Kidney Disease and Pulmonary Hypertension: A Deadly Duo

By Sankar Navaneethan, MD

Pulmonary hypertension (PH) is a progressive, fatal pulmonary circulatory disease that accompanies left or right ventricular failure.

Several factors lead to the development and worsening of PH, and kidney dysfunction and volume overload are common occurrences in clinical practice that can lead to increased pulmonary artery (PA) pressure. This decline in kidney function could be transiently related to hemodynamic changes during the treatment of volume overload associated with PH. These hemodynamic changes could lead to chronic kidney disease (CKD) if the insults are persistent or the underlying disease continues to worsen.

Examining CKD-PH Relationships

Since kidney disease in itself is a significant risk factor for death, it is relevant to examine its effects in the population with PH. Therefore, we attempted to determine if the presence of pre-existing non-dialysis-dependent CKD is an independent risk factor for death in patients with PH of varying etiology.

We studied 1,088 adult patients diagnosed with PH based on mean PA pressure > 25 mm Hg at rest as measured by right heart catheterization performed at our institution between 1996 and January 2011. The primary outcome of interest was all-cause mortality, which was ascertained from our electronic medical record and linkage of our data with the Social Security Death Index.

Patients were followed from their date of right heart catheterization until October 31, 2011. Mean age of the study cohort was 60 ± 15 years; 66 percent were females and 81 percent were white. Mean serum and estimated glomerular filtration rate (eGFR) was 72.2 ± 29 mL/min/1.73 m2. Mean PA pressure of the entire cohort was 47 ± 14 mm Hg. Among the 1,088 patients, 388 (36 percent) had evidence of CKD; 340 (31 percent) had stage 3 CKD and 48 (4 percent) had stage 4 CKD.

During the median follow-up period of 3.2 years (interquartile range 1.5 to 5.6 years), 559 (51 percent) of the total cohort died. Kaplan-Meier survival estimates at one year were 86 percent, 78 percent and 48 percent in those without CKD, with stage 3 CKD and with stage 4 CKD, respectively (log-rank p < 0.001; see Figure 1).

Figure 1. Survival based on eGFR in patients with pulmonary hypertension.

In the multivariable adjusted Cox proportional hazards model, the presence of eGFR < 60 mL/min/1.73 m2 was independently associated with mortality. When eGFR was examined as a continuous variable, every 5 mL/min/1.73 m2 decrease in eGFR was associated with a greater hazard for death (HR 1.05, 95% confidence interval [CI] 1.03-1.07). Presence of CKD did not seem to modify the associations between severity of PH and death.

Possible Explanations for CKD-PH-Associated Mortality

Pulmonary hypertension and CKD are disease states associated with poor outcomes. In this large cohort of patients with PH (based on right heart catheterization data), underlying CKD was highly prevalent. The observed association between CKD and mortality in our study could be explained by the higher prevalence of diastolic dysfunction and volume overload (resultant pulmonary congestion) in those with mild to moderate CKD.

In addition, other investigators have speculated on the potential influence of uremic toxins, bone mineral disorder and endothelial dysfunction on outcomes among those PH patients who are on dialysis. Particularly, these reports note that nitric oxide levels are reduced and release of nitric oxide is attenuated in patients on hemodialysis with PH. These deficiencies in nitric oxide often lead to increased pulmonary vascular tone, which in turn can promote arterial stiffness with resultant adverse consequences.

Whether such mechanistic pathways prevail in those with earlier stages of CKD, thereby causing higher mortality rates, is unknown and could be explored in CKD cohorts with longitudinal data relating to PH and left ventricular function. Our group is conducting these analyses, which might also help us identify novel risk stratification tools for our kidney disease patients.

Dr. Navaneethan is a staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Department of Nephrology and Hypertension.