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Cardiovascular consequences of chronic renal failure

Conséquences cardiovasculaires de l'insuffisance rénale chronique
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INTRODUCTION:

Cardiovascular disease is responsible for more than 50% of deaths in patients with renal failure treated with chronic hemodialysis. Heart complications alone account for 40% of mortality. Ventricular hypertrophy and heart failure as well as arterial atheroma are the main causes, while the incidence of pericarditis, a classic complication of terminal uremia, has decreased.

UREMIC PERICARDITIS:

It is a classic complication of chronic renal failure (CKD), of which it marked the end stage. There are two types according to the circumstances and the chronology of appearance.

“Early” classical form:

This pericarditis occurs in the terminal phase of renal failure or at the beginning of the locum treatment. It is currently found in less than 10% of patients in France. In its clinical, radiological and ultrasound expression, it does not differ from classical serofibrinic pericarditis. It is often associated with a polyserite with pleural effusion, even peritoneal. Its origin is attributed to the accumulation of “uremic toxins” because it is directly related to the severity of renal failure that reflects the importance of uremia. The institution of an effective replacement therapy for renal failure usually allows the rapid healing of effusion and pericardial inflammation. This variety of pericarditis is prevented by the early establishment of extra-renal cleansing, in practice before the urea exceeds 40 mmol / L.

Late form:

Pericarditis occurs in patients undergoing hemodialysis treatment and more rarely peritoneal dialysis. It differs from the classical form in that it is not directly related to the severity of the uremic syndrome, at least as can be assessed by measurements of urea or blood creatinine.

The most common etiopathogenic factors are: inadequate dialysis with retention of intermediate molecular weight toxic metabolites (“medium molecules”), hyperparathyroidism, water-overload, use of anticoagulants, viral infections.

The most common clinical symptoms are pericardial friction (seen in more than 90% of patients), fever, chest pain, hepatomegaly and cardiac arrhythmias. High venous pressure and hyperleucocytosis are found in the majority of cases. The inadequacy of ventricular filling during diastole explains why these patients very often manifest an intolerance to the ultrafiltration of the lymphangy and low blood pressure during hemodialysis sessions. The chest X-ray shows a typical enlargement of the cardiac figure and the electrocardiogram (ECG) is abnormal in more than 90% of cases (ST overcompensation, low voltage, extrasystoles, atrial fibrillation). The diagnosis is based on ultrasound echocardiography, which can detect asymptomatic forms, quantify the volume of the effusion and monitor its evolution.The treatment of these forms of pericarditis is based on the intensification of extra-renal cleansing with reduction or elimination of heparinization. The use of steroids or nonsteroidal anti-inflammatory drugs may be considered in case of fever and pronounced inflammatory syndrome.

Two complications must be feared: pericardial tamponade and, in the longer term, constrictive pericarditis.

Tamponade is most often associated with intrapericardial haemorrhage, and the classic signs are acute hypotension, tachycardia, sudden increase in venous pressure, and the appearance of a paradoxical pulse (a decrease in blood pressure). ‘inspiration). It is an emergency requiring pericardial drainage. The evolution towards the constriction is rare in the renal insufficiency. It usually occurs in the weeks or months following an episode of acute pericarditis by organizing the fibrinous and hemorrhagic effusion. Clinically, it does not differ from the constrictive pericarditis seen outside renal failure.

“CARDIOMYOPATHY URE MIQUES”:

The introduction of ultrasound echocardiography and pulsed Doppler in cardiovascular exploration has led to a better understanding and analysis of the pathophysiology of “primitive” uremic cardiomyopathies. The main morphological abnormalities observed in patients with renal failure are hypertrophy and dilation of the left ventricle (LV). They may be accompanied by altered diastolic or systolic function, or even heart failure. Left ventricular failure is typically responsible for 15 to 25% of all deaths in hemodialysis patients. The frequency of “heart disease” is explained by the multiple cardiovascular risk factors observed in this population. Some, nonspecific uremia, exert an additive effect.Others are specific to renal failure (uremic toxins, various deficiencies, anemia, hyperhydration, hyperparathyroidism) or its treatment (arteriovenous fistula, dialysis membranes, etc.). Often, they only precipitate functional decompensation of previously latent and clinically silent cardiovascular disease. Nevertheless, we also know the existence of cardiomyopathies of primitive appearance in the renal insufficiency.

Physiopathological reminder:

Left ventricular hypertrophy (LVH) is a compensatory mechanism that allows the ventricle to maintain a constant parietal tension against pressure or volume overload. It results from the interaction between hemodynamic constraints and numerous systemic neurohumoral trophic factors or local autocrine or paracrine activity. LVH has beneficial but sometimes deleterious effects. Among the first, the increase in the number of sarcomeres and the parietal thickness not only makes it possible to cope with increased work, but also to normalize the parietal tension of the VG and to regulate its energy expenditure. The law of Laplace gives us the relation between the parietal tension (T) the pressure (P) and the dimensions of the VG brought back to a hollow sphere of radius R and thickness h (T = PR / 2h). The increase in T can therefore be due to an increase in pressure and / or volume, or the inability of the myocardial wall to thicken properly. HVG develops on a model specific to the type of overload. Pressure overload induces proliferation of sarcomeres in parallel with existing sarcomeres. The resulting increase in the thickness of the myocardium (h) makes it possible to maintain, for a given VG diameter, a normal parietal tension. The ratio R / h (relative wall thickness) is lowered (concentric HVG).

In volume overload, the increase in end-diastolic pressure and voltage induces serial proliferation of sarcomeres and LV dilation that limit the increase of end-diastolic pressure and tension.

At the same time, the increase in ventricular volume increases the telesystolic tension and induces a proliferation of sarcomeres in parallel and a hypertrophy of the walls. In this situation, and provided that the systolic pressure is constant, the increase of the diameter and the thickness of the LV is proportional and the ratio R / h remains constant (eccentric HVG). The morphological differences between HVG by pressure or volume overload are associated with a distinct cardiocyte phenotype and a different expression of the mRNAs (messenger ribonucleic acid) of the growth factors.

The deleterious effects of LVH are related to several factors including: decreased density of capillaries; decreased coronary reserve and subendocardial perfusion; the development of interstitial fibrosis responsible for a decrease in ventricular compliance with diastolic filling disorders; the appearance of ectopic foci and re-entry circuits; disorders of ventricular relaxation, etc.

When ventricular overload becomes chronic, the harm prevails and leads to the development of cardiopathy overload and ventricular failure

Left ventricular hypertrophy in renal failure:

LVH is observed in 40% of renal failure patients before dialysis and in 60-80% of hemodialysis patients. It is an independent factor of mortality. Its pathophysiology is complex and although the hemodynamic factors can not be held solely responsible, the increase in cardiac work, related to both a volume overload and a pressure overload is the main reason. The LVH of renal failure associates the characteristics of eccentric hypertrophy with those of concentric hypertrophy.

Volume overload and ventricular hypertrophy in patients with renal impairment:

The increase of the internal diameter of the LV (but also of the left atrium) is frequent in the renal insufficiency. It is found in 28% of subjects at the time of their hemodialysis. It is moderate, at the upper limit of normal values. It is due to a volume overload and a chronic increase in cardiac output. Three factors involved: fistula and arteriovenous (AV) short circuits; water-overload; anemia.

If these factors are not specific to uremia, their association in the same patient may be considered specific.

Arteriovenous fistula:

The opening of an arteriovenous fistula (AVF) is accompanied by an immediate increase in cardiac flow and work related to a decrease in venous return resistance (increase in preload) and arterial resistance (decrease of the afterload ). At first, however, this increase in cardiac output is not sufficient to prevent a decrease in mean arterial pressure, leading to an activation of cardiovascular reflexes. This results in an increase in venous return by venoconstriction and an increase in cardiac chronotropism and inotropism. Cardiomegaly with heart failure, a classic complication of traumatic central vein FAV, is exceptional in peripheral AVFs. Early studies in hemodialysis confirmed this notion, and the creation of AVF in the limbs seemed innocuous until the first observations of heart failure associated with high-rate fistulas. The derogatory role of AVF, as evidenced by the correlation between AVF flow and LV size, has been demonstrated by the return to normal heart function after surgical reduction of flow.

Hydrosoduced retention:

Several studies in hemodialysis patients have established the role of water-soluble retention in LV dilatation and there is a correlation between blood volume and LV volume. In addition, predialytic blood volume is often high, resulting in an increase in the volume of heart chambers, all things corrected during a dialysis session.

Anemia:

Whatever the causes, anemia is accompanied by an increase in cardiac output by increasing heart rate and stroke volume. The peripheral resistance is low, both by decreasing blood viscosity and by anoxic vasodilatation. In addition, resistance to venous return decreases, and because of the activation of the sympathetic system, cardiac inotropism and chronotropism increase. This achieves chronic volume overload conditions responsible for LV dilatation and septal thickening on ultrasound.

In renal failure there is a correlation between the end-diastolic volume (and mass) of LV and the degree of anemia. In addition, in patients with renal impairment, anemia is an independent factor in the development of heart failure and cardiovascular mortality. The permanent correction of anemia by erythropoietin is accompanied by a decrease in the size of the LV and left atrium, as well as a decrease in the mass of LV.

Pressure overload and left ventricular hypertrophy in patients with renal insufficiency:

As in hypertension (hypertension), there is a thickening of the ventricular walls in the renal failure. Nevertheless, although the link between hypertension and the degree of wall hypertrophy is well established in the general population, it is far from being so obvious in uremic patients. Indeed, although 80 to 90% of patients with end-stage renal disease are hypertensive and remain for 10 to 25% of them when treated by hemodialysis, the correlation between blood pressure figures and left ventricular mass is relatively low, even absent in the uremic. This is partly because conventional blood pressure is an imperfect reflection of the “pressure load”. This is determined by three factors which are: vascular resistance; arterial compliance (distensibility) intensity and coupling of arterial reflection waves.

Physiopathological recall:

Vascular resistance represents vascular opposition to continuous blood flow. Vascular resistance is a determinant of mean arterial pressure. Considering that the pressure / flow relations are linear, the resistance (R) represents the slope of this relation. It can be calculated using the Poiseuille formula: Q = r 4 ΔP / 8μL according to which the flow rate (Q) is proportional to the fourth power of the radius ® and to the longitudinal gradient of pressure (ΔP / L) and inversely proportional to the viscosity (μ). In practice, it is valued by the relation R = P / Q, P being the mean arterial pressure and Q the cardiac output. It depends on the radius ® and the number of arterioles and terminal arteries and to a lesser extent on the blood viscosity. The arterial compliance and the coupling of the arterial reflection waves oppose the pulsatility of the blood flow. Whereas arterial compliance (δD / δP) measures the diastolosystolic variation of the arterial diameter (δD) under the influence of differential pressure (δP), the arterial distensibility (δD / δP.D) is defined as the relative variation of this diameter (δD / D, D being the diastolic diameter of the artery). The inverse of the distensibility expresses the arterial rigidity. The decrease in compliance is responsible for an increase in differential and systolic pressures for two reasons: the ejection by the ventricle of a given blood volume in a rigid artery induces a shock wave (incident pressure wave) of great amplitude; the increase in arterial stiffness is responsible for an increase in the rate at which the pressure wave (VOP: velocity of the pulse wave) propagates in the arterial system and an early return of the wave at the level of the ascending aorta which, by superimposing itself on the incident pressure wave, increases the amplitude of the differential and systolic pressure at this level.

Pressure and LVH Constraints in Chronic Renal Failure:

Except in cases where there is severe or malignant systolic or diastolic HTA, arterial resistance is normal in CKD or can only be considered elevated in relation to an increase in cardiac output. Moreover, there is no correlation between the rise in peripheral resistance and the degree of LVH. Clinical and epidemiological studies have shown that 32% of hemodialysis patients have isolated systolic hypertension and / or elevation of differential pressure, due primarily to increased arterial stiffness and early return of arterial reflection waves. These two abnormalities, typically observed in chronic renal failure, are responsible for an increase in LV telesystolic stress and are a major cause of ventricular hypertrophy.

The increase in arterial stiffness in the uremic is closely related to the remodeling of the arteries under the influence of haemodynamic stresses similar to those affecting the LV and responsible for a parallel evolution of cardiac and arterial abnormalities.

Non-hemodynamic factors and ventricular hypertrophy in uremic:

The clinical impact of LVH in response to mechanical overload is influenced by many factors including age, gender, race, and the importance of interstitial fibrosis that accompanies hypertrophy. Myocardial fibrosis is more marked in pressure overload than in volume overload. Its causes are many, such as senescence, ischemia, as well as the effects of many vasoactive substances such as angiotensin II, catecholamines, aldosterone, etc.

It can contribute to the development of inadequate hypertrophy resulting in increased cardiac stress and ventricular failure. Myocardial fibrosis is characteristic of renal failure. The responsible factors are not known with certainty.Parathyroid hormone, which could be the cause of inadequate hypertrophy of LV and dilated cardiomyopathy, is suspected; Myocardial fibrosis is more pronounced in pressure surges accompanied by increased activity of the renin-angiotensin-aldosterone system (RAA). The administration of angiotensin-converting enzyme inhibitors to renal failure induces a regression of ventricular hypertrophy independent of the antihypertensive effect. This suggests that activation of the tissue RAA system may play a role in the development of LVH and fibrosis. In addition, experimental studies have shown that aldosterone can induce LVH and interstitial fibrosis. Due to metabolic acidosis and hyperkalemia, plasma aldosterone is elevated in renal failure and may play a role in myocardial fibrosis; increased sympathetic activity and plasma catecholamines.

Functional repercussions of ventricular hypertrophy:

Cardiac function is influenced by the intrinsic properties of the myocardium, as well as ventricular pre- and afterload conditions. This is all the more crucial in patients with renal insufficiency undergoing hemodialysis with large volemic, volitional and ionic variations during hemodialysis sessions. Ventricular function should be assessed according to these various factors, especially when the evaluation is performed immediately after a session. Indeed the volume contraction can increase (or even induce de novo) disorders of ventricular filling, and on the contrary increase a disorder of systolic function. Similarly, increased plasma levels of ionized calcium during hemodialysis sessions may have a positive inotropic effect in acute and lower ventricular failure. For all these reasons, it is preferable to evaluate the morphology and ventricular function at a distance from a hemodialysis session, preferably 24 hours after the session. In fact, it is at this moment that the blood volume is closest to that of a control population and the balance is dialyzed. This method is not very reproducible and can only serve as an adjunct to other clinical parameters to assess the degree of hydration of patients.

Systolic function:

According to the literature data, 30 to 60% of hemodialysis patients have a lowering of the LV ejection fraction. This lowering of the functional indices is observed especially in subjects with cardiac disorders pre-existing to renal insufficiency (or when left ventricular dilatation and dilated cardiopathy appear). Renal insufficiency free of such antecedents and presenting a simple LVH, have indices of systolic contraction generally equal to those of control subjects, sometimes even superior (hypertrophic hyperkinetic cardiopathy). Due to the chronic volume stress, the cardiac output and filling pressure of the LV are high, with no anomaly in the pressure-flow relationship (Frank-Starling ventricular function curves). Moreover, because of decreased vascular resistance (due to anemia, and fistula) and increased heart rate, ventricular function curves are often staggered so that for filling pressure given, the cardiac output is higher in the uremic. The main consequence of these abnormalities is the chronic increase in myocardial oxygen consumption, some of whose determinants (telesystolic stress, heart rate, even cardiac inotropy) are or can be elevated in hemodialysis. This increased consumption of oxygen is all the more prejudicial as it is added to pre-existing heart disease, often to coronary insufficiency.

Basal systolic function is normal or elevated, but at the expense of the “functional reserve” which is started. This partly explains the poor adaptation to acute metabolic needs, such as those triggered by physical exertion.

Diastolic function:

Invasive studies of the pressure-volume relationship of LV and ultrasonographic studies showed that hemodialysis significantly reduced the ratio of E / A to transmittal velocities, indicating LV filling anomalies. They can be due to the HVG itself and the alterations of the geometry that it induces (decrease in chamber compliance). On the other hand, as some experimental work has demonstrated, myocardial function may also be impaired (decreased wall compliance) due to the intense proliferation of fibroblasts and the fibrous tissue development that characterizes LVH. . The decrease in compliance of VG is characterized by a very marked influence of volume on pressure. Thus, a small increase in LV volume may induce pulmonary congestion and acute pulmonary edema even if ventricular systolic function is normal or increased.

Inversely, the ultrafiltration perdialytique and the depletion hydrosodée can be accompanied by a sudden fall of the pressure of filling, all the more that the hypovolemia is accompanied by a decrease of the passive filling of the VG (decrease of the peak E of the transmitral velocity), which is only assured by the left atrial contraction. This chronic solicitation of the left atrium is responsible for its hypertrophy and dilation typically observed in patients with renal insufficiency.

Hypertrophy and decreased compliance of LV may have two other potential consequences: decreased coronary reserve and increased incidence of arrhythmias and sudden death. This seems particularly true in hemodialysis.

Recall that unexplained cardiac arrest accounts for 12% of the causes of death in these patients.

Therapeutic considerations:

The increase in ventricular diameter associated with hyperpulsatility and increased arterial systolic pressure induces in chronic hemodialysis a rise in LV wall stress and increased oxygen consumption. This condition does not cause contraction disorders and can be perfectly tolerated for years in the absence of primary cardiac pathology. The same can not be said of patients with pre-existing cardiac disease in whom therapeutic measures regress LVH. Thus, the correction of   erythropoietin anemia provides a partial regression of LVH, as well as correction of fistula hyperfeeds and compliance with rules limiting water-soluble intakes. The treatment of hypertension is essential. The most recent studies have shown that ACE inhibitors are able to effectively reduce LVH outside of their antihypertensive effects. It has been said sometimes dramatic hemodynamic incidence of abnormalities of diastolic function. They require close monitoring of the water-soluble balance, caution in the ultrafiltration of patients and thus in the shortening of dialysis times. Positive inotropic drugs are inoperative in subjects with normal or increased systolic function. It is the same vasodilators.

ARTERIAL INJURY IN THE CHRONIC RENAL FAILURE:

Physiopathological reminder:

The arterial system has two distinct functions: to minimize the tension fluctuations that result from the intermittency of cardiac contractions – the damping function; deliver a proper amount of blood to organs and tissues – the duct function.

The effectiveness of the damping function is related above all to the viscoelastic and geometric properties of the arteries, that is to say to their compliance or distensibility. It is the main cause of alteration of the damping function.

Arteriosclerosis is primarily a degenerative and generalized attack of the media of the entire arterial tree. It is accompanied by diffuse dilatation of the arterial system, intimomedial hypertrophy of the arteries and increased rigidity.These changes are more pronounced at the aorta and central arteries than at the limb level. Arteriosclerosis is often considered a “physiological” phenomenon related to aging, and often accelerated by hypertension.

The efficiency of arterial duct function is primarily related to the size of the arteries and their low resistance to flow, allowing the maintenance of an almost constant mean arterial pressure between the aorta and the terminal arteries.The abnormalities of the duct function are due to the existence of occlusive lesions, resulting in the decrease of the arterial diameter and the ischemia downstream of these lesions.

Atherosclerosis is the most common cause. It is a disease of the intima, characterized by the presence of plaques having a predilection for certain territories such as the coronaries, the abdominal aorta, the internal carotid artery or the femoral arteries. The mechanisms of atherogenesis are complex and include lipid disorders, smoking, activation of coagulation factors, activation of the immune system and mediators of inflammation, and the effect of mechanical stresses, which they are tension constraints or shear stresses.

Arteriosclerosis in renal failure:

This is characterized by diffuse dilatation of the arterial system and hypertrophy of vessel walls. This intimomedial hypertrophy of the arterial walls can be seen without any presence of atheromatous plaques and is close to the changes observed during aging. The main changes are closely related to the hemodynamic abnormalities seen in renal failure, particularly to volume overload and chronic increase in systemic blood flow. When no stenosing atherosclerotic lesions are added, these arterial abnormalities are not accompanied by infusion disorders under basal conditions. On the other hand, there is a decrease in vasodilator response, whether it is a response to induced ischemia or a response to nitrated vasodilators. Functionally, arteriosclerosis is accompanied by a loss of distensibility responsible for an increase in differential pressure and systolic pressure, and ventricular afterload.

Atherosclerosis in renal failure:

This is a worrying complication in uremics. In particular, it results in an increased frequency of ischemic coronary events, responsible for 8 to 15% of the deaths at the origin of the theory of accelerated atherogenesis in these patients.

Although this theory seems to be verified in uremic women, particularly because of early menopause, it remains controversial in men. In fact, when comparing a uremic population to a control population with identical risk factors, neither the epidemiological data nor the clinical observations made it possible to reveal differences in the frequency of coronary diseases. This varies according to demographic and geographical characteristics. As in the general population, the incidence of coronary insufficiency is greater among Anglo-Saxons and Nordic populations than among Mediterranean peoples, and its frequency increases with age, smoking and diabetes.

The diagnosis of coronary ischemia is often difficult. Effort ECG is often not very contributive because of the low tolerance of many uremic patients to physical exercise because of complications such as anemia, amyotrophy, polyneuritis, etc. Thallium myocardial scintigraphy, unreliable when performed at rest, gives better results if it is sensitized by a dipyridamole infusion which provides a tachycardia comparable to that of a stress test as well as coronary vasodilatation. This examination is usefully complemented by the search for segmental dyskinesia in two-dimensional echocardiography and / or dobutamine stress echocardiography. Angiography remains the best diagnostic tool for assessing the severity, topography, and extent of coronary lesions. This examination is not without risk in the dialysis patient because the osmotic power of the contrast agents used (1500 to 2000 mOsm / L) leads to a volume expansion sometimes responsible for a circulatory overload. That is to say the advantage of using osmotically less active products and to perform hemodialysis as soon as possible after the examination. Coronary angiography should be reserved for symptomatic patients who are resistant to medical treatment and who have a high risk of acute accidents, and who can be considered for a therapeutic procedure.

The treatment of coronary insufficiency has no specific character in renal failure; at the very most, the importance of the risk factors associated with uremia and hemodialysis should be limited. It is important to correct anemia and hypertension, to avoid blood instability during hemodialysis (dialysate sodium adjustment, ultrafiltration control, bicarbonate dialysate, use of biocompatible membranes, etc.). In the case of refractory angina, coronary bypass can be considered. Nevertheless, caution should be exercised in these indications as perioperative mortality varies widely from 3 to 20% depending on the team, and postoperative mortality of 24%, four to five times higher than that observed in a population with normal renal function. The main indication is tight and isolated stenosis of the left coronary artery.Surgery is not indicated in chronic angina with multi-rectal involvement if the ventricular ejection fraction is greater than 50%. Angioplasty gives relatively satisfactory results in the short term but with an incidence of restenosis (60 to 80%) at 4 months, significantly higher than in a control population.

Apart from any pre-existing cardiovascular disease or the presence of classical risk factors, 25 to 30% of hemodialysis patients with clinical symptoms of coronary insufficiency are free of hemodynamically significant coronary trunk lesions. Under these circumstances, ischemia may be related to microangiopathy or decreased coronary reserve related to hypertrophy and decreased left ventricular compliance, decreased arterial distensibility, and as already mentioned, anemia and increased cardiac work.

Ventricular hypertrophy is accompanied by a decrease in the density of myocardial capillaries and an increase in the diffusion distance between the capillary and the myocyte. Moreover, there is uremic thickening of the walls of myocardial arterioles. Decreased arterial compliance is accompanied by an early return of reflection waves resulting in an increase in systolic pressure and a lowering of diastolic pressure. The increase in systolic pressure increases the oxygen consumption, whereas the decrease in the diastolic is responsible for a fall in the coronary perfusion pressure gradient, especially since the diastolic pressure of the LV tends to rise. due to anomalies in the filling function of the VG. Finally, myocardial ischemia may be increased by the existence of oxidative metabolism disorders, decreased production of ATP and phosphocreatine / ATP ratio, deficiencies of L-carnitine, and others.

CALCIFYING VALVULOPATHIES IN RENAL FAILURE:

Echocardiographic studies showed that 30-50% of chronic hemodialysis patients had intracardiac valvular calcifications. These calcifications are more readily observed in the elderly, but the age of onset, which is usually greater than 70 years in the general population, is much earlier in patients with renal insufficiency and symptomatic valvular calcifications can be seen in the elderly. subjects under 40 years old. Among these, aortic calcification is of particular concern because it is associated in 3 to 20% of cases with hemodynamically significant aortic stenosis. They have the special character of evolving very rapidly and it is not uncommon to see a tight aortic stenosis develop within 15 to 18 months. The risk factors invoked are age, duration of treatment, atherosclerosis, and phosphocalcic disorders, particularly secondary hyperparathyroidism. Apart from the age and duration of hemodialysis treatment, none of these factors can be conclusively incriminated. The prognosis is bad, half of the patients dying within 2 or 3 years if no intervention is attempted; hence the importance of regular monitoring and early indication of intervention.

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