Phenotyping renal and metabolic hyperuricemia: what BSA-corrected eGFR reveals
Janis Timsans, Raine Tiihonen, Jenni Kauppi, Vappu Rantalaiho, Anne Kerola, Kia Hakkarainen, Tiina Lehto, Hannu Kautiainen, Markku Kauppi
Affiliation(s):
Wellbeing Services County Of Päijät-häme, Päijät-häme Central Hospital, Department Of Rheumatology, Lahti, Finland
Background: Recent Finnish studies have reported differential mortality associations across phenotypically distinct forms of hyperuricemia. Individuals with metabolic hyperuricemia—defined as elevated serum uric acid (SUA) in the absence of renal dysfunction—exhibit higher mortality risk than those with renal hyperuricemia (elevated SUA with renal dysfunction), suggesting that kidney function modifies hyperuricemia-related mortality risk. In these studies, kidney function was estimated using the CKD-EPI creatinine–cystatin C equation, which indexes estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73 m². However, emerging evidence indicates that excess mortality associated with renal hyperfiltration is attenuated when eGFR is indexed to an individual’s actual BSA. Building on these observations, we investigated whether accounting for individual BSA in eGFR calculations alters the apparent modifying effect of kidney function on hyperuricemia-related mortality.
Methods: We used data from the GOAL (GOod Ageing in the Lahti region) study, a prospective cohort of 2,673 adults aged 52–76 years. Glomerular filtration rate was estimated using the CKD-EPI creatinine–cystatin C equation and indexed both to a BSA of 1.73 m² and to each participant’s actual BSA, calculated using the Mosteller formula. The individually corrected eGFR was derived as: eGFR (mL/min) = eGFR (mL/min/1.73 m²) × (BSA / 1.73). Participants with SUA ≥420 μmol/L were classified as hyperuricemic. Mortality was assessed over a 19-year follow-up period. Associations between hyperuricemia (SUA ≥420 vs <420 μmol/L) and mortality hazard ratios (HRs) across continuous eGFR values were evaluated using Cox proportional hazards models with restricted cubic splines, with four knots placed at the 5th, 35th, 65th, and 95th percentiles. Models were adjusted for age, sex, education, smoking status, alcohol consumption, body mass index, hypertension, dyslipidemia, diabetes, and the Charlson Comorbidity Index.
Results: During 19 years of follow-up, individuals with hyperuricemia had higher adjusted all-cause mortality than those without hyperuricemia (adjusted HR 1.18; 95% CI 1.04 to 1.34). Mortality estimates were similar whether eGFR was indexed to the BSA of 1.73 m² or to each participant’s actual BSA (Figures 1–2). When eGFR was indexed to actual BSA, the association between hyperuricemia and mortality displayed a U-shaped pattern, with elevated risk among individuals with at least moderate kidney impairment and a renewed increase at individually corrected eGFR values above 80 mL/min. This pattern was more pronounced for cardiovascular mortality but was also evident for all-cause mortality (Figure 3).
Conclusions: Our study demonstrates that although adjusting eGFR for individual BSA modestly attenuated the previously observed modifying effect of kidney function on hyperuricemia-related mortality, this effect persisted. Hyperuricemia-related cardiovascular mortality remained higher among individuals with preserved renal function than among those with mild to moderate kidney impairment. These findings lend further support to the concept of two phenotypically distinct forms of hyperuricemia, likely reflecting different underlying etiologies: renal hyperuricemia, primarily driven by impaired renal uric acid excretion, and metabolic hyperuricemia, which is more often associated with increased uric acid production in the absence of overt renal dysfunction.
