Risk Factors for Pulmonary Hypertension in Patients With CKD
Overview
There are no proper longitudinal studies detailing the natural history of pulmonary hypertension in CKD, from its early stages to kidney failure. The factors responsible for pulmonary hypertension in patients with NDD-CKD5 and HD patients, particularly alterations that influence the control of vascular tone in the lung, are poorly defined. As previously reported, most cases of pulmonary hypertension in patients with CKD are classified as WHO class II. In these patients, pulmonary wedge pressure is >15 mm Hg and depends on associated LV disorders. WHO class I, for which pulmonary wedge pressure is ≤15 mm Hg, is caused by high arteriolar tone similar to that of idiopathic forms of pulmonary artery hypertension or pulmonary artery hypertension secondary to systemic disorders such as scleroderma. This section discusses a list of factors for which the role in pulmonary hypertension in patients with CKD has been reasonably well assessed. Most patients with CKD are affected by one or more comorbid conditions that by themselves may induce and/or exacerbate pulmonary hypertension, with the particular mechanism(s) varying according to the patient's concomitant LV disorders. Furthermore, as discussed next, CKD and HD treatment may trigger other risk factors acting at the precapillary level.
LV Disorders, Volume Overload, and Lung Disease
Hypertension and diabetes mellitus, 2 dominant causes of kidney disease, trigger LV diastolic dysfunction, an alteration bound to increase pulmonary venous and arterial pressure. Chronic volume overload, a factor implicated in LV disorders and in the high venous return in patients with CKD, may induce pulmonary venous hypertension by both increasing pulmonary blood flow and adversely affecting LV function. In addition, myocardial stiffness secondary to myocardial infarction, another frequent complication of CKD, may contribute to pulmonary hypertension. In categorical terms, patients with LV disorders and/or volume overload constitute group II of the WHO classification, whereas patients with lung diseases, either restrictive (ie, obese patients with CKD) or obstructive (ie, patients with chronic obstructive pulmonary disease), are grouped in WHO class III. In chronic obstructive pulmonary disease, the main mechanism underlining increased pulmonary pressure is chronic hypoxia, a potent pulmonary vasoconstrictor. If sustained, vasoconstriction in the lung leads to extensive remodeling of the pulmonary vessels and a steady reduction in vessel compliance, a phenomenon which in and of itself contributes to pulmonary hypertension.
Pulmonary capillary wedge pressure is considered to be a reliable marker for LV end-diastolic pressure. However, determining whether left-sided cardiac disease is present on the basis of pulmonary capillary wedge pressure is unreliable in patients with pulmonary hypertension because ~50% of patients who are considered to have pulmonary artery hypertension on the basis of pulmonary capillary wedge pressure eventually may turn out to have WHO class II pulmonary hypertension instead when diagnosed on the basis of LV end-diastolic pressure. Thus, when there is a choice between pulmonary capillary wedge pressure and LV end-diastolic pressure in a patient with pulmonary hypertension, LV end-diastolic pressure should be regarded as the gold standard for the diagnostic definition of pulmonary hypertension.
Arteriovenous Fistula
AVFs, be they the result of trauma or intentionally created, have profound hemodynamic effects. An AVF leads to decreased systemic vascular resistances, enhanced venous return, and increased cardiac output to maintain proper blood flow to all organs and tissues. These adaptations increase pulmonary blood flow and set the stage for pulmonary hypertension. Because pressure is the product of flow and resistance, increased pulmonary flow necessarily leads to increased pressure at any level of pulmonary vascular resistance. Well-performed studies show that pulmonary pressure increases in strict temporal relationship with AVF creation and that pulmonary hypertension tends to worsen over time in this population. Accordingly, in HD patients, AVF flow and AVF duration are related independently to the severity of pulmonary hypertension. AVF compression by a sphygmomanometer or surgical AVF closure induces a rapid decrease in mean cardiac output followed by a stable decrease in pulmonary pressure. As discussed, AVFs may explain in part why the prevalence of pulmonary hypertension is higher in HD patients than in PD patients.
Exposure to Dialysis Membranes
Neutrophil activation secondary to blood–dialysis membrane contact accompanied by reversible neutrophil sequestration in the lung, a phenomenon that was intensively investigated in the 1980s, contributes to causing or worsening microvascular lung disease in HD patients. This phenomenon is particularly pronounced when dialysis is performed using cellulosic membranes and is attenuated but not abolished with synthetic and modified cellulosic membranes. In a crossover trial of a series of 74 patients without an AVF who were dialyzed through a central venous catheter, use of high-flux polysulfone filters was associated with a more pronounced decrease in postdialysis pulmonary pressure than the use of cellulose acetate filters. The hypothesis that volume overload and LV disorders triggered or exacerbated by kidney disease and repeated exposure to dialysis membranes may cause pulmonary hypertension independently of the AVF and other factors is supported by the demonstration that kidney transplantation may revert pulmonary artery pressure to normal in patients who still have a functioning AVF.
Systemic Diseases Associated With CKD
Pre-existing connective tissue diseases and superimposed infectious, hematologic, and liver diseases can all contribute to pulmonary hypertension in patients with CKD by mechanisms that interfere with the control of microvascular tone in the lung (WHO class I; Fig 2). However, collectively, these factors largely fail to explain the high prevalence of pulmonary hypertension in dialysis patients because most patients with CKD exhibit pulmonary hypertension even in the absence of these diseases.
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Figure 2.
Main mechanisms proposed to explain the pathogenesis of pulmonary hypertension (PH) in patients with chronic kidney disease. Abbreviations: AV, arteriovenous, COPD, chronic obstructive pulmonary disease; LV, left ventricular.
Endothelial Dysfunction
Endothelial dysfunction is a main trigger of pulmonary hypertension. This link is even more relevant in pulmonary hypertension in patients with CKD, in whom endothelial dysfunction is pervasive. The impaired capacity of the endothelium to regulate vascular tone in patients with CKD depends on an imbalance between vasoconstrictors (eg, high levels of endothelin 1) and vasodilators (reduced generation of nitric oxide [NO]). The role of endothelial dysfunction in HD patients with pulmonary hypertension is supported by cross-sectional findings that show that plasma NO levels are decreased in HD patients with pulmonary hypertension compared with those without pulmonary hypertension and by the observation that HD treatment increases NO levels in patients without pulmonary hypertension to a greater extent than in those with pulmonary hypertension. In this respect, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase that is synthesized abundantly at lung level and that accumulates in CKD, has been implicated strongly in experimental and primary forms of pulmonary hypertension. ADMA attains very high concentrations in patients with kidney disease. Thus, ADMA is a prime uremic toxin potentially implicated in pulmonary hypertension in this population.
Sleep-disordered Breathing
Sleep apnea is a factor of paramount importance for the high risk of pulmonary hypertension in the setting of CKD. Episodes of nocturnal hypoxia, the key pathophysiologic effect of sleep apnea, are frequent in patients with CKD regardless of whether they are dialysis dependent. As we discuss next, volume overload is a major factor in sleep apnea, particularly in patients with kidney disease. Nocturnal hypoxemia arising from sleep apnea is a strong trigger of pulmonary hypertension in experimental models, and a close link between oxygen saturation and pulmonary artery pressure has been established in clinical physiology experiments in both healthy persons and patients with chronic obstructive pulmonary disease. Sympathetic activation is the main mechanism whereby hypoxemia increases pulmonary pressure. In this respect, it is interesting to note that patients with sleep-disordered breathing have increased ADMA levels. Furthermore, circulating levels of this NO synthase inhibitor are associated with sympathetic nerve activity (as assessed by measurements in the peroneal nerve) in patients with CKD and with norepinephrine levels in dialysis patients. Given the strong vasoconstriction potential of ADMA in the lung vasculature and the observation that sympathetic nervous system activity and ADMA seem to share a common pathogenic pathway that is conducive to LV hypertrophy in patients with CKD and to cardiovascular events in dialysis patients, it appears possible that the same pathogenic pathway be implicated in pulmonary hypertension in these patients.
Risk Factors Specific to CKD
PASP was related directly to pulse and systolic pressure, as well as to age, in the Olmsted study, which suggests that in the community setting, pulmonary artery stiffening may have a role in pulmonary hypertension. As part of a systemic phenomenon, arterial rigidity is increased in patients with CKD and calcium deposits can be demonstrated in the pulmonary artery in patients with kidney disease, thus implicating arterial stiffness in pulmonary hypertension in this population. Stiffness aside, experimental studies in dogs show that parathyroid hormone levels may increase pulmonary resistances. However, 2 independent studies in patients with kidney disease failed to show an association between severity of pulmonary calcifications and parathyroid hormone level. Furthermore, parathyroid hormone levels do not differ between patients with and without pulmonary hypertension. Severe anemia is an established cardiovascular risk factor in CKD and its impact on the cardiovascular system extends to pulmonary circulation because low hemoglobin levels can contribute to pulmonary hypertension by aggravating hypoxia triggered by concomitant conditions.