Does uric acid-lowering treatment slow the progression of chronic kidney disease? A meta-analysis of randomized controlled trials

IntroductionHyperuricemia has been proposed as an independent factor in the development and progression of chronic kidney disease (CKD). However, the effect of uric acid-lowering therapies on delaying CKD progression is still uncertain. Therefore, this systemic review aims to assess the effect of uric acid-lowering therapies on renal outcomes in pre-dialysis CKD patients.MethodsPubMed, Cochrane Library, and Lilacs databases were searched until April 24, 2021, for randomized clinical trials of CKD patients on uric acid-lowering treatment with xanthine-oxidase (XO) inhibitors. The weighted mean difference (WMD) or standard mean difference (SMD) with confidence interval (CI) were pooled using a random-effects model.ResultsAmong 567 studies found, eighteen met the inclusion criteria (n = 2463 participants). Compared to the patient's control group, the WMD for the glomerular filtration ratio (GFR) and serum creatinine changes of the treated group was 2.02 ml/min/1.73 m² (95%CI 0.41 to 3.63, P = 0.014) and −0.19 mg/dl (95%CI −0.34 to −0.04, I² = 86.2%, P = 0.011), respectively. Subgroup analyses showed that the difference in follow-up time and CKD population type in the studies may explain the controversy about the role of uric acid-lowering therapies in CKD progression. The GFR and creatinine outcomes analysis by types of XO inhibitors showed no difference between the control and treated groups. Uric acid-lowering therapies were strongly associated with decreased serum uric acid and urinary protein–creatinine ratio and urinary albumin–creatinine ratio.ConclusionsThese findings suggest that uric acid-lowering treatment may slow CKD progress and reduce protein and albumin excretion. However, larger and properly powered randomized clinical trials with specific CKD populations are needed to confirm these findings.     

Prevention of kidney function decline using uric acid-lowering therapy in chronic kidney disease patients: a systematic review and network meta-analysis

Clinical Rheumatology - Several previous studies have suggested that uric acid-lowering therapy (ULT) can slow the progression of chronic kidney disease (CKD). Although crucial for CKD patients,...     

Hyperuricaemia and gout in cardiovascular,metabolic and kidney disease

During the last century, there has been an increasing prevalence of hyperuricaemia noted in many populations. While uric acid is usually discussed in the context of gout, hyperuricaemia is also associated with hypertension, chronic kidney disease, hypertriglyceridaemia, obesity, atherosclerotic heart disease, metabolic syndrome, and type 2 diabetes. Here we review the connection between hyperuricaemia and cardiovascular, kidney and metabolic diseases. Contrary to the popular view that uric acid is an inert metabolite of purine metabolism, recent studies suggest serum uric acid may have a variety of pro-inflammatory, pro-oxidative and vasoconstrictive actions that may contribute to cardiometabolic diseases. Hyperuricaemia is a predictive factor for the development of hypertension, metabolic syndrome, type 2 diabetes, coronary artery disease, left ventricular hypertrophy, atrial fibrillation, myocardial infarction, stroke, heart failure and chronic kidney disease. Treatment with uric acid-lowering therapies has also been found to improve outcomes in patients with hypertension and kidney disease, in some but not all studies. In conclusion, uric acid is emerging as a potentially treatable risk factor for cardiometabolic diseases, and more clinical trials investigating the potential benefit of lowering serum uric acid are recommended in individuals with hyperuricaemia with and without deposition and concomitant hypertension, metabolic syndrome or chronic kidney disease.     

Chronic kidney disease and cardiovascular risk

Chronic kidney disease (CKD) is a global public health concern, and there is emerging a strong relationship between CKD and increased cardiovascular disease (CVD) risk. CKD in the presence of other co-morbidities such as type 2 diabetes mellitus (T2DM) and hypertension (HTN) can lead to early progression to end-stage renal disease (ESRD/stage V CKD) and confer a greater risk for CVD morbidity and mortality. CVD events are the leading cause of premature death in patients with CKD, even before their progression to ESRD, with the rate of CVD progression being twice as common compared with the general population. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. This review will elaborate on the pathophysiology of CVD in CKD and will discuss the role of microalbuminuria (MAU)-proteinuria as a potential diagnostic and prognostic tool for CVD in CKD risk assessment.     

Defining,Treating, and Understanding Chronic Kidney Disease—A Complex Disorder

Chronic kidney disease (CKD) is prevalent in more than 20 million people in the United States. The majority of care provided to patients with this disease comes from primary care physicians, although it is often poorly understood. After an extensive literature review, it is clear that it can be difficult to classify and there are many barriers to care. Risk factors for both incident CKD and disease progression include hypertension, poor glycemic control, sociodemographic factors, acute kidney injury, metabolic acidosis, and possibly hyperuricemia and dietary factors. Treatment of patients with CKD should focus on mitigating risk factors, as well as common comorbidities such as cardiovascular disease, anemia, and bone mineral disease. Novel therapies such as pirfenidone, pentoxifylline, and endothelin‐1 antagonists are being investigated with promising results.     

Challenges of conducting a trial of uric-acid-lowering therapy in CKD

Observational studies have shown that asymptomatic hyperuricemia is associated with increased risks of hypertension, chronic kidney disease (CKD), end-stage renal disease, cardiovascular events, and mortality. Whether these factors represent cause, consequence or incidental associations, however, remains uncertain. Hyperuricemia could be a consequence of impaired kidney function, diuretic therapy or oxidative stress, such that elevated serum urate level represents a marker, rather than a cause, of CKD. On the other hand, small, short-term, single-center studies have shown improvements in blood-pressure control and slowing of CKD progression following serum urate lowering with allopurinol. An adequately powered randomized controlled trial is required to determine whether uric-acid-lowering therapy slows the progression of CKD. This article discusses the rationale for and the feasibility of such a trial. International collaboration is required to plan and conduct a large-scale multicenter trial in order to better inform clinical practice and public health policy about the optimal management of asymptomatic hyperuricemia in patients with CKD.     

Uric Acid, Hypertension, and Cardiovascular and Renal Complications

Over the last decade, the biologic interference of uric acid with the cardiovascular (CV) system and the kidney has been intensively investigated, and several experimental studies in animal models and in vitro documented that hyperuricemia may trigger hypertension and incite endothelial dysfunction, vascular damage and renal disease. A substantial proportion of epidemiological studies are compatible with the hypothesis that hyperuricemia may be noxious to the CV system and the kidney as well. However, there are still no well-powered trials testing whether uric acid–lowering interventions may reduce BP or attenuate the risk for adverse CV and renal outcomes. Evidence still remains largely insufficient to recommend changes in the current policy of not prescribing uric acid–lowering drugs to individuals with asymptomatic hyperuricemia.     

Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease

Abstract. Stenvinkel P (Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden). Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease (Review). J Intern Med 2010; 268 : 456–467. The epidemics of cardiovascular disease, obesity, diabetes, HIV and cancer have all received much attention from the public, media and policymakers. By contrast, chronic kidney disease (CKD) has remained largely a ‘silent’ epidemic. This is unfortunate because early diagnosis of renal disease based on proteinuria and/or reduced estimated glomerular filtration rate could enable early intervention to reduce the high risks of cardiovascular events, end‐stage renal disease (ESRD) and death that are associated with CKD. Given the global increase in the incidence of the leading causes of CKD – hypertension, obesity and diabetes mellitus – better disease management and prevention planning are needed, as effective strategies are available to slow the progression of CKD and reduce cardiovascular risk. CKD may be regarded as a clinical model of accelerated vascular disease and premature ageing, and the risk‐factor profile changes during the progression from mild/moderate CKD to ESRD. Although many randomized controlled trials in patients with mild to moderate CKD have shown beneficial effects of interventions aimed at preventing the progression of CKD, most trials have been unable to demonstrate a beneficial effect of interventions aimed at improving outcome in ESRD. Thus, novel treatment strategies are needed in this high‐risk patient group.     

Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study

The kidney is one of the organs most prominently affected by aging. This can be seen by a loss of renal mass which is caused by a decrease in the number of nephrons resulting in hyperfiltration, hypertrophy and elevations in glomerular pressure. The factors influencing aging of the kidney are not fully elucidated. Epidemiological, experimental and interventional studies resulted in inconsistent results and have not firmly established whether uric acid levels affect progression of Chronic Kidney Disease (CKD). Therefore, we analyzed whether uric acid levels predict the progression of CKD in the Mild to Moderate Kidney Disease Study comprising at baseline 227 Caucasian patients aged 18-65 years with primary non-diabetic CKD of various degrees of renal impairment. Of them, 177 completed a prospective follow-up of 7 years. Primary endpoint was progression of CKD defined as doubling of baseline serum creatinine and/or terminal renal failure. Patients who reached a progression endpoint (n =6 5) were significantly older, had higher baseline serum creatinine and protein excretion rates as well as lower Glomerular Filtration Rate (GFR). Uric acid levels were only higher in patients with progression of disease when patients with uric acid-lowering drugs were excluded from the analysis. Cox regression analysis revealed that increasing uric acid levels predict disease progression only when the analysis was not adjusted for baseline kidney function parameters. As soon as we adjusted the analysis for GFR and proteinuria this association completely vanished. In summary, our prospective 7 year follow-up study in patients with non-diabetic primary CKD did not support uric acid as an independent predictor for CKD progression.     

Finerenona: completando el abordaje del paciente con enfermedad renal y diabetes

Despite current treatments, that include renin angiotensin system blockers and SGLT2 inhibitors, the risk of renal disease progression among patients with diabetes and chronic kidney disease (CKD) remains unacceptably high. The pathogenesis of CKD in patients with diabetes is complex and includes hemodynamic and metabolic factors, as well as inflammation and fibrosis. Finerenone is a nonsteroidal highly selective mineralocorticoid antagonist that, in contrast to current therapies, may directly reduce inflammation and fibrosis, supporting an added value in the management of these patients. In fact, finerenone decreased albuminuria and slowed CKD progression in persons with diabetes. We now review the mechanisms of action of finerenone, the results of recent clinical trials and a practical approach to integrate the kidney and cardiovascular protection afforded by finerenone in the routine care of patients with diabetes and CKD.     

Potential Role of Uric Acid in Metabolic Syndrome, Hypertension, Kidney Injury, and Cardiovascular Diseases: Is It Time for Reappraisal?

Elevated serum uric acid concentration is a common laboratory finding in subjects with metabolic syndrome/obesity, hypertension, kidney disease and cardiovascular events. Hyperuricemia has been attributed to hyperinsulinemia in metabolic syndrome and to decreased uric acid excretion in kidney dysfunction, and is not acknowledged as a main mediator of metabolic syndrome, renal disease, and cardiovascular disorder development. However, more recent investigations have altered this traditional view and shown, by providing compelling evidence, to support an independent link between hyperuricemia and increased risk of metabolic syndrome, diabetes, hypertension, kidney disease and cardiovascular disorders. However, despite these new findings, controversy regarding the exact role of uric acid in inducing these diseases remains to be unfolded. Furthermore, recent data suggest that the high-fructose diet in the United State, as a major cause of hyperuricemia, may be contributing to the metabolic syndrome/obesity epidemic, diabetes, hypertension, kidney disease and cardiovascular disorder. Our focus in this review is to discuss the available evidence supporting a role for uric acid in the development of metabolic syndrome, hypertension, renal disease, and cardiovascular disorder; and the potential pathophysiology mechanisms involved.     

Gout,Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect?

Gout and hyperuricemia have long been suspected to be risk factors for cardiovascular disease. However, studies have frequently failed to distinguish whether these entities have an independent effect on cardiovascular risk or serve as markers for other risk factors. In vitro and animal studies suggest that uric acid is a biologically active compound that can increase inflammatory mediators known to lead to vascular damage. In contrast, uric acid also has potentially protective effects as a strong antioxidant, approaching the potency of vitamin C. Large clinical trials demonstrate a consistent relationship between elevated serum uric acid and a variety of cardiovascular diseases, although the strength of association varies greatly. We review the evidence for and against an independent role for hyperuricemia and/or gout in cardiovascular pathology.     

慢性肾脏病脂质异常的治疗及意义

血脂异常是慢性肾脏病患者的常见表现,它与慢性肾脏病的进展互为因果,共同参与慢性肾脏病高发心血管并发症和病死率。治疗中除了生活方式改变,强调他汀类药物治疗在慢性肾脏病患者血脂异常的早期治疗,副反应较一般人群无明显增加。已经看到他汀类药物治疗能够降低慢性肾脏病患者高发心血管事件和全因病死率,对降低尿蛋白和延缓肾脏病进展的益处还需要更多证据来证实。     

Evidence-based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease

Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.     

Spectrum of cardiorenal disease

Cardiorenal disease 　　The modern day,worldwide epidemics of obesity and hypertension (HTN) are central drivers of a secondary epidemic of type 2 diabetes with combined chronic kidney disease (CKD)and cardiovascular disease (CVD).1 Approximately half of those with diabetes will develop CKD.2 Conversely,half of all cases of end-stage renal disease (ESRD) are due to diabetic nephropathy.With the aging of the general population and cardiovascular care shifting towards the elderly,an understanding of why decreasing levels of renal function act as a major adverse prognostic factor after a variety of cardiac events is imperative.The heart and kidney are inextricably linked via hemodynamic and neurohumoral function (Fig.1).Considerable evidence shows that CKD accelerates atherosclerosis,myocardial disease,valvular disease,and promotes an array of cardiac arrhythmias.3……     

Uric Acid as a Marker for Renal Dysfunction in Hypertensive Women on Diuretic and Nondiuretic Therapy

Hyperuricemia is a common finding in hypertensive patients, especially among those who are on diuretic therapy. However, its clinical relevance regarding cardiovascular and chronic kidney disease (CKD) has not clearly been established. The authors assessed whether, in a population of 385 hypertensive women categorized according to diuretic therapy, the stratification in quartiles by uric acid levels would identify a gradient of changes in renal function and in risk factors for cardiovascular disease. The following were evaluated: serum uric acid, glycemia, total and fractional cholesterol, triglycerides, apolipoprotein (Apo) B, Apo A-I, and C-reactive protein. Renal function was assessed by serum creatinine, albuminuria, and estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease equation, whereas cardiovascular risk was estimated through the Framingham score. A total of 246 women were on diuretic therapy; 139 were taking other antihypertensive medications. There was a reduction in eGFR parallel to the increase in uric acid levels, regardless of diuretic use and without a concomitant increase in albuminuria. In both groups, higher uric acid levels translated into an increase in metabolic syndrome components, in markers of insulin resistance, triglyceride/high-density lipoprotein levels, and Apo B/Apo A-I ratios, as well as in Framingham scores. Hyperuricemia was associated with an increase in inflammatory markers only in patients on diuretic therapy. In a binary logistic regression, hyperuricemia (uric acid >6.0 mg/dL) was independently associated with CKD (eGFR <60 mL/min/1.73 m²) (odds ratio, 2.63; 95% confidence interval, 1.61–4.3; P <.001). In hypertensive women, the presence of hyperuricemia indicated a substantial degree of kidney dysfunction as well as a greater cardiovascular risk profile.     

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近年研究表明,合并高尿酸血症的高血压患者发生心血管事件的危险性增加。文章介绍了高尿酸血症与高血压、心血管疾病相互关系的流行病学依据,重点阐述高血压并发高尿酸血症患者降尿酸药物的选择及高血压药物对尿酸排泄的影响。     

Chronic kidney disease and statins: Improving cardiovascular outcomes

The burden of chronic kidney disease (CKD) continues to increase worldwide. Patients with CKD are at greater risk of mortality from cardiovascular events than end-stage renal disease. This review describes the pathogenesis of dyslipidemia in CKD patients and the role of statins in reducing coronary heart disease morbidity and mortality. The major clinical trials with statins in CKD patients are reviewed along with a discussion of statin safety. Although statin dosing and safety in patients with early CKD (Stage I or II) are similar to those of the general population, dose adjustments are required in advanced CKD (Stages III–V) due to differences in statin pharmacokinetics and renal excretion. Although the use of statins to reduce cardiovascular events in patients with mild to moderate CKD is strongly supported by existing clinical trials, no clinical benefit has been demonstrated in two large clinical trials involving hemodialysis patients.     

Hypertension, dyslipidemia and cardiovascular risk in chronic renal disease]

Cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The presence of CKD whether manifested by albuminuria or reduction in glomerular filtration rate is an independent risk factor for cardiovascular outcome. This is mainly due to both an overexpression of traditional cardiovascular risk factors, and the onset of new factors which are peculiar of CKD. In this revision the role of arterial hypertension and of dyslipidemia is analyzed in detail. Most interventional trials have demonstrated that a reduction of blood pressure and the normalization of lipid profile are associated with a significant reduction in the incidence of major cardiovascular events and mortality. According to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommendations, patients with CKD, regardless of the stage of disease, should be considered the highest risk group for cardiovascular events. For these patients the NKF-K/DOQI guidelines recommend strict blood pressure control, renin-angiotensin system blockade, and the use of statins with target LDL cholesterol levels < 100 mg/dl.     

Effect of Allopurinol in Chronic Kidney Disease Progression and Cardiovascular Risk

Background and objectives: Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease.Design, setting, participants, & measurements: We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes.Results: Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 ± 1.2 ml/min per 1.73 m², and in the allopurinol group, eGFR increased 1.3 ± 1.3 ml/min per 1.73 m² after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 ± 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy.Conclusions: Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.In patients with renal disease, there is decreased uric acid (UA) urinary excretion, and whether this will give rise to hyperuricemia depends on the gastrointestinal excretory compensation. By this, the prevalence of elevated serum UA in patients with chronic kidney disease (CKD) is higher (1). Elevated serum UA has been related to increased risk for the development of hypertension and cardiovascular disease (2). Chronic hyperuricemia would stimulate the renin-angiotensin system and inhibit release of endothelial nitric oxide, contributing to renal vasoconstriction and increasing BP, at the same time, high levels of UA may have a pathogenetic role in interstitial inflammation and progression of renal disease (3,4).Allopurinol decreases serum UA level by inhibiting the enzyme xanthine oxidase. For animal models of established renal diseases, correction of the hyperuricemic state can significantly improve BP control, decreasing proteinuria and slowing the progression of renal disease (4). There are few data on patients with CKD that confirm these findings.Recently, two studies of patients with CKD have been published that show a relationship between serum UA levels and cardiovascular mortality (5,6). However, prospective studies are necessary to show that reduction of UA levels prevent cardiovascular events.The primary objective of this study was to analyze the effect of allopurinol in patients with moderate CKD in reduction of inflammatory markers and renal disease progression. The secondary objective was to analyze the effect of allopurinol treatment in cardiovascular and hospitalization risk.