Pulmonary Hypertension Associated with Poor Survival in Patients with CKD

Approximately 21% to 41% of patients with chronic kidney disease (CKD) are diagnosed with pulmonary hypertension (PH); in patients with kidney failure requiring dialysis, the percentage is 60%. There are no targeted treatments available for PH in patients with CKD. In previous studies of PH in this patient population, diagnosis and quantification of PH severity has relied on transthoracic echocardiography. Right heart catheterization can provide more detailed insight into potential underlying mechanisms of PH.

PH is defined as mean pulmonary artery pressure ≥25 mm Hg on right heart catheterization at rest. PH can be stratified into subtypes, including precapillary PH, isolated postcapillary PH, and combined pre- and postcapillary PH. There are few data available on how CKD affects PH subtypes. Among patients with CKD with PH, the combined pre- and postcapillary subtype may contribute to the overall PH burden due to a combination of: (1) chronic volume overload; (2) pulmonary vascular remodeling due to increases in vasoactive factors such as nitric oxide, prostacyclin, and endothelin; (3) inflammation; and (4) comorbid lung disease.

Daniel L. Edmonston, MD, and colleagues conducted an observational retrospective study designed to examine the prevalence and consequences of subtypes of PH in patients with CKD. Results of the study were reported in the American Journal of Kidney Diseases [2020; 75(5):713-724].

The outcome of interest was all-cause mortality. The researchers hypothesized that combined pre-and postcapillary PH would be the most common PH subtype and would be predictive of the highest mortality risk in the CKD patient population.

Patients were stratified by CKD severity at baseline using the Kidney Disease Improving Global Outcomes glomerular filtration rate (GFR) categories: CKD G3a (estimated GFR [eGFR], 45 to 49 mL/min/1.73 m²); G3b (eGFR, 30 to 44 mL/min/1.73 m²⁾; G4 (eGFR, 15 to 29 mL/min/1.73 m²), and G5/G5D (<15 mL/min/1.73 m² or on hemodialysis). Patients with eGFRs ≥60 mL/min/1.73 m² were classified as not having CKD.

The researchers utilized the Duke Databank for Cardiovascular Disease to identify all right heart catheterizations performed at Duke University Hospital from January 1, 2000, to December 31, 2014. Following application of exclusion and inclusion criteria, the study cohort included 12,618 patients.

The average age for patients with CKD was 69 years compared with 57 years in patients without CKD. In the CKD cohort, patients without PH tended to be older; age did not differ among PH subtypes. Within the CKD G5/G5D group, 70.5% were on dialysis. Regardless of CKD status, African American patients were disproportionately affected by PH; African American patients represented the highest proportion of patients with the combined pre- and postcapillary PH subtype (31.7% of patients with combined pre- and postcapillary PH and CKD, 33.9% of patients with combined pre- and postcapillary PH but no CKD).

Compared with other PH subtypes, precapillary PH predominantly affected women in both the CKD and non-CKD cohorts: 59.7% of precapillary PH in the CKD cohort and 60.7% of precapillary PH in patients in the non-CKD cohort. Chronic obstructive pulmonary disease and scleroderma were over-represented in the precapillary PH subtype; heart failure and diabetes mellitus were more prominent in the isolated postcapillary and combined pre- and postcapillary PH subtypes. In the CKD cohort, GFR tended to be worse in the isolate postcapillary PH and combined pre- and postcapillary PH subtypes.

In the CKD cohort, the prevalence of PH was 73.4%; in the non-CKD cohort, the prevalence was 56.9%. In all patients with CKD, the most common PH subtypes were isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%). In the non-CKD cohort, the most prevalent PH subtype was precapillary PH (35.9%).

In the CKD group, patients with the combined pre- and postcapillary PH subtype had the poorest survival; in the non-CKD group, the worst survival was in the patients with precapillary PH subtype. The association of PH subtype with mortality was modified but the presence or absence of CKD (P for interaction <.001), but severity of CKD did not modify the association within those with CKD (P for interaction =.3). In both unadjusted and adjusted analyses, among patients with no CKD and compared with no PH as the reference group, precapillary PH had the highest hazard ratio (HR) for mortality (HR, 2.27; 95% confidence interval [CI], 2.00-2.57). Isolated postcapillary PH and combined pre- and postcapillary PH also had significantly greater mortality.

Compared with no PH as the reference group, within each CKD GFR category, the highest HR of mortality was associated with combined pre- and postcapillary PH. For patients in the G5/G5D cohort, only the combined pre- and postcapillary PH subtype had higher risk for mortality compared with the reference group (HR, 1.63; 95% CI, 1.12-2.36).

There were some study limitations cited by the authors, including the single-center design perhaps limiting the generalizability of the findings; variations in operator technique for the right heart catheterizations that may have affected the uniformity of certain catheterization parameters; not excluding patients on peritoneal dialysis; and lack of data for vascular access in the hemodialysis patients in the study.

In summary, the researchers said, “PH remains an under-recognized 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 treatment exists. 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 postcapillary PH are a particularly vulnerable subgroup with the highest risk for mortality. As demonstrated by trials of vasodilator therapy in patients with heart failure and combined pre- and postcapillary PH, the recognition of this large combined pre- and postcapillary PH cohort in CKD may present new therapeutic options.”

Takeaway Points

1. In patients with chronic kidney disease (CKD), pulmonary hypertension (PH) is associated with increased risk for cardiovascular disease and mortality. Researchers conducted a study to examine the prevalence and outcomes of PH subtypes in patients with CKD.
2. The most common subtypes of PH in the CKD cohort were isolated postcapillary (39.0%) and combined pre- and postcapillary PH (38.3%). In the non-CKD cohort, precapillary PH was most common.
3. In the CKD cohort, compared with no PH, combined pre- and postcapillary PH was associated with the highest risk for mortality in adjusted analyses.