Renal osteodystrophy : bone histomorphometric studies in dialysis patients and kidney transplant recipients

Aims This study’s first aim was to observe the evolution of bone turnover in waitlisted patients on dialysis and after kidney transplantation. An additional aim was to investigate the role of bone biopsy in transplant recipients with persistent hyperparathyroidism and to evaluate whether bone biomarkers can recognize high bone turnover disease. The final aim was to define the prevalence of low bone volume and incident fractures in kidney transplant recipients. Methods Two patient cohorts were studied to accomplish these aims. The evolution of bone turnover in dialysis patients and after kidney transplantation was investigated in a cohort of 61 patients who had been on maintenance dialysis for at least one month and were planned or waitlisted for kidney transplantation from a deceased donor. Patients were treated and followed up in the Hospital District of Helsinki and Uusimaa during the study. Iliac crest bone biopsy, dual energy x-ray absorptiometry scans, and bone biomarkers were obtained at baseline in this prospective, longitudinal study and repeated after two years in patients who continued on maintenance dialysis. The second biopsy was taken two years after engraftment in kidney transplant recipients. Demographic characteristics and data on immunosuppressive and mineral metabolism therapy were obtained from electronic patient charts (Study I and II). Bone histomorphometric findings of 114 bone biopsies obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover were retrospectively analyzed to investigate the role of bone biomarkers in recognizing increased bone turnover after kidney transplantation. Electronic patient charts were concurrently reviewed for demographics, medication, and laboratory findings (Study III). The histomorphometric findings of 109 bone biopsies obtained from transplant recipients were retrospectively evaluated to study the prevalence of low bone volume and incident fractures after kidney transplantation. Relevant demographics and data on mineral metabolism therapy at the time of biopsy, laboratory findings, the results of dual-energy x-ray absorptiometry scans, and incident fractures were concurrently collected from electronic patient records, including surgery reports and documents of imaging examinations (Study IV). Results Fifty-two specimens were qualified for the histomorphometric analysis at baseline. Thirty-seven out of 56 participants received a kidney transplant during the two-year follow-up. Twenty-seven transplant recipients underwent successful repeat bone biopsy. The proportion of high bone turnover in these patients declined from 63% at baseline to 19%, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on maintenance dialysis after two years, 13 were successfully re-biopsied. The proportion of patients continuing on dialysis with high bone turnover decreased from 69% to 31%, while low bone turnover increased from 8% to 38%. The proportion of abnormal bone mineralization increased in transplant recipients from 33% to 44% but decreased in patients remaining on dialysis from 46% to 15%. The proportion of patients with low trabecular bone volume was unchanged in transplant recipients but increased in patients remaining on dialysis. Bone biomarkers did not predict bone turnover in either transplant recipients or dialysis patients. Bone mineral density at the femoral neck correlated with bone volume in dialysis patients, but no correlation between bone mineral density and bone volume was found in Study II. High bone turnover was identified in Study III in approximately 10% of all the patients who had received a kidney transplant between 2000 and 2015. Seventy percent of the patients had high turnover in bone biopsy despite this study solely including patients with bone biopsies performed due to the clinical suspicion of high bone turnover. A logistic regression model combining three variables (alkaline phosphatase, natural logarithmic parathyroid hormone, and ionized calcium) recognized the presence of high bone turnover in a reasonably accurate manner. Bone turnover was classified in Study IV as high in 78 (72%) and normal or low in 31 (28%) patients. The prevalence of low bone volume was 43%. Patients with low/normal turnover had a higher prevalence of low volume compared to patients with high turnover [18 (58%) vs. 29 (37%), P = 0.047]. Thirty-seven fragility fractures occurred in 23 (21%) transplant recipients corresponding to a fracture incidence of 15 per 1000 person-years during a median follow-up of 9.1 (interquartile range, 6.3-12.1) years. Bone mineral density at the lumbar spine correlated with trabecular bone volume but not with incident fractures. Trabecular bone volume accordingly did not correlate with incident fractures. The cumulative corticosteroid dose was an important determinant of low bone volume but not of incident fractures (Study IV). Conclusions Bone turnover decreased over time both in patients continuing on dialysis and in kidney transplant recipients. Bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens. High bone turnover was verified in approximately 10% of all transplant recipients and in 70% of patients biopsied due to the clinical suspicion of high bone turnover. The presented logistic regression model discriminated high bone turnover from non-high in a moderately accurate manner among transplant recipients with increased prevalence of high bone turnover. This model may serve as a non-invasive tool in recognizing high bone turnover after engraftment if bone biopsy is not readily available. Post-transplantation bone loss affects almost half of kidney transplant recipients, and the incidence of fractures is considerable compared to the general population. A bone biopsy is an important tool for determining bone turnover and mineralization, but it is presumably not the best measure of bone volume. The lack of association between bone trabecular volume and fractures suggests that bone microarchitecture and bone cortical component have crucial roles in the fractures of kidney transplant recipients.