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The Effect of Allopurinol on Renal Function

Aneesa Krishnamurthy, DO; Deana Lazaro, MD; Dimitre G. Stefanov, PhD; David Blumenthal, MD; Donald Gerber, MD; Sheetal
Patel, MD

J Clin Rheumatol. 2017;23(1):1-5.

Abstract and Introduction

Abstract

Background: Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of
allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at
higher risk of hypersensitivity reaction.

Objectives: The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans.

Methods: This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the
Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a
serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of
treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic
control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a
change in the laboratory analyzer, making further comparisons inappropriate.

Results: On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR
(95% confidence interval, 4.811.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on
the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher
initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.0030.20
mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4
years. There were 5 mild adverse events in the treated cases.

Conclusions: Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant
improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should
consider this potential benefit of allopurinol in the treatment of patients with hyperuricemia, those with overall maintained renal
function.

Introduction

Unlike most mammals, humans lack the enzyme uricase, which breaks down uric acid (UA) to allantoin.[1] Chronically elevated
UA can lead to gout, which affects approximately 3.8% of the US population.[2] Animal models[3,4] and human studies[5,6]
suggest that chronic hyperuricemia also has a deleterious effect on renal function, although the impact of urate-lowering therapy
on renal function in humans is unclear. Currently, some clinicians use urate-lowering medications, such as allopurinol, "off-label"
in patients with very high UA levels, irrespective of gout history.[7] Although allopurinol is well tolerated in a majority of patients,
potentially lethal hypersensitivity reactions may occur, particularly in patients with chronic kidney disease, and so the benefits of
urate-lowering therapy must be weighed against these risks.[8] The objective of this study is to determine the effect of allopurinol
on kidney function in a male veteran population.

Materials and Methods

This is a retrospective cohort study of patients enrolled at the Veterans Administration New York Harbor Healthcare System,
identified by pharmacy and laboratory data. The treatment group consisted of 50 consecutive patients with hyperuricemia
defined as serum UA greater than 7 mg/dL, newly started on allopurinol for any reason and with evidence of treatment
compliance. Treatment compliance was determined by review of medication refills, provider notes, and significant decrease in
UA. Most patients were started on allopurinol for gout (mainly clinical diagnosis), but 4 patients received allopurinol for urate
nephrolithiasis, and 1 patient received allopurinol for asymptomatic hyperuricemia. Control subjects were patients with
hyperuricemia who were not treated with allopurinol. Thirty-three of the control subjects had asymptomatic hyperuricemia. The
remaining patients had a history of gout but were not exposed to allopurinol prior to or during the observation period, per primary
care. Control patients were matched to the treated cases by race, sex, initial age, and estimated glomerular filtration rate
(EGFR). Patients on hemodialysis and with history of prior UAlowering therapy, and acute kidney failure during the observation
period were excluded. Two patients were excluded in the treatment group: one because of deteriorating renal function from
gastrointestinal bleed, the other from nephrolithiasis. Of the control subjects, 3 patients were excluded because of

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nephrolithiasis and dehydration, and 1 patient with unclear cause of acute renal failure. Analysis was from October 2000 to
November 2006, at which time there was a change in analyzers in the laboratory, making further comparisons inappropriate.
Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula, which accounts for
age, race, sex, and serum creatinine. t Test was used to compare means between groups, and Fisher exact test and Spearman
correlation coefficients were used to test for association, as appropriate.

Posttreatment EGFR, creatinine, and UA were compared between the treatment and the control groups using analysis of
covariance, adjusting for the corresponding pretreatment measurement and age. The 2 outcomes were analyzed separately.
Robust regression with M-estimation and bi-square weighting was used to adjust for outliers. Interaction term (treatment
pretreatment level) was considered for each of the outcomes to test whether treatment effect depended on pretreatment levels.
All analyses were conducted using SAS version 9.3 (SAS Institute, Cary NC). P < 0.05 was considered statistically significant.

Results

There was no significant difference between the control and treatment groups in terms of means of age, initial blood pressure,
initial serum UA, or initial EGFR (EGFRi), although hypertension was diagnosed more often in the allopurinol group ().

Table 1. P Values Based on t Test Analysis or Fisher Exact Test, as Appropriate

Allopurinol Treated Control Subjects P

Age 68.9 (10.4) y 68.2 (9.8) y 0.74
Range 4596 y 3988 y
Race black:white, n 27:23 27:23 1.0
Sex All male All male N/A
Medical history (no. of patients with disease) HTN: 39 HTN: 29 0.05
DM: 17 DM: 16 1.00
Kidney stones: 8 Kidney stones: 2 0.09
BPH: 7 BPH: 2 0.16
Prostate cancer: 3 Prostate cancer: 5 0.72
NSAID CKD: 1 NSAID CKD: 0 1.00
Hepatitis C: 1 Hepatitis C: 5 0.20
HIV: 1 HIV: 2 1.00
CHF: 3 CHF: 8 0.20
MM with proteinuria: 1 MM: 0 1.00
Sarcoidosis: 1 Sarcoidosis: 0 1.00
Initial SBP 135.4 (20.3)mm Hg 139.8 (23.9)mm Hg 0.32
Range 90186 mm Hg 110229 mm Hg 0.90
Initial DBP 78.9 (12.8)mm Hg 79.24 (13.4)mm Hg
Range 50107 mm Hg 60126 mm Hg
Initial serum UA 9.2 (1.3)mg/dL 8.7 (1.6)mg/dL 0.11
Range 6.712.9 mg/dL 7.113.6 mg/dL
Initial GFR 70.4 (26.4)mL/min 70.7 (25.4)mL/min 0.95
Range 29.5184.2 mL/min 30.0180.6 mL/min
Normal kidney function GFR 90 mL/min 5 6
Mild CKD GFR 6089 mL/min 27 27
Mild-moderate CKD GFR 4559 mL/min 10 12
Moderate-severe CKD GFR 3044 mL/min 7 5

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Severe CKD GFR 1529 mL/min 1 0
Initial creatinine 1.4 mg/dL (0.4) 1.3 mg/dL (0.4) 0.79
Range 0.62.8 mg/d 0.62.4 mg/dL
Dose of allopurinol 221 mg/d (96) 0 mg/d N/A

Data are presented as mean (SD), unless otherwise specified. P < 0.05 is considered significant.
HTN indicates hypertension; DM, diabetes mellitus; BPH, benign prostatic hypertrophy; NSAID, nonsteroidal anti-inflammatory
drug; CKD, chronic kidney disease; HIV, human immunodeficiency virus; CHF, congestive heart failure; MM, multiple myeloma;
SBP, systolic blood pressure; DBP, diastolic blood pressure.

Treatment with a mean 221 (SD, 95.9) mg/d dose of allopurinol resulted in a mean UA of 6.4 (SD, 1.4) mg/dL, compared with
control mean UA 8.9 (SD, 1.7) mg/dL (Fig. 1). The difference in final UA (UAf) between the treatment and control groups was
2.5 mg/dL (95% confidence interval [CI], 2.03.1 mg/dL; P < 0.0001), after adjusting for initial UA (UAi) and age. The mean final
creatinine (Crf) levels were 1.36 (SD, 1.01) mg/dL and 1.34 (SD, 0.63) mg/dL in the treatment and control groups, respectively
(Fig. 2). The allopurinol-treated patients had a 0.10 mg/dL lower Crf level (95% CI, 0.0030.20 mg/dL; P = 0.04) than did the
control subjects, adjusted for initial creatinine and age. The mean final EGFR (EGFRf) levels were 83.2 mL/min (SD, 36.8) in the
treatment group and 74.2 mL/min (SD, 31.0) in the control group (Fig. 3). The allopurinol-treated patients achieved on average
11.9 mL/min higher GFR (95% CI, 4.811.9 mL/min; P = 0.01) than did the control group, after adjusting for EGFRi and age.
Treatment effect depended on the EGFRi, as indicated by the significant treatment pretreatment EGFR interaction (P = 0.004).
Treatment effect on EGFRf was estimated at 3 different levels of EGFRi and was most significant for higher EGFRi. At EGFRi
90 mL/min, allopurinol-treated patients had a mean improvement of 21.7 mL/min (95% CI, 11.831.5 mL/min; P < 0.0001),
whereas at EGFRi 75 mL/min, the mean improvement was 14.8 mL/min (95% CI, 7.322.2 mL/min; P = 0.0002). At EGFRi 45
mL/min, the treatment effect was not significant, with a mean increase of 1 mL/min (95% CI, 9.3 to 11.3 mL/min; P = 0.84).

Figure 1.

Data are presented as SEM.

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Figure 2.

Data are presented as SEM.

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Figure 3.

Data are presented as SEM.

separates the allopurinol-treated group and control subjects by initial stage of kidney function. The Spearman correlation
coefficient for EGFRf and UAf was not significant in the allopurinol group (r = 0.12; P = 0.41), and there was a negative weak
correlation in the control group (r = 0.29; P = 0.048). The Spearman correlation for the change in EGFR and the change in UA
was not significant in the allopurinol group (r = 0.11; P = 0.48), but had a moderate negative correlation in the control group (r =
0.45; P = 0.002). Thus, the improvement in the allopurinol-treated EGFR had no significant correlation with the drop in UA, and
the higher the EGFR, the lower the UA in the control group.

Table 2. Treatment and Control Patients Categorized by Initial Stage of Kidney Function, with Final Changes in Uric Acid and
Kidney Function

EGFRi Number of
Group Variable Label Mean SD SE Minimum Maximum
Stagea patients
Allopurinol-treated
1 5 EGFRf EGFRf 128.6 29.1 13.0 91.2 172.8
group
Crf Crf 0.8 0.1 0.1 0.6 0.9
UAf UAf 6.7 1.5 0.7 5.0 8.5
UAi UAi 8.5 1.0 0.4 7.3 9.8
UA diff 1.8 1.7 0.8 4.0 0.6
2 27 EGFRf EGFRf 97.7 24.7 4.8 59.7 172.3
Crf Crf 1.0 0.2 0.0 0.5 1.4
UAf UAf 6.2 1.4 0.3 3.4 9.1
UAi UAi 8.9 1.0 0.2 7.1 11.5

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UA diff 2.8 1.5 0.3 6.4 0.5

3 17 EGFRf EGFRf 50.8 23.2 5.6 11.1 93.2
Crf Crf 2.0 1.3 0.3 1.0 6.4
UAf UAf 6.4 1.5 0.4 3.9 9.9
UAi UAi 9.5 1.3 0.3 6.7 11.4
UA diff 3.2 2.0 0.5 6.8 0.2
4 1 EGFRf EGFRf 16.5 . . 16.5 16.5
Crf Crf 4.6 . . 4.6 4.6
UAf UAf 7.0 . . 7.0 7.0
UAi UAi 12.9 . . 12.9 12.9
UA diff 5.9 . . 5.9 5.9
Control group 1 6 EGFRf EGFRf 110.4 39.3 17.6 78.6 178.0
Crf Crf 0.9 0.2 0.1 0.6 1.2
UAf UAf 8.6 0.5 0.2 8.0 9.1
UAi UAi 8.1 0.9 0.4 7.4 9.6
UA diff 0.9 0.4 0.2 0.4 1.4
2 27 EGFRf EGFRf 83.8 26.7 5.2 34.3 144.2
Crf Crf 1.1 0.3 0.1 0.7 2.0
UAf UAf 8.6 1.1 0.2 5.9 10.5
UAi UAi 8.4 1.5 0.3 4.7 11.2
UA diff 0.2 1.5 0.3 2.6 2.7
3 17 EGFRf EGFRf 51.6 15.3 3.5 11.3 79.7
Crf Crf 1.7 0.8 0.2 1.0 4.9
UAf UAf 9.5 2.2 0.5 7.2 15.7
UAi UAi 9.3 1.8 0.4 7.2 13.6
UA diff 0.3 1.2 0.3 2.3 2.2

aStage 1, normal kidney function (GFR 90); stage 2, mild kidney dysfunction (GFR 6089); stage 3, moderate kidney
dysfunction (GFR 3059); stage 4, severe kidney dysfunction (GFR 1529).

The average length of follow-up was 3.4 (SD, 1.6) years. Adverse events were as follows in the treatment group: 1 episode of
elevated liver function tests, diarrhea in 1 patient, nausea in 1 patient, and gout attacks in 2 patients.

Discussion

There is controversy over whether hyperuricemia is simply a byproduct of reduced glomerular filtration or whether it has a
pathogenic role in kidney dysfunction.[9] Prior to the development of urate-lowering treatment, renal impairment was reported in
up to 40% of gout patients, and death from renal failure occurred in up to 25% of gout patients.[10,11] "Gouty nephropathy" was
seen in nearly all gout patients on autopsy, which included arteriolar and glomerular sclerosis, interstitial fibrosis, and medullary
urate deposits.[10] Many large cohort epidemiologic studies[5,9,12] have shown an association between elevated UA and
worsening of renal function, in patients with normal kidney function and those with chronic kidney disease.

There are many hypotheses for induction of renal failure by UA, including the direct association between hyperuricemia and
future development of hypertension and renal urate deposition.[13] In the National Health and Nutrition Evaluation Study, serum
UA greater than as low as 5.5 mg/dL was associated with a higher risk of hypertension.[14] Interestingly, urate nephropathy
glomerular arteriolosclerosis is indistinguishable from hypertensive renal disease. When hyperuricemia is induced in study rats,
it causes renal injury via renal vasoconstriction and activation of the renal angiotensin system followed by preglomerular smooth
muscle proliferation, interstitial fibrosis, and glomerular hypertension.[3,4] Even after adequate blood pressure control, these rats
continued to develop classic arteriosclerosis renal lesions, suggesting that UA may cause microvascular disease independent of
hypertension.[3] In our study of patients with mainly mild to moderate kidney disease, treatment with allopurinol resulted in better6/8
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hypertension.[3] In our study of patients with mainly mild to moderate kidney disease, treatment with allopurinol resulted in better
renal outcomes for patients with higher GFR. There was no correlation between the lowering of UA and the improvement of
kidney function, suggesting that allopurinol may help improve renal function via other mechanisms aside from its effects on UA.
Perhaps treatment with allopurinol of hyperuricemic patients prior to renal disease leads to better outcomes, because once
renovascular and glomerular changes such as fibrosis have occurred, renal damage may progress independent of UA levels
and blood pressure control.

The latest American College of Rheumatology guidelines recommend urate-lowering therapy to achieve a minimum serum urate
of less than 6 mg/dL, for gout patients with any of the following: tophus/tophi, more than 2 attacks of gout per year, past kidney
stones, or stage 2 or worse chronic kidney disease.[15] Prior "off-label" recommendations included treating hyperuricemic
patients with at least 12 or 13 mg/dL, irrespective of gout history.[7] In this study, treatment of patients with even lower mean UA
levels resulted in an improvement of renal function, most significantly in those with an overall maintained renal function. It
remains to be seen if more aggressive treatment with allopurinol would further substantiate renal function outcomes.

The possible benefit of allopurinol on renal function must be weighed against the risk of Allopurinol hypersensitivity syndrome, a
potentially lethal reaction to allopurinol estimated to occur in 0.1% of treated patients.[8] There were no significant adverse
reactions to allopurinol in this group, despite observation of a population with multiple comorbidities. This suggests that benefits
may outweigh risks of allopurinol treatment in certain subsets of patients.

This study has limitations. The retrospective case-control design can introduce sampling error, which was mitigated by using
consecutive patients from pharmacy and laboratory data. The proxy for allopurinol adherence was reduction in serum UA and
review of medication refills, similar to the medication possession ratio used in other retrospective studies. Patients were not
matched for medication use or medical history, although there was no significant difference between the 2 groups in terms of
common medical conditions that can affect renal function such as diabetes and hypertension. The results are from a male
veteran population at 1 institution. Further studies are needed to ascertain whether the results are generalizable to other
populations. The strength of the study is that it reflects outcomes in a real clinical setting with usual care.

References

1. Ejaz AA, Mu W, Kang DH, et al. Could uric acid have a role in acute renal failure? Clin J Am Soc Nephrol. 2007;2:1621.

2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and
Nutrition Examination Survey 20072008. Arthritis Rheum. 2011;63:31363141.

3. KangDH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol.
2002;13:28882897.

4. Snchez-Lozada LG, Tapia E, Santamara J. Mild hyperuricemia induces vasoconstriction and maintains glomerular
hypertension in normal and remnant kidney rats. Kidney Int. 2005;67:237247.

5. Iseki K, Oshiro S, Tozawa M, et al. Significance of hyperuricemia on the early detection of renal failure in a cohort of
screened subjects. Hypertens Res. 2001;24:691697.

6. Iseki K, Ikemiya Y, Inoue T, et al. Significance of hyperuricemia as a risk factor for developing ESRD in a screened
cohort. Am J Kidney Dis. 2004;44:642650.

7. Dincer HE, Dincer AP, Levinson DJ. Asymptomatic hyperuricemia: to treat or not to treat. Cleve Clin J Med. 2002;69:594.

8. Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and
adverse events. Semin Dial. 2007;5:391395.

9. Chonchol M, Shlipak MG, Katz R, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis.
2007;50:239247.

10. Talbott JH, Terplan KL. The kidney in gout. Medicine (Baltimore). 1960;39:405467.

11. Berger L, Y TF. Renal function in gout. IV. An analysis of 524 gouty subjects including long-term follow-up studies. Am J
Med. 1975;59:605613.

12. Obermayr RP, Temml C, Knechtelsdorfer M, et al. Predictors of new-onset decline in kidney function in a general Middle-
European population. Nephrol Dial Transplant. 2008;23:12651273.

13. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359:18111821.

14. Goldstein HS, Manowitz P. Relation between serum uric acid and blood pressure in adolescents. Ann Hum Biol.
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15. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout.
Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res
(Hoboken). 2012;64:14311446.

This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of
Research and Development.

J Clin Rheumatol. 2017;23(1):1-5. 2017 Lippincott Williams & Wilkins

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