Avascular Osteonecrosis and Accompanying Anemia, Leucocytosis, and Decreased Bone Mineral Density in Renal Transplant Recipients S. Paydas, M. Balal, E. Demir, Y. Sertdemir, and U. Erken ABSTRACT Background. Avascular osteonecrosis (AVN) is a complication of renal transplantation. In this study, we present 12 cases of AVN associated with renal transplantation. Methods. Renal transplant recipients (RTRs) with AVN (group I [GI]) were evaluated by using magnetic resonance imaging and blood urea nitrogen, creatinine, glucose, calcium, phosphorus, magnesium, alkaline phosphatase, parathyroid hormone, and urine analysis. We evaluated bone mineral density (BMD) of the femoral neck and lumbar vertebrae. All patients were treated with steroids, cyclosporine, or tacrolimus plus mycophenolate mofetil. Twenty-six RTRs (GII) without AVN were randomly selected as control subjects. Results. The mean ages of GI and GII, were 33.81 ⫾ 6.72 and 34.00 ⫾ 7.65 years respectively (P ⬎ .05). The mean interval between transplantation and development of AVN was 12.08 ⫾ 6.48 months. Although levels of blood urea nitrogen, creatinine, calcium, magnesium, and parathyroidhormone, as well as glucocorticoid doses in the first 12 months were similar in GI and GII, there were significant differences in serum alkaline phosphatase, hemoglobin levels, and white blood cell count between GI and GII (P ⬍ .05 for each). BMD T score ⬍⫺1.5 was observed in 8/9 GI and 15/26 patients in GII. All of the patients with AVN except 1, were followed with conservative measures including calcium, magnesium, and vitamin D replacement therapies, bisphosphonate, and reduced or ceased glucocorticoid treatment. Although T scores of the femoral head were similar in GI and GII, the lumbar vertebral T score was significantly lower in GI than in GII (P ⬍ .052). Conclusion. AVN developed within the first year after transplantation. Decreased lumbar vertebral BMD, which can be an indicator of glucocorticoid effect, accompanied AVN in nearly all patients. Despite the absence of renal dysfunction, increased bone destruction, anemia, and leucocytosis were coincidental or accompanying findings in our patients with AVN. steonecrosis of the femoral head and other articulating bones have been described after kidney transplantation in adults.1– 4 The occurrence of osteonecrosis in this setting varies between 4% and 24%.1,4 The known risk factors for avascular osteonecrosis (AVN) after solid organ transplantation include higher cumulative doses of steroids,1,2 greater blood urea nitrogen levels,1 hypofibrinolysis due to variant plasminogen activator inhibitor 1 genotype,5 and allograft rejection.6 Impaired blood flow caused by arterial ischemia and/or venous thrombosis, leading to ischemic necrosis in some parts of the femoral head con-
O
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 43, 863– 866 (2011)
tributes to the pathogenesis of AVN. In the present study we evaluated 12 symptomatic renal transplant recipients with AVN in the femoral neck and knee for biochemical
From the Department of Nephrology (S.P., M.B.), Department of Urology (E.D., U.E.), and Department of Biostatistics (Y.S.), Cukurova University Faculty of Medicine, Adana, Turkey. Address reprint requests to Saime Paydas, Department of Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey 01330. E-mail:
[email protected] 0041-1345/–see front matter doi:10.1016/j.transproceed.2011.02.072 863
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PAYDAS, BALAL, DEMIR ET AL
indices and bone mineral density (BMD) T scores compared with patients withour AVN.
PATIENTS AND METHODS Patients We evaluated retrospectively 12 subjects with AVN (GI) diagnosed between January 2000 and January 2010. All patients were first transplantations. AVN was evaluated in patients who had symptoms suggesting AVN, such as walking disability, pain, weakness, or restriction of movement. Magnetic resonance imaging (MRI) was used for the diagnosis of AVN. All patients had been treated with a combination of steroid plus cyclosporine or tacrolimus plus mycophenolate mofetil. Azathiopurine and mammalian target of rapamycin were prescribed for some patients owing to drug-related side effects. We randomly selected 26 subjects without AVN as a control group (GII). Acute rejection episodes were treated with glucocorticoid (250 mg daily for 5 days) Antithymocyte globulin was used for steroidresistant patients. We recorded serial biochemical parameters, including complete blood count (Beckman-Coulter), blood urea nitrogen, Creatinine, glucose, Ca, P, Mg, alkaline phospatase (ALP) (Roche Moduler DPP instruments), parathyroid hormone (PTH) (Roche Elecys-170), urine analysis. tacrolimus (ArchitectAbbott), and cyclosporine C2 level (Cobas-Integra-800). Standard levels were targeted for tacrolimus and cyclosporine. The mean cumulative steroid dose was calculated for the 12 posttransplant months. Femoral neck and lumbar vertebral dual-energy x-ray absorptiometly (DEXA) were evaluated with DEXA ODR series x-ray bone densitometers. BMD T score ⬍⫺1.5 was accepted as osteopenia and ⬍⫺2.5 as osteoporosis.
Statistical Analysis The statistical analysis was performed using SPSS 18.0. All continuous variables were summarized using their mean values ⫾ standard deviations as well as (min, max). Group comparisons of continuous variables used Mann-Whitney tests. Group comparisons of categoric variables used the chi-square test. We considered P values of ⱕ.05 to be statistically significant.
RESULTS
Patient characteristics, including biochemical parameters and BMD T scores are presented in Tables 1 and 2. AVN developed in the first year. Steroids had been used for primary renal disease in the pretransplantation period of 1 patient with AVN and 1 without AVN. No patient had a history of systemic lupus erythematosus, sickle cell disease, previous history of bone fracture, venous thromboembolism, or alcohol abuse in either group. Interestingly, symptomatic cases with AVN showed significantly different levels of hemoglobin, ALP and white blood cell count from control subjects (P ⬍ .05 for all). Hypomagnesemia was observed among 5/12 and 8/26 of GI and GII, respectively. Serum Mg levels, which were lower in GI, were not different from GII. Lumbar vertebra BMD T score was significantly lower in GI than in GII. BMD T score ⬍⫺1.5 was found in 8/9 cases with AVN, and 15/26 cases without AVN. There was no correlation between serum Mg levels and BMD. PTH, Ca, and P levels were similar in GI and GII, and as expected, ALP was higher in GI than that of GII. Patients with AVN, except 1, were followed with conservative measures, including Ca, Ma, and vitamin D replacement therapy, bisphosphonate treatment, and reduced doses or cessation of glucocorticoid. DISCUSSION
AVN is a musculoskeletal complication in kidney allograft recipients. The reported incidence in recent series ranges from 3% to 16%.7,8 The most common sites of AVN involvement are the femoral heads, followed by the knees, humeral heads, and elbows.9 Among our patients, AVN was observed in the femoral head of 7 patients and the knee of 5 patients. We diagnosed AVN with MRI in symptomatic patients at 12.08 ⫾ 6.48 months after transplantation (range, 5–24 months) MRI is sensitive and specific for detection of AVN.10 In several earlier prospective studies with longer follow-up periods, nearly all occurrences of
Table 1. The Characteristics and Biochemical Parameters of the Patients
Age, y Duration of RT, mo Hemoglobin, g/dL White blood cell count Platelet Glucocorticoid dose, mg/12 mo Magnesium, mg/dL Alkaline phosphatase, IU/L Parathyroid hormone, pg/mL Creatinine, mg/dL Calcium, mg/dL Phosphorus, mg/dL Femur neck T score Lumbar vertebra T score
Control Patients
Patients with AVN
P Value
33.81 ⫾ 6.72 (23–49) 58.50 ⫾ 35.24 (12–156) 13.73 ⫾ 2.04 (10.4–17.0) 8961.54 ⫾ 3117.44 (5000–20000) 270230.77 ⫾ 93796.50 (134000–558000) 3071.07 ⫾ 349.06 (2148–4548) 1.72 ⫾ 0.15 (1.4–2.2) 181.31 ⫾ 73.57 (96–411) 107.81 ⫾ 99.29 (31.5–481.9) 1.21 ⫾ 0.28 (0.6–1.9) 9.81 ⫾ 0.43 (8.7–10.5) 3.35 ⫾ 0.53 (2.3–4.3) ⫺1.72 ⫾ 0.84 (⫺3.5–⫺0.4) ⫺1.75 ⫾ 1.20 (⫺3.4–2.1)
34.00 ⫾ 7.65 (20–48) 12.08 ⫾ 6.48 (5–24) 12.14 ⫾ 1.96 (8–14.2) 12776.96 ⫾ 5839.82 (6600–25900) 214615.38 ⫾ 79779.42 (102000–383000) 3057.23 ⫾ 778.4 (2208–4488) 1.68 ⫾ 0.27 (1.3–2.2) 260.13 ⫾ 87.19 (138–370) 146.80 ⫾ 25.73 (128.6–165.0) 1.26 ⫾ 0.50 (0.6–2.5) 9.43 ⫾ 0.67 (8.3–10.4) 2.69 ⫾ 0.75 (1.9–4.2) ⫺2.08 ⫾ 0.66 (⫺3.4–⫺1.0) ⫺2.69 ⫾ 1.06 (⫺4.2–⫺0.9)
.59 .001 .04 .019 .066 .670 .48 .022 .129 .904 .1 .126 .173 .052
Values are presented as mean ⫾ SD (min–max).
AVASCULAR OSTEONECROSIS AFTER KIDNEY TRANSPLANTATION
865
Table 2. The Characteristics and Biochemical Parameters in Each Patient with Avascular Necrosis Patient
1
2
3
4
5
Age/gender 41/M 26/M 32/M 32/F 43/M Dialysis duration, mo H/3 H/11 H/42 PD/18 PD/3 *Creatinine, mg/dL 1/1.3 1.1/1.3 0.7/1.2 2.5/1 1.1/1.1 *Calcium, mg/dL 9.1/10.7 10.2/10 10/9.8 9.9/9.5 9.6/9.7 *Phosphorus, mg/dL 2.9/4.1 2.8/4 1.9/3.1 4.2/3.8 2.2/2.6 *Magnesium, mg/dL 1.9/1.9 1.5/1.8 ⫺/1.5 2.2/2.1 1.7/1.5 *ALP, IU/L 161/224 357/320 317/218 292/250 138/147 *PTH, pg/mL 218/98 128/82 —/69 55/165 165/— Tacro/cyclo ⫹/⫺ ⫹/⫺ ⫺/⫹ ⫺/⫹ ⫹/⫺ Steroid ⫹ ⫹ ⫹ ⫹ ⫹ Vitamin D3 ⫹ ⫹ ⫹ ⫹ ⫺ Bisphoshanate ⫺ ⫺ ⫺ ⫺ ⫺ Mg treatment ⫹ ⫺ ⫺ ⫺ ⫹ Vertebra T score ⫺4.1 ⫺2.1 ⫺2.6 ⫺ ⫺0.9 Femur T score ⫺2.7 ⫺1.5 ⫺1.6 ⫺ ⫺1 AVN time (mo) 6 24 14 5 24 AVN femur/knee ⫹/⫺ ⫺/⫹ ⫹/⫺ ⫺/⫹ ⫹/⫺ Bilateral/Unilateral ⫺/⫹ ⫺/⫹ ⫺/⫹ ⫹/⫺ ⫺/⫹ Cessation/reduced ⫹/⫺ ⫺/⫹ ⫹/⫺ ⫺/⫹ ⫹/⫺ steroid Surgery ⫹ ⫺ ⫺ ⫺ ⫺
6
26/F HD/12 0.6/1.2 9.7/9.4 3.8/2.9 — —/123 — ⫺/⫹ ⫹ ⫹ ⫺ ⫺ ⫺1.7 ⫺2.8 5 ⫹/⫺ ⫺/⫹ ⫹/⫺ ⫺
7
8
9
34/F 30/M 48/M PD/132 PD/18 HD/84 0.9/0.9 1.4/1.4 1.6/1.4 10.4/10.2 10.1/8.7 8.9/9 2/3.6 2/3 3.7/3 1.5/2.4 1.3/1.8 1.7/2 220/303 — 226/— —/189 — ⫹/⫺ ⫹/⫺ ⫺/⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺4.2 ⫺2.5 ⫺3.6 ⫺2.1 ⫺2.1 ⫺2.1 17 12 9 ⫹/⫺ ⫹/⫺ ⫺/⫹ ⫺/⫹ ⫹/⫺ ⫺/⫹ ⫺/⫹ ⫹/⫺ ⫺/⫹ ⫺
⫺
⫺
10
11
12
39/F HD/30 0.9/1.6 8.9/8.5 3.1/4.7 —/1.8 —/307 — ⫺/⫹ ⫹ ⫹ ⫺ ⫹ ⫺ ⫺ 12 ⫺/⫹ ⫺/⫹ ⫹/⫺
36/M PD/2 1.4/1.9 8.9/10.1 8.9/10.1 — 370/681 —/126 ⫹/⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ 7 ⫺/⫹ ⫺/⫹ ⫹/⫺
35/F HD/96 1.6/1 8.3/8.4 3.2/2.7 2.2/2.8 196/— — ⫹/⫺ ⫹ ⫹ ⫺ ⫺ ⫺2.1 ⫺2.1 14 ⫹/⫺ ⫹/⫺ ⫺/⫹
⫺
⫺
⫺
*First year/second year.
AVN were identified by MRI in the first 3 months after transplantation.11–13 However, a more recent report suggested that delayed presentation of AVN is possible. In 2/7 patients it occurred at 8 and 10 months after transplantation.14 In our symptomatic patients AVN was diagnosed between 5 and 24 months (mean, 12.08 ⫾ 6.48 months). This seems to be late, but we must not forget that we did not have serial MRIs after transplantation. Another study, with results, similar to ours, showed 12.3 ⫾ 1.8 months to be the mean interval between renal transplantation and AVN.15 Although the exact mechanism remains controversial, cortcosteroid therapy appears to play a central role in the pathogenesis of AVN. Lousten et al.16 reported that the cumulative steroid dose was higher among cases with AVN compared with those without AVN. However, we did observe a difference in corticosteroid dosage between patients with versus without AVN, as reported by Lee et al.15 Hypomagnesemia was found in 5/12 and 8/26 patients with versus without AVN, respectively. We did not note a correlation between serum Mg levels and BMD. However, there was a significant difference for levels of ALP, hemoglobin and white blood cell count among patients with versus without AVN. Although renal functions were similar, anemia and increased WBC were noted in AVN patients. These findings may be related to inflammation accompaning AVN or may be a coincidental finding. As expected the BMD T score of the lumbar vertabrae was significantly lower in AVN patients. Femoral head BMD T scores were similar in the 2 groups. The BMD T score was abnormal in 8/9 and 15/26 patients with versus without AVN, respectively. PTH, Ca, and P levels were similar in GI and GII, but ALP was higher in GI than in GII. We
speculated that despite high ALP levels, bone loss was more severe in AVN patients. This may be secondary to steroid effects or continued hyperparathyroidism. But steroid dose, PTH levels, and femoral head BMD T score were similar in the 2 groups. AVN was treated with surgery or replacement therapies according to its severity. We followed our AVN cases, except 1, with conservative measures, including Ca, Mg, and vitamin D replacement therapy, bisphosphonate, and reduced doses of glucocorticoids or cessation of steroids. In conclusion, AVN as diagnosed by MRI developed in the first year, without accompanying renal dysfunction. Although the steroid doses were similar in the 2 groups, there was a more severe loss of lumbar vertebral BMD among AVN patients which may be indicator of glucocorticoid effect. Interestingly the observations of anemia and leucocytosis among AVN patients may be coincidental or companion findings.
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866 5. Ferrari P, Schroeder V, Anderson S, et al: Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroidtreated renal allograft recipients. Transplantation 27:1147, 2002 6. Abbott KC, Oglesby RJ, Agodoa LY: Hospitalized avascular necrosis after renal transplantation in the United States. Kidney Int 62:2250, 2002 7. Elmstedt E, Svahn T: Skeletal complications following renal transplantation. Acta Orthop Scand 52:279, 1981 8. Nielson HE, Melson F, Christensen MS: Aseptic necrosis of bone following renal transplantation. Acta Med Scand 202:27, 1977 9. Spencer JD, Maisey M: A prospective scintigraphic study of avascular necrosis of bone in renal transplant patients. Clin Orthop 201:125, 1985 10. Lavernia CJ, Sierra RJ, Grieco FR: Osteonecrosis of the femoral head. J Am Acad Orthop Surg 7:250, 1999 11. Fink B, Degenhardt S, Paselk C, et al: Early detection of avascular necrosis of the femoral head following renal transplantation. Arch Orthop Trauma Surg 16:151, 1997
PAYDAS, BALAL, DEMIR ET AL 12. Kubo T, Yamazoe S, Sugano N, et al: Initial MRI findings of non-traumatic osteonecrosis of the femoral head in renal allograft recipients. Magn Reson Imaging 15:1017, 1997 13. Kopecky KK, Braunstein EM, Brandt KD, et al: Apparent vascular necrosis of the hip: appearance and spontaneous resolution of MR findings in renal allograft recipients. Radiology 179: 523, 1991 14. Marston SB, Gillingham K, Bailey RF, Cheng EY: Osteonecrosis of the femoral head after solid organ transplantation: a prospective study. J Bone Joint Surg Am 84A:2145, 2002 15. Lee EJ, Lee KH, Huh WS, et al: Incidence and radio-uptake patterns of femoral head avascular osteonecrosis at 1 year after renal transplantation: a prospective study with planar bone scintigraphy Nucl Med 27:919, 2006 16. Lausten GS, Lemser T, Jensen PK, Egfjord M: Necrosis of the femoral head after kidney transplantation. Clin Transplant 12:572, 1998
