Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD

Background and objectives

High levels of serum polyclonal combined Ig free light chains are associated with inflammation and decreased excretory kidney function, and they are an independent risk factor for mortality. Whether combined Ig free light chain predicted mortality and progression to ESRD in a stages 3–5 CKD cohort was assessed.

Design, setting, participants, & measurements

This was a prospective cohort study of 872 patients with stages 3–5 CKD (nondialysis) recruited into the Chronic Renal Insufficiency Standards Implementation Study. Patients were recruited to the Chronic Renal Insufficiency Standards Implementation Study in an unselected manner from secondary care nephrology clinics between 2004 and 2010. Combined Ig free light chain was measured at recruitment and analyzed by quartiles. The cohort was followed up for a median of 41.4 months (interquartile range =28.3–68.0 months). Cox regression analysis was undertaken to determine the variables associated with mortality and progression to ESRD.

Results

Combined Ig free light chain quartiles were <49.4, 49.4–68.8, 68.9–100.7, and >100.7 mg/L. An independent association with death and progression to ESRD was associated with the third and fourth combined Ig free light chain quartiles (quartile 3: death: hazard ratio, 1.49; 95% confidence interval, 1.02 to 2.18; P=0.04; ESRD: hazard ratio, 1.72; 95% confidence interval, 1.0 to 2.97; P=0.05; quartile 4: death: hazard ratio, 1.99; 95% confidence interval, 1.34 to 2.93; P<0.001; ESRD: hazard ratio, 3.73; 95% confidence interval, 2.1 to 6.3; P<0.001). The other independent risk factors were (1) preexisting cardiovascular disease, age >65 years old, and eGFR=15–30 ml/min per 1.73 m² for death and (2) age ≤65 years old, eGFR<30 ml/min per 1.73 m², urinary protein-to-creatinine ratio >30 mg/mmol, and serum phosphate level >4.65 mg/dl for progression to ESRD.

Conclusions

An elevated serum combined Ig free light chain level is an independent risk factor for mortality and progression to ESRD in patients with stages 3–5 CKD managed in secondary care.     

The Association of Inhaled Corticosteroid Use with Serum Glucose Concentration in a Large Cohort

Background

Inhaled corticosteroids (ICSs) are widely used in the treatment of obstructive lung disease. ICSs have been shown to be systemically absorbed. The association between ICS and serum glucose concentration is unknown.

Methods

To explore the association of ICS dosing with serum glucose concentration, we used a prospective cohort study of US veterans enrolled in 7 primary care clinics between December 1996 and May 2001 with 1 or more glucose measurements while at least 80% adherent to ICS dosing. The association between ICS dose from pharmacy records standardized to daily triamcinolone equivalents and serum glucose concentration was examined with generalized estimating equations controlling for confounders, including systemic corticosteroid use.

Results

Of the 1698 subjects who met inclusion criteria, 19% had self-reported diabetes. The mean daily dose of ICS in triamcinolone equivalents was 621 μg (standard deviation 555) and 610 μg (standard deviation 553) for subjects with and without diabetes, respectively. After controlling for systemic corticosteroid use and other potential confounders, no association between ICS and serum glucose was found for subjects without diabetes. However, among subjects with self-reported diabetes, every additional 100 μg of ICS dose was associated with an increased glucose concentration of 1.82 mg/dL (P value .007; 95% confidence interval [CI], 0.49-3.15). Subjects prescribed antiglycemic medications had an increase in serum glucose of 2.65 mg/dL (P value .003; 95% CI, 0.88-4.43) for every additional 100 μg ICS dose.

Conclusion

Among diabetic patients, ICS use is associated with an increased serum glucose concentration in a dose-response manner.     

Association of Markers of Iron Stores with Outcomes in Patients with Nondialysis-Dependent Chronic Kidney Disease

Background and objectives: Assessments of iron stores by serum iron saturation ratio (ISAT) and ferritin are used to direct anemia therapy in chronic kidney disease (CKD) and are associated with clinical outcomes in patients on dialysis. The association of ISAT and ferritin with outcomes in patients with nondialysis-dependent CKD (NDD-CKD) has not been studied.Design, setting, participants, & measurements: All-cause mortality and progression of CKD [slopes of estimated GFR (eGFR)] were examined in 453 men with NDD-CKD. Mortality and the composite of mortality and ESRD were studied in Cox models. Slopes of eGFR were examined in mixed-effects models.Results: Lower ISAT was associated with higher mortality; adjusted hazard ratio [95% confidence interval (CI)] with ISAT of <12%, 13 to 17%, and >23% versus 18 to 23%; 1.40 (0.99 to 1.98), 1.20 (0.82 to 1.76), and 0.97 (0.67 to 1.41), P = 0.025 for trend. ISAT was also associated with steeper slopes of eGFR (one log-unit higher ISAT associated with a slope of −0.89 ml/min/1.73m² /yr (95% CI: −1.75, −0.02, P = 0.044). Serum ferritin level showed no significant association with outcomes overall, but a trend for higher mortality was observed in patients with a serum ferritin level >250 ng/ml.Conclusions: Higher ISAT is associated with lower mortality and with more progressive CKD. Clinical trials are needed to examine if correction of low iron levels can improve mortality without affecting kidney function in NDD-CKD.Iron is an essential trace element which plays an important role in the catalysis of oxidative reactions and in the transport of soluble gases (1). Assessment of iron stores is done routinely in everyday nephrology practice (2), through measurement of total iron saturation (ISAT; also known as transferrin saturation) and serum ferritin (3).Iron deficiency is common in patients with nondialysis-dependent chronic kidney disease (NDD-CKD) (4,5), but it is unclear to what extent levels of ISAT and ferritin are associated with outcomes in this population. Examining hard endpoints is especially important given the concern that exceeding certain limits of ISAT or ferritin may be deleterious through excess iron deposition and induction of oxidative stress (6–9). We examined the associations of these iron markers with all-cause mortality, the composite of predialysis mortality or ESRD, and the slopes of estimated GFR (eGFR) in 453 men with moderate and advanced NDD-CKD.     

Implantable Cardioverter-Defibrillators in Patients with CKD: A Propensity-Matched Mortality Analysis

Background and objectives

Benefits of transvenous implantable cardioverter-defibrillators (ICDs) in prevention of sudden cardiac death among the general population are proven. However, the benefit of ICDs remains unclear in CKD. A propensity-matched analysis was conducted to examine the survival benefits of ICDs placed for primary prevention in those with CKD not on dialysis (eGFR<60 ml/min per 1.73 m²).

Design, setting, participants, & measurements

The Cleveland Clinic CKD registry was utilized to identify individuals who had an echocardiogram at the institution (between 2001 and October 2011). A propensity score of the likelihood of receiving an ICD was developed with the following variables: demographics, comorbid conditions, use of cardioprotective medications, eGFR, left ventricular ejection fraction, and ventricular arrhythmia. One-to-one greedy matching was used with 0.1 caliper width to match patients with and without an ICD. A Cox proportional hazards model was used to examine survival of matched patients with and without an ICD.

Results

This study included 1053 ICD patients and 9435 potential controls. Of 1053 ICD patients (60%), 631 were matched to the control group. During a median follow-up of 2.9 years (25th and 75th percentiles, 1.5, 4.7), 578 patients died. After adjusting for covariates, the hazard of mortality among propensity-matched patients was 0.69 (95% confidence interval [95% CI], 0.59 to 0.82) for the ICD group compared with the non-ICD group. A significant interaction was found between ICDs and eGFR (P=0.04). Presence of an ICD was associated with a lower risk of death among those with eGFRs of 45–59 ml/min per 1.73 m² (hazard ratio [HR], 0.58; 95% CI, 0.44 to 0.77) and 30–44 ml/min per 1.73 m² (HR, 0.65; 95% CI, 0.50 to 0.85), but not among those with eGFRs<30 ml/min per 1.73 m² (HR, 0.98; 95% CI, 0.71 to 1.35).

Conclusions

Transvenous ICDs placed for primary prevention are associated with a survival benefit in those with stage 3 CKD, but not in those with stage 4 CKD.     

Ferric Citrate Hydrate for the Treatment of Hyperphosphatemia in Nondialysis-Dependent CKD

Background and objectives

Ferric citrate hydrate is a novel iron-based phosphate binder being developed for hyperphosphatemia in patients with CKD.

Design, setting, participants, & measurements

A phase 3, multicenter, randomized, double blind, placebo-controlled study investigated the efficacy and safety of ferric citrate hydrate in nondialysis-dependent patients with CKD. Starting in April of 2011, 90 CKD patients (eGFR=9.21±5.72 ml/min per 1.73 m²) with a serum phosphate≥5.0 mg/dl were randomized 2:1 to ferric citrate hydrate or placebo for 12 weeks. The primary end point was change in serum phosphate from baseline to the end of treatment. Secondary end points included the percentage of patients achieving target serum phosphate levels (2.5–4.5 mg/dl) and change in fibroblast growth factor-23 at the end of treatment.

Results

The mean change in serum phosphate was −1.29 mg/dl (95% confidence interval, −1.63 to −0.96 mg/dl) in the ferric citrate hydrate group and 0.06 mg/dl (95% confidence interval, −0.20 to 0.31 mg/dl) in the placebo group (P<0.001 for difference between groups). The percentage of patients achieving target serum phosphate levels was 64.9% in the ferric citrate hydrate group and 6.9% in the placebo group (P<0.001). Fibroblast growth factor-23 concentrations were significantly lower in patients treated with ferric citrate hydrate versus placebo (change from baseline [median], −142.0 versus 67.0 pg/ml; P<0.001). Ferric citrate hydrate significantly increased serum iron, ferritin, and transferrin saturation compared with placebo (P=0.001 or P<0.001). Five patients discontinued active treatment because of treatment-emergent adverse events with ferric citrate hydrate treatment versus one patient with placebo. Overall, adverse drug reactions were similar in patients receiving ferric citrate hydrate or placebo, with gastrointestinal disorders occurring in 30.0% of ferric citrate hydrate patients and 26.7% of patients receiving placebo.

Conclusion

In patients with nondialysis-dependent CKD, 12-week treatment with ferric citrate hydrate resulted in significant reductions in serum phosphate and fibroblast growth factor-23 while simultaneously increasing serum iron parameters.     

Pain and Mortality Risk in a Cohort of HIV-Infected Persons with Alcohol Use Disorders

Pain has been associated with increased risk for mortality in some studies. We analyzed data from a cohort study [HIV-longitudinal interrelationships of viruses and ethanol (HIV-LIVE)] of HIV-infected persons with alcohol use disorders enrolled 2001–2003 to explore whether reporting moderate or greater pain interference was associated with mortality. The main independent variable was pain that at least moderately interfered with work based on a single question from the SF-12. Primary analyses dichotomized at “moderately” or above. Cox proportional hazards models assessed the association between pain interference and death adjusting for demographics, substance use, CD4 count, HIV viral load and co-morbidities. Although significant in unadjusted models (HR = 1.58 (95 % CI 1.03–2.41; p value = 0.04)), after adjusting for confounders, ≥moderate pain interference was not associated with an increased risk of death [aHR = 1.30 (95 % CI 0.81–2.11, p value = 0.28)]. Among HIV-infected persons with alcohol use disorders, we did not detect a statistically significant independent association between pain interference and risk of death after adjustment for potential confounders.     

Association of Fluid Overload with Cardiovascular Morbidity and All-Cause Mortality in Stages 4 and 5 CKD

Background and objectives

Fluid overload is a common characteristic associated with renal progression in CKD. Additionally, fluid overload is an independent predictor of all-cause or cardiovascular mortality in patients on dialysis, but its influence on patients not on dialysis is uncertain. The aim of the study was to assess the relationship between the severity of fluid status and clinical outcomes in an advanced CKD cohort.

Design, setting, participants, & measurements

In total, 478 predialysis patients with stages 4 and 5 CKD in the integrated CKD care program were enrolled from January of 2011 to December of 2011 and followed-up until August of 2013. The clinical outcomes included cardiovascular morbidity and all-cause mortality. The relative hydration status (overhydration/extracellular water) was used as the presentation of the severity of fluid status and measured using a body composition monitor. Overhydration/extracellular water >7% was defined as fluid overload.

Results

Over a median follow-up period of 23.2 (12.6–26.4) months, 66 (13.8%) patients reached all-cause mortality or cardiovascular morbidity. The adjusted hazard ratio of the combined outcome of all-cause mortality or cardiovascular morbidity for every 1% higher overhydration/extracellular water was 1.08 (95% confidence interval, 1.04 to 1.12; P<0.001). The adjusted overhydration/extracellular water for the combined outcome of all-cause mortality or cardiovascular morbidity in participants with overhydration/extracellular water ≥7% compared with those with overhydration/extracellular water <7% was 1.93 (95% confidence interval, 1.01 to 3.69; P=0.04). In subgroup analysis, higher overhydration/extracellular water was consistently associated with increased risk for the combined outcome independent of diabetes, cardiovascular disease, and serum albumin. There was no significant interaction between all subgroups.

Conclusions

These findings suggest that fluid overload is an independent risk factor of the combined outcome of all-cause mortality or cardiovascular morbidity in patients with advanced CKD.     

Glycated Hemoglobin Level and Mortality in a Nondiabetic Population with CKD

Background and objectives

Glycated hemoglobin (HbA_1c) is used to diagnose diabetes mellitus (DM) and guide its management. The association between higher HbA_1c and progression to ESRD and mortality has been demonstrated in populations with DM. This study examined the association between HbA_1c and these end points in a population with CKD and without DM.

Design, setting, participants, & measurements

In the hospital-based NephroTest cohort study, measured GFR (mGFR) was taken by ⁵¹Cr-EDTA renal clearance and HbA_1c in 1165 adults with nondialysis CKD stages 1–5 and without DM between January 2000 and December 2010. The median follow-up was 3.48 years (interquartile range, 1.94–5.82) for the competing events of ESRD and pre-ESRD mortality. Time-fixed and time-dependent Cox models were used to estimate hazard ratios (HRs) for ESRD and mortality according to HbA_1c, treated continuously or in tertiles.

Results

At inclusion, the mean mGFR was 42.2±19.9 ml/min per 1.73 m², and the mean HbA_1c value was 5.5%±0.5%. During follow-up, 109 patients died, and 162 patients reached ESRD. Pre-ESRD mortality was significantly associated with HbA_1c treated continuously: for every 1% higher HbA_1c, the crude HR was 2.16 (95% confidence interval [95% CI], 1.27 to 3.68), and it was 1.85 (95% CI, 1.05 to 3.24) after adjustment for mGFR and other risk factors of death. After excluding incident diabetes over time, the updated mean of HbA_1c remained significantly associated with higher mortality risk: adjusted HR for the highest (5.7%–6.4%) versus the lowest tertile (<5.3%) was 2.62 (95% CI, 1.16 to 5.91). There was no association with ESRD risk after adjustment for risk factors of CKD progression.

Conclusions

In a CKD cohort, HbA_1c values in the prediabetes range are associated with mortality. Such values should be therefore included among the risk factors for negative outcomes in CKD populations.     

Markers of Inflammation and Mortality in a Cohort of Patients With Alcohol Dependence

Inflammation and intestinal permeability are believed to be paramount features in the development of alcohol-related liver damage. We aimed to assess the impact of 3 surrogate markers of inflammation (anemia, fibrinogen, and ferritin levels) on mid-term mortality of patients with alcohol dependence.This longitudinal study included patients with alcohol dependence admitted for hospital detoxification between 2000 and 2010. Mortality was ascertained from clinical charts and the mortality register. Associations between markers of inflammation and all-cause mortality were analyzed with mortality rates and Cox proportional hazards regression models.We also performed a subgroup analysis of mortality rates in patients with anemia, based on their mean corpuscular volume (MCV).We included 909 consecutive patients with alcohol dependence. Patients were mostly male (80.3%), had a median age of 44 years (interquartile range [IQR]: 38–50), and upon admission, their median alcohol consumption was 192 g/day (IQR: 120–265). At admission, 182 (20.5%) patients had anemia; 210 (25.9%) had fibrinogen levels >4.5 mg/dL; and 365 (49.5%) had ferritin levels >200 ng/mL. At the end of follow-up (median 3.8 years [IQR: 1.8–6.5], and a total of 3861.07 person-years), 118 patients had died (12.9% of the study population). Cox regression models showed that the presence of anemia at baseline was associated with mortality (hazard ratio [HR]: 1.67, 95% confidence interval [CI]: 1.11–2.52, P < 0.01); no associations were found between mortality and high fibrinogen or high ferritin levels.A subgroup of patients with anemia was analyzed and compared to a control group of patients without anemia and a normal MCV. The mortality ratios of patients with normocytic and macrocytic anemia were 3.25 (95% CI: 1.41–7.26; P < 0.01) and 3.39 (95% CI: 1.86–6.43; P < 0.01), respectively.Patients with alcohol dependence admitted for detoxification had an increased risk of death when anemia was present at admission. More accurate markers of systemic inflammation are needed to serve as prognostic factors for poor outcomes in this subset of patients.     

Cancer-Specific Mortality in Chronic Kidney Disease: Longitudinal Follow-Up of a Large Cohort

Summary

Background and objectives

Chronic kidney disease (CKD) is known to be associated with increased all-cause and cardiovascular mortality, but no large studies examined the cancer-specific mortality in non–dialysis-dependent CKD patients. Such outcome data are needed for proper allocation of resources and would help to develop better preventive services.

Design, setting, participants, & measurements

Between 1998 and 1999, 123,717 adults were recruited from four health screening centers in Taiwan. The estimated glomerular filtration rate was calculated using the four-variable Modification of Diet in Renal Disease Study equation for the Chinese. Mortality was ascertained by computer linkage to the national death registry after a median follow-up of 7.06 years. Cox proportional hazards regression models were used to estimate the impact of CKD on cancer-specific mortality.

Results

A higher risk for overall cancer mortality was found in CKD patients compared with non-CKD patients (adjusted hazard ratio, 1.2). CKD was associated with increased mortality from liver cancer, kidney cancer, and urinary tract cancer, with an adjusted hazard ratio of 1.74, 3.3, and 7.3, respectively. A graded relationship between the severity of renal impairment and cancer mortality was also found.

Conclusions

Patients with CKD had a higher mortality risk of liver cancer, kidney cancer, and urinary tract cancer. This is the first large study that showed an inverse association between renal function and liver cancer mortality. The increased mortality could be caused by higher cancer incidence or worse response to cancer treatment. Future research is warranted to clarify the mechanism.     

Investigating Genetic Mutations in a Large Cohort of Iranian Patients with Congenital Hyperinsulinism

Objective:Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI.Methods:A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients.Results:Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in ABCC8, 3 (12%) in KCNJ11, 3 (12%) in HADH, and 1 patient had a mutation in KMT2D. These included five novel mutations in ABCC8, KCNJ11, and KMT2D.Conclusion:This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.     

Systolic BP and Mortality in Older Adults with CKD

Background and objectives

Optimal BP targets for older adults with CKD are unclear. This study sought to determine whether a nonlinear relationship between BP and mortality—as described for the broader CKD population and for older adults in the general population—is present for older adults with CKD.

Design, setting, participants, & measurements

A cohort of 21,015 adults age 65–105 years with a moderate or severe reduction in eGFR (<60 ml/min per 1.73 m²) were identified within the Kaiser Permanente Northwest Health Maintenance Organization population. The relationship between baseline systolic BP (SBP; ≤120, 121–130, 131–140, 141–150, >150 mmHg; referent, 131–140 mmHg) and all-cause mortality across age groups (65–70, 71–80, and >80 years) was examined; patients were followed for up to 11 years after cohort entry.

Results

The median times at risk were 3.15 years, 3.53 years, and 2.76 years for adults age 65–70, 71–80, and >80 years, respectively. Mortality during follow-up was 19.6% for those age 65–70 years, 33.4% for those age 71–80 years, and 55.7% for those age >80 years. The relationship between SBP and mortality varied as a function of age. The risk of death was highest for patients with the lowest SBP in all age groups. Only among adults age 65–70 years was an SBP>140 mmHg associated with a higher risk of death compared with the referent category. Patterns of age modification of the relationship between SBP and mortality were consistent in all sensitivity analyses.

Conclusions

In a cohort of older adults, the relationship between SBP and mortality varied systematically with age. A relationship between higher SBP and mortality was present only for younger members of this cohort and not for those older than 70. These results raise the question of whether the relative benefits and harms of lowering BP to recommended targets for older adults with CKD may vary as a function of age.     

Self-Reported Sleep and Nap Habits and Risk of Mortality in a Large Cohort of Older Women

OBJECTIVES: To determine the association between self-reported sleep and nap habits and mortality in a large cohort of older women.
DESIGN: Study of Osteoporotic Fractures prospective cohort study.
SETTING: Four communities within the United States.
PARTICIPANTS: Eight thousand one hundred one Caucasian women aged 69 and older (mean age 77.0).
MEASUREMENTS: Sleep and nap habits were assessed using a questionnaire at the fourth clinic visit (1993/94). Deaths during 7 years of follow-up were confirmed with death certificates. Underlying cause of death was assigned according to the International Classification of Diseases, Ninth Revision, Clinical Modification.
RESULTS: In multivariate models, women who reported napping daily were 44% more likely to die from any cause (95% confidence interval (CI)=1.23–1.67), 58% more likely to die from cardiovascular causes (95% CI=1.25–2.00), and 59% more likely to die from noncardiovascular noncancer causes (95% CI=1.24–2.03) than women who did not nap daily. This relationship remained significant in relatively healthy women (those who reported no comorbidities). Women who slept 9 to 10 hours per 24 hours were at greater risk of death from cardiovascular and other (noncardiovascular, noncancer) causes than those who reported sleeping 8 to 9 hours.
CONCLUSION: Older women who reported napping daily or sleeping at least 9 hours per 24 hours are at greater risk of death from all causes except cancer. Future research could determine whether specific sleep disorders contribute to these relationships.     

Pulmonary Hemodynamics and Outcome in a Large Cohort of Patients with Sinus Venosus Septal Defect

Background: Left-to-right shunt in sinus venosus septal defect (SVSD) may affect resistive (pulmonary vascular resistance–PVR) and elastic (pulmonary artery compliance-PAC) pulmonary artery properties. This study aimed at evaluating (1) impact of age, (2) pulmonary hemodynamics, and (3) outcome in a large cohort of SVSD patients. Methods: This study included 136 patients with SVSD (median age at diagnosis 14 (IQR 5–48) years, 47% male) of which 87 underwent catheterization. Pressures were measured and cardiac output was evaluated using the Fick principle at diagnosis. PVR, PAC and their product (RC time) were calculated. Results: Surgical repair was performed in 128 (94%) at a median age of 13 (IQR 5– 43) years. During a median follow-up time of 31 (IQR 17–55) years, 12 (9%) patients died, 13 (10%) developed heart failure, 4 (3%) Eisenmenger syndrome, 19 (14%) atrial arrhythmia, 6 (4%) sick sinus syndrome and 7 (5%) required pacemaker implantation. In those who underwent catheterization, median shunt ratio was 2.5 (IQR 2.0–2.9). Thirty (34%) had mean PA pressure ≥25 mmHg. PVR indexed, PAC indexed, and RC time was 3.5 (IQR 2.4–7.5) WU.m², 1.8 (IQR 1.3–2.5) mL/mmHg.m² and 0.39 (0.26–0.53) sec with an inverse hyperbolic relationship between PVR and PAC. Mean PA pressure (P < 0.0001); wedge pressure (P = 0.001), PVR indexed (P = 0.002) and PAC indexed (P = 0.002) changed significantly with age at diagnosis, but shunt ratio did not. Conclusion: SVSD has good long-term outcome, albeit with late morbidities. Thirty-four percent has mean PA pressure ≥25 mmHg, but Eisenmenger syndrome is rare (3%). PVR and PAC are inversely related and change significantly with older age.