Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension

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1 Association of Serum Creatinine With Abnormal Hemodynamics and Mortality in Pulmonary Arterial Hypertension Sanjiv J. Shah, MD; Thenappan Thenappan, MD; Stuart Rich, MD; Lu Tian, ScD; Stephen L. Archer, MD; Mardi Gomberg-Maitland, MD, MSc Background Renal dysfunction predicts mortality in patients with cardiovascular disease. How renal dysfunction relates to hemodynamics and mortality in pulmonary arterial hypertension (PAH) remains unclear. Methods and Results We performed a cohort study of 500 patients with World Health Organization group I PAH from 1982 to 2006 with data on demographics, comorbidities, medications, functional class, laboratory tests, exercise testing results, and hemodynamics. Serum creatinine (SCr) was determined on entry into the study (initial PAH clinic visit). Vital status was determined from hospital records and the Social Security Death Index. We used a Cox proportional hazards analysis to determine whether SCr was an independent predictor of mortality. Mean age on entry into the study was years, and 79% of subjects were female. Mean SCr was mg/dl. Elevated SCr was associated with higher right atrial pressure and lower cardiac index. During a median follow-up of 3.5 years, 279 deaths (55.8% of the cohort) occurred. Compared with patients with SCr 1.0 mg/dl, those with SCr 1.0 to 1.4 mg/dl and SCr 1.4 mg/dl had an increased hazard ratio of death (unadjusted hazard ratio 1.65, 95% confidence interval 1.26 to 2.17, P for SCr 1.0 to 1.4 mg/dl; unadjusted hazard ratio 2.54, 95% confidence interval 1.73 to 3.71, P for SCr 1.4 mg/dl). On multivariable analysis, we found a significant interaction between SCr and right atrial pressures (interaction P ); increased SCr best predicted death in patients with right atrial pressure 10 mm Hg. Conclusions Renal dysfunction is associated with a worse hemodynamic profile and is an independent predictor of mortality in PAH. Measurement of SCr is practical and offers a simple way to noninvasively predict outcome. (Circulation. 2008;117: ) Key Words: hypertension, pulmonary kidney mortality hemodynamics ethnicity Pulmonary arterial hypertension (PAH) is a devastating disease of the pulmonary vasculature that results in right heart failure and death. 1,2 Current risk prediction in PAH is based on findings from a National Institutes of Health (NIH) registry that uses data collected in the early 1980s. 3 All patients in the NIH study had primary pulmonary hypertension, and the current risk prediction model is based on hemodynamic variables obtained during invasive testing. 4 Functional class and exercise testing have also been identified as important risk factors for death in PAH. 5,6 Novel risk predictors would therefore be helpful in further identification of patients at risk for death. Clinical Perspective p 2483 Renal dysfunction is a potent and independent predictor of cardiovascular morbidity and mortality Serum creatinine (SCr), although a crude measure of renal function, is readily available clinically and easily entered into equations that estimate glomerular filtration rate (egfr) at the bedside. 16,17 Biological plausibility exists for SCr as a predictor of outcome in PAH because increases in SCr often reflect impaired renal perfusion, which is a common consequence of the diminished right heart function that portends death and disability in PAH, and PAH patients may have decreased renal responsiveness to cardiac natriuretic peptides, which links the kidney to cardiac function in PAH. 18 Therefore, even subtle deterioration in renal function could signal abnormal hemodynamics and an increased risk for mortality in PAH. We hypothesized that renal dysfunction is associated with abnormal hemodynamics and is an independent predictor of mortality in patients with World Health Organization (WHO) group I PAH. We aimed to determine whether SCr and egfr were independent risk predictors of mortality in PAH and whether upper-normal to mildly increased SCr (1.0 to 1.4 Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received June 5, 2007; accepted March 12, From the Division of Cardiology, Department of Medicine (S.J.S.) and Department of Preventive Medicine (L.T.), Northwestern University Feinberg School of Medicine, Chicago, Ill; and Section of Cardiology, Department of Medicine (T.T., S.R., S.L.A., M.G.-M.), University of Chicago, Chicago, Ill. Correspondence to Mardi Gomberg-Maitland, MD, MSc, Director of Pulmonary Hypertension, University of Chicago, 5841 S Maryland Ave, MC 2016, Chicago, IL mgomberg@medicine.bsd.uchicago.edu 2008 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 2476 Circulation May 13, 2008 mg/dl) predicted increased mortality compared with SCr 1.0 mg/dl. Methods Study Sample We studied patients in the Pulmonary Hypertension Connection (PHC) registry, which was initiated in March All patients evaluated at a single United States practice over time at 3 different university hospitals (University of Illinois at Chicago, Rush University Medical Center, and University of Chicago, all in Chicago, Ill) between 1982 and 2006 were entered into the database. Over the study period, 4 physicians acquired all the clinical data. Data were collected by chart review and entered with an Internet-based electronic data capture system. Patients were entered retrospectively from 1982 to February 2004 and prospectively from March 2004 through Since the initiation of the registry, only 2 investigators, both of whom had expertise in data management and understanding of clinical care of PAH patients, entered the data. Neither of these investigators participated in the care of the patients in the registry, and both were blinded to eventual outcome. Informed consent for participation in the registry was obtained during initial evaluation for new patients or during routine office visits for patients who were already being followed up before initiation of the registry ( 1% refused entry into the study). Data entry occurred after the complete initial evaluation. For all variables, outliers were verified by chart review to minimize data entry errors. The PHC registry was approved by the respective institutional review boards based on the location of the practice, and all actively seen patients gave informed consent to be entered into the registry. A total of 1360 patients referred to our practice from 1982 to 2006 for the evaluation of pulmonary hypertension were entered into the registry (812 entered retrospectively and 548 prospectively). More than 95% of the patients in the registry were seen as outpatients during initial evaluation (the remaining were inpatients transferred from the referring institution). We collected baseline data on demographics, clinical phenotype, medication, exercise test, and cardiac catheterization on all patients examined by our practice. From the PHC registry, we identified all adult patients ( 18 years of age at time of referral) with group I PAH (n 578). Per the WHO clinical classification, 19 patients were excluded if they had evidence of non group I causes of pulmonary hypertension: pulmonary venous hypertension diagnosed by pulmonary capillary wedge pressure 15 mm Hg; obstructive lung disease diagnosed by reduced expiratory flow rates (forced expiratory volume in 1 second/forced vital capacity 70% of predicted); interstitial lung disease diagnosed by typical appearance on computed tomography scan; chronic pulmonary thromboembolic disease diagnosed by ventilation perfusion scan (other than normal or low probability), contrast-enhanced chest computed tomography, or pulmonary angiography if necessary; and pulmonary hypertension associated with sarcoidosis and other infiltrative diseases. Of the 578 patients with group I PAH, 73 were excluded because baseline measurement of SCr was lacking and 5 were excluded because of the presence of end-stage renal disease. The remaining 500 patients constituted our study cohort (85 [17%] of these patients were entered prospectively, and the remaining patients were entered retrospectively). Renal Function SCr, the primary index of renal function in the present study, was measured on entry into the study (initial PAH clinic visit). All patients who were taking diuretics were receiving a stable dose at the time of SCr measurement. To determine the egfr, we used the Mayo Clinic Quadratic formula (MCQ), 16 and in the 218 patients with ethnicity data available, we used the Modified Diet in Renal Disease (MDRD). We defined chronic kidney disease (CKD) as MCQ egfr 60 ml/min per 1.73 m Patient Characteristics and Laboratory Measurements We analyzed the following baseline variables at the time of referral for characterization of clinical phenotype: demographic data, including age, sex, and ethnicity; comorbidities; WHO functional class; medications; albumin; diffusing capacity of carbon monoxide; and exercise treadmill testing with the Naughton-Balke protocol, 21 which has been found to be equivalent and possibly superior to the 6-minute walk test. 22 Invasive Hemodynamics Of the 500 subjects included in the present analysis, 460 underwent baseline hemodynamic testing by right heart catheterization, the majority ( 95%) of which procedures were performed at our institution by pulmonary hypertension specialists. All hemodynamic testing performed at our institution was completed within 1 month of initial referral, and all patients were hemodynamically stable at the time of catheterization. Additionally, patients were instructed to take their usual morning medications on the day of catheterization. Hemodynamic testing included measurement of right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index (by the thermodilution method, which has been validated in patients with pulmonary hypertension 23 ), and pulmonary artery oxygen saturation. Acute vasodilator challenge was performed during right heart catheterization with adenosine, as described previously. 24 Mortality Vital statistics were collected for all patients by chart review and by query of the Social Security Death Index. For each death, the date of death was documented. Social Security Death Index data were available on all patients, although survival time was missing in 8 (1.6%) of 500 patients. Among patients who were not identified as deceased by the Social Security Death Index (n 217), we were able to confirm vital status in 201 (93%). Statistical Analysis We first compared groups of patients depending on baseline SCr, dividing the cohort into 3 groups for descriptive purposes: SCr 1.0, 1.0 to 1.4, and 1.4 mg/dl. We purposely included patients with upper-normal SCr (1.0 to 1.2 mg/dl) in the middle SCr group because we hypothesized that these patients were a higher-risk subset, given that most patients with PAH are debilitated and are women and therefore are likely to have lower SCr. Among the SCr groups, we compared demographics, clinical characteristics, laboratory tests, and hemodynamics with ANOVA and Kruskal-Wallis tests for continuous variables and 2 and Fisher exact tests for categorical variables. To better understand the relationship between renal function and the various demographic, clinical, laboratory, and hemodynamic variables, we performed univariate linear regression with SCr and MCQ egfr as the dependent variables. We used the Kaplan Meier method to estimate survival rates, and Kaplan Meier survival curves were compared by log-rank test. To determine the univariate and multivariate risk of death by various measures of kidney function, we used a Cox proportional hazards analysis, and the proportionality assumption was tested and confirmed for all models. From the present univariate analysis of variables associated with SCr at P 0.05 and from the NIH study of mortality in PAH, 4 we determined that the following covariates should be entered into our multivariate model: age, sex, cause of PAH, systemic hypertension, diabetes mellitus, coronary disease, diuretic use, albumin, and hemodynamic variables (mean right atrial pressure, mean pulmonary artery pressure, and cardiac index). Functional class and exercise capacity (measured in metabolic equivalents) were highly correlated (Pearson correlation coefficient 0.74, P ), so only functional class was retained in the multivariable model to avoid multicollinearity. The carbon monoxide diffusing capacity was not included in the multivariable analysis to retain statistical power, because many patients did not have data on this parameter. We then performed univariate and multivariate regression analysis using a Cox proportional hazards model to determine the independent effect of renal function on mortality, with SCr groups and tertiles of MCQ egfr used as categorical predictors.

3 Shah et al Serum Creatinine and Mortality in PAH 2477 Because renal dysfunction is closely associated with fluid retention and volume overload, and because we found that renal dysfunction is closely associated with several hemodynamic variables, we created multiplicative interaction terms to evaluate for effect modification by right atrial pressure and other hemodynamic variables. Because the relationship between renal function and death appeared to be modified by right atrial pressure (due to the presence of a significant interaction between renal function and right atrial pressure), we constructed figures plotting multivariate hazard ratios (HRs) as a function of right atrial pressure. We also plotted the pointwise 95% confidence intervals (CIs) so that the significance level for the HR could be ascertained at any given level of right atrial pressure. Finally, because a prior study showed an increased risk of death in PAH associated with black and Asian race, 25 and because of the significant association between diuretic use and renal function in the present study, we also examined the association between race and mortality and between diuretic use and mortality in the Cox models. Statistical analyses were performed with Stata (version 9, StataCorp LP, College Station, Tex). The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Results Mean age on entry into the study was years, and 79% of participants were women. Ethnicity data, available in 218 patients (73% white, 15% black, and 11% other), were not associated with SCr or mortality. Specifically, blacks did not have an increased hazard of death (unadjusted HR 0.91, 95% CI 0.43 to 1.93, P 0.77), and the combined group of blacks and Asians did not have an increased hazard of death (unadjusted HR 0.54, 95% CI 0.26 to 1.15, P 0.11) compared with whites. Mean SD SCr was mg/dl, and MCQ egfr ranged from 15.9 to ml/min per 1.73 m 2 with a mean SD of ml/min per 1.73 m 2. Sixty-two (12%) of the patients had evidence of CKD. When divided into tertiles, egfr was distributed as follows: tertile I 81, tertile II 81 to 102, and tertile III 102 ml/min per 1.73 m 2. Table 1 lists the demographic, clinical, laboratory, exercise testing, and hemodynamic data for the entire cohort, as well as differences between those with SCr 1.0, 1.0 to 1.4, and 1.4 mg/dl. Of note, only 6 patients had known human immunodeficiency virus (HIV), none of whom had HIV-associated nephropathy. Table 2 lists all of the variables that were associated with SCr, and with MCQ egfr, on univariate analysis with a significance of P Older patients and male patients, as well as those with systemic hypertension, diabetes mellitus, or coronary disease and those taking diuretics at the time of referral, had worse renal function. Diuretic use was associated with an increased HR for mortality (unadjusted HR 1.68, 95% CI 1.31 to 2.16, P ). However, within the group of patients taking diuretics (n 250), no individual type of diuretic was associated with increased mortality. No differences in renal function were found amongst the different causes of PAH. Worse functional class, hypoalbuminemia, decreased carbon monoxide diffusing capacity, and worse exercise tolerance were all also associated with higher SCr. Increased SCr was associated with a worse hemodynamic profile, and those with higher SCr had decreased augmentation of cardiac index during adenosine vasodilator testing. Median follow-up time was 3.5 years (maximum follow-up time 21.3 years). A total of 279 deaths occurred during follow-up. Rates of death increased with increasing levels of SCr and decreasing levels of egfr (Table 3). We found an interaction between SCr groups and right atrial pressure (P for the interaction term). No significant interaction was found between SCr and cardiac index (P 0.11) or SCr and mean pulmonary artery pressure (P 0.39). Similar to SCr, we found an interaction between egfr tertiles and right atrial pressure (P 0.009). Table 3 summarizes the univariate relationships between SCr groups and mortality and between tertiles of egfr and mortality. SCr 1.0 to 1.4 mg/dl, SCr 1.4 mg/dl, and the lowest tertile of egfr were each associated with an increased risk of death. CKD was also associated with an increased risk of death (unadjusted HR 1.98, 95% CI 1.44 to 2.72, P ). Figures 1 and 2 display differences in Kaplan Meier curves for mortality by SCr groups (Figure 1) and by egfr tertiles (Figure 2). Figures 3 and 4 display the results of the multivariable Cox proportional hazards analysis, showing the dependency of the multivariate HR on the level of right atrial pressure. SCr 1.0 to 1.4 mg/dl, SCr 1.4 mg/dl, and the lowest tertile of egfr were all independent predictors of mortality on multivariate analysis. The association between renal function and death was most prominent at right atrial pressures 10 mm Hg, which was the median value for right atrial pressure in the present study. Discussion We found that renal dysfunction was associated with a worse hemodynamic profile and was a powerful independent predictor of mortality among patients with WHO group I PAH. The association between renal dysfunction and mortality persisted after we controlled for demographic and clinical factors, cause of PAH (including connective tissue disease), functional class, diffusing capacity of carbon monoxide, and hemodynamic variables. By utilizing various methods of defining renal dysfunction (mildly increased SCr versus normal or low SCr; tertiles of egfr), we were able to comprehensively show that renal dysfunction, whether mild or moderate, was clearly associated with adverse outcomes. The finding that SCr is associated with mortality is both mechanistically intriguing and practical in that it offers a simple measurement that noninvasively predicts outcome. Reasons for the independent association between mildly increased SCr and mortality are likely multifactorial. As in other studies of PAH, 3,26 most of the patients in the present study cohort were women, and many patients with PAH are debilitated, with low muscle mass. Therefore, even mild elevations in SCr could reflect significant decreases in glomerular filtration rate. However, the mean MCQ egfr in the mildly increased SCr group was 83 ml/min per 1.73 m 2. Although this rate of glomerular filtration is not normal, it does not meet the definition of CKD (glomerular filtration rate 60 ml/min). Mildly increased SCr could be a sensitive indicator of decreased cardiac output, which is a powerful predictor of mortality in PAH; however, controlling for cardiac output did not weaken the association between mildly increased SCr and death. Mild renal dysfunction may also lead to fluid retention, which could add further stress to the

4 2478 Circulation May 13, 2008 Table 1. Baseline Demographic, Clinical, Laboratory, Hemodynamic, and Mortality Characteristics by SCr Groups by SCr Characteristic All Patients (n 500) SCr 1.0 mg/dl (n 219) SCr mg/dl (n 232) SCr 1.4 mg/dl (n 49) P Age, y Women, n (%) 394 (79) 193 (88) 170 (73) 31 (63) Cause of PAH, n (%) Idiopathic/familial 234 (47) 101 (46) 110 (47) 23 (47) Connective tissue disease 153 (31) 56 (26) 82 (35) 15 (31) Congenital heart disease 54 (11) 32 (15) 19 (8) 3 (6) Portal hypertension, anorexigen, or HIV 59 (12) 30 (14) 21 (9) 8 (16) Medications, n (%) Angiotensin receptor blocker or ACE inhibitor 82 (16) 31 (14) 41 (18) 10 (20) 0.44 Diuretics 250 (50) 91 (42) 127 (55) 32 (65) Calcium channel blockers 155 (31) 58 (26) 80 (35) 17 (35) 0.16 Digoxin 90 (18) 37 (17) 40 (17) 13 (27) 0.26 Warfarin 139 (28) 65 (30) 63 (27) 11 (22) 0.57 Prostacyclins 12 (2) 7 (3) 5 (2) 0 (0) 0.52 Endothelin blockers 18 (4) 6 (3) 10 (4) 2 (4) 0.63 Phosphodiesterase inhibitors 5 (1) 2 (1) 3 (1) 0 (0) 0.99 Comorbidities, n (%) Systemic hypertension 148 (30) 49 (22) 79 (34) 20 (41) Diabetes mellitus 33 (7) 15 (7) 12 (5) 6 (12) 0.17 Obesity 71 (14) 30 (14) 34 (15) 7 (14) 0.93 Coronary artery disease 22 (4) 5 (2) 13 (6) 4 (8) WHO functional class (n 489), n (%) Class I 31 (6) 19 (9) 12 (5) 0 (0) Class II 67 (14) 43 (20) 21 (9) 3 (6) Class III 242 (49) 93 (43) 125 (55) 24 (51) Class IV 149 (30) 59 (28) 70 (31) 20 (42) Laboratory tests Creatinine, mg/dl egfr by MCQ equation, ml/min per 1.73 m egfr by MDRD equation (n 218), ml/min per 1.73 m Albumin, g/dl (n 459) Diffusing capacity of carbon monoxide, % predicted (n 369) Treadmill exercise capacity, METs (n 299) Hemodynamics (n 460) Aortic systolic pressure, mm Hg Aortic diastolic pressure, mm Hg Right atrial pressure, mm Hg Mean PA pressure, mm Hg Cardiac index, L min 1 m Pulmonary vascular resistance, WU PA saturation, % Adenosine vasodilator testing (n 382) Change in mean PA pressure, mm Hg Change in cardiac index, L min 1 m Change in pulmonary vascular resistance, WU METs indicates metabolic equivalents; WU, Wood units; and PA, pulmonary artery. *Data complete for all characteristics except as listed. P based on univariate analysis (using ANOVA and Kruskal-Wallis tests for continuous variables and 2 and Fisher exact tests for categorical variables).

5 Shah et al Serum Creatinine and Mortality in PAH 2479 Table 2. Variables Associated With SCr and egfr on Univariate Analysis SCr egfr Variable -Coefficient (95% CI) P -Coefficient (95% CI) P Age* 0.04 (0.02 to 0.06) ( 10.7 to 8.1) Female 0.17 ( 0.24 to 0.09) ( 15.4 to 4.8) Systemic hypertension 0.10 (0.03 to 0.16) ( 19.0 to 9.9) Diabetes mellitus 0.10 ( 0.02 to 0.22) ( 19.0 to 1.8) Coronary artery disease 0.19 (0.04 to 0.34) ( 25.8 to 5.0) Diuretics 0.12 (0.05 to 0.18) ( 14.9 to 6.3) WHO functional class II vs I ( 0.13 to 0.16) 6.5 ( 16.8 to 3.2) III vs I 0.13 (0.008 to 0.25) 15.2 ( 24.3 to 6.3) IV vs I 0.15 (0.025 to 0.28) 19.4 ( 26.7 to 10.0) Albumin, g/dl 0.06 (0.005 to 0.11) ( 9.2 to 1.6) Diffusing capacity of carbon monoxide, % predicted 0.02 (0.005 to 0.04) ( 3.6 to 1.3) Treadmill exercise capacity, METs (0.008 to 0.041) ( 4.3 to 1.7) Right atrial pressure, mm Hg 0.08 (0.05 to 0.10) ( 5.6 to 2.2) Cardiac index, L min 1 m (0.021 to 0.061) ( 7.9 to 2.5) Pulmonary vascular resistance, WU (0.008 to 0.045) ( 1.9 to 1.3) 0.72 Pulmonary artery saturation 0.08 (0.05 to 0.10) ( 6.6 to 2.9) METs indicates metabolic equivalents; WU, Wood units. *Per decade increase. P is for likelihood ratio test with 3 degrees of freedom. Per 1-unit decrease. Per 10% decrease. Per 5-unit increase. right ventricle in a disease in which many patients continually live a delicate balance on a hemodynamic tightrope. We found that diuretic use was associated with both worse renal function and increased mortality, associations that have previously been identified in studies of left-sided heart failure 27,28 and that are thought to be due to neurohormonal activation. However, in the present study, adjustment for diuretic use did not attenuate the association between renal dysfunction and death. In addition, because diuretic doses were relatively stable at the time of entry into the study, we believe that they reflect disease severity and are not a direct cause of increased risk of death (although we cannot exclude this possibility). The present results support the association of renal dysfunction, fluid retention, and mortality. Increased right atrial pressure, which has been shown to be predictive of mortality in PAH in prior studies, is a poor prognostic sign because it reflects the required hypertrophic response to chronically increased afterload, increased right ventricular filling pressures due to severe right ventricular diastolic dysfunction, alteration of right atrial and right ventricular compliance, and, in some cases, significant tricuspid regurgitation. Renal dysfunction, whether overt or subtle, may lead to upregulation of the renin-angiotensin-aldosterone system, increases in sympathetic nervous system activity, and impaired sodium handling, 32 which may lead to increased fluid retention, elevated right atrial pressure, and further stress on the right ventricle. We found a significant interaction between right atrial pressure and renal function as predictors of mortality. As shown in Figures 3 and 4, after multivariable adjustment, it appeared that renal function best Table 3. Unadjusted HRs for SCr Groups and Tertiles of Glomerular Filtration Rate as Predictors of Mortality Predictor Deaths, n/n (%) HR (95% CI) P P for Trend SCr group mg/dl (referent group) 96/219 (44) mg/dl 142/232 (61) 1.65 ( ) mg/dl 41/49 (84) 2.54 ( ) Tertile of egfr Tertile III (highest tertile; referent group) 71/164 (43) Tertile II (middle tertile) 89/165 (54) 1.34 ( ) Tertile I (lowest tertile) 115/162 (71) 2.37 ( )

6 2480 Circulation May 13, 2008 Survival Log-rank p< SCr < 1.0 mg/dl SCr mg/dl SCr > 1.4 mg/dl Time (years) Figure 1. Kaplan Meier survival curves for patients with normal, mildly elevated, and moderately elevated SCr. Number at risk: SCr < SCr SCr > predicted death at right atrial pressures 10 mm Hg. Possible reasons for this finding include the following: (1) Worse renal function in patients with low right atrial pressure may signify poor renal perfusion, with increased risk of adverse outcomes. (2) As right atrial pressure increases, there may be a progressive dilutional effect on SCr (due to significant volume overload) that may result in a falsely low SCr, thereby obscuring the association between SCr and death. (3) Right atrial pressure is one of the most powerful predictors of death in PAH, and significant Survival Time (years) elevation in right atrial pressure may overshadow the predictive power of increased SCr and other indices of abnormal renal function. Although the interaction between renal function and right atrial pressure merits further study, 50% of the patients in the present study had a right atrial pressure 10 mm Hg, and after multivariable analysis, abnormal renal function continued to independently predict death in these patients. The present findings are consistent with those in left-sided heart failure, in which SCr, egfr, and other measures of renal Log-rank p< Tertile III Tertile II Tertile I Figure 2. Kaplan Meier survival curves by tertile of egfr. Tertile I indicates egfr 81 ml/min per 1.73 m 2 ; tertile II, egfr 81 to 102 ml/min per 1.73 m 2 ; and tertile III, egfr 102 ml/min per 1.73 m 2. Number at risk: Tertile III Tertile II Tertile I

7 Shah et al Serum Creatinine and Mortality in PAH 2481 Figure 3. Multivariate HRs as a function of right atrial pressure for SCr. Dashed lines represent upper and lower limits of 95% CI; adjusted for age, sex, cause of PAH, diabetes mellitus, systemic hypertension, coronary disease, diuretic use, serum albumin, functional class, and hemodynamic variables (mean right atrial pressure, mean pulmonary artery pressure, and cardiac index). function, such as cystatin C, have been found to be powerful independent predictors of adverse outcomes. 12,33 36 Although less well studied, it may be that similar to the left ventricle, the right ventricle responds poorly to worsening renal function, or it may be that the kidney is a sensitive indicator of poor overall hemodynamic status of the right ventricle. The present findings may also influence future clinical trials in PAH. Current trials rarely report baseline SCr, and renal function is not currently thought of as a prognostic indicator in PAH. 5 The present findings may help stimulate investigators to pay more attention to the beneficial or adverse effect of various treatments on renal function in PAH. Strengths of the present study include the large sample size and the long duration of follow-up, which increased our power to detect an association between renal dysfunction (even mildly increased SCr) and death. To the best of our knowledge, only 1 small study of 118 patients with isolated PAH has evaluated renal function as a risk marker for mortality. 37 That study had fewer patients, shorter follow-up, and used CKD (egfr 60 ml/min per 1.73 m 2 ) as the risk predictor, and it found that CKD was associated with a 1.62-fold increased risk of death during a mean follow-up of 10 months (P 0.05). Although we found the same association between CKD and increased mortality, relatively few patients with PAH have CKD (12% in the present study). The low prevalence of traditionally defined CKD likely reflects the young age and absence of cardiovascular comorbidities in most patients with PAH. Thus, by examining both SCr and egfr as Figure 4. Multivariate HRs as a function of right atrial pressure for egfr. Dashed lines represent upper and lower limits of 95% CI, adjusted for age, gender, cause of PAH, diabetes mellitus, systemic hypertension, coronary disease, diuretic use, serum albumin, functional class, and hemodynamic variables (mean right atrial pressure, mean pulmonary artery pressure, and cardiac index).

8 2482 Circulation May 13, 2008 categorical predictors, we were able to show that even mild renal dysfunction is independently associated with mortality. Study Limitations Data collection for the present study started in 2004, so the majority of patients were entered retrospectively. Weight data were unavailable, so we could not examine the association between body mass and SCr; however, it is likely that worse clinical status would be associated with muscle wasting (and therefore lower muscle mass and lower SCr), which would have biased our results in the opposite direction of our findings. Incomplete data on race are another potential limitation, because it is known that blacks have increased SCr. 38 However, in the 218 patients with race data available in the present study, we did not find any differences in SCr between whites and blacks. Race may also be a risk factor for mortality in PAH. In 1 study (n 84) of patients with idiopathic pulmonary hypertension, the combined group of black and Asian patients had a decreased rate of transplant-free survival. 25 However, in the present larger sample of patients with race data available (n 218), we found that neither black nor Asian race was associated with increased mortality. We therefore do not believe that lack of race data in some patients alters the present finding of an association between worse renal function and mortality in PAH. The MDRD egfr equation also requires knowledge of race, 17 but as shown in Table 1, the MDRD egfr underestimated the MCQ egfr, which mirrors other studies that have found that the MDRD equation underestimates the true glomerular filtration rate in patients with normal or relatively normal kidney function. 16,39 The MCQ egfr equation appears to be superior to the MDRD and Cockcroft-Gault formulas in patients without CKD, 16 and studies have shown that the MCQ egfr does not underestimate normal glomerular filtration rate. 16,39 Additionally, the MDRD egfr has been shown to be suboptimal as a renal risk predictor in patients with cardiovascular disease. 40 Other limitations include a study population composed of patients cared for by a single tertiary referral practice, lack of systematic evaluation of right ventricular systolic function by echocardiography, and the choice of arbitrary SCr cut points to define normal and abnormal SCr groups. However, no perfect cutoff exists for abnormal SCr, and we were able to show that low egfr also predicted mortality. In addition, we purposely included upper-normal SCr (1.0 to 1.2 mg/dl) as part of the mildly elevated SCr group to show that even SCr values that may be considered normal still predict death. Another limitation was the use of SCr (and creatinine-based egfr) as the primary indicators of renal function, which may be inferior to cystatin C as both a measure of kidney function and a predictor of death. Finally, data on cause of death were not available in the majority of patients in the present study, so we cannot comment on the association of renal dysfunction with specific causes of death in this study. In summary, we found that SCr and egfr were powerful independent predictors of mortality in PAH. Further research into the cardiopulmonary-renal connection in patients with PAH is necessary and may provide novel insights into prognosis and treatment of this lethal disease. Acknowledgments We would like to acknowledge Vallerie V. McLaughlin, MD, for her expert evaluation and care of many of the patients included in the Pulmonary Hypertension Connection registry. Sources of Funding Dr Shah was supported by a Heart Failure Society of America Research Fellowship Award. Dr Gomberg-Maitland is supported by a Doris Duke Clinical Scientist Development Award. Dr Archer s research is supported by the Canadian Institutes for Health Research and by NIH grant HL Disclosures Dr Rich previously served as a salaried employee at United Therapeutics; his employment concluded in January Dr Archer holds patents for mitochondrial modulators for treatment of cancers and potassium channel replacement therapy for vascular diseases, including PAH. Dr Gomberg-Maitland has received research grant support from Actelion, Co-Therix, Encysive, Gilead, Lilly/Icos, Pfizer, and United Therapeutics and has served as a consultant and/or on advisory boards for Encysive, Gilead, Pfizer, and United Therapeutics. The remaining authors report no conflicts. References 1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351: Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351: Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, Levy PS, Reid LM, Vreim CE, Williams GW. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107: D Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. 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Nephrol Dial Transplant. 2007;22: Smith GL, Shlipak MG, Havranek EP, Foody JM, Masoudi FA, Rathore SS, Krumholz HM. Serum urea nitrogen, creatinine, and estimators of renal function: mortality in older patients with cardiovascular disease. Arch Intern Med. 2006;166: CLINICAL PERSPECTIVE Pulmonary arterial hypertension is a devastating disease of the pulmonary vasculature that ultimately leads to right heart failure and death. Novel risk predictors for mortality in pulmonary arterial hypertension may assist in the identification of high-risk patients and may also lead to a better understanding of disease pathophysiology. Several studies have found serum creatinine (SCr) and SCr-based estimates of glomerular filtration rate to be potent predictors of poor outcome in patients with cardiovascular diseases such as coronary artery disease and heart failure. We sought to determine whether elevated SCr was associated with abnormal hemodynamics and predicted death in 500 patients with World Health Organization group I pulmonary arterial hypertension who were followed up for a median of 3.5 years (maximum follow-up 21 years). We found that SCr was significantly associated with abnormal hemodynamics and poor functional status. Furthermore, a single baseline measurement of SCr predicted death. Compared with patients with SCr 1.0 mg/dl, those with SCr 1.0 to 1.4 mg/dl and SCr 1.4 mg/dl had an increased hazard ratio of death (unadjusted hazard ratio 1.65, 95% confidence interval 1.26 to 2.17, P for SCr 1.0 to 1.4 mg/dl; unadjusted hazard ratio 2.54, 95% confidence interval 1.73 to 3.71, P for SCr 1.4 mg/dl). On multivariable analysis, we found a significant interaction between SCr and right atrial pressures, whereby increased SCr best predicted death in patients with right atrial pressure 10 mm Hg. Our results show that measurement of SCr is practical and offers a simple way to noninvasively predict abnormal hemodynamics and death. Go to to take the CME quiz for this article.