Diagnosis and Management of Pulmonary Hypertension in Patients With CKD

Abstract

Pulmonary hypertension (PH) is a highly prevalent and important condition in adults with CKD. In this review, we summarize the definition of PH, discuss its pathophysiology and classifications, and describe diagnostic and management strategies in CKD patients, including those with kidney failure treated by kidney replacement therapy. In the general population, PH is classified into five groups based on clinical presentation, pathology, hemodynamics, and management strategies. In this classification system, PH in CKD is placed in a diverse group with unclear or multifactorial mechanisms, although underlying cardiovascular disease may account for the majority of cases. CKD may itself directly incite pulmonary circulatory dysfunction and remodeling through uremic toxins, inflammation, endothelial dysfunction, and altered vasoregulation. Despite several studies describing the higher prevalence of PH in CKD and kidney failure, along with an association with poor outcomes, high-quality evidence is not available for its diagnostic and management strategies in those with CKD. In CKD not requiring kidney replacement therapy, volume management along with treatment of underlying risk factor of PH is critical. In those on hemodialysis, options are limited and transition to peritoneal dialysis may be considered if recurrent hypotension precludes optimal volume control.

Clinical vignette

A 60-year-old man with hypertension, type 2 diabetes, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD) with glomerular filtration rate category 4 and albuminuria category 2 (G4 A2) presents with shortness of breath and leg swelling for 2 months. His symptoms have worsened despite being on furosemide 80 mg twice daily and adhering to a low sodium diet (<2 g/d). His oxygen saturation is 96% on room air and 92% on exercise. He has a loud P2, bibasilar inspiratory crackles, and symmetric pitting edema (3mm) to the knees. Hemoglobin concentration is 11 g/dl, serum albumin is 3.8 g/dl, and eGFR is 25 ml/min/1.73 m². A chest x-ray shows increased lung volumes, and transthoracic echocardiography (TTE) shows mild concentric left ventricular hypertrophy, left ventricular ejection fraction (LVEF) of 55%, normal right ventricular size and systolic function, and estimated pulmonary artery systolic pressure (ePASP) of 55–60 mm Hg (increased from 35 mm Hg two years ago). His furosemide dose is increased to 120mg twice daily, and metolazone 5mg once daily is added. Since his symptoms persisted, a right heart catheterization is performed for accurate measurement of pulmonary pressures. Mean pulmonary artery pressure (mPAP) is 40 mmHg, and pulmonary capillary wedge pressure is 20 mmHg, with normal cardiac output, suggesting primarily Group 2 pulmonary hypertension (i.e., due to left heart disease). Hence, his diuretic regimen is further intensified, and sodium intake monitored.

Introduction

Cardiovascular disease continues to be the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), whether kidney replacement therapy (KRT) requiring or not. While heart failure, coronary heart disease, and cardiac arrhythmias are common in CKD, there is growing recognition that pulmonary hypertension (PH) may also be another highly prevalent and important condition in patients with CKD. However, the complex pathophysiologic interplay of the kidney and the cardiovascular system, variable and dynamic volume status, and highly comorbid patient population make understanding, diagnosing, and managing PH in CKD challenging. Numerous studies have described the prevalence of PH (variably defined) in CKD in general and in kidney failure in particular, and the association of PH with poor outcomes in these patients. However, high-quality evidence is not available for its diagnostic and management strategies. Addressing the underlying etiology and optimizing volume status are central for PH management in populations with CKD. This review summarizes the definition of PH, discusses its pathophysiology and classifications, and describes diagnostic and management strategies in patients with CKD with or without requirement for KRT.

Definition and Classification of PH

Pulmonary hypertension (elevated pressure within the pulmonary circulation) has been defined as a mean pulmonary arterial pressure (PAPm) ≥ 25 mmHg at rest assessed by right heart catheterization, although a recent international task force has proposed changing the threshold to 20 mmHg.^1–3 Among healthy adults, the PAPm is 14 +/− 3 (standard deviation) mmHg, with 20 mmHg considered the upper limit of normal.^2,4 Pulmonary arterial hypertension (PAH) or group 1 PH refers to a subgroup of PH defined by hypertension limited to the pre-capillary pulmonary vasculature, in the absence of certain other diseases (discussed further later in this article).^1,2 This is identified by the absence of elevated post-capillary pressures (pulmonary artery wedge pressure [PAWP] ≤15mmHg) and elevated resistance across the pulmonary circulation (pulmonary vascular resistance [PVR] > 3 Woods units).¹ Unfortunately, most studies in adults with CKD lack the confirmation of PH by right heart catheterization,⁵ and thus the true prevalence and the impact of the proposed definitional changes for patients with CKD is unclear.

PH is classified into five groups based on clinical presentation, pathology, hemodynamics, and management strategies (Box 1 and Table 1).^2,6

Box 1.

Classification Groups and Causes of Pulmonary Hypertension

Group 1. Pulmonary arterial hypertension (PAH)

Idiopathic

Heritable

BMPR2 mutation

Other mutations

Drug and toxin induced

Associated with:

Connective tissue disease

HIV infection

Portal hypertension

Congenital heart diseases

Schistosomiasis

1’ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

Group 2. Pulmonary hypertension due to left heart disease

Left ventricular systolic dysfunction

Left ventricular diastolic dysfunction

Valvular disease

Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

Group 3. Pulmonary hypertension due to lung diseases and/or hypoxia

Chronic obstructive pulmonary disease

Interstitial lung disease

Other pulmonary diseases with mixed restrictive and obstructive pattern

Sleep-disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Developmental lung diseases

Group 4. Chronic thromboembolic pulmonary hypertension (CTEPH)

Group 5. Pulmonary hypertension with unclear multifactorial mechanisms

Hematologic disorders

Systemic disorders

Metabolic disorders

Others, including chronic renal failure

BMPR2: bone morphogenic protein receptor type 2; CAV1: caveolin 1; ENG: endoglin; HIV: human immunodeficiency virus.

Adapted from Simonneau et al⁶ with permission of Elsevier; original content © 2013 by the American College of Cardiology Foundation.

Table 1.

Hemodynamic definitions of pulmonary hypertension (PH)^*

Definition	Right heart catheterization measurements	Clinical groups
5th World Symposium on PH (2013)1,2,6
PH	mPAP ≥ 25 mmHg	1–5
Pre-capillary PH	mPAP ≥ 25 mmHg PAWP ≤ 15mmHg	1, 3, 4, and 5
Post-capillary PH	mPAP ≥ 25 mmHg PAWP > 15mmHg	2 and 5
Isolated post-capillary PH	Post-capillary PH criteria, in addition to DPG < 7 mmHg and/or PVR ≤ 3 WU	2 and 5
Combined pre- and post-capillary PH	Post-capillary PH criteria, in addition to DPG ≥ 7 mmHg and/or PVR > 3 WU	2 and 5
6th World Symposium on PH (2018) (proposed)3
Pre-capillary PH	mPAP > 20 mmHg PAWP ≤ 15mmHg PVR ≥ 3WU	1, 3, 4, and 5
Isolated post-capillary PH	mPAP > 20 mmHg PAWP > 15mmHg PVR < 3WU	2 and 5
Combined pre- and post-capillary PH	mPAP > 20 mmHg PAWP > 15mmHg PVR ≥ 3WU	2 and 5

^*Measurements are by right heart catheterization, at rest.

PH: pulmonary HTN; mPAP: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; DPG: diastolic pressure gradient (diastolic pulmonary artery pressure minus mean pulmonary artery wedge pressure); PVR: pulmonary vascular resistance; WU: Wood Units. PH due to unclear or multifactorial etiology (Group 5) can present with or without pre-capillary PH. PH due to left heart disease (Group 2) does not present with isolated pre-capillary PH and is characterized by post-capillary PH. PH due to lung disease, hypoxia (Group 3) or chronic thromboembolism (Group 4) does not present with post-capillary PH and is characterized by pre-capillary PH.

Pulmonary arterial hypertension (Group 1)

PAH (Group 1 PH) is a rare disease, with an estimated incidence of 2–7 cases per million adults/year,⁷ and an estimated prevalence of 15–60 per million adults.⁸ All causes of PAH are characterized by pathologic pulmonary vasoconstriction and vascular remodeling.⁹ This proliferative vascular remodeling, usually with hypertrophy and hyperplasia affecting all vessel layers, causes severe reduction in vessel cross-sectional area and increases flow resistance.^9,10 Vasoactive molecules play an important role in development and progression of PAH, with alterations in several substances, with both vasoactive (vasodilatory or vasoconstrictive) and cellular proliferative effects, including endothelin, prostacyclin, nitric oxide, prostaglandin I₂, and cyclic guanosine monophosphate.^11–13

Treatment generally targets treatment of the PH itself, but in some instances, such as HIV, treatment of the underlying cause is possible and complementary. Treatments target the prostacyclin, nitric oxide, and endothelin pathways, and improve functional status, hemodynamics, and survival.¹⁴ Lung transplantation is a last resort. Among patients with Group 1 PH, lower levels of kidney function have been associated with increased mortality, and Group 1 PH may decrease kidney function through renal venous congestion, low cardiac output, and neurohormonal activation.¹⁵ Treatment of PAH with sildenafil can increase eGFR, but the mechanism and clinical relevance of this remains unclear.¹⁶

Pulmonary hypertension due to left heart disease (Group 2)

Given the high prevalence of left heart disease this is thought to be the most common cause of PH, and it is especially relevant to CKD.¹⁷ Increasing recognition that PH develops early in the course of even aggressively treated heart failure (HF) has led to growing interest in this disease process.¹⁸ Elevated pulmonary venous pressures in left heart disease can lead to pulmonary arterial and arteriolar remodeling.¹⁹ Group 2 PH can occur in both HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).¹⁸ Pressure injury to the capillary walls, with disruption of the alveolar-capillary interface and increasing endothelial permeability, is a distinctive characteristic of Group 2 PH.^18,20 Treatment is currently through management of the underlying heart disease.

Pulmonary hypertension due to lung diseases and/or hypoxia (Group 3)

PH can complicate many chronic lung diseases, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), cystic fibrosis, and sleep-disordered breathing.^21–23 The majority of patients with severe COPD have elevated pulmonary artery pressures, and severe elevations are not uncommon.²⁴ Hypoxic pulmonary vasoconstriction, an adaptive strategy limiting blood flow to hypoxic alveoli for ventilation-perfusion matching, persists permanently in chronic lung disease, resulting in chronic vasoconstriction and vascular remodeling.²⁵ Eventually, this causes precapillary obliteration and a substantial decrease in total capillary cross section. Treatment is targeted at the underlying lung disease and reversing hypoxemia. COPD itself is associated with increased risk of CKD, likely related to underlying factors such as diabetes, increased oxidative stress, and systemic inflammation. Indeed the coexistence of COPD and CKD is associated with substantially increased mortality.^26,27

Chronic thromboembolic pulmonary hypertension (Group 4)

Chronic thromboembolic pulmonary hypertension (CTEPH), in which occlusion of the pulmonary arterial vasculature results in pulmonary arterial remodeling, has an incidence of 5 per million person-years.² It is a known complication of acute pulmonary embolism (PE), but estimates of the risk of development vary widely, ranging from 0.1–9.1% incidence within 2 years after an episode of symptomatic PE.² Persistence of thrombi following an acute thromboembolic event, with organization and infiltration with fibroblasts and connective tissue, and small vessel alterations, characterize the disease.^28–30 Pulmonary thromboendarterectomy is a potentially curative therapy for chronic thromboembolic pulmonary hypertension, and lifelong anticoagulation is necessary.² Pharmacologic agents are also available for the treatment of CTEPH. The causal and prognostic relationships between chronic thromboembolic pulmonary hypertension and CKD remain to be investigated.

Pulmonary hypertension with unclear multifactorial mechanisms, including PH attributed to kidney disease (Group 5)

This categorizes a wide variety of disease processes that do not fit into the other groups and that share complex or unclear causation.² This heterogeneity prevents accurate estimates of incidence and prevalence.³¹ Contributing mechanisms include pulmonary vasoconstriction, proliferative disease of the vasculature, extrinsic vascular compression, and high output heart failure.² Coexistent systemic diseases include hematologic disorders (chronic myeloproliferative diseases, post-splenectomy state, sickle cell disease), sarcoidosis, thyroid disease, and kidney failure. It is unclear how to assign causality to kidney failure alone, and disentangle the effects of reduced kidney function, systemic hypertension, and subtle cardiac dysfunction.³¹ Management is aimed at the underlying disease processes.

Epidemiology and Pathophysiology of Pulmonary Hypertension in CKD

Epidemiology and Outcomes

Several studies in CKD, summarized in Table 2, suggest that PH by echocardiographic criteria is common in this population.^5,32 Among 2959 non-KRT-requiring CKD patients in the Chronic Renal Insufficiency Cohort (CRIC), 21% showed evidence of PH (ePASP>35mmHg or tricuspid regurgitant velocity > 2.5m/s [a more inclusive definition than the more commonly used 2.8m/s threshold], estimated from Doppler echocardiogram).³³ Prevalence of PH increased with CKD severity, from 21% in CKD G3a to 32.8% in CKD G5. Older age, anemia, reduced left ventricular ejection fraction (LVEF), and LV hypertrophy were associated with greater risk of PH on adjusted analysis; eGFR was not independently associated with PH risk.³³ Presence of PH was associated with a 38% increased risk of mortality and 23% increased risk of cardiovascular events, but was not associated with increased risk of progression of kidney disease.³³ Several other studies have provided widely varying estimates of the prevalence of PH in severe CKD, ranging from 9–39% in CKD G5, 19–69% in hemodialysis patients, and 0–42% in peritoneal dialysis patients.³² This wide variation likely reflects differences in measurement techniques and cohort phenotypes. A recent meta-analysis of 2 studies in non-KRT-requiring CKD (including the CRIC study above), 10 studies in patients treated by maintenance dialysis (CKD G5D), and the 2 studies in kidney transplant recipients demonstrated that that the presence of PH doubled mortality risk (relative risk [RR], 2.04; 95% CI, 1.71–2.44). Meta-analysis of subsets of these studies reporting particular outcomes demonstrated that cardiovascular mortality and cardiovascular events approximately doubled with the presence of PH (RRs of 2.20 [95%CI, 1.53–3.51] for mortality and 1.97 [95%CI, 1.45–2.68] for CV events).⁵ Among cohorts with pulmonary arterial hypertension (PAH, or Group 1 PH) the prevalence of CKD is estimated at 4–36%.¹⁵

Table 2.

Selected observational studies of echocardiographically identified pulmonary hypertension in CKD

Study	Inclusion criteria	PH definition	N	Prevalence	Outcomes (PH versus no PH), adjusted risk estimate*
CKD G1–G5
Navaneethan, 201633	eGFR 20–70 ml/min/1.73m2	PASP>35mmHg or TRV>2.5m/s	2959	21%	Death: 1.38 (1.10–1.72) CV events: 1.23 (1.00–1.52) Renal events: 1.13 (0.93–1.36)
Bolignano, 201574	eGFR 15–60 ml/min/1.73m2	PASP≥35mmHg	468	23%	CV events: 1.75 (1.05–2.91)
Selvaraj, 201775	eGFR < 60 ml/min/1.73 m2 or spot UACR > 30mg/g (3% dialysis)	PASP≥35mmHg	408	22%	HF hospitalization: 2.37 (1.15–4.86) HF hospitalization or mortality: 1.84 (1.09–3.10)
Reque, 201776	eGFR <60 ml/min/1.73m2	PASP≥35mmHg	353	27%	Death: 1.84 (1.06–3.18) CV events: 2.77 (2.00–3.25)
CKD G5D
Xu, 201577	Incident PD	PASP≥35mmHg	618	16%	Death: 2.10 (1.35–3.27) CV death: 2.60 (1.48–4.56)
Li, 201478	HD	PASP≥35mmHg after HD	278	35%	Death: 1.85 (1.03–3.34) CV death: 2.36 (1.05–5.31) CV events: 2.27 (1.44–3.58)
Agarwal, 201279	HD	PASP>35mmHg after HD	288	38%	Death: 2.17 (1.31–3.61)

UACR: urine albumin-creatinine ratio; CV: Cardiovascular; PD, peritoneal dialysis; HD, hemodialysis; HF, heart failure; G, glomerular filtration rate category; D, dialysis

^*values shown are hazard ratios with 95% confidence intervals

Fewer studies have confirmed PH using right heart catheterization in CKD. A single-center retrospective study of 1873 patients with CKD who underwent right heart catheterization showed that post-capillary disease (consistent with Group 2 or Group 5) was the predominant phenotype, accounting for 76% of cases.³⁴ The fact that the majority in this clinically selected group were diagnosed with post-capillary disease confirms the predominance of Group 2 (or Group 5) disease in CKD. A recent single-center study of 3,504 patients with CKD found that combined pre-and post-capillary PH was the most common phenotype, and the phenotype with the highest mortality.³⁵ A single-center study was performed of 62 patients with severe CKD (G4, G5, or G5D) and dyspnea, but without uncontrolled hypertension, HFrEF, valvular dysfunction, or lung disease. They underwent right heart catheterization (post-dialysis in those on dialysis), which showed postcapillary PH in 65% of patients receiving hemodialysis and 71% of patients with non-KRT-requiring CKD.³⁶ Pre-capillary PH was identified in 13% of hemodialysis patients and 6% of patients not requiring KRT.

Pathophysiology

Non-KRT-requiring CKD

Little is known about the pathophysiologic differences of PH in patients with CKD and others within the same PH groups. Any of the numerous recognized contributors to cardiovascular disease in CKD would be expected to increase pulmonary pressures, by modulating pulmonary vascular resistance, left ventricular systolic and diastolic function, and volume overload. CKD-associated changes in the systemic vasculature, with vascular stiffening caused by the fibrous and fibro-elastic thickening and calcification in the arteries secondary to CKD, have been described and are likely contributing factors.^37–39 Systemic autoimmune diseases, such as systemic lupus erythematosus and systemic sclerosis, are causes of both kidney disease and pulmonary circulatory disease. Other diseases that can affect diffuse microvascular beds, such as thrombotic microangiopathies and sickle cell disease, can harm the microvasculature of both the kidneys and the lungs causing comorbid CKD and PH. Liver disease causing portal hypertension can lead to both PH and kidney disease. Intravascular volume overload alone can increase pulmonary artery pressures, likely one mechanism of PH in CKD, and in those on dialysis, pulmonary artery pressure declines significantly after a hemodialysis session.⁴⁰

CKD may itself directly incite pulmonary circulatory dysfunction and remodeling through uremic toxins, inflammation, endothelial dysfunction, and altered vasoregulation.⁴¹ CKD is a pro-inflammatory state, with elevated systemic inflammatory biomarkers and oxidative stress.⁴² Local arterial inflammation has been demonstrated in CKD in the systemic arteries, driven by transendothelial migration of circulating macrophages, and this could potentially affect the pulmonary circulation as well.⁴³ Numerous other potential mechanisms through which CKD could incite PH, include, in addition to what was discussed previously, anemia, altered mineral metabolism, hypoalbuminemia, and elevated endogenous cardiotonic steroids.^32,44,45 Determining the importance and intervention potential for these various mechanisms would require extensive additional investigation. PH can affect the kidneys as well. Among patients with Group 1 PH (PAH), lower kidney function is an independent predictor of mortality, and PAH is thought to decrease kidney function through renal venous congestion, low cardiac output, and neurohormonal activation.¹⁵

KRT-requiring CKD

Arteriovenous fistulas (AVFs) for dialysis access have long been suggested as possible contributors to PH, because they can increase cardiac output and reduce compliance of pulmonary vasculature, leading to increased pulmonary artery pressure.⁴¹ Nevertheless, the role of AVFs in promoting PH is uncertain, with conflicting results from small studies. Several small series demonstrated no correlation between fistula blood flow and pulmonary artery pressure, and no increase in PAP after AVF placement and maturation.^46–48 However, a study of eight selected patients with PH showed that systolic pulmonary artery pressure transiently declined with temporary AV access occlusion.⁴⁹ The reports of high-output cardiac failure reversal with AV access modification or ligation provide further evidence that AV access could be important in some cases.⁵⁰ Bio-incompatible dialysis membrane exposure, resulting in neutrophil activation and migration to the lung, is another potential contributor to PH in hemodialysis.³² All mechanisms discussed in non-KRT-requiring CKD (discussed in the previous section) would be operant in dialysis as well.

Clinical Manifestations of Pulmonary Hypertension

PH manifests with non-specific cardiopulmonary symptoms, including shortness of breath, fatigue, chest pain, and lightheadedness.^2,51 Initially symptoms are present only with exertion, with rest symptoms manifesting in advanced disease.² Progressive RV dysfunction can cause edema and abdominal distension. These symptoms can cause functional impairment and reduce patients’ physical, psychological, and social wellness. Clinical suspicion for the diagnosis must be entertained, especially when other, more common causes are not present on initial clinical workup for dyspnea, syncope, or chest pain.¹

Diagnostic and management considerations of PH in CKD

Diagnostic and monitoring studies

Electrocardiogram (ECG) findings reflecting RV abnormalities may be present in PH, but are not sensitive enough to rule out the diagnosis.² Chest radiograph may show characteristic findings of PAH, such as enlargement of the central pulmonary arteries with attenuation of the peripheral vessels, and can inform the differential diagnosis for other causes. Pulmonary function tests can also assist with the differential diagnosis and assessment.² Transthoracic echocardiography with doppler can identify structural heart changes causing or caused by PH, and can estimate pulmonary artery pressures. A presumptive diagnosis of PH can be made using echocardiography if multiple echocardiographic measurements are consistent with the diagnosis; however, right heart catheterization is considered essential for diagnosis confirmation before targeted treatment.^1,2 On transthoracic echocardiography, the right ventricular systolic pressure can be estimated using the peak tricuspid regurgitation velocity and adding the estimated right atrial pressure. In the absence of pulmonary valve stenosis, the right ventricular systolic pressure will be similar to the PA pressure. Imaging of the right ventricle, right atrium, inferior vena cava, and pulmonary artery, and Doppler interrogation of the pulmonary valve regurgitation and hepatic vein can provide corroborating information.²

Diagnostic approaches

There is little evidence to guide the surveillance and management of PH specifically in CKD, and to support different practices in patients with and without CKD, but there are many important diagnostic clinical considerations in the CKD population. We provide a suggested algorithm for diagnosis and management in three common clinical scenarios in Figure 1. We suggest it is appropriate to consider a diagnosis of PH in all patients with CKD with compatible signs and symptoms, even though these are non-specific and highly prevalent in the CKD population. Patients with CKD of any stage, but especially those on maintenance dialysis, are plagued by dyspnea, exercise intolerance, and other classic heart failure symptoms.^52,53 These are usually attributed to left heart diastolic and systolic dysfunction, in addition to volume overload, and are managed with measures intended to improve cardiac function, and diuretics or increased ultrafiltration to reduce intravascular volume. Given the high prevalence of PH on non-invasive testing discussed above, poor outcomes associated with PH, and use of transthoracic echocardiography for workup of dyspnea and other compatible symptoms, it is appropriate that nephrologists attend to tricuspid regurgitant jet velocities and derived pulmonary artery pressures, in addition to right ventricular function. Echocardiography is likely to be most useful when performed in an optimized volume state (soon after midweek dialysis in those on hemodialysis, or after optimization of diet and dietary recommendation in non-KRT-requiring CKD) because of the sensitivity of pulmonary pressures to volume overload. The probability of PH can then be determined, based on tricuspid regurgitant jet velocity and other echocardiographic evidence of PH (Figure 1).^2,54,55

Figure 1. Suggested algorithm for PH identification and management in persons with non-dialysis or dialysis-dependent CKD.

References:

¹Galiè et al.²

²Vachiery et al.⁵⁶

Abbreviations: PH pulmonary hypertension; SLE, systemic lupus erythematosus; SS systemic sclerosis; HD hemodialysis; TRV tricuspid regurgitant velocity; RHC right heart catheterization; HTN hypertension; AF atrial fibrillation; LA left atrium; HRCT high resolution CT; PFTs pulmonary function tests; PAH pulmonary arterial hypertension; CTEPH chronic thromboembolic PH; AV access arteriovenous HD access

If there is a low probability of PH based on these assessments, then further evaluation of PH is unlikely to be beneficial. Moderate or high probabilities of PH may increase the probability that further workup will result in altered management, and referral to a PH specialist should be considered at this time if the clinician feels it is appropriate. The nephrologist can assess for whether left heart disease is likely a sufficient explanation for the elevated pulmonary pressures in the patient, especially if there is severe LV systolic dysfunction or severe valvular dysfunction, in which case cardiac optimization with the assistance of a cardiologist is most important. Many patients with CKD and elevated pulmonary pressures will not have these obvious findings but may still have left heart disease substantial enough to be the sole cause. Factors including age>70, obesity, hypertension, atrial fibrillation, and left atrial dilatation increase the probability of left heart disease as sole PH cause.⁵⁶ If initial cardiac workup is unrevealing, evaluation for chronic lung disease and hypoxia should be undertaken, with high-resolution CT of the chest, pulmonary function testing, and a 6-minute walk test. If no cause is identified after pulmonary evaluation, then PH specialist consultation is essential (if not already made), as diagnoses such as PAH or chronic thromboembolic pulmonary hypertension for which effective therapies exist become more likely, and right heart catheterization and other tests may be needed.

Specific therapies for PH in CKD

Pulmonary arterial hypertension-Group 1 PH

Treatment for PAH, targeting the prostacyclin, nitric oxide, and endothelin pathways (with prostacyclin analogues, prostacyclin receptor agonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase inhibitors), has improved in recent years.⁵⁶ In optimizing these therapies, close communication between the nephrologist and PH specialist will be essential to assure consensus about management and close, efficient follow-up. There are limited data to guide specific modifications for PAH therapy in CKD in general or in maintenance dialysis in particular owing to little study of these agents in these contexts (Table 3).⁵⁷ Some adverse effects of PAH therapy (edema, pain, gastrointestinal [GI] effects) overlap with common CKD complications, raising the possibility of negative synergism. The endothelin receptor antagonists (bosentan, ambrisentan, and macitentan) inhibit binding of endothelin 1 (ET-1) to endothelin receptors, inhibiting pulmonary vasoconstriction and vascular smooth muscle proliferation.⁵⁸ ET-1 is present in high concentrations in the lung in PAH patients.^58,59 Randomized trials have demonstrated improvements in hemodynamic measures, exercise capacity, and dyspnea.⁶⁰ Liver toxicity is a risk with these agents, as are peripheral edema and anemia, a problem for some CKD patients.^59,61 Dosage adjustment is not needed with CKD.

Table 3.

Pharmacologic therapy considerations for pulmonary arterial hypertension (Group 1 pulmonary hypertension) in CKD

Therapeutic class	Mechanism of action	Medication s	Clinical benefits	Adverse effects	CKD considerations
Endothelin receptor antagonists	Blocks ET-1 binding to its receptors, inhibiting pulmonary vasoconstriction and vascular SMC proliferation	Bosentan, ambrisentan, macitentan	Improved dyspnea and exercise capacity	Liver toxicity, peripheral edema, anemia	-Could worsen pre-existing peripheral edema -No dosage adjustment needed
Prostacyclin pathway agonists	Activates prostacyclin signaling, causing vascular smooth muscle relaxation, reduction of SMC proliferation, and inhibition of platelet aggregation	epoprosteno I, treprostinil, iloprost, selexipag	Improved survival (with continuous IV infusion), exercise capacity, dyspnea, quality of life	Flushing, tachycardia, diarrhea, nausea, headaches, pain; sepsis, hemorrhage, pulmonary embolism with IV infusions	-Catheter-related issues with IV preparations may add risk in dialysis; -chronic pain and nausea are common in CKD -No dosage adjustment needed, except for iloprost, which has decreased clearance in kidney failure, 50% decrease in initial dose has been recommended
Nitric oxide pathway enhancers	Increases vascular SMC cGMP concentrations, causing vasodilation and antiproliferation	PDE5 inhibitors: sildenafil, tadalafil, vardenafil; guanylate cyclase stimulant: riociguat	PDE5 inhibitors: improved survival and exercise capacity; guanylate cyclase stimulant: improved functional class, possibly exercise capacity	Headache, Gl upset, myalgias, flushing, dizziness, hemoptysis with guanylate cyclase stimulant; hypotension if combined with nitrates	-Sildenafil: no adjustment in CKD or dialysis -Tadalafil: avoid use if CLcr < 30 ml/min or HD; start at 50% usual dose for CLcrl 30–80 ml/min -vardenafil: avoid use in dialysis -riociguat: not recommended if CLcr < 15 ml/min

IV : intravenous; cGMP: cyclic guanosine monophosphate; I: gastrointestinal; CLC_cr: creatinine clearance; ET-1, endothelin 1; IV, intravenous; SMC, smooth muscle cell

Prostacyclin pathway agonists (epoprostenol, treprostinil, iloprost, selexipag), delivered by intravenous, inhaled, or oral routes, cause vascular smooth muscle relaxation, antiproliferation, and inhibition of platelet aggregation through activation of the prostacyclin pathway signaling.^61,62 Meta-analysis of randomized trials shows that prostacyclin agonists improve survival (continuous intravenous infusions), exercise capacity, dyspnea, and quality of life.⁶³ Nitric oxide pathway enhancers (the phosphodiesterase type 5 [PDE5] inhibitors sildenafil, tadalafil, and vardenafil, and the guanylate cyclase stimulant riociguat) cause vascular smooth muscle relaxation and antiproliferation through increasing cyclic guanosine monophosphate (cGMP) concentrations.⁶¹ Randomized trials have demonstrated improved functional class, increased exercise capacity, and improved survival with PDE5 inhibitors in PAH. Meta-analysis of trials of riociguat showed improved functional class, and possibly improved exercise capacity, in PAH.⁶⁴ Adverse effects of PDE5 inhibitors are headache, gastrointestinal upset, and myalgias.⁶⁵ Observational studies suggest the calcium channel blockers nifedipine, amlodipine, diltiazem, may be effective in some patients with PAH, but trial data confirming this are lacking in both CKD and non-CKD population.^64,66

Volume Management in Group 2 and 5 PH

Achieving and maintaining euvolemia is one of the great challenges nephrologists face in managing patients with CKD, and pulmonary arterial pressures can be quite sensitive to intravascular volume, especially in Group 2 PH, with pulmonary venous hypertension driving elevated arterial pressures.⁶⁷ Clinical assessment of fluid status is challenging, and classic findings such as edema have limited sensitivity.⁶⁸ Volume overload is very common in non-KRT-requiring CKD, even in the absence of physical findings,⁶⁸ and thus probing lower goal weights in the setting of suspected Group 2 or Group 5 PH may be useful, with close monitoring for adverse effects, and perhaps repeat echocardiography to assess for improvements. Use of combination diuretic regimens and titration of regimens with patient involvement and daily self-weighing similar to chronic heart failure measurement may be beneficial.⁶⁹

Volume management in maintenance dialysis patients, including setting and maintaining dry weights, can be even more challenging, and is dependent in large part on physician judgment and shared decision making, in the absence of high-quality evidence. For management of PH in hemodialysis where occult volume overload is suspected, probing the dry weight with progressive decreases and close monitoring, in a similar manner to as has been studied for the management of hypertension, is reasonable.^70,71 Intradialytic hypotension or symptoms limiting volume removal with hemodialysis are common problems, and potentially mitigating techniques such as extended duration or more frequent treatments are often not available. For dialysis planning in patients with pre-existing PH, peritoneal dialysis may be preferred, to prevent the need for an AV access and potentially increased pulmonary artery pressures. For those with an existing AV access, evaluation for elevated flow rate and a corrective procedure (possibly ligation) could be considered. Provision of hemodialysis through a catheter and non-creation or ligation of an AV access would be a last resort.

Other considerations

Other routine aspects of kidney disease care, including management of systemic hypertension, anemia, and CKD-metabolic bone disease, may take on even more importance for prevention and management of PH, but there is no evidence to guide specific management alterations in PH.

When considering KRT-requiring CKD patients in this article, we have focused on the dialysis population. Recent comprehensive reviews have addressed the evaluation and management of PH in kidney transplant candidates and recipients.⁷² While some series reported improvement in pulmonary pressure with kidney transplantation, the presence of PH is associated with worse outcomes among kidney transplant recipients.⁷³ A 2012 AHA/ACC recommendation provides guidance for evaluating PH among those being considered for kidney transplantation (Box 2). The safety and efficacy of PAH therapies in kidney transplant recipients have not been studied, and studies addressing management strategies in those with PH are lacking.

Box 2.

AHA/ACC Consensus Recommendations for PH in Kidney Transplant Candidates^*

1. It is reasonable to evaluate kidney transplantation candidates with echocardiographic evidence of significant pulmonary hypertension for underlying causes (e.g., obstructive sleep apnea, left heart disease).

2. It may be reasonable to confirm echocardiographic evidence of elevated pulmonary arterial pressures in kidney transplantation candidates by right heart catheterization. Echocardiographic evidence of significant pulmonary hypertension in this population is defined by right ventricular systolic pressure more than 45 mm Hg or ancillary evidence of right ventricular pressure overload.

3. If right heart catheterization confirms the presence of significant pulmonary arterial hypertension (as defined by mean pulmonary artery pressure >25 mm Hg, pulmonary capillary wedge <15 mm Hg, and pulmonary vascular resistance of >3 Wood units) in the absence of an identified secondary cause (e.g., obstructive sleep apnea, left heart disease), referral to a consultant with expertise in pulmonary arterial hypertension management and advanced vasodilator therapies is reasonable.

^*Recommendations were class II (conflicting evidence and/or divergence of opinion), evidence level C (case series, or extrapolations from other types of observational studies) and are from Lentine et al⁸⁰.

Review of Clinical Vignette and Conclusions

Over the ensuing years, the patient’s COPD and CKD progressed, and he is started on home oxygen and in-center hemodialysis but has frequent intradialytic hypotensive episodes limiting ultrafiltration. Intradialytic hypotension persists, despite minimization of interdialytic sodium and fluid intake, reassessment of the target weight, moving antihypertensive medication dosing to after dialysis, maximizing hemodialysis session time, and dialysate cooling, ultimately to 35°C. Repeat TTE now shows right ventricular dilatation and reduced right ventricular systolic function. The patient is switched to peritoneal dialysis in an attempt to better maintain his intravascular volume with prolonged ultrafiltration, and experiences some improvement in his volume status. This scenario exemplifies some of the challenges, uncertainties, and management options in caring for multimorbid patients with CKD and pulmonary hypertension.

The complex interplay of the kidneys and other organs is a nephrologist’s perennial challenge. There is limited evidence to guide diagnosis and management of PH specifically in CKD patients, and thus clinician judgment and shared decision-making are of the utmost importance, to avoid overdiagnosis while catching cases of uncommon, but treatable, diagnoses such as PAH or CTEPH. A better understanding of the role of CKD in the pathogenesis and outcomes of PH is needed (Box 3), and measurement of kidney health and function in multiple dimensions may help in further understanding the complex bidirectional relationship between CKD and PH.

Box 3.

Research recommendations

Conduct comprehensive studies including RHC to characterize the prevalence of different types of PH in those with mild to moderate CKD Assess the impact of various diuretic regimens in those Class 2 PH and CKD Study the role of dialysis prescription including ultrafiltration and fluid management in the development and worsening of PH in hemodialysis patients Study the comparative benefits of hemodialysis and peritoneal dialysis in those with PH and kidney failure Evaluate the efficacy and safety of various agents (approved for general population) used to treat PAH in those with CKD who otherwise qualify for therapy