The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access

Background. We recently have shown a high incidence of unexplained pulmonary hypertension (PHT) in end-stage renal disease (ESRD) patients on chronic haemodialysis (HD) therapy via arterio-venous (A-V) access. This study evaluated the possibility that PHT in these patients is triggered or aggravated by chronic HD via surgical A-V access, and the role of endothelin-1 (ET-1) and nitric oxide (NO) in this syndrome. Methods. Forty-two HD patients underwent clinical evaluation. Pulmonary artery pressure (PAP) was evaluated using Doppler echocardiography. Levels of ET-1 and NO metabolites in plasma were determined before and after the HD procedure and were compared between subgroups of patients with and without PHT. Results. Out of 42 HD patients studied, 20 patients (48%) had PHT (PAP=46 +/- 2; range 36-82 mmHg) while the rest had a normal PAP (29 +/- 1 mmHg) (P<0.0001). HD patients with PHT had higher cardiac output compared with those with normal PAP (6.0 +/- 1.2 vs 5.2 +/- 0.91/min, P<0.034). HD patients, with or without PHT, had elevated plasma ET-I levels compared with controls (1.6 +/- 0.7 and 2.4 +/- 0.8 fmol/ml vs 1.0 +/- 0.2, P<0.05) that remained unchanged after the HD procedure. HD patients without PHT and control subjects showed similar basal plasma levels of NO2 + NO3 (24.2 +/- 5.2 vs 19.7 +/- 3.1 mu M, P>0.05) that was significantly higher compared with HD patients with PHT (14.3 +/- 2.3 mu M, P<0.05). HD therapy caused a significant increase in plasma NO metabolites that was greater in patients without PHT (from 24.2 +/- 5.2 to 77.1 +/- 9.6 mu M, P<0.0001, and from 14.3 +/- 2.3 to 39.9 +/- 11.4 mu M, P<0.0074, respectively). Significant declines in PAP (from 49.8 +/- 2.8 to 38.6 +/- 2.2 mmHg, P<0.004) and cardiac output (CO) (from 7.6 +/- 0.6 to 6.1 +/- 0.3 l/min, P<0.03) were found in 11 HD patients with PHT that underwent successful transplantation. Similarly, temporary closure of the A-V access by a sphygmomanometer in eight patients with PHT resulted in a transient decrease in CO (from 6.4 +/- 0.6 to 5.3 +/- 0.5 l/min, P = 0.18) and systolic PAP (from 47.2 +/- 3.8 to 34.6 +/- 2.8 mmHg, P < 0.028). Conclusions. This study demonstrates a high prevalence of PHT among patients with ESRD on chronic HD via a surgical A-V fistula. In view of the vasodilatory and antimitogenic properties of NO, it is possible that the attenuated basal and HD-induced NO production in patients with PHT contributes to the increased pulmonary vascular tone. Furthermore, the partial restoration of normal PAP and CO in HD patients that underwent either temporal A-V shunt closure or successful transplantation indicates that excessive pulmonary blood flow is involved in the pathogenesis of the disease.