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Parvovirus B19 infection and IGF system components in relation to erythropoiesis in dialyzed patients and kidney transplant recipients
Parvovirus B19 Infection and IGF System Components in Relation to Erythropoiesis in Dialyzed Patients and Kidney Transplant Recipients J. Małyszko, T. Hryszko, J.S. Małyszko, S. Wołczyn´ski, and M. Mys´liwiec
A
NEMIA is a common feature among patients on maintenance dialysis. Although successful kidney transplantation often improves anemia, sometimes it persists, even in subjects with good and stable graft function. One parvovirus, designated B19, is known to be a human pathogen. The spectrum of manifestations of B19 infections in humans varies from the fifth disease (erythema infectiosum) agent, which presents as a benign disease in childhood1 to arthritis, fetal complications including fetal death, transient aplastic crisis, and various other conditions. Many of the severe manifestations of B19 viremia relate to the propensity of the virus to infect and lyse erythroid precursors cells in the bone marrow. Parvovirus B19 infection, particularly among patients on immunosuppression or subjects with impaired immunity, may become chronic, resulting in persistent severe anemia2 due to the failure of immunodeficient patients to clear B19 viremia. Guiserix et al3 in their study of 62 hemodialyzed patients suggested that B19 infections were not responsible for chronic anemia in these subjects. On the other hand, IGF-1 has been shown to be an important regulator of erythropoiesis both in vitro4 and in vivo.5 The synthesis of erythroid cells depends on the presence of cytokines, stem cell factor, erythropoietin, and (IGF)-1.6 In our previous study,7 we suggested a probable functional interrelationship between IGF system components, erythropoietin treatment in dialyzed patients, and bone metabolism in renal replacement therapy patients. Here we have assessed the prevalence of B19 infections among patients on renal replacement therapy in the form of dialysis or kidney transplantation and its relation to erythropoiesis and IGF system components. MATERIALS AND METHODS The two groups of clinically stable patients were group I: 47 kidney allograft recipients (age range 25 to 63 years, mean 47.0 ⫾ 12.5 years, mean body mass index (BMI) 24.7 ⫾ 3.7 kg/m2) and group II: 242 chronically dialyzed patients (223 on hemodialysis [HD] and 19 on chronic ambulatory peritoneal dialysis [CAPD], (age range 18 to 84 years, mean age 52.3 ⫾ 14.9 years, mean BMI 25.0 ⫾ 2.7 kg/m2, mean time on dialysis 34.4 ⫾ 30.0 months, median time 22 months, range 3 to 178 months). The immunosuppressive regimen of kidney transplant recipients consisted of cyclosporine CyA (3.2 ⫾ 1.05 mg/kg body weight, mean blood trough CyA levels: 142.2 ⫾ 63.0 ng/mL), prednisone (5 to 12.5 mg daily, mean dose 7.5 ⫾ 0.98 mg), and azathioprine (50 to 150 mg daily, mean dose 68.5 ⫾ 45.6 mg).
The recipients had been engrafted for a period of 8 months to 9 years (mean time 45.2 ⫾ 29.8 months, median time 37 months). All patients has received hemodialysis prior to transplantation for 37.2 ⫾ 21.1 months (median time 36 months). All kidney allograft recipients maintained stable graft function (mean serum creatinine ⫽ 1.85 ⫾ 0.7 mg/dL) with no clinical signs of rejection. The white blood cell and platelet counts remained within normal limits. They were nonsmokers and none displayed proteinuria. In HD patients blood was drawn from the arterial line of hemodialysis system in the morning between 8 and 9 a.m. before the beginning of the dialysis session and heparin administration. All patients required regular hemodialysis for 4 to 5 hours a day three times a week. Blood flow was usually 150 to 200 mL/min with a dialysate flow rate of 500 mL/min. The degree of ultrafiltration varied according to the patient’s actual weight. In CAPD subjects blood samples were drawn in the morning when subjects, receiving their normal diet, appeared for routine office assessment of dialysis therapy after an overnight fast. All CAPD patients were performing four 2-liter exchanges, using the Baxter Twin Bag system on the Fresenius Andy Plus system. Dwell times were generally 4 to 6 hours during the day and 8 hours overnight. The osmotic pressure of the CAPD fluid was adjusted in accordance with the extent of ultrafiltration in each patient. The patient’s height and weight were recorded. All patients were informed about the aim of the study and gave their consent. The study was approved by local ethical committee. The following parameters were assessed by means of standard laboratory methods: hemoglobin, red blood cell count, total protein, albumin, cholesterol, triglycerides, and serum creatinine. Human serum immunoglobin M (IgM) and IgG antibodies were detected using commercially available kits from Genzyme (Virotech, Germany). Endogeneous erythropoietin concentration was assayed using commercially available kits EPO EIA (Boehringer Mannheim, German). Serum erythropoietin and IGF system components were assessed in 115 dialyzed patients and all kidney transplant recipients. Concentrations of IGF-1 were measured by radioimmunoassay (RIA) using commercially available kits (Biosource, Europe S.A., Belgium); IGF-BP-1 and 3, by IRMA using commercially available kits (Diagnostic Systems Laboratories, USA). Data, expressed as mean values ⫾ SD, were analyzed using Statistica 5.1. computer software. ANOVA or Kruskal-Wallis From the Department of Nephology and Gynecological Endocrinology, Medical Academy of Białystok, Białystok, Poland. Address reprint requests to Jolanta Małyszko, Department of Nephrology and Internal Medicine, Medical Academy of Białystok, 15-540 Białystok, Zurawia 14, Poland. E-mail: jolmal@ poczta.onet.pl
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03653-9
Transplantation Proceedings, 34, 3211–3214 (2002)
3211
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MAŁYSZKO, HRYSZKO, MAŁYSZKO ET AL
Table 1. Hemoglobin, Erythrocyte Count; Serum Lipids; Serum Erythropoietin; Erythropoietin Requirements; and IGF-1, IFGBP-1, IGFBP-3 in the Dialyzed Patients
Hb (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) Erythropoietin dose (U/week) Serum erythropoietin (mIU/mL) IGF-1 (ng/mL) IGFBP-1 (ng/mL) IGFBP-3 (ng/mL)
IgM (⫹)
IgM (⫺)
10.2 ⫾ 1.56 3.33 ⫾ 0.49 175.8 ⫾ 58.6 147.8 ⫾ 68.0 2492 ⫾ 2292 14.1 ⫾ 11.4 198.3 ⫾ 79.4 117.2 ⫾ 54.1 4489 ⫾ 1532
9.93 ⫾ 1.59 3.26 ⫾ 0.57 179.0 ⫾ 45.8 135.8 ⫾ 78.9 2688 ⫾ 2836 12.2 ⫾ 10.6 246.9 ⫾ 105.9 114.9 ⫾ 51.9 4763 ⫾ 1651
IgG (⫹)
10.23 ⫾ 1.59 3.45 ⫾ 0.54 177.8 ⫾ 43.8 143.70 ⫾ 76.8 2828 ⫾ 2614 12.8 ⫾ 8.2 208.5 ⫾ 89.2 102.1 ⫾ 63.2 4469 ⫾ 1260
IgG (⫺)
9.73 ⫾ 1.52 3.19 ⫾ 0.57 179.6 ⫾ 45.3 134.7 ⫾ 45.3 2500 ⫾ 2913 13.1 ⫾ 12.4 222.7 ⫾ 99.4 115.7 ⫾ 52.4 4526 ⫾ 1334
P was not significant for all comparisons.
ANOVA, Pearson, or Spearman correlations were used in statistical analysis, when appropriate. P values less than .05 was considered to be statistically significant.
RESULTS
Dialyzed patients and kidney transplant recipients did not differ with respect to age, BMI, and duration of renal replacement therapy. IgM anti-B19 antibodies were detected in 16% of dialyzed patients and 23% of kidney transplant recipients. IgG anti-B19 antibodies were detected in 49% of dialyzed patients and 65% of kidney transplant recipients. Dialyzed patients with and without acute or chronic B19 infection did not differ according to their values of Hb; erythrocyte count, erythropoietin concentration and rHuEPO requirements (rHuEPO dose), or IGF-1, IGFBP-1, and IGFBP-3 concentrations (Table 1). Similarly, kidney transplant recipients with chronic B19 infection (IgG carriers) did not differ in regard to their values of Hb; erythrocyte count; erythropoietin concentration and rHuEPO requirements (rHuEPO dose); as well as IGF-1, IGFBP-1 and IGFBP-3 concentrations when compared to subjects without IgG antibodies (Table 2). However, among kidney transplant recipients displaying IgM (acute infection) antibodies, serum hemoglobin values, and erythrocyte counts were significantly higher than in patients without IgM antibodies (P ⫽ .048 for Hb and P ⫽ .03 for erythrocyte count. Renal transplant patients with IgM anti-B19 antibodies displayed higher concentrations of IG-
FBP-3 compared to patients without IgM antibodies (P ⫽ 0.01). The concentration of IGFBP-3 was significantly higher in kidney transplant recipients with IgM antibodies compared with patients with IgG antibodies (P ⫽ .03). The difference between IGF-1 concentrations in patients with IgG antibodies and with IgM antibodies was statistically significant (P ⫽ .048). There were no correlations between IgM or IgG antibody concentrations and hepatic viral infection (HBV, HCV), serum erythropoietin, rHuEPO requirements, time on renal replacement therapy (time on dialyses, time on dialyses prior to transplantation, time after transplantation), age, or components of IGF system. In dialyzed patients a positive correlation was found between Hb and IgG antibody concentrations (r ⫽ 0.43, P ⫽ .015), whereas kidney transplant recipients showed a negative correlation between Hb and IgG antibodies that almost reached statistical significance (r ⫽ 0.36, P ⫽ .05) (Fig 1). DISCUSSION
To the authors’ knowledge, this is the first report about the prevalence of B19 infections in patients on renal replacement therapy. Among kidney transplant recipients the seropositivity rate (IgG antibodies) was higher than that usually reported in adults (about 50%),8 whereas it was similar among dialysis patients (47%). The high prevalence kidney allograft recipients may be due to increased susceptibility to viral infections in this population, particularly during the first postoperative months. The virus may spread
Table 2. Hemoglobin; Erythrocyte Count; Serum Lipids; Serum Erythropoietin; and IGF-1, IFGBP-1, IGFBP-3 in Kidney Transplant Recipients
Hb (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) IGF-1 (ng/mL) IGFBP-1 (ng/mL) IGFBP-3 (ng/mL) Values given are means ⫾ SD. *P ⬍ .05 IgM (⫹) vs IgM (⫺). # P ⬍ .05 IgM (⫹) vs IgG (⫹).
IgM (⫹)
IgM (⫺)
IgG (⫹)
IgG (⫺)
13.43 ⫾ 2.64* 4.38 ⫾ 1.08* 206 ⫾ 39 130 ⫾ 51 10.1 ⫾ 7.0 291 ⫾ 82 96 ⫾ 49 4105 ⫾ 646*
11.27 ⫾ 3.16 3.75 ⫾ 1.01 217 ⫾ 42 160 ⫾ 51 19.1 ⫾ 14.0 250 ⫾ 105 110 ⫾ 42 3509 ⫾ 915
12.92 ⫾ 3.08 4.25 ⫾ 1.11 217 ⫾ 33 137 ⫾ 58 18.2 ⫾ 14.1 238 ⫾ 78# 106 ⫾ 42 3615 ⫾ 831#
12.87 ⫾ 2.69 4.18 ⫾ 1.06 207 ⫾ 51 136 ⫾ 47 10.8 ⫾ 9.7 286 ⫾ 123 109 ⫾ 47 3744 ⫾ 919
PARVOVIRUS B19 INFECTION
3213
Fig 1. Correlation between hemoglobin concentration and B19 IgG antibodies in kidney transplant recipients (r ⫽ .3617, P ⫽ .05).
nosocomially, through respiratory or direct contact, or through blood or blood products.9 However, in the present study we did not observe a correlation between the incidence and time on dialysis or time after transplantations or blood transfusions. In a previous study by Guiserix et al3 hemodialyzed patients who had a contact with B19 displayed higher Hb levels and had been treated longer on HD. In our study the population of dialyzed patients was much longer and we found that IgG anti-B19 virus positive patients had slightly higher Hb and erythrocyte counts than patients without IgG antibodies. However, these differences were not statistically significant; there were no correlations between time on dialysis and IgG antibodies. Therefore, our study did not confirm the data of Guiserix et al.3 Since IGF-1 has been shown to be an important regulator of erythropoiesis,4,5 and since anemia is a constant feature of renal failure which is reversed by successful kidney transplantation, we assessed IGF-1 concentrations in patients on various types of renal replacement therapy. Because IGF-1 levels are influenced by the presence of binding proteins, we also measured the levels of IGFBP-1 and IGFBP-3, two major regulators of IGF-1 function.10 After kidney transplantation, many forms of secondary erythrocytosis may occur. One varient—posttransplant erythrocytosis— has been reported to show an anomaly in IGF-1 and its binding proteins 1 and 3.11 To establish the possible association between IGF-1, IGFBPs, erythropoietin, and B19 infection in the present study of subjects with posttransplant erythrocytosis, we excluded all patients with liver dysfunction, receiving ACE inhibitors, or displaying erythropoietin resistance. We have previously reported8 that IGF system components were influenced by erythropoietin therapy, but were not related to serum erythropoietin levels or rHuEPO requirements. We observed that kidney transplant recipients with acute B19 infections
showed significantly higher concentrations of IGFBP-3 compared to patients without IgM antibodies. IGFBP-3, the quantitatively predominant IGFBP in circulation, is positively regulated by growth factor and modulates IGF action under most conditions.12 IGFBP-3 has the unique property of being able to associate with an acid-labile subunit after IGF binding, thus forming a 150kD complex. This large complex increases the plasma half-life of IGF from a few minutes to several hours. IGF is often coexpressed with IFGBPs in various tissues (ie, liver, kidney, bone). During acute viremia, the liver may produce many proteins (acute phase reactants) such as low molecular IGFBP-3 forms, which might be responsible for elevation in IGFBP-3 concentration.13 However, one should bear in mind that when proteolytic fragments are present (low molecular weight IGFBP-3 forms), the RIA method overestimates IGFBP-3 levels (intact IGFBP-3 levels are normal).14 Since nutrition is a major determinant of IGF and IGFBPs levels, we studied possible relationships between these parameters but found no correlations. In conclusion, it remains to be established why prevalence of B19 infection is higher among kidney allograft recipients than usually reported for the general population and whether the usual precautions are sufficient to prevent transmission of this infection. B19 infection should be considered in anemic patients, particularly among new onset or worsening of anemia. REFERENCES 1. Anderson LJ: J Infect Dis 161:603, 1990 2. Torok TJ: In Stollerman GH, Lamont JT, Leonard JJ, Siperstein M (eds): Advances in Internal Medicine. St. Louis, MO; Mosby-Year Book; 1992, p 421 3. Guiserix J, Ramdane M, Hoarau JM, et al: Nephron 72:719, 1996 4. Aron DC: Biofactors 3:211, 1992 5. Brox AG, Zhang F, Guyda H, et al: Kidney Int 50:937, 1996
3214 6. Boyer SH, Bishop TR, Rogers OC, et al: Blood 80:2503, 1992 7. Malyszko J, Wolczyn ´ski S, Zbroch E, et al: Nephron 90:282, 2002 8. Blacklow NR: Harrison’s Principles of Internal Medicine, 14th ed. New York: McGraw-Hill; 1998 9. Anderson LJ: Pediatr Infect Dis 6:711, 1987 10. Jones JI, Clemmons DR: Endocr Rev 16:3, 1995
MAŁYSZKO, HRYSZKO, MAŁYSZKO ET AL 11. Brox AG, Mangel J, Hanley JA, et al: Transplantation 66:1053, 1998 12. Jehle PM, Ostertag A, Schulten K, et al: Kidney Int. 57:423, 2000 13. Hussenet F, Dousset B, Gervais P, et al: Transplant Proc 28:3615, 1996 14. Blum WF, Breier BH: Growth Reg 4(suppl 1):11, 1994
A
NEMIA is a common feature among patients on maintenance dialysis. Although successful kidney transplantation often improves anemia, sometimes it persists, even in subjects with good and stable graft function. One parvovirus, designated B19, is known to be a human pathogen. The spectrum of manifestations of B19 infections in humans varies from the fifth disease (erythema infectiosum) agent, which presents as a benign disease in childhood1 to arthritis, fetal complications including fetal death, transient aplastic crisis, and various other conditions. Many of the severe manifestations of B19 viremia relate to the propensity of the virus to infect and lyse erythroid precursors cells in the bone marrow. Parvovirus B19 infection, particularly among patients on immunosuppression or subjects with impaired immunity, may become chronic, resulting in persistent severe anemia2 due to the failure of immunodeficient patients to clear B19 viremia. Guiserix et al3 in their study of 62 hemodialyzed patients suggested that B19 infections were not responsible for chronic anemia in these subjects. On the other hand, IGF-1 has been shown to be an important regulator of erythropoiesis both in vitro4 and in vivo.5 The synthesis of erythroid cells depends on the presence of cytokines, stem cell factor, erythropoietin, and (IGF)-1.6 In our previous study,7 we suggested a probable functional interrelationship between IGF system components, erythropoietin treatment in dialyzed patients, and bone metabolism in renal replacement therapy patients. Here we have assessed the prevalence of B19 infections among patients on renal replacement therapy in the form of dialysis or kidney transplantation and its relation to erythropoiesis and IGF system components. MATERIALS AND METHODS The two groups of clinically stable patients were group I: 47 kidney allograft recipients (age range 25 to 63 years, mean 47.0 ⫾ 12.5 years, mean body mass index (BMI) 24.7 ⫾ 3.7 kg/m2) and group II: 242 chronically dialyzed patients (223 on hemodialysis [HD] and 19 on chronic ambulatory peritoneal dialysis [CAPD], (age range 18 to 84 years, mean age 52.3 ⫾ 14.9 years, mean BMI 25.0 ⫾ 2.7 kg/m2, mean time on dialysis 34.4 ⫾ 30.0 months, median time 22 months, range 3 to 178 months). The immunosuppressive regimen of kidney transplant recipients consisted of cyclosporine CyA (3.2 ⫾ 1.05 mg/kg body weight, mean blood trough CyA levels: 142.2 ⫾ 63.0 ng/mL), prednisone (5 to 12.5 mg daily, mean dose 7.5 ⫾ 0.98 mg), and azathioprine (50 to 150 mg daily, mean dose 68.5 ⫾ 45.6 mg).
The recipients had been engrafted for a period of 8 months to 9 years (mean time 45.2 ⫾ 29.8 months, median time 37 months). All patients has received hemodialysis prior to transplantation for 37.2 ⫾ 21.1 months (median time 36 months). All kidney allograft recipients maintained stable graft function (mean serum creatinine ⫽ 1.85 ⫾ 0.7 mg/dL) with no clinical signs of rejection. The white blood cell and platelet counts remained within normal limits. They were nonsmokers and none displayed proteinuria. In HD patients blood was drawn from the arterial line of hemodialysis system in the morning between 8 and 9 a.m. before the beginning of the dialysis session and heparin administration. All patients required regular hemodialysis for 4 to 5 hours a day three times a week. Blood flow was usually 150 to 200 mL/min with a dialysate flow rate of 500 mL/min. The degree of ultrafiltration varied according to the patient’s actual weight. In CAPD subjects blood samples were drawn in the morning when subjects, receiving their normal diet, appeared for routine office assessment of dialysis therapy after an overnight fast. All CAPD patients were performing four 2-liter exchanges, using the Baxter Twin Bag system on the Fresenius Andy Plus system. Dwell times were generally 4 to 6 hours during the day and 8 hours overnight. The osmotic pressure of the CAPD fluid was adjusted in accordance with the extent of ultrafiltration in each patient. The patient’s height and weight were recorded. All patients were informed about the aim of the study and gave their consent. The study was approved by local ethical committee. The following parameters were assessed by means of standard laboratory methods: hemoglobin, red blood cell count, total protein, albumin, cholesterol, triglycerides, and serum creatinine. Human serum immunoglobin M (IgM) and IgG antibodies were detected using commercially available kits from Genzyme (Virotech, Germany). Endogeneous erythropoietin concentration was assayed using commercially available kits EPO EIA (Boehringer Mannheim, German). Serum erythropoietin and IGF system components were assessed in 115 dialyzed patients and all kidney transplant recipients. Concentrations of IGF-1 were measured by radioimmunoassay (RIA) using commercially available kits (Biosource, Europe S.A., Belgium); IGF-BP-1 and 3, by IRMA using commercially available kits (Diagnostic Systems Laboratories, USA). Data, expressed as mean values ⫾ SD, were analyzed using Statistica 5.1. computer software. ANOVA or Kruskal-Wallis From the Department of Nephology and Gynecological Endocrinology, Medical Academy of Białystok, Białystok, Poland. Address reprint requests to Jolanta Małyszko, Department of Nephrology and Internal Medicine, Medical Academy of Białystok, 15-540 Białystok, Zurawia 14, Poland. E-mail: jolmal@ poczta.onet.pl
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03653-9
Transplantation Proceedings, 34, 3211–3214 (2002)
3211
3212
MAŁYSZKO, HRYSZKO, MAŁYSZKO ET AL
Table 1. Hemoglobin, Erythrocyte Count; Serum Lipids; Serum Erythropoietin; Erythropoietin Requirements; and IGF-1, IFGBP-1, IGFBP-3 in the Dialyzed Patients
Hb (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) Erythropoietin dose (U/week) Serum erythropoietin (mIU/mL) IGF-1 (ng/mL) IGFBP-1 (ng/mL) IGFBP-3 (ng/mL)
IgM (⫹)
IgM (⫺)
10.2 ⫾ 1.56 3.33 ⫾ 0.49 175.8 ⫾ 58.6 147.8 ⫾ 68.0 2492 ⫾ 2292 14.1 ⫾ 11.4 198.3 ⫾ 79.4 117.2 ⫾ 54.1 4489 ⫾ 1532
9.93 ⫾ 1.59 3.26 ⫾ 0.57 179.0 ⫾ 45.8 135.8 ⫾ 78.9 2688 ⫾ 2836 12.2 ⫾ 10.6 246.9 ⫾ 105.9 114.9 ⫾ 51.9 4763 ⫾ 1651
IgG (⫹)
10.23 ⫾ 1.59 3.45 ⫾ 0.54 177.8 ⫾ 43.8 143.70 ⫾ 76.8 2828 ⫾ 2614 12.8 ⫾ 8.2 208.5 ⫾ 89.2 102.1 ⫾ 63.2 4469 ⫾ 1260
IgG (⫺)
9.73 ⫾ 1.52 3.19 ⫾ 0.57 179.6 ⫾ 45.3 134.7 ⫾ 45.3 2500 ⫾ 2913 13.1 ⫾ 12.4 222.7 ⫾ 99.4 115.7 ⫾ 52.4 4526 ⫾ 1334
P was not significant for all comparisons.
ANOVA, Pearson, or Spearman correlations were used in statistical analysis, when appropriate. P values less than .05 was considered to be statistically significant.
RESULTS
Dialyzed patients and kidney transplant recipients did not differ with respect to age, BMI, and duration of renal replacement therapy. IgM anti-B19 antibodies were detected in 16% of dialyzed patients and 23% of kidney transplant recipients. IgG anti-B19 antibodies were detected in 49% of dialyzed patients and 65% of kidney transplant recipients. Dialyzed patients with and without acute or chronic B19 infection did not differ according to their values of Hb; erythrocyte count, erythropoietin concentration and rHuEPO requirements (rHuEPO dose), or IGF-1, IGFBP-1, and IGFBP-3 concentrations (Table 1). Similarly, kidney transplant recipients with chronic B19 infection (IgG carriers) did not differ in regard to their values of Hb; erythrocyte count; erythropoietin concentration and rHuEPO requirements (rHuEPO dose); as well as IGF-1, IGFBP-1 and IGFBP-3 concentrations when compared to subjects without IgG antibodies (Table 2). However, among kidney transplant recipients displaying IgM (acute infection) antibodies, serum hemoglobin values, and erythrocyte counts were significantly higher than in patients without IgM antibodies (P ⫽ .048 for Hb and P ⫽ .03 for erythrocyte count. Renal transplant patients with IgM anti-B19 antibodies displayed higher concentrations of IG-
FBP-3 compared to patients without IgM antibodies (P ⫽ 0.01). The concentration of IGFBP-3 was significantly higher in kidney transplant recipients with IgM antibodies compared with patients with IgG antibodies (P ⫽ .03). The difference between IGF-1 concentrations in patients with IgG antibodies and with IgM antibodies was statistically significant (P ⫽ .048). There were no correlations between IgM or IgG antibody concentrations and hepatic viral infection (HBV, HCV), serum erythropoietin, rHuEPO requirements, time on renal replacement therapy (time on dialyses, time on dialyses prior to transplantation, time after transplantation), age, or components of IGF system. In dialyzed patients a positive correlation was found between Hb and IgG antibody concentrations (r ⫽ 0.43, P ⫽ .015), whereas kidney transplant recipients showed a negative correlation between Hb and IgG antibodies that almost reached statistical significance (r ⫽ 0.36, P ⫽ .05) (Fig 1). DISCUSSION
To the authors’ knowledge, this is the first report about the prevalence of B19 infections in patients on renal replacement therapy. Among kidney transplant recipients the seropositivity rate (IgG antibodies) was higher than that usually reported in adults (about 50%),8 whereas it was similar among dialysis patients (47%). The high prevalence kidney allograft recipients may be due to increased susceptibility to viral infections in this population, particularly during the first postoperative months. The virus may spread
Table 2. Hemoglobin; Erythrocyte Count; Serum Lipids; Serum Erythropoietin; and IGF-1, IFGBP-1, IGFBP-3 in Kidney Transplant Recipients
Hb (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) IGF-1 (ng/mL) IGFBP-1 (ng/mL) IGFBP-3 (ng/mL) Values given are means ⫾ SD. *P ⬍ .05 IgM (⫹) vs IgM (⫺). # P ⬍ .05 IgM (⫹) vs IgG (⫹).
IgM (⫹)
IgM (⫺)
IgG (⫹)
IgG (⫺)
13.43 ⫾ 2.64* 4.38 ⫾ 1.08* 206 ⫾ 39 130 ⫾ 51 10.1 ⫾ 7.0 291 ⫾ 82 96 ⫾ 49 4105 ⫾ 646*
11.27 ⫾ 3.16 3.75 ⫾ 1.01 217 ⫾ 42 160 ⫾ 51 19.1 ⫾ 14.0 250 ⫾ 105 110 ⫾ 42 3509 ⫾ 915
12.92 ⫾ 3.08 4.25 ⫾ 1.11 217 ⫾ 33 137 ⫾ 58 18.2 ⫾ 14.1 238 ⫾ 78# 106 ⫾ 42 3615 ⫾ 831#
12.87 ⫾ 2.69 4.18 ⫾ 1.06 207 ⫾ 51 136 ⫾ 47 10.8 ⫾ 9.7 286 ⫾ 123 109 ⫾ 47 3744 ⫾ 919
PARVOVIRUS B19 INFECTION
3213
Fig 1. Correlation between hemoglobin concentration and B19 IgG antibodies in kidney transplant recipients (r ⫽ .3617, P ⫽ .05).
nosocomially, through respiratory or direct contact, or through blood or blood products.9 However, in the present study we did not observe a correlation between the incidence and time on dialysis or time after transplantations or blood transfusions. In a previous study by Guiserix et al3 hemodialyzed patients who had a contact with B19 displayed higher Hb levels and had been treated longer on HD. In our study the population of dialyzed patients was much longer and we found that IgG anti-B19 virus positive patients had slightly higher Hb and erythrocyte counts than patients without IgG antibodies. However, these differences were not statistically significant; there were no correlations between time on dialysis and IgG antibodies. Therefore, our study did not confirm the data of Guiserix et al.3 Since IGF-1 has been shown to be an important regulator of erythropoiesis,4,5 and since anemia is a constant feature of renal failure which is reversed by successful kidney transplantation, we assessed IGF-1 concentrations in patients on various types of renal replacement therapy. Because IGF-1 levels are influenced by the presence of binding proteins, we also measured the levels of IGFBP-1 and IGFBP-3, two major regulators of IGF-1 function.10 After kidney transplantation, many forms of secondary erythrocytosis may occur. One varient—posttransplant erythrocytosis— has been reported to show an anomaly in IGF-1 and its binding proteins 1 and 3.11 To establish the possible association between IGF-1, IGFBPs, erythropoietin, and B19 infection in the present study of subjects with posttransplant erythrocytosis, we excluded all patients with liver dysfunction, receiving ACE inhibitors, or displaying erythropoietin resistance. We have previously reported8 that IGF system components were influenced by erythropoietin therapy, but were not related to serum erythropoietin levels or rHuEPO requirements. We observed that kidney transplant recipients with acute B19 infections
showed significantly higher concentrations of IGFBP-3 compared to patients without IgM antibodies. IGFBP-3, the quantitatively predominant IGFBP in circulation, is positively regulated by growth factor and modulates IGF action under most conditions.12 IGFBP-3 has the unique property of being able to associate with an acid-labile subunit after IGF binding, thus forming a 150kD complex. This large complex increases the plasma half-life of IGF from a few minutes to several hours. IGF is often coexpressed with IFGBPs in various tissues (ie, liver, kidney, bone). During acute viremia, the liver may produce many proteins (acute phase reactants) such as low molecular IGFBP-3 forms, which might be responsible for elevation in IGFBP-3 concentration.13 However, one should bear in mind that when proteolytic fragments are present (low molecular weight IGFBP-3 forms), the RIA method overestimates IGFBP-3 levels (intact IGFBP-3 levels are normal).14 Since nutrition is a major determinant of IGF and IGFBPs levels, we studied possible relationships between these parameters but found no correlations. In conclusion, it remains to be established why prevalence of B19 infection is higher among kidney allograft recipients than usually reported for the general population and whether the usual precautions are sufficient to prevent transmission of this infection. B19 infection should be considered in anemic patients, particularly among new onset or worsening of anemia. REFERENCES 1. Anderson LJ: J Infect Dis 161:603, 1990 2. Torok TJ: In Stollerman GH, Lamont JT, Leonard JJ, Siperstein M (eds): Advances in Internal Medicine. St. Louis, MO; Mosby-Year Book; 1992, p 421 3. Guiserix J, Ramdane M, Hoarau JM, et al: Nephron 72:719, 1996 4. Aron DC: Biofactors 3:211, 1992 5. Brox AG, Zhang F, Guyda H, et al: Kidney Int 50:937, 1996
3214 6. Boyer SH, Bishop TR, Rogers OC, et al: Blood 80:2503, 1992 7. Malyszko J, Wolczyn ´ski S, Zbroch E, et al: Nephron 90:282, 2002 8. Blacklow NR: Harrison’s Principles of Internal Medicine, 14th ed. New York: McGraw-Hill; 1998 9. Anderson LJ: Pediatr Infect Dis 6:711, 1987 10. Jones JI, Clemmons DR: Endocr Rev 16:3, 1995
MAŁYSZKO, HRYSZKO, MAŁYSZKO ET AL 11. Brox AG, Mangel J, Hanley JA, et al: Transplantation 66:1053, 1998 12. Jehle PM, Ostertag A, Schulten K, et al: Kidney Int. 57:423, 2000 13. Hussenet F, Dousset B, Gervais P, et al: Transplant Proc 28:3615, 1996 14. Blum WF, Breier BH: Growth Reg 4(suppl 1):11, 1994