The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Urate-Lowering Therapy and Chronic

Kidney Disease Progression
Daniel I. Feig, M.D., Ph.D., M.P.H.

The prevalence and severity of chronic kidney patients completed the trial, although the planned
disease (CKD) has been increasing for decades. enrollment was 620 participants. As in the PERL
Because of its tremendous financial and health trial, treatment with allopurinol in CKD-FIX had
burden, both to persons and to health systems, no significant effect on the rate of GFR decline.
mitigation of the progression of CKD is of criti- The potential role of uric acid in the progres-
cal importance. Two articles in this issue of the sion of kidney disease has been argued about for
Journal report the primary results of separate decades.3 Epidemiologic studies consistently im-
randomized, controlled clinical trials that address plicate serum uric acid as a risk factor for CKD;
the use of urate-lowering therapy for the preven- however, in one study, statistical correction for
tion of kidney disease progression. Doria et al.1 the effects of hypertension or cardiovascular dis-
present the results of the Preventing Early Renal ease caused the apparent interaction to fade.4
Loss in Diabetes (PERL) trial, which investigated The challenge in interpreting such evaluations is
the use of a xanthine oxidase inhibitor, allopuri- that if serum uric acid contributes to CKD pro-
nol, in patients with type 1 diabetes mellitus gression in part by the exacerbation of hyperten-
and CKD of stages 1 to 3. A total of 530 patients, sion or cardiovascular disease, then correcting for
with a mean age of 51 years and a mean dura- those contributions may substantially attenuate
tion of diabetes of 35 years, were randomly as- the association and obscure a mechanistic link.
signed to receive allopurinol or placebo. Almost Observational studies, as discussed in the review
all the patients were taking a renin–angiotensin by Bonino et al.,4 have also noted that the asso-
system inhibitor. The primary end point, the ciation between elevated serum uric acid and
measured glomerular filtration rate (GFR) after progression of CKD is strongest in younger pa-
3 years, did not differ significantly between the tients, those with less severe CKD, and those
two groups, thus indicating that allopurinol did without proteinuria.5
not slow the rate of GFR decline among adults Cell culture and studies in animals shed some
with long-standing type 1 diabetes. light on the variability of the effect of uric acid
In the Controlled Trial of Slowing of Kidney according to age and disease severity. Unregu-
Disease Progression from the Inhibition of Xan- lated fructose metabolism in proximal tubular
thine Oxidase (CKD-FIX), Badve et al.2 enrolled cells causes ATP-to-ADP conversion and activa-
patients who had stage 3 or 4 CKD with a rapid tion of purine disposal pathways ending in uric
decline in the estimated GFR or clinically sig- acid and increased intracellular and serum levels
nificant proteinuria at baseline. Enrollment cri- of uric acid. The increases in uric acid levels in
teria did not require patients to have hyperurice- turn cause endothelial dysfunction, activation of
mia, although most patients did; more than 75% the renin–angiotensin–aldosterone system, vascu-
of the patients were treated with renin–angio- lar injury, tubulointerstitial inflammation, and
tensin–aldosterone system blockade. Patients re- elevated blood pressure. These mechanisms can
ceived allopurinol or placebo for 2 years; 276 initially be abrogated by a reduction in the uric

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 Editorial

acid level but, in time, lead to irreversible loss of CKD-FIX) do not have a reduction in CKD pro-
vascular compliance and renal tubulointerstitial gression beyond standard of care with renin–
injury.6 If parallel mechanisms are present in angiotensin system inhibition when treated with
humans, urate-lowering therapy would be expect- allopurinol indicates that for such patients, allo­
ed to have benefits in young persons and in those purinol is not indicated for CKD control. How-
with early stages of CKD but to have less effect ever, these trials did not address urate-lowering
at later points in the disease process. therapy, either pharmacologic or dietary, in young-
Data from a clinical trial suggest that early er patients or in those with earlier stages of
intervention may have a different effect. In CKD. As is often the conclusion in clinical re-
FEATHER (Febuxostat versus Placebo Random- search, more high-quality randomized, controlled
ized Controlled Trial Regarding Reduced Renal trials are needed.
Function in Patients with Hyperuricemia Com- Disclosure forms provided by the author are available with the
plicated by Chronic Kidney Disease Stage 3), a full text of this editorial at NEJM.org.

total of 467 patients with stage 3 CKD were From the Department of Pediatrics, Division of Pediatric Ne-
randomly assigned to receive either febuxostat, phrology, University of Alabama School of Medicine, Birmingham.
a nonpurine inhibitor of xanthine oxidase, or
1. Doria A, Galecki AT, Spino C, et al. Serum urate lowering
placebo.7 Similar to the results of the two trials with allopurinol and kidney function in type 1 diabetes. N Engl
reported in this issue, 2 years of urate-lowering J Med 2020;​382:​2493-503.
therapy did not mitigate CKD progression, as 2. Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on
the progression of chronic kidney disease. N Engl J Med 2020;​
compared with placebo. However, in the sub- 382:​2504-13.
groups of patients without proteinuria or with 3. Johnson RJ, Bakris GL, Borghi C, et al. Hyperuricemia, acute
better initial kidney function, febuxostat attenu- and chronic kidney disease, hypertension and cardiovascular
disease: report of a scientific workshop organized by the Na-
ated the decline in the GFR.7 A similar dichotomy tional Kidney Foundation. Am J Kidney Dis 2018;​71:​851-65.
is seen in the effect of urate-lowering therapy on 4. Bonino B, Leoncini G, Russo E, Pontremoli R, Viazzi F. Uric
blood pressure. Adolescent patients with newly acid in CKD: has the jury come to the verdict? J Nephrol 2020
January 13 (Epub ahead of print).
identified elevated blood pressure had a statisti- 5. Tsai CW, Lin SY, Kuo CC, Huang CC. Serum uric acid and
cally and clinically significant reduction in am- progression of kidney disease: a longitudinal analysis and mini-
bulatory blood pressure in response to uric acid review. PLoS One 2017;​12(1):​e0170393.
6. Nakagawa T, Johnson RJ, Andres-Hernando A, et al. Fruc-
reduction therapy, regardless of pharmacologic tose production and metabolism in the kidney. J Am Soc Nephrol
mechanism,8 whereas older patients did not.9 2020;​31:​898-906.
Well-designed clinical trials are the standard 7. Kimura K, Hosoya T, Uchida S, et al. Febuxostat therapy for
patients with stage 3 CKD and asymptomatic hyperuricemia:
for decisions on clinical efficacy. Intention-to- a randomized trial. Am J Kidney Dis 2018;​72:​798-810.
treat analyses, as in the PERL trial and CKD-FIX, 8. Soletsky B, Feig DI. Uric acid reduction rectifies prehyper-
provide guidance about the real-world efficacy of tension in obese adolescents. Hypertension 2012;​60:​1148-56.
9. McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect
clinical interventions. However, generalizations of uric acid lowering on renin-angiotensin system activation and
must be made with caution. The finding that ambulatory BP: a randomized controlled trial. Clin J Am Soc
middle-aged persons with diabetic nephropathy Nephrol 2017;​12:​807-16.
(as in the PERL trial) or with advanced, rapidly DOI: 10.1056/NEJMe2015886
progressing proteinuric kidney disease (as in Copyright © 2020 Massachusetts Medical Society.

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