Role of Kidneys in Congestive Heart Failure

Physiology Term Paper Fall 2011

Aditi Deshpande 12/2/2011

Role of Kidneys in Congestive Heart Failure

By Aditi Deshpande

Introduction:
Renal dysfunction has been a constant and co-existing complication of Congestive Heart Failure (CHF). Not long ago it was established that renal failure is a vital indicator of mortality in patients with heart failure. Sodium and water retention are marking features in CHF, causing Edema a major type of manifestation of the disease. A main player in these conditions in the Renin-Angiotensin-Aldosterone System (RAAS) which can be triggered off by haemodynamic changes such as reduced blood volume and renal hypoperfusion. The RAAS causes vasoconstriction, sodium and water retention and release of Anti-Diuretic Hormone (ADH) leading to increased blood pressure (hypertension) which exacerbates the underlying conditions of CHF. This paper talks about the role of the kidney in the pathogenesis of Congestive Heart Failure by describing the RAAS its working and effects, renal haemodynamics and salt and water regulation in CHF leading to edema, renal sympathetic activity in heart failure and finally, therapeutics to prevent and control renal dysfunction to alleviate heart failure conditions.

Overview of Congestive Heart Failure:

Heart failure is a pathological condition in which, over a period of time, the heart is unable to supply sufficient blood flow to meet the requirements of the body for adequate perfusion. Congestive heart failure is mostly caused when blood volume is reduced and the cardiac output falls low triggering complex haemodynamic and neurohormonal responses leading to excessive fluid accumulation and congestion. This condition of the impairment of the hearts pumping action can be caused by several [1] mechanisms such as: (i) Cardiomyopathy: Heart muscle damage causing a reduction in the force of contraction which can be caused by amyloidosis, coronary artery disease ,long high standing blood pressure etc. (ii) Myocardial Infarction: A heart attack which may rapidly lead to either cardiac arrest or damage to the left ventricle. This causes improper functioning of the heart leading to heart failure. (iii) Hypertension: Abnormally high blood pressure puts a higher load on the left ventricle to pump the blood out, damaging and weakening the hearts pumping efficiency, leading to heart failure. (iv) Heart valve defects: Incompetent valves (improperly shutting valves)

allowing regurgitation cause accumulation of blood in the body especially in the lungs. Stenotic valves (improperly opening valves) create an extra workload on the heart. Both of these valve defects can lead to heart failure. (v) Abnormal heart rhythms and other factors. Left heart failure causes compromised aortic flow to the body and the brain and the fluid collects in the lungs causing pulmonary edema whereas Right heart failure causes insufficient pulmonary blood flow and causing excessive fluid in the lower extremities leading to pitting edema. As stated by Eugene A. Stead, Jr. (1951) [2] Edema in congestive heart failure is of two types; a) Edema caused by improper distribution of fluid in the body and b) Edema caused by an increase in the total fluid in the body caused by excessive retention. The first case has fluid from the tissues into the bloodstream which collects in the lungs causing a sudden pulmonary edema due to myocardial infarction (or) fluid collection in the lower limbs due to right heart failure. The second type of edema is caused by a failure of the kidneys to excrete the fluid efficiently leading to a higher level of fluid intake compared to the output over a longer period of time. This is the renal effect in heart failure whose mechanism is our subject of interest.

Renin - Angiotensin - Aldosterone System:

In earlier times, the efficacy of the treatment of Congestive Heart Failure made us overlook the underlying pathophysiology of the disease which limited our knowledge regarding the mechanisms of action of the RAAS in heart failure as well as the working of the drugs administered for treatment [3]. Angiotensinogen, an inactive peptide, is released into the circulation by the liver. When blood volume is low and the perfusion of the Juxtaglomerular Apparatus in the kidney decreases, the juxtaglomerular cells sense this reduction and secrete the enzyme renin. The plasma Renin then cleaves the Angiotensinogen, converting it into the decapeptide Angiotensin I. This is further disintegrated into Angiotensin II in the endothelial layer of the blood vessels, particularly in lungs, by the Angiotensin Converting Enzyme (ACE). This Angiotensin II is a potent vaso-active peptide which is the key activator of the effects of the RAAS. This cycle is depicted in Figure 1. Angiotensin II triggers various haemodynamic responses such as arterial vasoconstriction, stimulation of thirst, salt and water retention by the kidney, release of antidiuretic hormone from the posterior pituitary, augmentation of norepinephrine release from sympathetic nerve endings (and inhibition of its reuptake), and remodeling of the heart and blood vessels [4] .

Fig. 1: The Renin-AngiotensinAldosterone Cycle. Image reprinted from The

Renal Renin Angiotensin System by Lisa M. Harrison-Bernard. (2009). Advan in Physiol Edu 33:270-274, 2009. . Copyright 2009 by the American Physiological Society. ISSN: 1043-4046, ESSN: 1522-1229

Angiotensin II is a vasoconstrictor of the arterioles. In the renal system, it constricts the Glomerular arterioles, affecting the efferent arterioles more than the afferent ones. This results in reduced renal blood flow. As presented by Harrison-Bernard (2009), Angiotensin II can cause rapid vaso-constriction upto 60% of the vessel diameter. It is further stated that Angiotensin II causes contraction of mesenglial cells which is thought to lower the Ultrafiltration Coefficient and decrease the GFR [5]. When the concentration level of intrarenal Angiotensin II increases, the Tubologlomerular Feedback Mechanism

becomes much more sensitive. This occurs with a lowered intake of Sodium Chloride which causes the kidneys to conserve salt and water. Angiotensin II decreases blood flow to the medullary region which aids the water retention process and concentrates the urine. Angiotensin II also has an effect on the adrenal cortex, causing it to release Aldosterone, which acts on the tubules in the kidneys causing them to further absorb water and salt from the urine. This increases blood volume in the body and therefore largely increases blood pressure. The tubular effects of Angiotensin II are not confined to this. It also causes hypertrophy of the renal tubule cells, further leading to sodium reabsorption. Angiotensin II also causes the release of Anti-Diuretic Hormone (ADH), also called vasopressin which is released from the posterior pituitary gland. It is a peptide hormone that increases peripheral vascular resistance, raising the blood pressure. It increases urine osmolality by increasing the water permeability of distal tubule and collecting ducts in the kidney causing water reabsorption and heightening the urine concentration. ADH increases the permeability of the inner medulla of the collecting duct, to urea, which facilitates its reabsorption into the interstitium. It also acts on the Central Nervous System, increasing a persons thirst and appetite for salt, which is the last thing a person with Congestive Heart Failure needs. Activation of the RAAS, due to the effects of Angiotensin II, Aldosterone and ADH cause Hyponatremia a condition in which excess water accumulates in the body. All these ill-effects of the Renin Angiotensin - Aldosterone system (which are necessary in a normal state but hazardous in CHF conditions) together

contribute to the major symptom of Congestive Heart Failure - Edema (pulmonary or pitting), making it a key factor in the pathophysiology of Congestive Heart Failure.

Renal Regulation of Salt and Water in Congestive Heart Failure:

As stated by Barger, Muldowney and Liebowitz (1959), for a long time, it was quite uncertain if renal dysfunction actually aggravates the condition of CHF in a patient or is merely one of the deleterious effects of heart failure. But several studies have shown worsening renal function (WRF) associated to congestive heart failure along with statistical studies and it has been proved that both the diseases go hand in hand [6]. The pathophysiology of salt and water regulation in heart failure by the kidneys involves a complex interplay of neurohormonal and haemodynamic mechanisms. Arterial underfilling is also a vital factor which can set off the retention of salt and water by the kidneys in conditions of congestive heart failure. Arterial underfilling occurs due to vasodilataion and reduced cardiac output, this in turn activates reflexes which provoke fluid and salt retention [7]. The arterial underfilling is sensed by the baroreceptors in the aorta, carotid sinus and the renal afferent arterioles which cause sympathetic stimulation and activation of the Renin - Angiotensin Aldosterone System which, as discussed in the previous section, causes vasoconstriction, aldosterone and ADH release and finally leads to salt and water retention.

Fig 2. Working of Sympathetic nervous system and activation of RAAS. Image

reprinted from Sodium and Water Retention in Heart Failure and Diuretic Therapy: Basic Mechanisms By Domenic A. Sica. (2005). Cleveland Clinic Journal of Medicine. Volume 73.

The Juxtaglomerular Apparatus of the renal afferent arterioles is one of the most well developed high pressure receptors associated with the regulation of body fluid volume. It reacts to a decrease in the stretch or an escalated renal sympathetic activity with a heightened renin secretion amount, thus activating the RAAS. Though the working is not explicitly known, experimental studies show that certain chemoreceptors also have an afferent role in fluid retention during

heart failure. For example, vagal and sympathetic nerve endings in lungs and the heart respond to an array of chemical receptors like Bradykinenin, Prostaglandins, Phenyldiguanidine etc.

Let us now stream our discussion to the efferent mechanisms of the renal water and salt regulation. The constriction of the renal efferent arterioles causes an increase in the GFR to plasma ratio in heart failure patients due to a decrease in the renal blood flow and a higher renal vascular resistance. These changes in the GFR cause the proximal tubular retention of fluid to increaseby altering the hydrostatic forces in the peritubular capillaries. Thus, to summarise the figuratively presented mechanism of renal sodium and water retention by Hosenpud and Greenberg (2007), the chain of reactions is mainly as follows; Cardiac failure leads to a lowered peripheral vascular resistance and a decreased cardiac output which cause a reduction in the adequate arterial circulation. This system, through its own mechanism (as described earlier) activates the Renin-Angiotensin-Aldosterone System, increases the renal sympathetic activity and releases a higher amount of vasopressin. All these events in turn lead to Diminished renal water and salt excretion.

levels care caused not only by increased release of NE but also by a decreased clearance of it. A study on human heart failure documented selective cardiorenal sympathetic activation [9]. In this, the cardiac and renal spillover rates were much higher (in the order of 500% and 200%) whereas some organ specific spillover rates (for example, the lungs) were normal. This cardiorenal adrenergic activation in the early stages of congestive heart failure activates the RAAS, causes peripheral vaso-constriction, retention of water and salt by the kidneys and all the other above mentioned detrimental effects of the RAAS. Thus it was concluded that increased sympathetic activity (NE release) aids in the progression of heart failure [10]. A study performed on rats depicted that the constriction of the efferent arterioles caused by NE secretion alters the peritubular haemodynamics which in turn increases the level of tubular reabsorption of Sodium [11]. Increased renal sympathetic activity is accompanied by renal nerve stimulation which have an immediate effect on sodium reabsorption in the proximal convoluted tubule [12].

The Cardio-Renal Syndrome:

The cardio-renal syndrome is a condition in which Worsening Renal Function (WRF) is accompanied by Heart Failure and one disease precipitates the other. This concomitant renal and cardiac dysfunction is a hallmark of renal failure and CHF. Several studies have outlined and demonstrated an increased mortality rate, longer duration of hospitalization, exacerbated conditions of the already existing heart failure due to renal involvement. In a study of over 65,000

Sympathetic Activity in CHF:

After performing some direct and indirect methods of measurement of increased sympathetic activity in heart failure, studies [8] [9] have demonstrated an increased level of venous plasma norepinephrine in patients at an early stage of heart failure itself. High venous plasma

admitted patients for heart failure, abnormal renal function turned out to be the strongest predictor of morbidity and mortality [13]. WRF can contribute to the progression of CHF in many ways such as activation of the RAAS, sympathetic activation, an increase of volume in the left ventricle etc. These mechanisms remodel the myocardium and can cause conditions like worsening mitral regurgitation, myocardial fibrosis, myocyte apoptosis and increased left ventricular mass [4].

diuretics which though shown to be effective, is enhanced by ACE inhibitors, Adrenergic Receptor Blockers and Vasodilators. Angiotensin Converting Enzyme inhibitors are drugs which inhibit the conversion of Angiotensin I to Angiotensin II and hence lowering arteriolar resistance, increasing venous capacity, decreasing blood pressure and improving the cardiac output.

Conclusion:
Though the above mentioned strategies alleviate the WRF conditions and improve mortality rate, there still are no effective methods applied to completely reverse or prevent the renal complications of CHF. A further improved understanding of the cardio-renal mechanisms pertaining to heart failure gives us scope for a highly beneficial treatment.

Therapeutics to control the Worsening-Renal-Function effect on Congestive Heart Failure:

Congestive Heart Failure is an old and prevailing condition that affects a vast number of people, especially after the age of 65. Treatment options for Congestive Heart Failure also aimed at simultaneously treating the renal failure have been tried, experimented and successfully implemented. The major treatment methods commonly used today for treating these conditions are listed below. Diuretics are drugs that elevate the rate of urination and cause excretion of the accumulated water and salt. Loop diuretics such as Furosemide inhibit the Sodium reabsorption at the ascending loop in the nephron. These can cause increased excretion upto 20%. Thiazide diuretics similarly inhibit water and salt retention in the distal convoluted tubule and cause increased excretion. Significant reduction of Edema and blood pressure was seen in patients treated with loop diuretics [14]. The conventional treatment of heart failure with WRF is dietary restrictions and

References:
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[11] Meyers BD, Deen WM, Brenner BM. (1975). Effects of norepinephrine and angiotensin II on the determinants of glomerular ultrafiltration and proximal tubule fluid reabsorption in the rat. Circ Res. 1975(37):101110. [12] Bello-Reuss E, Trevino DL, Gottschalk CW. (1976). Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest. 1976(57):11041107. [13] Fonarow GC, Adams KF, Jr., Abraham WT, et al. (2005). Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. 2005;293(5):572580. [14] Faris RF, Flather M, Purcell H, Poole-Wilson P, Coats AJS. (2009). Diuretics for heart failure. Retrieved from: http://summaries.cochrane.org/CD003838/diuretics -for-heart-failure-in-adults