Edited by Dong-Ryeol Ryu, Ewha Womans University, Seoul, Korea
Hyperuricemia is associated with the development and progression of chronic kidney disease (CKD) as well as cardiovascular diseases. However, there is no consistent recommendation regarding the treatment of asymptomatic hyperuricemia (AHU) in CKD patients. Here, we surveyed Korean physicians’ perceptions regarding the diagnosis and management of AHU in CKD patients.
Questionnaires on the management of AHU in CKD patients were emailed to regular members registered with the Korean Society of Nephrology.
A total of 158 members answered the questionnaire. Among the respondents, 49.4%/41.1% were considered hyperuricemic in male CKD patients whereas 36.7%/20.9% were considered hyperuricemic in female CKD patients when defined by serum uric acid level over 7.0/8.0 mg/dL, respectively. A total of 80.4% reported treating AHU in CKD patients. The most important reasons to treat AHU in CKD patients were renal function preservation followed by cerebro-cardiac protection. Majority of respondents (59.5%) thought that uric acid-lowering agents (ULAs) were the most effective method for controlling serum uric acid levels. Approximately 80% chose febuxostat as the preferred medication. A total of 32.3% and 31.0%, respectively, initiated ULA treatment if the serum uric acid level was more than 8.0 or 9.0 mg/dL, respectively. In addition, 39.2% and 30.4% answered that target serum uric acid levels of less than 6.0 or 7.0 mg/dL, respectively, were appropriate. The two major hurdles to prescribing ULAs were concerns of adverse reactions and the existing lack of evidence (i.e., the absence of Korean guidelines).
Most Korean physicians treat AHU in CKD patients to prevent CKD progression and cerebro-cardiovascular complications.
Hyperuricemia is a very common biochemical aberration and the prevalence is increasing due to changes in diet, an aging population, and earlier screenings [
Although the incidence of hyperuricemia and gout in Korean adults is also increasing, epidemiologic studies remain limited. The prevalence of hyperuricemia (> 7.0 mg/dL) was 4.6% in a hospital medical check-up cohort in 2003 [
Hyperuricemia is thought to be associated with decreased renal function through increased oxidative stress, increased endothelial dysfunction, systemic glomerular hypertension, and reduced renal blood flow [
We hypothesize that lowering the serum uric acid level could delay renal disease progression and reduce cardiovascular complications. In addition, an effective way to control serum uric acid levels is the prescription of uric acid-lowering agents (ULAs) such as allopurinol, febuxostat, and uricosuric agents.
The Japanese Society of Gout and Nucleic Acid Metabolism recommends treating AHU when either serum uric acid level is greater than 9 mg/dL or when serum uric acid is greater than 8 mg/dL and is accompanied by renal damage, urinary lithiasis, hypertension, ischemic heart disease, diabetes, or metabolic syndrome [
The practice pattern of the management of AHU in CKD patients has not yet been surveyed. This study aimed to clarify how Korean nephrologists manage AHU in CKD patients.
We performed a questionnaire survey to determine physicians’ perceptions of AHU in CKD patients from July 9, 2018 to August 6, 2018. We sent and received emails to and from regular members registered with the Korean Society of Nephrology (KSN). The questionnaire was designed as follows: 1) definition of hyperuricemia in CKD patients (> 6.0, > 7.0, > 8.0, > 9.0, and > 10.0 mg/dL); 2) necessities and effective methods of lowering serum uric acid levels (yes vs. no); 3) the purpose of managing AHU (gout prevention, nephrolithiasis prevention, renal preservation, and cerebro-cardiovascular protection); 4) evaluation of the urinary uric acid excretion (yes vs. no); 5) the initial (> 6.0, > 7.0, > 8.0, > 9.0, > 10.0 mg/dL) and the target (< 4.0, < 5.0, < 6.0, < 7.0, < 8.0 mg/dL) serum uric acid levels for prescribing ULAs; 6) preferred medication (allopurinol vs. febuxostat vs. benzbromarone vs. others); 7) evaluation of the HLA-B58:01 allele before prescribing allopurinol (yes vs. no); 8) prescribing doses of allopurinol and febuxostat (open question about the initial and the maximum doses); and 9) hurdles to prescribing ULAs (multiple-choice format [choices of two out of seven], including nonpharmacologic intervention first, too many concomitant medications, fear of adverse reactions, unclear treatment effects, the lack of evidence [i.e., the absence of Korean guidelines], patients’ refusal, not fitting insurance criteria).
This study was approved and got a waiver of informed consent by the Institutional Review Board of the National Medical Center in Seoul, Korea (H-1811-096-001).
Descriptive statistics were used to summarize survey responses. The chi-square test was used to compare categorical variables between groups. All statistical analyses were performed with the IBM SPSS Statistics version 20.0 software program (IBM Corp., Armonk, NY, USA). A
We sent email communications to a total of 1,258 regular members who were registered with the KSN and received answers back from 158 (12.6%) of them.
The mean (median) age of the study participants was 45 (43) years old, and 100 (63.3%) of the participants were men. Most of the participants were affiliated with referral hospitals (secondary hospitals [34.8%], tertiary or university-associated hospitals [48.7%]). The baseline characteristics of the participants are summarized in
Among the respondents, 3.2%, 49.4%, 36.8%, 8.9%, and 1.9% were considered hyperuricemic in male CKD patients to be greater than 6.0, 7.0, 8.0, 9.0, and 10.0 mg/dL, respectively, while 27.2%, 41.1%, 20.9%, 8.0%, and 1.3% were considered hyperuricemic in female CKD patients to be greater than 6.0, 7.0, 8.0, 9.0, and 10.0 mg/dL (
A majority of respondents (80.4%) reported treating AHU in CKD patients. There was no significant difference in treating AHU according to the hospital hierarchy (88.5 vs. 76.4 vs. 80.5%) (linear-by-linear association
When we separated the condition according to eGFR, 7.6%, 8.2%, and 18.4% of respondents disagreed about treating AHU in patients with eGFR values of less than 30, 30 to 60, and 60 mL/min/1.73 m2 or more, respectively. ULAs were thought to be the most effective method of controlling serum uric acid levels (59.5%), followed by lifestyle modification (31.0%) and a change in prescription to alternative medicines (9.5%). The most important reasons for treating AHU in CKD patients were renal function preservation followed by cerebro-cardiovascular protection (
Only 15.2% evaluated urinary uric acid excretion by using 24-hour urine uric acid, fractional excretion of uric acid from random urine, and urinary stone evaluation through abdominal sonography. In addition, only 4.4% performed the HLA-B*58:01 allele test, which is the marker for allopurinol-induced severe cutaneous adverse reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis.
Regarding ULA type, 78.1%, 19.7%, and 2.2% of respondents preferred febuxostat, allopurinol, and benzbromarone, respectively. A total of 32.3% and 31.0% of the respondents answered they start the prescription of ULAs when serum uric acid level was greater than 8.0 or 9.0 mg/dL, respectively. Additionally, 39.2% and 30.4% of participants targeted serum uric acid levels of less than 6.0 or 7.0 mg/dL, respectively (
Hurdles to prescribing ULAs were as follows: 1) use of a nonpharmacologic intervention first (9.7%), 2) too many concomitant medications (0.6%), 3) fear of adverse reactions (36.1%), 4) unclear treatment effects (11.0%), 5) lack of evidence (i.e., the absence of Korean guidelines) (36.5%), 6) refusal by patients (5.5%), and 7) Not fitting insurance criteria (0.6%) (
To our knowledge, this study is the first survey concerning the management of AHU in CKD patients in Korea. However, the low response rate to the survey reflects the idea that hyperuricemia in CKD patients is not a priority subject even within the KSN.
About half of the responders considered hyperuricemia in CKD patients to be greater than 7.0 mg/dL of serum uric acid, although approximately one-third chose greater than 8.0 mg/dL of serum uric acid, regardless of sex, and another one-third chose greater than 6.0 mg/dL of serum uric acid in female CKD patients. Most respondents (80.4%) attending CKD patients replied that uric acid-lowering therapy for AHU in CKD patients is necessary. Approximately, 84–89% and 63% of Japanese nephrologist agreed to treat AHU in patients with stages 3 to 5 CKD and stage 5D CKD patients, respectively, while only 4% of rheumatologists in the US prescribed ULAs to patients with AHU [
About two-thirds of respondents stated that they prescribed ULAs if the serum uric acid level was greater than 8.0 mg/dL and targeted a serum uric acid level of less than 7.0 mg/dL (< 6.0 mg/dL, 39.2% and < 7.0 mg/dL, 30.4%). Nakaya et al [
Fear of adverse reactions and the lack of evidence are important hurdles to prescribing ULAs. In addition, the dosage of ULAs was inversely associated with the eGFR.
As mentioned above, several studies have reported an association between hyperuricemia and CKD [
In addition, several trials on the effects of febuxostat, topiroxostat, and newer ULAs on renal function and cardiovascular diseases have been published. Both febuxostat and topiroxostat delayed eGFR decline [
Nephrologists manage CKD patients by using renin angiotensin aldosterone receptor blockers, statins, and other verified renoprotective medicines, but many CKD patients still progress to ESRD. Thus, another option to improve renal and patient outcomes in CKD patients is needed. Our focus has therefore expanded to uremic toxins and inflammatory mediators. Moreover, the management of serum uric acid is an attractive option based on experimental and clinical evidence. Currently, the CKD FIX (a placebo-controlled study giving allopurinol to CKD patients in stages 3 and 4 with proteinuria) [
Although decreased renal function can increase the serum uric acid level and a cohort or a prospective study to find the causal relationship between AHU and patient outcomes in Korean CKD patients is needed, we think that the systemic impact of hyperuricemia does not differ with the presence of CKD. Therefore, we carefully suggest adopting the definition of hyperuricemia as a serum uric acid level of greater than 7.0 mg/dL for the general population, irrespective of CKD stage. In addition, we suggest prescribing ULAs if the serum uric acid level exceeds 8.0 mg/dL with the consideration of tissue solubility of uric acid and targeting the serum uric acid level to less than 6.0 mg/dL, as is the guideline for gout patients. However, more research is needed to establish a conclusion regarding the management of AHU in CKD patients.
This survey has a limitation, in that only 12.6% of members responded to the questionnaire. Therefore, the findings of this report may not represent the real practice patterns of nephrologists who care for CKD patients in Korea.
In conclusion, a number of registered members in the KSN caring for CKD patients treat AHU to prevent CKD progression or cerebro-cardiovascular complications mainly by using febuxostat and allopurinol. We must establish and share Korean guidelines for the management of AHU in CKD patients.
All authors have no conflicts of interest to declare.
Ran-hui Cha, Chul Woo Yang, and Duk-Hee Kang participated in conception or design. Ran-hui Cha participated in analysis and interpretation of data, and drafting the article or revising. Su Hyun Kim, Eun Hui Bae, Mina Yu, Beom Soon Choi, Hoon Young Choi, Sun Woo Kang, Jungho Shin, and Sang Youb Han participated in providing intellectual content of critical importance to the work. All authors read and approved of the final version to be published.
CKD, chronic kidney disease.
(A) eGFR < 30 mL/min/1.73 m2; (B) eGFR ≥ 30 mL/min/1.73 m2.
eGFR, estimated glomerular filtration rate.
(A) eGFR < 30 mL/min/1.73 m2; (B) eGFR ≥ 30 mL/min/1.73 m2.
eGFR, estimated glomerular filtration rate.
Baseline characteristics of survey participants
Variable | Data (n = 158) |
---|---|
Age (yr) | 45 ± 9 (31–70) |
< 40 | 54 (34.2) |
40–49 | 56 (35.4) |
50–59 | 39 (24.7) |
≥60 | 7 (4.4) |
Hospital | |
Primary | 26 (16.5) |
Secondary | 55 (34.8) |
≥Tertiary | 77 (48.7) |
Medical license issuance year | |
< 1990 | 9 (5.7) |
1990–1999 | 36 (22.8) |
2000–2009 | 56 (35.4) |
≥2010 | 55 (34.8) |
Data are presented as mean ± standard deviation and median (range) for continuous variables or number (%) for categorical variables.
1978–2018.
Important reasons to treat asymptomatic hyperuricemia in CKD patients in CKD patients
Variable | GFR (mL/min/1.73 m2) | |||
---|---|---|---|---|
| ||||
< 30 | 30–60 | > 60 | ||
No treatment | 12 (7.6) | 13 (8.2) | 29 (18.4) | 0.034 |
Gout prevention | 26 (16.5) | 21 (13.3) | 40 (25.3) | 0.145 |
Nephrolithiasis prevention | 2 (1.3) | 1 (0.6) | 4 (2.5) | 0.415 |
Renal preservation | 81 (51.3) | 98 (62.0) | 45 (28.5) | 0.002 |
Cerebro-cardiovascular protection | 35 (22.2) | 22 (13.9) | 39 (24.7) | 0.661 |
Data are presented as number (%).
CKD, chronic kidney disease; GFR, glomerular filtration rate.
Linear-by linear.