Cardiovascular and Renal Surrogate Markers in the Clinical Management of Hypertension

INTRODUCTION: Surrogate markers represent a significant contribution to early diagnosis, longitudinal prognoses, and outcome prediction in cases of hypertension. They often enable detection of disease and disease potential when the disease is still subclinical and are useful noninvasive tools for designing and evaluating therapeutic programs. Surrogate markers are increasingly employed as predictive endpoints for treatment.

METHODS: Key studies supporting the importance of surrogate markers as diagnostic and prognostic predictors of cardiovascular and renal clinical outcomes in hypertension, as well as what is known about the effects of renin-angiotensin-aldosterone system-blocking agents on these biomarkers were reviewed. RESULTS: Clinical data supporting the use of surrogate markers for heart failure, such as brain natriuretic peptide (BNP) and N-terminal prohormone BNP; markers for renal function, such as urinary albumin to creatinine ratio (UACR), urinary albumin excretion rates (UAER), and creatinine, reflecting glomerular filtration; and markers of cardiac remodeling, such as left ventricular hypertrophy and calculations of left ventricular mass index (LVMI), were reviewed for their utility in improving prognosis and treatment efficacy. Finally, hypertension treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and potentially direct renin inhibitors can significantly improve outcomes predicted by surrogate markers.

CONCLUSIONS: BNP, UACR, UAER, and LVMI, among others, have been increasingly established as valid surrogate markers with significant value for hypertension prognosis and therapy. The benefits of using surrogate markers to gauge the effectiveness of hypertension therapy in reducing renal and cardiac complications can be seen in improved morbidity and mortality

Coronary Care Unit and Heart Failure Program, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, Cardiology Section, mc 9111A, San Diego, CA, 92161, USA,

Emerging therapies for chronic kidney disease: what is their role?

The prevalence of chronic kidney disease (CKD) is increasing worldwide. The best therapies currently available focus on the control of blood pressure and optimization of renin-angiotensin-aldosterone system blockade. Currently available agents are only partially effective against hard end points such as the development of end-stage renal disease and are not discussed in this Review. Many other agents have been shown to reduce proteinuria and delay progression in animal models of CKD. Some of these agents, including tranilast, sulodexide, thiazolidinediones, pentoxifylline, and inhibitors of advanced glycation end-products and protein kinase C, have been tested to a limited extent in humans. A small number of randomized controlled human trials of these agents have used surrogate markers such as proteinuria as end points rather than hard end points such as end-stage renal disease or doubling of serum creatinine level. Emerging therapies that specifically target and reverse pathological hallmarks of CKD such as inflammation, fibrosis and atrophy are needed to reduce the burden of this chronic disease and its associated morbidity. This Review examines the evidence for emerging pharmacological strategies for slowing the progression of CKD.

Westmead Hospital, Westmead, NSW, Australia.

Renin

Renin also known as angiotensinogenase, is a circulating enzyme that activates the renin-angiotensin systemby producing angiotensin I from angiotensinogen. Human Reninis released mainly by juxtaglomerular cells in the juxtaglomerular apparatus of the kidneys in response to low blood volume or decreased serum NaCl concentration, mediated through the rapid release of prostaglandins. Although it has hormone-like actions, it cleaves a protein precursor in the circulation rather than working on a cellular target. Thus it is not truly a hormone [1]. Sympathetic activation of membrane β1- and α1-adrenergic receptors on JGA cells also cause renin release, probably by altering tubular sodium content or macula densa function. [2] The normal concentration in adult human plasma is 1.98-24.6 ng/L in the upright position. [3]

The primary structure of renin precursor consists of 406 amino acids with a pre and a pro segment carrying 20 and 46 amino acids respectively. Mature Renin contains 340 amino acids and has a mass of 37 kD.

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE , the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, leading to increased blood pressure.


1.J. Clin. Invest. 114:805-812 (2004).
2.Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. pp.2118-2119
3.Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual.