Günter Kirste

BONE FRACTURE AND OSTEODENSITOMETRY WITH DUAL ENERGY X-RAY ABSORPTIOMETRY IN KIDNEY TRANSPLANT RECIPIENTS

Kidney transplant recipients have multiple factors leading to osteoporosis. The purpose of this study was to determine the fracture rate after kidney transplantation and the significance of osteodensitometry with dual energy x-ray absorptiometry (DXA) in identifying the risk patients. Bone mineral density (BMD) was measured with DXA in 100 graft recipients (mean interval 63 +/- 53 months after transplantation) and correlated with the incidence of fractures. Fracture rate of peripheral bones increased from 0.009 before transplantation and 0.012 on hemodialysis to 0.032 fractures per patient and year after transplantation. Seventeen fractures of peripheral bones occurred in 11% of the patients within a mean of 103 +/- 59 months after transplantation. Three additional patients had fractures of the lumbar spine. Patients with fractures were characterized by low or low-normal BMD (0.93 +/- 0.23 versus 1.04 +/- 0.17 g/cm2 at lumbar spine), a frequent history of parathyroidectomy (21% versus 6%), and a longer transplant interval (103 +/- 59 versus 57 +/- 49 months). Fractures occurred in patients with low and normal BMD. DXA at the femoral neck proved to be of no value to define patients at risk of fractures. DXA at the lumbar spine also proved to be of limited value for this question. Therefore, alternatively, more sensitive methods of BMD and of bone architecture measurements are necessary for identifying the kidney transplant recipients at risk of fracture.

A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.

BACKGROUND T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.

Bone mineral density after kidney transplantation : a cross-sectional study in 190 graft recipients up to 20 years after transplantation

Kidney transplant recipients are exposed to multiple factors that lead to osteoporosis after kidney transplantation. Recent short-term longitudinal studies revealed a strong decline of bone mineral density (BMD) within 1 year after transplantation. The long-term course of BMD after transplantation is still unknown. Therefore, we performed a cross-sectional study to determine BMD in 190 renal graft recipients (mean age 44 years, range 20-71 years) by dual-energy x-ray absorptiometry at various time intervals up to 20 years after transplantation (range 0-237 months). Mean BMD of graft recipients was lower than BMD values of an age- and sex-matched European reference collective at every time of measurement after renal transplantation (P < 0.01). Lowest mean BMD values were measured 12-24 months after transplantation. No loss of BMD occurred after the second posttransplant year beyond the normal age- and sex-dependent decline of BMD. Mean daily prednisone dosage was significantly higher within the first 2 posttransplant years compared with the later posttransplant period (13.1 +/- 6.2 vs. 6.7 +/- 3.4 mg/day). Other drugs or metabolic causes, including daily dosage of CsA, AZA, parathormone level, and graft function, did not show additional important differences before and after the second posttransplant year. Interpreting the results of a cross-sectional study in light of a time-dependent process, we suggest that the preexisting low BMD of kidney transplant recipients at the time of transplantation is further strongly reduced within the initial 2 posttransplant years, probably due mainly to the effect of prednisone therapy. After that time, when prednisone dosage is below a threshold of 7.5 mg/day, only a moderate, normal loss of BMD is apparent, even in patients up to 20 years after transplantation.

Treatment of osteopenia and osteoporosis after kidney transplantation.

BACKGROUND Osteopenia and osteoporosis are frequent complications after kidney transplantation. Data for the treatment of low bone mass after kidney transplantation are not available. METHODS To test the efficacy of antiresorptive treatment, 46 patients with osteopenia or osteoporosis after kidney transplantation (bone mineral density < or =1.5 SD below normal) were randomly assigned to three groups cyclically treated as follows: group 1 with daily oral clodronate (800 mg) and group 2 with daily intranasal calcitonin (200 IU) for 2 weeks every 3 months. These two groups were compared with a control group (group 3). Every patient was supplemented with 500 mg of calcium per day. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at the lumbar spine and femoral neck before and after the 12-month treatment period. RESULTS BMD at the lumbar spine was increased by 4.6% in the clodronate group (n=15, P=0.005), by 3.2% in the calcitonin group (n=16, P=0.034), and by 1.8% in the control group (n=15, P=0.265). However, the differences in BMD changes among the groups were not statistically significant. During therapy, serum calcium decreased slightly in all groups by 4.6%; however, parathyroid hormone values increased significantly in the treatment groups by 116%. Therapy was well tolerated without impact on graft function. CONCLUSIONS Cyclical therapy with clodronate or calcitonin appears to induce a gain in BMD at the lumbar spine in patients with low bone mass after kidney transplantation. This treatment had no adverse impact on graft function but may aggravate preexisting secondary hyperparathyroidism.

Glycoprotein B genotype correlates with cell tropism in vivo of human cytomegalovirus infection.

Human cytomegalovirus (HCMV) strains can be classified into four genotypes of the glycoprotein B (gB). In a previous study, the gB genotype 1 was found more frequently in bone marrow transplant recipients with nonfatal HCMV infection than in patients who died from HCMV disease [Fries et al. (1994): Journal of Infectious Diseases 169:769–774]. The distribution and cell tropism of different gB types in vivo were investigated. The gB type of HCMV was determined in blood or urine specimen from 76 organ and 47 bone marrow transplant recipients using PCR and restriction fragment length polymorphism (RFLP). The leukocyte populations (polymorphonuclear leukocytes, monocytes, T lymphocytes, non‐T lymphocytes) of 20 viremic patients were purified by a fluorescence‐activated cell sorter (FACS) and examined for HCMV infection by PCR. Sequence analysis of four randomly selected strains showed that gB types were similar to published sequences and no atypical gB types were found. Within the compartments blood and urine, the gB types were almost equally distributed, whereas the gB type 1, in contrast to gB types 2 and 3, did not infect T lymphocytes in vivo. These data show that the gB type correlates with viral tropism in vivo and thus provides further evidence that the gB variation may indeed influence the virulence of HCMV. J. Med. Virol. 54:75–81, 1998.

A report of the Lisbon Conference on the care of the kidney transplant recipient

An International Conference on the Care of the Kidney Transplant Recipient was convened in Lisbon, Portugal from February 2– 4, 2006 under the auspices of the National Kidney Foundation and Kidney Disease: Improving Global Outcomes (KDIGO), and in cooperation with The Transplantation Society. Conference participants included over 100 experts and leaders in kidney transplantation, representing more than 40 countries from around the world, including participants from Africa, Asia, Australia, Europe, North American, and South America (Appendix). The goal of the conference was to develop recommendations to improve the outcomes of kidney transplant recipients worldwide with regard to the following basic medical issues: cardiovascular disease (Work Group I), cancer and infection (Work Group II), and anemia, bone disease, reproductive issues, growth and development (Work Group III). Work Groups I, II, and III addressed the preand posttransplant care of kidney transplant recipients by the following components: timelines of preand posttransplantation, immunosuppression, level of kidney allograft function, and burden of disease (prior history of dialysis or preemptive transplant and how that history affects outcome). A graft maintenance section (Work Group IV) addressed: 1) recipient (and donor) selection; 2) surgical aspects and immediate posttransplant care of recipients including consideration of minimal surgical infrastructure; 3) immunosuppression including an assessment of the incremental expected value of more complex and expensive regimens in comparison to simpler and less expensive regimens, generics, midand long-term immunosuppression; 4) living donor versus deceased donor transplantation; and 5) midand long-term posttransplant care and monitoring of allograft function. In addition, conference participants were asked to examine the issue of applicability of the recently published Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for chronic kidney disease (CKD) in kidney allograft recipients (1). Specifically, Work Group V addressed the role of estimated glomerular filtration rate (eGFR) in monitoring kidney function after transplantation, as well as the stratification for intervention according to eGFR values.

The critical pathway for deceased donation: reportable uniformity in the approach to deceased donation

The critical pathway of deceased donation provides a systematic approach to the organ donation process, considering both donation after cardiac death than donation after brain death. The pathway provides a tool for assessing the potential of deceased donation and for the prospective identification and referral of possible deceased donors.

ABO‐incompatible kidney transplantation using antigen‐specific immunoadsorption and rituximab: a single center experience

Abstract: Background: For years ABO‐incompatible kidney transplantations were preferentially performed in Japanese centers. In order to overcome the increased risk of humoral rejections, patients were treated with multiple sessions of plasmapheresis, intensified immunosuppressive therapy and splenectomy before transplantation. Despite good long‐term results regarding patient and organ survival rates, increased morbidity during the early post‐transplant period prevented a broad application of this method. Recently, a new protocol including the anti‐CD20‐antibody (Ab) rituximab and blood group‐specific immunoadsorption instead of splenectomy and plasmapheresis was published with excellent short‐term results.

Mycophenolate mofetil in pediatric renal transplantation without induction therapy: results after 12 months of treatment. German Pediatric Renal Transplantation Study Group.

Background. Acute rejection episodes (ARE) of kidney transplants are considered as risk factor in the development of chronic rejection. In adult renal transplantation (RTx), ARE have been significantly reduced by mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) and steroids (Pred). Reports of pediatric RTx on a maintenance immuno-suppression with MMF are restricted to patients (P) after antibody induction therapy. Methods. The efficacy and safety of MMF combined with CyA and Pred in pediatric RTx without induction therapy were evaluated in an open-labeled multicenter study. Results. From 10/1996 to 6/1999, 65 pediatric P (MMF group) were followed for at least 6 months, 58 of 65 for 12 months. These P were compared with 54 retrospectively analyzed pediatric P who were transplanted between 1990 and 1996 and had received CyA, Pred, and azathioprine for immunosuppression (historic AZA group). Within the first 6 months after RTx, 18 of 65 (MMF group) and 32 of 54 (historic AZA group) P showed clinical signs of acute rejection (P <0.01). Thereafter only one further P in the MMF group developed a first ARE. Graft loss due to rejection occurred in one MMF- and seven AZA-treated P (P <0.05). The creatinine-clearance 3 and 6 months after RTx was higher in the MMF group. Major adverse events (MMF group) included infections of the urinary and the upper respiratory tract, diarrhea, and leukopenia. Cytomegalovirus-infection occurred in 13 P and 2 P developed cytomegalovirus disease. One P developed PTLD 10 months after RTx and recovered after the reduction of immunosuppression. Conclusions. The combination of MMF, CyA, and Pred reduced ARE in pediatric RTx without incurring major side effects.

Expression profiling on chronically rejected transplant kidneys.

Background. Chronic transplant nephropathy remains a poorly defined inflammatory process that limits the survival rate of most renal transplants. We analyzed the gene profile of chronically rejected kidney transplants to identify candidate genes that characterize chronic transplant nephropathy. Methods. To distinguish genes present in normal renal tissue or specific for end-stage renal failure, we compared the gene profiles of 13 chronically rejected kidney transplants with 16 normal kidneys and 12 end-stage polycystic kidneys using a 7K human cDNA microarray. After elimination of genes with signals close to background, 2,190 genes were available for statistical analysis. Results. More than 20% of the examined genes were significantly regulated when compared with the expression level of normal renal tissue (P <0.0003). Hierarchic clustering based on 571 genes differentiated normal and transplant tissue, and transplant and polycystic kidney tissue. Most of these genes encoded proteins involved in cellular metabolism, transport, signaling, transcriptional activation, adhesion, and the immune response. Notably, comprehensive gene profiling of chronically rejected kidneys revealed two distinct subsets of chronically rejected transplants. Neither clinical data nor histology could explain this genetic heterogeneity. Conclusions. Microarray analysis of rejected kidneys may help to define different entities of transplant nephropathy, reflecting the multifactorial cause of chronic rejection.