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Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values
Kidney International, Vol. 66 (2004), pp. 806–810
Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values MORDECHAI YIGLA, ZOHAR KEIDAR, ISRA SAFADI, NAVEH TOV, SHIMON A. REISNER, and FARID NAKHOUL Division of Pulmonary Medicine; Department of Nuclear Medicine; Department of Cardiology; and Department of Nephrology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
In a recently published study [7], we evaluated the incidence of pulmonary hypertension (PHT) in ESRD patients using Doppler echocardiography. Almost 40% of HD patients had systolic PAP above 35 mm Hg, and their cardiac-output (CO) was significantly higher compared with HD patients without PHT. Because the study population had no obvious cause for PHT, we assumed that both ESRD and HD therapy via arteriovenous (A-V) access might be involved in the pathogenesis of this syndrome. Increased CO per se does not cause PHT unless the capacity of the pulmonary circulation is diminished. Pulmonary calcification in the vascular compartment of HD patients is a possible explanation. X-ray film and computerized tomography (CT) of the chest, high resolution computed tomography scan with mediastinal images, technetium 99m–labeled [99m Tc]– MDP bone scanning, and magnetic resonance imaging (MRI) have all shown variable diagnostic values in detecting PC [8–15]. 99m Tc-MDP bone scintigraphy is considered to be a sensitive measure of PC in ESRD, and, in addition, enables semiquantitative evaluation of the PC [11]. This study evaluated the extent of pulmonary uptake of 99m Tc-MDP bone scintigraphy in a group of HD patients and correlated this uptake to the occurrence of PHT.
Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values. Background. End-stage renal disease (ESRD) patients receiving chronic hemodialysis (HD) via an arteriovenous (AV) access often develop unexplained pulmonary hypertension (PHT). This study evaluated the role of pulmonary calcification (PC) in this phenomenon. Methods. The clinical manifestations, systolic pulmonary artery pressure (PAP) values measured by Doppler echocardiography and the presence and the extent of PC expressed by lung uptake of 99m Tc-MDP bone scintigraphy, were studied in 49 patients with ESRD receiving chronic HD therapy via A-V access. The correlation between PC and PHT was investigated. Results. There were 36 men and 13 women with a mean age of 61.7 ± 13.2 years receiving HD therapy for 38.2 ± 43.7 months. Twenty (40.8%) patients had PC expressed by increased lung uptake of 99m Tc- MDP and 28 (57.1%) patients had PHT with a mean systolic PAP of 46 ± 11 mm Hg. No correlation was found between PC and PHT. Conclusion. The data suggest that PC expressed by lung uptake of 99m Tc-MDP has no role in the pathogenesis of PHT among ESRD patients undergoing HD therapy via A-V access.
Extraosseous pulmonary calcification (PC) is found most commonly in end-stage renal disease (ESRD) patients on chronic hemodialysis (HD) therapy [1–3]. Calcifications can occur in any tissue of the body but are found most commonly in the heart, lungs, kidney, and stomach. In the lungs, calcium deposits have been found in the interstitium of the alveolar septum, bronchiole walls, in the large airways, and even in the walls of the pulmonary vessels [4–6]. The clinical manifestations of PC are usually minimal. Occasionally, PC may cause profound respiratory disturbances [1, 2].
METHODS Patients Our local institutional clinical research ethics review board approved the research protocol. All participants signed an informed consent before entering the study. Patient selection
Key words: end-stage renal disease, hemodialysis, pulmonary calcification, pulmonary hypertension.
A total cohort of 110 ambulatory patients with ESRD receiving chronic HD therapy via a surgically created AV access in our institution was reviewed. Patients with known cardiac (N = 37), pulmonary (N = 6), and systemic diseases (N = 4) were excluded from the study. An additional 14 patients refused to participate in the study.
Received for publication April 1, 2003 and in revised form December 6, 2003 Accepted for publication February 20, 2004 C
2004 by the International Society of Nephrology 806
807
Yigla et al: Pulmonary calcification in hemodialysis patients
Exclusion criteria Presence of Cardiac disease (N = 37) Lung diseases (N = 6) Systemic diseases (N = 4)
Systolic PAP
110 patients receiving HD via A-V access 14 refused
Patient evaluation Study group 49 patients
Pulmonary uptake of 99mTc -MDP bone scintigraphy Doppler echocardiography Clinical variables
Analysis Prevalence & extent of lung uptake of 99mTc-MDP Prevalence of PHT Comparisons Increased vs. normal uptake Correlation between PHT & lung uptake Fig. 1. Study flowchart.
The remaining 49 patients comprised the study population (Fig. 1). The study group underwent evaluation that included physical examination, chest radiography, and blood tests for calcium, phosphorus, and parathyroid hormone level. Age, sex, comorbidity, medications used, etiology of kidney disease, age at onset, and duration of HD therapy were recorded from patient files. Hemodialysis patients with systolic PAP above 35 mm Hg underwent further evaluation by a specialist pulmonologist that included computed tomography of the chest, complete pulmonary function tests, measurement of blood gases and O 2 saturation while breathing room air, and ventilatory perfusion radioisotope lung scan intended to disclose other causes of PHT. None of the patients was excluded from the study after this work-up. Echocardiography To avoid overestimation of PAP due to volume overload, all the Doppler measurements were performed within one hour after completion of dialysis. One experienced operator, masked with regard to the clinical status of the patient, performed all echocardiography studies using an Acuson Sequoia, Aspen, or 128 XP (Mountain View, CA, USA) and GE Vivid 3 (Milwaukee, WI, USA) ultrasound machine. Every patient underwent a complete two-dimensional, M-mode, and Doppler echocardiography study. A tricuspid regurgitation systolic jet was recorded from the parasternal or apical window with the continuous-wave Doppler probe. Systolic right ventricular (or pulmonary artery) pressure was calculated using
90 80 70 60 50 40 30 20 10 0
0
1
2 3 Pulmonary uptake
4
Fig. 2. Distribution of systolic pulmonary artery pressure (SPAP) according to degree of 99m Tc-MDP pulmonary uptake.
the modified Bernoulli equation given by: PAP = 4 × (tricuspid systolic jet)2 + 10 mm Hg (estimated right atrial pressure). PHT was defined as a systolic PAP ≥35 mm Hg. Cardiac output was estimated from the left ventricular outflow tract velocity time integral × diameter. 99m
Tc-MDP pulmonary uptake All patients underwent bone scintigraphy two hours after intravenous injection of 740 MBq of 99m Tc-MDP. Whole skeleton planner scintigraphy was performed using a dual- or a single-head digital gamma camera. The 99m Tc-MDP uptake in the lungs was evaluated for each patient from the planar view of the chest. The degree of lung uptake was determined by a nuclear medicine specialist, who was not aware of the patient’s clinical and laboratory data. The uptake was graded according to the following scale: 0 = no uptake, 1 = mild uptake, intensity less than bone uptake, 2 = lung uptake similar to bone uptake, 3 = lung uptake greater than bone uptake. Grade 0–1 uptakes were considered as normal (Fig. 3A), and grade 2–3 lung uptake of 99m Tc-MDP (Fig. 3B) were considered as elevated [11–13]. Data analysis The incidence and the degree of PC were compared between HD patients with and without PHT. The correlation between the extent of PC, systolic PAP, and clinical variables was evaluated using the two-tailed unpaired Student t test for continuous data and chi-square analysis for discrete data. Continuous data were expressed as the mean values ± standard deviation (SD). Statistical significance was set as P < 0.05. RESULTS Demographic and clinical data of the 49 HD patients studied are presented in Table 1. There were 36 men and 13 women with a mean age of 61.7 ± 13.2 years (range 29 to 82 years). Mean duration of HD was 38.2 ± 43.7 months (range 7 to 234). The three most common etiologies of renal failure were diabetes mellitus
808
Yigla et al: Pulmonary calcification in hemodialysis patients
A
B
Table 1. Data on 49 patients with ESRD on hemodialysis via surgical A-V shunt Age years Mean age Range Sex Male Female M/F ratio Etiology of renal failure Diabetes mellitus Hypertension Glomerulonephritis Chronic pyelonephritis Nephrolithiasis Polycystic kidney Unknown Duration of dialysis months Mean Range Systolic PAPa values mm Hg No. of patients with SPAPa >35 Mean SPAPa Pulmonary calcification Grade 0 and 1 normal uptake Grade 2–3 elevated uptake Equal to bone (grade 2) More than bone (grade 3) a
61.7 ± 13.2 29–82 36 (73.5%) 13 (26.5%) 2.8 14 (28.6%) 11 (22.4%) 9 (18.4%) 5 (10.2%) 5 (10.2%) 3 (5.1%) 2 (4.1%) 38.2 ± 43.7 7–234 28 (57.1%) 46 ± 11 30 (59.2%) 19 (40.8%) 17 3
PAP, pulmonary artery pressure.
Table 2. Distribution of systolic PAP among HD patients with normal and elevated 99m Tc-MDP pulmonary uptake 99m Tc-
SPAP <35 SPAP >34
MDP pulmonary uptake
0–1
2–3
11 18
10 10
grade 2 uptake (equal to the bone), and 3 had grade 3 (higher than the bone). Twenty-nine patients had normal uptake (grade 0–1). Review of the chest x-ray films of all the patients and computerized tomography of the chest of 35 patients (including all patients with PHT who underwent CT as a part of the work-up to disclose etiology for the PHT) revealed diffuse PC in only one patient with grade 2 lung uptake and elevated PAP. Fig. 3. Grade 3 lung uptake of 99m Tc-MDP. (A) Planar bone scintigraphy (anterior view-left, posterior view-right) of a 42-year-old woman with ESRD who had been receiving hemodialysis for the last eight years demonstrates abnormal diffuse lung uptake of the tracer, more prominent at the bases. Grade 0 lung uptake of 99m Tc-MDP. (B) Planar bone scintigraphy (anterior view-left, posterior view-right) of a 34-year-old male with ESRD who had been receiving hemodialysis for the last six years demonstrates normal distribution of the tracer with no evidence for lung uptake.
(28.6%), arterial hypertension (22.4%), and glomerulopathy (18.4%). Pulmonary calcification Increased lung uptake of 99m Tc-MDP (grade 2–3) was found in 20 (40.8%) patients. Seventeen patients had
Pulmonary artery pressure studies Systolic PAP of 28 (57.1%) patients was elevated. Their mean systolic PAP was 46 ± 11 (range 35 to 85). Twentyone patients had normal systolic PAP (Table 1). Correlations between increased uptake and PHT Data on the distribution of systolic PAP values according to the degree of 99m Tc-MDP lung uptake are presented in Figure 2 and Table 2. Note the proportion of PHT (18/29 vs. 10/20, respectively; P = 0.842) and the mean systolic PAP (37 ± 11 vs. 40 ± 15, respectively; P = 0.335) did not differ significantly between patients with and without elevated 99m Tc-MDP lung uptake. The data of 20 patients with and 29 patients without elevated 99m Tc-MDP were compared (Table 3). Age
Yigla et al: Pulmonary calcification in hemodialysis patients
Table 3. Clinical and laboratory data between patients with and without elevated pulmonary 99m Tc-MDP uptake
No. of patients Gender Males/females SPAPa >35 mm Hg (% of patients) SPAPa values mm Hg Mean Range Age years Mean Range Cardiac output L/min Mean Range Time interval monthsc Mean Range Medications Antihypertensive therapy Beta blockers Vasodilators Ca channel blockers ACE inhibitors Hemoglobin (mean ± SD) Hematocrit % PTHb level ng/L Mean value Range Ca-P product mg/dL Mean value Range c
Normal uptake
Elevated uptake
29 (59.2%)
20 (40.8%)
22/7 18/29
14/6 10/20
0.898 0.842
37 ± 11 20–65
40 ± 15 20–85
0.335
62.4 ± 140 29–80
60.8 ± 12.2 36–82
0.567
6.05 ± 1.1 4.8–8.4
5.75 ± .9 3.6–8
0.231
42.2 ± 53.5 17–234
32.4 ± 0.5 7–84
0.353
24
17
0.878
15
15
0.573
17 9 10.9 ± 1.8
12 6 11.3 ± 1.3
0.85 0.807 0.311
34.3 ± 5.8
32.4.2 ± 6.3
0.196
343 ± 266 11–1313
267 ± 165 50–602
0.179
46 ± 13 25–71
0.532
44.2 ± 11 29.25–76
P value
a SPAP, systolic pulmonary artery pressure; b PTH, parathyroid hormone; from onset of HD therapy to detection of pulmonary hypertension.
and gender distribution were similar for both subgroups, as well as comorbid conditions and medications used. Both groups had elevated cardiac output that did not differ significantly (6.05 ± 1.1 vs. 5.75 ± 0.9, respectively; P = 0.231). The mean duration of HD was nonsignificantly higher in the normal uptake group (42.2 ± 53.5 vs. 32.4 ± 20.5, respectively; P = 0.353). Both subgroups had reduced hemoglobin and hematocrit values, but the differences between these values did not reach statistical significance. DISCUSSION Vascular involvement is one of the most striking forms of extraosseous calcification in chronic renal failure [14– 16]. The aorta and the coronary arteries [17] are mainly affected, but peripheral small vessels in the systemic and the pulmonary circulation are also affected [5]. Affected vessels become stiffer independent of age or hypertension. The impact of this phenomenon on the pulmonary circulation has not been studied previously. Autopsy studies of HD patients [5–7] have shown that pulmonary vascular calcification occurs frequently. Of 15 patients studied [5], nine (66%) had evidence of vascu-
809
lar calcification; in its mild form, fine linear and granular deposits along the alveolar capillary wall were noted, while the more severe cases had linear calcification of the elastic laminae and muscle fibers that in some cases was accompanied by loose intimal fibrosis with narrowing of the vessel lumens. Another study of 56 HD patients [6] found PC in 75% of the cases (severe −48.2%), and noted that in general the vascular and the parenchymal changes were parallel. Contrary to pathologic studies, PC is seldom recognized clinically. This discrepancy is explained by the relatively minor tissue reaction evoked by the small size of deposited crystals. Pulmonary hypertension is a new entity in HD patients [7]. Its occurrence in patients with elevated cardiac output suggests failure of the pulmonary vasculture to maintain the A-V access–mediated elevated CO. Increased stiffness of pulmonary vasculture due to vascular calcification is a possible mechanism. This notion is supported by a study [18] of two subgroups of a dog model of ESRD, one with an intact parathyroid and the other parathyroidectomized. This study showed increased PTH activity, lung calcium content, and PAP values in the dogs with intact parathyroid glands, thus suggesting a link between PC to PHT through the parathyoid hormone. In this study, PC expressed by lung uptake of 99m TcMDP bone scintigraphy was present in 40% of the patients, but was not correlated to PAP values. Fifty percent of the patients with increased uptake had no PHT, while 62% of the patients with normal uptake had PHT. This study does not find a role for PC expressed by lung uptake of 99m Tc-MDP bone scintigraphy in the pathogenesis of PHT in HD patients. In other words, the high prevalence of lung uptake of 99m Tc-MDP reflects scinigraphic findings without hemodynamic significance. A possible explanation is that the lung uptake of the tracer used reflects pulmonary parenchymal rather than vascular calcification. Alternately, it could reflect the presence of nonsignificant vascular calcification. Two autopsy studies [5, 6] support the latter notion. As the marker used, 99m Tc-MDP is taken up only where calcium is actively deposited, and does not simply correlate with its anatomic presence [12]; its yield for the detection of vascular calcification is questionable. Others have limited its use in the population of HD patients because it has a relatively low uptake by amorphous whitelockite type mineral ([CaMg] 3 [PO 4 ] 2 ), the predominant calcium salt in ESRD-associated metastatic calcification [2]. 99m Tc-MDP bone scan is considered a sensitive but not specific measure for the detection of PC. Of 23 HD patients with normal chest radiograph, 14 (61%) had increased 99m Tc-MDP lung uptake [11]. Another study demonstrated markedly increased 99m Tc-MDP lung uptake confirmed by histology in only 1 of 30 HD patients [13]. Although elevated chest-to-spine ratio was found
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Yigla et al: Pulmonary calcification in hemodialysis patients
in 66% of the patients, it was considered inconclusive for the presence of PC due to lack of histologic proof. The present study shows similar data: 40% prevalence of 99m Tc-MDP lung uptake without corresponding findings in x-ray films or CT of the chest. Because histologic lung studies are not always available, there is a need for noninvasive measures for the presence and the extent of PC. The standard chest xray is relatively insensitive for the detection of diffuse PC. Conger [5] reported abnormal chest x-ray in only 1/15 HD patients with microscopic PC. High-resolution CT of the chest occupying a mediastinal window with or without densitometry measurements provides better results; however, false-negatives may result from the microscopic size of calcium salt crystals or from signalaveraging from a relative large soft tissue component [8– 10]. Electron beam CT and spiral CT are highly sensitive techniques for detecting coronary artery calcification, and are being used with increasing frequency for screening asymptomatic individuals at risk for the development of coronary artery disease [19]. MRI is relatively insensitive for detecting PC because neither calcium nor air in the lung typically transmits a signal, thereby failing to produce a contrast [20]. Our previous observation [7] of reversibility of PHT among HD patients who underwent successful kidney transplantation, although their A-V access remained patent, indicates a role for a humoral factor in this syndrome. In a more recent study [21], we noted that decreased NO production under basal and stimulatory conditions in the population of patients with PHT confirms this observation. It appears that HD therapy is associated with reversible endothelial dysfunction. Coexistence of PC and PHT in the population of ESRD patients raises several points of interest. Pulmonary vascular calcification and even arteriosclerosis have been described in several conditions characterized by increased vessel wall shear stress, such as increased pulmonary blood flow and PHT caused by congenital left-to-right shunt [22, 23]. The population of HD patients shares similar hemodynamic features that might contribute further to the development of PC.
CONCLUSION Based on our observations, we conclude that an insubstantial number of ESRD patients receiving HD therapy have increased lung uptake of 99m Tc-MDP on bone scan, not correlated to PAP values.
ACKNOWLEDGMENT The authors thank Mrs. M. Perlmutter for her help in the preparation of this paper.
Reprint requests to Dr. M. Yigla, Division of Pulmonary Medicine, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E-mail: m [email protected]
REFERENCES 1. BENDAYAN D, BARZIV Y, KRAMER MR: Pulmonary calcifications: A review. Respir Med 94:190–193, 2000 2. CHAN ED, MORALES DV, WELSH CH, et al: Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 165:1654–1669, 2002 3. KERR DNS: Hypercalcemia and metastatic calcification. Cardiovasc Res 36:293–297, 1997 4. WANG N-S, STEELE AA: Pulmonary calcification: Scanning electron microscopic and X-ray energy-dispersive analysis. Arch Pathol Lab Med 103:252–253, 1979 5. CONGER JD, HAMMOND WS, ALFREY AC, et al: Pulmonary calcification in chronic dialysis patients: Clinical and pathologic studies. Ann Intern Med 83:330–336, 1975 6. KUZELA DC, HUFFER WE, CONGER JD, et al: Soft tissue calcification in chronic dialysis patients. Am J Pathol 86:403–424, 1977 7. YIGLA M, NAKHOUL F, SABAG A, et al: Pulmonary hypertension in end-stage renal disease patients. Chest 123:1577–1582, 2003 8. BROWN K, MUND DF, ABERLE DR, et al: Intra-thoracic calcifications: Radiographic features and differential diagnosis. Radiographics 14:1247–1261, 1994 9. LINGAM RK, TEH J, SHARMA A, FRIEDMAN E: Metastatic pulmonary calcification in renal failure: A new HRCT pattern. Br J Radiol 75:74–77, 2002 10. JOHOKOH T, IKEZOE J, NAGAREDA T, et al: Metastatic pulmonary calcification: Early detection by high-resolution CT. J Computed Assist Tomogr 17:471–473, 1993 11. FAUBERT PF, SHAPIRO WB, PORUSH JG, et al: Pulmonary calcification in hemo-dialyzed patients detected by technetium-99m diphosphonate scanning. Kidney Int 18:95–102, 1980 12. KOK M, CASE D, BILLINGSLY J: The use of bone scintigraphy to evaluate metastatic calcification caused by end-stage renal disease and secondary hyperparathyroidism. Clin Nucl Med 28:144–145, 2003 13. DE-GRAFF P, SCHICUT IM, PAUWELS EKJ, et al: Bone scinitigraphy in uremic pulmonary calcification. J Nucl Med 20:201–206, 1979 14. QUINIBI WY, NOLAN CA, AYUS JC: Cardiovascular calcification in patients with end-stage renal disease: A century-old phenomenon. Kidney Int 82:s73–s80, 2002 15. DAVIES MR, HRUSKA KA: Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int 60:472–479, 2001 16. NITTA K, AKIBA T, UCHIDA K, et al: The progression of vascular calcification and serum osteoprotegrin levels in patients on longterm hemodialysis. Am J Kidney Dis 42:303–309, 2003 17. GOODMAN WG, GOLDIN J, KUIZON BD, et al: Coronary artery calcification in young adults with end-stage renal disease who are undergoing hemodialysis. N Engl J Med 342:1478–1483, 2000 18. AKMAL M, BARNATT RR, ANSARI AN, et al: Excess PTH in CRF induces pulmonary calcification, pulmonary hypertension and right ventricular hypertrophy. Kidney Int 47:158–163, 1995 19. ACHENBACH S, MOSHAGE W, ROPERS D, et al: Value of electron-beam computed tomography for the non-invasive detection of high-grade coronary artery stenosis and occlusion. N Engl J Med 339:1964– 1971, 1998 20. TAGUHCI Y, FUYUNO G, SHIOYA S, et al: MR appearance of pulmonary metastatic calcification. J Computed Assist Tomogr 20:38– 41, 1996 21. NAKHOUL F, YIGLA M, GELMAN R, et al: The pathogenesis of pulmonary hypertension in hemodialysis patients via arterial-venous access. Chest, submitted for publication 22. COHEN BA, GALE JT, MENDELSON DS, MITTY HA: Computerized tomography demonstration of pulmonary artery calcification in Eisenmenger’s syndrome. J Comput Tomogr 99:153–156, 1985 23. STEINBERG I: Calcification of pulmonary artery and enlargement of right ventricle: A sign of congenital heart disease, Eisenmenger syndrome, pulmonary hypertension, increased pulmonary artery resistance and reversal of blood flow. Am J Roentgenol 98:369–377, 1966
Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values MORDECHAI YIGLA, ZOHAR KEIDAR, ISRA SAFADI, NAVEH TOV, SHIMON A. REISNER, and FARID NAKHOUL Division of Pulmonary Medicine; Department of Nuclear Medicine; Department of Cardiology; and Department of Nephrology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
In a recently published study [7], we evaluated the incidence of pulmonary hypertension (PHT) in ESRD patients using Doppler echocardiography. Almost 40% of HD patients had systolic PAP above 35 mm Hg, and their cardiac-output (CO) was significantly higher compared with HD patients without PHT. Because the study population had no obvious cause for PHT, we assumed that both ESRD and HD therapy via arteriovenous (A-V) access might be involved in the pathogenesis of this syndrome. Increased CO per se does not cause PHT unless the capacity of the pulmonary circulation is diminished. Pulmonary calcification in the vascular compartment of HD patients is a possible explanation. X-ray film and computerized tomography (CT) of the chest, high resolution computed tomography scan with mediastinal images, technetium 99m–labeled [99m Tc]– MDP bone scanning, and magnetic resonance imaging (MRI) have all shown variable diagnostic values in detecting PC [8–15]. 99m Tc-MDP bone scintigraphy is considered to be a sensitive measure of PC in ESRD, and, in addition, enables semiquantitative evaluation of the PC [11]. This study evaluated the extent of pulmonary uptake of 99m Tc-MDP bone scintigraphy in a group of HD patients and correlated this uptake to the occurrence of PHT.
Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values. Background. End-stage renal disease (ESRD) patients receiving chronic hemodialysis (HD) via an arteriovenous (AV) access often develop unexplained pulmonary hypertension (PHT). This study evaluated the role of pulmonary calcification (PC) in this phenomenon. Methods. The clinical manifestations, systolic pulmonary artery pressure (PAP) values measured by Doppler echocardiography and the presence and the extent of PC expressed by lung uptake of 99m Tc-MDP bone scintigraphy, were studied in 49 patients with ESRD receiving chronic HD therapy via A-V access. The correlation between PC and PHT was investigated. Results. There were 36 men and 13 women with a mean age of 61.7 ± 13.2 years receiving HD therapy for 38.2 ± 43.7 months. Twenty (40.8%) patients had PC expressed by increased lung uptake of 99m Tc- MDP and 28 (57.1%) patients had PHT with a mean systolic PAP of 46 ± 11 mm Hg. No correlation was found between PC and PHT. Conclusion. The data suggest that PC expressed by lung uptake of 99m Tc-MDP has no role in the pathogenesis of PHT among ESRD patients undergoing HD therapy via A-V access.
Extraosseous pulmonary calcification (PC) is found most commonly in end-stage renal disease (ESRD) patients on chronic hemodialysis (HD) therapy [1–3]. Calcifications can occur in any tissue of the body but are found most commonly in the heart, lungs, kidney, and stomach. In the lungs, calcium deposits have been found in the interstitium of the alveolar septum, bronchiole walls, in the large airways, and even in the walls of the pulmonary vessels [4–6]. The clinical manifestations of PC are usually minimal. Occasionally, PC may cause profound respiratory disturbances [1, 2].
METHODS Patients Our local institutional clinical research ethics review board approved the research protocol. All participants signed an informed consent before entering the study. Patient selection
Key words: end-stage renal disease, hemodialysis, pulmonary calcification, pulmonary hypertension.
A total cohort of 110 ambulatory patients with ESRD receiving chronic HD therapy via a surgically created AV access in our institution was reviewed. Patients with known cardiac (N = 37), pulmonary (N = 6), and systemic diseases (N = 4) were excluded from the study. An additional 14 patients refused to participate in the study.
Received for publication April 1, 2003 and in revised form December 6, 2003 Accepted for publication February 20, 2004 C
2004 by the International Society of Nephrology 806
807
Yigla et al: Pulmonary calcification in hemodialysis patients
Exclusion criteria Presence of Cardiac disease (N = 37) Lung diseases (N = 6) Systemic diseases (N = 4)
Systolic PAP
110 patients receiving HD via A-V access 14 refused
Patient evaluation Study group 49 patients
Pulmonary uptake of 99mTc -MDP bone scintigraphy Doppler echocardiography Clinical variables
Analysis Prevalence & extent of lung uptake of 99mTc-MDP Prevalence of PHT Comparisons Increased vs. normal uptake Correlation between PHT & lung uptake Fig. 1. Study flowchart.
The remaining 49 patients comprised the study population (Fig. 1). The study group underwent evaluation that included physical examination, chest radiography, and blood tests for calcium, phosphorus, and parathyroid hormone level. Age, sex, comorbidity, medications used, etiology of kidney disease, age at onset, and duration of HD therapy were recorded from patient files. Hemodialysis patients with systolic PAP above 35 mm Hg underwent further evaluation by a specialist pulmonologist that included computed tomography of the chest, complete pulmonary function tests, measurement of blood gases and O 2 saturation while breathing room air, and ventilatory perfusion radioisotope lung scan intended to disclose other causes of PHT. None of the patients was excluded from the study after this work-up. Echocardiography To avoid overestimation of PAP due to volume overload, all the Doppler measurements were performed within one hour after completion of dialysis. One experienced operator, masked with regard to the clinical status of the patient, performed all echocardiography studies using an Acuson Sequoia, Aspen, or 128 XP (Mountain View, CA, USA) and GE Vivid 3 (Milwaukee, WI, USA) ultrasound machine. Every patient underwent a complete two-dimensional, M-mode, and Doppler echocardiography study. A tricuspid regurgitation systolic jet was recorded from the parasternal or apical window with the continuous-wave Doppler probe. Systolic right ventricular (or pulmonary artery) pressure was calculated using
90 80 70 60 50 40 30 20 10 0
0
1
2 3 Pulmonary uptake
4
Fig. 2. Distribution of systolic pulmonary artery pressure (SPAP) according to degree of 99m Tc-MDP pulmonary uptake.
the modified Bernoulli equation given by: PAP = 4 × (tricuspid systolic jet)2 + 10 mm Hg (estimated right atrial pressure). PHT was defined as a systolic PAP ≥35 mm Hg. Cardiac output was estimated from the left ventricular outflow tract velocity time integral × diameter. 99m
Tc-MDP pulmonary uptake All patients underwent bone scintigraphy two hours after intravenous injection of 740 MBq of 99m Tc-MDP. Whole skeleton planner scintigraphy was performed using a dual- or a single-head digital gamma camera. The 99m Tc-MDP uptake in the lungs was evaluated for each patient from the planar view of the chest. The degree of lung uptake was determined by a nuclear medicine specialist, who was not aware of the patient’s clinical and laboratory data. The uptake was graded according to the following scale: 0 = no uptake, 1 = mild uptake, intensity less than bone uptake, 2 = lung uptake similar to bone uptake, 3 = lung uptake greater than bone uptake. Grade 0–1 uptakes were considered as normal (Fig. 3A), and grade 2–3 lung uptake of 99m Tc-MDP (Fig. 3B) were considered as elevated [11–13]. Data analysis The incidence and the degree of PC were compared between HD patients with and without PHT. The correlation between the extent of PC, systolic PAP, and clinical variables was evaluated using the two-tailed unpaired Student t test for continuous data and chi-square analysis for discrete data. Continuous data were expressed as the mean values ± standard deviation (SD). Statistical significance was set as P < 0.05. RESULTS Demographic and clinical data of the 49 HD patients studied are presented in Table 1. There were 36 men and 13 women with a mean age of 61.7 ± 13.2 years (range 29 to 82 years). Mean duration of HD was 38.2 ± 43.7 months (range 7 to 234). The three most common etiologies of renal failure were diabetes mellitus
808
Yigla et al: Pulmonary calcification in hemodialysis patients
A
B
Table 1. Data on 49 patients with ESRD on hemodialysis via surgical A-V shunt Age years Mean age Range Sex Male Female M/F ratio Etiology of renal failure Diabetes mellitus Hypertension Glomerulonephritis Chronic pyelonephritis Nephrolithiasis Polycystic kidney Unknown Duration of dialysis months Mean Range Systolic PAPa values mm Hg No. of patients with SPAPa >35 Mean SPAPa Pulmonary calcification Grade 0 and 1 normal uptake Grade 2–3 elevated uptake Equal to bone (grade 2) More than bone (grade 3) a
61.7 ± 13.2 29–82 36 (73.5%) 13 (26.5%) 2.8 14 (28.6%) 11 (22.4%) 9 (18.4%) 5 (10.2%) 5 (10.2%) 3 (5.1%) 2 (4.1%) 38.2 ± 43.7 7–234 28 (57.1%) 46 ± 11 30 (59.2%) 19 (40.8%) 17 3
PAP, pulmonary artery pressure.
Table 2. Distribution of systolic PAP among HD patients with normal and elevated 99m Tc-MDP pulmonary uptake 99m Tc-
SPAP <35 SPAP >34
MDP pulmonary uptake
0–1
2–3
11 18
10 10
grade 2 uptake (equal to the bone), and 3 had grade 3 (higher than the bone). Twenty-nine patients had normal uptake (grade 0–1). Review of the chest x-ray films of all the patients and computerized tomography of the chest of 35 patients (including all patients with PHT who underwent CT as a part of the work-up to disclose etiology for the PHT) revealed diffuse PC in only one patient with grade 2 lung uptake and elevated PAP. Fig. 3. Grade 3 lung uptake of 99m Tc-MDP. (A) Planar bone scintigraphy (anterior view-left, posterior view-right) of a 42-year-old woman with ESRD who had been receiving hemodialysis for the last eight years demonstrates abnormal diffuse lung uptake of the tracer, more prominent at the bases. Grade 0 lung uptake of 99m Tc-MDP. (B) Planar bone scintigraphy (anterior view-left, posterior view-right) of a 34-year-old male with ESRD who had been receiving hemodialysis for the last six years demonstrates normal distribution of the tracer with no evidence for lung uptake.
(28.6%), arterial hypertension (22.4%), and glomerulopathy (18.4%). Pulmonary calcification Increased lung uptake of 99m Tc-MDP (grade 2–3) was found in 20 (40.8%) patients. Seventeen patients had
Pulmonary artery pressure studies Systolic PAP of 28 (57.1%) patients was elevated. Their mean systolic PAP was 46 ± 11 (range 35 to 85). Twentyone patients had normal systolic PAP (Table 1). Correlations between increased uptake and PHT Data on the distribution of systolic PAP values according to the degree of 99m Tc-MDP lung uptake are presented in Figure 2 and Table 2. Note the proportion of PHT (18/29 vs. 10/20, respectively; P = 0.842) and the mean systolic PAP (37 ± 11 vs. 40 ± 15, respectively; P = 0.335) did not differ significantly between patients with and without elevated 99m Tc-MDP lung uptake. The data of 20 patients with and 29 patients without elevated 99m Tc-MDP were compared (Table 3). Age
Yigla et al: Pulmonary calcification in hemodialysis patients
Table 3. Clinical and laboratory data between patients with and without elevated pulmonary 99m Tc-MDP uptake
No. of patients Gender Males/females SPAPa >35 mm Hg (% of patients) SPAPa values mm Hg Mean Range Age years Mean Range Cardiac output L/min Mean Range Time interval monthsc Mean Range Medications Antihypertensive therapy Beta blockers Vasodilators Ca channel blockers ACE inhibitors Hemoglobin (mean ± SD) Hematocrit % PTHb level ng/L Mean value Range Ca-P product mg/dL Mean value Range c
Normal uptake
Elevated uptake
29 (59.2%)
20 (40.8%)
22/7 18/29
14/6 10/20
0.898 0.842
37 ± 11 20–65
40 ± 15 20–85
0.335
62.4 ± 140 29–80
60.8 ± 12.2 36–82
0.567
6.05 ± 1.1 4.8–8.4
5.75 ± .9 3.6–8
0.231
42.2 ± 53.5 17–234
32.4 ± 0.5 7–84
0.353
24
17
0.878
15
15
0.573
17 9 10.9 ± 1.8
12 6 11.3 ± 1.3
0.85 0.807 0.311
34.3 ± 5.8
32.4.2 ± 6.3
0.196
343 ± 266 11–1313
267 ± 165 50–602
0.179
46 ± 13 25–71
0.532
44.2 ± 11 29.25–76
P value
a SPAP, systolic pulmonary artery pressure; b PTH, parathyroid hormone; from onset of HD therapy to detection of pulmonary hypertension.
and gender distribution were similar for both subgroups, as well as comorbid conditions and medications used. Both groups had elevated cardiac output that did not differ significantly (6.05 ± 1.1 vs. 5.75 ± 0.9, respectively; P = 0.231). The mean duration of HD was nonsignificantly higher in the normal uptake group (42.2 ± 53.5 vs. 32.4 ± 20.5, respectively; P = 0.353). Both subgroups had reduced hemoglobin and hematocrit values, but the differences between these values did not reach statistical significance. DISCUSSION Vascular involvement is one of the most striking forms of extraosseous calcification in chronic renal failure [14– 16]. The aorta and the coronary arteries [17] are mainly affected, but peripheral small vessels in the systemic and the pulmonary circulation are also affected [5]. Affected vessels become stiffer independent of age or hypertension. The impact of this phenomenon on the pulmonary circulation has not been studied previously. Autopsy studies of HD patients [5–7] have shown that pulmonary vascular calcification occurs frequently. Of 15 patients studied [5], nine (66%) had evidence of vascu-
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lar calcification; in its mild form, fine linear and granular deposits along the alveolar capillary wall were noted, while the more severe cases had linear calcification of the elastic laminae and muscle fibers that in some cases was accompanied by loose intimal fibrosis with narrowing of the vessel lumens. Another study of 56 HD patients [6] found PC in 75% of the cases (severe −48.2%), and noted that in general the vascular and the parenchymal changes were parallel. Contrary to pathologic studies, PC is seldom recognized clinically. This discrepancy is explained by the relatively minor tissue reaction evoked by the small size of deposited crystals. Pulmonary hypertension is a new entity in HD patients [7]. Its occurrence in patients with elevated cardiac output suggests failure of the pulmonary vasculture to maintain the A-V access–mediated elevated CO. Increased stiffness of pulmonary vasculture due to vascular calcification is a possible mechanism. This notion is supported by a study [18] of two subgroups of a dog model of ESRD, one with an intact parathyroid and the other parathyroidectomized. This study showed increased PTH activity, lung calcium content, and PAP values in the dogs with intact parathyroid glands, thus suggesting a link between PC to PHT through the parathyoid hormone. In this study, PC expressed by lung uptake of 99m TcMDP bone scintigraphy was present in 40% of the patients, but was not correlated to PAP values. Fifty percent of the patients with increased uptake had no PHT, while 62% of the patients with normal uptake had PHT. This study does not find a role for PC expressed by lung uptake of 99m Tc-MDP bone scintigraphy in the pathogenesis of PHT in HD patients. In other words, the high prevalence of lung uptake of 99m Tc-MDP reflects scinigraphic findings without hemodynamic significance. A possible explanation is that the lung uptake of the tracer used reflects pulmonary parenchymal rather than vascular calcification. Alternately, it could reflect the presence of nonsignificant vascular calcification. Two autopsy studies [5, 6] support the latter notion. As the marker used, 99m Tc-MDP is taken up only where calcium is actively deposited, and does not simply correlate with its anatomic presence [12]; its yield for the detection of vascular calcification is questionable. Others have limited its use in the population of HD patients because it has a relatively low uptake by amorphous whitelockite type mineral ([CaMg] 3 [PO 4 ] 2 ), the predominant calcium salt in ESRD-associated metastatic calcification [2]. 99m Tc-MDP bone scan is considered a sensitive but not specific measure for the detection of PC. Of 23 HD patients with normal chest radiograph, 14 (61%) had increased 99m Tc-MDP lung uptake [11]. Another study demonstrated markedly increased 99m Tc-MDP lung uptake confirmed by histology in only 1 of 30 HD patients [13]. Although elevated chest-to-spine ratio was found
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Yigla et al: Pulmonary calcification in hemodialysis patients
in 66% of the patients, it was considered inconclusive for the presence of PC due to lack of histologic proof. The present study shows similar data: 40% prevalence of 99m Tc-MDP lung uptake without corresponding findings in x-ray films or CT of the chest. Because histologic lung studies are not always available, there is a need for noninvasive measures for the presence and the extent of PC. The standard chest xray is relatively insensitive for the detection of diffuse PC. Conger [5] reported abnormal chest x-ray in only 1/15 HD patients with microscopic PC. High-resolution CT of the chest occupying a mediastinal window with or without densitometry measurements provides better results; however, false-negatives may result from the microscopic size of calcium salt crystals or from signalaveraging from a relative large soft tissue component [8– 10]. Electron beam CT and spiral CT are highly sensitive techniques for detecting coronary artery calcification, and are being used with increasing frequency for screening asymptomatic individuals at risk for the development of coronary artery disease [19]. MRI is relatively insensitive for detecting PC because neither calcium nor air in the lung typically transmits a signal, thereby failing to produce a contrast [20]. Our previous observation [7] of reversibility of PHT among HD patients who underwent successful kidney transplantation, although their A-V access remained patent, indicates a role for a humoral factor in this syndrome. In a more recent study [21], we noted that decreased NO production under basal and stimulatory conditions in the population of patients with PHT confirms this observation. It appears that HD therapy is associated with reversible endothelial dysfunction. Coexistence of PC and PHT in the population of ESRD patients raises several points of interest. Pulmonary vascular calcification and even arteriosclerosis have been described in several conditions characterized by increased vessel wall shear stress, such as increased pulmonary blood flow and PHT caused by congenital left-to-right shunt [22, 23]. The population of HD patients shares similar hemodynamic features that might contribute further to the development of PC.
CONCLUSION Based on our observations, we conclude that an insubstantial number of ESRD patients receiving HD therapy have increased lung uptake of 99m Tc-MDP on bone scan, not correlated to PAP values.
ACKNOWLEDGMENT The authors thank Mrs. M. Perlmutter for her help in the preparation of this paper.
Reprint requests to Dr. M. Yigla, Division of Pulmonary Medicine, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E-mail: m [email protected]
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