A recent AJKD In Practice article by Walther et al outlines the approach to diagnosing and managing pulmonary hypertension (PH) in CKD. A summary is presented here by NSMC Intern, Sai Sudha @drM_sudha.

It is well-known that chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD) and mortality. However, modifying established CVD risk factors such as lipids and blood pressure of CVD have not yielded the expected benefit for patients with dialysis dependent kidney disease when compared to the general population. There is growing recognition that novel risk factors such as pulmonary hypertension may be playing a complicated role in this process.

What is Pulmonary Hypertension?

Elevated pressures within the pulmonary arterial circulation is called pulmonary hypertension (PH). Normal pulmonary artery pressures are 14 +/-3 mm of Hg with the upper limit being 20 mm of Hg. PH is a syndrome characterized by the presence of mean pulmonary artery pressure ≥25 mm Hg at rest as measured at right-sided cardiac catheterization.

Types of Pulmonary Hypertension

5 “types” of PH has been recognized, and the following nomenclature is described in the paper. We are not the biggest fans of this classification, but basically type 1 is primary, type 2 is related to the heart, type 3 is related to the lung, and type 4 is related to the vasculature. Type 5 (in which CKD falls) is a grab-bag of “I’m not sure what’s happening here”.

Box 1 from Walther et al, AJKD © National Kidney Foundation

Epidemiology of PH in CKD

The exact prevalence of Type 5 PH, particularly PH due to CKD, is underestimated and is difficult to estimate precisely because epidemiologic data for this disorder is scarce and based mainly on retrospective data and/or small studies with many limitations. From what we do know, prevalence increases with the severity of CKD. Prevalence of PH was 5.9, 10.9%, 21%, 21.9%, 26.5%, and 32.8% in those with stages 1, 2, 3a, 3b, 4, and 5, respectively. Unsurprisingly, the increase continues as PH is higher in dialysis than even those with non-dialysis dependent stage 5 CKD.

What is the mechanism of PH in CKD and its importance?

A decrease in kidney function is increasingly being recognized as an important trigger for the development of PH.  Let’s explore this further.

Potential Risk Factors for PH in CKD

1. Left ventricular disorders, volume overload, and lung disease: Presence of diabetes and hypertension leads to left ventricular hypertrophy and Presence of diabetes and hypertension leads to left ventricular hypertrophy and diastolic dysfunction and subsequent chronic volume overload with increased pulmonary venous and arterial pressures. The chronic volume overload leads to a high venous return which then increases pulmonary venous flow and venous pressure anddecreased LV function. Presence of COPD or other lung diseases can also compound the volume overload in CKD via low oxygen tension which leads to chronic pulmonary arterial vasoconstriction, vascular remodeling, and decreased arterial compliance.
2. A-V fistulas: A-V fistulas decrease systemic resistance and lead to increased venous return then then increases pulmonary venous flow and venous pressure and can lead to decreased LV function and pulmonary hypertension as described above. In hemodialysis (HD) patients, AVF flow and AVF duration are related independently to the severity of pulmonary hypertension. This also explains why PH is more prevalent in HD than in peritoneal dialysis (PD) patients.
3. Exposure to dialysis membrane: Blood-dialysis membrane contact (particularly cellulose membrane) can activate neutrophils and lead to neutrophil sequestration in the lung.
4. Systemic diseases associated with CKD: Pre-existing connective tissue diseases and superimposed infectious, hematologic, and liver diseases can lead to vascular remodeling of pulmonary arteries and PH.
5. Endothelial dysfunction: The uremic toxins with advanced kidney disease can lead to increased asymmetric dimethylarginine (ADMA) ⇒ decreased Nitric Oxide (NO) ⇒ PH
6. Sleep-disordered breathing: Sleep apnea is common in patients with kidney disease and nocturnal hypoxia can lead to pulmonary arterial remodeling and vasoconstriction and PH.
   
7. Other aspects specific to CKD:CKD ⇒ Increased arterial rigidity ⇒ pulmonary artery stiffening ⇒ PHCKD-MBD (Mineral Bone Disorder) ⇒ arterial calcifications ⇒ PHAnemia ⇒ Hypoxia ⇒ PH
   

   Main mechanisms proposed to explain the pathogenesis of pulmonary hypertension (PH) in patients with chronic kidney disease. Figure 2 from Bolignaro et al, AJKD © National Kidney Foundation

Clinical Manifestations of PH

Patients usually present with non-specific symptoms like shortness of breath, chest pain, lightheadedness, and fatigue. Symptoms start on exertion initially and can be seen at rest as disease worsens. A high index of suspicion is needed once the common causes of chest pain, dyspnea, and fatigue are ruled out.

Diagnosis

Electrocardiogram (EKG) can show RV abnormalities but is not sensitive. Characteristic findings on chest radiography include enlargement of the central pulmonary arteries with attenuation of the peripheral vessels. Pulmonary function tests can assist in diagnosing underlying lung issues.

Transthoracic echocardiography with doppler can identify structural heart changes, and can estimate pulmonary artery pressures. However, right heart catheterization is the gold standard and considered essential for diagnosis confirmation.

Due to sensitivity of pulmonary pressures to volume overload, timing at which echocardiography or right heart catheterization is performed is important. Both are 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-dialysis dependent CKD).

Suggested algorithm for PH identification and management in persons with nondialysis or dialysis-dependent CKD. Abbreviations: AF, atrial fibrillation; AV access, arteriovenous hemodialysis access; CTEPH, chronic thromboembolic pulmonary hypertension; echo, echocardiographic; HD, hemodialysis; HTN, hypertension; HRCT, high-resolution computed tomography; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PFTs, pulmonary function tests; RHC, right heart catheterization; RV, right ventricle; SLE, systemic lupus erythematosus; SS, systemic sclerosis; TRV, tricuspid regurgitant velocity. Figure 1 from Walther et al, AJKD © National Kidney Foundation

Management

Management depends on etiology and is quite complicated. Those with WHO Type 1 PH (primary pulmonary hypertension) benefit from targeting the prostacyclin, nitric oxide, and endothelin pathways (with prostacyclin analogues, prostacyclin receptor agonists, phosphodiesterase type 5 inhibitors, and guanylate cyclase inhibitors). Patients on dialysis with WHO Type 5 PH benefit from achieving and maintaining euvolemia. However, this is easier said than done, as these patients also are pre-load dependent and volume sensitive. Intradialytic hypotension is common, and extended duration and more frequent treatments may be considered in these patients.

Table 3 from Walther et al, AJKD © National Kidney Foundation

No specific intervention trial aimed at reducing pulmonary hypertension in patients with CKD has been performed to date. The treatment of underlying LV dysfunction and correcting volume overload are the fundamental basis for management for relieving pulmonary hypertension in patients with CKD.  This involves optimizing body fluid volume by diuresis and salt restriction. Nephrologists should be aware if their patients are at risk for sleep apnea, are experiencing high flows through their fistulas, and trying to control their CKD-MBD and anemia to optimally manage PH.

– Post prepared by Sai Sudha Mannemuddhu @drM_sudha, AJKDBlog Guest Contributor

To view Walther et al (subscription required), please visit AJKD.org.

Title: Diagnosis and Management of Pulmonary Hypertension in Patients With CKD
Author: Carl P. Walther, Vijay Nambi, Nicola A. Hanania, and Sankar D. Navaneethan
DOI: 10.1053/j.ajkd.2019.12.005