Incident Renal Transplant Recipients Research Articles

MO573CNI AND MTORI-BASED REGIMENS ON FIVE-YEAR COURSE OF BONE MINERAL DENSITY SCORES AFTER RENAL TRANSPLANTATION

Abstract Background and Aims Since glucocorticoids are used in low maintenance doses today, the relationship between calcineurin inhibitors (CNI) and osteoporosis after solid organ transplantation has gained clinical significance. In contrast, (mammalian target of rapamycin inhibitors) mTORi agents are shown to have an antiresorptive effect on bone by reducing osteoclastic activity in vitro and in vivo. We investigated the bone mineral density (BMD) changes on an extremely selective group of incident renal transplant recipients under CNI or mTORi-based maintenance treatment regimens during the first five-year posttransplant course. Method This study consists of renal allograft recipients with a dialysis history of less than one year. Patients older than 50 years old, using CNI - mTORi combinations, patients with a history of a prior renal transplant, acute rejection, CNI – mTORi switch after posttransplantation first three months, bisphosphonate treatment, parathyroidectomy, diuretic use, and malignancy excluded to eliminate all confounding factors for bone mineral loss. First and fifth-year BMD scores and simultaneous laboratory parameters were evaluated. Results CNI (n=21) and mTORi (n=17) groups had similar demographics, dialysis vintages, cumulative steroid doses, first and fifth-year parathormone, calcium, phosphate, magnesium, alkaline phosphatase, and 25-OH-vitamin D levels. The femur neck scores of the CNI group decreased from -0.82(±0.96) to -1.52(±0.92) (p=0.020). We observed a significant decrease in the CNI group compared to the mTORi group [-0.70(±0.68) and 0.30(±0.36), respectively; p<0.01] when BMD score changes evaluated among years. The mean femur neck score of the mTORi group insignificantly increased from -1.13(±0.65) to -0.82(±0.56) at the fifth-year DXA scan (p=0.230). Although statistically insignificant, similar trends were also observed in L1-4 scores. Conclusion Our study suggests that CNI-based treatment is associated with decreased femur neck and L1-4 BMD scores, and mTORi-based treatment tends to be beneficial presumably due to their antiresorptive effects in the posttransplant five-year follow-up. Our findings may shed light on long-term maintenance therapy management in renal transplant patients with bone disease if supported by future studies.

Microscopic nephrocalcinosis in chronic kidney disease patients.

Experimental data indicate that microscopic calcium phosphate deposition in the kidney (nephrocalcinosis) may accelerate progression of chronic kidney disease (CKD). Data on the prevalence, risk factors and implications of nephrocalcinosis in CKD patients are scarce. A mineral metabolism disorder could play an important pathogenetic role, as suggested by recent protocol biopsy findings in incident renal transplant recipients. Kidney biopsy cylinders of CKD patients, collected between January 1989 and December 2007, were screened for the presence of nephrocalcinosis. Only patients with ≥1 parathyroid hormone (PTH) level available within 180 days of the biopsy were eligible for inclusion (n = 211). Demographics and mineral metabolism parameters were retrieved from medical files. Data on renal death (up to December 2012) were obtained from the Flemish ESRD registry. Baseline biopsies from 110 deceased kidney transplant donors served as controls. The prevalence of nephrocalcinosis in kidney donors and patients with CKD 1-2, CKD 3-4 and CKD 5-5D was 4.6, 14.3, 20.2 and 54.0%, respectively (P < 0.0001). Among CKD patients, patients with nephrocalcinosis were characterized by lower estimated GFR, lower serum bicarbonate level and higher serum PTH and calcium level. In multivariate regression analysis, high serum PTH, calcium and creatinine level, and low serum bicarbonate level were all significantly and independently associated with nephrocalcinosis. Serum phosphorus level, but not nephrocalcinosis predicted renal death, independent of renal function. Our data demonstrate that prevalence rates of nephrocalcinosis increase with increasing CKD stage to reach more than 50% in end-stage renal disease patients and suggest that acid-base and mineral metabolism disturbances are implicated in its pathogenesis.

Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients

Renal transplant recipients have an increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) and aortic calcifications (ACs) are well-known CV risk factors in patients with chronic kidney disease. We aimed to determine the prognostic value of AS and AC in incident renal transplant recipients (RTRs). We conducted a prospective study in 253 single RTR. AC were scored by means of lumbar X-ray. Carotid-femoral pulse wave velocity (PWV) was assessed in a subgroup of 115 patients. AC were present in 61% of patients. After a mean follow-up of 36months, 32 CV events occurred in the overall group and 13 events in the PWV subgroup. When we accounted for age, gender, and CV history, AC score (HR, hazard ratio 1.09 per 1 unit increase; 95% CI 1.02-1.17) and PWV (HR 1.45 per 1m/s; 95% CI 1.16-1.8) remained an independent predictor of CV events in Cox-regression analyses. Using receiver operating characteristics, the area under the curve for predicting CV events amounted to 0.80 and 0.72 for sum AC and PWV, respectively. Both AS and AC are strong predictors of future CV events in an incident RTR population. These vascular assessments are readily available and easy to perform, making them ideal tools for further risk stratification. (ClinicalTrials.gov number: NCT00547040).

Serum Concentrations of Polyclonal Free Light Chains Predict Post Transplantation Infections

Polyclonal immunoglobulin (Ig) free light chains (FLC) represent the activity of the adaptive immune system. However unlike intact Ig, FLCs are principally cleared by the kidneys and have short serum half lives. Previous work has demonstrated that serum FLC concentrations are influenced by the dose of immunosuppressants used post transplantation. The purpose of this study was to determine if polyclonal FLC concentrations predict the future risk of infective episodes in renal transplant recipients. Methods: Serial serum samples collected from 79 incident renal transplant recipients were assessed for FLCs, Ig and cystatin C concentrations. Combined polyclonal FLC (cFLC) concentration was calculated by summating k+l. A correction for renal function was then made with cystatin C ([k+l]/cysC). Clinical data was captured prospectively. Statistical significance was assessed using Kruskall-Wallace with Dunn's post-test and Pearson's Chi-square test. Results: By day 14 post-transplant, the median eGFR was 47.50ml/min this remained stable at 12 months (median 47ml/min, range 7-90). Median serum cFLC pre-transplant was increased at 145.9mg/L (range 21.27-442.5mg/L; normal range 9.33-44.27mg/L). cFLC was significantly reduced by day 14 median 25.67mg/L, p< 0.001, and remained reduced at 12 months (median 30.64mg/L, p< 0.001). Baseline corrFLC was 28.7mg/L (range 12.7-77.3mg/L) these decreased to 13.7mg/L, p< 0.001 by day 14, but then steadily increased over the follow up period (p< 0.001). A similar pattern was observed with IgG (baseline vs. day 14 p< 0.001, 1 month vs. 12 months p< 0.05). Sixty of the 79 patients (76%) experienced at least one infective episode during the first 12 months post transplantation. Patients with a low corrFLC level were more likely to experience an infection in the 90 days following the sample (78%) than patients within or above the normal range (43%) (p=0.002). Increases in corrFLC concentrations mirrored infective episodes. There was no difference in FLC concentrations between patients who received an ABO incompatible kidney (19/79 patients). Conclusion: Serum concentrations of polyclonal FLCs represent a dynamic marker of immune activity and can be used to identify patients at higher risk of infective episodes post transplantation. Future work is now required to determine if the doses of immunosuppressants can be modified ‘real-time’ in relationship to the cFLC levels.

Micro–MR Imaging–based Computational Biomechanics Demonstrates Reduction in Cortical and Trabecular Bone Strength after Renal Transplantation

To examine the ability of three-dimensional micro-magnetic resonance (MR) imaging-based computational biomechanics to detect mechanical alterations in trabecular bone and cortical bone in the distal tibia of incident renal transplant recipients 6 months after renal transplantation and compare them with bone mineral density (BMD) outcomes. The study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained from all subjects. Micro-MR imaging of distal tibial metaphysis was performed within 2 weeks after renal transplantation (baseline) and 6 months later in 49 participants (24 female; median age, 44 years; range, 19-61 years) with a clinical 1.5-T whole-body imager using a modified three-dimensional fast large-angle spin-echo pulse sequence. Micro-finite-element models for cortical bone, trabecular bone, and whole-bone section were generated from each image by delineating the endosteal and periosteal boundaries. Mechanical parameters (stiffness and failure load) were estimated with simulated uniaxial compression tests on the micro-finite-element models. Structural parameters (trabecular bone volume fraction [BV/TV, bone volume to total volume ratio], trabecular thickness [TbTh], and cortical thickness [CtTh]) were computed from micro-MR images. Total hip and spine areal BMD were determined with dual-energy x-ray absorptiometry (DXA). Parameters obtained at the follow-up were compared with the baseline values by using parametric or nonparametric tests depending on the normality of data. All mechanical parameters were significantly lower at 6 months compared with baseline. Decreases in cortical bone, trabecular bone, and whole-bone stiffness were 3.7% (P = .03), 4.9% (P = .03), and 4.3% (P = .003), respectively. Decreases in cortical bone, trabecular bone, and whole-bone failure strength were 7.6% (P = .0003), 6.0% (P = .004), and 5.6% (P = .0004), respectively. Conventional structural measures, BV/TV, TbTh, and CtTh, did not change significantly. Spine BMD decreased by 2.9% (P < .0001), while hip BMD did not change significantly at DXA. MR imaging-based micro-finite-element analysis suggests that stiffness and failure strength of the distal tibia decrease over a 6-month interval after renal transplantation.

Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study

The calcimimetic cinacalcet is approved for treating secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Biochemical profiles and clinical outcomes in patients discontinuing cinacalcet at the time of transplantation are scarce. We performed a prospective observational cohort study, including 303 incident renal transplant recipients, of whom 21 were on cinacalcet treatment at the time of transplantation. Parameters of mineral metabolism and incidence of parathyroidectomy and nephrocalcinosis in patients discontinuing cinacalcet at the time of transplantation patients ("cinacalcet +") were compared to cinacalcet-naïve patients ("cinacalcet -"). Mean follow-up was 35.6 ± 15.8 months. At the time of transplantation, parameters of mineral metabolism were similar in both groups. Conversely, at month 3, serum ionized calcium (p = 0.0007), calcitriol (p = 0.02), biointact parathyroid hormone (p = 0.06) levels and urinary fractional excretion of phosphorus (p = 0.06) were higher, while serum phosphorus levels (p = 0.06) were lower in "cinacalcet +." Analysis based on matching at the time of initiation showed that the course of post-transplant mineral metabolism in cinacalcet-treated patients (median treatment period 12.5 months) vs. cinacalcet-naïve patients was identical. "Cinacalcet +" patients are characterized by a high-incidence proportion of both post-transplant nephrocalcinosis (45% at month 3) and parathyroidectomy (28.6%). No difference in renal function was observed between "cinacalcet +" and "cinacalcet-" patients. Cinacalcet does not affect the course of secondary hyperparathyroidism in patients awaiting kidney transplantation. Biochemical profiles and a high parathyroidectomy rate suggest rebound hyperparathyroidism in renal transplant recipients discontinuing cinacalcet at the time of transplantation, which may be related to the short exposure time specific to this population. Risk/benefit studies are urgently required to define the role of continued calcimimetic treatment in renal transplant recipients and to determine the optimal treatment of secondary hyperparathyroidism in patients listed for transplantation.

Prevalence and determinants of anemia in the immediate postkidney transplant period

At the time of renal transplantation, erythropoiesis-stimulating agents and iron supplementation are routinely discontinued in the prospect of recovery of renal function. This recovery, however, is often delayed and suboptimal. In addition, blood loss because of frequent diagnostic phlebotomies may be substantial. Renal transplant recipients may thus be considered at high risk of anemia in the immediate post-transplant period. We performed a single-center observational study, including 391 recipients of a single kidney. Hemoglobin levels and parameters of iron metabolism were monitored during the immediate post-transplant period, i.e., the first 3 months after transplantation. Hemoglobin levels decreased by 3.8 ± 1.5 g/dl to reach a nadir of 9.1 ± 1.2 g/dl at day 7. Transient severe anemia was observed in 91.3% of the patients. Donor age, gender, renal diagnosis of polycystic disease, pretransplant hemoglobin and ferritin level, estimated glomerular filtration rate at month 3, and duration of initial hospitalization were observed to be independently associated with the hemoglobin level at month 3. Transient severe anemia is an almost universal observation in incident renal transplant recipients. Poor graft function, high donor age, and low iron stores are independently associated with low hemoglobin levels at month 3.

Thymic function, anti-thymocytes globulins, and cancer after renal transplantation

Background Prolonged CD4 T cell lymphopenia after polyclonal antithymocyte globulins (ATG) is associated with an increased rate of cancers. Here, we examined whether pre-transplant thymic function estimated by TREC levels is predictive of cancer occurrence following ATG treatment. Patients and methods The impact of TREC on cancer occurrence was analyzed in 115 consecutive incident renal transplant recipients having received ATG. Results Mean follow-up was 7.5 ± 2.6 years. After ATG induction, patients with the lowest pre-transplant TREC values had lower post-transplant CD4 + and CD4 + CD45RA + CD45RO − T cell counts, and a higher frequency of T cells with a regulatory phenotype (CD127 +CD4 +CD25 +Foxp3 +). Log-transformed pre-transplant TREC values were significantly lower in patients who developed cancer after transplantation ( p < 0.0001). The cumulative incidence of cancer was higher in patients having the lowest pre-transplant TREC values (T1 [low]: 47.4%, T2 [medium]: 12.5%, and T3 [high]: 2.7%; p < 0.0001). In multivariate analysis, pre-transplant TREC value was the only predictive factor of cancer (HR, 0.39; 95% CI, 0.16 to 0.97, for one log (TREC/10 6 PBMC); p = 0.046). Conclusions Pre-transplant thymic function is associated with an increased rate of post-transplant cancer in patients having received ATG. Omitting ATG in recipients with low pre-transplant TREC values should be considered.

Measuring Total Blood Calcium Displays a Low Sensitivity for the Diagnosis of Hypercalcemia in Incident Renal Transplant Recipients

Hypercalcemia is a common complication in renal transplant recipients and has been associated with nephrocalcinosis and poor graft outcome. The performance of total calcium (tCa) in the diagnosis of blood calcium disturbances in renal transplant recipients is unknown. We compared the ability of total tCa concentration to identify low, normal, or high ionized calcium (iCa) concentration, i.e., the gold standard, in an unselected cohort of 268 renal transplant recipients. All patients were studied 3 and 12 months after successful engraftment. Hypercalcemia, defined as a iCa >1.29 mmol/L, was present in 58.6 and 44.8% of the patients at months 3 and 12, respectively. tCa concentrations >10.3 mg/dl, conversely, were observed in only 13.1% of the patients. Measuring tCa had a low sensitivity (20.3 and 24.2% at months 3 and 12, respectively) for the diagnosis of hypercalcemia. The agreement (κ coefficient [95% confidence interval]) between tCa concentrations and iCa was poor (month 3: 0.11 [0.05 to 0.17]; month 12: 0.20 [0.11 to 0.30]). The risk for underestimating iCa was increased by a low total bicarbonate concentration. Metabolic acidosis was observed in 48.1 and 37.3% of the patients at months 3 and 12, respectively. Total calcium greatly underestimates the diagnosis of hypercalcemia in incident renal transplant recipients. This is mainly explained by the high prevalence of metabolic acidosis in these patients.

Fibroblast Growth Factor-23 and Parathyroid Hormone Are Associated with Post-Transplant Bone Mineral Density Loss

Among the multiple factors contributing to bone mineral density (BMD) loss after renal transplantation, hypophosphatemia is increasingly recognized to play an important role. Hypophosphatemia occurs in up to 90% of the renal transplant recipients in the early post-transplant period and is caused by renal phosphate wasting. We hypothesized that a high pretransplant level of the recently described phosphaturic hormone fibroblast growth factor 23 (FGF-23) is a risk factor for accelerated BMD loss occurring within the first post-transplant year. We performed a two-center observational retrospective cohort study in 127 incident renal transplant recipients. Serum full-length FGF-23, parathyroid hormone (PTH), and parameters of mineral metabolism were determined at the time of transplantation. BMD was assessed by osteodensitometry at the time of transplantation and 1 year later. A moderate decrease of BMD was observed during the first post-transplant year. High FGF-23 levels were associated with BMD loss at the lumbar spine and total hip region, whereas low PTH levels were associated with BMD loss at all three regions. Cumulative doses of prednisone and post-transplant serum phosphate level were not correlated with BMD changes. Our data indicate that patients with a high serum FGF-23 level and/or a low PTH level at the time of transplantation are at risk for increased BMD loss during the first post-transplant year.

Inflammation, coronary artery calcification and cardiovascular events in incident renal transplant recipients

Objective Coronary artery calcification (CAC) predicts cardiovascular events in the general population. We conducted a prospective study to determine if inflammatory markers were predictive of CAC and if CAC predicted cardiovascular events and mortality in incident renal transplant recipients. Methods A prospective cohort of 112 asymptomatic incident renal transplant recipients who had no prior history of coronary artery revascularization or myocardial infarction had coronary calcifications measured early post-transplant and at least 18 months later by Agatston score and volume method. Results The mean CAC score was 367.7 (682.3). Inflammatory markers such as WBC and CRP were predictive of CAC severity. Recipients with cardiovascular events ( n = 11) or death ( n = 12) during the follow-up period had higher mean [675.1 (669.3) vs. 296.8 (669.0), p = 0.02] and median [434.8 vs. 28.9, p = 0.01] CAC score compared to those without them. Recipients with CAC score less than 100 had a better cumulative survival rate compared to the recipients with CAC score greater than 100 [95.1% vs. 82.3%, p = 0.03]. We found a significant unadjusted and adjusted association between CAC score and cardiovascular events and mortality. A quarter (25.9%) of recipients had CAC progression. Coronary calcification progression also predicted cardiovascular events and mortality after adjustment for diabetes and dialysis vintage. Conclusion CAC is prevalent in renal recipients and is predictive of cardiovascular events and mortality. Coronary calcification progression is common and predict clinical outcomes. Inflammatory markers are predictive of CAC severity at time of transplant, but are not predictive of future cardiovascular event or mortality.

Prolonged CD4 T Cell Lymphopenia Increases Morbidity and Mortality after Renal Transplantation

Prolonged CD4 T cell lymphopenia after administration of polyclonal anti-thymocyte globulins increases the rate of posttransplantation morbidity, but whether impaired immune reconstitution affects survival is unknown. We studied the effect of CD4 T cell lymphopenia on survival in 302 consecutive prevalent renal transplant recipients and the role of thymic function in CD4 T cell reconstitution and posttransplantation outcomes in 100 consecutive incident renal transplant recipients. We followed the prevalent cohort for a mean duration of 92 months. Of these 302 patients, 81 (27%) had persistent CD4 T cell counts <300/mm3 and 36 (12%) died during follow-up. We observed a higher death rate in patients with CD4 T cell lymphopenia persisting for >1 year (24.1 versus 7.6%; P < 0.001). Furthermore, in Cox regression analysis, CD4 T cell lymphopenia associated with a nearly five-fold risk for death (adjusted hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.91 to 10.65; P = 0.001). In the incident cohort, we estimated thymic function by T cell receptor excision circles (TRECs) per 150,000 CD3+ cells, which predicted efficient CD4 T cell reconstitution. Higher pretransplantation TREC values associated with lower risks for cancer (adjusted HR 0.39; 95% CI 0.15 to 0.97; P = 0.046) and infection (HR 0.29; 95% CI 0.11 to 0.78; P = 0.013). In summary, prolonged polyclonal anti-thymocyte globulin-induced CD4 T cell lymphopenia is an independent risk factor for death. Determination of pretransplantation thymic function may identify patients at higher risk for CD4 T cell lymphopenia and posttransplantation morbidity, including cancer and infections.