Risk of Mortality Higher in Patients with Kidney Disease and Pulmonary Hypertension

Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) commonly experience pulmonary hypertension. Depending on the methods used to diagnose pulmonary hypertension and evaluate the stages of CKD, the prevalence ranges from 10% to 70%. One factor in the presence of pulmonary hypertension in patients with kidney disease is the pathophysiologic sequelae of CKD, including volume overload, congestive heart failure, endothelial dysfunction, and arteriovenous fistulas.

The typical definition of pulmonary hypertension is pulmonary artery mean pressure >25 mm Hg at rest, measured by right-sided cardiac catheterization. Because cardiac catheterization is invasive, pulmonary hypertension is often diagnosed using echocardiography to calculate estimated pulmonary artery systolic pressure (PASP). There are five categories of pulmonary hypertension defined by the World Health Organization based on cause: pulmonary arterial hypertension, pulmonary hypertension due to left-sided cardiac disease, pulmonary hypertension due to lung disease or hypoxia, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension due to unclear multifactorial mechanisms.

Results of previous studies have suggested that there may be an association between pulmonary hypertension and increased risk for adverse outcomes in patients with CKD and ESRD. However, there are few data available on the magnitude of the association between pulmonary hypertension and mortality. In addition, the optimal management strategy for patients with pulmonary hypertension complicating CKD and ESRD is unclear. Mangyao Tang, MD, MPH, and colleagues conducted a systematic review and meta-analysis designed to review the literature on the impact of pulmonary hypertension on clinical outcomes in patients with CKD and ESRD. Results were reported in the American Journal of Kidney Diseases [2018;72(1):75-83].

The study population was patients with ESRD or earlier stages of CKD. Selection criteria for studies were observational studies that reported clinical outcomes in patients with coexisting pulmonary hypertension and CKD or ESRD. Eligible studies were identified using a systematic  search of PubMed and Embase. The outcomes of interest were all-cause mortality, cardiovascular mortality, and cardiovascular events.

The search strategy identified 842 unique records; following screening of titles and abstracts, 30 of the 842 were potentially eligible for the current review. Of those, 16 were included in the final meta-analysis, representing 7112 patients with CKD and ESRD.

The prevalence of pulmonary hypertension was 23% in the study population. Mean sample size was 247 (range, 36-2959), and mean follow-up ranged from 1 to 7 years. Three studies recruited patients with CKD stages 1 to 5, two were of kidney transplant recipients, and the remaining 11 included patients with ESRD undergoing dialysis. Of the 11 studies of dialysis populations, seven were limited to hemodialysis, two were limited to peritoneal dialysis, and two included both modalities.

In all 16 studies, pulmonary hypertension was diagnosed based on measurements using Doppler echocardiography. Ten studies used the diagnostic standard estimated PASP >35 mm Hg; four used alternative cutoff values (30, 37, 45, and 50 mm Hg), one adopted tricuspid regurgitant velocity >2.5 m/s as the diagnostic method, and another defined  pulmonary hypertension as estimated PASP >35 mm Hg and/or tricuspid regurgitant velocity >2.5 m/s.

Fourteen studies included data on all-cause mortality, representing 6472 participants. There were associations between pulmonary hypertension and increased risk for all-cause mortality among patients with CKD stages 1 to 5 (relative risk [RR], 1.44; 95% confidence interval [CI], 1.17-1.76; P<.001), patients with ESRD receiving dialysis (RR, 2.32; 95% CI, 1.91-2.83; P<.001), and recipients of kidney transplants (RR, 2.08; 95% CI, 1.35-3.20; P=.001), with low heterogeneity (I2=31%; 95% CI, 0%-64%).

In subgroup analyses, including CKD stage, pulmonary hypertension measure, age, sex, adjustment for baseline cardiovascular disease, type of risk estimate, country, duration of follow-up, and dialysis modality, there was significant modification of risk estimates of the association between pulmonary hypertension and morality by CKD stage: patients with ESRD receiving dialysis had greater risk compared with CKD stages 1 to 5 (RR, 1.44 vs 2.32; P=.008). There were no other effect modifications in all other subgroups.

Four studies representing 1959 participants reported the hazard ratio (HR) of cardiovascular mortality. In patients with CKD and ESRD, there was an association between pulmonary hypertension and increased risk for cardiovascular mortality (RR, 2.20; 95% CI, 1.53-3.15; P<.001), with low heterogeneity (I2=0%; 95% CI, 0%-85%).

Seven studies involving 4601 participants assessed the higher risk for pulmonary hypertension on cardiovascular events. Results of meta-analysis revealed an increased risk for cardiovascular events in patients with CKD with pulmonary hypertension (RR, 1.67; 95% CI, 1.07-2.60; P=.02), with moderate heterogeneity (I2=65%; 95% CI, 22%-85%). There was also an association between higher risk for cardiovascular events in patients with ESRD receiving dialysis and pulmonary hypertension (RR, 2.33; 95% CI, 1.76-3.08; P<.001), with low heterogeneity (I2=0%; 95% CI, 0%-71%).

There were some limitations to the review cited by the authors, including the inability to control for confounding factors, the observational design of the study that precluded assessment of causality, the scarcity of data regarding the impact of pulmonary hypertension in patients with CKD stages 1 to 5, the possibility of outcome reporting bias, and the limited evidence for the two secondary outcomes (cardiovascular mortality and cardiovascular events).

The researchers said, “In conclusion, pulmonary hypertension is consistently associated with adverse outcomes, including all-cause mortality and cardiovascular events, in patients with advanced kidney disease. Risk stratification of CKD and ESRD could consider pulmonary hypertension as a significant predictor for long-term survival. Ultimately, randomized studies are needed to determine whether pulmonary hypertension treatments in patients with decreased kidney function can improve the excess mortality burden associated with the coexistence of these conditions.”

Takeaway Points

  1. Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) commonly experience pulmonary hypertension, but there are few data available on the impact of pulmonary hypertension in those patient populations.
  2. Results of a recent systematic review and meta-analysis demonstrated an association between pulmonary hypertension and a substantially increased risk for all-cause mortality and cardiovascular events in patients with CKD and ESRD.
  3. Compared with patients with CKD stages 1 to 5, the risk was higher in patients with ESRD receiving dialysis.