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American Journal of Kidney Diseases

Pulmonary Hypertension in CKD

Published:November 19, 2012DOI:https://doi.org/10.1053/j.ajkd.2012.07.029
      Pulmonary arterial hypertension is a rare disease often associated with positive antinuclear antibody and high mortality. Pulmonary hypertension, which rarely is severe, occurs frequently in patients with chronic kidney disease (CKD). The prevalence of pulmonary hypertension ranges from 9%-39% in individuals with stage 5 CKD, 18.8%-68.8% in hemodialysis patients, and 0%-42% in patients on peritoneal dialysis therapy. No epidemiologic data are available yet for earlier stages of CKD. Pulmonary hypertension in patients with CKD may be induced and/or aggravated by left ventricular disorders and risk factors typical of CKD, including volume overload, an arteriovenous fistula, sleep-disordered breathing, exposure to dialysis membranes, endothelial dysfunction, vascular calcification and stiffening, and severe anemia. No specific intervention trial aimed at reducing pulmonary hypertension in patients with CKD has been performed to date. Correcting volume overload and treating left ventricular disorders are factors of paramount importance for relieving pulmonary hypertension in patients with CKD. Preventing pulmonary hypertension in this population is crucial because even kidney transplantation may not reverse the high mortality associated with established pulmonary hypertension.

      Index Words

      During the last 2 decades, evidence has accrued documenting that mild to moderate forms of pulmonary hypertension are much more common than traditionally has been thought.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      These forms often remain undetected because the disease has a long preclinical asymptomatic phase and pulmonary hypertension often is suspected only when the clinical signs and symptoms of right ventricular dysfunction, namely progressively worsening fatigue, dyspnea, and syncope, are manifest.
      • Badesch D.B.
      • Champion H.C.
      • Sanchez M.A.
      • et al.
      Diagnosis and assessment of pulmonary arterial hypertension.
      It increasingly is being recognized that pulmonary hypertension in patients with chronic kidney disease (CKD) is not confined to those with connective tissue and systemic diseases and that the decrease in kidney function per se may be a trigger for the development of this disturbance. Here, we focus on the clinical epidemiology of pulmonary hypertension in patients with CKD in a framework that considers the World Health Organization (WHO) criteria for classifying the disease, as well as the relationship between the prevalence of this condition and CKD staging.

      Diagnostic Criteria

      The WHO classifies pulmonary hypertension into 5 categories
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      (Table 1). Strictly speaking, pulmonary hypertension is a syndrome characterized by the presence of mean pulmonary artery pressure ≥25 mm Hg at rest as measured at right-sided cardiac catheterization.
      • Badesch D.B.
      • Champion H.C.
      • Sanchez M.A.
      • et al.
      Diagnosis and assessment of pulmonary arterial hypertension.
      In addition, for the diagnosis of pulmonary artery hypertension, formerly called precapillary pulmonary hypertension (group I in the WHO classification
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      ), pulmonary wedge pressure should be ≤15 mm Hg and pulmonary vascular resistance should be ≥3 Woods units.
      • Badesch D.B.
      • Champion H.C.
      • Sanchez M.A.
      • et al.
      Diagnosis and assessment of pulmonary arterial hypertension.
      Noninvasive estimates of pulmonary pressure also can be made by Doppler echocardiography studies. However, the diagnosis of pulmonary hypertension and particularly the diagnosis of pulmonary artery hypertension require right-sided cardiac catheterization. In Doppler echocardiography studies, measurement of pulmonary artery systolic pressure (PASP) is based on the tricuspid regurgitation jet, a phenomenon that can be recorded in most physiologic and pathologic conditions. In the absence of pulmonary stenosis, right ventricular systolic pressure PASP is estimated by the calculation of right ventricular systolic pressure by a modified Bernoulli equation and is computed as 4 times the square of maximum tricuspid regurgitation jet velocity (TRV), plus right atrial pressure (which in turn can be estimated from the vena cava diameter and degree of its inspiratory collapse).
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      Often, a fixed estimate of right atrial pressure is added when the inferior vena cava is not evaluated during echocardiography. In Doppler echocardiography studies, the presence of pulmonary hypertension is considered most probable when PASP is >50 mm Hg and/or TRV is faster than 3.4 m/s. PASP values of 35-49 and TRV values of 2.8-3.4 m/s are considered to suggest but not to diagnose pulmonary hypertension. It is important to emphasize that although superior to clinical history and physical examination,
      • Berger M.
      • Haimowitz A.
      • Van Tosh A.
      • Berdoff R.L.
      • Goldberg E.
      Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound.
      • Himelman R.B.
      • Struve S.N.
      • Brown J.K.
      • Namnum P.
      • Schiller N.B.
      Improved recognition of cor pulmonale in patients with severe chronic obstructive pulmonary disease.
      Doppler measurements of pulmonary pressure may be inaccurate when the tricuspid regurgitation jet is difficult to visualize.
      • Fisher M.R.
      • Forfia P.R.
      • Chamera E.
      • et al.
      Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension.
      Moreover, even when technically feasible, the method's estimates of pulmonary pressure frequently may be inaccurate.
      • Fisher M.R.
      • Forfia P.R.
      • Chamera E.
      • et al.
      Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension.
      Other echocardiographic parameters (namely right ventricular size, thickness, and function; right and left atrial volume; left ventricle systolic and diastolic function; valve anatomy and functioning; and assessment of the presence of pericardial effusion) provide useful complementary information for the diagnosis and prognostic appraisal of pulmonary hypertension.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      The strengths and limitations of Doppler echocardiography for the diagnosis of pulmonary hypertension are reviewed elsewhere.
      • Mathai S.
      • Hassoun P.
      The role of echocardiography in the diagnosis and assessment of pulmonary hypertension.
      Table 1WHO Diagnostic Classification of Pulmonary Hypertension
      ClassDefinitionConditions
      IIdiopathic, familial, and associated PAHConnective tissue diseases, HIV infection, congenital heart disease, portal hypertension and pulmonary veno-occlusive disease, drugs and toxins
      IIPH associated with left-sided heart diseaseLeft-sided heart systolic dysfunction, left-sided heart diastolic dysfunction, left-sided valvular disease (mitral and/or aortic)
      IIIPH associated with lung diseases and/or hypoxiaCOPD, interstitial lung disease, sleep apnea
      IVChronic thromboembolic PHObstruction of pulmonary arterial vessels (proximal or distal) by thromboemboli, tumors, or foreign bodies
      VPH with unclear or multifactorial causesDialysis-dependent CKD; several hematologic, systemic, and metabolic disorders; miscellaneous
      Note: Class I PH formerly was referred to as precapillary PH; class II, as postcapillary PH.
      Abbreviations: CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; WHO, World Health Organization.

      Epidemiology of Pulmonary Hypertension

      General Population

      Information about pulmonary hypertension at the community level is based mainly on the Olmsted County study, a cohort study in a random sample of the general population of one county.
      • Lam C.S.
      • Borlaug B.A.
      • Kane G.C.
      • Enders F.T.
      • Rodeheffer R.J.
      • Redfield M.M.
      Age-associated increases in pulmonary artery systolic pressure in the general population.
      In individuals older than 45 years in this population, the prevalence of pulmonary hypertension, defined as Doppler-derived PASP >35 mm Hg, was ∼5%. Most cases detected in Olmsted County were related to underlying left ventricular (LV) disorders: PASP was associated with both systemic hypertension and high pulse pressure and with diastolic dysfunction as measured by the E/e′ ratio (early transmitral flow velocity [E] to early mitral annular tissue velocity [e′]). The prevalence of pulmonary artery hypertension of the WHO class I diagnostic category, which includes a variety of diseases ranging from sporadic and idiopathic pulmonary hypertension to pulmonary hypertension attributable to connective tissue diseases, drugs, and various toxic agents, is much more rare at around 15 cases per million.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      In this diagnostic category, the prevalence of pulmonary artery hypertension related to background diseases is 7%-12% in systemic sclerosis,
      • Hachulla E.
      • Gressin V.
      • Guillevin L.
      • et al.
      Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study.
      • Mukerjee D.
      • St George D.
      • Coleiro B.
      • et al.
      Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach.
      2%-6% in portal hypertension,
      • Hadengue A.
      • Benhayoun M.K.
      • Lebrec D.
      • Benhamou J.P.
      Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics.
      • Krowka M.J.
      • Swanson K.L.
      • Frantz R.P.
      • McGoon M.D.
      • Wiesner R.H.
      Portopulmonary hypertension: results from a 10-year screening algorithm.
      and ∼30% in congenital heart disease.
      • Friedman W.F.
      Proceedings of National Heart, Lung, and Blood Institute Pediatric Cardiology Workshop: pulmonary hypertension.
      Pulmonary hypertension is exceedingly prevalent (15%-20%) in patients with sleep apnea (WHO diagnostic category III).
      • Kessler R.
      • Chaouat A.
      • Weitzenblum E.
      • et al.
      Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.
      A large survey in the United States that registered data for all forms of pulmonary hypertension from 1980-2002 documented that the death rate in patients with pulmonary hypertension during these 2 decades was stable, ranging from 5.2-5.4 deaths/100,000.
      • Hyduk A.
      • Croft J.B.
      • Ayala C.
      • et al.
      Pulmonary hypertension surveillance—United States, 1980-2002.
      • Martin K.B.
      • Klinger J.R.
      • Rounds S.I.
      Pulmonary arterial hypertension: new insights and new hope.

      Patients With CKD

      The prevalence of pulmonary hypertension in patients with CKD is difficult to estimate precisely because epidemiologic data for this disorder in patients with CKD are scarce and based mainly on retrospective data and/or small studies with methodological limitations. Although an international group of experts recommended that the diagnosis of pulmonary hypertension should be based on right-sided cardiac catheterization and defined as the presence of mean pulmonary artery pressure ≥25 mm Hg,
      • Badesch D.B.
      • Champion H.C.
      • Sanchez M.A.
      • et al.
      Diagnosis and assessment of pulmonary arterial hypertension.
      only one study has measured PASP with invasive methods in patients with CKD.
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      In most studies of patients with CKD, pulmonary artery pressure has been estimated as Doppler-derived PASP, but there is no uniformity in diagnostic criteria. Various PASP cutoffs have been applied, ranging from 25 to ≥45 mm Hg,
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      • Bozbas S.S.
      • Akcay S.
      • Altin C.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      • Amin M.
      • Fawzy A.
      • Hamid M.A.
      • Elhendy A.
      Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
      • Tarrass F.
      • Benjelloun M.
      • Medkouri G.
      • Hachim K.
      • Benghanem M.G.
      • Ramdani B.
      Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis.
      • Mahdavi-Mazdeh M.
      • Alijavad-Mousavi S.
      • Yahyazadeh H.
      • Azadi M.
      • Yoosefnejad H.
      • Ataiipoor Y.
      Pulmonary hypertension in hemodialysis patients.
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      • Unal A.
      • Sipahioglu M.
      • Oguz F.
      • et al.
      Pulmonary hypertension in peritoneal dialysis patients: prevalence and risk factors.
      • Casas-Aparicio G.
      • Castillo-Martínez L.
      • Orea-Tejeda A.
      • Abasta-Jiménez M.
      • Keirns-Davies C.
      • Rebollar-González V.
      The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      • Zlotnick D.M.
      • Axelrod D.A.
      • Chobanian M.C.
      • et al.
      Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      • Kiykim A.A.
      • Horoz M.
      • Ozcan T.
      • Yildiz I.
      • Sari S.
      • Genctoy G.
      Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
      and in one study, TRV ≥2.5 m/s was adopted as the major criterion to make the diagnosis of pulmonary hypertension.
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      The variability of the criteria adopted in these studies explains the wide range of the reported prevalence of pulmonary hypertension in patients with CKD and hinders crude comparisons among studies (Table 2). Of note, no data for the prevalence of pulmonary hypertension in patients with CKD stages 1-3 currently are available. In about half the studies of patients with CKD, PASP was estimated after creation of an arteriovenous fistula (AVF), which itself may provoke pulmonary hypertension (discussed later). In patients with non–dialysis-dependent CKD stage 5 (NDD-CKD5), the prevalence of pulmonary hypertension ranges from 9%-39%
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      (Fig 1). Thus, NDD-CKD5 is a condition with a prevalence of pulmonary hypertension that is about 2-8 times higher than in the general population. Figure 1 also shows the prevalence of pulmonary hypertension in relation to various diagnostic cutoffs and CKD stages. As expected, the prevalence of pulmonary hypertension is related inversely to the pulmonary pressure cutoff. Furthermore, pulmonary hypertension prevalence is higher in the dialysis population than in patients with NDD-CKD5. In the only study that measured pulmonary artery pressure by right-sided cardiac catheterization,
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      pulmonary hypertension was observed in 81% of hemodialysis (HD) patients and 71% of patients with CKD stages 4-5. The very high prevalence in this study arises because it enrolled only individuals with dyspnea that was unexplained by other causes, as opposed to previous studies involving unselected populations. In this selected population, the prevalence of pulmonary artery hypertension (WHO class I) was 6% in patients with CKD stages 4-5 and 13% in HD patients, and the prevalence of WHO class II pulmonary hypertension was 71% and 65%, respectively. Of note, in HD patients, pulmonary artery hypertension was unmasked by studies that were performed after dialysis. Thus, these findings suggest that pulmonary artery hypertension should be suspected in both dialysis patients and patients with NDD-CKD4-5 if they have unexplained dyspnea, and they further suggest that diagnostic studies by right-sided cardiac catheterization in HD patients should be made after dialysis.
      Table 2Studies of PH in Patients With CKD
      StudyCountryNPH Criteria
      Values are given in mm Hg.
      PH Prevalence (%)NotesStudy Quality
      Because studies with different designs were appraised, a 3-level classification of quality was developed considering the completeness of reporting of title/abstract, introduction, methods, results, discussion, and other information, as indicated in the STROBE checklist of 22 items.38 Good quality indicates more than 15 items correctly addressed; medium quality, 5-15 items addressed; and low quality, fewer than 5 items.
      PH in CKD5
      Pabst
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      (2012)
      This study enrolled only patients in WHO functional class higher than II with dyspnea unexplained by other causes. Some patients had CKD stage 4 (exact number not reported).
      DE31mPASP ≥2571PAH (WHO I) in 6% and WHO II in 71%Medium
      Yigla
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      (2009)
      IL127ePASP ≥4513.4PH before HD initiation associated with higher risk of death (HR, 3.6)Good
      Issa
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      (2008)
      US215
      This retrospective study analyzed data from 215 transplant candidates, including those with CKD5 and CKD5D (HD/PD). The exact number of patients in those subcategories was not specified.
      ePASP ≥3525PASP ≥50 independently associated with reduced post-Tx survival (HR, 3.75)Medium
      Abdelwhab
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      (2008)
      EG31ePASP ≥3532.3Mean PASP significantly higher in HD pts than CKD ptsMedium
      Yigla
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      (2003)
      IL12ePASP ≥358.3After HD initiation, PH developed in 2/3 of CKD pts with initially normal PASPMedium
      Havlucu
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      (2007)
      TR23ePASP ≥3539.144% of CKD pts with PH had an AVFMedium
      PH in CKD5D
      Pabst
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      (2012)
      This study enrolled only patients in WHO functional class higher than II with dyspnea unexplained by other causes. Some patients had CKD stage 4 (exact number not reported).
      DE31 HDmPASP≥258PH (WHO II) in 77% and WHO I in 13%; significant post-HD decrease in mPAP and PCWPMedium
      Yigla
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      (2009)
      IL127 HDePASP ≥4529.1PH after HD initiation associated with higher risk of death (HR, 2.4)Good
      Ramasubbu
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      (2012)
      US90 HDTRJ ≥2.5 m/s47After 12 mo, pts with PH had increased mortality (26%) vs those without (6%)Good
      Nakhoul
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
      (2005)
      IL42 HDePASP ≥25 (at rest) or ≥30 (with exercise)48Higher cardiac output and lower circulating levels of NO metabolites in pts with PH vs those withoutMedium
      Issa
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      (2008)
      US215 NDD-CKD/HD/PD
      This retrospective study analyzed data from 215 transplant candidates, including those with CKD5 and CKD5D (HD/PD). The exact number of patients in those subcategories was not specified.
      ePASP ≥3532No difference in mean PH in HD vs PD pts; PASP ≥50 independently associated with reduced post-Tx survival (HR, 3.75)Medium
      Abdelwhab
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      (2008)
      EG45 HDePASP ≥3544.4PASP correlated with AVF blood flow, pro-BNP, and LVDDMedium
      Yigla
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      (2003)
      IL58 HD; 5 PDePASP ≥3539.7 HD; 0 PDHigher mortality rate in HD pts with PH (30.8%) vs those without (3.5%)Medium
      Havlucu
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      (2007)
      TR25 HDePASP ≥3556PASP correlated directly with AVF flow and duration and inversely with residual urine volumeMedium
      Bozbas
      • Bozbas S.S.
      • Akcay S.
      • Altin C.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
      (2009)
      TR432 HD; 68 PDePASP ≥3018.8 HD; 5.9 PDNo differences in prevalence of COPD, asthma, smoking, HTN, and DM in pts with vs without PHMedium
      Yigla
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      (2004)
      IL49 HDePASP ≥3557.1No correlations between severity of pulmonary calcifications and PHGood
      Amin
      • Amin M.
      • Fawzy A.
      • Hamid M.A.
      • Elhendy A.
      Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
      (2003)
      EG51 HDePASP ≥3529No correlations between PH and PTH levels or pulmonary calcificationsMedium
      Tarrass
      • Tarrass F.
      • Benjelloun M.
      • Medkouri G.
      • Hachim K.
      • Benghanem M.G.
      • Ramdani B.
      Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis.
      (2006)
      MA86 HDePASP ≥3526.7No correlations between PH and PTH levelsLow
      Mahdavi-Mazdeh
      • Mahdavi-Mazdeh M.
      • Alijavad-Mousavi S.
      • Yahyazadeh H.
      • Azadi M.
      • Yoosefnejad H.
      • Ataiipoor Y.
      Pulmonary hypertension in hemodialysis patients.
      (2008)
      IR62 HDePASP ≥3551.6Hb and albumin levels significantly lower in pts with PHLow
      Etemadi
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      (2011)
      IR278 HD; 145 PDePASP ≥3541.1 HD; 18.7 PDSerum iron and Hb levels significantly lower in pts with PHLow
      Unal
      • Unal A.
      • Sipahioglu M.
      • Oguz F.
      • et al.
      Pulmonary hypertension in peritoneal dialysis patients: prevalence and risk factors.
      (2009)
      TR135 PDePASP ≥3512.6PASP independently associated with ECW and LVMIMedium
      Casas-Aparicio
      • Casas-Aparicio G.
      • Castillo-Martínez L.
      • Orea-Tejeda A.
      • Abasta-Jiménez M.
      • Keirns-Davies C.
      • Rebollar-González V.
      The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
      (2010)
      MX35 HDePASP ≥4048.6After kidney Tx, LVF and ePASP significantly improved and PH prevalence decreased to 15.3%Medium
      Fabbian
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      (2011)
      IT29 HD; 27 PDePASP ≥3558.6 HD; 18.5 PDPH independently associated with dialysis vintage and DBPLow
      Zlotnick
      • Zlotnick D.M.
      • Axelrod D.A.
      • Chobanian M.C.
      • et al.
      Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
      (2010)
      US55 HDePASP ≥3538PH in HD pts associated with increased risk of early graft dysfunctionMedium
      Kumbar
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.
      (2007)
      US36 PDePASP ≥3542PASP correlated with serum phosphorus and PTH levels, and Ca × PLow
      Agarwal

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      (2011)
      US288 HDePASP ≥3538In multivariate analyses, PH an independent predictor for all-cause mortality (HR, 2.17; 95% CI, 1.31-3.61; P < 0.01)Good
      Kiykim
      • Kiykim A.A.
      • Horoz M.
      • Ozcan T.
      • Yildiz I.
      • Sari S.
      • Genctoy G.
      Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
      (2010)
      TR74 HDePASP ≥3068.8Decrease in pulmonary artery pressure after HD with high-flux polysulfone membraneLow
      Note: Search strategy and selection process are provided in Item S1 (available as online supplementary material). Class I PH formerly was referred to as precapillary PH; class II, as postcapillary PH.
      Abbreviations: AVF, arteriovenous fistula; Ca × P, calcium-phosphorus product; CI, confidence interval; CKD, chronic kidney disease; CKD5(D), chronic kidney disease stage 5 (treated by dialysis); COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; DE, Germany; DM, diabetes mellitus; ECW, extracellular water; EG, Egypt; ePASP, estimated pulmonary artery pressure (echocardiography); Hb, hemoglobin; HD, hemodialysis; HR, hazard ratio; HTN, hypertension; IL, Israel; IR, Iran; IT, Italy; LVDD, left ventricular diastolic dysfunction; LVF, left ventricular function; LVMI, left ventricular mass index; MA, Morocco; mPASP, measured pulmonary artery pressure (by right-sided cardiac catheterization); MX, Mexico; NDD-CKD, non–dialysis-dependent chronic kidney disease; NO, nitric oxide; PAH, pulmonary artery hypertension, PASP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PD, peritoneal dialysis; PH, pulmonary hypertension; pro-BNP, pro–B-type natriuretic peptide; pt, patient; PTH, parathyroid hormone; TRJ, tricuspid regurgitation jet; TR, Turkey; Tx, transplantation; WHO, World Health Organization.
      a Values are given in mm Hg.
      b Because studies with different designs were appraised, a 3-level classification of quality was developed considering the completeness of reporting of title/abstract, introduction, methods, results, discussion, and other information, as indicated in the STROBE checklist of 22 items.
      • Vandenbroucke J.P.
      • von Elm E.
      • Altman D.G.
      • et al.
      Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.
      Good quality indicates more than 15 items correctly addressed; medium quality, 5-15 items addressed; and low quality, fewer than 5 items.
      c This study enrolled only patients in WHO functional class higher than II with dyspnea unexplained by other causes. Some patients had CKD stage 4 (exact number not reported).
      d This retrospective study analyzed data from 215 transplant candidates, including those with CKD5 and CKD5D (HD/PD). The exact number of patients in those subcategories was not specified.
      Figure thumbnail gr1
      Figure 1Prevalence of pulmonary hypertension (PH) in existing studies in relationship to (A) diagnostic cutoffs and (B) chronic kidney disease (CKD) stage. Reference numbers are indicated next to cutoff points. Abbreviations: HD, hemodialysis; NDD-CKD, non–dialysis-dependent chronic kidney disease; PD, peritoneal dialysis.
      Most studies of patients with CKD were performed in Middle Eastern populations
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      • Bozbas S.S.
      • Akcay S.
      • Altin C.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      • Amin M.
      • Fawzy A.
      • Hamid M.A.
      • Elhendy A.
      Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
      • Tarrass F.
      • Benjelloun M.
      • Medkouri G.
      • Hachim K.
      • Benghanem M.G.
      • Ramdani B.
      Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis.
      • Mahdavi-Mazdeh M.
      • Alijavad-Mousavi S.
      • Yahyazadeh H.
      • Azadi M.
      • Yoosefnejad H.
      • Ataiipoor Y.
      Pulmonary hypertension in hemodialysis patients.
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      • Unal A.
      • Sipahioglu M.
      • Oguz F.
      • et al.
      Pulmonary hypertension in peritoneal dialysis patients: prevalence and risk factors.
      • Kiykim A.A.
      • Horoz M.
      • Ozcan T.
      • Yildiz I.
      • Sari S.
      • Genctoy G.
      Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
      ; limited information is available regarding CKD populations in other countries.
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      • Casas-Aparicio G.
      • Castillo-Martínez L.
      • Orea-Tejeda A.
      • Abasta-Jiménez M.
      • Keirns-Davies C.
      • Rebollar-González V.
      The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      • Zlotnick D.M.
      • Axelrod D.A.
      • Chobanian M.C.
      • et al.
      Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      In 5 studies performed in the United States,
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      • Zlotnick D.M.
      • Axelrod D.A.
      • Chobanian M.C.
      • et al.
      Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      the prevalence of pulmonary hypertension ranged from 25%-47%; values were more consistent (32%-42%) in the 4 studies that adopted an identical diagnostic cutoff (Doppler-derived PASP ≥35 mm Hg).
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      • Zlotnick D.M.
      • Axelrod D.A.
      • Chobanian M.C.
      • et al.
      Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      For the relationship between pulmonary hypertension and dialysis type, Fig 1 shows that the prevalence of pulmonary hypertension is lower in patients treated with peritoneal dialysis (PD; 0%-42%) than HD (18.8%-68.8%).
      • Bozbas S.S.
      • Akcay S.
      • Altin C.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      • Unal A.
      • Sipahioglu M.
      • Oguz F.
      • et al.
      Pulmonary hypertension in peritoneal dialysis patients: prevalence and risk factors.
      • Casas-Aparicio G.
      • Castillo-Martínez L.
      • Orea-Tejeda A.
      • Abasta-Jiménez M.
      • Keirns-Davies C.
      • Rebollar-González V.
      The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      • Kumbar L.
      • Fein P.A.
      • Rafiq M.A.
      • Borawski C.
      • Chattopadhyay J.
      • Avram M.M.
      Pulmonary hypertension in peritoneal dialysis patients.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      • Kiykim A.A.
      • Horoz M.
      • Ozcan T.
      • Yildiz I.
      • Sari S.
      • Genctoy G.
      Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
      In studies that directly compare patients with CKD stage 5 at the same institution who are treated with HD with those treated with PD and that take into account the presence of a fistula, pulmonary hypertension was much less frequent in PD patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Bozbas S.S.
      • Akcay S.
      • Altin C.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      After kidney transplantation, pulmonary hypertension often is related to the evolution of associated LV disorders; that is, pulmonary hypertension frequently improves in patients who exhibit improved LV function.
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
      • Casas-Aparicio G.
      • Castillo-Martínez L.
      • Orea-Tejeda A.
      • Abasta-Jiménez M.
      • Keirns-Davies C.
      • Rebollar-González V.
      The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
      No data currently are available comparing clinical outcomes in patients with CKD stage 5 with and without pulmonary hypertension. However, observations in a cohort of 500 patients with WHO class I pulmonary hypertension
      • Shah S.J.
      • Thenappan T.
      • Rich S.
      • Tian L.
      • Archer S.L.
      • Gomberg-Maitland M.
      Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension.
      suggest that CKD conveys a higher risk of pulmonary hypertension. In this cohort, elevated serum creatinine levels were associated with higher right atrial pressure, lower cardiac index, and increased death risk.
      Information about the impact of pulmonary hypertension on clinical outcomes in patients with kidney disease on HD therapy was gathered in only 4 cohort studies.
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      Two
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      are based largely on the same cohort, but had different patient accrual and used different diagnostic criteria. In the first analysis of 58 patients in this cohort,
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      patients with Doppler-derived PASP ≥35 mm Hg had a higher mortality rate (30.8%) compared with those with PASP ≤35 mm Hg (3.5%). In the second analysis, which investigated 127 patients in the same cohort,
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      pulmonary hypertension (here defined as Doppler-derived PASP ≥45 mm Hg) was an independent risk factor for death whether it was detected before initiating dialysis therapy or after beginning regular HD treatment (hazard ratios [HRs] of 3.6 and 2.4, respectively). In the third study
      • Ramasubbu K.
      • Deswal A.
      • Herdejurgen C.
      • Aguilar D.
      • Frost A.E.
      A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
      of 90 maintenance HD patients with AVFs, pulmonary hypertension (defined as TRV ≥2.5 m/s) was explained by impaired left systolic ventricular function and elevated pulmonary capillary wedge pressure. Furthermore, mortality was 4-fold higher in patients with pulmonary hypertension (26% per year) compared with those without pulmonary hypertension (6%). Finally, in a very recent study,

      Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

      pulmonary hypertension had a 38% prevalence in a cohort of 228 HD patients and conveyed a high risk of death (HR, 2.17; 95% confidence interval, 1.31-3.61; P < 0.01) in adjusted analyses. Of note, in a study of 215 patients on maintenance dialysis therapy, the presence of pulmonary hypertension before kidney transplantation predicted risk of death after transplantation, which suggests that transplantation may not reverse the excess risk associated with established pulmonary hypertension.
      • Issa N.
      • Krowka M.J.
      • Griffin M.D.
      • Hickson L.J.
      • Stegall M.D.
      • Cosio F.G.
      Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
      Large prospective studies adopting well-standardized criteria including right-sided cardiac catheterization are needed to assess the risk of developing pulmonary hypertension in patients with NDD-CKD5 and dialysis patients. Importantly, these studies should specifically assess whether pulmonary hypertension is a corollary to concomitant LV disorders but by itself has only a modest direct impact on clinical outcomes or whether pulmonary hypertension represents a truly independent risk factor for death and adverse cardiovascular outcomes for patients with CKD. Furthermore, epidemiologic studies that specifically focus on the members of CKD population who are receiving conservative treatment and do not have an AVF are required to assess the potential impact of pulmonary hypertension on clinical outcomes independently of pre-existing cardiovascular or pulmonary diseases. Well-designed intervention studies are needed in both dialysis patients and those with NDD-CKD to definitively establish whether pulmonary hypertension in CKD represents a modifiable risk factor.

      Risk Factors for Pulmonary Hypertension in Patients With CKD

      Overview

      There are no proper longitudinal studies detailing the natural history of pulmonary hypertension in CKD, from its early stages to kidney failure. The factors responsible for pulmonary hypertension in patients with NDD-CKD5 and HD patients, particularly alterations that influence the control of vascular tone in the lung, are poorly defined. As previously reported, most cases of pulmonary hypertension in patients with CKD are classified as WHO class II.
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      In these patients, pulmonary wedge pressure is >15 mm Hg and depends on associated LV disorders. WHO class I, for which pulmonary wedge pressure is ≤15 mm Hg, is caused by high arteriolar tone similar to that of idiopathic forms of pulmonary artery hypertension or pulmonary artery hypertension secondary to systemic disorders such as scleroderma. This section discusses a list of factors for which the role in pulmonary hypertension in patients with CKD has been reasonably well assessed. Most patients with CKD are affected by one or more comorbid conditions that by themselves may induce and/or exacerbate pulmonary hypertension, with the particular mechanism(s) varying according to the patient's concomitant LV disorders. Furthermore, as discussed next, CKD and HD treatment may trigger other risk factors acting at the precapillary level.

      LV Disorders, Volume Overload, and Lung Disease

      Hypertension and diabetes mellitus, 2 dominant causes of kidney disease, trigger LV diastolic dysfunction, an alteration bound to increase pulmonary venous and arterial pressure.
      • Tiengo A.
      • Fadini G.P.
      • Avogaro A.
      The metabolic syndrome, diabetes and lung dysfunction.
      Chronic volume overload, a factor implicated in LV disorders and in the high venous return in patients with CKD, may induce pulmonary venous hypertension by both increasing pulmonary blood flow and adversely affecting LV function. In addition, myocardial stiffness secondary to myocardial infarction, another frequent complication of CKD, may contribute to pulmonary hypertension. In categorical terms, patients with LV disorders and/or volume overload constitute group II of the WHO classification, whereas patients with lung diseases, either restrictive (ie, obese patients with CKD) or obstructive (ie, patients with chronic obstructive pulmonary disease), are grouped in WHO class III.
      • Badesch D.B.
      • Champion H.C.
      • Sanchez M.A.
      • et al.
      Diagnosis and assessment of pulmonary arterial hypertension.
      In chronic obstructive pulmonary disease, the main mechanism underlining increased pulmonary pressure is chronic hypoxia, a potent pulmonary vasoconstrictor.
      • Evans A.M.
      • Hardie D.G.
      • Peers C.
      • Mahmoud A.
      Hypoxic pulmonary vasoconstriction: mechanisms of oxygen-sensing.
      If sustained, vasoconstriction in the lung leads to extensive remodeling of the pulmonary vessels and a steady reduction in vessel compliance, a phenomenon which in and of itself contributes to pulmonary hypertension.
      • Sakao S.
      • Tatsumi K.
      • Voelkel N.F.
      Reversible or irreversible remodeling in pulmonary arterial hypertension.
      Pulmonary capillary wedge pressure is considered to be a reliable marker for LV end-diastolic pressure. However, determining whether left-sided cardiac disease is present on the basis of pulmonary capillary wedge pressure is unreliable in patients with pulmonary hypertension because ∼50% of patients who are considered to have pulmonary artery hypertension on the basis of pulmonary capillary wedge pressure eventually may turn out to have WHO class II pulmonary hypertension instead when diagnosed on the basis of LV end-diastolic pressure.
      • Halpern S.C.
      • Taichman D.B.
      Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure.
      Thus, when there is a choice between pulmonary capillary wedge pressure and LV end-diastolic pressure in a patient with pulmonary hypertension, LV end-diastolic pressure should be regarded as the gold standard for the diagnostic definition of pulmonary hypertension.

      Arteriovenous Fistula

      AVFs, be they the result of trauma or intentionally created, have profound hemodynamic effects. An AVF leads to decreased systemic vascular resistances, enhanced venous return, and increased cardiac output to maintain proper blood flow to all organs and tissues. These adaptations increase pulmonary blood flow and set the stage for pulmonary hypertension. Because pressure is the product of flow and resistance, increased pulmonary flow necessarily leads to increased pressure at any level of pulmonary vascular resistance. Well-performed studies show that pulmonary pressure increases in strict temporal relationship with AVF creation
      • Abassi Z.
      • Nakhoul F.
      • Khankin E.
      • Reisner S.A.
      • Yigla M.
      Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective.
      and that pulmonary hypertension tends to worsen over time in this population.
      • Havlucu Y.
      • Kursat S.
      • Ekmekci C.
      • et al.
      Pulmonary hypertension in patients with chronic renal failure.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
      Accordingly, in HD patients, AVF flow and AVF duration are related independently to the severity of pulmonary hypertension.
      • Abdelwhab S.
      • Elshinnawy S.
      Pulmonary hypertension in chronic renal failure patients.
      AVF compression by a sphygmomanometer
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      or surgical AVF closure
      • Clarkson M.R.
      • Giblin L.
      • Brown A.
      • Little D.
      • Donohoe J.
      Reversal of pulmonary hypertension after ligation of a brachiocephalic arteriovenous fistula.
      induces a rapid decrease in mean cardiac output followed by a stable decrease in pulmonary pressure. As discussed, AVFs may explain in part why the prevalence of pulmonary hypertension is higher in HD patients than in PD patients.
      • Yigla M.
      • Nakhoul F.
      • Sabag A.
      • et al.
      Pulmonary hypertension in patients with end-stage renal disease.
      • Etemadi J.
      • Zolfaghari H.
      • Firoozi R.
      • et al.
      Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
      • Fabbian F.
      • Cantelli S.
      • Molino C.
      • Pala M.
      • Longhini C.
      • Portaluppi F.
      Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.

      Exposure to Dialysis Membranes

      Neutrophil activation secondary to blood–dialysis membrane contact accompanied by reversible neutrophil sequestration in the lung, a phenomenon that was intensively investigated in the 1980s,
      • Craddock P.R.
      • Fehr J.
      • Dalmasso A.P.
      • Brigham K.L.
      • Jacob H.S.
      Hemodialysis leucopenia.
      • Craddock P.R.
      • Fehr J.
      • Brigham K.L.
      • Kronenberg R.S.
      • Jacob H.S.
      Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis.
      contributes to causing or worsening microvascular lung disease in HD patients.
      • Yigla M.
      • Abassi Z.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary hypertension in hemodialysis patients: an unrecognized threat.
      This phenomenon is particularly pronounced when dialysis is performed using cellulosic membranes and is attenuated but not abolished with synthetic and modified cellulosic membranes. In a crossover trial of a series of 74 patients without an AVF who were dialyzed through a central venous catheter, use of high-flux polysulfone filters was associated with a more pronounced decrease in postdialysis pulmonary pressure than the use of cellulose acetate filters.
      • Kiykim A.A.
      • Horoz M.
      • Ozcan T.
      • Yildiz I.
      • Sari S.
      • Genctoy G.
      Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
      The hypothesis that volume overload and LV disorders triggered or exacerbated by kidney disease and repeated exposure to dialysis membranes may cause pulmonary hypertension independently of the AVF and other factors is supported by the demonstration that kidney transplantation may revert pulmonary artery pressure to normal in patients who still have a functioning AVF.
      • Nakhoul F.
      • Yigla M.
      • Gilman R.
      • Reisner S.A.
      • Abassi Z.
      The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.

      Systemic Diseases Associated With CKD

      Pre-existing connective tissue diseases and superimposed infectious, hematologic, and liver diseases can all contribute to pulmonary hypertension in patients with CKD by mechanisms that interfere with the control of microvascular tone in the lung (WHO class I; Fig 2). However, collectively, these factors largely fail to explain the high prevalence of pulmonary hypertension in dialysis patients because most patients with CKD exhibit pulmonary hypertension even in the absence of these diseases.
      • Yigla M.
      • Abassi Z.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary hypertension in hemodialysis patients: an unrecognized threat.
      Figure thumbnail gr2
      Figure 2Main mechanisms proposed to explain the pathogenesis of pulmonary hypertension (PH) in patients with chronic kidney disease. Abbreviations: AV, arteriovenous, COPD, chronic obstructive pulmonary disease; LV, left ventricular.

      Endothelial Dysfunction

      Endothelial dysfunction is a main trigger of pulmonary hypertension.
      • Giaid A.
      Nitric oxide and endothelin-1 in pulmonary hypertension.
      This link is even more relevant in pulmonary hypertension in patients with CKD, in whom endothelial dysfunction is pervasive.
      • Zoccali C.
      The endothelium as a target in renal diseases.
      The impaired capacity of the endothelium to regulate vascular tone in patients with CKD depends on an imbalance between vasoconstrictors (eg, high levels of endothelin 1) and vasodilators (reduced generation of nitric oxide [NO]).
      • Giaid A.
      Nitric oxide and endothelin-1 in pulmonary hypertension.
      • Giaid A.
      • Saleh D.
      Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.
      The role of endothelial dysfunction in HD patients with pulmonary hypertension is supported by cross-sectional findings that show that plasma NO levels are decreased in HD patients with pulmonary hypertension compared with those without pulmonary hypertension and by the observation that HD treatment increases NO levels in patients without pulmonary hypertension to a greater extent than in those with pulmonary hypertension.
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      In this respect, asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase that is synthesized abundantly at lung level
      • Arrigoni F.I.
      • Vallance P.
      • Haworth S.G.
      • Leiper J.M.
      Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia.
      and that accumulates in CKD,
      • Zoccali C.
      • Bode-Böger S.
      • Mallamaci F.
      • et al.
      Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.
      has been implicated strongly in experimental
      • Sasaki A.
      • Doi S.
      • Mizutani S.
      • Azuma H.
      Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats.
      and primary
      • Kielstein J.T.
      • Bode-Böger S.M.
      • Hesse G.
      • et al.
      Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension.
      forms of pulmonary hypertension. ADMA attains very high concentrations in patients with kidney disease.
      • Zoccali C.
      • Bode-Böger S.
      • Mallamaci F.
      • et al.
      Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.
      Thus, ADMA is a prime uremic toxin potentially implicated in pulmonary hypertension in this population.

      Sleep-Disordered Breathing

      Sleep apnea is a factor of paramount importance for the high risk of pulmonary hypertension in the setting of CKD. Episodes of nocturnal hypoxia, the key pathophysiologic effect of sleep apnea, are frequent in patients with CKD regardless of whether they are dialysis dependent.
      • Sakaguchi Y.
      • Shoji T.
      • Kawabata H.
      • et al.
      High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in Japan: a cross-sectional study.
      • Zoccali C.
      • Mallamaci F.
      • Tripepi G.
      Nocturnal hypoxemia predicts incident cardiovascular complications in dialysis patients.
      As we discuss next, volume overload is a major factor in sleep apnea, particularly in patients with kidney disease. Nocturnal hypoxemia arising from sleep apnea is a strong trigger of pulmonary hypertension in experimental models,
      • Ressl J.
      • Urbanová D.
      • Widimský J.
      • Ostádal B.
      • Pelouch V.
      • Procházka J.
      Reversibility of pulmonary hypertension and right ventricular hypertrophy induced by intermittent high altitude hypoxia in rats.
      and a close link between oxygen saturation and pulmonary artery pressure has been established in clinical physiology experiments in both healthy persons and patients with chronic obstructive pulmonary disease.
      • Ward J.P.
      • McMurtry I.F.
      Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem.
      Sympathetic activation is the main mechanism whereby hypoxemia increases pulmonary pressure.
      • Sica A.L.
      • Greenberg H.E.
      • Ruggiero D.A.
      • Scharf S.M.
      Chronic-intermittent hypoxia: a model of sympathetic activation in the rat.
      In this respect, it is interesting to note that patients with sleep-disordered breathing have increased ADMA levels.
      • Barceló A.
      • de la Peña M.
      • Ayllón O.
      • et al.
      Increased plasma levels of asymmetric dimethylarginine and soluble CD40 ligand in patients with sleep apnea.
      Furthermore, circulating levels of this NO synthase inhibitor are associated with sympathetic nerve activity (as assessed by measurements in the peroneal nerve) in patients with CKD
      • Grassi G.
      • Seravalle G.
      • Ghiadoni L.
      • et al.
      Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease.
      and with norepinephrine levels in dialysis patients.
      • Mallamaci F.
      • Tripepi G.
      • Maas R.
      • Malatino L.
      • Böger R.
      • Zoccali C.
      Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease.
      Given the strong vasoconstriction potential of ADMA in the lung vasculature and the observation that sympathetic nervous system activity and ADMA seem to share a common pathogenic pathway that is conducive to LV hypertrophy
      • Grassi G.
      • Seravalle G.
      • Ghiadoni L.
      • et al.
      Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease.
      in patients with CKD and to cardiovascular events in dialysis patients,
      • Tripepi G.
      • Mattace Raso F.
      • Sijbrands E.
      • et al.
      Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients.
      it appears possible that the same pathogenic pathway be implicated in pulmonary hypertension in these patients.

      Risk Factors Specific to CKD

      PASP was related directly to pulse and systolic pressure, as well as to age, in the Olmsted study, which suggests that in the community setting, pulmonary artery stiffening may have a role in pulmonary hypertension.
      • Lam C.S.
      • Borlaug B.A.
      • Kane G.C.
      • Enders F.T.
      • Rodeheffer R.J.
      • Redfield M.M.
      Age-associated increases in pulmonary artery systolic pressure in the general population.
      As part of a systemic phenomenon, arterial rigidity is increased in patients with CKD and calcium deposits can be demonstrated in the pulmonary artery in patients with kidney disease, thus implicating arterial stiffness in pulmonary hypertension in this population.
      • Nitta K.
      • Akiba T.
      • Uchida K.
      • et al.
      The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis.
      Stiffness aside, experimental studies in dogs show that parathyroid hormone levels may increase pulmonary resistances.
      • Akmal M.
      • Barndt R.R.
      • Ansari A.N.
      • Mohler J.G.
      • Massry S.G.
      Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy.
      However, 2 independent studies in patients with kidney disease
      • Yigla M.
      • Keidar Z.
      • Safadi I.
      • Tov N.
      • Reisner S.A.
      • Nakhoul F.
      Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
      • Amin M.
      • Fawzy A.
      • Hamid M.A.
      • Elhendy A.
      Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
      failed to show an association between severity of pulmonary calcifications and parathyroid hormone level. Furthermore, parathyroid hormone levels do not differ between patients with and without pulmonary hypertension.
      • Amin M.
      • Fawzy A.
      • Hamid M.A.
      • Elhendy A.
      Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
      Severe anemia is an established cardiovascular risk factor in CKD and its impact on the cardiovascular system extends to pulmonary circulation because low hemoglobin levels can contribute to pulmonary hypertension by aggravating hypoxia triggered by concomitant conditions.
      • Buemi M.
      • Senatore M.
      • Gallo G.C.
      • et al.
      Pulmonary hypertension and erythropoietin.

      Treating Pulmonary Hypertension in Patients With CKD

      The treatment of pulmonary hypertension in patients with CKD has not been investigated in specific studies to date. The high prevalence of LV disorders in patients with CKD probably explains why most cases of pulmonary hypertension in this population are WHO class II.
      • Pabst S.
      • Hammerstingl C.
      • Hundt F.
      • et al.
      Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
      In the absence of specific studies, recommendations for the treatment of WHO class II pulmonary hypertension in the general population
      • Akmal M.
      • Barndt R.R.
      • Ansari A.N.
      • Mohler J.G.
      • Massry S.G.
      Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy.
      also can be extended provisionally to patients with CKD. In particular, treating underlying LV disorders appears fundamental in both patients with NDD-CKD5 and dialysis patients. Careful attention to optimizing body fluid volume in patients with CKD by diuretics, reducing dietary salt intake, and/or appropriate dialysis treatment intensification cannot be overemphasized. In patients with CKD with WHO class II pulmonary hypertension (pulmonary hypertension secondary to LV disorders), vasodilator therapy, which currently is recommended for WHO class I patients,
      • Barst R.J.
      • Gibbs J.S.
      • Ghofrani H.A.
      Updated evidence-based treatment algorithm in pulmonary arterial hypertension.
      should be avoided because it potentially is harmful. A randomized trial testing epoprostenol in 471 patients with pulmonary hypertension and severe LV dysfunction
      • Califf R.M.
      • Adams K.F.
      • McKenna W.J.
      • et al.
      A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST).
      was terminated early due to an increase in mortality.
      As discussed, sleep apnea, a frequent complication in patients with NDD-CKD5 and dialysis patients, is a potent trigger of pulmonary hypertension. Thus, sleep apnea should be suspected and systematically investigated in patients with CKD with high PASP. Sleep apnea is attributed in large part to edema in the hypopharynx (rostral edema). Supine position and hypopharynx relaxation during nocturnal sleep aggravate rostral edema.
      • Redolfi S.
      • Arnulf I.
      • Pottier M.
      • Bradley T.D.
      • Similowski T.
      Effects of venous compression of the legs on overnight rostral fluid shift and obstructive sleep apnea.
      Reducing or correcting volume excess by PD
      • Tang S.C.
      • Lam B.
      • Lai A.S.
      • et al.
      Improvement in sleep apnea during nocturnal peritoneal dialysis is associated with reduced airway congestion and better uremic clearance.
      or by intensifying HD
      • Hanly P.J.
      • Pierratos A.
      Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis.
      produces a dramatic improvement in sleep apnea. However, we still have no proof that this translates into a meaningful decrease in PASP in dialysis patients. Based on observations in patients with other forms of sleep apnea, it seems likely that such treatment would have a beneficial effect on pulmonary hypertension in dialysis patients. In patients with pulmonary hypertension and high AVF flow, interventions aimed at reducing AVF flow may be considered when clinically indicated.
      As we have discussed, in symptomatic HD patients, repeated exposure to dialysis membranes may adversely affect lung microcirculation,
      • Vandenbroucke J.P.
      • von Elm E.
      • Altman D.G.
      • et al.
      Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.
      and the high frequency of pulmonary artery hypertension in symptomatic dialysis patients
      • Yigla M.
      • Fruchter O.
      • Aharonson D.
      • et al.
      Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
      further supports this possibility. In dialysis patients with persisting pulmonary hypertension after volume overload has been corrected and LV disorders have been treated adequately, right-sided cardiac catheterization and measurement of pulmonary wedge pressure will determine whether the clinical assessment is accurate and can distinguish whether further treatment for volume overload and/or LV dysfunction is needed or if treatment directed at pulmonary artery hypertension is indicated. In patients with CKD with WHO class I pulmonary artery hypertension, specific approved therapies may be considered based on the individual's risk-benefit profile.
      • Barst R.J.
      • Gibbs J.S.
      • Ghofrani H.A.
      Updated evidence-based treatment algorithm in pulmonary arterial hypertension.

      Conclusions

      Pulmonary hypertension is prevalent in patients with CKD, particularly in patients with stage 5 maintained on HD. Pulmonary hypertension in patients with CKD potentially is a reversible process because, along with associated LV disorders, it may regress after kidney transplantation. Several risk factors, including LV dysfunction, sleep apnea, AVFs, and an imbalance between endogenous vasoconstrictor and vasodilator substances, are implicated in pulmonary hypertension in patients with CKD. Pulmonary hypertension has been associated with a higher risk of death in 4 small cohort studies involving patients with NDD-CKD5 and dialysis patients. In dialysis patients with established pulmonary hypertension, the excess risk of death may persist after kidney transplantation. Only with large prospective studies that use standardized criteria and perform right-sided cardiac catheterization can the true risk of pulmonary hypertension be assessed in patients with NDD-CKD5 and dialysis patients.

      Acknowledgements

      With the exception of L. Gargani, the authors constitute EURECA-m (European Renal and Cardiovascular Medicine), a working group of the ERA-EDTA (European Renal Association–European Dialysis Transplantation Association).
      Support: None.
      Financial Disclosure: The authors declare that they have no relevant financial interests.

      Supplementary data

      References

        • Simonneau G.
        • Robbins I.M.
        • Beghetti M.
        • et al.
        Updated clinical classification of pulmonary hypertension.
        J Am Coll Cardiol. 2009; 54: S43-S54
        • Badesch D.B.
        • Champion H.C.
        • Sanchez M.A.
        • et al.
        Diagnosis and assessment of pulmonary arterial hypertension.
        J Am Coll Cardiol. 2009; 54: S55-S66
        • Rudski L.G.
        • Lai W.W.
        • Afilalo J.
        • et al.
        Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
        J Am Soc Echocardiogr. 2010; 7: 685-713
        • Berger M.
        • Haimowitz A.
        • Van Tosh A.
        • Berdoff R.L.
        • Goldberg E.
        Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound.
        J Am Coll Cardiol. 1985; 6: 359-365
        • Himelman R.B.
        • Struve S.N.
        • Brown J.K.
        • Namnum P.
        • Schiller N.B.
        Improved recognition of cor pulmonale in patients with severe chronic obstructive pulmonary disease.
        Am J Med. 1988; 84: 891-898
        • Fisher M.R.
        • Forfia P.R.
        • Chamera E.
        • et al.
        Accuracy of Doppler echocardiography in the hemodynamic assessment of pulmonary hypertension.
        Am J Respir Crit Care Med. 2009; 179: 615-621
        • Mathai S.
        • Hassoun P.
        The role of echocardiography in the diagnosis and assessment of pulmonary hypertension.
        Adv Pulm Hypertens. 2008; 7: 379-385
        • Lam C.S.
        • Borlaug B.A.
        • Kane G.C.
        • Enders F.T.
        • Rodeheffer R.J.
        • Redfield M.M.
        Age-associated increases in pulmonary artery systolic pressure in the general population.
        Circulation. 2009; 119: 2663-2670
        • Hachulla E.
        • Gressin V.
        • Guillevin L.
        • et al.
        Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study.
        Arthritis Rheum. 2005; 52: 3792-3800
        • Mukerjee D.
        • St George D.
        • Coleiro B.
        • et al.
        Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach.
        Ann Rheum Dis. 2003; 62: 1088-1093
        • Hadengue A.
        • Benhayoun M.K.
        • Lebrec D.
        • Benhamou J.P.
        Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics.
        Gastroenterology. 1991; 100: 520-528
        • Krowka M.J.
        • Swanson K.L.
        • Frantz R.P.
        • McGoon M.D.
        • Wiesner R.H.
        Portopulmonary hypertension: results from a 10-year screening algorithm.
        Hepatology. 2006; 44: 1502-1510
        • Friedman W.F.
        Proceedings of National Heart, Lung, and Blood Institute Pediatric Cardiology Workshop: pulmonary hypertension.
        Pediatr Res. 1986; 20: 8-11
        • Kessler R.
        • Chaouat A.
        • Weitzenblum E.
        • et al.
        Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences.
        Eur Respir J. 1996; 9: 787
        • Hyduk A.
        • Croft J.B.
        • Ayala C.
        • et al.
        Pulmonary hypertension surveillance—United States, 1980-2002.
        MMWR Surveill Summ. 2005; 54: 1
        • Martin K.B.
        • Klinger J.R.
        • Rounds S.I.
        Pulmonary arterial hypertension: new insights and new hope.
        Respirology. 2006; 11: 6-17
        • Pabst S.
        • Hammerstingl C.
        • Hundt F.
        • et al.
        Pulmonary hypertension in patients with chronic kidney disease on dialysis and without dialysis: results of the PEPPER-Study.
        PLoS One. 2012; 7: e35310
        • Yigla M.
        • Fruchter O.
        • Aharonson D.
        • et al.
        Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients.
        Kidney Int. 2009; 75: 969-975
        • Ramasubbu K.
        • Deswal A.
        • Herdejurgen C.
        • Aguilar D.
        • Frost A.E.
        A prospective echocardiographic evaluation of pulmonary hypertension in chronic hemodialysis patients in the United States: prevalence and clinical significance.
        Int J Gen Med. 2010; 3: 279-286
        • Nakhoul F.
        • Yigla M.
        • Gilman R.
        • Reisner S.A.
        • Abassi Z.
        The pathogenesis of pulmonary hypertension in haemodialysis patients via arterio-venous access.
        Nephrol Dial Transplant. 2005; 20: 1686-1692
        • Issa N.
        • Krowka M.J.
        • Griffin M.D.
        • Hickson L.J.
        • Stegall M.D.
        • Cosio F.G.
        Pulmonary hypertension is associated with reduced patient survival after kidney transplantation.
        Transplantation. 2008; 86: 1384-1388
        • Abdelwhab S.
        • Elshinnawy S.
        Pulmonary hypertension in chronic renal failure patients.
        Am J Nephrol. 2008; 28: 990-997
        • Yigla M.
        • Nakhoul F.
        • Sabag A.
        • et al.
        Pulmonary hypertension in patients with end-stage renal disease.
        Chest. 2003; 123: 1577-1582
        • Havlucu Y.
        • Kursat S.
        • Ekmekci C.
        • et al.
        Pulmonary hypertension in patients with chronic renal failure.
        Respiration. 2007; 74: 503-510
        • Bozbas S.S.
        • Akcay S.
        • Altin C.
        • et al.
        Pulmonary hypertension in patients with end-stage renal disease undergoing renal transplantation.
        Transplant Proc. 2009; 41: 2753-2756
        • Yigla M.
        • Keidar Z.
        • Safadi I.
        • Tov N.
        • Reisner S.A.
        • Nakhoul F.
        Pulmonary calcification in hemodialysis patients: correlation with pulmonary artery pressure values.
        Kidney Int. 2004; 66: 806-810
        • Amin M.
        • Fawzy A.
        • Hamid M.A.
        • Elhendy A.
        Pulmonary hypertension in patients with chronic renal failure: role of parathyroid hormone and pulmonary artery calcifications.
        Chest. 2003; 124: 2093-2097
        • Tarrass F.
        • Benjelloun M.
        • Medkouri G.
        • Hachim K.
        • Benghanem M.G.
        • Ramdani B.
        Doppler echocardiograph evaluation of pulmonary hypertension in patients undergoing hemodialysis.
        Hemodial Int. 2006; 10: 356-359
        • Mahdavi-Mazdeh M.
        • Alijavad-Mousavi S.
        • Yahyazadeh H.
        • Azadi M.
        • Yoosefnejad H.
        • Ataiipoor Y.
        Pulmonary hypertension in hemodialysis patients.
        Saudi J Kidney Dis Transpl. 2008; 19: 189-193
        • Etemadi J.
        • Zolfaghari H.
        • Firoozi R.
        • et al.
        Unexplained pulmonary hypertension in peritoneal dialysis and hemodialysis patients.
        Rev Port Pneumol. 2012; 18: 10-14
        • Unal A.
        • Sipahioglu M.
        • Oguz F.
        • et al.
        Pulmonary hypertension in peritoneal dialysis patients: prevalence and risk factors.
        Perit Dial Int. 2009; 29: 191-198
        • Casas-Aparicio G.
        • Castillo-Martínez L.
        • Orea-Tejeda A.
        • Abasta-Jiménez M.
        • Keirns-Davies C.
        • Rebollar-González V.
        The effect of successful kidney transplantation on ventricular dysfunction and pulmonary hypertension.
        Transplant Proc. 2010; 42: 3524-3528
        • Fabbian F.
        • Cantelli S.
        • Molino C.
        • Pala M.
        • Longhini C.
        • Portaluppi F.
        Pulmonary hypertension in dialysis patients: a cross-sectional Italian study.
        Int J Nephrol. 2010; 11: 463-475
        • Zlotnick D.M.
        • Axelrod D.A.
        • Chobanian M.C.
        • et al.
        Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.
        Nephrol Dial Transplant. 2010; 25: 3090-3096
        • Kumbar L.
        • Fein P.A.
        • Rafiq M.A.
        • Borawski C.
        • Chattopadhyay J.
        • Avram M.M.
        Pulmonary hypertension in peritoneal dialysis patients.
        Adv Perit Dial. 2007; 23: 127-131
      1. Agarwal R. Prevalence, determinants and prognosis of pulmonary hypertension among hemodialysis patients [published online ahead of print Jamuary 30, 2012]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr661.

        • Kiykim A.A.
        • Horoz M.
        • Ozcan T.
        • Yildiz I.
        • Sari S.
        • Genctoy G.
        Pulmonary hypertension in hemodialysis patients without arteriovenous fistula: the effect of dialyzer composition.
        Ren Fail. 2010; 32: 1148-1152
        • Vandenbroucke J.P.
        • von Elm E.
        • Altman D.G.
        • et al.
        Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.
        Epidemiology. 2007; 18: 805-835
        • Shah S.J.
        • Thenappan T.
        • Rich S.
        • Tian L.
        • Archer S.L.
        • Gomberg-Maitland M.
        Association of serum creatinine with abnormal hemodynamics and mortality in pulmonary arterial hypertension.
        Circulation. 2008; 19: 2475-2483
        • Tiengo A.
        • Fadini G.P.
        • Avogaro A.
        The metabolic syndrome, diabetes and lung dysfunction.
        Diabetes Metab. 2008; 34: 447-454
        • Evans A.M.
        • Hardie D.G.
        • Peers C.
        • Mahmoud A.
        Hypoxic pulmonary vasoconstriction: mechanisms of oxygen-sensing.
        Curr Opin Anaesthesiol. 2011; 24: 13-20
        • Sakao S.
        • Tatsumi K.
        • Voelkel N.F.
        Reversible or irreversible remodeling in pulmonary arterial hypertension.
        Am J Respir Cell Mol Biol. 2010; 43: 629-634
        • Halpern S.C.
        • Taichman D.B.
        Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure.
        Chest. 2009; 136: 37-43
        • Abassi Z.
        • Nakhoul F.
        • Khankin E.
        • Reisner S.A.
        • Yigla M.
        Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective.
        Curr Opin Nephrol Hypertens. 2006; 15: 353-360
        • Clarkson M.R.
        • Giblin L.
        • Brown A.
        • Little D.
        • Donohoe J.
        Reversal of pulmonary hypertension after ligation of a brachiocephalic arteriovenous fistula.
        Am J Kidney Dis. 2002; 40: e8
        • Craddock P.R.
        • Fehr J.
        • Dalmasso A.P.
        • Brigham K.L.
        • Jacob H.S.
        Hemodialysis leucopenia.
        J Clin Invest. 1977; 59: 879-888
        • Craddock P.R.
        • Fehr J.
        • Brigham K.L.
        • Kronenberg R.S.
        • Jacob H.S.
        Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis.
        N Engl J Med. 1977; 296: 769-774
        • Yigla M.
        • Abassi Z.
        • Reisner S.A.
        • Nakhoul F.
        Pulmonary hypertension in hemodialysis patients: an unrecognized threat.
        Semin Dial. 2006; 19: 353-357
        • Giaid A.
        Nitric oxide and endothelin-1 in pulmonary hypertension.
        Chest. 1998; 114: 208S-212S
        • Zoccali C.
        The endothelium as a target in renal diseases.
        J Nephrol. 2007; 20: 39-44
        • Giaid A.
        • Saleh D.
        Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension.
        N Engl J Med. 1995; 333: 214-221
        • Arrigoni F.I.
        • Vallance P.
        • Haworth S.G.
        • Leiper J.M.
        Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia.
        Circulation. 2003; 107: 1195-1201
        • Zoccali C.
        • Bode-Böger S.
        • Mallamaci F.
        • et al.
        Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study.
        Lancet. 2001; 358: 2113-2117
        • Sasaki A.
        • Doi S.
        • Mizutani S.
        • Azuma H.
        Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats.
        Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1480-L1487
        • Kielstein J.T.
        • Bode-Böger S.M.
        • Hesse G.
        • et al.
        Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1414-1418
        • Sakaguchi Y.
        • Shoji T.
        • Kawabata H.
        • et al.
        High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in Japan: a cross-sectional study.
        Clin J Am Soc Nephrol. 2011; 6: 995-1000
        • Zoccali C.
        • Mallamaci F.
        • Tripepi G.
        Nocturnal hypoxemia predicts incident cardiovascular complications in dialysis patients.
        J Am Soc Nephrol. 2002; 3: 729-733
        • Ressl J.
        • Urbanová D.
        • Widimský J.
        • Ostádal B.
        • Pelouch V.
        • Procházka J.
        Reversibility of pulmonary hypertension and right ventricular hypertrophy induced by intermittent high altitude hypoxia in rats.
        Respiration. 1974; 31: 38-46
        • Ward J.P.
        • McMurtry I.F.
        Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem.
        Curr Opin Pharmacol. 2009; 9: 287-296
        • Sica A.L.
        • Greenberg H.E.
        • Ruggiero D.A.
        • Scharf S.M.
        Chronic-intermittent hypoxia: a model of sympathetic activation in the rat.
        Respir Physiol. 2000; 121: 173-184
        • Barceló A.
        • de la Peña M.
        • Ayllón O.
        • et al.
        Increased plasma levels of asymmetric dimethylarginine and soluble CD40 ligand in patients with sleep apnea.
        Respiration. 2009; 77: 85-90
        • Grassi G.
        • Seravalle G.
        • Ghiadoni L.
        • et al.
        Sympathetic nerve traffic and asymmetric dimethylarginine in chronic kidney disease.
        Clin J Am Soc Nephrol. 2011; 6: 2620-2627
        • Mallamaci F.
        • Tripepi G.
        • Maas R.
        • Malatino L.
        • Böger R.
        • Zoccali C.
        Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease.
        J Am Soc Nephrol. 2004; 15: 435-444
        • Tripepi G.
        • Mattace Raso F.
        • Sijbrands E.
        • et al.
        Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients.
        Clin J Am Soc Nephrol. 2011; 6: 1714-1721
        • Nitta K.
        • Akiba T.
        • Uchida K.
        • et al.
        The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis.
        Am J Kidney Dis. 2003; 42: 303-309
        • Akmal M.
        • Barndt R.R.
        • Ansari A.N.
        • Mohler J.G.
        • Massry S.G.
        Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy.
        Kidney Int. 1995; 47: 158-163
        • Buemi M.
        • Senatore M.
        • Gallo G.C.
        • et al.
        Pulmonary hypertension and erythropoietin.
        Kidney Blood Press Res. 2007; 30: 248-252
        • Barst R.J.
        • Gibbs J.S.
        • Ghofrani H.A.
        Updated evidence-based treatment algorithm in pulmonary arterial hypertension.
        J Am Coll Cardiol. 2009; 54: S78-S84
        • Califf R.M.
        • Adams K.F.
        • McKenna W.J.
        • et al.
        A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST).
        Am Heart J. 1997; 134: 44-54
        • Redolfi S.
        • Arnulf I.
        • Pottier M.
        • Bradley T.D.
        • Similowski T.
        Effects of venous compression of the legs on overnight rostral fluid shift and obstructive sleep apnea.
        Respir Physiol Neurobiol. 2011; 175: 390-393
        • Tang S.C.
        • Lam B.
        • Lai A.S.
        • et al.
        Improvement in sleep apnea during nocturnal peritoneal dialysis is associated with reduced airway congestion and better uremic clearance.
        Clin J Am Soc Nephrol. 2009; 4: 410-418
        • Hanly P.J.
        • Pierratos A.
        Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis.
        N Engl J Med. 2001; 11: 102-107

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