Int Urol Nephrol DOI 10.1007/s11255-014-0889-5

NEPHROLOGY - ORIGINAL ARTICLE

Secondary hyperparathyroidism is associated with pulmonary hypertension in older patients with chronic kidney disease and proteinuria Gultekin Genctoy · Serap Arikan · Olcay Gedik 

Received: 11 October 2014 / Accepted: 12 November 2014 © Springer Science+Business Media Dordrecht 2014

Abstract  Purpose  Hyperparathyroidism is associated with pulmonary vascular calcification and pulmonary hypertension (PH) in a chronic kidney failure dog model, and increased prevalence of PH and a PH–hyperparathyroidism relationship in pre-dialysis chronic kidney disease (CKD) and hemodialysis patients are reported. This study investigated the prevalence of PH and relationships between PH and metabolic abnormalities in patients with stage 1–4 proteinuria CKD. Methods  One-hundred and ninety patients (mean age 61 ± 17.4, 116 males) with proteinuria CKD and no coronary diseases, congestive heart failure, smoking history, and pulmonary diseases were enrolled. Estimated glomerular filtration rate was 39.7 ± 23 ml/min. CKD etiology was diabetes mellitus in 52 (27.3 %), chronic glomerulonephritis or tubulointerstitial nephritis in 56 (29.4 %), hypertension in 36 (19 %), and other etiologies (nephrolithiasis, obstructive nephropathy, and amyloidosis) in 46 (25.3 %) patients. Echocardiography was performed, and systolic pulmonary artery pressure (PAP) and left ventricular ejection fraction were determined. Laboratory tests examined G. Genctoy (*)  Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Alanya Hastanesi, Baskent University, Saray mah.Yunus Emre Cad. No. 1, Alanya, Antalya 07400, Turkey e-mail: [email protected] S. Arikan  Department of Biochemistry, Faculty of Medicine, Baskent University, Alanya, Antalya, Turkey O. Gedik  Department of Cardiology, Faculty of Medicine, Baskent University, Alanya, Antalya, Turkey

lipid parameters, serum albumin, urea, creatinine, calcium, phosphorus, C-reactive protein, parathyroid hormone, ferritin, and hemoglobin levels. Results  PH (PAP >35 mmHg) was detected in 68 patients (35.9 %). Patients with PH were older (68 ± 12.3 vs. 52.1 ± 16.7, p  = 0.03), had lower ejection fractions (51.3  ± 13.4 vs. 60.8 ± 9.1 %, p  = 0.003), lower hemoglobin (11.3 ± 1.5 vs. 12.1 ± 1.9, p  = 0.05), and higher parathyroid hormone (218 ± 159.3 vs. 127.7 ± 67.4 pg/ml, p  = 0.05) levels. The remaining parameters were similar between groups. Conclusions  Older age, lower ejection fraction, and secondary hyperparathyroidism may contribute to PH in stage 1–4 proteinuria CKD. Keywords  Chronic kidney disease · Pulmonary hypertension · Proteinuria · Secondary hyperparathyroidism

Introduction Pulmonary hypertension (PH) has been traditionally defined as a mean pulmonary artery pressure of at least 25 mmHg at rest, with a pulmonary capillary wedge pressure of 15 mmHg or less. Cardiac catheterization revealed a prevalence of PH in 71 % of patients with pre-dialysis chronic kidney disease (CKD) [1]. Doppler echocardiography studies reported a prevalence of PH ranging between 9 and 39 % in pre-dialysis patients with stage 5 CKD [2–5]. Numerous clinical, hemodynamic, and metabolic abnormalities have been suggested to have a role in the pathogenesis of PH in patients with pre-dialysis CKD and patients on hemodialysis and peritoneal dialysis [5–8]. These abnormalities include anemia, fluid overload, and

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increased cardiac output because of arteriovenous fistula, oxidative stress, and alterations in the release of vasoactive mediators, such as endothelin-1 and nitric oxide. Although there remain no data on the prevalence of PH in patients with stage 1–3 CKD according to the Kidney Disease Outcome Quality Initiative, Yang and Bao [9] have reported a prevalence of 28.9 % in patients with stage 1–3 CKD. The authors reported that patients with PH were of older age, had a lower ejection fraction percentage (EF%), had lower estimated glomerular filtration rate (eGFR), had increased concentrations of brain natriuretic peptide, and had elevated mean arterial blood pressure and left ventricular mass index compared with a nonpulmonary hypertension group from China. Additionally, PH induced by increased parathyroid hormone (PTH) levels associated with pulmonary vascular calcification has been demonstrated in an experimental dog model of CKD [10]. Additionally, a correlation between secondary hyperparathyroidism and PH in pre-dialysis patients with CKD and patients on dialysis has been reported previously [7, 11]. The present study investigated the prevalence of and possible risk factors for PH in patients with stage 1–4 CKD with different degrees of proteinuria and different etiologies.

Int Urol Nephrol

Exclusion criteria Patients with known acute or chronic pulmonary disease, chronic atrial fibrillation, uncontrolled hyperphosphatemia, uncontrolled hypertension, adherence problems to diet and medication, active malignancies and inflammation, and infectious or hepatic diseases were excluded. No patient was taking fish oil, active vitamin D, or derivatives at the time of the study. Additionally, no patient had a history of bone disease, an active bone fracture, or diseases causing intestinal malabsorption. Biochemical analyses Blood samples were drawn from the antecubital vein using the standard method after an overnight fast. Intact PTH was measured by chemiluminescence immunometric assay using a Siemens Immulite 2000 System (Siemens Healthcare Diagnostics, Deerfield, IL, USA). Calcium, phosphorus, albumin, and C-reactive protein (CRP) were measured by standard laboratory methods using a c8000 Architect Clinical Chemistry Analyzer (Abbott Laboratories, Abbott Park, IL, USA). Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and plasma triglyceride concentrations were measured with an oxidase-based technique using a Roche/Hitachi Modular System (Roche Diagnostics, Mannheim, Germany).

Patients and methods Echocardiography Patients A total of 190 patients (mean age 61 ± 17.4 years, 116 males) who were diagnosed with stage 1–4 CKD with different degrees of proteinuria were enrolled in the study. No patient was undergoing immunosuppressive or steroid treatments at the time of the study. Etiologies of CKD were chronic glomerulonephritis (focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and IgA nephropathy) in 78 patients (41.1 %), diabetic nephropathy in 63 (33.2 %), polycystic kidney disease in 11 (5.7 %), hypertensive nephrosclerosis in 16 (8.4 %), and unknown (most probably undiagnosed glomerular disease) in 22 (11.6 %) patients. Each patient’s history of diabetes, rheumatism, cardiac or vascular diseases, primary kidney diseases, smoking habits, and medications was recorded at baseline from patient interviews. eGFR was calculated using the Modification of Diet in Renal Disease Study equation. There were 13 patients at stage 1, 13 patients at stage 2, 97 patients at stage 3, and 67 patients at stage 4 CKD. Patients were divided in two groups based on earlystage 1–2 CKD (26 patients) and advanced stage 3–4 CKD (164 patients) to compare the risk factors for PH in the groups separately.

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All patients underwent two-dimensional echocardiography (Sonos 4500; HP, Westerville, OH, USA) with a 2.5 MHz multiphase array probe while in the left decubitus position. All echocardiographs were performed according to recommendations of the American Society of Echocardiography and were analyzed by a single experienced cardiologist who was blind to all clinical details [12]. Pulmonary artery systolic pressure (PAP) was obtained by adding the estimated right atrial pressure to the tricuspid regurgitation velocity (v), shown by the equation: PAP = 4v2  + estimated right atrial pressure. Right atrial pressure was estimated as 5 mmHg if there was no engorgement in the inferior vena cava (more than 50 % difference in diameter by tidal inspiration) and 10 mmHg if there was less than 50 % difference in the diameter of the inferior vena cava. PAP >35 mmHg is generally accepted as the definition of PH in echocardiography-based studies [13–15]. Statistical analyses Statistical analyses were performed using SPSS 11.0.1 software (April 2002; IBM Corp., New York, NY, USA). Assumption of normal (Gaussian) distribution was tested

Int Urol Nephrol Table 1  Baseline demographic data and laboratory characteristics of the study population Minimum Maximum Mean

SD

Age Albumin (g/dl) CRP (mg/dl) LDL cholesterol (mg/dl)

19 2.85 0.27 32.00

90 5.20 44.00 245.00

61.1 3.8329 12.1 112.19

17.1 0.49 15.37 35.10

Triglyceride (mg/dl) Uric acid (mg/dl) Left ventricular ejection fraction (%) PTH (ng/ml) PAP (mmHg)

46.00 2.70 25.00

489.00 12.00 77.00

154.50 6.67 58.60

78.28 1.68 10.63

3.00 15.00

689.00 73.00

182.9 31.37

151.80 13.65

Creatinine (mg/dl) eGFR (ml/min) Ferritin (ng/ml) 24-h urine protein excretion (g/day)

0.59 16.00 4.60 543

4.49 124.00 1,174.00 20,246.00

1.97 39.68 172.80 1,965.64

0.87 23.01 189.49 3,483.59

Hemoglobin (g/dl)

8.03

14.70

11.94

1.89

PAP pulmonary artery pressure, PH pulmonary hypertension, PTH parathyroid hormone, CRP C-reactive protein, eGFR estimated glomerular filtration rate, LDL low-density lipoprotein

using the one-sample Kolmogorov–Smirnov test. Simple correlations were performed using Pearson’s or Spearman’s correlation analysis, as appropriate. Comparisons of variables between groups were made using Student’s t tests or Mann–Whitney U tests in accordance with the distribution pattern of the variable. Multiple linear regression analyses were performed to detect the effects of PTH, albumin, calcium, phosphorus, EF%, hemoglobin, lipid parameters, and uric acid on PAP. Binary logistic regression analysis was used to determine the independent effects of the variables on PH. All tests were performed in patients with early (stage 1–2) and advanced (stage 3–4) CKD separately.

Results Baseline demographic characteristics and baseline laboratory results of the study group are summarized in Table 1. Echocardiography revealed PH (PAP >35 mmHg) in 68 (35.9 %) patients. PAP showed a significant negative correlation with left ventricular EF% (r = −0.457, p = 0.0001) and positive correlations with PTH (r = 0.372, p = 0.02) and uric acid levels (r  = 0.294, p  = 0.025). PTH was negatively correlated with EF% (r = −0.469, p = 0.001). Patients with PH were older (68 ± 12.3 vs. 52.1 ± 16.7, p  = 0.03), had lower EF% (51.3 ± 13.4 vs. 60.8 ± 9.1, p  = 0.003), had lower hemoglobin (11.3 ± 1.5 vs. 12.1 ± 1.9, p = 0.05), and had higher PTH (218 ± 159.3 vs. 127.7 ± 67.4 pg/ml, p  = 0.05) levels compared with

patients without PH (Fig. 1). Age, sex, prevalence of diabetes, eGFR, CRP, albumin, calcium, phosphorus, ferritin, lipid parameters, and degree of proteinuria were similar between groups (Table 2). Linear regression analysis included as independent variables age, EF%, PTH, hemoglobin, and uric acid and as the dependent variable PAP. This revealed that age had a positive association (t = 0.206, p = 0.048) and EF% had negative association (t = −2.2, p = 0.038) with PAP (Table 3). A binary logistic regression analysis model in which PH (PAP ≥35 mmHg) was defined as the dependent variable, and age, EF%, eGFR, uric acid, CRP, PTH, albumin, and triglyceride as independent variables revealed that older age (odds ratio 1.046) and lower EF% (odds ratio 0.92) were independently associated with increased risk of PH (Table 3). Patients in the early stages of CKD (stage 1–2, n = 26) showed a lower prevalence of PH compared with patients in the advanced stages (stage 3–4, n = 164) (19.2 vs. 39 %, respectively, Chi-squared p  0.05). PAP showed stronger relationships with EF% (r = −0.487, p  = 0.0001) and PTH (r  = 0.449, p  = 0.005) in patients with advanced CKD compared with early-stage CKD.

Discussion The results showed 35.9 % prevalence for PH in patients with proteinuria stage 1–4 CKD. This finding is consistent with the previously reported prevalence (9–39 %) in predialysis patients [2–5, 11]. Patients with PH were older, had lower EF%, and had lower hemoglobin levels than patients with normal PAP. This finding was also consistent with a recent study examining stage 1–3 CKD that reported that patients with PH were older and had lower EF% than patients without PH [1]. Although that study did not include hemoglobin, PTH, and other biochemical analyses, the authors reported lower eGFR and higher brain natriuretic peptide levels in patients with PH compared with those with normal PAP. In the present study, although eGFR was similar in patients with and without PH, the prevalence of PH was higher in patients with stage 3–4 CKD compared with stage 1–2 CKD. An association between lower hemoglobin levels and PH has been reported by Buemi et al. [3]. In that study, the authors suggested that tissue hypoxia triggered by lower hemoglobin levels may increase PAP in CKD. Endothelial dysfunction is suggested to be a main trigger of PH [16], and this link is reported even in patients with CKD, whose endothelial dysfunction is pervasive [17]. The impaired capacity of endothelium to regulate vascular tone in CKD patients is because of disturbances between

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Int Urol Nephrol

Fig. 1  Comparison of age, parathyroid hormone and hemoglobin levels, and ejection fraction percentages between patients with and without pulmonary hypertension. Normal PAP normal systolic pulmonary artery pressure, PH pulmonary hypertension

Table 2  Comparison of patients with and without pulmonary hypertension

PAP pulmonary artery pressure, PH pulmonary hypertension, PTH parathyroid hormone, CRP C-reactive protein, eGFR estimated glomerular filtration rate, LDL low-density lipoprotein

PAP ≥ 35 mmHg

PAP 

Secondary hyperparathyroidism is associated with pulmonary hypertension in older patients with chronic kidney disease and proteinuria.

Hyperparathyroidism is associated with pulmonary vascular calcification and pulmonary hypertension (PH) in a chronic kidney failure dog model, and inc...
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