Multiphasic effects of blood pressure on survival in hemodialysis patients
Authors: Thierry Hannedouche, Hubert Roth, Thierry Krummel, Gérard M. London, Guillaume Jean, Jean-Louis Bouchet, Tilman B. Drüeke, Denis Fouque, Lahcene Attroun, Raymond Azar, Pierre Bories, Agnès Caillette-Beaudouin, Bernard Canaud, Gabriel Choukroun, Vincent Esnault, Mohamed Hammadi, Thierry Hannedouche, Patrick Henri, Philippe Honoré, Belkacem Issad, Dominique Joly, Eric Laruelle, Gildas Le Mao, Sylvain Marchais, Benoît Vendrely, Philippe Zaoui, Larbi Aazib, Abdelhamid Abbassi, Elias Abdullah, Habib Abou-Bekr, Carine Achard-Hottelart, Geneviève Achin, Salima Ahriz-Saksi, Mahen Albadawy, Catherine Albert, Samir Albitar, Farideh Alenabi, Mahmoud Allouache, Amar Amaouche, Brahim Amara, Mounia Ammor, Kim Seng Ang, Ubald Assogba, Lynda Azzouz, Chérif Badid, Juliette Baleynaud, Evelyne Bargas, Emmanuel Baron, François Basse, Jean-Marie Batho, Marc Bauwens, Dorothée Bazin, Abdelmajid Ben Aicha, Seddik Benarbia, Larbi Bencheikh, Jean-Christophe Bendini, Djeleddine Benyakoub, Dominique Bergua, Catherine Bessin, Luc Billaux, Stéphane Billion, Haïat Bittar, Jean-Paul Bocquet, Hervé Bonarek, Claude Bonniol, Jean-Sébastien Borde, Samir Boubenider, Rémi Boudet, Waël Boudi, Loreley Boudier, Djema Bouguern, M Boukelmoune, Fatha Zohra Boukhalfa, Henri Boulanger, Philippe Bouvier, Mouloud Bouzernidj, Mohamed Brahim Bounab, José Brasseur, Laura Braun, Marie Briet, Doan Bui-Quang, Sebastien Canet, Eric Canivet, Jorge Cardozo, Carlos Cardozo, Baher Chaghouri, Mokhtar Chawki, Charles Chazot, Philippe Choulet, Pierre Clavel, Jean-Philippe Coindre, Olivier Coldefy, M.A. Colomina, François Combarnous, Christian Dabot, Djamal Dahmane, Ahmed Dahmani, Daniel Daubresse, Jean-François De Fremont, Valérie De Precigout, Françoise Dehais, M. Dehina, Caroline Delclaux, Yashou Delmas, Coralia Denicola, Jean-Philippe Devaux, Raji Diab, Zineddine Diddaoui, None Didelot, Yves Dimitrov, Assia Djema, Patrick Donnadieu, Valérie Drouillat, Olivier Drouineau, Geneviève Dumont, Philippe Dupuy, Pierre-Yves Durand, Stéphane Edet, Hamid El Ali, Khuzama El Nasser, Christian Emond, Baya Fadel, Mohamed Fakir, Jean-Paul Faucon, André Faure, Assia Ferhat-Carre, Hafedh Fessi, Rocsana Fickl, Mahammed Fodil-Cherif, Jacques Fourcade, Philippe Fournier, Rabah Fraoui, Olivier Fritz, Elke Gaboriau, Alexandre Ganea, Roula Galland, Jacqes Gaultier, Eric Gauthier, Sylvie Geffroy Guiberteau, Sandrine Genestier, Patrick Giraud, Françoise Glowacki, Christophe Goupy, Pierre Grimal, Mounir Guergour, Jean Gugliotta, Marie-Paule Guillodo, Marie-Claude Guimont, Toufic Hachache, Sabria Hacini, Imad Haddad, Mohamed Hadj-Abdelkader, Pascale Halin, Patrick Hallonet, Nasser Hamdini, Didier Hamel, Françoise Heibel, Alain Hermelin, Alim Heyani, Philippe Hiernaux, Maxime Hoffmann, Valérie Hugot, Richard Ibos, Dominque Jacq, Jean-Paul Jaulin, Guillaume Jean, Philippe Jousset, Benoît Jonon, Véronique Joyeux, Laurent Juillard, Amer Kamal, Mimi Kareche Chibout, Rateb Khayat, Franklin Khazine, Karim Khellaf, Arnaud Klisnick, Yannick Knefati, A. Kolko-Labadens, Amir Kolta, Niloufar Kossari, Olivier Kourilsky, Nicolas Krayem, Marc Kribs, Thierry Krummel, François Kuentz, Kristian Kunz, Christian Lamotte, Jean-Marc Lanau, Isabelle Landru, Achour Laradi, Nicole Larroumet, Olivier Lavelle, Frank Le Roy, Alejandra Lenz, Denis Lerda, Fanny Leroy, Marc Leteif, Martial Levannier, Thierry Lobbedez, Hassan Lockmane, Nathalie Longlune, Christie Lorriaux Mortuaire, Alain Lyon, Ghassan Maakaroun, Mehadji Maaz, Eric Magnant, Ghandour Majdalani, Jean-Luc Mahe, Edward Maksour, Stéphane Martin, Catherine Martinat-Calvo, Valérie Masson, Delia May, Claire Maynard, Brice Mayor, Omar Mazouz, Hocine Mehama, Dominique Mercier, Gilles Messier, Robert Milongo, Nicole Monnier, Karine Moreau, Xavier Moreau-Gaudry, Bertrand Morel, Luc Moulonguet Doleris, Alexandre Mouneimne, Catherine Mourey-Epron, Françoise Moussion, Blanca Muniz, J. Mustel, Rachida Nebbad, Fazia Nemmar, Sylvie Neuville, Tien Nguyen-Quang, Patrice Nolen, Michel Normand, Emerson N’Sembani, Jacques Ollier, Jean-Paul Ortiz, Messaoud Ouziala, Bernard Painchart, Pedro Palacin, Josette Pengloan, Franck Perrin, Bruno Perrone, Philippe Petitjean, Dominique Petregne, Jean-Baptiste Philit, Vincent Planquois, Marc Pocheville, Jacky Potier, Jean-Michel Poux, Olivier Puyoo, Catherine Quere-Maurouard, Ahmed Rachi, Anderson Ratsimbazafy, Matthieu Reberolle, Henri Renaud, Bernard Richalet, Sarah Richter, Philippe Rieu, Michel Rince, Odile Rivault, Alain Robert, Jacques Rottembourg, Philippe Rousseau, Sophie Rubens Duval, Christa Roubicek, Piotr Seniuta, Pascal Seris, Irina Shahapuni, Reda Sharobeem, Milad Shenouda, Hélène Sichez Com, Danlèle Simonin, Nadia Soltani, Marc Souid, Hadia Sow, Jean-Christophe Szelag, Catherine Taddei, Zafer Takla, Dominque Teboulle, Jean-Claude Terrat, Patrick Thomas, Adam Tifoura, Jacques Toulon, Dominique Touzard, Pablo Urena Torres, Hans Van der Pijl, Thierry Vanel, Carlos Vela, Isabelle Vernier, Cathy Verove, François Pascal Wambergue, Bassem Wehbe, Maeva Wong-Fat, Fatima Yazbeck, Djamal Yousfi, Maan Youssef, Abdelaziz Ziane
Journal: Kidney International (2016)

Dialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death. Dialysis patients exhibit an inverse, L- or U-shaped association between blood pressure and mortality risk, in contrast to the linear association in the general population. We prospectively studied 9333 hemodialysis patients in France, aiming to analyze associations between predialysis systolic, diastolic, and pulse pressure with all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular endpoints for a median follow-up of 548 days. Blood pressure components were tested against outcomes in time-varying covariate linear and fractional polynomial Cox models. Changes throughout follow-up were analyzed with a joint model including both the time-varying covariate of sequential blood pressure and its slope over time. A U-shaped association of systolic blood pressure was found with all-cause mortality and of both systolic and diastolic blood pressure with cardiovascular mortality. There was an L-shaped association of diastolic blood pressure with all-cause mortality. The lowest hazard ratio of all-cause mortality was observed for a systolic blood pressure of 165 mm Hg, and of cardiovascular mortality for systolic/diastolic pressures of 157/90 mm Hg, substantially higher than currently recommended values for the general population. The 95% lower confidence interval was approximately 135/70 mm Hg. We found no significant correlation for either systolic, diastolic, or pulse pressure with myocardial infarction or nontraumatic amputations, but there were significant positive associations between systolic and pulse pressure with stroke (per 10-mm Hg increase: hazard ratios 1.15, 95% confidence interval 1.07 and 1.23; and 1.20, 1.11 and 1.31, respectively). Thus, whereas high pre-dialysis blood pressure is associated with stroke risk, low pre-dialysis blood pressure may be both harmful and a proxy for comorbid conditions leading to premature death. More than 2 million patients are receiving long-term dialysis therapy worldwide, and their survival rate is unacceptably low. In the general population, the risk of cardiovascular and all-cause mortality increases continuously and linearly with the increase in blood pressure (BP), without any evidence of a threshold.1Lewington S. Clarke R. Qizilbash N. et al.Prospective Studies CollaborationAge-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7683) Google Scholar Conversely, reduction in BP by antihypertensive drugs decreases the cardiovascular risk in proportion to the BP-lowering effect, albeit with a small residual risk.2Law M.R. Morris J.K. Wald N.J. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.BMJ. 2009; 338: b1665Crossref PubMed Scopus (2074) Google Scholar Recent evidence pointed to a J-curve association between BP and mortality in elderly adults and patients with pre-existing coronary artery disease.3Boutitie F. Gueyffier F. Pocock S. et al.INDANA Project Steering CommitteeINdividual Data ANalysis of Antihypertensive intervention. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data.Ann Intern Med. 2002; 136: 438-448Crossref PubMed Scopus (264) Google Scholar, 4Dorresteijn J.A. van der Graaf Y. Spiering W. et al.Secondary Manifestations of Arterial Disease Study GroupRelation between blood pressure and vascular events and mortality in patients with manifest vascular disease: J-curve revisited.Hypertension. 2012; 59: 14-21Crossref PubMed Scopus (113) Google Scholar The risk of mortality is higher at lower levels of BP achieved under treatment. The nadir of the J curve is considered the target BP, at least in patients with a high coronary risk, although the value of the precise inflection point is still a matter of debate. In dialysis patients, nearly all observational studies have reported a U-shaped or even an L-shaped association between BP and all-cause mortality, with higher mortality at low BP values and either no or only a small increase in mortality with increasing BP.5Li Z. Lacson Jr., E. Lowrie E.G. et al.The epidemiology of systolic blood pressure and death risk in hemodialysis patients.Am J Kidney Dis. 2006; 48: 606-615Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 6Kalantar-Zadeh K. Kilpatrick R.D. McAllister C.J. et al.Reverse epidemiology of hypertension and cardiovascular death in the hemodialysis population: the 58th annual fall conference and scientific sessions.Hypertension. 2005; 45: 811-817Crossref PubMed Scopus (195) Google Scholar, 7Stidley C.A. Hunt W.C. Tentori F. et al.Medical Directors of Dialysis Clinic IncChanging relationship of blood pressure with mortality over time among hemodialysis patients.J Am Soc Nephrol. 2006; 17: 513-520Crossref PubMed Scopus (123) Google Scholar, 8Chang T.I. Friedman G.D. Cheung A.K. et al.Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.J Hum Hypertens. 2011; 25: 98-105Crossref PubMed Scopus (40) Google Scholar, 9Robinson B.M. Tong L. Zhang J. et al.Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2012; 82: 570-580Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 10Molnar M.Z. Lukowsky L.R. Streja E. et al.Blood pressure and survival in long-term hemodialysis patients with and without polycystic kidney disease.J Hypertens. 2010; 28: 2475-2484PubMed Google Scholar These paradoxical findings have been coined “reverse epidemiology” as they largely differ from the association observed in the general population and have generated some form of therapeutic nihilism regarding the treatment of hypertension in the dialysis population. For example, data from a large US cohort indicates that the BP of as many as 60% of dialysis patients was either untreated or inadequately treated, whereas the prevalence of arterial hypertension was nearly 90%.11Agarwal R. Nissenson A.R. Batlle D. et al.Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States.Am J Med. 2003; 115: 291-297Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar Several explanations, which are not mutually exclusive, have been proposed to explain the so-called reverse epidemiology, including poor assessment of BP, measurement of the wrong components of BP (i.e., pulse pressure [PP] vs. systolic BP [SBP]),12Klassen P.S. Lowrie E.G. Reddan D.N. et al.Association between pulse pressure and mortality in patients undergoing maintenance hemodialysis.JAMA. 2002; 287: 1548-1555Crossref PubMed Scopus (360) Google Scholar confounding factors affecting the association between BP and mortality, and interference of antihypertensive drugs, most of which also have cardioprotective effects. In the current study, we took advantage of the large observational prospective French Observatory cohort of chronic hemodialysis patients to clarify the association between BP and mortality or morbidity in patients on long-term hemodialysis. The study sample consisted of 9333 prospectively enrolled long-term hemodialysis patients, representing ∼30% of the total hemodialysis population in France. Participation was proposed to a random draw of 400 nephrologists from a national database to ensure at least 250 nephrologists participating on a voluntary basis, and the center selection was representative of the overall population compared with the national French Renal Epidemiology and Information Network (REIN) registry.13REIN Registry. 2010 Annual report. Agence de Biomedecine. Available at: http://www.agence-biomedecine.fr/IMG/pdf/2012_rapport_annuel_rein.pdf. Accessed September 9, 2014.Google Scholar Distribution of age, sex, and initial comorbidities was similar to that of the prevalent REIN cohort in the year 2010 (Table 1), although the proportions of patients with diabetes and those with a history of cardiovascular disease were slightly underrepresented.Table 1Patient demographic characteristics, baseline characteristics, and prescribed treatments at study entryObservatory cohortREIN Registry 2010Age, yr67.5 ± 14.767.5 ± 15.6Male, n (%)5546 (59.4)(60.0)Body mass index, kg/m225.0 ± 5.324.7 ± 5.4Duration of dialysis at study entry, mo44 (23:82)3.0History of cardiovascular disease, n (%)5404 (57.9)(59.4)Diabetes mellitus, n (%)2606 (27.9)(35.9)Systolic blood pressure, mm Hg137 ± 22NADiastolic blood pressure, mm Hg71 ± 14NAPulse pressure, mm Hg66 ± 19NAAntihypertensive drugs, n (%)5423 (58.1)NASerum phosphate, mmol/l – mg/dl1.58 (0.52) – 4.87 (1.58)NASerum total calcium, mmol/l – mg/dl2.20 (0.19) – 8.86 (0.76)NASerum albumin (technique-corrected), g/l38.8 ± 5.035.8 ± 5.2Plasma iPTH (kit-corrected), pg/ml228 (123:395)NANormalized protein catabolic rate, g/kg/day1.11 ± 0.36NASerum C-reactive protein, mg/l5 (2.4:12.1)NABlood hemoglobin, g/dl11.5 ± 1.411.3 ± 1.4iPTH, intact parathyroid hormone; NA, not available.Continuous variables are expressed as mean ± SD for normally distributed data and median (Q1:Q3) (25th and 75th percentile values) for nonnormally distributed data (n = 9333). Data from the nationwide REIN registry in France, year 2010, are given in the right column for comparison purposes. Open table in a new tab iPTH, intact parathyroid hormone; NA, not available. Continuous variables are expressed as mean ± SD for normally distributed data and median (Q1:Q3) (25th and 75th percentile values) for nonnormally distributed data (n = 9333). Data from the nationwide REIN registry in France, year 2010, are given in the right column for comparison purposes. Of the whole cohort, data on 1141 patients were provided only at study entry and were not available later on. These patients were therefore excluded from survival analyses. At the final visit for the studied 9333 patients, 57.0% (n = 5317) remained on dialysis treatment, 20.9% (n = 1946) had died, 16.0% (n = 1492) had been lost to follow-up, and 6.2% (n = 578) had undergone renal transplantation. The mean ± SD and median (25th and 75th percentile values [Q1:Q3]) duration of follow-up was 550 ± 290 and 548 (245: 914) days, respectively. The flowchart of patients included in the final analysis is presented in Supplementary Figure S1. At study entry, the mean ± SD age of the patient population was 67.5 ± 14.7 years (59.4% males) with a median hemodialysis vintage of 44 months. More than one-half of the population (57.9%) had a history of cardiovascular disease (Table 1). A total of 8130 patients with complete data obtained for BP, sex, age, dialysis vintage, serum values of corrected albumin, C-reactive protein, phosphate and uncorrected total calcium, plasma levels of intact parathyroid hormone (PTH), blood hemoglobin concentrations, diabetes, history of cardiovascular disease and smoking, and antihypertensive therapy were included in the Cox survival analyses. There were 1717 deaths (21.1%), 788 of which were cardiovascular deaths (45.9%). The remaining patients were censored for renal transplantation (n = 502, 6.2%), lost to follow-up (n = 1373, 16.9%), or end of the study (n = 4538, 55.8%). There were 826 major cardiovascular events in 769 patients (8.2%), including 353 nonfatal myocardial infarctions, 176 nonfatal strokes, and 297 nontraumatic amputations. Due to the U- or L-shaped hazard ratios (HRs) among SBP, DBP, or PP and all-cause or cardiovascular mortality, fractional polynomials of degree 2 were used to model these 3 parameters in the Cox analyses (Table 2). There was a U-shaped association of SBP with all-cause mortality (Figure 1a) and of SBP and DBP with cardiovascular mortality (Figure 2a and b), an L-shaped association of DBP (Figure 1b) and PP with all-cause mortality, and of PP with cardiovascular mortality. However, after adjustment for SBP, the association between PP and cardiovascular mortality was no longer significant.Table 2HRs of covariates in a multivariate Cox model for all-cause and cardiovascular mortality (sex, age, and dialysis vintage are forced)CovariatesAll-cause mortalityCardiovascular mortalityHRP value95% CIHRP value95% CIFemale sex0.930.1760.83–1.030.900.1830.76–1.05CV history1.43<0.0011.28–1.602.21<0.0011.84–2.66Diabetes1.180.0021.06–1.311.54<0.0011.33–1.79Antihypertensive treatment0.83<0.0010.75–0.910.840.0170.73–0.97Smoking Ex1.080.2120.95–1.231.060.5290.88–1.27 Yes1.35<0.0011.16–1.591.350.0091.08–1.69Age, yr1.04<0.0011.04–1.051.04<0.0011.03–1.05Albumin, g/l0.95<0.0010.94–0.960.980.0050.96–0.99Hemoglobin, g/dl0.929<0.0010.895–0.9640.9210.0020.874–0.970Dialysis vintage, mo0.990.170.99–1.011.000.5790.99–1.00CRP, mg/l1.01<0.0011.004–1.011.00<0.0011.00–1.01Fractional polynomialsaValues in brackets represent the powers used in the fractional polynomials for the best fit: P [−2 2]: ln(HR) = (β1 × [P]−2) + (β2 × [P]2) + βk Xk Total calcium [−2 −0.5]: ln(HR) = (β3 × [Ca]−2) + (β4 × [Ca]−0.5) + βk Xk Intact PTH [0 1]: ln(HR) = (β5 × ln[iPTH]) + (β6 × [iPTH]) + βk Xk β1–β6: coefficients. βk Xk represents the k other covariates.Coeff.Coeff.Phosphate, mmol/l [−2]0.080.0250.01–0.150.050.175−0.02 to 0.13Phosphate, mmol/l [2]0.030.0360.00–0.070.060.0040.02–0.11Total calcium, mmol/l [−2]7.39<0.0014.20–10.5811.09<0.0017.81–14.36Total calcium, mmol/l [−0.5]−9.44<0.001−14.56 to −4.32−14.99<0.001−21.00 to −8.99Intact PTH, pg/ml [0]−0.100.006−0.18 to −0.03−0.060.25−0.17 to 0.04Intact PTH, pg/ml [1]0.390.0040.13–0.650.310.083−0.04 to 0.67CI, confidence interval; CRP, C-reactive protein; CV, cardiovascular; HR, hazard ratio; PTH, parathyroid hormone.a Values in brackets represent the powers used in the fractional polynomials for the best fit:P [−2 2]: ln(HR) = (β1 × [P]−2) + (β2 × [P]2) + βk XkTotal calcium [−2 −0.5]: ln(HR) = (β3 × [Ca]−2) + (β4 × [Ca]−0.5) + βk XkIntact PTH [0 1]: ln(HR) = (β5 × ln[iPTH]) + (β6 × [iPTH]) + βk Xkβ1–β6: coefficients. βk Xk represents the k other covariates. Open table in a new tab Figure 2Multivariate-adjusted hazard ratios (95% confidence intervals) of cardiovascular mortality associated with systolic blood pressure (a) and diastolic blood pressure (b). Values were calculated in time-varying covariate Cox models using fractional polynomials for the blood pressures and adjusted for sex, age, dialysis vintage, serum values of corrected albumin, C-reactive protein, phosphate, and uncorrected total calcium, plasma corrected intact parathyroid hormone level, blood hemoglobin concentration, use of antihypertensive therapy, diabetes mellitus, and history of cardiovascular disease and smoking. The histograms depict the number of patients at inclusion for each incremental bracket of 5 mm Hg. Powers of fractional polynomials: SBP [2 2], DBP [2 2] (see explanation in the footnote in Table 2). DBP, diastolic blood pressure; SBP, systolic blood pressure.View Large Image Figure ViewerDownload (PPT) CI, confidence interval; CRP, C-reactive protein; CV, cardiovascular; HR, hazard ratio; PTH, parathyroid hormone. The nadir of SBP, at which the all-cause mortality risk was at its lowest, was 165 mm Hg; however, due to the L-shaped association, there was no particular DBP value that was indicative of minimal risk. For cardiovascular mortality, the lowest HR was observed for an SBP value of 157 mm Hg and a DBP value of 90 mm Hg. The lower limits of the 95% confidence interval were ∼135/70 mm Hg (Figure 1b). Interestingly, compared with the baseline fractional polynomials of degree 2 Cox model (using initial BP only), the time-varying covariate (TVC) fractional polynomials of degree 2 Cox model was significantly superior and had a lower deviance (21,365 vs. 28,507 for all-cause mortality and 9893 vs. 13,164 for cardiovascular mortality) but nonetheless yielded similar results, that is, a similar U-shaped association between SBP and all-cause and cardiovascular mortality, respectively (data not shown). However, the nadir of SBP for the baseline fractional polynomials of degree 2 Cox model was lower (146 mm Hg vs. 165 mm Hg for all-cause mortality and 150 mm Hg vs. 157 mm Hg for cardiovascular mortality). Interactions to test were chosen among the covariates commonly known to be associated with BP variation, namely age, serum albumin, diabetes, and cardiovascular and smoking history. The U-shaped association of SBP with all-cause or cardiovascular mortality was tested for potential interactions with continuous variables including age and serum albumin (at inclusion and as a TVC), and qualitative variables including diabetes status, cardiovascular history, smoking habit, dialysis vintage (incident, ≤1 year patients or prevalent, >1 year patients), and treatment with antihypertensive drugs. Overall, the U-shaped association was similar for all tested variables (including treatment with antihypertensive drugs) and all-cause and cardiovascular mortality, with no significant interaction (Figure 3).Figure 3Multivariate-adjusted hazard ratios (95% confidence intervals) of all-cause mortality associated with systolic blood pressure according to cardiovascular history (0 = no, 1 = yes) (a), antihypertensive treatment (0 = no, 1 = yes) (b), and prevalent (dialysis vintage >12 months) versus incident (≤12 months) patients.(c). Values were calculated in time-varying covariate Cox models using fractional polynomials for systolic blood pressure and adjusted for sex, age, dialysis vintage, serum values of corrected albumin, C-reactive protein, phosphate, and uncorrected total calcium, plasma corrected intact parathyroid hormone level, blood hemoglobin concentration, use of antihypertensive therapy, diabetes mellitus, and history of cardiovascular disease and smoking. The histograms depict the number of patients at inclusion for each incremental bracket of 5 mm Hg. CV, cardiovascular; SBP, systolic blood pressure.View Large Image Figure ViewerDownload (PPT) Joint models were subsequently used to further characterize the associations between the trend in BP variations over time and outcomes. When the slope of the variable was added in the survival submodel, there was an association between SBP and PP with all-cause but not cardiovascular mortality. Specifically, a slight increase in SBP or PP rate of change over time (+1 mm Hg/6 months) was significantly associated with a decrease in all-cause but not cardiovascular mortality (SBP: HR 0.77 [0.62:0.96], P = 0.018; PP: HR 0.04 [0.03:0.05], P < 0.001). In the time-varying component–adjusted Cox model, neither SBP nor DBP or PP was predictive of myocardial infarction or nontraumatic amputation, except PP for nontraumatic amputation (per 10-mm Hg increase: HR 1.10 [1.03:1.17], P = 0.004, even when adjusting for SBP or DBP). However, both SBP and PP had predictive power for stroke (per 10-mm Hg increase: HR 1.15 [1.07:1.23], P < 0.001; HR 1.19 [1.10:1.30], P < 0.001, respectively). The predictive power of PP for stroke remained significant when adjusted for either SBP or DBP (HR 1.16 [1.01:1.34], P = 0.033; HR 1.20 [1.11:1.31], P < 0.001. respectively). In this nationwide prospective study of patients receiving hemodialysis therapy, we found a U-shaped association of SBP with all-cause mortality, as well as both SBP and DBP with cardiovascular mortality, and an L-shaped association between DBP and all-cause mortality, confirming previous mostly retrospective studies.5Li Z. Lacson Jr., E. Lowrie E.G. et al.The epidemiology of systolic blood pressure and death risk in hemodialysis patients.Am J Kidney Dis. 2006; 48: 606-615Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 6Kalantar-Zadeh K. Kilpatrick R.D. McAllister C.J. et al.Reverse epidemiology of hypertension and cardiovascular death in the hemodialysis population: the 58th annual fall conference and scientific sessions.Hypertension. 2005; 45: 811-817Crossref PubMed Scopus (195) Google Scholar, 7Stidley C.A. Hunt W.C. Tentori F. et al.Medical Directors of Dialysis Clinic IncChanging relationship of blood pressure with mortality over time among hemodialysis patients.J Am Soc Nephrol. 2006; 17: 513-520Crossref PubMed Scopus (123) Google Scholar, 8Chang T.I. Friedman G.D. Cheung A.K. et al.Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.J Hum Hypertens. 2011; 25: 98-105Crossref PubMed Scopus (40) Google Scholar, 9Robinson B.M. Tong L. Zhang J. et al.Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2012; 82: 570-580Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 10Molnar M.Z. Lukowsky L.R. Streja E. et al.Blood pressure and survival in long-term hemodialysis patients with and without polycystic kidney disease.J Hypertens. 2010; 28: 2475-2484PubMed Google Scholar Of particular interest, the predictive power of low BP for mortality was readily apparent using only 1 inclusion value of BP and was only slightly improved by the TVC model that integrated all BP values recorded over time. Agarwal14Agarwal R. Exploring the paradoxical relationship of hypertension with mortality in chronic hemodialysis.Hemodial Int. 2004; 8: 207-213Crossref PubMed Scopus (16) Google Scholar proposed a hypothetical model to explain this apparently paradoxical observation also found in populations with other chronic diseases such as heart failure. This author suggested that the U curve describing the association between BP and outcomes in dialysis patients may result from the summation of different associations in 2 discrete patient subgroups. The first subgroup with heart failure would exhibit an inverse association between BP and mortality, similar to that observed in patients with advanced chronic heart failure but in the absence of chronic kidney disease. In these patients, low BP would be a proxy for low cardiac output and, hence, closely associated with worse outcomes in the short term. The second group would correspond to patients without heart failure but with arterial hypertension as a consequence of sympathetic activation, volume overload, and arterial stiffness. These patients would be primarily exposed to the deleterious effects of hypertension and exhibit the typical direct association between BP and mortality over the long term. Accordingly, among patients on hemodialysis, the ability to raise an elevated blood pressure further in response to fluid accumulated between hemodialysis sessions may represent a sign of relative health. However, the same U-shaped association was found among hemodialyzed participants with preserved ejection fraction.15Bansal N. McCulloch C.E. Rahman M. et al.CRIC Study InvestigatorsBlood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the Chronic Renal Insufficiency Cohort study.Hypertension. 2015; 65: 93-100Crossref PubMed Scopus (107) Google Scholar Evidence of reverse causality with a U-shaped association between BP and mortality has been limited to short-term observations and disappeared with prolonged follow-up. In agreement with the phenomenon of reverse causality, 1 study found that low SBP was associated with increased mortality in the first 2 years after inception, whereas the usual adverse effect of high BP on survival became apparent only after 3 years.7Stidley C.A. Hunt W.C. Tentori F. et al.Medical Directors of Dialysis Clinic IncChanging relationship of blood pressure with mortality over time among hemodialysis patients.J Am Soc Nephrol. 2006; 17: 513-520Crossref PubMed Scopus (123) Google Scholar However, in the current study, sensitivity analyses found a similar U-shaped association when excluding comorbidities from the model (age, diabetes, and previous cardiovascular disease) and also dialysis vintage, supporting a more direct, potentially causal link between low BP and mortality. Indeed, these patients are more prone to intradialytic hypotension and may experience organ hypoperfusion and myocardial stunning during aggressive ultrafiltration,16Davenport A. Cox C. Thuraisingham R. Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension.Kidney Int. 2008; 73: 759-764Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 17McIntyre C.W. Effects of hemodialysis on cardiac function.Kidney Int. 2009; 76: 371-375Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar especially those with high degrees of preexisting myocardial fibrosis and myocyte/capillary mismatch.18Amann K. Breitbach M. Ritz E. Mall G. Myocyte/capillary mismatch in the heart of uremic patients.J Am Soc Nephrol. 1998; 9: 1018-1022PubMed Google Scholar Accordingly, a recent study showed that dialysis centers with a greater proportion of hemodialysis patients reaching the recommended target, that is, SBP <140 mm Hg, had higher rates of symptomatic intradialytic hypotension.16Davenport A. Cox C. Thuraisingham R. Achieving blood pressure targets during dialysis improves control but increases intradialytic hypotension.Kidney Int. 2008; 73: 759-764Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Similarly, a higher mortality rate was found with higher perdialytic BP decreases in a large cohort of hemodialysis patients.19Park J. Rhee C.M. Sim J.J. et al.A comparative effectiveness research study of the change in blood pressure during hemodialysis treatment and survival.Kidney Int. 2013; 84: 795-802Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 20Lertdumrongluk P. Streja E. Rhee C.M. et al.Changes in pulse pressure during hemodialysis treatment and survival in maintenance dialysis patients.Clin J Am Soc Nephrol. 2015; 10: 1179-1191Crossref PubMed Scopus (19) Google Scholar A recent study showed that the U-shaped association between BP and mortality was not present when BP was measured out of the dialysis unit.15Bansal N. McCulloch C.E. Rahman M. et al.CRIC Study InvestigatorsBlood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the Chronic Renal Insufficiency Cohort study.Hypertension. 2015; 65: 93-100Crossref PubMed Scopus (107) Google Scholar Indeed, this study found a direct, quasilinear association between out-of-the dialysis-unit SBP and mortality. The sample size of the cohort was relatively small, however, and included highly selected patients (who volunteered to enroll in the CRIC [Chronic Renal Insufficiency Cohort] study). Of note, “standardized BP measurement out-of-the-dialysis-unit” referred in this study to sitting SBP recordings that apparently were performed only once in the majority of patients, a potential limitation of the study. We also found a weak association between a progressive decrease in SBP and an increase in all-cause mortality over a median follow-up of 458 days. As such an association was not observed for cardiovascular mortality, this suggests that decreasing SBP within months before death may result from, rather than cause, the acute illness ultimately leading to death.8Chang T.I. Friedman G.D. Cheung A.K. et al.Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.J Hum Hypertens. 2011; 25: 98-105Crossref PubMed Scopus (40) Google Scholar Thus, lower BP may well be a marker of comorbid conditions not entirely captured by other scores. With some uncertainty related to the wide 95% confidence interval, the U-shaped association between BP and either all-cause or cardiovascular mortality allows one to speculate on “optimal” BP targets in hemodialysis patients (i.e., BP values associated with the lowest outcome risk—still a controversial issue). The best outcomes in our study were associated with predialysis SBP/DBP values of 157/90 mm Hg, a figure substantially higher than that proposed by current, although somewhat dated, recommendations of <140/90 mm Hg and <130/80 mm Hg, before and after the hemodialysis session, respectively.21K/DOQI WorkgroupK/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.Am J Kidney Dis. 2005; 45: S1-S153Google Scholar, 22Treatment of Adults and Children with Renal Failure Standards and Audit Measures. 3rd ed. Renal Association Standards, Royal College of Physicians London, London2002Google Scholar In the higher range of BP values, the confidence interval was too wide to secure an upper limit beyond which mortality would increase. Only 2% to 3% of the patients had a predialysis SBP ≥180 mm Hg at any given time, an insufficient statistical power to detect an effect of very high BP on mortality. However, the association was more robust for low BP and increased mortality risk. The optimal predialysis BP range may be higher than predicted based on data from the general population because predialysis BP represents the peak of the 48 to 72 hour interdialytic cycle and hypervolemia. In addition, patients are stressed immediately before the puncture is made to gain vascular access for hemodialysis, thus causing an overestimation of average BP. Moreover, nephrologists often instruct hemodialysis patients to withhold antihypertensive drugs on the dialysis day for fear of intradialytic hypotension, a practice that would further overestimate BP relying on predialysis measurements. Agarwal et al.23Agarwal R. Peixoto A.J. Santos S.F. Zoccali C. Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure.Clin J Am Soc Nephrol. 2006; 1: 389-398Crossref PubMed Scopus (178) Google Scholar reported an average overestimation by 13 mm Hg of casual predialysis SBP measurements compared with 48-hour ambulatory BP monitoring. In light of this, our data are compatible with the view that intentional decreases in predialysis values of <135 mm Hg for SBP and <70 mm Hg for DBP should be avoided whenever possible. These data are suggestive of recent findings in nondiabetic patients with non-dialysis chronic kidney disease in which the combination of low SBP and low DBP was associated with the highest mortality rates.24Kovesdy C.P. Bleyer A.J. Molnar M.Z. et al.Blood pressure and mortality in U.S. veterans with chronic kidney disease: a cohort study.Ann Intern Med. 2013; 159: 233-242Crossref PubMed Scopus (160) Google Scholar In addition, DBP values <∼70 mm Hg appear to confer increased mortality rates even in patients with SBP within the normal range. There are only scarce data in the literature on the association between BP and nonfatal cardiovascular complications in hemodialysis patients, likely because these events are harder to be accurately captured in retrospective studies. Stidley et al.7Stidley C.A. Hunt W.C. Tentori F. et al.Medical Directors of Dialysis Clinic IncChanging relationship of blood pressure with mortality over time among hemodialysis patients.J Am Soc Nephrol. 2006; 17: 513-520Crossref PubMed Scopus (123) Google Scholar found an inverse association of low SBP and DBP with atherosclerotic cardiovascular disease in a retrospective study done in an incident cohort. In the current series, however, we found a more direct linear correlation of SBP and PP with stroke, in line with a causal association, as observed in the general population. In contrast, there was no association of SBP, DBP, or PP with nonfatal myocardial infarctions or nontraumatic amputations. Our failure to observe an increase in the incidence of myocardial infarction at low SBP or DBP values appears to contradict the hypothesis of increased mortality at low BP secondary to worsening of myocardial ischemia in response to reduced coronary perfusion during diastole. The major strengths of our study include a large contemporary and representative nationwide cohort, representing ∼30% of the total hemodialysis patient population in France, as well as the use of averaged BP values from numerous measurements over an extended follow-up period. In addition, data were collected prospectively over 30 months with <16% of loss to follow-up, while outcomes were predefined end points including both all-cause and cardiovascular mortality and other prespecified well-defined cardiovascular events. Finally, analyses were adjusted for case mix and a large number of covariates as potential confounders, including serum albumin, serum C-reactive protein, and major comorbidities. However, several limitations also need mentioning. First, BP measurements were obtained during routine patient care rather than with the standard Kidney Disease Outcomes Quality Initiative protocol.21K/DOQI WorkgroupK/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.Am J Kidney Dis. 2005; 45: S1-S153Google Scholar As already mentioned, there may be a significant overestimation between usual and standardized BP measurements among hemodialysis patients.23Agarwal R. Peixoto A.J. Santos S.F. Zoccali C. Pre- and postdialysis blood pressures are imprecise estimates of interdialytic ambulatory blood pressure.Clin J Am Soc Nephrol. 2006; 1: 389-398Crossref PubMed Scopus (178) Google Scholar Predialysis BP is, however, still supported by Kidney Disease Outcomes Quality Initiative guidelines because of better applicability in clinical practice. Second, per- and postdialysis BP values were not collected in our study. In 1 study, postdialysis BP was found to best correlate with mean interdialytic BP assessed by ambulatory BP monitoring.25Kooman J.P. Gladziwa U. Böcker G. et al.Blood pressure during the interdialytic period in haemodialysis patients: estimation of representative blood pressure values.Nephrol Dial Transplant. 1992; 7: 917-923PubMed Google Scholar However, the association of postdialysis BP and outcomes remains controversial. In a small hemodialysis patient cohort (N = 115), an increase >5 mm Hg in postdialysis SBP was associated with higher mortality (HR 3.9),26Yang C.Y. Yang W.C. Lin Y.P. Postdialysis blood pressure rise predicts long-term outcomes in chronic hemodialysis patients: a four-year prospective observational cohort study.BMC Nephrol. 2012; 13: 12-22Crossref PubMed Scopus (27) Google Scholar a feature thought to reflect persistent hypervolemia. However, in the prospective HEMO (Hemodialysis) study, postdialysis BP was not consistently associated with clinical outcome.8Chang T.I. Friedman G.D. Cheung A.K. et al.Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.J Hum Hypertens. 2011; 25: 98-105Crossref PubMed Scopus (40) Google Scholar Similarly, in the large international DOPPS (Dialysis Outcomes and Practice Patterns Study), no interaction effect was found between predialysis SBP and changes in postdialysis SBP.9Robinson B.M. Tong L. Zhang J. et al.Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study.Kidney Int. 2012; 82: 570-580Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Third, information on cardiovascular function or echocardiography was not collected, which could have helped to elucidate the observed association between low BP, cardiac dysfunction, and higher mortality. However, a similar U-shaped association between BP and mortality was found among hemodialyzed participants with preserved ejection fraction.15Bansal N. McCulloch C.E. Rahman M. et al.CRIC Study InvestigatorsBlood pressure and risk of all-cause mortality in advanced chronic kidney disease and hemodialysis: the Chronic Renal Insufficiency Cohort study.Hypertension. 2015; 65: 93-100Crossref PubMed Scopus (107) Google Scholar Fourth, there was no available information on specific antihypertensive drugs, some of which may have cardioprotective effects beyond BP lowering, such as beta-blockers and renin-angiotensin system blockers, although we did have information on whether patients were receiving antihypertensive drugs. We did not find any interaction in the U-shaped association between SBP and mortality and treatment or no treatment with antihypertensive drugs. There may be an indication bias, however, because beta-blockers, renin-angiotensin system blockers, and diuretics can be prescribed for both hypertension and heart failure. As to the possible role of antihypertensive drugs in the so-called reverse epidemiology phenomenon, there are only a few randomized, controlled trials in dialysis patients. Two recent meta-analyses concluded that there was a benefit of these treatments, with an overall 20% reduction in mortality.27Agarwal R. Sinha A.D. Cardiovascular protection with antihypertensive drugs in dialysis patients: systematic review and meta-analysis.Hypertension. 2009; 53: 860-866Crossref PubMed Scopus (156) Google Scholar, 28Heerspink H.J. Ninomiya T. Zoungas S. et al.Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials.Lancet. 2009; 373: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar It is unknown whether part of this effect may be attributed to an intrinsic cardioprotective effect (e.g., beta-blocker in dialysis patients with congestive heart failure).29Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar Fifth, our cohort has a slight underrepresentation of diabetic patients compared with the global dialysis patient population in France and some other countries, which may have affected our results and conclusions. Finally, as with all observational studies, causality cannot be determined, and adjustment for confounders is limited to those that are recognized and measured. In this large, nationwide, prospective hemodialysis patient cohort, we were able to confirm the U-shaped association between SBP and mortality, although we identified a more direct, positive association of SBP and PP with stroke. The absence of an association between BP and nonfatal myocardial infarction do not support a major pathophysiological role of worsened myocardial ischemia at low BP.