early-onset hypertension, TKV, and increased risk of ESRD (33).
Next, I observed a negative correlation between hyperuricemia and ΔeGFR/year. However, after adjusting factors such as age, sex, blood pressure, and initial eGFR, the influence of hyperuricemia was not statistically significant. Similarly, the risk of developing ESRD was higher in patients with hyperuricemia by Kaplan-Meier survival analysis. However, multivariate analysis using Cox regression model indicated that the initial eGFR was only predictive factor for ESRD progression.
This result may be explained by the small difference in sUA level between patients with and without hyperuricemia in this study because I excluded high-risk patients with hyperuricemia who were already being treated. Moreover, the follow-up duration was relatively short. The median follow-up duration was only 73.5 months, and 41.6% of the patients were followed up for <5 years.
I examined the effect of hyperuricemic treatment on the slope of change in eGFR.
Intervention with hypouricemic medications reduced ΔeGFR/year, especially in patients in early CKD stages (1~3a), supporting the finding that hyperuricemia is a risk factor for renal function deterioration. This is consistent with the previous finding that allopurinol therapy preserved serum creatinine level and lowered the risk of renal progression in hyperuricemic patients with mild to moderate CKD (11,24). However, in this study, hypouricemic treatment had no effect on preserving eGFR in patients with CKD stage 3b to 4. This result is in line with previous study showing that serum uric acid was independently associated with eGFR only in stage 3 CKD, not in stage 4 or 5 CKD (38). To the best of my knowledge, no previous studies included patients with severe renal insufficiency and did subgroup analysis according to CKD stages. This finding suggests the beneficial effects of hypouricemic therapy may disappear in advanced CKD stage, which may further provide the guideline to treat hyperuricemia in CKD patients.
Several mechanisms were proposed to explain renal dysfunction by hyperuricemia.
First, association between increased sUA level and cardiovascular disease has been reported (39). However, in this study, no difference in cardiovascular event was observed between the normouricemic and hyperuricemic groups [data not shown]. Cardiovascular events occurred only in 7.1% in this study population during the follow-up period, much fewer than the previously reported incidence rate (40). Second, hyperuricemia may induce direct renal injury through the activation of the renin-angiotensin aldosterone system (RAS). Renal cyst enlargement in ADPKD is known to be associated with stimulation of the circulating and intrarenal RAS (41). Helal et al (33) speculated that endothelial dysfunction, which is a well-known characteristic of ADPKD (42), and activation of RAS induced by hyperuricemia would contribute to the progression of ESRD in ADPKD.
Endothelial dysfunction and early-onset hypertension are important prognostic factors for the deterioration of renal function in ADPKD (43). In addition, soluble uric acid might activate inflammatory pathways such as tumor necrosis factor alpha (TNF-α) and chemokines (44) and C-reactive protein (45), possibly leading to interstitial fibrosis. In CKD patients, association between hyperuricemia and increased urinary transforming growth factor beta (TGF-β) was also reported (46).
The pathogenic role of hyperuricemia in renal progression need to be further investigated in regard to urate handling in ADPKD. In ADPKD, altered tubular membrane transport process might affect renal urate handling and homeostasis.
Compared with that in the general population, a higher prevalence of uric acid stone was noted in ADPKD. However, previous studies showed inconsistent data about urate handling in ADPKD (31,32). To confirm the possibility of altered tubular membrane transport process, we performed immunohistochemical staining of 4 urate transporters, which were known to play significant role in renal urate transport in human (47).
All kidney specimens were from the patients who were normouricemic and not taking uric acid lowering agents. Urate transporters were stained strongly along the compressed renal tubular epithelial cells in ADPKD. The specimen PKD-CKD1 from ADPKD patient with normal GFR showed strong staining of URAT1 and GLUT9 compared to control tissue from the patient with similar sUA level.
Although we tested the limited number of specimens and did not evaluate genetic variations, this results suggested the possibility of altered urate handling in ADPKD that may lead to hyperuricemia.
This study has several limitations. This is a single-center retrospective study.
Additionally, genetic factor, which is the strongest predictor of renal progression, has not been evaluated. However, this result suggest that hyperuricemia is an important risk factor for reduced eGFR and its deterioration in ADPKD. Even though hyperuricemia was not an independent risk factor for renal function deterioration, control of hyperuricemia with uric acid lowering agents improved renal function. This results suggest that treatment of hyperuricemia would be beneficial for preservation of renal function in ADPKD. A well-designed prospective randomised controlled study is needed to verify the impact of hyperuricemia control on disease progression in ADPKD.