Información de la revista
Vol. 40. Núm. 3.Mayo - Junio 2020
Páginas 213-370
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Visitas
...
Vol. 40. Núm. 3.Mayo - Junio 2020
Páginas 213-370
Original article
DOI: 10.1016/j.nefro.2019.09.005
Open Access
Impact of hepatitis virus infection on arterial calcification among incident hemodialysis patients
Impacto de la infección por el virus de la hepatitis en la calcificación arterial en nuevos pacientes en hemodiálisis
Visitas
...
Ahmed Fayeda, Ahmed Solimana, Hossam El Mahdyb, Wael Hamzac, Dina O. Abdulazimd, Mona M. Saleme, Usama A. Sharaf El Dina,
Autor para correspondencia
usamaaas@gmail.com

Corresponding author.
, on behalf of the Vascular Calcification Group (VCG)
a Nephrology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
b Vascular surgery unit, General Surgery Department, School of Medicine, Cairo University, Egypt
c Pathology Department, School of Medicine, Cairo University, Egypt
d Rheumatology and Rehabilitation Department, School of Medicine, Cairo University, Egypt
e Endocrinology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
Información del artículo
Resumen
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Tablas (9)
Table 1. Site and Pattern of calcification in the 3 studied groups.
Table 2. Site of calcification and calcification score in seronegative versus hepatitis B & C positive patients according to severity of viremia.
Table 3. Demographic and laboratory parameters in seronegative versus hepatitis B positive patients.
Table 4. Demographic and laboratory parameters in seronegative versus hepatitis B positive patients according to severity of viremia.
Table 5. demographic and laboratory parameters in seronegative versus hepatitis C positive patients.
Table 6. demographic and laboratory parameters in seronegative versus hepatitis C positive patients according to severity of viremia.
Table 7. Impact of diabetes on site and pattern of calcification.
Table 8. Impact of Age on site and pattern of calcification.
Table 9. Impact of Gender on site and pattern of calcification.
Mostrar másMostrar menos
Abstract
Background

The impact of hepatitis virus infection on arterial calcification (AC) was not studied.

Objective

To study the prevalence, severity and distribution of AC in incident hemodialysis patients with hepatitis B and C viral infection.

Cases and methods

172 stage 5 CKD adults (98 male and 74 female) were included; 58 of them were seronegative for both hepatitis B and C (SN group), 48 were positive for hepatitis B virus infection (HBV group) and 66 were hepatitis C virus positive (HCV group). Beside histopathology of the obtained arterial samples, all these cases were examined for body mass index (BMI), serum calcium (Ca), phosphorus (P), alkaline phosphatase (AP), serum albumin, uric acid (UA), alanine transaminase (ALT), parathormone (PTH), fibroblast growth factor 23(FGF23), interleukin 6 (IL6), and 25 hydroxy vitamin D (25 (OH) vit D), hemoglobin concentration, and serum ferritin.

Results

86 (50%) of the cases had AC; 11 of them were in SN group (19%), 9 in HBV group (18.8%) and all the 66 HCV group (100%). In SN group, 4 had intimal calcification, 5 had medial calcification, and 2 had both intimal and medial calcification. In HBV group, 9 had intimal calcification, while no cases were encountered with either medial or both site calcifications. In HCV group, 16 had intimal calcification, 31 had medial calcification, and 19 had both intimal and medial calcification. Calcification was in the form of spots in one case in SN group, and 6 cases in HBV group, a single plaque of calcification in 5 cases of SN group, 3 cases of HBV group, and 16 cases of HCV group, multiple plaques were detected in 4 cases in SN group, and 31 cases in HCV group, and diffuse calcification in one case in SN group, and 19 cases in HCV group.

In HBV group, calcification was only detected in patients with high viremia, while all patients with low or moderate viremia were devoid of calcification. In HCV group, all patients with low viremia had intimal solitary plaque of calcification, all patients with moderate viremia had multiple plaques of medial calcification, while all patients with high viremia had diffuse intimal and medial calcification. Both groups of viral hepatitis were significantly different in comparison to SN group in either distribution or calcification score (P<0.001 in all).

HBV group had significantly lower serum P, CaxP and PTH in comparison to SN group (4.6±0.66 vs. 5.45±0.77mg/dL, 36.4±7.2 vs. 44.1±8.69, and 348±65.4 vs. 405.9±83.2pg/mL, P<0.001, <0.001, and 0.035 respectively). On the other hand, HCV group did not show any significant difference in any of the studied parameters compared to SN group.

Conclusion

HCV positive patients are more prone to develop AC that is more extensive. HBV positive patients were less likely to have arterial medial calcification, probably related to lower serum phosphorus, CaxP product and PTH. HCV infection should be added as risk factor for AC among CKD patients. Further studies are needed to confirm these findings.

Keywords:
CKD
Vascular calcification
Hepatitis B
Hepatitis C
Phosphorus
Arterial biopsy
Parathormone
FGF23
Resumen
Antecedentes

No se había estudiado el impacto de la infección por el virus de la hepatitis en la calcificación arterial (CA).

Objetivo

Estudiar la prevalencia, la intensidad y la distribución de la CA en nuevos pacientes en hemodiálisis con infección por hepatitis B y C.

Casos y métodos

Se incluyeron 172 pacientes con ERC en estadio 5 (98 varones 74 mujeres); 58 de ellos eran seronegativos para el virus de la hepatitis B y de la hepatitis C (grupo SN), 48 eran positivos para infección por el virus de la hepatitis B (grupo VHB) y 66 eran positivos para el virus de la hepatitis C (grupo VHC). Además de analizar la histopatología de las muestras arteriales obtenidas, todos estos casos se examinaron para determinar el índice de masa corporal (IMC), la concentración sérica de calcio (Ca), el fósforo (P), la fosfatasa alcalina (FA), la albúmina sérica, el ácido úrico (AU), la alanina transaminasa (ALT), la paratohormona (PTH), el factor de crecimiento de fibroblastos 23 (FGF23), la interleucina 6 (IL6) y la 25 hidroxivitamina D (25 (OH)), la concentración de hemoglobina y la ferritina sérica.

Resultados

Ochenta y seis (50%) de los casos presentaron CA; 11 del grupo SN (19%), 9 del grupo VHB (18,8%) y los 66 del grupo VHC (100%). En el grupo SN, 4 presentaron calcificación de la íntima, 5 calcificación de la media y 2 calcificación tanto de la íntima como de la media. En el grupo de VHB, 9 presentaron calcificación de la íntima, mientras que no se hallaron casos de calcificación de la media ni de calcificación de ambas capas. En el grupo de VHC, 16 presentaron calcificación de la íntima, 31 calcificación de la media y 19 calcificación tanto de la íntima como de la media. La calcificación se presentó en forma de puntos en un caso del grupo SN y en 6 casos del grupo VHB; en forma de una sola placa de calcificación en 5 casos del grupo SN, 3 casos del grupo VHB y 16 casos del grupo VHC; en forma de múltiples placas en 4 casos del grupo SN y 31 casos del grupo VHC; y en forma de calcificación difusa en un caso del grupo SN y 19 casos del grupo VHC.

En el grupo VHB, solo se detectó calcificación en pacientes con viremia alta, mientras que todos los pacientes con viremia baja o moderada no presentaron calcificación. En el grupo VHC, todos los pacientes con viremia baja presentaron una sola placa de calcificación en la íntima, todos los pacientes con viremia moderada presentaron múltiples placas de calcificación de la media y todos los pacientes con viremia alta presentaron calcificación difusa de la íntima y la media. Ambos grupos de hepatitis vírica fueron significativamente diferentes en comparación con el grupo SN tanto en la distribución como en la puntuación de calcificación (p<0,001 en todos).

El grupo VHB presentó concentraciones séricas de P, CaxP y PTH, significativamente menores respecto a las del grupo SN (4,6±0,66 frente a 5,45±0,77mg/dl, 36,4±7,2 frente a 44,1±8,69 y 348±65,4 frente a 405,9±83,2pg/ml; p<0,001, p<0,001 y p<0,035, respectivamente). Por el contrario, el grupo VHC no mostró ninguna diferencia significativa en ninguno de los parámetros estudiados respecto al grupo SN.

Conclusión

Los pacientes positivos para el VHC tienen más tendencia a desarrollar CA más extensa. Los pacientes positivos para el VHB presentaron menor probabilidad de presentar calcificación de la media arterial, probablemente relacionada con concentraciones séricas menores de fósforo, producto de CaxP y PTH. La infección por VHC debe añadirse como factor de riesgo para la CA en los pacientes con ERC. Se precisan más estudios para confirmar estos resultados.

Palabras clave:
ERC
Calcificación vascular
Hepatitis B
Hepatitis C
Fósforo
Biopsia arterial
Paratohormona
FGF23
Texto completo
Introduction

AC is one of the predictors of increased cardiovascular mortality among CKD patients.1 AC affects almost all arteries within the body of CKD patients.2,3 In these patients, AC develops within the tunica intima on top of atherosclerotic disease or in the tunica media induced by local inflammation, elastin degradation, vascular smooth muscle cell degeneration, or phenotypic switch within smooth muscle cells.4,5 Beside the variations in anatomical location and histologic site within the arterial wall, AC in CKD patients also varies in its pattern of presentation. Micro calcification or spotty calcification usually complicates atherosclerotic plaques. This type of calcification is usually difficult to diagnose using regular radiologic techniques. AC might present as solitary plaque of calcification within the intimal or the medial layers, as multiple plaques or diffuse calcification that usually involve the medial layer.5–9 While spotty calcification negatively affects atheromatous plaque stability,9 plaque and diffuse calcification increase arterial wall stiffness.7 The underlying risk factors of accelerated AC in CKD patients are divided into classic and non-classic factors.10

Hepatitis B and C viral infections are frequently encountered among pre-dialysis CKD patients.11,12 The association between viral hepatitis and AC among incident hemodialysis CKD patients was not previously looked for.

Aim of work

The aim of this study is to estimate the prevalence, severity and distribution of arterial wall calcification in incident hemodialysis patients undergoing radio-cephalic vascular access surgery for hemodialysis in a trial to look for the impact of hepatitis B and C viral infection on these parameters.

Patients and methods

The patients recruited in this study were candidates for creation of radio-cephalic fistula as a vascular access for hemodialysis. All sero-negative patients underwent this procedure in Cairo University hospitals, while most of the hepatitis positive patients underwent this procedure in 2 fever hospitals within the Cairo city capital, namely, Abbasia and Imbaba fever hospitals. 172 stage 5 CKD adults (98 male and 74 female) were included; 58 of them were sero-negative for both hepatitis B and C (SN group), 48 were positive for hepatitis B virus infection (HBV group) and 66 were hepatitis C virus positive (HCV group). Polymease chain reaction (PCR) was done for HBV DNA polymerase to confirm active infection in HBV group. According to the magnitude of viremia, HBV patients were subdivided into low (16–103copies/mL), moderate (>103–105copies/ml), and high viremia (>105copies/ml). Similarly, PCR for HCV RNA was done for HCV group and were subdivided into low (16–103copies/ml), moderate (>103–106copies/ml), and high viremia (>106copies/ml).

An arterial tissue biopsy including all layers of the artery wall was selected carefully during the creation of the radio-cephalic fistula and thoroughly excised from both arterial walls dedicated for the anastomosis with an approximate length equal to the planned anastomotic suture line and a width of 1mm. The arterial biopsy specimens were formalin-fixed, processed in alcohol, cleared in xylene and incubated in paraffin blocks. Four sets of slides were prepared from serial cuts (5μ thick); stained with hematoxylin/eosin, Masson's trichrome, Alizarin red and Verhoeff-van Gieson stains. All stained slides were examined under light microscope to evaluate the presence of arterial wall calcification, the site of calcification if restricted to intimal, medial or both layers and the extent of the deposits in the arterial wall if discrete intimal spots of calcification, single segment of calcification involving one 10× field, more than one 10× field of calcification, or diffuse arterial wall calcification.

In addition, BMI, serum Ca, P, AP, serum albumin, UA, ALT, intact PTH, intact FGF23, IL6, and 25 (OH) vit D, hemoglobin concentration, and serum ferritin were estimated in all cases. Blood samples were collected after 6h fasting and then centrifuged to separate plasma that was either immediately assayed or stored below −70°C. Serum level of Intact PTH was determined by enzyme-amplified sensitivity immunoassay (Roche Diagnostics, IN, USA). Intact FGF23 was measured by using a two-site (NH2-terminal/C-terminal) enzyme-linked immunosorbent assay (Immutopics, CA, USA). Serum IL6 was measured using ELISA (Bioscience, ESP) immediately after blood collection. Assays were performed according to the manufacturer's guidelines. The sensitivity of the kit was 2pg/ml and inter- and intra-assay assessments of reliability of the kits were conducted. Serum 25 (OH) vit D was assessed using HPLC.

Statistical analysis was done by SPSS computer package. Quantitative variables were summarized using mean±S.D. Comparison between groups was evaluated using Student's t-test. Comparison between more than 2 independent groups was evaluated using ANNOVA test. Chi square was used to look for impact of age, gender and diabetic state on the pattern and distribution of arterial calcification.

Results

Results are summarized in Tables 1–9. AC was encountered in 86 of the study cases; 66 of them in HCV group, 9 in HBV group and 11 in SN group. Calcification was more extensive in HCV group; while four of the eleven patients in SN had intimal calcification, 5 cases had medial calcification and only 2 had both intimal and medial calcification, 16 patients in HCV group had intimal calcification, 31 had medial calcification and 19 had calcification in both sites. On the other hand all cases of AC in HBV group had only intimal calcification (P<0.001) (Table 1). In addition, the score of calcification was significantly higher in HCV group; while one case of SN group had calcification spots, 5 cases had single plaque, 4 had multiple plaques and only one case had diffuse calcification, none of the cases of HCV group had calcification spots, 16 had single plaque, 31 had multiple plaques and 19 had diffuse calcification. On the other hand, 6 cases in HBV group had calcification spots and 3 had single plaque of calcification, while non of the cases in this group had either multiple plaques or diffuse calcification (P<0.001 in all) (Table 2).

Table 1.

Site and Pattern of calcification in the 3 studied groups.

Site of calcification in the 3 studied groups
Site of calcification  Intimal  Medial  Intimal & medial 
Study group       
Sero-negative group  4/58 (6.9%)  5/58 (8.6%)  2/58 (3.45%) 
HBV group  9/48 (18.8%)  0/48 (0%)  0/48 (0%) 
HCV group  16/66 (24.2%)  31/66 (47%)  19/66 (28.9%) 
P value  <0.001
Pattern of calcification in the 3 studied groups
Pattern of calcification  Spots  Single segment  Multiple segments  Diffuse 
Study group         
Sero-negative group  1/58 (1.7%)  5/58 (8.6%)  4/58 (6.9%)  1/58 (1.7%) 
HBV group  6/48 (12.5%)  3/48 (6.25%)  0/48 (0%)  0/48 (0%) 
HCV group  0/66 (0%)  16/66 (24.1%)  31/66 (47%)  19/66 (28.9%) 
P value  <0.001
Table 2.

Site of calcification and calcification score in seronegative versus hepatitis B & C positive patients according to severity of viremia.

HBV viremia
  None  Low  Moderate  High  P value 
Site of calcification
Mean±SD  1.25±1.14  0±0±1±<0.001
Median(iqr)  1(0–2)  0(0–0)  0(0–0)  1(1–1) 
Calcification score
Mean±SD  1.84±1.56  0±0±1.33±0.5  <0.001
Median(iqr)  2(0–3)  4(0–0)  0(0–0)  1(1–2) 
HCV viremia
  None  Low  Moderate  High  P value 
Site of calcification
Mean±SD  0.27±0.64  1±2±3±<0.001
Median(iqr)  0(0–0)  1(1–1)  2(2–2)  3(3–3) 
Calcification score
Mean±SD  1.18±0.53  2±3±4±<0.001
Median(iqr)  1(1–1)  2(2–2)  3(3–3)  4(4–4) 
Table 3.

Demographic and laboratory parameters in seronegative versus hepatitis B positive patients.

Item  Seronegative (58)Hepatitis B positive (48)P value 
  Range  Mean±S.D.  Range  Mean±S.D.   
Age (years)  24–62  41±9.63  25–62  42±9.79  0.52 
BMI (kg/m217.5–30  22.9±3.28  17.5–30  22.6±3.26  0.91 
ALT (IU/L)  15–94  37±25.6  15–78  26.5±9.9  <0.001 
Alk. phosphatase (IU/L)  134–200  160±17.02  124–200  161±14.6  0.81 
Serum albumin (g/dL)  3–4.1  3.7±0.23  3–4.1  3.6±0.26  0.3 
S. calcium (mg/dL)  6.7–10  8±0.85  6.2–10  8.05±0.73  0.81 
S. phosphorus (mg/dL)  3.5–7  5.45±0.77  3–5.8  4.6±0.66  <0.001 
Ca×P product  25.2–64  44.1±8.69  23.1–56.3  36.4±7.2  <0.001 
Serum PTH (pg/mL)  307–613  405.9±83.2  307–536  348±65.4  0.035 
Serum IL6 (ng/L)  21–41  25±5.58  21–41  24±4.6  0.082 
S. 25 OH vit D (ng/mL)  8–32  15.4±5.76  8.7–32  17.7±6.07  0.24 
S.FGF23 (ng/mL)  209–312  257±24.1  211–310  261±24.5  0.27 
S. Uric acid (mg/dL)  2.5–14  5±2.44  2.5–11  5.1±1.6  0.58 
Hemoglobin conc. (g/dL)  6.5–14.3  9.55±1.86  5.9–15.6  9.55±1.95  0.21 
S. ferritin (ng/mL)  113–191.1  162±21.71  113–195  167±18.7  0.19 

BMI, body mass index; ALT, serum alanine transaminase; PTH, parathyroid hormone; IL6, interleukin 6; 25 OH vit D, 25 hydroxy vitamin D; FGF23, fibroblast growth factor 23.

Table 4.

Demographic and laboratory parameters in seronegative versus hepatitis B positive patients according to severity of viremia.

Item  Seronegative (58)Hepatitis B positive (48)F value  P 
      Low viremia (14)Moderate viremia (25)Severe viremia (9)   
  Range  Mean±S.D.  Range  Mean±S.D.  Range  Mean±S.D.  Range  Mean±S.D.     
Age (years)  24–62  41±9.63  25–62  40.5±14.6  30–55  41±7.3  41–55  45±5.7  0.81  0.49 
BMI (kg/m217.5–30  22.9±3.28  17.5–27  19.5±3.37  17.5–28  23±2.24  18.5–30  22.6±4.43  2.49  0.065 
ALT (IU/L)  15–94  37±25.6  15–37  26.5±7.6  18–78  27±11.97  17–36  26±6.6  5.5  0.0012 
Alk. phosphatase (IU/L)  134–200  160±17.02  144–194  163±12.7  138–200  160±15.4  124–170  158±14.6  0.77  0.51 
Serum albumin (g/dL)  3–4.1  3.7±0.23  3–4.1  3.65±0.33  3.2–3.9  3.6±0.19  3.2–4  3.4±0.3  1.2  0.3 
S. calcium (mg/dL)  6.7–10  8±0.85  7.2–9.7  8.15±0.64  6.9–10  8±0.77  6.2–8.5  7.9±0.73  0.77  0.51 
S. phosphorus (mg/dL)  3.5–7  5.45±0.77  3–5.8  4.6±0.71  3.4–5.4  4.8±0.63  3–5.5  4.3±0.71  10.6  <0.001 
Ca×P product  25.2–64  44.1±8.69  26.4–56.3  37±7.13  24.48–54  38.5±7.7  23.1–43.5  35.7±6.34  <0.001 
Serum PTH (pg/mL)  307–613  405.9±83.2  307–466  378±62  307–536  383±73.5  307–439  360±42  1.63  0.19 
Serum IL6 (ng/L)  21–41  25±5.58  21–33  23.9±2.88  21–41  23.7±5.44  21–33  24±4.4  1.15  0.33 
S. 25 OH vit D (ng/mL)  8–32  15.4±5.76  10.6–23  18.8±4.8  8.7–32  16.8±6.5  8.7–26.8  16.8±7.2  0.5  0.68 
S.FGF23 (ng/mL)  209–312  257±24.1  225–310  258.5±25.5  220–298  274±19.4  211–274  226±20  5.3  0.002 
S. Uric acid (mg/dL)  2.5–14  5±2.44  2.5–8  4.8±1.38  3.5–11  5.9±1.6  2.5–8.2  5.1±2.08  0.46  0.71 
Hemoglobin conc. (g/dL)  6.5–14.3  9.55±1.86  8–15.6  10.65±2.19  7.3–15  9.3±1.58  5.9–14.3  10±2.4  1.7  0.17 
S. ferritin (ng/mL)  113–191.1  162±21.71  141–184.5  172.5±13.6  113–195  162±22  127–176  169±14.8  1.04  0.37 

BMI, body mass index; ALT, serum alanine transaminase; PTH, parathyroid hormone; IL6, interleukin 6; 25 OH vit D, 25 hydroxy vitamin D; FGF23, fibroblast growth factor 23.

Table 5.

demographic and laboratory parameters in seronegative versus hepatitis C positive patients.

Item  Seronegative (58)Hepatitis C positive (66)P value 
  Range  Mean±S.D.  Range  Mean±S.D.   
Age (years)  24–62  41±9.63  24–62  41±9.48  0.88 
BMI (kg/m217.5–30  22.9±3.28  17.5–28  22±2.53  0.086 
ALT (IU/L)  15–94  37±25.6  15–96  33.5±25.6  0.8 
Alk. Phosphatase (IU/L)  134–200  160±17.02  134–186  162±11.25  0.98 
Serum albumin (g/dL)  3–4.1  3.7±0.23  3–4.1  3.6±0.25  0.26 
S. calcium (mg/dL)  6.7–10  8±0.85  6.7–9.3  8.1±0.56  0.98 
S. phosphorus (mg/dL)  3.5–7  5.45±0.77  3.4–7.5  5.3±0.95  0.65 
Ca×P product  25.2–64  44.1±8.69  25.5–63.8  42.9±8.8  0.68 
Serum PTH (pg/mL)  307–613  405.9±83.2  307–613  397±89.8  0.88 
Serum IL6 (ng/L)  21–41  25±5.58  21–41  25±5.66  0.89 
S. 25 OH vit D (ng/mL)  8–32  15.4±5.76  8.7–32  16.8±5.94  0.69 
S. FGF23 (ng/mL)  209–312  257±24.1  205–316  256.5±24.3  0.63 
S. Uric acid (mg/dL)  2.5–14  5±2.44  2.5–11  5.8±1.67  0.91 
Hemoglobin conc. (g/dL)  6.5–14.3  9.55±1.86  5.7–12.8  9±1.6  0.34 
S. ferritin (ng/mL)  113–191.1  162±21.71  113–191  163.5±19.5  0.5 

BMI, body mass index; ALT, serum alanine transaminase; PTH, parathyroid hormone; IL6, interleukin 6; 25 OH vit D, 25 hydroxy vitamin D; FGF23, fibroblast growth factor 23.

Table 6.

demographic and laboratory parameters in seronegative versus hepatitis C positive patients according to severity of viremia.

Item  Seronegative (58)Hepatitis C positive (66)F value  P 
      Low viremia (16)Moderate viremia (31)Severe viremia (19)   
  Range  Mean±S.D.  Range  Mean±S.D.  Range  Mean±S.D.  Range  Mean±S.D.     
Age (years)  24–62  41±9.63  33–62  45±8.55  24–55  38±9.9  27–62  41±8.9  1.4  0.24 
BMI (kg/m217.5–30  22.9±3.28  18.9–28  22.75±2.6  17.5–26  21±2.2  17.5–26  22.6±2.4  3.8  0.012 
ALT (IU/L)  15–94  37±25.6  18–62  25±15.9  15–92  34±25.7  15–96  34±30.2  1.34  0.26 
Alk. phosphatase (IU/L)  134–200  160±17.02  134–170  160±10.1  146–184  164±10.6  140–186  160±12.6  0.78  0.50 
Serum albumin (g/dL)  3–4.1  3.7±0.23  3.3–4.1  3.6±0.21  3–4.1  3.6±0.26  3–3.9  3.6±0.24  2.15  0.098 
S. calcium (mg/dL)  6.7–10  8±0.85  6.7–8.5  8±0.5  7.3–9.2  8.2±0.53  7–9.3  8±0.63  0.78  0.50 
S. phosphorus (mg/dL)  3.5–7  5.45±0.77  3.4–5.9  4.75±0.8  3.6–7.5  5.3±0.99  4–7  6±0.8  3.88  0.011 
Ca×P product  25.2–64  44.1±8.69  25.5–49.3  38±7.87  27–63.8  42.3±28–58  47.3±7.4  3.1  0.03 
Serum PTH (pg/mL)  307–613  405.9±83.2  307–577  473±82.1  307–613  341.5±98.1  307–591  369.2±72.7  1.78  0.15 
Serum IL6 (ng/L)  21–41  25±5.58  22.6–41  23.6±6.3  21–41  24±4.97  21–39  27±5.85  1.43  0.24 
S. 25 OH vit D (ng/mL)  8–32  15.4±5.76  8.7–26.8  16.5±5.8  8.7–26.8  15.4±5.9  9–32  17.5±6.27  0.27  0.85 
S.FGF23 (ng/mL)  209–312  257±24.1  220–293  241±22.8  205–316  257±25  219–294  268±23.2  1.37  0.25 
S. Uric acid (mg/dL)  2.5–14  5±2.44  2.5–10  5.5±2.07  3.5–11  6±1.5  2.5–8.2  5±1.5  0.4  0.75 
Hemoglobin conc. (g/dL)  6.5–14.3  9.55±1.86  5.7–11.1  9±1.7  6–12.5  9±1.65  7.4–12.8  9.5±1.4  1.43  0.23 
S. ferritin (ng/mL)  113–191.1  162±21.71  113–191  162.8±22.7  113–191  163.5±18.8  114.5–183  169±18.5  0.26  0.85 

BMI, body mass index; ALT, serum alanine transaminase; PTH, parathyroid hormone; IL6, interleukin 6; 25 OH vit D, 25 hydroxy vitamin D; FGF23, fibroblast growth factor 23.

Table 7.

Impact of diabetes on site and pattern of calcification.

Study group  Site of calcification in the 3 studied groups
  IntimalMedialIntimal & medial
  Diabetic cases  Non-diabetic  Diabetic cases  Non-diabetic  Diabetic cases  Non-diabetic 
Sero-negative  2/58 (3.4%)  2/58 (3.4%)  2/58 (3.4%)  3/58 (5.2%)  0/58 (0%)  2/58 (3.4%) 
HBV group  2/48 (4.2%)  7/48 (14.6%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  3/66 (4.5%)  13/66 (20%)  6/66 (9%)  25/66 (38%)  3/66 (5%)  17/66 (26%) 
Chi-square  0.0062
P value  0.937458
Study group  Pattern of calcification in the 3 studied groups
  SpotsSingle segmentMultiple segmentsDiffuse
  Diabetic cases  Non-diabetic  Diabetic cases  Non-diabetic  Diabetic cases  Non-diabetic  Diabetic cases  Non-diabetic 
Sero-negative  0/58 (0%)  1/58 (1.7%)  2/58 (3.4%)  3/58 (5.2%)  2/58 (3.4%)  2/58 (3.4%)  0/58 (0%)  1/58 (1.7%) 
HBV group  2/48 (4.2%)  4/48 (8.4%)  0/48 (0%)  3/48 (6.3%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  0/66 (0%)  0/66 (0%)  3/66 (4.5%)  13/66 (19.7%)  6/66 (9.1%)  25/66 (37.9%)  3/66 (4.5%)  17/66 (25.8%) 
Chi-square  0.0062
P value  0.937458
Table 8.

Impact of Age on site and pattern of calcification.

Study group  Site of calcification in the 3 studied groups
  IntimalMedialIntimal & medial
  Age 52–62  Age<52  Age 52–62  Age<52  Age 52–62  Age<52 
Sero-negative  2/58 (3%)  2/58 (3.4%)  1/58 (2%)  4/58 (6.9%)  1/58 (0%)  1/58 (1.7%) 
HBV group  2/48 (4%)  7/48 (15%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  2/66 (3%)  14/66 (21%)  3/66 (5%)  28/66 (42%)  3/66 (5%)  16/66 (24%) 
Chi-square  0.1812
P value  0.6703
Study group  Pattern of calcification in the 3 studied groups
  SpotsSingle segmentMultiple segmentsDiffuse
  Age 52–62  Age<52  Age 52–62  Age<52  Age 52–62  Age<52  Age 52–62  Age<52 
Sero-negative  1/58 (1.7%)  0/58 (0%)  1/58 (1.7%)  4/58 (6.8%)  2/58 (3.4%)  2/58 (3.4%)  0/58 (0%)  1/58 (1.7%) 
HBV group  1/48 (2.1%)  5/48 (10.4%)  1/48 (2.1%)  2/48 (4.2%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  0/66 (0%)  0/66 (0%)  2/66 (3%)  14/66 (21.2%)  3/66 (4.5%)  28/66 (42.4%)  3/66 (4.5%)  16/66 (24.2%) 
Chi-square  0.1812
P value  0.670307
Table 9.

Impact of Gender on site and pattern of calcification.

Study group  Site of calcification in the 3 studied groups
  IntimalMedialIntimal & medial
  Male  Female  Male  Female  Male  Female 
Sero-negative  1/58 (1.7%)  2/58 (3.4%)  0/58 (0%)  2/58 (3.4%)  0/58 (0%)  2/58 (3.4%) 
HBV group  3/48 (6.3%)  6/48 (12.5%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  6/66 (9.1%)  10/66 (15%)  19/66 (29%)  12/66 (18%)  15/66 (23%)  4/66 (6.1%) 
Chi-square  0.7039
P value  0.401479
Study group  Pattern of calcification in the 3 studied groups
  SpotsSingle segmentMultiple segmentsDiffuse
  Male  Female  Male  Female  Male  Female  Male  Female 
Sero-negative  1/58 (1.7%)  0/58 (0%)  0/58 (0%)  3/58 (5.2%)  0/58 (0%)  3/58 (5.2%)  0/58 (0%)  0/58 (0%) 
HBV group  2/48 (4.2%)  4/48 (8.3%)  1/48 (2.1%)  2/48 (4.2%)  0/48 (0%)  0/48 (0%)  0/48 (0%)  0/48 (0%) 
HCV group  0/66 (0%)  0/66 (0%)  6/66 (9.1%)  10/66 (15.2%)  19/66 (28.8%)  12/66 (18.2%)  15/66 (22.7%)  4/66 (6.1%) 
Chi-square  0.7039
P value  0.401479

In HBV group, calcification was only encountered in patients with high viremia, while all patients in HCV group had calcification. The level of viremia had an influence on the site and pattern of calcification in HCV group. While all low viremia cases showed intimal solitary plaque of calcification, all cases with moderate viremia had multiple plaques of medial calcification, all patients suffering high viremia had diffuse calcification involving both intimal and medial layers (P<0.001 in all) (Table 2).

Table 3 shows statistical analysis of the different clinical and biochemical parameters studied in HBV group in comparison to SN group. HBV group had significantly higher serum ALT and lower serum P, CaxP product and PTH in comparison to SN group. On comparison of SN group to HBV subgroups with different grades of viremia, significant differences were encountered. In addition there was significant difference in serum FGF23 likely due to lower level in patients with high viremia (Table 4).

There is no significant difference between the SN and HCV group in any of the studied clinical and laboratory parameters (Table 5). On the other hand, there was significant difference in BMI, serum P and serum Ca x P product between SN group and HCV subgroups with different grades of viremia (Table 6).

Diabetic status, patient age or gender did not have any significant impact on the incidence, pattern or distribution in the different studied groups (Tables 7–9).

Discussion

In our previous study of the prevalence of hepatitis virus infection among incident hemodialysis patients, HCV antibody was encountered in 22.9% 0f patients and HBsAg was detected in 1.4% of patients.13 Although arterial calcification was thoroughly studied in incident hemodialysis patients,2,14–16 its association with hepatitis infection was not analyzed. The only study of arterial calcification in HCV infected CKD patient has looked for aortic arch calcification among prevalent hemodialysis patients.17 On the other hand, the association of HBV infection with vascular calcification among CKD patients was not studied before.

In the current study, we used arterial samples obtained during the creation of radio-cephalic fistula before starting hemodialysis treatment. Although the histo-pathologic examination can detect tiny calcification spots not readily detected by radiologic techniques, this examination is limited to the site of sampling contrary to radiologic examination. However, histo-pathologic examination did facilitate the proper judgment of the site and pattern of arterial calcification.

The findings obtained in the current study were striking. First, they confirmed the increased tendency of HCV patients to develop calcification. Second, the HCV group did develop AC whatever the magnitude of viremia. Third, contrary to SN and HBV groups, HCV patients do not develop calcification spots; all HCV patient had either segmental or diffuse calcification. Fourth, the higher the level of viremia the more is the calcification score; while patients with low viremia had solitary calcification plaque, patients with moderate viremia showed multiple calcification plaques and high viremia patients had diffuse calcification. If these findings would be confirmed by future studies, they should stimulate for early detection and treatment of HCV infection among CKD patients.

On the contrary, HBV infection seems to suppress the development of medial calcification. This finding needs verification in future studies. All patients that had calcification in this group were in the high viremia subgroup. All these patients had intimal calcification that was in the form of microcalcification in two-thirds of the affected cases while the remaining one third had solitary calcification plaque. Although there was a significant difference in serum P and Ca×P product in between the SN and HBV subgroups, these parameters were lower in the high viremia group that developed intimal calcifications. A similar finding is observed among low viremia HCV subgroup. Disturbance in mineral metabolism cannot thus explain the increased tendency and severity of calcification among the HCV group nor the intimal calcification among the high viremia HBV subgroup. This can be also applied to age, gender, diabetic state, serum PTH, 25 (OH) vit. D, FGF23 and IL6.

According to this study, HCV infection should be added as one of the non-traditional risk factors of AC in CKD patients. However, many inquiries have been created and need further intensive work to find the proper answers.

Funds

This study did not receive funds.

Conflict of interest

The authors have declared that no conflict of interest exists.

Acknowledgments

Professor Usama suggested this study, he also revised the manuscript. Prof. Mona Salem has put the study design, Dr. Ahmed Fayed, collected the biopsy and blood samples and shared in statistical analysis, Dr. Hossam El Mahdy is the vascular surgeon that offered the arterial samples. Dr. Wael Hamza is the pathologist that examined the arterial samples. Dr. Dina, and Dr. Ahmed Soliman collected the references and wrote the manuscript.

References
[1]
S. Kumar, R. Bogle, D. Banerjee.
Why do young people with chronic kidney disease die early?.
World J Nephrol, 3 (2014), pp. 143-155
[2]
M.M. Nasrallah, A.R. El-Shehaby, M.M. Salem, N.A. Osman, E. El Sheikh, U.A. Sharaf El Din.
Fibroblast growth factor-23 (FGF-23) is independently correlated to aortic calcification in haemodialysis patients.
Nephrol Dial Transplant, 25 (2010), pp. 2679-2685
[3]
G.A. Adeseun, D. Xie, X. Wang, M.M. Joffe, M.M. Joffe, E.R. Mohler 3rd, et al.
Carotid plaque, carotid intima-media thickness, and coronary calcification equally discriminate prevalent cardiovascular disease in kidney disease.
Am J Nephrol, 36 (2012), pp. 342-347
[4]
N.J. Paloian, C.M. Giachelli.
A current understanding of vascular calcification in CKD.
Am J Physiol Renal Physiol, 307 (2014), pp. F891-F900
[5]
P. Lanzer, M. Boehm, V. Sorribas, M. Thiriet, J. Janzen, T. Zeller, et al.
Medial vascular calcification revisited: review and perspectives.
Eur Heart J, 35 (2014), pp. 1515-1525
[6]
K. Amann.
Media calcification and intima calcification are distinct entities in chronic kidney disease.
Clin J Am Soc Nephrol, 3 (2008), pp. 1599-1605
[7]
C.Y. Ho, C.M. Shanahan.
Medial arterial calcification: an overlooked player in peripheral arterial disease.
Arterioscler Thromb Vasc Biol, 36 (2016), pp. 1475-1482
[8]
R.H. Mackey, L. Venkitachalam, K. Sutton-Tyrrell.
Calcifications, arterial stiffness and atherosclerosis.
Adv Cardiol, 44 (2007), pp. 234-244
[9]
A.E. Ewence, M. Bootman, H.L. Roderick, J.N. Skepper, G. McCarthy, M. Epple, et al.
Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization.
Circ Res, 103 (2008), pp. e28-e34
[10]
M. Cozzolino, D. Brancaccio, M. Gallieni, E. Slatopolsky.
Pathogenesis of vascular calcification in chronic kidney disease.
Kidney Int, 68 (2005), pp. 429-436
[11]
D. Sit, A.K. Kadiroglu, H. Kayabasi, M.E. Yilmaz, V. Goral.
Seroprevalence of hepatitis B and C viruses in patients with chronic kidney disease in the predialysis stage at a university hospital in Turkey.
Intervirology, 50 (2007), pp. 133-137
[12]
P. Cacoub, A.C. Desbois, C. Isnard-Bagnis, D. Rocatello, C. Ferri, C. Hepatitis.
virus infection and chronic kidney disease: time for reappraisal.
J Hepatol, 65 (2016), pp. S82-S94
[13]
B. Zayed, U.A. elazim, M. Mansour.
Prevalence of HCVAb and HBsAg in incident hemodialysis patients in suburban areas of Cairo, Egypt.
US-China Med Sci, 8 (2010), pp. 90-98
[14]
F. Kronenberg, M. Mündle, M. Längle, U. Neyer.
Prevalence and progression of peripheral arterialcal cifications in patients with ESRD.
Am J Kidney Dis, 41 (2003), pp. 140-148
[15]
A. Galassi, D.M. Spiegel, A. Bellasi, G.A. Block, P. Raggi.
Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders.
Nephrol Dial Transplant, 21 (2006), pp. 3215-3222
[16]
H. Rhee, S.H. Song, I.S. Kwak, S.B. Lee, D.W. Lee, E.Y. Seong, et al.
Persistently low intact parathyroid hormone levels predict a progression of aortic arch calcification in incident hemodialysis patients.
Clin Exp Nephrol, 16 (2012), pp. 433-441
[17]
K. AbouSeif, D. Sany, Y. Elshahawy, A. Seddik, K. Rahman, M. Gaber.
Association of conjunctival and corneal calcification with vascular calcification among hepatitis-C-seropositive hemodialysis patients.
Saudi J Kidney Dis Transpl, 27 (2016), pp. 1168-1181
Idiomas
Nefrología

Suscríbase a la newsletter

Opciones de artículo
Herramientas
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.