The effect of kidney function on the urate lowering effect and safety of increasing allopurinol above doses based on creatinine clearance: a post hoc analysis of a randomized controlled trial

A 24-month open, randomized, controlled, parallel-group, comparative clinical trial was undertaken (ACTRN12611000845932). Ethical approval was obtained from the Multi-Regional Ethics Committee, New Zealand. Written informed consent was obtained from each participant. Full methods have been reported previously [10, 11]. In brief, 183 people with gout as defined by the American Rheumatism Association 1977 preliminary classification criteria for gout [12], receiving at least the CrCl based dose of allopurinol for  ≥ 1 month and with SU ≥6 mg/dl were recruited. People with a history of intolerance to allopurinol and those receiving azathioprine were excluded. Chronic kidney disease was not an exclusion criterion. Participants were randomized to continue current dose allopurinol for 12 months and then enter the dose escalation phase (control/DE) or to begin allopurinol dose escalation immediately (DE/DE). Allopurinol was increased monthly until SU was <6 mg/dl; in those with CrCL ≤60 ml/min allopurinol was increased by 50 mg increments and in those with CrCL >60 ml/min it was increased by 100 mg. Participants were not stratified by renal function at randomization. For the purposes of this post hoc analysis, participants were grouped according to kidney function at baseline as having (1) none/mild impairment, CrCL ≥60 ml/min (CKD stage 1 and 2), (2) moderate impairment, CrCL ≥30 to <60 ml/min (CKD stage 3) and (3) severe impairment, CrCL <30 ml/min (CKD stage 4 and 5).

Treatment-emergent adverse events (AE) were defined as any AE occurring after entry into the study until the end of month 24. Worsening laboratory-defined AEs were those where there was an increase in AE grade from baseline between month 12 and month 24, using the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

The primary efficacy outcome was reduction in SU at the final visit (month 24 or the final visit for those deceased or lost to follow up). Secondary efficacy outcomes included (1) the proportion of participants reaching target SU levels from baseline to months 12 and 24 and from months 12 to 24, (2) the percentage reduction in SU from baseline to months 12 and 24 and from months 12 to 24 and (3) the dose of allopurinol required to achieve SU <6 mg/dl. The primary safety outcome was serious adverse events (SAEs) and treatment-emergent or worsening AEs related to liver or kidney function.

Baseline demographics and clinical features were summarized using standard descriptive statistics including mean, standard deviation (SD), range, frequency and percent as appropriate.

There were 183 participants who entered the study; 93 in the control/DE group (n = 14 with CrCL <30 ml/min; n = 31 with CrCL ≥30 to <60 ml/min; n = 48 with CrCL ≥60 ml/min 48) and 90 in the DE/DE group (n = 10 with CrCL <30 ml/min; n = 40 with CrCL ≥30 to <60 ml/min; n = 40 with CrCL ≥60 ml/min). There were 143 participants who completed the month-12 visit; 73 in the control/DE group (n = 8 with CrCL <30 ml/min; n = 24 with CrCL ≥30 to <60 ml/min; n = 41 with CrCL ≥60 ml/min) and 70 in the DE/DE group (n = 7 with CrCL <30 ml/min; n = 35 with CrCL ≥30 to <60 ml/min; n = 28 with CrCL ≥60 ml/min). There were 137 participants who completed the month-24 visit; 68 in the control/DE group (n = 7 with CrCL <30 ml/min; n = 22 with CrCL ≥30 to <60 ml/min; n = 39 with CrCL ≥60 ml/min) (73.1%) and 69 in the DE/DE group (n = 7 with CrCL <30 ml/min; n = 33 with CrCL ≥30 to <60 ml/min; n = 29 with CrCL ≥60 ml/min). Demographics for each of the randomized groups according to baseline kidney function group are outlined in Table 1.

In both the control/DE and DE/DE groups the mean baseline SU was significantly higher in those with CrCL <30 ml/min compared to those with CrCL ≥30 to <60 ml/min and ≥60 ml/min (Fig. 1a). Mean SU was below 6 mg/dl in all kidney function groups by month 24 (Fig. 1a). The percentage with SU <6 mg/dl at the final visit by randomization and by kidney function groups is shown in Fig. 1b. Irrespective of randomization, there was no significant difference in the percentage of those with CrCL <30 ml/min who achieved SU <6 mg/dl at the final visit compared to those with CrCL ≥30 to <60 ml/min and ≥60 ml/min, with percentages of 64.3% vs. 76.4% vs. 75.0%, respectively (p = 0.65). The mean (standard error (SE)) change in SU from baseline to month 24 irrespective of randomization, was significantly higher in those with CrCL <30mls/min; mean change -2.23 (0.88) mg/dl in those with CrCL <30mls/min, -1.98 (0.23) mg/dl in those with CrCL ≥30 to <60 ml/min and -1.00 (0.79) mg/dl in those with CrCL ≥60 ml/min (p = 0.002). The mean change in SU by kidney function and randomization group is shown in Table 2.

The mean percentage change in SU by randomization and by kidney function groups is shown in Fig. 1c. Irrespective of randomization, the mean (SE) percentage change in SU from baseline to final visit in those with CrCL <30 ml/min was similar to those with CrCL ≥30 to <60 ml/min and significantly higher than those with CrCL ≥60 ml/min (-27.7% (5.0%) vs. -24.1% (2.7%) vs. -13.0% (2.5%) (p = 0.003)).

Mean allopurinol dose during the study period by randomization and by kidney function groups is shown in Fig. 1d. Irrespective of randomization, mean (SE) allopurinol dose at baseline was lower in those with lower CrCL; 146 (18) mg/day, 243 (10) mg/day and 323 (9) mg/day (p < 0.001) in those with CrCL <30mls/min, ≥30 to <60 ml/min and ≥60 ml/min, respectively. Irrespective of randomization, the mean (SE) allopurinol dose at month 24 was significantly lower in those with CrCL <30 ml/min as compared to those with CrCL ≥30 to <60 ml/min or CrCL ≥60 ml/min (250 (43) mg/day, 365 (22) mg/day and 460 (19) mg/day, respectively (p < 0.001)). Allopurinol dose in those with SU <6 mg/dl at month 24 is shown in Fig. 2.

The allopurinol dose required to achieve target SU was associated with baseline kidney function (Table 2). Of those with CrCL <30 ml/min (n = 14), only one participant in the control/DE and one in the DE/DE group required >300 mg/day to achieve target SU. In those with higher CrCL, the number of participants requiring >300 mg/day allopurinol to achieve target SU was higher (Table 2). Irrespective of randomization, the mean (range) allopurinol dose required to achieve target SU was higher in those with better kidney function (311.1 mg/day (150–600) vs. 393.9 mg/day (200–700) vs. 462.8 mg/day (300–900)).

There were 17 deaths during the study period, details of these have been published previously [10, 11]. During the RCT phase of the study there were five deaths in the control group of which four occurred in those with CrCL <30mls/min. In comparison none of the five deaths in the dose escalation groups had a CrCL <30 ml/min (Fig. 3). During the open extension phase of the study there were four deaths in the control/DE group, of which one occurred in those with CrCL <30mls/min. In comparison, there were three deaths in the DE/DE group, of which one occurred in those with CrCL <30mls/min. Of note there were high rates of co-morbidities and in particular cardiovascular disease at baseline in those with CrCL <30 ml/min (Table 1). The number of SAEs according to kidney function group and randomization group are shown in Table 3. The type and number of SAEs was as expected and was similar between groups. The percentage of participants with treatment emergent or worsening gamma glutamyl transferase (GGT), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatinine and CrCL by kidney function groups are shown in Fig. 3.