Abstract
Rationale & Objective.
Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD.
Study Design.
Observational retrospective cohort study.
Setting & Participants.
We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000 to December 31, 2014.
Exposures.
Baseline kidney function stratified by CKD glomerular filtration rate (GFR) category and PH subtype.
Outcomes.
All-cause mortality.
Analytical Approach.
Multivariable Cox proportional hazards analysis.
Results.
In this cohort, 73.4% of patients with CKD had PH, compared to 56.9% of patients without CKD. Isolated post-capillary PH (39.0%) and combined pre- and post-capillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, pre-capillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both CKD and non-CKD cohorts. Compared to those with non-PH, pre-capillary PH conferred the highest mortality risk among patients without CKD (hazard ratio [HR], 2.27; 95% confidence interval [CI], 2.00 – 2.57). By contrast, in those with CKD, combined pre- and post-capillary PH was associated with the highest risk of mortality in CKD in adjusted analyses (compared to no PH, HRs of 1.89 [95% CI, 1.57 – 2.28], 1.87 [95% CI, 1.52 – 2.31], 2.13 [95% CI, 1.52 – 2.97], 1.63 [95% CI, 1.12 – 2.36] for GFR categories G3a, G3b, G4, and G5/G5D).
Limitations.
The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality.
Conclusions.
In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and post-capillary PH was common and portended the worst survival for patients with CKD.
INDEX WORDS: Pulmonary hypertension (PH), PH subtype, chronic kidney disease (CKD), combined pre- and post-capillary PH, diagnostic catheterization, pulmonary capillary wedge pressure, hemodialysis, end-stage renal disease (ESRD), heart failure, mortality, pulmonary disease, cardiovascular complication
INTRODUCTION
Pulmonary hypertension (PH) affects 21–41% of patients with chronic kidney disease (CKD) and up to 60% of patients with kidney failure receiving hemodialysis.1–6 Despite the high prevalence and increased mortality conferred by PH,7 no targeted treatments exist for PH in patients with CKD. While most studies of PH in this population rely on transthoracic echocardiography to diagnose and quantify severity of PH, invasive characterization of PH subtypes with the gold standard, right heart catheterization, can provide more detailed insight into potential underlying mechanisms of PH.
PH is defined by mean pulmonary artery pressure ≥25 mmHg on right heart catheterization at rest.8 PH is hemodynamically characterized by estimates of left ventricular filling pressures, using pulmonary capillary wedge pressure, and pulmonary arterial pressures, using pulmonary diastolic pressure gradient or pulmonary vascular resistance. Using these measures, PH can be further stratified into the following subtypes: Pre-capillary PH, Isolated post-capillary PH and Combined pre-capillary and post-capillary PH (Figure 1). Pre-capillary PH or pulmonary arterial hypertension, which can be idiopathic or secondary to collagen vascular disease, infection (e.g. human immunodeficiency virus) or portal hypertension, is characterized by a normal pulmonary capillary wedge pressure (≤15 mmHg).8, 9 Isolated post-capillary PH, typically caused by heart failure and valvular disease,10 is defined by an elevated pulmonary capillary wedge pressure (>15 mmHg) with normal pulmonary vascular resistance (diastolic pressure gradient <7 mmHg and pulmonary vascular resistance ≤3 Wood Units).8 Combined pre-capillary and post-capillary PH occurs when the pulmonary capillary wedge pressure and pulmonary vascular resistance (diastolic pressure gradient ≥7 mmHg or pulmonary vascular resistance >3 Wood Units) are elevated.8
Figure 1. Schematic of pulmonary hypertension subtypes.
Pre-PH, pre-capillary pulmonary hypertension; Cpc-PH, combined pre- and post-capillary pulmonary hypertension; Ipc-PH, isolated post-capillary pulmonary hypertension; VC, vena cavae; RA, right atrium; RV, right ventricle; PA, pulmonary artery; PC, pulmonary capillaries; PV, pulmonary veins; LA, left atrium; LV, left ventricle; Ao, aorta.
Our understanding of how CKD affects PH subtypes is limited due to the methods by which PH was characterized in prior studies, which either did not report PH subtypes or relied only on pulmonary capillary wedge pressure without incorporating estimates of pulmonary vascular resistance.2, 11, 12 Among CKD patients with PH, the combined pre- and post-capillary PH subtype (elevated pulmonary capillary wedge pressure with increased pulmonary vascular resistance) may be a substantial contributor to the overall PH burden in CKD, due to a combination of (1) chronic volume overload, (2) pulmonary vascular remodeling due to increases in vasoactive factors (i.e. nitric oxide, prostacyclin, endothelin, among others), (3) inflammation and (4) comorbid lung disease (e.g. obstructive sleep apnea and chronic obstructive pulmonary disease) that are commonly associated with CKD.13 Understanding the prevalence and pathophysiology of combined pre- and post-capillary PH in CKD may illuminate a subpopulation at significant risk of mortality, similar to heart failure patients with combined pre- and post-capillary PH,14,15 and identify novel therapies.16
We investigated the prevalence of different PH subtypes and their association with all-cause mortality stratified by CKD severity using 15 years of right heart catheterization data from the Duke Databank for Cardiovascular Disease (DDCD). We hypothesized that combined pre- and post-capillary PH would be the most common PH subtype and portend the highest risk of mortality in patients with CKD.
METHODS
Study population
The DDCD, which includes diagnostic catheterizations for greater than 100,000 patients, has been described in detailed previously.17 Briefly, baseline demographic information, medical history, active medications, and laboratory data are obtained at the time of the diagnostic catheterization. Patients with a left-heart catheterization are followed longitudinally with questionnaires dispensed at 6 months, 12 months, and then annually. Telephone interviews are attempted for those failing to respond to surveys.
We examined the DDCD for all right heart catheterizations performed at Duke University Hospital from January 1, 2000 to December 31, 2014 (Figure 2). We excluded patients less than 18 years of age at the time of catheterization. Since the DDCD data was collected within the context of clinical care, patients may have been referred for left heart catheterization or other procedures at the time of right heart catheterization. We excluded patients with a diagnosis of acute coronary syndrome within seven days of the right heart catheterization per International Classification of Diseases, Ninth Revision (ICD-9) codes. We excluded kidney transplant recipients from this analysis because we could not account for their differential accumulation of cardiovascular risk due to variable durations of kidney failure prior to transplantation, which we could not ascertain. Interstitial lung disease has a stronger association with pulmonary hypertension than CKD. Thus, we specifically excluded patients with this diagnosis. We also excluded patients with a lung or heart transplant to similarly avoid catheterizations obtained at the extremes of cardiopulmonary pathophysiology. Patients without a serum creatinine (Scr) measurement in the six months prior to right heart catheterization or with insufficient hemodynamic data to define PH subtype were also excluded. To limit the influence of right heart catheterizations obtained to monitor responses to PH treatment (e.g. vasodilator therapy), we only included the first right heart catheterization for each patient after application of other exclusion criteria. The Duke Institutional Review Board approved this study. Due to the retrospective nature of this study, individual-level informed consent was waived.
Figure 2. Flow diagram of exclusions and study participants.
RHC, right heart catheterization; N, number; ACS, acute coronary syndrome; ILD, interstitial lung disease.
Chronic Kidney Disease Definition
We utilized the median of Scr data in the six months preceding the right heart catheterization to calculate estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We did not have sufficient proteinuria data to include it as a metric for CKD classification. Using the KDIGO GFR (G) categories, we separated patients into baseline categories: CKD G3a (eGFR 45–49 ml/min/1.73 m2), G3b (30–44 ml/min/1.73 m2), G4 (15–29 ml/min/1.73 m2), and G5/G5D (<15 ml/min/1.73 m2 or on hemodialysis).18 Due to small sample sizes relative to other CKD GFR categories, and their similar prevalence of PH and similar rates of specific PH subtypes, we combined patients with CKD G5 with those patients on dialysis (CKD G5D) for the purposes of this analysis. We classified patients with an eGFR of 60 ml/min/1.73 m2 or greater as not having CKD for the purposes of this study.
Pulmonary Hypertension Subtypes
Consistent with the European Society of Cardiology/European Respiratory Society 2015 guidelines, we defined PH as a mean pulmonary artery pressure of ≥25 mmHg at rest.19 We then separated PH into subtypes based on pulmonary capillary wedge pressure, diastolic pulmonary gradient, and pulmonary vascular resistance. Pre-capillary PH was defined as PH with a normal pulmonary capillary wedge pressure (≤15 mmHg). Isolated post-capillary PH was defined as PH with an elevated pulmonary capillary wedge pressure (>15 mmHg) and normal pulmonary vascular resistance (pulmonary vascular resistance ≤3 Wood Units and diastolic pressure gradient <7 mmHg). Combined post- and precapillary PH was defined as PH with an elevated pulmonary capillary wedge pressure (>15 mmHg) and abnormal pulmonary vascular resistance (pulmonary vascular resistance >3 Wood Units or diastolic pressure gradient ≥7 mm Hg).
Covariates
We obtained covariates from the standard data that is entered in the DDCD at the time of right heart catheterization and supplemented it with additional data from querying Duke’s electronic health record using Duke Enterprise Data Unified Content Explorer (DEDUCE).20 Covariates include age, sex, race, body mass index (BMI), medical history (diabetes mellitus, heart failure, hypertension, cirrhosis, systemic lupus erythematosus, scleroderma, obstructive sleep apnea, chronic obstructive pulmonary disease, moderate/severe aortic valve disease, moderate/severe mitral value disease, human immunodeficiency virus infection, smoking), left ventricular ejection fraction (LVEF), and hemoglobin. If LVEF, valvular data, or hemoglobin was not present at the time of the catheterization, this data was obtained from a transthoracic echocardiogram that was closest to the time of the right heart catheterization within 6 months.
Outcome
The primary outcome of this analysis was all-cause mortality. We ascertained death events using the DDCD longitudinal follow-up protocol and supplemented these data with a query of the National Death Index.
Statistical Analysis
We utilized descriptive statistics to report baseline demographic and clinical characteristics of the study population according to presence or absence of CKD and stratified by PH subtype. We report counts with percentages for categorical covariates and medians with interquartile range for continuous covariates. We generated Kaplan-Meier survival curves for each of the four PH subtype strata (no PH, pre-capillary PH, isolated post-capillary PH, and combined pre- and post-capillary PH) separately for patients with and without CKD. We tested for statistical differences between survival curves of the different PH subtypes using the log-rank test.
To investigate multivariable-adjusted associations of each PH subtype with all-cause mortality, we first evaluated the interaction term between PH subtype and CKD GFR category. Using the non-PH group as the referent, we used Cox proportional hazards modeling to generate hazard ratios (HR) with 95% confidence intervals (95% CI) for all-cause mortality for the different PH subtypes stratified by CKD GFR category. We then performed analyses adjusted for the covariates listed above.
Using Cox proportional hazards regression, we also evaluated the association of right heart catheterization parameters (mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, and mean right atrial pressure) with mortality stratified by the presence or absence of CKD. Based on the nonlinear relationship between these hemodynamic parameters with mortality, we evaluated associations with mean pulmonary artery pressure and right atrial pressure using two linear splines with a single knot at a mean pulmonary artery pressure of 55 mmHg and right atrial pressure of 5 mmHg. To address the violation of the linearity assumption for the mean pulmonary capillary wedge pressure, we analyzed the relationship between pulmonary capillary wedge pressure and mortality using categories (10–30 mmHg and >30 mmHg versus <10 mmHg). We present the multivariable-adjusted associations between the hemodynamic parameters and risk of mortality graphically.
RESULTS
Study Population
We evaluated 12,618 patients with a qualifying right heart catheterization. Baseline characteristics for patients with and without CKD stratified by PH subtype are listed in Tables 1 and 2. The average age for patients with CKD was 69 years compared to 57 years in patients without CKD. While patients without PH tended to be older in the CKD cohort, age did not differ among PH subtypes. Within the CKD G5/G5D group, 70.5% were on dialysis. Regardless of CKD status, PH disproportionately affected African American patients, and African Americans represented the highest proportion of patients with the combined pre- and post-capillary PH subtype (31.7% of patients with combined pre- and post-capillary PH and CKD, 33.9% of patients with combined pre- and post-capillary PH but not CKD). Compared to other PH subtypes, pre-capillary PH predominantly affected women in both the CKD and non-CKD cohorts (59.7% of pre-capillary PH in CKD, 60.7% of pre-capillary PH in patients without CKD). COPD and scleroderma were overrepresented in the pre-capillary PH subtype whereas heart failure and diabetes mellitus dominated the PH subtypes with an elevated pulmonary capillary wedge pressure (isolated post-capillary PH and combined pre- and post-capillary PH). Within the CKD cohort, GFR tended to be worse in the isolated post-capillary PH and combined pre- and post-capillary PH subtypes. Valvular heart disease tended to be more prevalent and LVEF lower in the isolated post-capillary PH and combined pre- and post-capillary PH subtypes. The mean pulmonary artery pressure and mean RA pressures were also higher for the isolated post-capillary PH and combined pre- and post-capillary PH subtypes.
Table 1.
Baseline patient characteristics stratified by pulmonary hypertension subtype for patients with chronic kidney disease
| No PH (n=1268) | PH | Total (N=4772) | |||
|---|---|---|---|---|---|
| Variable | Precapillary (n=794) | Isolated postcapillary (n=1367) | Combined* (n=1343) | ||
| Demographics | |||||
| Age | 71.0 (62.0, 78.0) | 68.0 (60.0, 76.0) | 68.0 (59.0, 75.0) | 68.0 (59.0, 76.0) | 69.0 (60.0, 76.0) |
| Race | |||||
| Caucasian | 983 (79.1%) | 528 (68.0%) | 1000 (74.3%) | 869 (65.6%) | 3380 (72.1%) |
| African American | 220 (17.7%) | 217 (27.9%) | 319 (23.7%) | 420 (31.7%) | 1176 (25.1%) |
| Native American | 19 (1.5%) | 8 (1.0%) | 11 (0.8%) | 11 (0.8%) | 49 (1.0%) |
| Other | 20 (1.6%) | 24 (3.1%) | 15 (1.1%) | 24 (1.8%) | 83 (1.8%) |
| Male sex | 705 (55.6%) | 320 (40.3%) | 813 (59.5%) | 630 (46.9%) | 2468 (51.7%) |
| Vitals and Medical History | |||||
| BMI | 27.0 (23.8, 31.4) | 27.9 (24.1, 33.1) | 29.5 (25.3, 35.3) | 28.2 (24.3, 33.7) | 28.1 (24.4, 33.2) |
| Smoking | 436 (34.4%) | 259 (32.6%) | 451 (33.0%) | 418 (31.1%) | 1564 (32.8%) |
| COPD | 60 (4.7%) | 64 (8.1%) | 87 (6.4%) | 72 (5.4%) | 283 (5.9%) |
| PVD | 97 (7.6%) | 55 (6.9%) | 114 (8.3%) | 119 (8.9%) | 385 (8.1%) |
| CVD | 154 (12.1%) | 72 (9.1%) | 162 (11.9%) | 191 (14.2%) | 579 (12.1%) |
| Cirrhosis | 26 (2.1%) | 17 (2.1%) | 35 (2.6%) | 18 (1.3%) | 96 (2.0%) |
| HF | 824 (65.0%) | 529 (66.6%) | 1173 (85.8%) | 1167 (86.9%) | 3693 (77.4%) |
| DM | 328 (25.9%) | 222 (28.0%) | 537 (39.3%) | 555 (41.3%) | 1642 (34.4%) |
| HIV | 7 (0.6%) | 4 (0.5%) | 10 (0.7%) | 10 (0.7%) | 31 (0.6%) |
| HTN | 871 (68.7%) | 493 (62.1%) | 948 (69.3%) | 943 (70.2%) | 3255 (68.2%) |
| HLD | 645 (50.9%) | 320 (40.3%) | 677 (49.5%) | 636 (47.4%) | 2278 (47.7%) |
| SLE | 16 (1.3%) | 20 (2.5%) | 12 (0.9%) | 11 (0.8%) | 59 (1.2%) |
| Scleroderma | 13 (1.0%) | 30 (3.8%) | 3 (0.2%) | 5 (0.4%) | 51 (1.1%) |
| Laboratory Data | |||||
| Scr | 1.4 (1.2, 1.7) | 1.4 (1.2, 1.8) | 1.6 (1.3, 2.2) | 1.6 (1.3, 2.0) | 1.5 (1.3, 1.9) |
| eGFR | 46.9 (36.2, 54.0) | 45.8 (34.2, 53.8) | 41.8 (29.1, 51.7) | 41.7 (30.1, 50.8) | 43.6 (32.1, 52.6) |
| Hemoglobin | 12.2 (10.9, 13.7) | 12.1 (10.8, 13.7) | 11.2 (9.7, 12.8) | 11.5 (10.1, 13.1) | 11.7 (10.3, 13.3) |
| CAD | 482 (38.0%) | 189 (23.8%) | 420 (30.7%) | 371 (27.6%) | 1462 (30.6%) |
| Imaging and Hemodynamic Data | |||||
| Valvular heart disease | 191 (15.1%) | 91 (11.5%) | 228 (16.7%) | 237 (17.6%) | 747 (15.7%) |
| AV diseasec | 113 (8.9%) | 46 (5.8%) | 113 (8.3%) | 112 (8.3%) | 384 (8.0%) |
| MV diseasec | 5 (0.4%) | 6 (0.8%) | 58 (4.2%) | 72 (5.4%) | 141 (3.0%) |
| LVEF | 58.8 (42.0, 66.4) | 58.9 (43.1, 67.2) | 53.4 (36.2, 63.0) | 53.3 (35.0, 64.6) | 55.5 (38.5, 65.2) |
| mPAP | 20.0 (17.0, 22.0) | 32.0 (27.0, 43.0) | 33.0 (29.0, 38.0) | 42.0 (37.0, 48.0) | 32.0 (24.0, 41.0) |
| PCWP | 10.0 (8.0, 13.0) | 12.0 (10.0, 14.0) | 23.0 (20.0, 27.0) | 23.0 (20.0, 27.0) | 18.0 (12.0, 24.0) |
| RA mean | 5.0 (3.0, 7.0) | 8.0 (6.0, 12.0) | 12.0 (9.0, 17.0) | 14.0 (10.0, 19.0) | 10.0 (6.0, 15.0) |
PH, pulmonary hypertension; BMI, body mass index; COPD, chronic obstructive pulmonary disease; PVD, peripheral vascular disease; CVD, cerebrovascular disease; HF, heart failure; DM, diabetes mellitus; HIV, human immunodeficiency virus; HTN, hypertension; HLD, hyperlipidemia; SLE, systemic lupus erythematosus; eGFR, estimated glomerular filtration rate; CAD, coronary artery disease; AV, aortic value; MV, mitral value; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RA, right atrium; Scr, serum creatinine.
Covariates presented as count (percentage) or median [interquartile range].
Moderate or severe valvular disease
Combined precapillary and postcapillary
Table 2.
Baseline patient characteristics stratified by pulmonary hypertension subtype for patients without chronic kidney disease
| Variable | No PH (n=3381) | PH | Total (N=7846) | ||
|---|---|---|---|---|---|
| Precapillary (n=1604) | Isolated postcapillary (n=1516) | Combined* (n=1345) | |||
| Demographics | |||||
| Age | 56.0 (45.0, 66.0) | 56.0 (46.0, 66.0) | 58.0 (47.0, 67.0) | 57.0 (48.0, 67.0) | 57.0 (46.0, 67.0) |
| Race | |||||
| Caucasian | 2588 (78.8%) | 966 (62.4%) | 1028 (69.4%) | 815 (61.9%) | 5397 (70.7%) |
| African American | 543 (16.5%) | 490 (31.7%) | 393 (26.5%) | 447 (33.9%) | 1873 (24.5%) |
| Native American | 34 (1.0%) | 15 (1.0%) | 19 (1.3%) | 14 (1.1%) | 82 (1.1%) |
| Other | 121 (3.7%) | 76 (4.9%) | 41 (2.8%) | 41 (3.1%) | 279 (3.7%) |
| Male sex | 1842 (54.5%) | 631 (39.3%) | 900 (59.4%) | 625 (46.5%) | 3998 (51.0%) |
| Vitals and Medical History | |||||
| BMI | 26.8 (23.5, 31.1) | 27.7 (23.4, 32.9) | 29.8 (25.3, 35.5) | 28.7 (24.5, 34.5) | 27.8 (23.9, 32.8) |
| Smoking | 1037 (30.7%) | 536 (33.4%) | 527 (34.8%) | 435 (32.3%) | 2535 (32.3%) |
| COPD | 207 (6.1%) | 209 (13.0%) | 94 (6.2%) | 94 (7.0%) | 604 (7.7%) |
| PVD | 79 (2.3%) | 40 (2.5%) | 41 (2.7%) | 55 (4.1%) | 215 (2.7%) |
| CVD | 236 (7.0%) | 76 (4.7%) | 119 (7.8%) | 97 (7.2%) | 528 (6.7%) |
| Cirrhosis | 49 (1.4%) | 19 (1.2%) | 31 (2.0%) | 12 (0.9%) | 111 (1.4%) |
| HF | 1526 (45.1%) | 791 (49.3%) | 1124 (74.1%) | 1082 (80.4%) | 4523 (57.6%) |
| DM | 455 (13.5%) | 284 (17.7%) | 360 (23.7%) | 323 (24.0%) | 1422 (18.1%) |
| HIV | 10 (0.3%) | 7 (0.4%) | 8 (0.5%) | 5 (0.4%) | 30 (0.4%) |
| HTN | 1522 (45.0%) | 694 (43.3%) | 845 (55.7%) | 733 (54.5%) | 3794 (48.4%) |
| HLD | 1122 (33.2%) | 395 (24.6%) | 555 (36.6%) | 459 (34.1%) | 2531 (32.3%) |
| SLE | 36 (1.1%) | 34 (2.1%) | 12 (0.8%) | 13 (1.0%) | 95 (1.2%) |
| Scleroderma | 44 (1.3%) | 60 (3.7%) | 2 (0.1%) | 8 (0.6%) | 114 (1.5%) |
| Laboratory Data | |||||
| Scr | 0.9 (0.8, 1.0) | 0.9 (0.8, 1.0) | 1.0 (0.8, 1.1) | 0.9 (0.8, 1.1) | 0.9 (0.8, 1.1) |
| eGFR | 84.1 (72.7, 97.4) | 86.3 (71.9, 100.1) | 80.8 (70.0, 93.8) | 78.7 (68.6, 92.5) | 82.9 (71.1, 96.6) |
| Hemoglobin | 13.5 (12.3, 14.6) | 13.2 (11.9, 14.5) | 12.9 (11.5, 14.1) | 12.8 (11.3, 14.0) | 13.2 (11.9, 14.4) |
| CAD | 702 (20.8%) | 241 (15.0%) | 418 (27.6%) | 301 (22.4%) | 1662 (21.2%) |
| Imaging and Hemodynamic Data | |||||
| Valvular heart disease | 615 (18.2%) | 126 (7.9%) | 341 (22.5%) | 289 (21.5%) | 1371 (17.5%) |
| AV diseasec | 332 (9.8%) | 48 (3.0%) | 152 (10.0%) | 99 (7.4%) | 631 (8.0%) |
| MV diseasec | 37 (1.1%) | 13 (0.8%) | 117 (7.7%) | 145 (10.8%) | 312 (4.0%) |
| LVEF | 59.4 (48.5, 66.4) | 60.3 (48.6, 67.7) | 55.6 (34.4, 65.4) | 54.4 (32.5, 63.8) | 58.1 (43.4, 66.1) |
| mPAP | 19.0 (16.0, 22.0) | 32.0 (27.0, 45.0) | 32.0 (28.0, 36.0) | 42.0 (36.0, 50.0) | 26.0 (20.0, 37.0) |
| PCWP | 10.0 (7.0, 12.0) | 11.0 (8.0, 13.0) | 22.0 (18.0, 26.0) | 23.0 (19.0, 28.0) | 13.0 (9.0, 20.0) |
| RA mean | 5.0 (3.0, 7.0) | 8.0 (5.0, 10.0) | 11.0 (8.0, 15.0) | 13.0 (9.0, 17.0) | 8.0 (5.0, 12.0) |
PH, pulmonary hypertension; BMI, body mass index; COPD, chronic obstructive pulmonary disease; PVD, peripheral vascular disease; CVD, cerebrovascular disease; HF, heart failure; DM, diabetes mellitus; HIV, human immunodeficiency virus; HTN, hypertension; HLD, hyperlipidemia; SLE, systemic lupus erythematosus; eGFR, estimated glomerular filtration rate; CAD, coronary artery disease; AV, aortic value; MV, mitral value; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RA, right atrium; Scr, serum creatinine.
Moderate or severe valvular disease
Combined precapillary and postcapillary
Hemodynamic Data and Mortality
The association of right heart catheterization hemodynamic parameters with mortality is depicted in Figure 3. Relative to the median value of each parameter, mortality increased above a mean pulmonary artery pressure of 28 mmHg (Figure 3A), mean pulmonary capillary wedge pressure of 15 mmHg (Figure 3B), and a mean atrial pressure of approximately 7 mmHg (Figure 3C) in patients with and without CKD. In adjusted analyses, presence versus absence of CKD did not modify any of the relationships between hemodynamic parameters and mortality.
Figures 3A-3C. Association between Mortality Risk and (A) Mean Pulmonary Artery Pressure, (B) Mean Pulmonary Capillary Wedge Pressure, and (C) Mean Right Atrial Pressure.
CKD, chronic kidney disease. Hazard ratio with 95% confidence interval is relative to the median value of the parameter.
PH Subtype Distribution
The prevalence of PH in patients with CKD was 73.4% compared to 56.9% in those patients without CKD at the time of right heart catheterization. In all patients with CKD, isolated post-capillary PH (39.0%) and combined pre- and post-capillary PH (38.3%) were the most common PH subtypes. In patients without CKD, pre-capillary PH was the most prevalent PH subtype (35.9%). Figure 4 depicts the PH subtype distribution stratified across all CKD GFR categories. Both PH subtypes with elevated pulmonary capillary wedge pressure (isolated post-capillary and combined pre- and post-capillary PH) were the most common subtypes of PH at every CKD GFR category examined. Right ventricular size and function derived from the echocardiogram are presented in Tables 3–4. For both the CKD and non-CKD cohorts, right ventricular enlargement was most common in the pre-capillary PH subgroup. Impaired right ventricular function was most common in the pre-capillary and combined pre- and post-capillary PH subtypes.
Figure 4. Pulmonary hypertension subtype prevalence stratified by chronic kidney disease severity.
CKD, chronic kidney disease; PH, pulmonary hypertension; Pre-PH, pre-capillary pulmonary hypertension; Ipc-PH, isolated post-capillary pulmonary hypertension; Cpc-PH, combined pre- and post-capillary pulmonary hypertension.
Table 3.
Indices of RV Function in Patients with CKD
| No PH (n=1268) | PH | Total (N=4772) | |||
|---|---|---|---|---|---|
| Variable | Precapillary (n=794) | Isolated postcapillary (n=1367) | Combined* (n=1343) | ||
| RV Size | |||||
| Normal | 83.0% | 48.6% | 66.1% | 54.2% | 63.8% |
| Small | 0.8% | 0% | 0.2% | 0.1% | 0.3% |
| Enlarged | 16.2% | 51.4% | 33.7% | 45.7% | 35.9% |
| RV Functiona | |||||
| Normal | 85.2% | 52.0%) | 65.5% | 51.1% | 63.8% |
| Hypercontractile | 0% | 0% | 0% | 0.1% | 0% |
| Impaired | 14.8% | 48.0% | 34.5% | 48.8% | 36.2% |
PH, pulmonary hypertension; RV, right ventricle
Right ventricular function assessed qualitatively
Table 4.
Indices of RV Function in Patients without CKD
| Variable | No PH (n=3381) | PH | Total (N=7846) | ||
|---|---|---|---|---|---|
| Precapillary (n=1604) | Isolated postcapillary (n=1516) | Combined* (n=1345) | |||
| RV Size | |||||
| Normal | 81.0% | 45.1% | 73.3% | 57.3% | 67.4% |
| Small | 0.2% | 0% | 0.3% | 0.1% | 0.2% |
| Enlarged | 18.8% | 54.9% | 26.4% | 42.6% | 32.4% |
| RV Functiona | |||||
| Normal | 88.4% | 55.1% | 73.0% | 56.1% | 72.4% |
| Hypercontractile | 0% | 0.1% | 0.1% | 0% | 0.1% |
| Impaired | 11.6% | 44.8% | 26.9% | 43.9% | 27.5% |
PH, pulmonary hypertension; RV, right ventricle
Right ventricular function assessed qualitatively
Combined precapillary and postcapillary
PH Subtypes and Mortality
The Kaplan Meier survival curves for each PH subtype for patients with and without CKD are depicted in Figure 5A and B, respectively. Among CKD patients, the combined pre- and post-capillary PH subtype had the poorest survival; while in non-CKD patients, pre-capillary PH had the worst survival. The association of PH subtype with mortality was modified by the presence or absence of CKD (p for interaction < 0.001), but CKD severity did not modify the association the association within those with CKD (p for interaction = 0.3).
Figures 5A & 5B. Kaplan-Meier Survival Curves for patients (A) with chronic kidney disease and (B) without chronic kidney disease.
CKD, chronic kidney disease; PH, pulmonary hypertension; Pre-PH, pre-capillary pulmonary hypertension; Ipc-PH, isolated post-capillary pulmonary hypertension; Cpc-PH, combined pre- and post-capillary pulmonary hypertension.
The unadjusted and adjusted HR for all-cause mortality for each PH subtype stratified by CKD stage are reported in Table 5. Among patients without CKD, and compared to no PH as the reference group, pre-capillary PH had the highest HR for mortality in unadjusted and adjusted (HR, 2.27; 95% CI, 2.00 – 2.57) analyses. Both isolated post-capillary PH and combined pre- and post-capillary PH also had significantly significantly greater mortality.
Table 5.
Unadjusted and adjusted hazard ratios for all-cause mortality for each CKD GFR category, stratified by PH subtype
| CKD Stage and PH Subtype | Unadjusted HR (95% CI) | Adjusteda HR (95% CI) |
|---|---|---|
| No CKD | ||
| Precapillary PH | 2.17 (1.92 – 2.45) | 2.27 (2.00 – 2.57) |
| Isolated postcapillary PH | 1.66 (1.47 – 1.89) | 1.52 (1.34 – 1.74) |
| Combined pre/post capillary PH | 1.89 (1.66 – 2.15) | 1.76 (1.53 – 2.01) |
| No PH | 1.00 (reference) | 1.00 (reference) |
| CKD G3a | ||
| Precapillary PH | 1.35 (1.09 – 1.66) | 1.52 (1.23 – 1.88) |
| Isolated postcapillary PH | 1.14 (0.94 – 1.37) | 1.19 (0.98 – 1.44) |
| Combined pre/post capillary PH | 1.78 (1.48 – 2.14) | 1.89 (1.57 – 2.28) |
| No PH | 1.00 (reference) | 1.00 (reference) |
| CKD G3b | ||
| Precapillary PH | 1.52 (1.18 – 1.96) | 1.65 (1.28 – 2.14) |
| Isolated postcapillary PH | 1.56 (1.27 – 1.93) | 1.51 (1.22 – 1.88) |
| Combined pre/post capillary PH | 1.83 (1.49 – 2.25) | 1.87 (1.52 – 2.31) |
| No PH | 1.00 (reference) | 1.00 (reference) |
| CKD G4 | ||
| Precapillary PH | 1.42 (0.94 – 2.13) | 1.57 (1.04 – 2.36) |
| Isolated postcapillary PH | 1.73 (1.25 – 2.39) | 1.68 (1.21 – 2.34) |
| Combined pre/post capillary PH | 1.97 (1.41 – 2.74) | 2.13 (1.52 – 2.97) |
| No PH | 1.00 (reference) | 1.00 (reference) |
| CKD G5/G5D | ||
| Precapillary PH | 0.89 (0.56 – 1.43) | 1.04 (0.65 – 1.68) |
| Isolated postcapillary PH | 1.13 (0.79 – 1.61) | 1.18 (0.82 – 1.70) |
| Combined pre/post capillary PH | 1.46 (1.01 – 2.11) | 1.63 (1.12 – 2.36) |
| No PH | 1.00 (reference) | 1.00 (reference) |
CKD, chronic kidney disease; PH, pulmonary hypertension; Gn, glomerular filtration rate category n; GFR, glomerular filtration rate.
Cox proportional hazards model adjusted for age, sex, race, body mass index, diabetes mellitus, heart failure, hypertension, cirrhosis, systemic lupus erythematosus, scleroderma, obstructive sleep apnea, chronic obstructive pulmonary disease, moderate/severe aortic valve disease, moderate/severe mitral value disease, human immunodeficiency virus infection, smoking, left ventricular ejection fraction, and hemoglobin.
Within each CKD GFR category, combined pre- and post-capillary PH conferred the highest HR of mortality compared to no PH as the reference group. For the CKD G5/G5D cohort, only the combined pre- and post-capillary PH subtype had a higher risk of mortality compared to the no PH group (HR, 1.63; 95% CI, 1.12 – 2.36).
DISCUSSION
PH is a common but often-underrecognized driver of morbidity and mortality in patients with CKD.2, 7 We demonstrate high rates of PH in a cohort of patients with CKD referred for right heart catheterization. Both PH subtype and related mortality are strongly affected by the presence or absence of CKD. For those patients without CKD, pre-capillary PH was the predominant subtype and was associated with the highest risk of mortality. In contrast, combined pre- and post-capillary PH and isolated post-capillary PH comprised the majority of PH subtypes in CKD. However, patients with combined pre- and post-capillary PH consistently had the highest mortality risk across all CKD GFR categories.
The high rates of PH demonstrated in our study align with other CKD cohorts referred for right heart catheterization.12 In addition, the prevalence of pre-capillary PH in our cohort is nearly identical to that seen in the only other large-scale analysis of right heart catheterization data in patients with CKD.12 Unlike prior studies, the separation of the post-capillary PH into isolated post-capillary PH and combined pre- and post-capillary PH allowed for demonstration of a survival difference between PH subtypes in patients with CKD. Indeed, the poor survival of the combined pre- and post-capillary PH cohort aligns with studies of PH subtypes in patients with HF.14, 15
The reduced survival of combined pre- and post-capillary PH compared to other PH subtypes across all CKD GFR categories is a major finding of our study. Multiple factors may contribute to this phenomenon. Patients with both combined pre- and post-capillary PH had higher mean pulmonary artery and right atrial pressures compared to most other groups, which suggests more severe PH and right ventricular dysfunction. These findings are further supported by high rates of right ventricular enlargement and impairment in the combined pre- and post-capillary PH group. These right ventricular changes may reflect severe or longstanding PH, chronic volume overload, maladaptive responses to volume overload or elevated left-sided pressure which would portend a worse survival. The predominance of severe, life-limiting pulmonary diseases may explain the poor survival of pre-capillary PH patients in the non-CKD cohort. Additional studies targeted at providing further granularity to the differences among these PH subtypes in patients with CKD are needed to elucidate the mechanisms underlying this survival difference.
While the exact mechanisms underlying the high prevalence of PH in CKD are mostly unknown, factors related to decreased GFR and the management of kidney failure have been implicated. Volume overload dominates the current paradigm of PH progression and remains the predominant modifiable factor.11, 21 Of the patients with CKD and PH, over 77% had an elevated pulmonary capillary wedge pressure, which further highlights the important of volume management in these patients. However, the high prevalence of combined pre- and post-capillary PH in our CKD cohort suggests that volume overload often exists in concert with other factors that increase pulmonary vascular resistance. Chronic volume overload may accelerate pulmonary vascular remodeling and lead to combined pre- and post-capillary PH in certain susceptible subpopulations of CKD patients.22 Alternatively, non-volume related factors may contribute pulmonary vascular remodeling in subgroups of CKD patients. Longitudinal studies of PH subtypes in patients with CKD are needed to determine if combined pre- and post-capillary PH develops predominantly as a transformation from isolated post-capillary PH, pre-capillary PH, or de novo.
Apart from volume overload, other potential factors that contribute to altered pulmonary vascular resistance or remodeling must be considered. Nitric oxide signaling regulates pulmonary vascular tone and is a common target for drug therapies for patients with pulmonary arteriolar hypertension.24 Multiple mediators of nitric oxide metabolism are adversely affected by CKD such as asymmetric dimethylarginine (ADMA), L-arginine, and homocysteine.25–35 Fibroblast growth factor 23 (FGF-23) levels also increase in CKD and are associated with various cardiovascular complications including left ventricular hypertrophy (LVH) and HF.36 While FGF-23 correlates with pulmonary artery pressures in some populations,37 this relationship remains unclear in patients with CKD.38 CKD and hemodialysis also promote inflammation.39, 40 Various inflammatory markers are associated with PH including transforming growth factor β (TGF-β), interleukin 6 (IL-6), IL-10, IL-1 receptor α (IL-1Rα), and IL-1β.41–44
Our study also reports similar relationships of pulmonary artery, pulmonary capillary wedge, and right atrial pressures with mortality in the CKD and non-CKD cohorts. The relationship was nonlinear for each parameter, with inflection points present near cutoffs known to portend worse outcomes in other populations: pulmonary artery pressures above 25 mmHg and pulmonary capillary wedge pressures above 15 mmHg. These findings suggest that survival at a given severity of these hemodynamic parameters are comparable in patients with and without CKD. As evidenced by the substantial proportion of combined pre- and post-capillary PH in CKD, however, more patients with CKD experience the extremes of these hemodynamic parameters and this likely contributes to the poor overall survival for patients with both CKD and PH.
Our study has several limitations. Despite the large number of patients in this study, these data reflect a single-center experience and thus limits generalizability of the study findings. Most right heart catheterization referrals occurred at the discretion of the provider as part of routine clinical care. Variations in operator technique may affect uniformity of certain catheterization parameters. We did not exclude patients on peritoneal dialysis; the PH subtype distribution and association with mortality may differ by dialysis modality. We also do not have data on vascular access for hemodialysis in this study. Arteriovenous fistulas can contribute to high-output heart failure and may influence the risk of PH in this population. We excluded patients with heart or lung transplant to limit the inclusion of protocol right heart catheterizations in this analysis. Because interstitial lung disease has a stronger association with pulmonary hypertension than CKD, we specifically excluded patients with this diagnosis. Despite these exclusions, these limitations may limit the generalizability of our study findings. Future studies could address these limitations by obtaining right heart catheterizations in a random sample of individuals with CKD, including those treated by dialysis. Alternatively, because echocardiography is a more feasible method to study larger populations, future studies could investigate the ability of certain echocardiographic findings (e.g. right heart changes) and biomarker data to distinguish between pulmonary hypertension subtypes among individuals with CKD.
The assessment of baseline CKD status is also limited by the information available in the electronic health record. We chose to use the median of Scr data in the six months preceding the right heart catheterization to calculate baseline eGFR instead of mean Scr or cutoffs closer to the time of the catheterization employed in other studies.2, 12 We utilized this strategy to limit the influence of acute Scr changes near the time of catheterization. However, the absence of standardized Scr collection or quantification of proteinuria limits the accuracy of CKD classification in our analysis. We also combined patients with eGFR less than 15 ml/min/1.73m2 with those on dialysis. This heterogenous group may not reflect the risk profile of each group in isolation. Estimates of left-sided pressures may be influenced by the timing of the last dialysis treatment, which was not standardized in this retrospective study. Among other changes, the recent 6th World Symposium on PH proposed a lower cutoff for PH diagnosis.45 How this increased sensitivity will affect PH diagnosis in CKD remains to be seen.
PH remains an underrecognized yet significant cardiovascular complication for patients with CKD. Unlike other cardiovascular diseases in patients with CKD, the exact mechanism of this association remains largely unknown and no targeted treatments exist. Our study suggests that processes that increase pulmonary vascular resistance and/or remodeling represent a prominent mechanism and potential therapeutic target for patients with CKD that is complicated by PH. In addition, patients with combined pre- and post-capillary PH are a particularly vulnerable subgroup with the highest risk of mortality. As demonstrated by trials of vasodilator therapy in patients with heart failure and combined pre- and post-capillary PH,16 the recognition of this large combined pre- and post-capillary PH cohort in CKD may present new therapeutic options.
Acknowledgements:
The authors would like to acknowledge the significant contributions from Karen Chiswell, Ph.D. to the statistical analyses of this manuscript.
Support: This study was supported by National Institutes of Health (NIH) grant R01DK081374 (MW) and the American Society of Nephrology (AG). The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication.
Footnotes
Financial Disclosure: The authors declare that they have no relevant financial interests.
Peer Review: Received _______. Evaluated by 3 external peer reviewers and a statistician, with direct editorial input from an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form August 30, 2019. The involvement of an Acting Editor-in-Chief was to comply with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
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