Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney... Abstract Background Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. Methods We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. Results KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P < 0.01). In addition, male gender was independently associated with AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. Conclusions The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side. avascular osteonecrosis, calcineurin inhibitors, kidney transplantation, steroids INTRODUCTION Kidney transplant recipients (KTRs) have been suggested to be at increased risk of avascular necrosis (AVN) due to chronic kidney disease–mineral and bone disorder, steroid use and predisposing comorbidities such as diabetes, hypertension and autoimmune disease [1]. Despite the advances in the field of transplantation over the past decades, AVN represents a devastating complication after kidney transplantation, severely impacting quality of life. AVN results from bone cell necrosis unrelated to bacterial infection but rather related to a matter of perfusion. The incidence of AVN varies, with reports up to 40% in KTRs in the pre-calcineurin inhibitor (CNI) era [2]. Among KTRs, steroid-induced suppression of bone formation is the most important risk factor for bone loss [3–5]. Glucocorticoids are toxic to osteoblasts and induce osteoclast activity [6]. CNIs are also linked to osteoporosis and varying degrees of osteonecrosis. Cyclosporine A (CSA) is known to lead to high bone turnover and thus contributes to bone loss [7–9]. Reports suggest that there is a higher risk of AVN development under CSA-treated KTRs than when treated with tacrolimus [10–12]. However, the prevalence of AVN clearly decreased after CNI implementation [13]. A further reduction in bone loss could be attributed in part to the additional lower doses of glucocorticoids used in KTRs today [1, 14–16]. Bone mineral density (BMD) declines by 4–10% in the first 6 months after transplantation [8]. This decline in BMD contributes to an increased risk of fractures. In the first 5 years after transplantation, 22.5% of KTRs experience a fracture—an incidence that is four times higher than in the general population—highlighting the importance and morbidity of this mineral disorder in the modern era of transplantation [17]. The general outcome for KTRs who sustain a fracture is significantly worse, with a 60% increased risk in mortality compared with the general population [18–20]. The outcomes of KTRs receiving joint replacement therapy as a treatment for AVN and bone fractures have rarely described. In addition, the correlation between the choice of immunosuppression, location of the lesion and allograft site involving a possible perfusion conflict remains to be elucidated. Thus we tried to address risk factors of AVN and its outcome among KTRs in the modern era of immunosuppression. MATERIALS AND METHODS Patient characteristics This study was performed in compliance with the Declarations of Helsinki and Istanbul. We examined a total of 765 KTRs for the development of AVN at our centre at Charité Campus Virchow Clinic between 2001 and 2013. A total of 585 adult solitary deceased-donor KTRs and 180 adult living-donor KTRs were consecutively included in the analysis. We evaluated risk factors and patient and kidney allograft outcomes regarding infectious complications, comorbidities, rejections and donor and recipient characteristics. We also analysed initial induction therapy with maintenance immunosuppression in each patient population, including prior human leucocyte antigen (HLA) mismatches and panel reactive antibodies (PRAs). KTRs without AVN served as controls. Patients were followed until allograft loss, death or their last patient follow-up date in their aftercare plan. Kidney transplantation procedures Donor kidneys were procured from deceased or living donors with no evidence of renal dysfunction. Kidneys were placed in the recipient’s left or right iliac fossa with vascular anastomoses to the iliac vessels. Immunosuppressive therapy and rejection treatment Primary immunosuppression in KTRs was a triple-drug regimen with a CNI (tacrolimus or cyclosporine), mycophenolate mofetil (MMF) or mycophenolic acid and a steroid (Table 1). Tacrolimus was initially dosed as 0.15 mg/kg/day and trough levels were maintained at 8–10 ng/mL for 6 months and at 5–7 ng/mL afterwards. Initial daily MMF dosage was 2 g. Intravenous methylprednisolone doses included 500 mg pre-transplantation and 250 mg at 1 day and 125 mg at 2 days post-transplantation. Oral methylprednisolone was tapered to 4 mg daily over 3 weeks post-transplantation. All KTRs received induction therapy either with an interleukin-2 receptor antagonist (basiliximab) or with a lymphocyte-depleting agent (OKT 3, anti-thymocyte globulin or alemtuzumab). Table 1 AVN: clinical characteristics Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 * p< 0.05 statistically significant. GN, glomerulonephritis; IgA, immunoglobulin A; IL, interleukin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; ESRD, end-stage renal disease. Table 1 AVN: clinical characteristics Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 * p< 0.05 statistically significant. GN, glomerulonephritis; IgA, immunoglobulin A; IL, interleukin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; ESRD, end-stage renal disease. If acute rejection was suspected, a kidney biopsy was performed and the rejection was classified according to the Banff classification. Rejections were treated with 250–500 mg intravenous steroid for 3–5 days. Kidney biopsies with grade Banff IIA or higher were treated with a lymphocyte-depleting agent. Diagnosis and treatment of AVN Cases of symptomatic AVN were diagnosed by standard anterior–posterior X-ray views of the pelvis with the hips in neutral and frog leg positions, radioisotope bone scan or magnetic resonance imaging (MRI). Operative joint replacement surgery was evaluated and performed by the local traumatology department. The long-term course of AVN with and without joint replacement and potential complications associated with joint replacement, such as losing a prosthesis, infectious complications of the prosthesis, fractures and consecutive repeat surgeries, were evaluated with clinical examination and imaging techniques such as X-ray, computed tomography scan or MRI. Statistical methods Statistical tests were performed using SPSS version 22 (SPSS, Chicago, IL, USA). For comparisons of study groups, two-sided Mann–Whitney U-test for non-parametric independent samples was used. Outcomes were measured with Kaplan–Meier models and overall strata comparisons of cumulative incidence curves were measured by log-rank tests. Stepwise regression was performed to select variables that approached statistical significance in the univariate analysis. A P-value <0.10 was used for selection. Multivariate Cox regression was performed for selected variables. Clinical characteristics were compared across groups using Fisher’s exact test. Two-sided P-values <0.05 were considered statistically significant. RESULTS Incidence and timely onset of AVN Between 2001 and 2013, we examined 585 KTRs who were adult solitary deceased-donor KTRs and 180 who were adult living-donor KTRs for the development and incidence of AVN (Figure 1). Twenty-four of 765 KTRs (4.1%) developed AVN that was diagnosed at a median of 25 months post-transplantation (Figure 1). All KTRs showed stable kidney allograft function at the time of AVN diagnosis. No differences were observed for recipient age between KTRs developing AVN and the control group. Eight of 24 KTRs (33%) were <45 years of age, 8 of 24 KTRs (33%) were between 45 and 60 years and 8 of 24 KTRs (33%) were >60 years. FIGURE 1 View largeDownload slide Cumulative incidence curve for the development of AVN after kidney transplantation. The incidence rate of AVN after kidney transplantation remains constant in the long-term follow-up after kidney transplantation. FIGURE 1 View largeDownload slide Cumulative incidence curve for the development of AVN after kidney transplantation. The incidence rate of AVN after kidney transplantation remains constant in the long-term follow-up after kidney transplantation. Risk factors for AVN development Patient characteristics, donor characteristics and characteristics of AVN are shown in Tables 1 and 2. Upon multivariate analysis, the use of cyclosporine compared with tacrolimus (P  < 0.01) and male gender (P = 0.047) were identified as independent risk factors for the development of AVN (Figure 2A and B). Cyclosporine was a significant predictor of AVN with a hazard ratio (HR) of 3.901 [95% confidence interval (CI) 1.747–8.713; P  < 0.001]. Male KTRs were more likely to develop AVN, with an HR of 2.710 (95% CI 1.011–7.261; P = 0.047). Table 2 Characteristics of AVN Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Table 2 Characteristics of AVN Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) FIGURE 2 View largeDownload slide (A) Cumulative incidence curves for the development of AVN with respect to the use of cyclosporine or tacrolimus. There is a significantly higher incidence rate of AVN among KTRs treated with cyclosporine compared with tacrolimus (P < 0.01). (B) Cumulative incidence curves for the development of AVN with respect to recipient gender. There is a significantly higher incidence rate of AVN among male KTRs compared with female KTRs (P = 0.043). FIGURE 2 View largeDownload slide (A) Cumulative incidence curves for the development of AVN with respect to the use of cyclosporine or tacrolimus. There is a significantly higher incidence rate of AVN among KTRs treated with cyclosporine compared with tacrolimus (P < 0.01). (B) Cumulative incidence curves for the development of AVN with respect to recipient gender. There is a significantly higher incidence rate of AVN among male KTRs compared with female KTRs (P = 0.043). KTRs with anti-neutrophil cytoplasmic antibody (ANCA) vasculitis as the underlying disease showed an increased incidence of AVN post-transplantation (P = 0.007). The type of induction therapy, cumulative oral steroid doses post-transplantation and presence of PRAs did not influence the development of AVN in KTRs using Cox regression analysis (P > 0.05). Acute cellular rejection, intravenous steroid pulses for the treatment of acute cellular rejection and CMV viraemia as the time-dependent covariate did not impact the development of AVN using Cox regression analysis (P > 0.05). Comorbidities such as obesity [body mass index (BMI) > 30 kg/m2] and the presence of diabetes mellitus, or the use of statins, anticoagulation or bisphosphonates did not impact the development of AVN using Cox regression analysis. Manifestation side and treatment of AVN Twenty of 24 KTRs (83%) showed AVN of the femoral head, 8 of 24 KTRs (33%) showed bilateral AVN and 20 of 24 KTRs (83%) were treated operatively undergoing joint replacement. However, among KTRs with early AVN, 11 of 12 KTRs (92%) showed AVN at the allograft side, whereas only 6 of 12 KTRs (50%) with late AVN showed AVN at the allograft side (P = 0.068). Of all KTRs with AVN and joint replacement, none showed complications in the long-term course: there were no loss or infectious complications of the prosthesis and no fractures or surgeries associated with the joint replacement in the long-term follow-up. Factors with respect to the surgical technique, such as the number of kidney allograft arteries and the site of kidney allograft anastomosis, did not impact incidence, side or timely onset of AVN (Table 2; P > 0.05). DISCUSSION Solid organ transplantation has become fairly common and successful. As the number of transplant recipients has grown, new challenges have arisen in the management of post-transplant complications. It has been well established that a rapid decrease in BMD occurs in the first 6–12 months after successful renal transplantation and persists for many years [21, 22]. AVN is thus a common complication after organ transplantation [23]. Changes in bone metabolism after transplantation have been controversial. Some studies in a group of long-term renal transplant patients demonstrated that bone metabolism progressively improved as time after transplantation increased, approaching normal values after 10 years [24]. Similar results were found by Grotz et al. [25]. Nevertheless, other data contradict these findings [26]. Our study showed a constant incidence rate of AVN development after kidney transplantation. The lower incidence of AVN in our study compared with previous studies may be attributed to the modern era of maintenance immunosuppression using tacrolimus-based regimes [13, 27]. Changes in bone metabolism over time are often discussed in the context of renal osteodystrophy during chronic kidney disease. We found no evidence to correlate AVN development with the underlying renal diseases leading to end-stage renal disease and need for transplantation thereafter. Our data do not show any causality between age and AVN development. AVN findings were attributed to immunosuppressive therapy, mainly high steroid dosages. Steroid-induced osteonecrosis occurs in 9–40% of patients receiving long-term steroid therapy. It may also develop with short-term exposure after high steroid dosages such as rejection treatment [28]. Due to the significantly lower steroid dosages used after the introduction of CNIs to solid organ transplantation, the incidence of AVN decreased [29]. Our data support these reports with a general reduction of AVN incidences over the past years compared with the incidence described in the literature [16]. However, the observed higher incidence of AVN among KTRs with ANCA-associated vasculitis may be attributed to long-term pre-transplant steroid therapy in this group and call for greater awareness of cumulative steroid dosages. However, considering maintenance immunosuppressive therapy, there still seems to be an isolated higher risk for cyclosporine in the development of AVN compared with tacrolimus as described in several studies and supported by our findings. Previous studies suggest that cyclosporine may cause higher bone loss through direct effects on osteoclasts, leading to higher bone turnover compared with tacolimus. These effects may also be supported by a decrease in proliferation and an increase in apoptosis and induced impairment of osteoblast differentiation [30–33]. The fact that the development of AVN was more likely after living kidney donation with associated shorter time on dialysis can be attributed to the more frequent use of cyclosporine in this group. The impact of gender on the development of AVN has been inconsistent among previous studies. Our analysis demonstrated an increased risk of AVN among male KTRs that may be associated with differences in CNI metabolism [34, 35]. Considering other immunosuppressive aspects such as HLA mismatches, the evidence of PRAs and induction and rejection therapies, our data show no influence in our KTR population on AVN development in this regard. Several studies indicate alcohol consumption as an important risk factor for AVN due to decreased bone synthesis and lower BMD [36, 37]. Many reports have linked post-transplantation bone disease mainly to steroid excess, but some data show that it comprises a spectrum of metabolic alterations of bone remodelling that include the status of bone metabolism during dialysis (secondary hyperparathyroidism, adynamic bone disease, osteomalacia and mixed bone disease) [38]. The post-transplantation bone diseases, including disorders such as AVN, represent a complex array that could encompass the variable pre-existing renal osteodystrophy alterations. It is interesting that these bone lesions are observed frequently in patients who have relatively normal kidney function and often are independent of serum parathyroid hormone (PTH) levels. Our patient population shares these findings and shows no significant influence on PTH levels and 25-hydorxyvitamin D levels, even after parathyroidectomy or under bisphosphonate medication. Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought and found [39]. In most cases, AVN development affects the hip, knee or shoulder joints. In our study, total hip arthroplasty (THA) was performed in 20 KTRs (83%) with a good long-term outcome in our patient population [40]. The major complications after THA are infections, dislocations, osteolysis, sequelae from metal on metal, loss of fixation, periprosthetic fractures, implant failure or fracture, leg length discrepancy and heterotropic ossification. The main long-term problem associated with THA is loss of fixation, known as aseptic loosening. This is caused by wear of the prosthetic components. Other aetiologies including poor initial stability of the implant, failure of fixation and especially certain patient factors are significant key components. In this context, our patient population is exposed to an increased risk due to chronic kidney disease–mineral and bone disorder and side effects of immunosuppressive medications leading to a further altered mineral bone structure. However, all imaginable complications after joint replacement did not occur in our KTR patient population. There is a significant relationship between AVN location and allograft side. In our case, 92% of KTRs had AVN at the allograft side. This effect may possibly be explained by an ischaemic steal syndrome caused by the kidney allograft. AVN is among others defined as bone cell necrosis, unrelated to bacterial infection but rather related to perfusion [41]. Using contrast-enhanced MRI as a non-invasive measure may allow us to compare bone perfusion at the allograft and non-allograft side and thus address the impact of ischaemic steal syndrome on AVN. With respect to our data, we raise the hypothesis of a combined aetiology of AVN after kidney transplantation that includes ischaemic steal syndrome, particularly among those KTRs who develop early AVN on the allograft side, and drug-related side effects, particularly among those KTRs who develop late bilateral and contralateral AVN. Due to the small sample size of KTRs developing AVN, the additional impact of common risk factors that are associated with the development of AVN in the non-transplant population, such as alcohol, diabetes mellitus and others, cannot be addressed in this study. Although pre-existing AVN appears unlikely in most cases, it cannot be excluded that aggravation of pre-existing AVN after transplantation contributes to the pathogenesis, at least in some KTRs. In summary, our results suggest an increased incidence of AVN among male KTRs receiving cyclosporine compared with tacrolimus. This finding most likely explains the decreasing incidence of AVN over the study period due to the replacement of cyclosporine by tacrolimus. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney that may impact early AVN at the allograft side. ACKNOWLEDGEMENTS The authors gratefully thank Anett Sefrin, Cordula Giesler and Petra Hecker, who participated in the research of this study. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Iyer SP , Nikkel LE , Nishiyama KK et al. Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton . J Am Soc Nephrol 2014 ; 25 : 1331 – 1341 Google Scholar Crossref Search ADS PubMed 2 Veenstra DL , Best JH , Hornberger J et al. Incidence and long-term cost of steroid-related side effects after renal transplantation . Am J Kidney Dis 1999 ; 33 : 829 – 839 Google Scholar Crossref Search ADS PubMed 3 Pichette V , Bonnardeaux A , Prudhomme L et al. Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study . Am J Kidney Dis 1996 ; 28 : 105 – 114 Google Scholar Crossref Search ADS PubMed 4 Cunningham J. 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Acta Orthop Belg 2007 ; 73 : 720 – 728 Google Scholar PubMed 41 Mueller D , Schaeffeler C , Baum T et al. Magnetic resonance perfusion and diffusion imaging characteristics of transient bone marrow edema, avascular necrosis and subchondral insufficiency fractures of the proximal femur . Eur J Radiol 2014 ; 83 : 1862 – 1869 Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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10.1093/ndt/gfy148
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Abstract

Abstract Background Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. Methods We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. Results KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P < 0.01). In addition, male gender was independently associated with AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. Conclusions The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side. avascular osteonecrosis, calcineurin inhibitors, kidney transplantation, steroids INTRODUCTION Kidney transplant recipients (KTRs) have been suggested to be at increased risk of avascular necrosis (AVN) due to chronic kidney disease–mineral and bone disorder, steroid use and predisposing comorbidities such as diabetes, hypertension and autoimmune disease [1]. Despite the advances in the field of transplantation over the past decades, AVN represents a devastating complication after kidney transplantation, severely impacting quality of life. AVN results from bone cell necrosis unrelated to bacterial infection but rather related to a matter of perfusion. The incidence of AVN varies, with reports up to 40% in KTRs in the pre-calcineurin inhibitor (CNI) era [2]. Among KTRs, steroid-induced suppression of bone formation is the most important risk factor for bone loss [3–5]. Glucocorticoids are toxic to osteoblasts and induce osteoclast activity [6]. CNIs are also linked to osteoporosis and varying degrees of osteonecrosis. Cyclosporine A (CSA) is known to lead to high bone turnover and thus contributes to bone loss [7–9]. Reports suggest that there is a higher risk of AVN development under CSA-treated KTRs than when treated with tacrolimus [10–12]. However, the prevalence of AVN clearly decreased after CNI implementation [13]. A further reduction in bone loss could be attributed in part to the additional lower doses of glucocorticoids used in KTRs today [1, 14–16]. Bone mineral density (BMD) declines by 4–10% in the first 6 months after transplantation [8]. This decline in BMD contributes to an increased risk of fractures. In the first 5 years after transplantation, 22.5% of KTRs experience a fracture—an incidence that is four times higher than in the general population—highlighting the importance and morbidity of this mineral disorder in the modern era of transplantation [17]. The general outcome for KTRs who sustain a fracture is significantly worse, with a 60% increased risk in mortality compared with the general population [18–20]. The outcomes of KTRs receiving joint replacement therapy as a treatment for AVN and bone fractures have rarely described. In addition, the correlation between the choice of immunosuppression, location of the lesion and allograft site involving a possible perfusion conflict remains to be elucidated. Thus we tried to address risk factors of AVN and its outcome among KTRs in the modern era of immunosuppression. MATERIALS AND METHODS Patient characteristics This study was performed in compliance with the Declarations of Helsinki and Istanbul. We examined a total of 765 KTRs for the development of AVN at our centre at Charité Campus Virchow Clinic between 2001 and 2013. A total of 585 adult solitary deceased-donor KTRs and 180 adult living-donor KTRs were consecutively included in the analysis. We evaluated risk factors and patient and kidney allograft outcomes regarding infectious complications, comorbidities, rejections and donor and recipient characteristics. We also analysed initial induction therapy with maintenance immunosuppression in each patient population, including prior human leucocyte antigen (HLA) mismatches and panel reactive antibodies (PRAs). KTRs without AVN served as controls. Patients were followed until allograft loss, death or their last patient follow-up date in their aftercare plan. Kidney transplantation procedures Donor kidneys were procured from deceased or living donors with no evidence of renal dysfunction. Kidneys were placed in the recipient’s left or right iliac fossa with vascular anastomoses to the iliac vessels. Immunosuppressive therapy and rejection treatment Primary immunosuppression in KTRs was a triple-drug regimen with a CNI (tacrolimus or cyclosporine), mycophenolate mofetil (MMF) or mycophenolic acid and a steroid (Table 1). Tacrolimus was initially dosed as 0.15 mg/kg/day and trough levels were maintained at 8–10 ng/mL for 6 months and at 5–7 ng/mL afterwards. Initial daily MMF dosage was 2 g. Intravenous methylprednisolone doses included 500 mg pre-transplantation and 250 mg at 1 day and 125 mg at 2 days post-transplantation. Oral methylprednisolone was tapered to 4 mg daily over 3 weeks post-transplantation. All KTRs received induction therapy either with an interleukin-2 receptor antagonist (basiliximab) or with a lymphocyte-depleting agent (OKT 3, anti-thymocyte globulin or alemtuzumab). Table 1 AVN: clinical characteristics Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 * p< 0.05 statistically significant. GN, glomerulonephritis; IgA, immunoglobulin A; IL, interleukin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; ESRD, end-stage renal disease. Table 1 AVN: clinical characteristics Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 Patient characteristics AVN group (n = 24) Control group (n = 741) P-value Age (years), median (range) 50 (24–68) 52 (18–78) 0.345 Sex (male), n (%) 19 (79) 432 (58) 0.055 Causes of ESRD, n (%)   GN 10 (42) 208 (28) 0.168   FSGS 2 (8) 38 (5) 0.361   Membranous GN 1 (4) 25 (3) 1   IgA nephritis 3 (13) 92 (12) 1   Rapid progressive GN/vasculitis 4 (17) 22 (3) 0.007*   Others 0 (0) 31 (4) 0.618  Diabetic nephropathy 0 (0) 55 (7) 0.407  Nephroangiosclersosis 3 (13) 67 (9) 0.475  Polycystic kidney disease 1 (4) 101 (14) 0.234  Uropathy 1 (4) 56 (7) 1  Other or undetermined 9 (38) 254 (34) 0.828 Immunosuppression, n (%)  Cyclosporine 13 (54) 155 (21) <0.001*  Tacrolimus 11 (46) 586 (79) <0.001*  Mycophenolate 21 (88) 694 (94) 0.202  Sirolimus/everolimus 0 (0) 15 (2) 1  Steroids 24 (100) 714 (96) 1 Induction therapy, n (%)  IL-2 receptor antibodies 21 (87) 646 (87) 1  Lymphocyte depletion 3 (13) 95 (13) 1  ABO desensitization 2 (8) 24 (3) 0.194 HLA-A mismatch, n (%) 2 (8) 113 (15) 0.560 HLA-B mismatch, n (%) 10 (42) 221 (30) 0.258 HLA-DR mismatch, n (%) 4 (17) 149 (20) 0.801 Total HLA mismatch, n (%)   8 (33) 233 (31) 0.826 PRA, n (%)  0–10% 24 (100) 689 (93) 0.399  11–50% 0 (0) 31 (4) 0.618  >50% 0 (0) 21 (3) 1 Time on dialysis (weeks), median (range) 32 (0–115) 60 (0–194) 0.029* Donor data  Donor age (years), median (range) 51 (22–81) 53 (3–85) 0.276  Donor sex (male), n (%) 11 (46) 378 (51) 0.542  Deceased donor, n (%) 13 (54) 572 (77) 0.014* Outcomes, n (%)  CMV infection 10 (42) 256 (35) 0.516  BK viraemia 3 (13) 78 (11) 0.733  EBV viraemia 4 (17) 81 (11) 0.329 Septic complications, n (%) 5 (21) 77 (10) 0.167 Delayed graft function, n (%) 3 (13) 194 (26) 0.159 Acute cellular rejection, n (%) 11 (46) 263 (35) 0.387  Borderline/IA/IB 9 (38) 188 (25) 0.233  IIA/IIB/III 2 (8) 75 (10) 1 * p< 0.05 statistically significant. GN, glomerulonephritis; IgA, immunoglobulin A; IL, interleukin; CMV, cytomegalovirus; EBV, Epstein–Barr virus; ESRD, end-stage renal disease. If acute rejection was suspected, a kidney biopsy was performed and the rejection was classified according to the Banff classification. Rejections were treated with 250–500 mg intravenous steroid for 3–5 days. Kidney biopsies with grade Banff IIA or higher were treated with a lymphocyte-depleting agent. Diagnosis and treatment of AVN Cases of symptomatic AVN were diagnosed by standard anterior–posterior X-ray views of the pelvis with the hips in neutral and frog leg positions, radioisotope bone scan or magnetic resonance imaging (MRI). Operative joint replacement surgery was evaluated and performed by the local traumatology department. The long-term course of AVN with and without joint replacement and potential complications associated with joint replacement, such as losing a prosthesis, infectious complications of the prosthesis, fractures and consecutive repeat surgeries, were evaluated with clinical examination and imaging techniques such as X-ray, computed tomography scan or MRI. Statistical methods Statistical tests were performed using SPSS version 22 (SPSS, Chicago, IL, USA). For comparisons of study groups, two-sided Mann–Whitney U-test for non-parametric independent samples was used. Outcomes were measured with Kaplan–Meier models and overall strata comparisons of cumulative incidence curves were measured by log-rank tests. Stepwise regression was performed to select variables that approached statistical significance in the univariate analysis. A P-value <0.10 was used for selection. Multivariate Cox regression was performed for selected variables. Clinical characteristics were compared across groups using Fisher’s exact test. Two-sided P-values <0.05 were considered statistically significant. RESULTS Incidence and timely onset of AVN Between 2001 and 2013, we examined 585 KTRs who were adult solitary deceased-donor KTRs and 180 who were adult living-donor KTRs for the development and incidence of AVN (Figure 1). Twenty-four of 765 KTRs (4.1%) developed AVN that was diagnosed at a median of 25 months post-transplantation (Figure 1). All KTRs showed stable kidney allograft function at the time of AVN diagnosis. No differences were observed for recipient age between KTRs developing AVN and the control group. Eight of 24 KTRs (33%) were <45 years of age, 8 of 24 KTRs (33%) were between 45 and 60 years and 8 of 24 KTRs (33%) were >60 years. FIGURE 1 View largeDownload slide Cumulative incidence curve for the development of AVN after kidney transplantation. The incidence rate of AVN after kidney transplantation remains constant in the long-term follow-up after kidney transplantation. FIGURE 1 View largeDownload slide Cumulative incidence curve for the development of AVN after kidney transplantation. The incidence rate of AVN after kidney transplantation remains constant in the long-term follow-up after kidney transplantation. Risk factors for AVN development Patient characteristics, donor characteristics and characteristics of AVN are shown in Tables 1 and 2. Upon multivariate analysis, the use of cyclosporine compared with tacrolimus (P  < 0.01) and male gender (P = 0.047) were identified as independent risk factors for the development of AVN (Figure 2A and B). Cyclosporine was a significant predictor of AVN with a hazard ratio (HR) of 3.901 [95% confidence interval (CI) 1.747–8.713; P  < 0.001]. Male KTRs were more likely to develop AVN, with an HR of 2.710 (95% CI 1.011–7.261; P = 0.047). Table 2 Characteristics of AVN Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Table 2 Characteristics of AVN Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) Patient characteristics AVN group (n = 24) Transplant age at AVN (months), median (range) 25 (1–156) Site of AVN, n (%)  Femoral head 20 (83)  Knee 2 (8)  Other 2 (8) Bilateral AVN of femoral head, n (%) 8 (33) AVN at the allograft side, n (%) 17 (71) Number of kidney allograft arteries, n (%)  One artery 20 (83)  Two arteries 4 (17) Site of kidney allograft anastomosis, n (%)  Internal iliac artery 0 (0)  External iliac artery 24 (100) Treatment of AVN, n (%)  Non-operatively 4 (17)  Operatively 20 (83) Alcohol abuse, n (%) 1 (4) Parathyreoidectomy, n (%) 4 (17) PTH at AVN (pg/mL), median (range) 52 (2–416) 25-hydroxyvitamin D at AVN (μg/L) 56 (10–153) Hyperlipidaemia at AVN (mg/dL), median (range) 257 (65–642) Hyperuricaemia, median (range) 8.1 (2.7–12.8) Use of bisphosphonates, n (%) 1 (4) Use of anticoagulation, n (%) 6 (25) Use of statins, n (%) 12 (50) FIGURE 2 View largeDownload slide (A) Cumulative incidence curves for the development of AVN with respect to the use of cyclosporine or tacrolimus. There is a significantly higher incidence rate of AVN among KTRs treated with cyclosporine compared with tacrolimus (P < 0.01). (B) Cumulative incidence curves for the development of AVN with respect to recipient gender. There is a significantly higher incidence rate of AVN among male KTRs compared with female KTRs (P = 0.043). FIGURE 2 View largeDownload slide (A) Cumulative incidence curves for the development of AVN with respect to the use of cyclosporine or tacrolimus. There is a significantly higher incidence rate of AVN among KTRs treated with cyclosporine compared with tacrolimus (P < 0.01). (B) Cumulative incidence curves for the development of AVN with respect to recipient gender. There is a significantly higher incidence rate of AVN among male KTRs compared with female KTRs (P = 0.043). KTRs with anti-neutrophil cytoplasmic antibody (ANCA) vasculitis as the underlying disease showed an increased incidence of AVN post-transplantation (P = 0.007). The type of induction therapy, cumulative oral steroid doses post-transplantation and presence of PRAs did not influence the development of AVN in KTRs using Cox regression analysis (P > 0.05). Acute cellular rejection, intravenous steroid pulses for the treatment of acute cellular rejection and CMV viraemia as the time-dependent covariate did not impact the development of AVN using Cox regression analysis (P > 0.05). Comorbidities such as obesity [body mass index (BMI) > 30 kg/m2] and the presence of diabetes mellitus, or the use of statins, anticoagulation or bisphosphonates did not impact the development of AVN using Cox regression analysis. Manifestation side and treatment of AVN Twenty of 24 KTRs (83%) showed AVN of the femoral head, 8 of 24 KTRs (33%) showed bilateral AVN and 20 of 24 KTRs (83%) were treated operatively undergoing joint replacement. However, among KTRs with early AVN, 11 of 12 KTRs (92%) showed AVN at the allograft side, whereas only 6 of 12 KTRs (50%) with late AVN showed AVN at the allograft side (P = 0.068). Of all KTRs with AVN and joint replacement, none showed complications in the long-term course: there were no loss or infectious complications of the prosthesis and no fractures or surgeries associated with the joint replacement in the long-term follow-up. Factors with respect to the surgical technique, such as the number of kidney allograft arteries and the site of kidney allograft anastomosis, did not impact incidence, side or timely onset of AVN (Table 2; P > 0.05). DISCUSSION Solid organ transplantation has become fairly common and successful. As the number of transplant recipients has grown, new challenges have arisen in the management of post-transplant complications. It has been well established that a rapid decrease in BMD occurs in the first 6–12 months after successful renal transplantation and persists for many years [21, 22]. AVN is thus a common complication after organ transplantation [23]. Changes in bone metabolism after transplantation have been controversial. Some studies in a group of long-term renal transplant patients demonstrated that bone metabolism progressively improved as time after transplantation increased, approaching normal values after 10 years [24]. Similar results were found by Grotz et al. [25]. Nevertheless, other data contradict these findings [26]. Our study showed a constant incidence rate of AVN development after kidney transplantation. The lower incidence of AVN in our study compared with previous studies may be attributed to the modern era of maintenance immunosuppression using tacrolimus-based regimes [13, 27]. Changes in bone metabolism over time are often discussed in the context of renal osteodystrophy during chronic kidney disease. We found no evidence to correlate AVN development with the underlying renal diseases leading to end-stage renal disease and need for transplantation thereafter. Our data do not show any causality between age and AVN development. AVN findings were attributed to immunosuppressive therapy, mainly high steroid dosages. Steroid-induced osteonecrosis occurs in 9–40% of patients receiving long-term steroid therapy. It may also develop with short-term exposure after high steroid dosages such as rejection treatment [28]. Due to the significantly lower steroid dosages used after the introduction of CNIs to solid organ transplantation, the incidence of AVN decreased [29]. Our data support these reports with a general reduction of AVN incidences over the past years compared with the incidence described in the literature [16]. However, the observed higher incidence of AVN among KTRs with ANCA-associated vasculitis may be attributed to long-term pre-transplant steroid therapy in this group and call for greater awareness of cumulative steroid dosages. However, considering maintenance immunosuppressive therapy, there still seems to be an isolated higher risk for cyclosporine in the development of AVN compared with tacrolimus as described in several studies and supported by our findings. Previous studies suggest that cyclosporine may cause higher bone loss through direct effects on osteoclasts, leading to higher bone turnover compared with tacolimus. These effects may also be supported by a decrease in proliferation and an increase in apoptosis and induced impairment of osteoblast differentiation [30–33]. The fact that the development of AVN was more likely after living kidney donation with associated shorter time on dialysis can be attributed to the more frequent use of cyclosporine in this group. The impact of gender on the development of AVN has been inconsistent among previous studies. Our analysis demonstrated an increased risk of AVN among male KTRs that may be associated with differences in CNI metabolism [34, 35]. Considering other immunosuppressive aspects such as HLA mismatches, the evidence of PRAs and induction and rejection therapies, our data show no influence in our KTR population on AVN development in this regard. Several studies indicate alcohol consumption as an important risk factor for AVN due to decreased bone synthesis and lower BMD [36, 37]. Many reports have linked post-transplantation bone disease mainly to steroid excess, but some data show that it comprises a spectrum of metabolic alterations of bone remodelling that include the status of bone metabolism during dialysis (secondary hyperparathyroidism, adynamic bone disease, osteomalacia and mixed bone disease) [38]. The post-transplantation bone diseases, including disorders such as AVN, represent a complex array that could encompass the variable pre-existing renal osteodystrophy alterations. It is interesting that these bone lesions are observed frequently in patients who have relatively normal kidney function and often are independent of serum parathyroid hormone (PTH) levels. Our patient population shares these findings and shows no significant influence on PTH levels and 25-hydorxyvitamin D levels, even after parathyroidectomy or under bisphosphonate medication. Owing to the common coincidence of osteoporosis and vascular disease, pathophysiological links between both disorders have long been sought and found [39]. In most cases, AVN development affects the hip, knee or shoulder joints. In our study, total hip arthroplasty (THA) was performed in 20 KTRs (83%) with a good long-term outcome in our patient population [40]. The major complications after THA are infections, dislocations, osteolysis, sequelae from metal on metal, loss of fixation, periprosthetic fractures, implant failure or fracture, leg length discrepancy and heterotropic ossification. The main long-term problem associated with THA is loss of fixation, known as aseptic loosening. This is caused by wear of the prosthetic components. Other aetiologies including poor initial stability of the implant, failure of fixation and especially certain patient factors are significant key components. In this context, our patient population is exposed to an increased risk due to chronic kidney disease–mineral and bone disorder and side effects of immunosuppressive medications leading to a further altered mineral bone structure. However, all imaginable complications after joint replacement did not occur in our KTR patient population. There is a significant relationship between AVN location and allograft side. In our case, 92% of KTRs had AVN at the allograft side. This effect may possibly be explained by an ischaemic steal syndrome caused by the kidney allograft. AVN is among others defined as bone cell necrosis, unrelated to bacterial infection but rather related to perfusion [41]. Using contrast-enhanced MRI as a non-invasive measure may allow us to compare bone perfusion at the allograft and non-allograft side and thus address the impact of ischaemic steal syndrome on AVN. With respect to our data, we raise the hypothesis of a combined aetiology of AVN after kidney transplantation that includes ischaemic steal syndrome, particularly among those KTRs who develop early AVN on the allograft side, and drug-related side effects, particularly among those KTRs who develop late bilateral and contralateral AVN. Due to the small sample size of KTRs developing AVN, the additional impact of common risk factors that are associated with the development of AVN in the non-transplant population, such as alcohol, diabetes mellitus and others, cannot be addressed in this study. Although pre-existing AVN appears unlikely in most cases, it cannot be excluded that aggravation of pre-existing AVN after transplantation contributes to the pathogenesis, at least in some KTRs. In summary, our results suggest an increased incidence of AVN among male KTRs receiving cyclosporine compared with tacrolimus. This finding most likely explains the decreasing incidence of AVN over the study period due to the replacement of cyclosporine by tacrolimus. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney that may impact early AVN at the allograft side. ACKNOWLEDGEMENTS The authors gratefully thank Anett Sefrin, Cordula Giesler and Petra Hecker, who participated in the research of this study. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Iyer SP , Nikkel LE , Nishiyama KK et al. Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton . J Am Soc Nephrol 2014 ; 25 : 1331 – 1341 Google Scholar Crossref Search ADS PubMed 2 Veenstra DL , Best JH , Hornberger J et al. Incidence and long-term cost of steroid-related side effects after renal transplantation . Am J Kidney Dis 1999 ; 33 : 829 – 839 Google Scholar Crossref Search ADS PubMed 3 Pichette V , Bonnardeaux A , Prudhomme L et al. Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study . Am J Kidney Dis 1996 ; 28 : 105 – 114 Google Scholar Crossref Search ADS PubMed 4 Cunningham J. 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Acta Orthop Belg 2007 ; 73 : 720 – 728 Google Scholar PubMed 41 Mueller D , Schaeffeler C , Baum T et al. Magnetic resonance perfusion and diffusion imaging characteristics of transient bone marrow edema, avascular necrosis and subchondral insufficiency fractures of the proximal femur . Eur J Radiol 2014 ; 83 : 1862 – 1869 Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Nephrology Dialysis TransplantationOxford University Press

Published: Nov 1, 2018

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