Essential Hypertension, Progressive Renal Disease, and Uric Acid

Abstract

Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.

Elevated Uric Acid Increases the Risk for Kidney Disease

“…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an effect that was blocked by angiotensin-converting enzyme inhibitor treatment when allopurinol therapy was withdrawn, 34 which could not be examined in this study.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 function 32 ; therefore, it seems unlikely that accurate UA-lowering therapy can substantially confound the relationship between UA and development of new-onset kidney disease.…”

“…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 factor 11 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.…”

Very low-grade albuminuria reflects susceptibility to chronic kidney disease in combination with cardiovascular risk factors

“…Uric acid has been related to cardiovascular morbidity and mortality in a number of previous studies. 20,21 In the MONICA cohort, hyperuricemia was associated significantly with cardiovascular mortality, independent of body mass index, hypertension, diuretic or alcohol use and smoking. 22 Uric acid has also been identified as an independent predictor of microalbuminuria in healthy subjects.…”

Interaction between serum uric acid and triglycerides in relation to blood pressure

“…7,8 These studies imply a hypothesis that uric acid might have synergistic effects with other risk factors during atherogenesis. We particularly assessed the interactions between SUA and other metabolic risk factors in relation to hypertension.…”