Uric Acid Levels Increase Risk for New-Onset Kidney Disease - Editorial
J Am Soc Nephrol 19: 2251-2253, Nov 2008
Rajesh Mohandas* and Richard J. Johnson*,
* Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Florida; and Division of Renal Disease and Hypertension, University of Colorado, Denver, Denver, Colorado
"recent studies suggested that once uric acid enters a cell, it can cause oxidative stress, stimulate inflammatory mediators, cause endothelial dysfunction, and activate the local renin-angiotensin system.5-8 Raising uric acid in rats by blocking the degradative enzyme uricase also causes hypertension.....Importantly, raising uric acid also caused de novo renal disease as well as accelerated existing renal disease....The best way to evaluate the role of uric acid in the pathogenesis of CKD is to determine whether lowering uric acid slows renal progression. At least one recent trial involving a small number of patients did just that."
Despite our best efforts, the past decade has seen little progress in the treatment of chronic kidney disease (CKD). The mainstay of therapy continues to be controlling BP, blocking the renin-angiotensin system, and, for the patient with diabetes, tight control of blood sugar. Even with optimal therapy, we tend to retard, not to halt, the progression of kidney disease. Thus, the identification of novel risk factors and new treatments for CKD should remain a major goal of medical research.
Although the fields of genomics, proteomics, and metabolomics provide a novel way to search for new risk factors, in some cases, "old" risk factors are reemerging. One such risk factor is uric acid. For years, uric acid was considered a possible cause for the CKD observed in patients with gout. Indeed, both biopsy and autopsy studies confirm the presence of focal urate crystal deposition in the deeper regions of the cortex and medulla of patients with gout, often in association with arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis.1 "Gouty nephropathy" was the name given to the disease, and it was also thought to occur in some patients with asymptomatic hyperuricemia; however, many authors subsequently proposed that the renal lesions in patients with gout were due to other causes, such as hypertension or aging-related disease, and, besides, it was difficult to attribute focal crystal deposition as a cause for a disease that was diffusely present throughout the kidney. Thus, a "requiem" for gouty nephropathy was held, and, as a cause of kidney disease, uric acid was removed from the textbooks.2
There were other compelling reasons to view uric acid as a false risk factor for kidney disease. One reason is that uric acid is primarily excreted by the kidney. As GFR falls, there is both an increase in the fractional urinary excretion of uric acid and increased enteric excretion, but these processes do not fully compensate and serum uric acid levels rise. In patients initiating dialysis, approximately 50% have hyperuricemia3; therefore, CKD may be more likely a cause of hyperuricemia than the reverse. Furthermore, whereas uric acid crystals are known to be proinflammatory, soluble uric acid is an antioxidant that may be important in blocking aging and cancer-associated oxidative stress.4 Certainly, it would be difficult to consider an antioxidant as a risk factor for renal disease when oxidative stress seems to be such an important driving force for cardiovascular and renal disease.
A series of new experimental studies have challenged the paradigm that uric acid is either harmless or even beneficial in CKD. Although uric acid is indeed an antioxidant in the extracellular setting, recent studies suggested that once uric acid enters a cell, it can cause oxidative stress, stimulate inflammatory mediators, cause endothelial dysfunction, and activate the local renin-angiotensin system.5-8 Raising uric acid in rats by blocking the degradative enzyme uricase also causes hypertension, which is mediated initially by stimulation of the renin-angiotensin system and inhibition of the bioavailability of endothelial nitric oxide.9 Importantly, raising uric acid also caused de novo renal disease as well as accelerated existing renal disease.9,10 Micropuncture studies further showed that hyperuricemic rats develop preglomerular arteriolar disease that alters renal autoregulation, resulting in the combination of systemic and glomerular hypertension with renal vasoconstriction.11,12 Finally, none of these studies implicated urate crystals.
Clinical studies are now "relooking" at the relationship of uric acid with the development of CKD. For example, Iseki et al.13 followed 6403 adults in the Okinawa General Health Maintenance Association and found that a uric acid of 8.0 mg/dl conferred a 2.9-fold risk in men and a 10.4-fold risk in women for developing elevated creatinine after controlling for multiple risk factors. In another study of 13,338 adults from the Atherosclerosis Risks in Communities and the Cardiovascular Health Study, a change in 1 mg/dl uric acid was independently associated with a 7 to 11% increased risk for developing CKD.14 Alternatively, a study by Chonchol et al.15 could not confirm this association.
In this issue of JASN, Obermayr et al.16 report the results of a study on uric acid levels as a predictor of new-onset kidney disease in 21,457 healthy volunteers from the Vienna Health Screening Project followed for a period of 7 yr. The volunteers were stratified into three groups: Those with normal uric acid levels (<7.0 mg/dl), modestly elevated uric acid levels (7.0 to 8.9 mg/dl), and markedly elevated uric acid levels (9.0 mg/dl). CKD was defined as a GFR <60 ml/min per 1.73 m2 calculated using the Modification of Diet in Renal Disease (MDRD) formula. After adjustment for multiple risk factors, uric acid levels remained an independent risk factor for CKD in both men and women with a risk of 1.74 (95% confidence interval 1.45 to 2.09) and for 3.12 (95% confidence interval 2.29 to 4.25), respectively. The risks were greater in those with elevated BP. Interestingly, there was no relationship with proteinuria.
How should we interpret these data? First, one must recognize that independence does not necessarily equate with causality. For example, a risk factor could be independent and not causal if the true causal risk were not considered in the analysis. For example, if ischemia or oxidative stress were causal in CKD, then uric acid might be found to be an independent risk factor in these analyses, because uric acid levels rise in these settings and because these variables were not considered in the analysis. Likewise, a risk factor may not be independent but could still be causal. For example, if uric acid causes hypertension and this were the mechanism by which it caused kidney disease, then if both hypertension and uric acid are considered in a multivariable analysis, it is possible that uric acid would not be independent of hypertension as a cause of kidney disease. This is all the more relevant because recent experimental and clinical studies suggested uric acid is a cause of hypertension, especially in younger patients.17,18
The best way to evaluate the role of uric acid in the pathogenesis of CKD is to determine whether lowering uric acid slows renal progression. At least one recent trial involving a small number of patients did just that.19 In that study, 54 patients with hyperuricemia and CKD were treated with allopurinol or usual therapy for 1 yr. In patients receiving allopurinol, only 16% showed progression of renal disease (defined as a rise in creatinine level of 40%), whereas progression was observed in 46% of the control subjects (P = 0.015). Although the study is of interest, it was only a small sample size, and clearly more studies are needed before one can make a final conclusion. In addition, allopurinol can be associated with significant toxicities, including the Stevens-Johnson syndrome.
In conclusion, although the concept that uric acid might have a role in kidney disease once suffered a requiem, it has undergone a revival and seems deserving of additional study. If indeed it represents a remediable target for intervention, then a new chapter in the treatment of kidney diseases may result.
Elevated Uric Acid Increases the Risk for Kidney Disease
"Hyperuricemia was revealed as an important possibly independent risk factor for new-onset kidney disease. The relation between UA and new-onset kidney disease cannot be explained solely by the detected confounder variables. Clinical trials of UA lowering are needed to evaluate the causal inference of UA on the progression of CKD."
Rudolf P. Obermayr*, Christian Temml, Georg Gutjahr, Maarten Knechtelsdorfer*, Rainer Oberbauer,|| and Renate Klauser-Braun*
* Third Medical Department, Division of Nephrology, Diabetes and Hypertension, Donauspital, Sozialmedizinisches Zentrum Ost der Stadt Wien, Department of Health Prevention (MA 15/2, Gesundheit und Soziales), and Institute of Medical Statistics, || Medical University Vienna, Vienna, and Department of Nephrology, KH Elisabethinen, Linz, Austria
Recent epidemiologic studies suggest that uric acid predicts the development of new-onset kidney disease, but it is unclear whether uric acid is an independent risk factor. In this study, data from 21,475 healthy volunteers who were followed prospectively for a median of 7 yr were analyzed to examine the association between uric acid level and incident kidney disease (estimated GFR [eGFR] <60 ml/min per 1.73 m2). After adjustment for baseline eGFR, a slightly elevated uric acid level (7.0 to 8.9 mg/dl) was associated with a nearly doubled risk for incident kidney disease (odds ratio 1.74; 95% confidence interval 1.45 to 2.09), and an elevated uric acid (>/=9.0 mg/dl) was associated with a tripled risk (odds ratio 3.12; 95% confidence interval 2.29 to 4.25). These increases in risk remained significant even after adjustment for baseline eGFR, gender, age, antihypertensive drugs, and components of the metabolic syndrome (waist circumference, HDL cholesterol, blood glucose, triglycerides, and BP). In a fully adjusted spline model, the risk for incident kidney disease increased roughly linearly with uric acid level to a level of approximately 6 to 7 mg/dl in women and 7 to 8 mg/dl in men; above these levels, the associated risk increased rapidly. In conclusion, elevated levels of uric acid independently increase the risk for new-onset kidney disease.
The incidence of ESRD and concomitantly the number of patients on renal replacement therapy are increasing steadily.1-3 Established cardiovascular risk factors are associated with ESRD, hypertension and diabetes being the leading causes.1-3 Uric acid (UA) is strongly associated with renal failure and cardiovascular disease4,5 and is particularly common in people with hypertension and metabolic syndrome, associated with its metabolic abnormalities (e.g., dyslipidemia, insulin resistance). In humans, hyperuricemia has been found to be a risk factor for hypertension6,7 and, moreover, for proteinuria in rats,8,9 leading to the suggestion that this should promote initial kidney damage or its progression.10
Recent epidemiologic and experimental evidence suggests a role for UA not only as a marker of reduced kidney function and an independent cardiovascular risk factor11 but also as a causal risk factor for the development and progression of renal disease.5,9,12 Two large epidemiologic studies demonstrated that UA was a major predictor for the development of incident renal disease,13,14 but none of these studies evaluated the amount of its real role as an independent risk factor. Furthermore, hyperuricemia is associated with a greater incidence of ESRD.15 Findings from experimental animal and cell biologic studies support the suggested nephrotoxicity of elevated UA levels: UA plays a role in platelet adhesiveness16; hyperuricemia may be one of the key mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 systems in progressive renal disease, which could be mediated by its effect to upregulate angiotensin-1 receptors on vascular smooth muscle cells17,18; oxonic acid induced-hyperuricemia induced systemic hypertension, glomerular hypertrophy/hypertension, afferent arteriolar sclerosis, and macrophage infiltration in the rat kidney8; hyperuricemia induced arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension, and lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion19; direct entry of UA into both endothelial and vascular smooth muscle cells results in local inhibition of endothelial nitric oxide levels, stimulation of vascular smooth muscle cell proliferation, and stimulation of vasoactive and inflammatory mediators.20
The aim of this study was to provide epidemiologic evidence for hyperuricemia as a potential independent risk factor for the development of new-onset kidney disease; therefore confounder models using mixed-effect models with increasing levels of UA were fitted. The data file of the Vienna Health Screening Project was used for analysis.14
Baseline characteristics stratified by the clinically predefined UA groups are shown in Table 1: The reference group, UA <7.0 mg/dl; the slightly elevated UA group (SEUAG), UA = 7.0 to 8.9 mg/dl; and the elevated UA group (EUAG), UA >/=9.0 mg/dl. With increasing UA groups, we observed lower GFR, higher age, the widely known gender differences, higher waist circumference, higher triglycerides, lower HDL cholesterol, higher fasting serum glucose, higher mean arterial BP (MAP), and higher antihypertensive drug use.
Ascertainment of Confounders
Baseline variables were selected as confounders when they were significantly associated with the exposure variable at baseline (Table 1), as well as significantly and causally related with the development of stage 3 chronic kidney disease (CKD).21,22 The following confounders were detected: baseline estimated glomerular filtration rate (GFRb), gender, age, log-HDL cholesterol, log-triglycerides, waist circumference, fasting glucose (spline), MAP (spline), and antihypertensive drug use.
Ascertainment of the Relationship between UA Levels and the Development of stage 3 CKD by Stepwise Adjustment
The unadjusted odds ratio (OR) was 1.49 (95% confidence interval [CI] 1.23 to 1.80) in the SEUAG and 2.49 (95% CI 1.87 to 3.32) in the EUAG. After adjustment for GFRb, OR increased to 1.74 (95% CI 1.45 to 2.09) in the SEUAG and to 3.12 (95% CI 2.29 to 4.25) in the EUAG. Additional adjustment for gender and age decreased OR to 1.55 (95% CI 1.25 to 1.92) in the SEUAG and to 2.54 (95% CI 1.75 to 3.69) in the EUAG. Further adjustment for the metabolic factors of the metabolic syndrome (MF) decreased OR to 1.44 (95% CI 1.17 to 1.78) in the SEUAG and to 2.22 (95% CI 1.52 to 3.25) in the EUAG. Continuing the additional adjustment for MAP remarkably decreased OR to 1.29 (95% CI 1.01 to 1.64) in the SEUAG and to 1.76 (95% CI 1.20 to 2.59) in the EUAG. Final adjustment for antihypertensive drug use decreased OR to 1.26 (95% CI 1.02 to 1.55) in the SEUAG and to 1.63 (95% CI 1.18 to 2.27) in the EUAG (Figure 1). Effect decomposition concerning the influence of UA levels on the development of stage 3 CKD resulted in 35% of residual unexplained odds in the SEUAG and 30% in the EUAG, respectively.
Effects of increasing UA levels, modeled by splines, stratified by gender and hypertension groups,23 and adjusted for the remaining identified confounders, are plotted: The influence of UA levels on OR for the development of a GFR <60 ml/min per 1.73 m2 is roughly linear until approximately 6 to 7 mg/dl in women and 7 to 8 mg/dl in men. Subsequently, OR increase rapidly (Figure 2).
A few studies have found that hyperuricemia is associated with an increased risk for new-onset kidney disease,13,14 but this association could be confounded by some metabolic factors and other risk factors that were not included in these previous studies. A confounder model was performed to provide epidemiologic evidence for UA as a possible independent risk factor for the development of incident kidney disease.21
The unadjusted OR was 1.49 in the SEUAG and 2.49 in the EUAG, which represents the predictive strength of elevated UA for the development of new-onset kidney disease, but this does not allow causal interpretation.
GFRb was considered as the crucial confounder variable, because elevated serum UA levels usually are associated with defects of UA transport in the nephron when kidney function worsens.24 Adjustment of UA for GFRb in the respective UA groups allows examination of different UA levels at a GFR that is held constant in the statistical model; therefore, a possible detrimental effect of UA on kidney function can be investigated independent of the individual GFR. After adjustment of UA for GFRb, OR increased by 17% in the SEUAG and by 25% in the EUAG. This result suggests a direct or indirect (mediated) toxic effect of UA on the development of stage 3 CKD.22
Additional adjustment for gender and age decreased OR by 11% in the SEUAG and by 19% in the EUAG. Gender differences of UA levels are widely known. We used sum-to-zero constraints for the factor gender in all models. The interpretation of gender concerning the outcome should be done retentively as discussed in detail elsewhere.14 As generally known, kidney function decreases with aging.25,26
The American Heart Association defines the metabolic syndrome (MS) by the variables waist circumference, serum triglycerides, HDL cholesterol, fasting serum glucose, and BP.27 In this analysis, the MF and BP were analyzed separately. UA is suggested as a major determinant of the MS, and the prevalence of the MS increases substantially with increasing levels of serum UA levels.28,29 Moreover, numerous studies demonstrated that hyperuricemia is an independent risk factor for hypertension.10 Recently, one study could not confirm this association when UA levels were adjusted for several MF.30 Further adjustment for the MF in this study decreased OR by 8% in the SEUAG and by 13% in the EUAG. Additional adjustment for MAP and antihypertensive drug treatment decreased OR by 13% in the SEUAG and remarkably by 27% in the EUAG.
Alcohol consumption did not fulfill the criteria as a confounder variable in this study. Keeping in mind the generally known influence of alcohol consumption on UA levels as well as its possible protective influence on the outcome, we found an evaluation of its influence interesting.13 In this study, the effect was weak, the OR for the outcome variable remained nearly unchanged, and confounding could have been explained by only 2% in both elevated UA groups.
Proteinuria is a strong predictor for a decline in GFR and correlated with other covariates. Because its lack of association with UA, proteinuria did not fulfill the criteria as a potential confounder (Table 1). As expected, the calculated effect was weak: OR for the outcome variable remained nearly unchanged, and potential confounding could have been explained by only 4% in both elevated UA groups. Noteworthy, evidence for an association of hyperuricemia and greater proteinuria is weak and is provided only in rats.9
After adjustment of both elevated UA groups for all detected confounders (Figure 1), OR for the development of CKD stage 3 were 1.26 (95% CI 1.18 to 2.27) in the SEUAG and 1.63 (95% CI 1.18 to 2.27) in the EUAG. Moreover, effect decomposition showed that 35% of the influence of UA on the development of CKD stage 3 could not be explained by confounding in the SEUAG and 30% in the EUAG, respectively. Even when residual confounding remains, strong support for an independent (directly toxic) effect of elevated UA levels on the development of new-onset kidney disease exists. This major finding is supported by a differing recent study.31
These findings are supported by small clinical pilot trials in which allopurinol therapy decreased serum UA levels in patients with hyperuricemia and mild to moderate kidney disease. Its use was safe and helped preserve kidney function during 12 mo of therapy compared with control subjects.32 Moreover, indirect evidence was given when hyperuricemia decreased GFR in other trials, when allopurinol treatment was withdrawn.33,34
An additional interesting topic of this study was the examination of the interaction between elevated UA levels and hypertension concerning the development of stage 3 CKD; therefore, a model using splines for UA, stratified by gender and the defined BP groups adjusted for all detected confounders, was fitted (Figure 2).23 The influence of UA levels on OR for development of new-onset kidney disease is roughly linear until approximately 6 to 7 mg/dl in women and 7 to 8 mg/dl in men. Subsequently, OR increase rapidly. The observed effect of increased UA levels on OR for development of new-onset kidney disease is increasing rapidly with each hypertension group and is more pronounced in women, a finding that is supported by studies concerning the early detection of renal disease and its progression to ESRD.15,35 Noteworthy, mild hyperuricemia was shown to be associated with renal damage in untreated primary hypertension.36 All in all, we assume that the findings of the stratified spline analyses seem to be substantial from a public health viewpoint, because in the general adult population the prevalence of prehypertension and hypertension is approximately 60%,37 and the prevalence of hyperuricemia (defined as UA >6.0 mg/dl in women and UA >7.0 mg/dl in men) is approximately 17%.38 Future clinical trials might clarify whether lower UA treatment points should be entertained in this context.
The Vienna Health Screening Project is an ongoing study including new participants continuously. The sample size increased by approximately 20% compared with our previous analysis.14 A very comparable data set was used for this study; therefore, the detailed examination of UA must be considered as a post hoc analysis, but statistical power should be high enough to provide correct results. Moreover, this study may have been subject to a survival bias because participants had to attend follow-up examinations and 599 participants dropped out. Although unlikely (they showed very similar baseline data compared with the study cohort), it is possible that those individuals may have developed more severe risk factors after the baseline examination and could have had rapid disease progression in the interim. This may have led to underestimation of some findings. In addition using eGFR calculated by the Modification of Diet in Renal Disease (MDRD) formula to represent the severity of kidney disease is not a gold standard method, and correction of routine measured creatinine to "MDRD creatinine" is mandatory.39 Nevertheless, imprecision and bias are greater at a higher GFR, limiting the accuracy of classification in the mildly decreased GFR group.40 This may have led to an underestimation of GFR. A minor limitation is that the influence of the different antihypertensive drugs as confounder variables was not examined separately because of low use; however, antihypertensive drug use was a weak confounder. Especially diuretics are associated with an increase in serum UA levels, and it is suggested that raising UA levels can stimulate the renin-angiotensin-system accelerating the development of renal microvascular disease and thereby predispose the patient to renal disease progression.12 Thereupon, in humans, asymptomatic hyperuricemia induced progression of CKD and worsened control of hypertension, an effect that was blocked by angiotensin-converting enzyme inhibitor treatment when allopurinol therapy was withdrawn,34 which could not be examined in this study. Moreover, accurate UA-lowering therapy is safe and does not deteriorate kidney function32; therefore, it seems unlikely that accurate UA-lowering therapy can substantially confound the relationship between UA and development of new-onset kidney disease.
Hyperuricemia was revealed as an important possibly independent risk factor for new-onset kidney disease. The relation between UA and new-onset kidney disease cannot be explained solely by the detected confounder variables. Clinical trials of UA lowering are needed to evaluate the causal inference of UA on the progression of CKD.