Beneficial Effects of Pulmonary Vasodilators on Pre-Capillary Pulmonary Hypertension in Patients with Chronic Kidney Disease on Hemodialysis

Background: In patients with chronic kidney disease (CKD) on hemodialysis, comorbid pulmonary hypertension (PH) aggravates exercise tolerance and eventually worsens the prognosis. The treatment strategy for pre-capillary PH, including combined pre- and post-capillary PH (Cpc-PH), has not been established. Objectives: This study aimed to evaluate the impact of pulmonary vasodilators on exercise tolerance and pulmonary hemodynamics in patients with CKD on hemodialysis. Methods and Results: The medical records of 393 patients with suspected PH who underwent right heart catheterization were reviewed. Of these, seven patients had isolated pre-capillary PH and end-stage CKD on hemodialysis. Pulmonary vasodilators decreased pulmonary vascular resistance from 5.9 Wood units (interquartile range (IQR), 5.5–7.6) at baseline to 3.1 Wood units (IQR, 2.6–3.3) post-treatment (p = 0.02) as well as increased pulmonary capillary wedge pressure from 10 mmHg (IQR, 7–11) to 11 mmHg (IQR, 8–16) (p = 0.04). Pulmonary vasodilators increased the World Health Organization functional class I or II from 0% to 100% (p = 0.0002) and the 6 min walk distance from 273 m (IQR, 185–365) to 490 m (IQR, 470–550) (p = 0.03). Conclusions: Pulmonary vasodilators for PH in patients with CKD on hemodialysis decrease pulmonary vascular resistance and eventually improve exercise tolerance. Pulmonary vasodilators may help hemodialysis patients with pre-capillary PH, although careful management considering the risk of pulmonary edema is required.


Introduction
Approximately 720,000 patients in the United States and 340,000 patients in Japan are currently on maintenance hemodialysis [1,2]. Annually, 125,000 patients with chronic kidney disease (CKD) initiate hemodialysis in the United States. In Japan, hemodialysis is the standard treatment for bridging to kidney transplantation, and it is frequently used as a destination therapy for patients with end-stage kidney disease. Overall, 10-50% of patients on hemodialysis are reported to have pulmonary hypertension (PH) as a complication [3][4][5][6][7]. Comorbid PH in dialysis patients causes dysdialysis syndrome, including hemodialysisrelated hypotension, resulting in inadequate fluid management and eventually leading to resistant hypertension, heart failure, arrhythmia, and sudden death.
The pathogenesis of PH associated with hemodialysis is multifactorial [8][9][10][11][12]. This type of PH may be pre-capillary (pulmonary artery hypertension), post-capillary (left heart disease), or combined pre-and post-capillary PH (Cpc-PH). Increased cardiac output caused by dialysis shunt, renal anemia, and catheter-related bacteremia induces volume Life 2022, 12, 780 2 of 9 overload and worsens PH [4,6]. Therefore, PH associated with hemodialysis is classified as PH with unclear multifactorial mechanisms. Post-capillary PH is the most common type of hemodialysis-associated PH, which is caused by inappropriate fluid management and left heart diseases, such as hypertensive heart disease, cardiac amyloidosis, and coronary artery disease [4,13,14]. Furthermore, pre-capillary PH occurs in 13% of the patients [13]. The dialysis shunt increases vessel shear stress; mineral and bone metabolism dysregulation causes abnormal vascular calcification. These mechanisms cause endothelial damage and microvascular remodeling in the pulmonary vasculature.
PH is an independent predictor of mortality in patients with CKD who are on hemodialysis [15,16]. The five-year survival of patients with CKD-associated PH is 40%. Moreover, the treatment strategies for PH remain unestablished; thus, PH in patients with CKD on hemodialysis is a serious problem. Pivotal treatments for post-capillary PH consist of fluid management and dedicated treatment for left ventricular dysfunction. However, there is no established treatment for pre-capillary PH. The effect of pulmonary vasodilators on symptoms, exercise tolerance, and pulmonary hemodynamics in end-stage CKD patients on maintenance hemodialysis with pre-capillary PH was investigated in this study.

Methods
This retrospective observational study was approved by the Ethics Review Committee of Kyushu University Hospital (approval number: 29-526). The requirement of informed consent from patients was waived because of the retrospective observational study design. We reviewed medical records from our hospital between July 2014 and November 2020 and identified 393 patients with suspected PH who underwent right heart catheterization. Of these, seven patients who were on hemodialysis and had isolated pre-capillary PH or Cpc-PH were selected. The day after hemodialysis, a right heart catheterization was performed on these patients. Pre-capillary PH or Cpc-PH was defined as PH with a pulmonary vascular resistance of ≥3.0 Wood units and a mean pulmonary arterial pressure of >20 mmHg, according to the recommendations of the 6th World Symposium on Pulmonary Hypertension [17]. Age, sex, medical history, primary cause of kidney disease, and systolic and diastolic left ventricular function on echocardiogram were among the demographic and clinical data that were collected. All seven patients with isolated PH or Cpc-PH were treated with pulmonary vasodilators, including prostacyclin (an endothelin receptor antagonist) and phosphodiesterase 5 inhibitor. The treatment strategy is explained in the next section. Following this, we compared the World Health Organization (WHO, Geneva, Switzerland) functional class, six-minute walk distance, catheter-based pulmonary hemodynamics, heart rate, and mean systemic blood pressure at baseline and after treatment with pulmonary vasodilators.

Prevailing Treatment Strategy for Hemodialysis Patients with Pre-Capillary PH
The clinical management for pre-capillary PH in patients on hemodialysis was based on the guideline-directed medical therapy for idiopathic/heritable pulmonary arterial hypertension [18]. Pulmonary vasodilator therapy was initiated using a single drug that was carefully up-titrated by paying attention to hypotension and pulmonary congestion. If risk stratification of pulmonary arterial hypertension did not satisfy the low-risk profile, then another type of pulmonary vasodilator was added [18]. After 3-6 months of treatment, the WHO functional class, six-minute walk distance, and catheter-based pulmonary hemodynamics were re-evaluated.

Statistical Analysis
Data are presented as medians and interquartile ranges (IQRs). Continuous variables were tested using a paired t-test, whereas categorical variables were tested using the chisquare test. A p-value of <0.05 was considered statistically significant. Statistical analyses were performed using Statcel software, version 3.

Discussion
To the best of our knowledge, this is the first case series demonstrating the effect of pulmonary vasodilators on changes in symptoms, exercise tolerance, and pulmonary hemodynamics in pre-capillary PH patients with end-stage CKD on maintenance hemodialysis. The results of this study showed that pulmonary vasodilators improved the symptoms, exercise tolerance, and pulmonary vascular resistance. Moreover, pulmonary vasodilators improved the six-minute walk distance and WHO functional class, although there were no changes in mean pulmonary artery pressure.

Discussion
To the best of our knowledge, this is the first case series demonstrating the effect of pulmonary vasodilators on changes in symptoms, exercise tolerance, and pulmonary hemodynamics in pre-capillary PH patients with end-stage CKD on maintenance hemodialysis. The results of this study showed that pulmonary vasodilators improved the symptoms, exercise tolerance, and pulmonary vascular resistance. Moreover, pulmonary vasodilators improved the six-minute walk distance and WHO functional class, although there were no changes in mean pulmonary artery pressure.

Effects of Pulmonary Vasodilators on Hemodynamics and Exercise Tolerance
Pulmonary vasodilators for PH in patients with CKD on hemodialysis decreased pulmonary vascular resistance and improved exercise tolerance. However, pulmonary Life 2022, 12, 780 6 of 9 vasodilators were ineffective in Case 7, whose underlying disease was type 1 glycogen storage disease. Glycogen storage disease causes CKD and pulmonary artery hypertension because of glycogen deposition in multiple organs. It also suggests that Case 7 was not primarily the case of hemodialysis-related pulmonary artery hypertension. Further, the effect of pulmonary vasodilators might depend on a primary underlying disease.
The increase in the cardiac index by pulmonary vasodilators might explain the improvement in exercise tolerance and symptoms in the patients included in our study. The decrease in the resting heart rate after treatment with pulmonary vasodilators suggested increased stroke volume and improved left ventricular filling following the right-left volume shift. In the present case series, antihypertensives were discontinued during treatment with pulmonary vasodilators in all patients, and systemic blood pressure did not change after treatment compared with baseline. The hypotensive effect is a common adverse effect of pulmonary vasodilators. As systemic hypotension causes dysdialysis, dose readjustment or discontinuation of antihypertensives should be considered after the initiation of pulmonary vasodilators. To avoid the adverse hypotensive effect of pulmonary vasodilators, it is reasonable to consider discontinuing antihypertensive drugs in routine clinical practice. Pulmonary vasodilators increased pulmonary capillary wedge pressure unexpectedly in this series, possibly due to a right-to-left volume shift. Even if the dry weight remains unchanged, appropriate blood volume control by hemodialysis and its reduction (in most cases) is needed when starting or increasing doses of pulmonary vasodilators.

Comorbid Left Ventricular Diastolic Dysfunction in Patients on Hemodialysis Is a Pitfall in Treating Existing Pre-Capillary PH
Multiple factors are involved in the development of PH in patients on hemodialysis. Therefore, PH associated with hemodialysis is classified as group 5 (unclear or multifactorial mechanisms) of the NICE classification [18]. Edmonston et al. reported that post-capillary PH and Cpc-PH are the most common subtypes in patients with end-stage CKD on hemodialysis [16]. The current study found no Cpc-PH, probably due to strict fluid control before right-heart catheterization. We focused on pre-capillary PH and evaluated the effects of pulmonary vasodilators on symptoms, exercise tolerance, and hemodynamics. This study suggests that sequential combination therapy with pulmonary vasodilators safely and effectively improves symptoms, exercise tolerance, and pulmonary vascular resistance in hemodialysis patients with pre-capillary PH. However, post-capillary PH or Cpc-PH developed in almost all patients at the post-treatment evaluation. Most patients on hemodialysis have subclinical left ventricular diastolic dysfunction, such as left ventricular hypertrophy. Underlying diastolic left ventricular dysfunction and insufficient fluid management after drug administration increased pulmonary capillary wedge pressure. Fortunately, there were no patients with overt pulmonary edema, although all patients in this study had diastolic dysfunction. However, this research suggests that pulmonary vasodilators can increase the risk of pulmonary edema. To avoid pulmonary edema, pulmonary vasodilators should be initiated in a dehydrated state following hemodialysis, with careful monitoring by chest X-ray or echocardiography. Following the use of pulmonary vasodilators, cardiac catheterization is mandatory. The increased prevalence of left ventricular diastolic dysfunction and the right-to-left volume shift in hemodialysis patients may be a barrier when using pulmonary vasodilators for pre-capillary PH.

Treatment Algorithm for Pre-Capillary PH in Patients on Hemodialysis
Based on the latest recommended treatment algorithm for pulmonary hypertension from the 6th World Symposium on Pulmonary Hypertension [21], we have modified the previously reported treatment strategy for PH in dialysis patients and propose our treatment strategy in Figure 3. Patients with anemia, infection, or other conditions that may cause a high cardiac output state are highly susceptible to pulmonary edema. Such conditions must be treated before starting pulmonary vasodilators. While selecting pulmonary vasodilators, drug metabolism should be considered. Riociguat (a soluble guanylate cy-Life 2022, 12, 780 7 of 9 clase stimulator) and tadalafil (a phosphodiesterase-5 inhibitor) are contraindicated in patients on hemodialysis. Prostacyclin (an endothelin receptor antagonist) and sildenafil are other alternatives. To minimize pulmonary edema and dialysis-related hypotension, we recommend starting with oral monotherapy rather than dual combination therapy and gradually upregulating the dose. Although an indwelling venous catheter poses a risk of catheter infection, especially in patients on hemodialysis, subcutaneous or intravenous prostacyclin may be used in patients with a high-risk profile. Sequential add-on therapy should be considered until risk stratification reaches a low-risk profile with special attention to pulmonary edema and dysdialysis.
Based on the latest recommended treatment algorithm for pulmonary hypertension from the 6th World Symposium on Pulmonary Hypertension [21], we have modified the previously reported treatment strategy for PH in dialysis patients and propose our treatment strategy in Figure 3. Patients with anemia, infection, or other conditions that may cause a high cardiac output state are highly susceptible to pulmonary edema. Such conditions must be treated before starting pulmonary vasodilators. While selecting pulmonary vasodilators, drug metabolism should be considered. Riociguat (a soluble guanylate cyclase stimulator) and tadalafil (a phosphodiesterase-5 inhibitor) are contraindicated in patients on hemodialysis. Prostacyclin (an endothelin receptor antagonist) and sildenafil are other alternatives. To minimize pulmonary edema and dialysis-related hypotension, we recommend starting with oral monotherapy rather than dual combination therapy and gradually upregulating the dose. Although an indwelling venous catheter poses a risk of catheter infection, especially in patients on hemodialysis, subcutaneous or intravenous prostacyclin may be used in patients with a high-risk profile. Sequential add-on therapy should be considered until risk stratification reaches a low-risk profile with special attention to pulmonary edema and dysdialysis.

Limitation
This was a retrospective observational study with a small sample size. Hence, largescale, prospective randomized controlled trials are needed to confirm the efficacy of our proposed treatment strategy.

Conclusions
This case series shows that pulmonary vasodilators improve symptoms, exercise tolerance, and pulmonary hemodynamics in patients on hemodialysis with pre-capillary PH or Cpc-PH. Further, careful observation for post-capillary PH is required during up-titration of pulmonary vasodilators.

Limitation
This was a retrospective observational study with a small sample size. Hence, largescale, prospective randomized controlled trials are needed to confirm the efficacy of our proposed treatment strategy.

Conclusions
This case series shows that pulmonary vasodilators improve symptoms, exercise tolerance, and pulmonary hemodynamics in patients on hemodialysis with pre-capillary PH or Cpc-PH. Further, careful observation for post-capillary PH is required during uptitration of pulmonary vasodilators.