INTRODUCTION — Patients with end-stage kidney disease (ESKD), particularly those on hemodialysis, are at risk for development of or worsening of preexisting pulmonary hypertension (PH). Although multifactorial, the increased risk is due, in part, to the presence of an arteriovenous (AV) access.

PH among ESKD patents is presented in this topic review. The evaluation and management of AV fistula-associated heart failure and other complications of hemodialysis AV access are presented separately:

●(See "Evaluation and management of heart failure caused by hemodialysis arteriovenous access".)

●(See "Dialysis access steal syndrome".)

●(See "Arteriovenous fistula creation for hemodialysis and its complications", section on 'Complications of AV fistula placement'.)

●(See "Arteriovenous graft creation for hemodialysis and its complications", section on 'Complications of AV graft placement'.)

DEFINITION AND CLASSIFICATION — PH is now defined as a mean pulmonary artery pressure >20 mmHg at rest, and precapillary PH is defined as a mean pulmonary artery pressure >20 mmHg associated with a mean pulmonary capillary wedge pressure ≤15 mmHg and a pulmonary vascular resistance ≥3 Wood units [1]. PH is classified into the five groups given in the table (table 1) [1]. Patients with ESKD are considered to have group 5 PH, which refers to PH of unclear or multifactorial mechanism (table 1) [1]. However, some ESKD patients may also have PH from heart failure (group 2) or chronic lung disease (group 3).

EPIDEMIOLOGY AND RISK FACTORS — The reported prevalence of PH among ESKD patients has ranged from less than 10 percent to over 50 percent [2-15]. The wide range primarily relates to the technique used to diagnose PH (echo/Doppler versus catheterization), the variability in diagnostic criteria, and the presence or absence of symptoms [14]. In the only study in which the PH diagnosis was based on right-sided cardiac catheterization (the gold standard), all patients were selected for study based upon presence of unexplained dyspnea [15]. In this study, PH was present in 81 percent of hemodialysis patients and in 77 percent of nondialysis chronic kidney disease (CKD) patients. The mean pulmonary arterial pressure was higher in the patients on dialysis compared with the patients who were not on dialysis (42 versus 35 mmHg).

The risk appears to be higher among hemodialysis compared with peritoneal dialysis patients. In the four studies that directly compared hemodialysis patients with peritoneal dialysis patients, PH was higher in hemodialysis patients (19 to 59 percent versus <19 percent) [5,11-13].

Dialysis-specific risk factors — The major dialysis-specific risk factor among hemodialysis patients is the arteriovenous (AV) access (AV fistula or AV graft), particularly if the flow in the access increases over time. Studies have shown that the severity of PH directly correlates with duration of the AV access and the flow through it [3,5,16-23].

Other dialysis-specific factors include hypervolemia, left ventricular dysfunction, and hypoalbuminemia [10,14].

PATHOGENESIS IN END-STAGE KIDNEY DISEASE — The mechanisms that underlie the development of PH in patients with chronic kidney disease (CKD) with or without an arteriovenous (AV) access are unknown and poorly studied.

Several mechanisms have been proposed, the most logical of which is that PH in this population may relate to increased flow through the pulmonary vascular bed from chronic volume overload (from CKD itself) and increased venous return (from AV access). Evidence to support this theory is derived from the known hemodynamic effects of increased flow through the pulmonary bed and the known hemodynamic effects of AV fistula/grafts (eg, decreased systemic vascular resistance, enhanced venous return, and increased cardiac output). However, the development of PH in this setting most likely presumes a stiff left ventricle and the development of postcapillary PH (ie, pulmonary venous hypertension) (table 2). This is because, in patients with a normal or near-normal left heart filling pressure and normal kidney function, increased cardiac output and pulmonary blood flow due to an acquired AV shunt or traumatic peripheral fistula are generally not sufficient on their own to cause PH, since the pulmonary vasculature typically accommodates the increased flow with little or no increase in the pulmonary artery pressure. By contrast, in the setting of a stiff left ventricle, increased venous return from increased flow through the AV access markedly increases left ventricular diastolic, left atrial, pulmonary venous, and pulmonary capillary pressures, thereby predisposing patients to the development of PH. (See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults", section on 'Pathogenesis'.)

However, this is not the only mechanism likely to be at play. Other factors that have been cited, but do not have a well-understood role, include:

●Decreases in the vasodilator nitric oxide (NO), which are common in patients with CKD [24-27]

●Increased asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase [28]

●Pulmonary vascular calcification [29,30]

●Neutrophil activation related to exposure to bioincompatible dialysis membranes [31]

●Nocturnal hypoxemia (eg, from obstructive sleep apnea) [32,33]

By contrast, recurrent embolization from repeated AV access thrombectomies does not appear to be a risk factor for PH [34-36].

Similar to other forms of PH, PH in patients with CKD is progressive, and, while PH may initially be reversible, at some point, PH may become irreversible. This is supported by the observation that, in some patients who undergo kidney transplantation, PH resolves, as well as the observation that pulmonary pressures can normalize when flow through the AV fistula/graft is reduced. (See 'Access management' below and 'Diagnostic evaluation' below and 'Prognosis' below.)

Whether mechanisms similar to those involved in the pathogenesis of other forms of PH are also involved in PH associated with CKD is unknown.

●(See "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)", section on 'Pathogenetic mechanisms'.)

●(See "Pulmonary hypertension due to left heart disease (group 2 pulmonary hypertension) in adults".)

●(See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults", section on 'Pathogenesis'.)

●(See "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'Pathogenesis'.)

●(See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Pathogenesis and risk factors'.)

CLINICAL FEATURES — The symptoms and signs of PH are the same as in those without chronic kidney disease (CKD). The most common symptoms of PH are dyspnea with exertion and the signs and symptoms of right heart failure. Less commonly, patients present with exertional chest pain, exertional syncope, and gastrointestinal complaints due to liver congestion. The symptoms and signs of PH are discussed in detail separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Clinical manifestations'.)

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS IN DIALYSIS PATIENTS — The diagnosis of PH is difficult among patients with ESKD because the symptoms of volume overload (eg, dyspnea, edema, elevated jugular venous pressure) overlap with those of PH. Patients with ESKD and suspected PH should be co-evaluated and co-managed by experts in nephrology and experts in PH.

Suspecting PH in patients with ESKD — In patients with ESKD, PH should be suspected in the following groups:

●Patients who develop worsening symptoms after arteriovenous (AV) access placement

●Patients whose symptoms of dyspnea are not relieved by reducing dry weight and achieving euvolemia (see 'Dialysis management' below)

●Patients with dyspnea and hypervolemia who do not tolerate ultrafiltration

Differential diagnosis — The differential diagnosis of patients with suspected PH includes several pulmonary etiologies associated with dyspnea and several etiologies associated with right-sided heart failure (eg, left-sided heart failure, coronary artery disease, liver disease, and Budd-Chiari syndrome), the details of which are discussed separately. (See "Approach to the patient with dyspnea" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial differential diagnosis'.)

The differential diagnosis of dyspnea and intradialytic hemodynamic instability includes heart failure, or ischemic heart disease, which can be distinguished on transthoracic echocardiography (TTE) or stress testing. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Second-line approach'.)

Diagnostic evaluation — Evaluation and diagnosis of PH in patients with ESKD are similar to patients without ESKD. It typically begins with a TTE to exclude causes other than PH and to identify patients who need right heart catheterization (RHC). The details of this evaluation are discussed separately. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Initial diagnostic evaluation (noninvasive testing)'.)

Indications for diagnostic RHC in patients with ESKD are similar to patients without kidney function impairment. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization'.)

Among patients with AV access, the contribution of the AV access to PH can be initially assessed by manually compressing the AV access under heparinization and a tourniquet set to at least 30 mmHg above systolic blood pressure, for one minute, while measuring pulmonary hemodynamics on RHC. If a significant component of the patient's PH is related to the AV access, the mean pulmonary artery pressure, right atrial pressure, and possibly the pulmonary capillary wedge pressure and left ventricular end-diastolic pressure will significantly decrease by at least 20 percent or even normalize [5] when the AV access is compressed. However, the definition of what constitutes a significant decrease is not established and is highly subjective [5,23]. There may be some concern that such compression will lead to thrombosis of the access, particularly if the access is an AV graft; however, in practice, it is much harder to thrombose an AV access with manual compression than one would expect. In an effort to establish the diagnosis of PH, we do not hesitate to perform this maneuver. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Right heart catheterization'.)

KIDNEY DISEASE MANAGEMENT — Patients with PH should be co-managed with a clinician with expertise in PH.

Choice of dialysis modality in patients with preexisting PH — For patients with preexisting, symptomatic PH who are being considered for maintenance dialysis, we suggest evaluation for peritoneal dialysis preferentially over hemodialysis. This choice is based upon the rationale that even mildly symptomatic PH may worsen subsequent to arteriovenous (AV) access creation and that peritoneal dialysis obviates the need for AV access. In addition, peritoneal dialysis provides daily ultrafiltration that may prevent worsening of symptoms with interdialytic volume overload. However, among some patients with primary lung disease, peritoneal dialysis may decrease vital capacity, particularly at night if performing continuous cycler peritoneal dialysis. In addition, there are often multiple other reasons that a patient may not be able or willing to perform peritoneal dialysis. Patients should be individually evaluated. (See "Evaluating patients for chronic peritoneal dialysis and selection of modality", section on 'Available modalities'.)

For those who are not candidates for peritoneal dialysis because of comorbidities or other reasons, we suggest a tunneled catheter, rather than an AV access, for the reasons described above (see 'Pathogenesis in end-stage kidney disease' above). In addition, daily dialysis (home or in center) may provide a benefit because it minimizes volume accumulation. (See 'Pathogenesis in end-stage kidney disease' above and "Dialysis modality and patient outcome", section on 'Selection of dialysis modality'.)

If the patient is not a candidate for peritoneal dialysis and a tunneled catheter is not plausible, an AV access based off a small artery (eg, radiocephalic fistula) is a reasonable alternative but will require vigilant monitoring.

Monitoring for PH — Patients with known PH should be monitored for development of or worsening of symptoms of PH after initiating dialysis and particularly after creation of an AV access. As an example, those with known PH and dyspnea that does not improve or progresses despite dialysis or aggressive ultrafiltration may need further evaluation with another echocardiogram and/or a right heart catheterization (RHC) to evaluate for progressive disease.

In addition, for those who have an AV access, compression of the AV graft or fistula during RHC can determine the contribution of the access to the patients PH. (See 'Diagnosis and differential diagnosis in dialysis patients' above.)

An ultrasound/Doppler should also be obtained to determine whether the flow through the AV fistula/graft is too high. Patients with access flow of >1000 mL/min should be evaluated for plication to limit flow. (See 'Access management' below.)

Among patients with preexisting PH who do not worsen after dialysis or AV access placement, we typically obtain periodic echocardiograms, the frequency of which is based upon clinical judgment, to reassess heart size, function, and pulmonary hemodynamics, although the value of this approach is unproven.

Treatment of symptomatic patients

Dialysis management — All dialysis patients with significant PH should be managed with aggressive removal of volume. The estimated dry weight should be maintained as low as possible without causing intra- or interdialytic hypotension. This may require changes in the dialysis prescription to provide longer or more frequent dialysis sessions in order to safely achieve a lower dry weight. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Prevention of recurrent episodes'.)

Access management — If symptoms such as severe dyspnea or edema persist despite aggressive ultrafiltration, we evaluate the AV access blood flow. If the blood flow is higher than that minimally required for hemodialysis access (ie, approximately 500 mL/min [37]), flow reduction (eg, banding) should be undertaken. Pulmonary pressures may decrease following ligation of the AV fistula [22,38].

If symptoms do not improve after flow reduction, we ligate the fistula and transition patients to peritoneal dialysis, if appropriate, or place a tunneled catheter for those who are not candidates for peritoneal dialysis.

Pulmonary hypertension management — Patients with persistent, severe PH despite dialysis and AV fistula management should be referred to centers with expertise in the management of PH for possible evaluation in trials of PH specific therapy [14]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

PROGNOSIS — PH increases the risk of cardiovascular events and overall mortality. In various studies of hemodialysis patients, mortality was two- to threefold higher among those with PH [5,39-41].

In one study of 211 hemodialysis patients, among whom 44 percent had PH, PH was independently associated with an increased risk for cardiovascular events [42].

Pulmonary artery pressures may normalize following kidney transplantation, even among patients who still have a functioning arteriovenous (AV) fistula [4,5,23]. However, patients with PH require careful evaluation and optimal management prior to transplantation. Patients with severe PH may not be candidates for transplantation. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Pulmonary disease'.)

Although rare, PH may predispose a patient to the development of a paradoxical embolus if a patent foramen ovale or atrial septal defect is present [43]. There are several cases in the literature in which a devastating paradoxical embolus occurred after a thrombectomy of a dialysis access [44-48]. The most frequent sites of paradoxical embolism are the extremities (50 percent) and the brain (40 percent), while the heart, spleen, and kidney are more rarely affected [49].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Patients with end-stage kidney disease (ESKD), particularly those on hemodialysis, are at increased risk for development of or worsening of pulmonary hypertension (PH). The increased risk is related in part to the arteriovenous (AV) access, although other factors related to ESKD also contribute. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●PH is often related to noncompliance of the left ventricle with elevated pulmonary venous pressure, chronic volume overload and increased cardiac output, and an increase in pulmonary vascular resistance. The increased pulmonary resistance may be related to endothelial dysfunction or defects in neutrophil activation. (See 'Pathogenesis in end-stage kidney disease' above.)

●For patients with preexisting, symptomatic PH who are being considered for maintenance dialysis, we avoid AV access for hemodialysis, which may worsen PH. We prefer peritoneal dialysis when possible. Peritoneal dialysis obviates the need for AV access and provides daily ultrafiltration that may prevent worsening of symptoms with interdialytic volume overload.

A tunneled catheter for hemodialysis is an alternative to peritoneal dialysis. Tunneled catheters are less likely to worsen PH but carry a long-term higher risk for infection compared with AV fistulas.

Daily dialysis (home or in center) may provide a benefit because it minimizes volume accumulation. (See 'Choice of dialysis modality in patients with preexisting PH' above.)

●Patients on chronic hemodialysis should be closely monitored for symptoms of PH. (See 'Monitoring for PH' above.)

●Our approach to patients who develop or have worsening of symptoms of PH on dialysis is as follows (see 'Treatment of symptomatic patients' above):

•All patients should undergo aggressive ultrafiltration. We target the lowest dry weight that does not cause intra- or interdialytic hypotension or other symptoms. This may require changes in the dialysis prescription to provide longer or more frequent dialysis sessions in order to safely achieve a lower dry weight.

•If symptoms persist despite aggressive ultrafiltration, we confirm the diagnosis of PH and, if present, the contribution of the AV fistula to PH. In patients with confirmed PH secondary to AV fistula, we ligate the AV fistula. We switch patients who are candidates to peritoneal dialysis. We place a tunneled catheter in patients who are not peritoneal dialysis candidates.

•Patients with persistent, severe PH despite ligation of the AV fistula should be referred to centers with expertise in the management of PH for possible evaluation in trials of PH-specific therapy. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●PH increases the risk of cardiovascular events and overall mortality. (See 'Prognosis' above.)