Is the Kidney the Culprit in Some Forms of Pulmonary Hypertension?

Pulmonary hypertension is increasingly recognized in patients with chronic kidney disease (CKD). A recent review in the American Journal of Kidney Diseases discusses the risk factors unique to patients with CKD and patients on renal replacement therapy. Corresponding author Dr. Carmine Zoccali (CZ) of Reggio Calabria, Italy, discussed this article with Dr. Matthew Sparks (eAJKD), eAJKD Advisory Board member.

eAJKD: Why are you interested in this topic and why is it important to study?

CZ: Pulmonary hypertension in the general population is a relatively rare condition. I was struck by the high prevalence of pulmonary hypertension reported in patients on hemodialysis. Little attention has been devoted to pulmonary hypertension in CKD, and in the current World Health Organization (WHO) classification, pulmonary hypertension diagnosed in dialysis patients is grouped (WHO V) with pulmonary hypertension of “unclear or multi-factorial etiology”.

eAJKD: Can you briefly describe what are the clinical and diagnostic criteria for establishing the diagnosis of pulmonary hypertension? What is the gold standard test?

CZ: Based on the WHO classification, pulmonary hypertension has 5 categories. Class II, III, IV, and V are all from secondary causes. Class I is idiopathic or familial or autoimmune in nature, and also referred to as pulmonary arterial hypertension (PAH). Class V is listed as having CKD as a cause. The definitive diagnosis of PAH requires an invasive right heart catheterization. The diagnostic criteria are:

  • Mean pulmonary artery pressure ≥25 mmHg (normal 9-18 mmHg)
  • Pulmonary vascular resistance >3 Woods units (normal 0.25-1.6 Woods units)
  • Pulmonary wedge pressure ≤15 mmHg (normal 15 mmHg)

However, echo-Doppler studies can provide an estimate of the pulmonary artery systolic pressure (PASP), a surrogate of mean pulmonary artery pressure. This is calculated on the basis of the tricuspid regurgitation jet velocity (TRJV). Pulmonary hypertension by Doppler is very likely when:

  • PASP >50 mmHg
  • TRV is >3.4 m/sec
  • PASP in the 35-49 mmHg range and TRV between 2.8 m/sec and 3.4 m/sec are considered suggestive of pulmonary hypertension, but not diagnostic

The major limitation of echo-Doppler estimates is inaccuracy, particularly when the tricuspid regurgitation jet is difficult to visualize. Despite this, there is no question that echo-Doppler is fundamental for the screening of pulmonary hypertension, and this technique is central in the evaluation and management of patients with pulmonary hypertension.

eAJKD: From your paper, you describe the lack of well-conducted epidemiologic studies looking at pulmonary hypertension in all stages of CKD. Do you have a general sense of the prevalence?

CZ: Thresholds for mean pulmonary pressure as estimated by echo-Doppler have been adopted for the diagnosis of pulmonary hypertension. However, the diagnosis of pulmonary hypertension is best made with right heart catheterization. Only one study has applied right heart catheterization measurements in patients on hemodialysis. This study (PEPPER-study: PrEvalence of Precapillary Pulmonary arterial hypertension in patients with End-stage Renal disease) evaluated 73 patients on dialysis referred for unexplained dyspnea during ordinary physical activity to an academic department in Germany. Fifty-eight patients met the inclusion criteria, and 31 consented to undergo right heart catheterization. Among these patients, three met hemodynamic criteria for idiopathic pulmonary artery hypertension (WHO I) and one additional patient turned out to have pulmonary hypertension attributable to sleep apnea. A merit of this study was that right heart catheterization studies were repeated after dialysis in patients with PAP >25 mmHg. The 10% prevalence of idiopathic pulmonary hypertension reported in PEPPER-Study is staggering if these results are generalized to the population, which has 15-50 cases per million population. Even though this study was small, it unquestionably shows that pulmonary hypertension is exceedingly frequent in patients on dialysis. The largest study performed so far in dialysis patients in the US reports a 38% prevalence of pulmonary hypertension as assessed by echocardiography.

eAJKD: Some of the risk factor modification in CKD appears to correlate with high quality nephrology care, i.e., volume management, CVD risk reduction. Does exposure to good pre-ESRD care correlate with a decreased risk of pulmonary hypertension?

CZ: Having good nephrology care pre-dialysis may impact the disease course. However, no sufficient study has been performed in assessing the role of pre-dialysis care on the incidence of pulmonary hypertension.

eAJKD: There is a mention of reduced prevalence of pulmonary hypertension in patients on peritoneal dialysis. Is this also true for patient in more frequent hemodialysis programs (i.e., nocturnal or daily HD)?

CZ: Frequent dialysis has a positive impact on left ventricular anatomy and function, and may have a favorable impact on the prevention and treatment of pulmonary hypertension. However, no solid data on this issue are currently available.

eAJKD: Can you comment on how cellulose-based filters are more prone to neutrophil sequestration than synthetic-based filters?

CZ: Neutrophil activation secondary to blood membrane contact and reversible neutrophil sequestration in the lung, a phenomenon which was intensively investigated in the 1980s, contributes to and/or worsens microvascular lung disease in patients on hemodialysis. This phenomenon is pronounced with cellulosic membranes and is decreased significantly, but not abolished, with synthetic or modified cellulosic membranes. In a crossover trial of 74 patients dialyzed via a central venous catheter, the use of high flux polysulphone filters was associated with a more pronounced fall in post-dialysis pulmonary pressures than seen with use of cellulose acetate filters.

eAJKD: Sleep apnea was listed as an important risk factor for pulmonary hypertension. Can you briefly comment on this?

CZ: Sleep apnea has a high prevalence in the dialysis population (about 15%). Nocturnal hypoxemia, i.e., the most concerning disturbance triggered by sleep apnea, is a strong trigger of pulmonary hypertension. Sympathetic activation is the primary mechanism whereby hypoxemia increases pulmonary pressure. As mentioned, the PEPPER study suggests that sleep apnea may be responsible for about ¼ of cases of pulmonary artery hypertension in dialysis patients.

eAJKD: Are there any future ventures regarding pulmonary hypertension in dialysis patients?

CZ: The presence of an arterio-venous fistula, uncontrolled sleep apnea, and the accumulation of endogenous inhibitors of nitric oxide synthase all lead to insults in the pulmonary microcirculation. Exposure to dialysis membranes likely contribute to the unique propensity of dialysis patients to pulmonary hypertension. Careful evaluation of these risk factors in an investigational setting with confirmation by right heart catheterization and large surveys including patients with moderate to severe CKD are needed to advance our understanding of pulmonary hypertension in patients with CKD. Nephrologists should increase efforts to identify modifiable risk factors to improve the poor health outcomes of dialysis patients. Moving pulmonary hypertension from the “unclear or multi-factorial etiology” category (WHO V) where it now stands to a category of known etiology may be a significant step towards this goal.

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